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b25197cde1b4eed269cd6704f4703b9d534e2c6e | wikidoc | Portography | Portography
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Portography is a radiography of the portal vein after injection of radioopaque contrast material. | Portography
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Portography is a radiography of the portal vein after injection of radioopaque contrast material.
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Template:WS | https://www.wikidoc.org/index.php/Portography | |
f84d4ad4917db65c107ba91a706596f6a56d3460 | wikidoc | Positronium | Positronium
Positronium (Ps) is a system consisting of an electron and its anti-particle, a positron, bound together into an "exotic atom". The orbit of the two particles and the set of energy levels is similar to that of the hydrogen atom (electron and proton). However, because of the reduced mass, the frequencies associated with the spectral lines are less than half of those of the corresponding hydrogen lines.
# States
The ground state of positronium, like that of hydrogen, has two possible configurations depending on the relative orientations of the spins of the electron and the positron.
The singlet state with antiparallel spins (S = 0, Ms = 0) is known as para-positronium (p-Ps) and denoted Template:SubatomicParticle. It has a mean lifetime of 125 picoseconds and decays preferentially into two gamma quanta with energy of 511 keV each (in the center of mass frame). Detection of these photons allows for the reconstruction of the vertex of the decay and is used in the positron emission tomography. Para-positronium can decay into even number of photons (2, 4, 6,...), but the probability quickly decreases: the branching ratio for decay into 4 photons is 1.439(2)×10−6 .
The triplet state with parallel spins (S = 1, Ms = −1, 0, 1) is known as ortho-positronium (o-Ps) and denoted Template:SubatomicParticle. The triplet state in vacuum has a mean lifetime of 142.05±0.02 nanoseconds and the leading mode of decay is three gamma quanta. Other modes of decay are negligible; for instance, the five photons mode has branching ratio of ~1.0×10−6 .
Positronium in the 2S state is metastable having a lifetime of 1.1 μs against annihilation. If the positronium is created in such an excited state then it will quickly cascade down to the ground state where annihilation will occur more quickly. Measurements of these lifetimes, as well as of the positronium energy levels, have been used in precision tests of quantum electrodynamics.
Annihilation can proceed via a number of channels each producing one or more gamma rays. The gamma rays are produced with a total energy of 1022 keV (since each of the annihilating particles have mass of 511 keV/c²), the most probable annihilation channels produce two or three photons, depending on the relative spin configuration of the electron and positron. A single photon decay is only possible if another body (e.g. an electron) is in the vicinity of the annihilating positronium to which some of the energy from the annihilation event may be transferred. Up to five annihilation gamma rays have been observed in laboratory experiments, confirming the predictions of quantum electrodynamics to very high order.
The annihilation into a neutrino-antineutrino pair is also possible, but the probability is predicted to be negligible. The branching ratio for o-Ps decay for this channel is 6.2×10−18 (electron neutrino-antineutrino pair) and 9.5×10−21 (for each non-electron flavour) in predictions based on the Standard Model, but it can be gained by non-standard neutrino properties, like mass or relatively high magnetic moment. The experimental upper limits on branching ratio for this decay are: <1.7×10−6 (p-Ps) and <2.8×10−6 (o-Ps) .
# Energy levels
The similarity between positronium and hydrogen extends even to the equation that gives a rough estimate of the energy levels. The energy levels are different between the two because of a different value for the mass, m*, used in the energy equation
The reduced mass in this case is
Thus, for positronium, its reduced mass only differs from the rest mass of the electron by a factor of 2. This causes the energy levels to also roughly be half of what they are for the hydrogen atom.
So finally, the energy levels of positronium are given by
The lowest energy level of positronium (n = 1) is −6.8 electron volts (eV). The next highest energy level (n = 2) is −1.7 eV. The negative sign implies a bound state.
# Observation of di-positronium molecules
The first observation of di-positronium molecules — molecules consisting of two positronium atoms — was reported on 12 September 2007 by David Cassidy and Allen Mills from University of California at Riverside.
# Prediction and discovery
Croatian scientist Stjepan Mohorovičić predicted of the existence of positronium in 1934, in a paper published in Astronomische Nachrichten, in which he called the substance "electrum". Other sources credit Carl Anderson as having predicted its existence in 1932 while at Caltech. It was experimentally discovered by Martin Deutsch at MIT in 1951, and became known as positronium. | Positronium
Positronium (Ps) is a system consisting of an electron and its anti-particle, a positron, bound together into an "exotic atom". The orbit of the two particles and the set of energy levels is similar to that of the hydrogen atom (electron and proton). However, because of the reduced mass, the frequencies associated with the spectral lines are less than half of those of the corresponding hydrogen lines.
# States
The ground state of positronium, like that of hydrogen, has two possible configurations depending on the relative orientations of the spins of the electron and the positron.
The singlet state with antiparallel spins (S = 0, Ms = 0) is known as para-positronium (p-Ps) and denoted Template:SubatomicParticle. It has a mean lifetime of 125 picoseconds and decays preferentially into two gamma quanta with energy of 511 keV each (in the center of mass frame). Detection of these photons allows for the reconstruction of the vertex of the decay and is used in the positron emission tomography. Para-positronium can decay into even number of photons (2, 4, 6,...), but the probability quickly decreases: the branching ratio for decay into 4 photons is 1.439(2)×10−6 [1].
The triplet state with parallel spins (S = 1, Ms = −1, 0, 1) is known as ortho-positronium (o-Ps) and denoted Template:SubatomicParticle. The triplet state in vacuum has a mean lifetime of 142.05±0.02 nanoseconds[2] and the leading mode of decay is three gamma quanta. Other modes of decay are negligible; for instance, the five photons mode has branching ratio of ~1.0×10−6 [3].
Positronium in the 2S state is metastable having a lifetime of 1.1 μs against annihilation.[citation needed] If the positronium is created in such an excited state then it will quickly cascade down to the ground state where annihilation will occur more quickly. Measurements of these lifetimes, as well as of the positronium energy levels, have been used in precision tests of quantum electrodynamics. [4][1]
Annihilation can proceed via a number of channels each producing one or more gamma rays. The gamma rays are produced with a total energy of 1022 keV (since each of the annihilating particles have mass of 511 keV/c²), the most probable annihilation channels produce two or three photons, depending on the relative spin configuration of the electron and positron. A single photon decay is only possible if another body (e.g. an electron) is in the vicinity of the annihilating positronium to which some of the energy from the annihilation event may be transferred. Up to five annihilation gamma rays have been observed in laboratory experiments[5], confirming the predictions of quantum electrodynamics to very high order.
The annihilation into a neutrino-antineutrino pair is also possible, but the probability is predicted to be negligible. The branching ratio for o-Ps decay for this channel is 6.2×10−18 (electron neutrino-antineutrino pair) and 9.5×10−21 (for each non-electron flavour) [3] in predictions based on the Standard Model, but it can be gained by non-standard neutrino properties, like mass or relatively high magnetic moment. The experimental upper limits on branching ratio for this decay are: <1.7×10−6 (p-Ps) and <2.8×10−6 (o-Ps) [6].
# Energy levels
The similarity between positronium and hydrogen extends even to the equation that gives a rough estimate of the energy levels. The energy levels are different between the two because of a different value for the mass, m*, used in the energy equation
The reduced mass in this case is
Thus, for positronium, its reduced mass only differs from the rest mass of the electron by a factor of 2. This causes the energy levels to also roughly be half of what they are for the hydrogen atom.
So finally, the energy levels of positronium are given by
The lowest energy level of positronium (n = 1) is −6.8 electron volts (eV). The next highest energy level (n = 2) is −1.7 eV. The negative sign implies a bound state.
# Observation of di-positronium molecules
The first observation of di-positronium molecules — molecules consisting of two positronium atoms — was reported on 12 September 2007 by David Cassidy and Allen Mills from University of California at Riverside.[7][8]
# Prediction and discovery
Croatian scientist Stjepan Mohorovičić predicted of the existence of positronium in 1934, in a paper published in Astronomische Nachrichten, in which he called the substance "electrum".[9] Other sources credit Carl Anderson as having predicted its existence in 1932 while at Caltech.[10] It was experimentally discovered by Martin Deutsch at MIT in 1951, and became known as positronium.[10] | https://www.wikidoc.org/index.php/Positronium | |
2bdd242ddd027186c3f215d23eb5b7a601ce8435 | wikidoc | Potato chip | Potato chip
A potato chip or crisp is a thin slice of potato, deep fried or baked until crisp. Potato chips serve as an appetizer, side dish, or snack. Commercial varieties are packaged for sale, usually in bags. The simplest chips of this kind are just cooked and salted, but manufacturers can add a wide variety of seasonings (mostly made using herbs, spices, cheese, artificial additives or MSG). Chips are an important part of the snack food market in English-speaking countries and many other Western nations.
There is little consistency in the English speaking world for names of fried potato cuttings. North American English uses 'chips' for the above mentioned dish -- this term is also used in continental Europe -- and sometimes 'crisps' for the same made from batter, and 'French fries' for the hot crispy batons with a soft core. In the United Kingdom and Ireland, 'crisps' are the brittle slices eaten at room temperature and 'chips' refer to that hot dish (as in 'fish and chips'). In Australia, New Zealand and some parts of South Africa, both forms of potato product are simply known as 'chips', as are the larger "home-style" potato chips. Sometimes the distinction is made between 'hot chips' (French fried potatoes) and 'packet chips'.
Non-potato based chips also exist. Kumara (sweet potato) chips are eaten in New Zealand and Japan; parsnip crisps are available in the United Kingdom. There are also regional variations. For example, in parts of the North of England, fried sliced potatoes are sometimes called ("flakies"). India is famous for a large number of localized 'chips shops', selling not only potato chips but also other varieties such as plantain chips, yam chips and even carrot chips. In many countries potato chips have been criticized because of their high fat percentage (approx. 35%) and their acrylamide content.
# Origins
It is believed that the original potato chip recipe was created by Native American/African American chef George Crum, at Moon's Lake House near Saratoga Springs, New York, on August 24, 1853. He was fed up with a customer — by some accounts Cornelius Vanderbilt (although this has been called into question) — who continued to send his fried potatoes back, because he thought they were too thick and soggy. Crum decided to slice the potatoes so thin that they couldn't be eaten with a fork, nor fried normally in a pan, so he decided to stir-fry the potato slices. Against Crum's expectation, the guest was ecstatic about the new chips. They became a regular item on the lodge's menu under the name "Saratoga Chips." They soon became popular throughout New York and New England. Eventually, potato chips spread beyond chef-cooked restaurant fare and began to be mass produced for home consumption; Dayton, Ohio-based Mike-sell's Potato Chip Company, founded in 1910, calls itself the "oldest potato chip company in the United States". It takes approximately 4 pounds of potatoes to make a pound of potato chips.
An earlier reference is Alexis Soyer's recipe in "Shilling Cookery for People" (1845). Here raw potatoes, "almost shavings" are fried. Earlier still, Mary Randolph's book "The Virginia House-wife" (1824) has a part titled "To fry Sliced Potatoes" here raw potatoes are cut into slices or thin shavings and fried "till they are crisp."
Before the airtight sealed bag was developed, chips were stored in barrels or tins. The chips at the bottom were often stale and damp. Then Laura Scudder invented the bag by ironing together two pieces of waxed paper, thereby creating an airtight seal and keeping the chips fresh until opened. In 1934 Akron, Ohio, potato chip maker K.T. Salem was the first to distribute chips in glassine waxed paper bags. Today, chips are packaged in plastic bags, with nitrogen gas blown in prior to sealing to lengthen shelf life, and provide protection against crushing.
# Economy
The global potato chips market generated total revenues of 16.4 billion dollars in 2005. This accounted for 35.5% of the total savory snacks market in that year (46.1 billion dollars).
# Seasoned chips
Initially, chips went unseasoned until a twist of salt was placed inside the bag, to be added when required. This idea was originated by the Smiths Potato Crisps Company Ltd formed in 1920 . Frank Smith originally packaged them in greaseproof paper bags which were then sold around London, to give them some flavor, he would also include a twist of salt for flavoring. The idea was abandoned when the salting and flavoring process developed by Tayto was applied to crisps during manufacture. Walkers revived the idea of 'salt in a bag', following their take over of Smiths (UK) in 1979, with their Salt 'n' Shake potato crisps.
The potato chip remained unseasoned until an innovation by Joe "Spud" Murphy (1923 – 2001), the owner of an Irish crisp company called Tayto, who developed a technology to add seasoning in the 1950s. Though he had a small company, consisting almost entirely of his immediate family who prepared the crisps, the owner had long proved himself an innovator. After some trial and error, he produced the world's first seasoned crisps, "Cheese and Onion" and "Salt 'n' Vinegar".
The innovation became an overnight sensation in the food industry, with the heads of some of the biggest potato chip companies in the United States heading to the small Tayto company to examine the product and to negotiate the rights to use the new technology. When eventually the Tayto company was sold, it made the owner and the small family group who had changed the face of potato chip manufacture very wealthy. Companies worldwide sought to buy the rights to Tayto's technique.
The Tayto innovation changed the whole nature of the potato chip. Later chip manufacturers added natural and artificial seasonings to potato chips, with varying degrees of success. A product that had had a large appeal to a limited market on the basis of one seasoning now had a degree of market penetration through vast numbers of seasonings. Various other seasonings of chips are sold in different locales, including the original "Cheese and Onion", produced by Tayto, which remains by far Ireland's biggest manufacturer of crisps.
Perhaps the most extreme version of seasoned chips were the fruit flavoured chips that were (very) briefly sold in Canada in the late seventies (in orange, cherry and grape flavours). These were not a success, and they were rapidly discontinued.
## Regional varieties
- In the US, the most popular forms of seasoned potato chips include "sour cream and onion", "barbecue" and "ranch". In the Chesapeake Bay area, Utz distributes "crab chips", flavored with an Old Bay analogue seasoning.
- Within North America, wider varieties are available in parts of Canada, where seasonings include dill pickle, ketchup, poutine, salt & vinegar, bacon and curry. In Toronto and Vancouver, Lay's offers wasabi chips.
- The market in United Kingdom is dominated by Walkers which is known for its wide variety of crisps. Typical examples include salt & vinegar, cheese & onion, prawn cocktail, worcester sauce, roast chicken, beef & onion, smoky bacon,cheese, lamb & mint, ham & mustard, barbecue, BBQ rib, tomato ketchup, sausage & ketchup, pickled onion, Branston Pickle, Marmite and more exotic seasonings such as Thai sweet chilli, roast pork & creamy mustard sauce, lime and thai spices, lamb with Moroccan spices, sea salt and cracked black pepper, turkey & bacon, caramelised onion & sweet balsamic vinegar, stilton & cranberry and mango chilli. Kettle Foods Ltd's range of thick-cut crunchy crisps include gourmet flavours : Mexican Limes with a hint of Chilli, Salsa with Mesquite, Buffalo Mozzarella Tomato and Basil, Mature Cheddar with Adnams Broadside Beer, Soulmate Cheeses and Onion, and other previously listed flavours. Most seasonings contain only vegetarian-friendly ingredients, although some recent seasonings such as lamb & mint sauce contain meat extracts. In the early 1980s, there even existed 'Hedgehog flavoured crisps'; these were widely on sale and received large publicity. McCoys Crisps are also popular in the UK. In Northern Ireland Tayto (NI) Ltd. dominate the market. This company is entirely unrelated to the Tayto company in the Republic of Ireland.
- In Ireland, the common varieties of crisps are mostly the same or similar to the ones sold in the UK. However in Ireland, Tayto are synonymous with crisps (after the Tayto brand, Walkers crisps were launched there several years ago, but have failed to dominate the market.
- Japan also has a vast range of seasonings; they include nori & salt, consommé, wasabi, soy sauce & butter, takoyaki, kimchi, garlic, chilli, scallop with butter, ume, mayonnaise, yakitori and ramen. Major manufacturers are Calbee, Koikeya and Yamayoshi.
# Similar foods
Another type of potato chip, notably the Pringles and Lay's Stax brands, is made by extruding or pressing a dough made from ground potatoes into the familiar potato chip shape before frying. This makes chips that are very uniform in size and shape, which allows them to be stacked and packaged in rigid tubes. In America, the official term for Pringles is "crisps", but they are rarely referred to as such. Conversely Pringles may be termed "potato chips" in Britain, to distinguish them from traditional "crisps".
Some companies have also marketed baked potato chips as an alternative with lower fat content. Additionally, some varieties of fat-free chips have been made using artificial, and indigestible, fat substitutes. These became well-known in the media when an ingredient many contained, Olestra, was linked in some individuals to abdominal discomfort and loose stools.
The success of crisp fried potato chips also gave birth to fried corn chips, with such brands as Fritos, CC's and Doritos dominating the market. "Swamp chips" are similarly made from a variety of root vegetables such as parsnips, rutabagas and carrots. Japanese-style variants include extruded chips, like products made from rice or cassava. In South Indian snack cuisine,there is an item called vadam which is a chip made of an extruded rice/sago base.
There are many other products which might be called "crisps" in Britain, but would not be classed as "potato chips" because they aren't made with potato and/or aren't chipped (for example, Wotsits).
Kettle chips are made by leaving the chips in the fryer longer than the regular chip.
# In recipes
In American cuisine, a whole class of recipes exists that use crushed potato chips, often as one would use seasoned bread crumbs. Recipes include those for cookies, pies, breadings for meatloaves and hamburgers, crumb toppings for casseroles and soups, and in sauces or dips, among others. Dipping chips in a sour cream based dip is popular. Putting hot sauce on top of potato chips is popular in Mexico and parts of Texas.
A cheap recipe is the chip sandwich made from a base of two slices of white sandwich bread generously spread with mayonnaise. As many potato chips as possible are heaped on one of the slices, then the second slice is placed on top and pushed down hard until all the potato chips are crushed. This is a snack version of the traditional "chip butty", made with sliced, buttered bread and freshly made French fries. "Crisp sandwiches" are also popular in the UK – a student favorite sees them made with Vitalite spread; in Ireland white bread is spread on both sides with plenty of butter, before being filled with crisps and employing the aforementioned hand-crushing technique to ensure the contents stick to the butter and remain in the sandwich. Potato chips, particularly salt and vinegar , are also a possible addition to tuna salad sandwiches. The chips are layered on top of the tuna as an additional filling. Everything here described can be done also with either Doritos or Cheetos or a combination of all the three for maximum flavour experience.
In New Zealand, potato chips are added to bread with thinly spread Marmite to make a "Marmite And Chip Sandwich". The Australian version of the sandwich uses Vegemite instead of Marmite.
Not strictly a recipe, but another method of preparing crisps is to keep the crisps in the refrigerator, prior to serving. Commonly called ‘cold crisps’, they have a mixed level of acceptance, with some finding them abhorrent, and others seeing ‘cold crisps’ as the correct method of preparation. A common fault in vending machines often results in ‘cold crisps’ being issued, even if crisps at room temperature were desired. In parts of Canada, it is also common to store potato chips in the freezer, and eat them while still frozen. | Potato chip
A potato chip or crisp is a thin slice of potato, deep fried or baked until crisp. Potato chips serve as an appetizer, side dish, or snack. Commercial varieties are packaged for sale, usually in bags. The simplest chips of this kind are just cooked and salted, but manufacturers can add a wide variety of seasonings (mostly made using herbs, spices, cheese, artificial additives or MSG). Chips are an important part of the snack food market in English-speaking countries and many other Western nations.
There is little consistency in the English speaking world for names of fried potato cuttings. North American English uses 'chips' for the above mentioned dish -- this term is also used in continental Europe -- and sometimes 'crisps' for the same made from batter, and 'French fries' for the hot crispy batons with a soft core. In the United Kingdom and Ireland, 'crisps' are the brittle slices eaten at room temperature and 'chips' refer to that hot dish (as in 'fish and chips'). In Australia, New Zealand and some parts of South Africa, both forms of potato product are simply known as 'chips', as are the larger "home-style" potato chips. Sometimes the distinction is made between 'hot chips' (French fried potatoes) and 'packet chips'.
Non-potato based chips also exist. Kumara (sweet potato) chips are eaten in New Zealand and Japan; parsnip crisps are available in the United Kingdom. There are also regional variations. For example, in parts of the North of England, fried sliced potatoes are sometimes called ("flakies").[citation needed] India is famous for a large number of localized 'chips shops', selling not only potato chips but also other varieties such as plantain chips, yam chips and even carrot chips. In many countries potato chips have been criticized because of their high fat percentage (approx. 35%) and their acrylamide content.
# Origins
It is believed that the original potato chip recipe was created by Native American/African American chef George Crum, at Moon's Lake House near Saratoga Springs, New York, on August 24, 1853. He was fed up with a customer — by some accounts Cornelius Vanderbilt (although this has been called into question[1]) — who continued to send his fried potatoes back, because he thought they were too thick and soggy. Crum decided to slice the potatoes so thin that they couldn't be eaten with a fork, nor fried normally in a pan, so he decided to stir-fry the potato slices. Against Crum's expectation, the guest was ecstatic about the new chips. They became a regular item on the lodge's menu under the name "Saratoga Chips." They soon became popular throughout New York and New England. Eventually, potato chips spread beyond chef-cooked restaurant fare and began to be mass produced for home consumption; Dayton, Ohio-based Mike-sell's Potato Chip Company, founded in 1910, calls itself the "oldest potato chip company in the United States".[2] It takes approximately 4 pounds of potatoes to make a pound of potato chips.
An earlier reference is Alexis Soyer's recipe in "Shilling Cookery for People" (1845). Here raw potatoes, "almost shavings" are fried. Earlier still, Mary Randolph's book "The Virginia House-wife" (1824) has a part titled "To fry Sliced Potatoes" here raw potatoes are cut into slices or thin shavings and fried "till they are crisp."
Before the airtight sealed bag was developed, chips were stored in barrels or tins. The chips at the bottom were often stale and damp. Then Laura Scudder invented the bag by ironing together two pieces of waxed paper, thereby creating an airtight seal and keeping the chips fresh until opened. In 1934 Akron, Ohio, potato chip maker K.T. Salem was the first to distribute chips in glassine waxed paper bags. Today, chips are packaged in plastic bags, with nitrogen gas blown in prior to sealing to lengthen shelf life, and provide protection against crushing.
# Economy
The global potato chips market generated total revenues of 16.4 billion dollars in 2005. This accounted for 35.5% of the total savory snacks market in that year (46.1 billion dollars).[3]
# Seasoned chips
Initially, chips went unseasoned until a twist of salt was placed inside the bag, to be added when required. This idea was originated by the Smiths Potato Crisps Company Ltd formed in 1920 [4]. Frank Smith originally packaged them in greaseproof paper bags which were then sold around London, to give them some flavor, he would also include a twist of salt for flavoring. The idea was abandoned when the salting and flavoring process developed by Tayto was applied to crisps during manufacture. Walkers revived the idea of 'salt in a bag', following their take over of Smiths (UK) in 1979, with their Salt 'n' Shake potato crisps[5].
The potato chip remained unseasoned until an innovation by Joe "Spud" Murphy (1923 – 2001)[6], the owner of an Irish crisp company called Tayto, who developed a technology to add seasoning in the 1950s. Though he had a small company, consisting almost entirely of his immediate family who prepared the crisps, the owner had long proved himself an innovator. After some trial and error, he produced the world's first seasoned crisps, "Cheese and Onion" and "Salt 'n' Vinegar".
The innovation became an overnight sensation in the food industry, with the heads of some of the biggest potato chip companies in the United States heading to the small Tayto company to examine the product and to negotiate the rights to use the new technology. When eventually the Tayto company was sold, it made the owner and the small family group who had changed the face of potato chip manufacture very wealthy. Companies worldwide sought to buy the rights to Tayto's technique.
The Tayto innovation changed the whole nature of the potato chip. Later chip manufacturers added natural and artificial seasonings to potato chips, with varying degrees of success. A product that had had a large appeal to a limited market on the basis of one seasoning now had a degree of market penetration through vast numbers of seasonings. Various other seasonings of chips are sold in different locales, including the original "Cheese and Onion", produced by Tayto, which remains by far Ireland's biggest manufacturer of crisps.
Perhaps the most extreme version of seasoned chips were the fruit flavoured chips that were (very) briefly sold in Canada in the late seventies (in orange, cherry and grape flavours). These were not a success, and they were rapidly discontinued.
## Regional varieties
- In the US, the most popular forms of seasoned potato chips include "sour cream and onion", "barbecue" and "ranch". In the Chesapeake Bay area, Utz distributes "crab chips", flavored with an Old Bay analogue seasoning.[7]
- Within North America, wider varieties are available in parts of Canada, where seasonings include dill pickle, ketchup, poutine, salt & vinegar, bacon and curry. In Toronto and Vancouver, Lay's offers wasabi chips.[5]
- The market in United Kingdom is dominated by Walkers which is known for its wide variety of crisps. Typical examples include salt & vinegar, cheese & onion, prawn cocktail, worcester sauce, roast chicken, beef & onion, smoky bacon,cheese, lamb & mint, ham & mustard, barbecue, BBQ rib, tomato ketchup, sausage & ketchup, pickled onion, Branston Pickle, Marmite and more exotic seasonings such as Thai sweet chilli, roast pork & creamy mustard sauce, lime and thai spices, lamb with Moroccan spices, sea salt and cracked black pepper, turkey & bacon, caramelised onion & sweet balsamic vinegar, stilton & cranberry and mango chilli. Kettle Foods Ltd's range of thick-cut crunchy crisps include gourmet flavours : Mexican Limes with a hint of Chilli, Salsa with Mesquite, Buffalo Mozzarella Tomato and Basil, Mature Cheddar with Adnams Broadside Beer, Soulmate Cheeses and Onion, and other previously listed flavours. Most seasonings contain only vegetarian-friendly ingredients, although some recent seasonings such as lamb & mint sauce contain meat extracts. In the early 1980s, there even existed 'Hedgehog flavoured crisps'; these were widely on sale and received large publicity. McCoys Crisps are also popular in the UK. In Northern Ireland Tayto (NI) Ltd. dominate the market. This company is entirely unrelated to the Tayto company in the Republic of Ireland.
- In Ireland, the common varieties of crisps are mostly the same or similar to the ones sold in the UK. However in Ireland, Tayto are synonymous with crisps (after the Tayto brand, Walkers crisps were launched there several years ago, but have failed to dominate the market.
- Japan also has a vast range of seasonings; they include nori & salt, consommé, wasabi, soy sauce & butter, takoyaki, kimchi, garlic, chilli, scallop with butter, ume, mayonnaise, yakitori and ramen. Major manufacturers are Calbee, Koikeya and Yamayoshi.
# Similar foods
Another type of potato chip, notably the Pringles and Lay's Stax brands, is made by extruding or pressing a dough made from ground potatoes into the familiar potato chip shape before frying. This makes chips that are very uniform in size and shape, which allows them to be stacked and packaged in rigid tubes. In America, the official term for Pringles is "crisps", but they are rarely referred to as such. Conversely Pringles may be termed "potato chips" in Britain, to distinguish them from traditional "crisps".
Some companies have also marketed baked potato chips as an alternative with lower fat content. Additionally, some varieties of fat-free chips have been made using artificial, and indigestible, fat substitutes. These became well-known in the media when an ingredient many contained, Olestra, was linked in some individuals to abdominal discomfort and loose stools.[8]
The success of crisp fried potato chips also gave birth to fried corn chips, with such brands as Fritos, CC's and Doritos dominating the market. "Swamp chips" are similarly made from a variety of root vegetables such as parsnips, rutabagas and carrots. Japanese-style variants include extruded chips, like products made from rice or cassava. In South Indian snack cuisine,there is an item called vadam which is a chip made of an extruded rice/sago base.
There are many other products which might be called "crisps" in Britain, but would not be classed as "potato chips" because they aren't made with potato and/or aren't chipped (for example, Wotsits).
Kettle chips are made by leaving the chips in the fryer longer than the regular chip.
# In recipes
In American cuisine, a whole class of recipes exists that use crushed potato chips, often as one would use seasoned bread crumbs. Recipes include those for cookies, pies, breadings for meatloaves and hamburgers, crumb toppings for casseroles and soups, and in sauces or dips, among others. Dipping chips in a sour cream based dip is popular. Putting hot sauce on top of potato chips is popular in Mexico and parts of Texas.
A cheap recipe is the chip sandwich made from a base of two slices of white sandwich bread generously spread with mayonnaise. As many potato chips as possible are heaped on one of the slices, then the second slice is placed on top and pushed down hard until all the potato chips are crushed. This is a snack version of the traditional "chip butty", made with sliced, buttered bread and freshly made French fries. "Crisp sandwiches" are also popular in the UK – a student favorite sees them made with Vitalite spread; in Ireland white bread is spread on both sides with plenty of butter, before being filled with crisps and employing the aforementioned hand-crushing technique to ensure the contents stick to the butter and remain in the sandwich. Potato chips, particularly salt and vinegar , are also a possible addition to tuna salad sandwiches. The chips are layered on top of the tuna as an additional filling. Everything here described can be done also with either Doritos or Cheetos or a combination of all the three for maximum flavour experience.
In New Zealand, potato chips are added to bread with thinly spread Marmite to make a "Marmite And Chip Sandwich". The Australian version of the sandwich uses Vegemite instead of Marmite.
Not strictly a recipe, but another method of preparing crisps is to keep the crisps in the refrigerator, prior to serving. Commonly called ‘cold crisps’, they have a mixed level of acceptance, with some finding them abhorrent, and others seeing ‘cold crisps’ as the correct method of preparation. A common fault in vending machines often results in ‘cold crisps’ being issued, even if crisps at room temperature were desired. In parts of Canada, it is also common to store potato chips in the freezer, and eat them while still frozen. | https://www.wikidoc.org/index.php/Potato_chip | |
fceaf5676797a5acc357950f893d1ac84c1c093e | wikidoc | Pound-force | Pound-force
The pound-force or simply pound (abbreviations: lb, lbf, or lbf) is a unit of force.
# Definitions
The pound-force is approximately equal to the gravitational force exerted on a mass of one avoirdupois pound on the surface of Earth. Since the 18th century, the unit has been used in low-precision measurements, for which small changes in Earth's gravity (which varies from place to place by up to half a percent)
can safely be neglected.
The 20th century, however, brought the need for a more precise definition. A standardized value for acceleration due to gravity was therefore needed. Today, in accordance the General Conference on Weights and Measures, standard gravity is usually taken to be 9.80665 m/s² (approximately 32.17405 ft/s²) but other values have been used, including 32.16 ft/s² (approximately 9.80237 m/s²).
From the acceleration of the standard gravitational field and the international avoirdupois pound, we arrive at the following definition:
Sixteen avoirdupois ounces (as a unit of mass) are equal to one avoirdupois pound (as a unit of mass). Similarly one ounce-force is equal to a sixteenth of a pound-force.
# Use of pound as a unit of force
In some contexts, such as structural engineering applications, the term "pound" is used almost exclusively to refer to the unit of force and not the unit of mass. In those applications, the preferred unit of mass is the slug, i.e. lbf·s²/ft. In other contexts, the unit "pound" refers to a unit of mass. In circumstances where there may be ambiguity otherwise, the symbols "lbf" and "lbm" and the terms "pounds-force" and "pounds-mass" can be used to distinguish.
Three common, equally valid foot-pound-second (fps) systems of units for doing calculations with mass and force are summarized in the table below, which also includes the corresponding metric units.
In the "engineering" fps system, the weight of the mass unit (pound-mass) on Earth's surface is approximately equal to the force unit (pound-force). The price for this convenience is that the force unit is not equal to the mass unit multiplied by the acceleration unit—the use of Newton's Second Law, F = ma, requires another factor, gc, usually taken to be 32.17405 lb·ft/(lbf·s²). The "gravitational" fps system is a coherent system of units: by using the slug as the unit of mass, it avoids the need for such a constant. The "absolute" system is similarly coherent; the SI units are those of the "absolute" metric system. | Pound-force
The pound-force or simply pound (abbreviations: lb, lbf, or lbf) is a unit of force.
# Definitions
The pound-force is approximately equal to the gravitational force exerted on a mass of one avoirdupois pound on the surface of Earth. Since the 18th century, the unit has been used in low-precision measurements, for which small changes in Earth's gravity (which varies from place to place by up to half a percent)
can safely be neglected.[1]
The 20th century, however, brought the need for a more precise definition. A standardized value for acceleration due to gravity was therefore needed. Today, in accordance the General Conference on Weights and Measures, standard gravity is usually taken to be 9.80665 m/s² (approximately 32.17405 ft/s²)[2][3] but other values have been used, including 32.16 ft/s² (approximately 9.80237 m/s²).[4]
From the acceleration of the standard gravitational field and the international avoirdupois pound, we arrive at the following definition:[5]
Sixteen avoirdupois ounces (as a unit of mass) are equal to one avoirdupois pound (as a unit of mass). Similarly one ounce-force is equal to a sixteenth of a pound-force.
Template:Units of force
# Use of pound as a unit of force
In some contexts, such as structural engineering applications, the term "pound" is used almost exclusively to refer to the unit of force and not the unit of mass. In those applications, the preferred unit of mass is the slug, i.e. lbf·s²/ft. In other contexts, the unit "pound" refers to a unit of mass. In circumstances where there may be ambiguity otherwise, the symbols "lbf" and "lbm" and the terms "pounds-force" and "pounds-mass" can be used to distinguish.
Three common, equally valid foot-pound-second (fps) systems of units for doing calculations with mass and force are summarized in the table below, which also includes the corresponding metric units.
Template:GravEngAbs
In the "engineering" fps system, the weight of the mass unit (pound-mass) on Earth's surface is approximately equal to the force unit (pound-force). The price for this convenience is that the force unit is not equal to the mass unit multiplied by the acceleration unit[6]—the use of Newton's Second Law, F = ma, requires another factor, gc, usually taken to be 32.17405 lb·ft/(lbf·s²). The "gravitational" fps system is a coherent system of units: by using the slug as the unit of mass, it avoids the need for such a constant. The "absolute" system is similarly coherent; the SI units are those of the "absolute" metric system. | https://www.wikidoc.org/index.php/Pound-force | |
0392f73b683265fde16430b69e072c3a15a675aa | wikidoc | Pramipexole | Pramipexole
# Disclaimer
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# Overview
Pramipexole is a dopamine agonist that is FDA approved for the {{{indicationType}}} of idiopathic parkinson’s disease (PD), moderate-to-severe primary restless legs syndrome (RLS). Common adverse reactions include nausea, dizziness, somnolence, insomnia, constipation, asthenia, hallucinations, fatigue, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Doses should be increased gradually from a starting dose of 0.375 mg/day given in three divided doses and should not be increased more frequently than every 5 to 7 days. A suggested ascending dosage schedule that was used in clinical studies is shown in the following table:
- Maintenance Treatment
- MIRAPEX tablets were effective and well tolerated over a dosage range of 1.5 to 4.5 mg/day administered in equally divided doses three times per day with or without concomitant levodopa (approximately 800 mg/day).
- In a fixed-dose study in early Parkinson's disease patients, doses of 3 mg, 4.5 mg, and 6 mg per day of MIRAPEX tablets were not shown to provide any significant benefit beyond that achieved at a daily dose of 1.5 mg/day. However, in the same fixed-dose study, the following adverse events were dose related: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence reported with pramipexole at a dose of 1.5 mg/day was comparable to placebo.
- When MIRAPEX tablets are used in combination with levodopa, a reduction of the levodopa dosage should be considered. In a controlled study in advanced Parkinson's disease, the dosage of levodopa was reduced by an average of 27% from baseline.
- The recommended starting dose of MIRAPEX tablets is 0.125 mg taken once daily 2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days (Table 3). Although the dose of MIRAPEX tablets was increased to 0.75 mg in some patients during long-term open-label treatment, there is no evidence that the 0.75 mg dose provides additional benefit beyond the 0.5 mg dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pramipexole in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Oral pramipexole (initial dose 0.125 milligrams (mg) twice daily, increased by 0.25 mg/day every 3 to 5 days to target dose of 1 to 2.5 mg/day).
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pramipexole in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pramipexole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pramipexole in pediatric patients.
# Contraindications
- None
# Warnings
### Precautions
- Falling Asleep During Activities of Daily Living
- Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents. Although many of these patients reported somnolence while on pramipexole tablets, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment.
- Somnolence is a common occurrence in patients receiving pramipexole at doses above 1.5 mg/day (0.5 mg TID) for Parkinson’s disease. In controlled clinical trials in RLS, patients treated with MIRAPEX tablets at doses of 0.25-0.75 mg once a day, the incidence of somnolence was 6% compared to an incidence of 3% for placebo-treated patients. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
- Before initiating treatment with MIRAPEX tablets, advise patients of the potential to develop drowsiness and specifically asked about factors that may increase the risk with MIRAPEX tablets such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), MIRAPEX tablets should ordinarily be discontinued. If a decision is made to continue MIRAPEX tablets, advise patients not to drive and to avoid other potentially dangerous activities. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
- Symptomatic Orthostatic Hypotension
- Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, both Parkinson's disease patients and RLS patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk.
- In clinical trials of pramipexole, however, and despite clear orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hypotension was not greater among those assigned to pramipexole tablets than among those assigned to placebo. This result, especially with the higher doses used in Parkinson’s disease, is clearly unexpected in light of the previous experience with the risks of dopamine agonist therapy.
- While this finding could reflect a unique property of pramipexole, it might also be explained by the conditions of the study and the nature of the population enrolled in the clinical trials. Patients were very carefully titrated, and patients with active cardiovascular disease or significant orthostatic hypotension at baseline were excluded. Also, clinical trials in patients with RLS did not incorporate orthostatic challenges with intensive blood pressure monitoring done in close temporal proximity to dosing.
- Impulse Control/Compulsive Behaviors
- Case reports and the results of a cross-sectional study suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and/or other intense urges and the inability to control these urges while taking one or more of the medications, including MIRAPEX, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with MIRAPEX. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking MIRAPEX.
- Hallucinations
- In the three double-blind, placebo-controlled trials in early Parkinson's disease, hallucinations were observed in 9% (35 of 388) of patients receiving MIRAPEX tablets, compared with 2.6% (6 of 235) of patients receiving placebo. In the four double-blind, placebo-controlled trials in advanced Parkinson's disease, where patients received MIRAPEX tablets and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving MIRAPEX tablets compared with 3.8% (10 of 264) of patients receiving placebo. Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson's disease patients and 2.7% of the advanced Parkinson's disease patients compared with about 0.4% of placebo patients in both populations.
- Age appears to increase the risk of hallucinations attributable to pramipexole. In the early Parkinson's disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years. In the advanced Parkinson's disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years.
- In the RLS clinical program, one pramipexole-treated patient (of 889) reported hallucinations; this patient discontinued treatment and the symptoms resolved.
- Dyskinesia
- Mirapex tablets may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia.
- Renal Impairment
- Since pramipexole is eliminated through the kidneys, caution should be exercised when prescribing MIRAPEX tablets to patients with renal impairment.
- Rhabdomyolysis
- A single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson's disease treated with MIRAPEX tablets. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.
- Retinal Pathology
- Human Data
- A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared MIRAPEX tablets and immediate-release ropinirole. Two hundred thirty four Parkinson’s disease patients (115 on pramipexole, mean dose 3.0 mg/day and 119 on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical ophthalmological assessments. Of 234 patients who were evaluable, 196 had been treated for two years and 29 were judged to have developed clinical abnormalities that were considered meaningful (19 patients in each treatment arm had received treatment for less than two years). There was no statistical difference in retinal deterioration between the treatment arms; however, the study was only capable of detecting a very large difference between treatments. In addition, because the study did not include an untreated comparison group (placebo treated), it is unknown whether the findings reported in patients treated with either drug are greater than the background rate in an aging population.
- Animal Data
- Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.
- Events Reported with Dopaminergic Therapy
- Although the events enumerated below may not have been reported in association with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.
- Withdrawal-Emergent Hyperpyrexia and Confusion
- Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.
- Fibrotic Complications
- Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.
- Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists can cause them is unknown.
- Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the post marketing experience with MIRAPEX tablets. While the evidence is not sufficient to establish a causal relationship between MIRAPEX tablets and these fibrotic complications, a contribution of MIRAPEX tablets cannot be completely ruled out.
- Melanoma
- Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using MIRAPEX tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
- Rebound and Augmentation in RLS
- Reports in the literature indicate treatment of RLS with dopaminergic medications can result in rebound: a worsening of symptoms following treatment cessation with greater intensity than described before starting treatment. In a 26 week placebo controlled clinical trial in patients with RLS, a worsening of symptoms scores (IRLS) beyond their untreated baseline levels was reported more frequently by patients suddenly withdrawn from MIRAPEX (up to 0.75 mg once daily) compared to the group assigned to placebo (10% vs. 2%, respectively). The worsening of RLS symptoms was considered generally mild.
- Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. In a 26 week placebo controlled clinical trial in patients with RLS, augmentation was reported with greater frequency by patients treated with MIRAPEX (up to 0.75 mg once daily) compared to patients who received placebo (12% vs. 9%, respectively). The incidence of augmentation increased with increasing duration of exposure to MIRAPEX and to placebo.
- The frequency and severity of augmentation and/or rebound after longer-term use of MIRAPEX tablets and the appropriate management of these events have not been adequately evaluated in controlled clinical trials.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- During the premarketing development of pramipexole, patients with either early or advanced Parkinson's disease were enrolled in clinical trials. Apart from the severity and duration of their disease, the two populations differed in their use of concomitant levodopa therapy. Patients with early disease did not receive concomitant levodopa therapy during treatment with pramipexole; those with advanced Parkinson's disease all received concomitant levodopa treatment. Because these two populations may have differential risks for various adverse events, this section will, in general, present adverse-event data for these two populations separately.
- Because the controlled trials performed during premarketing development all used a titration design, with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse events.
- Early Parkinson's Disease
- In the three double-blind, placebo-controlled trials of patients with early Parkinson's disease, the most commonly observed adverse events (>5%) that were numerically more frequent in the group treated with MIRAPEX tablets were nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations.
- Approximately 12% of 388 patients with early Parkinson's disease and treated with MIRAPEX tablets who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared with 11% of 235 patients who received placebo. The adverse events most commonly causing discontinuation of treatment were related to the nervous system (hallucinations ; dizziness ; somnolence ; extrapyramidal syndrome ; headache and confusion ); and gastrointestinal system (nausea ).
- Adverse-event Incidence in Controlled Clinical Studies in Early Parkinson's Disease: Table 4 lists treatment-emergent adverse events that occurred in the double-blind, placebo-controlled studies in early Parkinson's disease that were reported by ≥1% of patients treated with MIRAPEX tablets and were numerically more frequent than in the placebo group. In these studies, patients did not receive concomitant levodopa. Adverse events were usually mild or moderate in intensity.
- The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse-event incidence rate in the population studied.
- Other events reported by 1% or more of patients with early Parkinson's disease and treated with MIRAPEX tablets but reported equally or more frequently in the placebo group were infection, accidental injury, headache, pain, tremor, back pain, syncope, postural hypotension, hypertonia, depression, abdominal pain, anxiety, dyspepsia, flatulence, diarrhea, rash, ataxia, dry mouth, extrapyramidal syndrome, leg cramps, twitching, pharyngitis, sinusitis, sweating, rhinitis, urinary tract infection, vasodilation, flu syndrome, increased saliva, tooth disease, dyspnea, increased cough, gait abnormalities, urinary frequency, vomiting, allergic reaction, hypertension, pruritus, hypokinesia, increased creatine PK, nervousness, dream abnormalities, chest pain, neck pain, paresthesia, tachycardia, vertigo, voice alteration, conjunctivitis, paralysis, accommodation abnormalities, tinnitus, diplopia, and taste perversions.
- In a fixed-dose study in early Parkinson's disease, occurrence of the following events increased in frequency as the dose increased over the range from 1.5 mg/day to 6 mg/day: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence with pramipexole at a dose of 1.5 mg/day was comparable to that reported for placebo.
- Advanced Parkinson's Disease
- In the four double-blind, placebo-controlled trials of patients with advanced Parkinson's disease, the most commonly observed adverse events (>5%) that were numerically more frequent in the group treated with MIRAPEX tablets and concomitant levodopa were postural orthostatic hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary frequency.
- Approximately 12% of 260 patients with advanced Parkinson's disease who received MIRAPEX tablets and concomitant levodopa in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared with 16% of 264 patients who received placebo and concomitant levodopa. The events most commonly causing discontinuation of treatment were related to the nervous system (hallucinations ; dyskinesia ; extrapyramidal syndrome ; dizziness ; confusion ); and cardiovascular system (postural orthostatic hypotension ).
- Adverse-event Incidence in Controlled Clinical Studies in Advanced Parkinson's Disease: Table 5 lists treatment-emergent adverse events that occurred in the double-blind, placebo-controlled studies in advanced Parkinson's disease that were reported by ≥1% of patients treated with MIRAPEX tablets and were numerically more frequent than in the placebo group. In these studies, MIRAPEX tablets or placebo was administered to patients who were also receiving concomitant levodopa. Adverse events were usually mild or moderate in intensity.
- The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse-events incidence rate in the population studied.
- Other events reported by 1% or more of patients with advanced Parkinson's disease and treated with MIRAPEX tablets but reported equally or more frequently in the placebo group were nausea, pain, infection, headache, depression, tremor, hypokinesia, anorexia, back pain, dyspepsia, flatulence, ataxia, flu syndrome, sinusitis, diarrhea, myalgia, abdominal pain, anxiety, rash, paresthesia, hypertension, increased saliva, tooth disorder, apathy, hypotension, sweating, vasodilation, vomiting, increased cough, nervousness, pruritus, hypesthesia, neck pain, syncope, arthralgia, dysphagia, palpitations, pharyngitis, vertigo, leg cramps, conjunctivitis, and lacrimation disorders.
- MIRAPEX tablets for treatment of RLS have been evaluated for safety in 889 patients, including 427 treated for over six months and 75 for over one year.
- The overall safety assessment focuses on the results of three double-blind, placebo-controlled trials, in which 575 patients with RLS were treated with MIRAPEX tablets for up to 12 weeks. The most commonly observed adverse events with MIRAPEX tablets in the treatment of RLS (observed in >5% of pramipexole-treated patients and at a rate at least twice that observed in placebo-treated patients) were nausea and somnolence. Occurrences of nausea and somnolence in clinical trials were generally mild and transient.
- Approximately 7% of 575 patients treated with MIRAPEX tablets during the double-blind periods of three placebo-controlled trials discontinued treatment due to adverse events compared to 5% of 223 patients who received placebo. The adverse event most commonly causing discontinuation of treatment was nausea (1%).
- Table 6 lists treatment-emergent events that occurred in three double-blind, placebo-controlled studies in RLS patients that were reported by ≥2% of patients treated with MIRAPEX tablets and were numerically more frequent than in the placebo group.
- The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse-event incidence rate in the population studied.
- Other events reported by 2% or more of RLS patients treated with MIRAPEX tablets but reported equally or more frequently in the placebo group, were: vomiting, nasopharyngitis, back pain, pain in extremity, dizziness, and insomnia.
- Table 7 summarizes data for adverse events that appeared to be dose related in the 12-week fixed dose study.
- General
- Adverse Events: Relationship to Age, Gender, and Race
- Among the treatment-emergent adverse events in patients treated with MIRAPEX tablets, hallucination appeared to exhibit a positive relationship to age in patients with Parkinson’s disease. Although no gender-related differences were observed in Parkinson’s disease patients, nausea and fatigue, both generally transient, were more frequently reported by female than male RLS patients. Less than 4% of patients enrolled were non-Caucasian: therefore, an evaluation of adverse events related to race is not possible.
- Laboratory Tests
- During the development of MIRAPEX tablets, no systematic abnormalities on routine laboratory testing were noted. Therefore, no specific guidance is offered regarding routine monitoring; the practitioner retains responsibility for determining how best to monitor the patient in his or her care.
- Other Adverse Events Observed During Phase 2 and 3 Clinical Trials
- MIRAPEX tablets have been administered to 1620 Parkinson’s disease patients and to 889 RLS patients in Phase 2 and 3 clinical trials. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing; similar types of events were grouped into a smaller number of standardized categories using MedDRA dictionary terminology. These categories are used in the listing below. Adverse events which are not listed above but occurred on at least two occasions (one occasion if the event was serious) in the 2509 individuals exposed to MIRAPEX tablets are listed below. The reported events below are included without regard to determination of a causal relationship to MIRAPEX tablets.
Anemia, iron deficiency anemia, leukocytosis, leukopenia, lymphadenitis, lymphadenopathy, thrombocythaemia, thrombocytopenia
Angina pectoris, supraventricular arrhythmia, atrial fibrillation, first degree atrioventricular block, second degree atrioventricular block, bradycardia, bundle branch block, cardiac arrest, cardiac failure, congestive cardiac failure, cardiomegaly, coronary artery occlusion, cyanosis, extrasystoles, left ventricular failure, myocardial infarction, nodal arrhythmia, sinus arrhythmia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, ventricular fibrillation, ventricular extrasystoles, ventricular hypertrophy
Atrial septal defect, congenital foot malformation, spine malformation
Deafness, ear pain, hearing impaired, hypoacusis, motion sickness, vestibular ataxia
Goiter, hyperthyroidism, hypothyroidism
Amaurosis fugax, blepharitis, blepharospasm, cataract, dacryostenosis acquired, dry eye, eye hemorrhage, eye irritation, eye pain, eyelid edema, eyelid ptosis, glaucoma, keratitis, macular degeneration, myopia, photophobia, retinal detachment, retinal vascular disorder, scotoma, vision blurred, visual acuity reduced, vitreous floaters
Abdominal discomfort, abdominal distension, aphthous stomatitis, ascites, cheilitis, colitis, ulcerative colitis, duodenal ulcer, duodenal ulcer hemorrhage, enteritis, eructation, fecal incontinence, gastric ulcer, gastric ulcer hemorrhage, gastritis, gastrointestinal hemorrhage, gastroesophageal reflux disease, gingivitis, haematemesis, haematochezia, hemorrhoids, hiatus hernia, hyperchlorhydria, ileus, inguinal hernia, intestinal obstruction, irritable bowel syndrome, esophageal spasm, esophageal stenosis, esophagitis, pancreatitis, periodontitis, rectal hemorrhage, reflux esophagitis, tongue edema, tongue ulceration, toothache, umbilical hernia
Chest discomfort, chills, death, drug withdrawal syndrome, face edema, feeling cold, feeling hot, feeling jittery, gait disturbance, impaired healing, influenza-like illness, irritability, localized edema, edema, pitting edema, thirst
Biliary colic, cholecystitis, cholecystitis chronic, cholelithiasis
Drug hypersensitivity
Abscess, acute tonsillitis, appendicitis, bronchiolitis, bronchitis, bronchopneumonia, cellulitis, cystitis, dental caries, diverticulitis, ear infection, eye infection, folliculitis, fungal infection, furuncle, gangrene, gastroenteritis, gingival infection, herpes simplex, herpes zoster, hordeolum, intervertebral discitis, laryngitis, lobar pneumonia, nail infection, onychomycosis, oral candidiasis, orchitis, osteomyelitis, otitis externa, otitis media, paronychia, pyelonephritis, pyoderma, sepsis, skin infection, tonsillitis, tooth abscess, tooth infection, upper respiratory tract infection, urethritis, vaginal candidiasis, vaginal infection, viral infection, wound infection
Accidental falls, drug toxicity, epicondylitis, road traffic accident, sunburn, tendon rupture
Cachexia, decreased appetite, dehydration, diabetes mellitus, fluid retention, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperuricemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, hypovitaminosis, increased appetite, metabolic alkalosis
Bone pain, fasciitis, flank pain, intervertebral disc disorder, intervertebral disc protrusion, joint effusion, joint stiffness, joint swelling, monarthritis, muscle rigidity, muscle spasms, musculoskeletal stiffness, myopathy, myositis, nuchal rigidity, osteoarthritis, osteonecrosis, osteoporosis, polymyalgia, rheumatoid arthritis, shoulder pain, spinal osteoarthritis, tendonitis, tenosynovitis
Abdominal neoplasm, adenocarcinoma, adenoma benign, basal cell carcinoma, bladder cancer, breast cancer, breast neoplasm, chronic lymphocytic leukemia, colon cancer, colorectal cancer, endometrial cancer, gallbladder cancer, gastric cancer, gastrointestinal neoplasm, hemangioma, hepatic neoplasm, hepatic neoplasm malignant, lip and/or oral cavity cancer, lung neoplasm malignant, lung cancer metastatic, lymphoma, malignant melanoma, melanocytic naevus, metastases to lung, multiple myeloma, oral neoplasm benign, neoplasm, neoplasm malignant, neoplasm prostate, neoplasm skin, neuroma, ovarian cancer, prostate cancer, prostatic adenoma, pseudo lymphoma, renal neoplasm, skin cancer, skin papilloma, squamous cell carcinoma, thyroid neoplasm, uterine leiomyoma
Ageusia, akinesia, anticholinergic syndrome, aphasia, balance disorder, brain edema, carotid artery occlusion, carpal tunnel syndrome, cerebral artery embolism, cerebral hemorrhage, cerebral infarction, cerebral ischemia, chorea, cognitive disorder, coma, convulsion, coordination abnormal, dementia, depressed level of consciousness, disturbance in attention, dizziness postural, dysarthria, dysgraphia, facial palsy, grand mal convulsion, hemiplegia, hyperaesthesia, hyperkinesia, hyperreflexia, hyporeflexia, hypotonia, lethargy, loss of consciousness, memory impairment, migraine, muscle contractions involuntary, narcolepsy, neuralgia, neuropathy, nystagmus, parosmia, psychomotor hyperactivity, sciatica, sedation, sensory disturbance, sleep phase rhythm disturbance, sleep talking, stupor, vasovagal syncope, tension headache
Affect lability, aggression, agitation, bradyphrenia, bruxism, suicide, delirium, delusional disorder persecutory type, disorientation, dissociation, emotional distress, euphoric mood, hallucination auditory, hallucination visual, initial insomnia, libido increased, mania, middle insomnia, mood altered, nightmare, obsessive thoughts, obsessive-compulsive disorder, panic reaction, parasomnia, personality disorder, psychotic disorder, restlessness, sleep walking, suicidal ideation
Chromaturia, dysuria, glycosuria, hematuria, urgency, nephrolithiasis, neurogenic bladder, nocturia, oliguria, pollakiuria, proteinuria, renal artery stenosis, renal colic, renal cyst, renal failure, renal impairment, urinary retention
Amenorrhea, breast pain, dysmenorrhea, epididymitis, gynaecomastia, menopausal symptoms, menorrhagia, metrorrhagia, ovarian cyst, priapism, prostatitis, sexual dysfunction, uterine hemorrhage, vaginal discharge, vaginal hemorrhage
Apnea, aspiration, asthma, choking, chronic obstructive pulmonary disease, dry throat, dysphonia, exertional dyspnea, epistaxis, haemoptysis, hiccups, hyperventilation, increased bronchial secretion, laryngospasm, nasal dryness, nasal polyps, obstructive airways disorder, pharyngolaryngeal pain, pleurisy, aspiration pneumonia, pneumothorax, postnasal drip, productive cough, pulmonary embolism, pulmonary edema, respiratory alkalosis, respiratory distress, respiratory failure, respiratory tract congestion, allergic rhinitis, rhinorrhea, sinus congestion, sleep apnoea syndrome, sneezing, snoring, tachypnea, wheezing
Acne, alopecia, cold sweat, dermal cyst, dermatitis, dermatitis bullous, dermatitis contact, dry skin, ecchymosis, eczema, erythema, hyperkeratosis, livedo reticularis, night sweats, periorbital edema, petechiae, photosensitivity allergic reaction, psoriasis, purpura, rash erythematous, rash maculo-papular, rash papular, rosacea, seborrhea, seborrheic dermatitis, skin burning sensation, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, skin irritation, skin nodule, skin odor abnormal, skin ulcer, urticaria
Aneurysm, angiopathy, arteriosclerosis, circulatory collapse, deep vein thrombosis, embolism, hematoma, hot flush, hypertensive crisis, lymphoedema, pallor, phlebitis, Raynaud’s phenomenon, shock, thrombophlebitis, thrombosis, varicose vein.
## Postmarketing Experience
- In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified during post-approval use of MIRAPEX tablets, primarily in Parkinson’s disease patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to pramipexole tablets. Similar types of reactions were grouped into a smaller number of standardized categories using the MedDRA terminology: abnormal behavior, abnormal dreams, accidents (including fall), blackouts, compulsive shopping, fatigue, hallucinations (all kinds), headache, hypotension (including postural hypotension), syndrome of inappropriate antidiuretic hormone secretion (SIADH), increased eating (including binge eating, compulsive eating, and hyperphagia), libido disorders (including increased and decreased libido, and hypersexuality), pathological gambling, pruritus, syncope, vomiting, and weight increase.
# Drug Interactions
- Dopamine Antagonists
- Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX tablets.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. MIRAPEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day (5 times the maximum recommended human dose (MRHD) for Parkinson’s disease of 4.5 mg/day on a body surface area (mg/m2) basis). Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis (gestation days 7 through 16) resulted in a high incidence of total resorption of embryos. The plasma AUC in rats at this dose was 4 times the AUC in humans at the MRHD. These findings are thought to be due to the prolactin-lowering effect of pramipexole, since prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not rabbits or humans). Because of pregnancy disruption and early embryonic loss in these studies, the teratogenic potential of pramipexole could not be adequately evaluated. There was no evidence of adverse effects on embryo-fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis (plasma AUC was 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately equivalent to the MRHD on a mg/m2 basis) or greater during the latter part of pregnancy and throughout lactation.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pramipexole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pramipexole during labor and delivery.
### Nursing Mothers
Studies have shown that pramipexole treatment resulted in an inhibition of prolactin secretion in humans and rats.
- A single-dose, radio-labeled study showed that drug-related material was present in rat milk at concentrations three to six times higher than those in plasma at equivalent time points. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MIRAPEX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of MIRAPEX in pediatric patients has not been established.
### Geriatic Use
- Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours.
- In clinical studies with Parkinson’s disease patients, 38.7% of patients were older than 65 years. There were no apparent differences in efficacy or safety between older and younger patients, except that the relative risk of hallucination associated with the use of MIRAPEX tablets was increased in the elderly.
- In clinical studies with RLS patients, 22% of patients were at least 65 years old. There were no apparent differences in efficacy or safety between older and younger patients.
### Gender
There is no FDA guidance on the use of Pramipexole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pramipexole with respect to specific racial populations.
### Renal Impairment
- The elimination of pramipexole is dependent on renal function. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis. Caution should be exercised when administering MIRAPEX tablets to patients with renal disease.
### Hepatic Impairment
There is no FDA guidance on the use of Pramipexole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pramipexole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pramipexole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Pramipexole in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pramipexole in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable although pulse rate increased to between 100 and 120 beats/minute. No other adverse events were reported related to the increased dose.
### Management
- There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Pramipexole in the drug label.
# Pharmacology
## Mechanism of Action
- Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.
- Parkinson’s Disease
- The precise mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in Parkinson’s disease is unknown.
- Restless Legs Syndrome (RLS)
- The precise mechanism of action of MIRAPEX tablets as a treatment for RLS is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron Emission Tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS.
## Structure
- MIRAPEX tablets contain pramipexole, a nonergot dopamine agonist. The chemical name of pramipexole dihydrochloride is (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate. Its empirical formula is C10 H17 N3 S · 2HCl · H2O, and its molecular weight is 302.26.
- The structural formula is:
- Pramipexole dihydrochloride is a white to off-white powder substance. Melting occurs in the range of 296°C to 301°C, with decomposition. Pramipexole dihydrochloride is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane.
- MIRAPEX tablets, for oral administration, contain 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, or 1.5 mg of pramipexole dihydrochloride monohydrate. Inactive ingredients consist of mannitol, corn starch, colloidal silicon dioxide, povidone, and magnesium stearate.
## Pharmacodynamics
- The effect of pramipexole on the QT interval of the ECG was investigated in a clinical study in 60 healthy male and female volunteers. All subjects initiated treatment with 0.375 mg extended release pramipexole tablets administered once daily, and were up-titrated every 3 days to 2.25 mg and 4.5 mg daily. No dose- or exposure-related effect on mean QT intervals was observed; however the study did not have a valid assessment of assay sensitivity. The effect of pramipexole on QTc intervals at higher exposures achieved either due to drug interactions (e.g., with cimetidine), renal impairment, or at higher doses has not been systematically evaluated.
- Although mean values remained within normal reference ranges throughout the study, supine systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate for subjects treated with pramipexole generally increased during the rapid up-titration phase, by 10 mmHg, 7 mmHg, and 10 bpm higher than placebo, respectively. Higher SBP, DBP, and pulse rates compared to placebo were maintained until the pramipexole doses were tapered; values on the last day of tapering were generally similar to baseline values. Such effects have not been observed in clinical studies with Parkinson’s disease patients, who were titrated according to labeled recommendations.
## Pharmacokinetics
- Pramipexole displays linear pharmacokinetics over the clinical dosage range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers. Steady-state concentrations are achieved within 2 days of dosing.
- Absorption
- Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism. Food does not affect the extent of pramipexole absorption, although the time of maximum plasma concentration (Tmax) is increased by about 1 hour when the drug is taken with a meal.
- Distribution
- Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation =20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2.
- Metabolism
- Pramipexole is metabolized only to a negligible extent (<10%). No specific active metabolite has been identified in human plasma or urine.
- Elimination
- Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min (CV=25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system.
- Pharmacokinetics in Specific Populations
- Because therapy with MIRAPEX tablets is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, race, or age is not necessary. However, renal insufficiency, which can cause a large decrease in the ability to eliminate pramipexole, may necessitate dosage adjustment.
- Gender
- Pramipexole clearance is about 30% lower in women than in men, but this difference can be accounted for by differences in body weight. There is no difference in half-life between males and females.
- Age
- Pramipexole clearance decreases with age as the half-life and clearance are about 40% longer and 30% lower, respectively, in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). This difference is most likely due to the reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance.
- Race
- No racial differences in metabolism and elimination have been identified.
- Parkinson's Disease Patients
- A cross-study comparison of data suggests that the clearance of pramipexole may be reduced by about 30% in Parkinson's disease patients compared with healthy elderly volunteers. The reason for this difference appears to be reduced renal function in Parkinson's disease patients, which may be related to their poorer general health. The pharmacokinetics of pramipexole were comparable between early and advanced Parkinson's disease patients.
- Restless Legs Syndrome Patients
- A cross-study comparison of data suggests that the pharmacokinetic profile of pramipexole administered once daily in RLS patients is similar to the pharmacokinetic profile of pramipexole in healthy volunteers.
- Hepatic Impairment
- The influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination.
- Renal Impairment
- Clearance of pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers. In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance.
- Drug Interactions
- Carbidopa/levodopa: Carbidopa/levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (N=10). Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa Cmax by about 40% and a decrease in Tmax from 2.5 to 0.5 hours.
- Selegiline: In healthy volunteers (N=11), selegiline did not influence the pharmacokinetics of pramipexole.
- Amantadine: Population pharmacokinetic analyses suggest that amantadine may slightly decrease the oral clearance of pramipexole.
- Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12).
- Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12).
- Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. Other known organic cation transport substrates and/or inhibitors (e.g., cisplatin and procainamide) may also decrease the clearance of pramipexole.
- CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 µM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the clinical dose of 4.5 mg/day (1.5 mg TID).
## Nonclinical Toxicology
- Two-year carcinogenicity studies with pramipexole have been conducted in mice and rats. Pramipexole was administered in the diet to mice at doses up to 10 mg/kg/day (or approximately 10 times the maximum recommended human dose (MRHD) for Parkinson’s disease of 4.5 mg/day on a mg/m2 basis). Pramipexole was administered in the diet to rats at doses up to 8 mg/kg/day. These doses were associated with plasma AUCs up to approximately 12 times that in humans at the MRHD. No significant increases in tumors occurred in either species.
- Pramipexole was not mutagenic or clastogenic in a battery of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) assays.
- In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m2 basis), prolonged estrus cycles and inhibited implantation. These effects were associated with reductions in serum levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.
- Retinal Pathology in Rats
- Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study with pramipexole. These findings were first observed during week 76 and were dose-dependent in animals receiving 2 or 8 mg/kg/day (plasma AUCs equal to 2.5 and 12.5 times that in humans at the MRHD). In a similar study of pigmented rats with 2 years exposure to pramipexole at 2 or 8 mg/kg/day, retinal degeneration was not observed. Animals given drug had thinning in the outer nuclear layer of the retina that was only slightly greater (by morphometric analysis) than that seen in control rats.
- Investigative studies demonstrated that pramipexole reduced the rate of disk shedding from the photoreceptor rod cells of the retina in albino rats, which was associated with enhanced sensitivity to the damaging effects of light. In a comparative study, degeneration and loss of photoreceptor cells occurred in albino rats after 13 weeks of treatment with 25 mg/kg/day of pramipexole (54 times the MRHD on a mg/m2 basis) and constant light (100 lux) but not in pigmented rats exposed to the same dose and higher light intensities (500 lux). Thus, the retina of albino rats is considered to be uniquely sensitive to the damaging effects of pramipexole and light. Similar changes in the retina did not occur in a 2-year carcinogenicity study in albino mice treated with 0.3, 2, or 10 mg/kg/day (0.3, 2.2 and 11 times the MRHD on a mg/m2 basis). Evaluation of the retinas of monkeys given 0.1, 0.5, or 2.0 mg/kg/day of pramipexole (0.4, 2.2, and 8.6 times the MRHD on a mg/m2 basis) for 12 months and minipigs given 0.3, 1, or 5 mg/kg/day of pramipexole for 13 weeks also detected no changes.
- The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.
- Fibro-osseous Proliferative Lesions in Mice
- An increased incidence of fibro-osseous proliferative lesions occurred in the femurs of female mice treated for 2 years with 0.3, 2.0, or 10 mg/kg/day (0.3, 2.2, and 11 times the MRHD on a mg/m2 basis). Similar lesions were not observed in male mice or rats and monkeys of either sex that were treated chronically with pramipexole. The significance of this lesion to humans is not known.
# Clinical Studies
- The effectiveness of MIRAPEX tablets in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of seven randomized, controlled trials. Three were conducted in patients with early Parkinson's disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson's disease who were receiving concomitant levodopa. Among these seven studies, three studies provide the most persuasive evidence of pramipexole's effectiveness in the management of patients with Parkinson's disease who were and were not receiving concomitant levodopa. Two of these three trials enrolled patients with early Parkinson's disease (not receiving levodopa), and one enrolled patients with advanced Parkinson's disease who were receiving maximally tolerated doses of levodopa.
- In all studies, the Unified Parkinson's Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV).
- Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. It is designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.
- Studies in Patients with Early Parkinson's Disease
- Patients (N=599) in the two studies of early Parkinson's disease had a mean disease duration of 2 years, limited or no prior exposure to levodopa (generally none in the preceding 6 months), and were not experiencing the "on-off" phenomenon and dyskinesia characteristic of later stages of the disease.
- One of the two early Parkinson's disease studies (N=335) was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6-month maintenance period. Patients could be on selegiline, anticholinergics, or both, but could not be on levodopa products or amantadine. Patients were randomized to MIRAPEX tablets or placebo. Patients treated with MIRAPEX tablets had a starting daily dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) total score was 1.9 in the group receiving MIRAPEX tablets and -0.4 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.0 in the group receiving MIRAPEX tablets and -0.8 in the placebo group, a difference that was also statistically significant. A statistically significant difference between groups in favor of MIRAPEX tablets was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day).
- The second early Parkinson's disease study (N=264) was a double-blind, placebo-controlled, parallel trial consisting of a 6-week dose-escalation period and a 4-week maintenance period. Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but could not be on levodopa products. Patients were randomized to 1 of 4 fixed doses of MIRAPEX tablets (1.5 mg, 3.0 mg, 4.5 mg, or 6.0 mg per day) or placebo. At the end of the 4-week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with MIRAPEX tablets, regardless of assigned dose group, and 0.3 in placebo-treated patients. The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with MIRAPEX tablets and 0.6 in placebo-treated patients. No dose-response relationship was demonstrated. The between-treatment differences on both parts of the UPDRS were statistically significant in favor of MIRAPEX tablets for all doses.
- No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race. Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs.
- Studies in Patients with Advanced Parkinson's Disease
- In the advanced Parkinson's disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of "on" and "off" time.
- Patients in the advanced Parkinson's disease study (N=360) had a mean disease duration of 9 years, had been exposed to levodopa for long periods of time (mean 8 years), used concomitant levodopa during the trial, and had "on-off" periods.
- The advanced Parkinson's disease study was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6-month maintenance period. Patients were all treated with concomitant levodopa products and could additionally be on concomitant selegiline, anticholinergics, amantadine, or any combination. Patients treated with MIRAPEX tablets had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At selected times during the 6-month maintenance period, patients were asked to record the amount of "off," "on," or "on with dyskinesia" time per day for several sequential days. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with MIRAPEX tablets and 0.5 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with MIRAPEX tablets and 2.8 in the placebo group, a difference that was statistically significant. A statistically significant difference between groups in favor of MIRAPEX tablets was seen at week 3 of the UPDRS part II (maximum dose 1.5 mg/day) and at week 2 of the UPDRS part III (maximum dose 0.75 mg/day). Dosage reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with MIRAPEX tablets versus 54% of placebo patients. On average, the levodopa dose was reduced 27%.
- The mean number of "off" hours per day during baseline was 6 hours for both treatment groups. Throughout the trial, patients treated with MIRAPEX tablets had a mean of 4 "off" hours per day, while placebo-treated patients continued to experience 6 "off" hours per day.
- No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.
- The efficacy of MIRAPEX tablets in the treatment of RLS was evaluated in a multinational drug development program consisting of 4 randomized, double-blind, placebo-controlled trials. This program included approximately 1000 patients with moderate to severe RLS; patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, and anemia) were excluded. All patients were administered MIRAPEX tablets (0.125 mg, 0.25 mg, 0.5 mg, or 0.75 mg) or placebo once daily 2-3 hours before going to bed. Across the 4 studies, the mean duration of RLS was 4.6 years (range of 0 to 56 years), mean age was approximately 55 years (range of 18 to 81 years), and approximately 66.6% were women.
- Key diagnostic criteria for RLS are: an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant leg sensations; symptoms begin or worsen during periods of rest or inactivity such as lying or sitting; symptoms are partially or totally relieved by movement such as walking or stretching at least as long as the activity continues; and symptoms are worse or occur only in the evening or night. Difficulty falling asleep may frequently be associated with symptoms of RLS.
- The two outcome measures used to assess the effect of treatment were the International RLS Rating Scale (IRLS Scale) and a Clinical Global Impression - Improvement (CGI-I) assessment. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I is designed to assess clinical progress (global improvement) on a 7-point scale.
- In Study 1, fixed doses of MIRAPEX tablets were compared to placebo in a study of 12 weeks duration. A total of 344 patients were randomized equally to the 4 treatment groups. Patients treated with MIRAPEX tablets (n=254) had a starting dose of 0.125 mg/day and were titrated to one of the three randomized doses (0.25, 0.5, 0.75 mg/day) in the first three weeks of the study. The mean improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the MIRAPEX tablets treatment groups compared to placebo are summarized in Table 8. All treatment groups reached statistically significant superiority compared to placebo for both endpoints. There was no clear evidence of a dose-response across the 3 randomized dose groups.
- Study 2 was a randomized-withdrawal study, designed to demonstrate the sustained efficacy of pramipexole for treatment of RLS after a period of six months. RLS patients who responded to MIRAPEX tablets treatment in a preceding 6-month open-label treatment phase (defined as having a CGI-I rating of “very much improved” or “much improved” compared to baseline and an IRLS score of 15 or below) were randomized to receive either continued active treatment (n=78) or placebo (n=69) for 12 weeks. The primary endpoint of this study was time to treatment failure, defined as any worsening on the CGI-I score along with an IRLS Scale total score above 15.
- In patients who had responded to 6-month open label treatment with MIRAPEX tablets, the administration of placebo led to a rapid decline in their overall conditions and return of their RLS symptoms. At the end of the 12-week observation period, 85% of patients treated with placebo had failed treatment, compared to 21% treated with blinded pramipexole, a difference that was highly statistically significant. The majority of treatment failures occurred within 10 days of randomization. For the patients randomized, the distribution of doses was: 7 on 0.125 mg, 44 on 0.25 mg, 47 on 0.5 mg, and 49 on 0.75 mg.
- Study 3 was a 6-week study, comparing a flexible dose of MIRAPEX tablets to placebo. In this study, 345 patients were randomized in a 2:1 ratio to MIRAPEX tablets or placebo. The mean improvement from baseline on the IRLS Scale total score was -12 for MIRAPEX-treated patients and -6 for placebo-treated patients. The percentage of CGI-I responders was 63% for MIRAPEX-treated patients and 32% for placebo-treated patients. The between-group differences were statistically significant for both outcome measures. For the patients randomized to MIRAPEX tablets, the distribution of achieved doses was: 35 on 0.125 mg, 51 on 0.25 mg, 65 on 0.5 mg, and 69 on 0.75 mg.
- Study 4 was a 3-week study, comparing 4 fixed doses of MIRAPEX tablets, 0.125 mg, 0.25 mg, 0.5 mg, and 0.75 mg, to placebo. Approximately 20 patients were randomized to each of the 5 dose groups. The mean improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the MIRAPEX tablets treatment groups compared to placebo are summarized in Table 9. In this study, the 0.125 mg dose group was not significantly different from placebo. On average, the 0.5 mg dose group performed better than the 0.25 mg dose group, but there was no difference between the 0.5 mg and 0.75 mg dose groups.
- No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.
# How Supplied
- MIRAPEX tablets are available as follows:
- 0.125 mg: white, round, tablet with "BI" on one side and "83" on the reverse side.
- Bottles of 90 NDC 0597-0183-90
- 0.25 mg: white, oval, scored tablet with "BI BI" on one side and "84 84" on the reverse side.
- Bottles of 90 NDC 0597-0184-90
- Unit dose packages of 100 NDC 0597-0184-61
- 0.5 mg: white, oval, scored tablet with "BI BI" on one side and "85 85" on the reverse side.
- Bottles of 90 NDC 0597-0185-90
- Unit dose packages of 100 NDC 0597-0185-61
- 0.75 mg: white, oval, debossed tablet with "BI” on one side and "101" on the reverse side.
- Bottles of 90 NDC 0597-0101-90
- 1 mg: white, round, scored tablet with "BI BI" on one side and "90 90" on the reverse side.
- Bottles of 90 NDC 0597-0190-90
- Unit dose packages of 100 NDC 0597-0190-61
- 1.5 mg: white, round, scored tablet with "BI BI" on one side and "91 91" on the reverse side.
- Bottles of 90 NDC 0597-0191-90
- Unit dose packages of 100 NDC 0597-0191-61
- Storage
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).
- Protect from light.
- Store in a safe place out of the reach of children.
## Storage
There is limited information regarding Pramipexole Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Dosing Instructions
- Instruct patients to take MIRAPEX tablets only as prescribed. If a dose is missed, advise patients not to double their next dose.
- MIRAPEX tablets can be taken with or without food. If patients develop nausea, they should be advised that taking MIRAPEX tablets with food may reduce the occurrence of nausea.
- Pramipexole is the active ingredient that is in both MIRAPEX tablets and extended-release pramipexole tablets. Ensure that patients do not take both extended-release pramipexole and MIRAPEX.
- Sedating Effects
- Patients should be alerted to the potential sedating effects associated with MIRAPEX tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with MIRAPEX tablets to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., conversations or eating) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with MIRAPEX tablets and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine).
- Impulse Control Symptoms Including Compulsive Behaviors
- Patients and their caregivers should be alerted to the possibility that they may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges, binge eating and/or other intense urges and the inability to control these urges while taking MIRAPEX.
- Hallucinations
- Patients should be informed that hallucinations can occur and that the elderly are at a higher risk than younger patients with Parkinson's disease. In clinical trials, patients with RLS treated with pramipexole rarely reported hallucinations.
- Postural (Orthostatic) Hypotension
- Advise patients that they may develop orthostatic hypotension, with or without symptoms such as dizziness, nausea, fainting or blackouts, and sometimes, sweating. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with MIRAPEX tablets.
- Pregnancy
- Because the teratogenic potential of pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, advise women to notify their physicians if they become pregnant or intend to become pregnant during therapy.
- Nursing Mothers
- Because of the possibility that pramipexole may be excreted in breast milk, advise women to notify their physicians if they intend to breast-feed or are breast-feeding an infant.
# Precautions with Alcohol
- Alcohol-Pramipexole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MIRAPEX®
# Look-Alike Drug Names
- Mirapex® — Hiprex®
- Mirapex® — Miralax®
# Drug Shortage Status
# Price | Pramipexole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
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# Overview
Pramipexole is a dopamine agonist that is FDA approved for the {{{indicationType}}} of idiopathic parkinson’s disease (PD), moderate-to-severe primary restless legs syndrome (RLS). Common adverse reactions include nausea, dizziness, somnolence, insomnia, constipation, asthenia, hallucinations, fatigue, and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Doses should be increased gradually from a starting dose of 0.375 mg/day given in three divided doses and should not be increased more frequently than every 5 to 7 days. A suggested ascending dosage schedule that was used in clinical studies is shown in the following table:
- Maintenance Treatment
- MIRAPEX tablets were effective and well tolerated over a dosage range of 1.5 to 4.5 mg/day administered in equally divided doses three times per day with or without concomitant levodopa (approximately 800 mg/day).
- In a fixed-dose study in early Parkinson's disease patients, doses of 3 mg, 4.5 mg, and 6 mg per day of MIRAPEX tablets were not shown to provide any significant benefit beyond that achieved at a daily dose of 1.5 mg/day. However, in the same fixed-dose study, the following adverse events were dose related: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence reported with pramipexole at a dose of 1.5 mg/day was comparable to placebo.
- When MIRAPEX tablets are used in combination with levodopa, a reduction of the levodopa dosage should be considered. In a controlled study in advanced Parkinson's disease, the dosage of levodopa was reduced by an average of 27% from baseline.
- The recommended starting dose of MIRAPEX tablets is 0.125 mg taken once daily 2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days (Table 3). Although the dose of MIRAPEX tablets was increased to 0.75 mg in some patients during long-term open-label treatment, there is no evidence that the 0.75 mg dose provides additional benefit beyond the 0.5 mg dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pramipexole in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- Oral pramipexole (initial dose 0.125 milligrams (mg) twice daily, increased by 0.25 mg/day every 3 to 5 days to target dose of 1 to 2.5 mg/day).
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pramipexole in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pramipexole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pramipexole in pediatric patients.
# Contraindications
- None
# Warnings
### Precautions
- Falling Asleep During Activities of Daily Living
- Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents. Although many of these patients reported somnolence while on pramipexole tablets, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment.
- Somnolence is a common occurrence in patients receiving pramipexole at doses above 1.5 mg/day (0.5 mg TID) for Parkinson’s disease. In controlled clinical trials in RLS, patients treated with MIRAPEX tablets at doses of 0.25-0.75 mg once a day, the incidence of somnolence was 6% compared to an incidence of 3% for placebo-treated patients. Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.
- Before initiating treatment with MIRAPEX tablets, advise patients of the potential to develop drowsiness and specifically asked about factors that may increase the risk with MIRAPEX tablets such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), MIRAPEX tablets should ordinarily be discontinued. If a decision is made to continue MIRAPEX tablets, advise patients not to drive and to avoid other potentially dangerous activities. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.
- Symptomatic Orthostatic Hypotension
- Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, both Parkinson's disease patients and RLS patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk.
- In clinical trials of pramipexole, however, and despite clear orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hypotension was not greater among those assigned to pramipexole tablets than among those assigned to placebo. This result, especially with the higher doses used in Parkinson’s disease, is clearly unexpected in light of the previous experience with the risks of dopamine agonist therapy.
- While this finding could reflect a unique property of pramipexole, it might also be explained by the conditions of the study and the nature of the population enrolled in the clinical trials. Patients were very carefully titrated, and patients with active cardiovascular disease or significant orthostatic hypotension at baseline were excluded. Also, clinical trials in patients with RLS did not incorporate orthostatic challenges with intensive blood pressure monitoring done in close temporal proximity to dosing.
- Impulse Control/Compulsive Behaviors
- Case reports and the results of a cross-sectional study suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and/or other intense urges and the inability to control these urges while taking one or more of the medications, including MIRAPEX, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson’s disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with MIRAPEX. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking MIRAPEX.
- Hallucinations
- In the three double-blind, placebo-controlled trials in early Parkinson's disease, hallucinations were observed in 9% (35 of 388) of patients receiving MIRAPEX tablets, compared with 2.6% (6 of 235) of patients receiving placebo. In the four double-blind, placebo-controlled trials in advanced Parkinson's disease, where patients received MIRAPEX tablets and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving MIRAPEX tablets compared with 3.8% (10 of 264) of patients receiving placebo. Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson's disease patients and 2.7% of the advanced Parkinson's disease patients compared with about 0.4% of placebo patients in both populations.
- Age appears to increase the risk of hallucinations attributable to pramipexole. In the early Parkinson's disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years. In the advanced Parkinson's disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years.
- In the RLS clinical program, one pramipexole-treated patient (of 889) reported hallucinations; this patient discontinued treatment and the symptoms resolved.
- Dyskinesia
- Mirapex tablets may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia.
- Renal Impairment
- Since pramipexole is eliminated through the kidneys, caution should be exercised when prescribing MIRAPEX tablets to patients with renal impairment.
- Rhabdomyolysis
- A single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson's disease treated with MIRAPEX tablets. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.
- Retinal Pathology
- Human Data
- A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared MIRAPEX tablets and immediate-release ropinirole. Two hundred thirty four Parkinson’s disease patients (115 on pramipexole, mean dose 3.0 mg/day and 119 on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical ophthalmological assessments. Of 234 patients who were evaluable, 196 had been treated for two years and 29 were judged to have developed clinical abnormalities that were considered meaningful (19 patients in each treatment arm had received treatment for less than two years). There was no statistical difference in retinal deterioration between the treatment arms; however, the study was only capable of detecting a very large difference between treatments. In addition, because the study did not include an untreated comparison group (placebo treated), it is unknown whether the findings reported in patients treated with either drug are greater than the background rate in an aging population.
- Animal Data
- Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.
- Events Reported with Dopaminergic Therapy
- Although the events enumerated below may not have been reported in association with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.
- Withdrawal-Emergent Hyperpyrexia and Confusion
- Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in antiparkinsonian therapy.
- Fibrotic Complications
- Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.
- Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists can cause them is unknown.
- Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the post marketing experience with MIRAPEX tablets. While the evidence is not sufficient to establish a causal relationship between MIRAPEX tablets and these fibrotic complications, a contribution of MIRAPEX tablets cannot be completely ruled out.
- Melanoma
- Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.
- For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using MIRAPEX tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
- Rebound and Augmentation in RLS
- Reports in the literature indicate treatment of RLS with dopaminergic medications can result in rebound: a worsening of symptoms following treatment cessation with greater intensity than described before starting treatment. In a 26 week placebo controlled clinical trial in patients with RLS, a worsening of symptoms scores (IRLS) beyond their untreated baseline levels was reported more frequently by patients suddenly withdrawn from MIRAPEX (up to 0.75 mg once daily) compared to the group assigned to placebo (10% vs. 2%, respectively). The worsening of RLS symptoms was considered generally mild.
- Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. In a 26 week placebo controlled clinical trial in patients with RLS, augmentation was reported with greater frequency by patients treated with MIRAPEX (up to 0.75 mg once daily) compared to patients who received placebo (12% vs. 9%, respectively). The incidence of augmentation increased with increasing duration of exposure to MIRAPEX and to placebo.
- The frequency and severity of augmentation and/or rebound after longer-term use of MIRAPEX tablets and the appropriate management of these events have not been adequately evaluated in controlled clinical trials.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- During the premarketing development of pramipexole, patients with either early or advanced Parkinson's disease were enrolled in clinical trials. Apart from the severity and duration of their disease, the two populations differed in their use of concomitant levodopa therapy. Patients with early disease did not receive concomitant levodopa therapy during treatment with pramipexole; those with advanced Parkinson's disease all received concomitant levodopa treatment. Because these two populations may have differential risks for various adverse events, this section will, in general, present adverse-event data for these two populations separately.
- Because the controlled trials performed during premarketing development all used a titration design, with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse events.
- Early Parkinson's Disease
- In the three double-blind, placebo-controlled trials of patients with early Parkinson's disease, the most commonly observed adverse events (>5%) that were numerically more frequent in the group treated with MIRAPEX tablets were nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations.
- Approximately 12% of 388 patients with early Parkinson's disease and treated with MIRAPEX tablets who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared with 11% of 235 patients who received placebo. The adverse events most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [3.1% on MIRAPEX tablets vs 0.4% on placebo]; dizziness [2.1% on MIRAPEX tablets vs 1% on placebo]; somnolence [1.6% on MIRAPEX tablets vs 0% on placebo]; extrapyramidal syndrome [1.6% on MIRAPEX tablets vs 6.4% on placebo]; headache and confusion [1.3% and 1.0%, respectively, on MIRAPEX tablets vs 0% on placebo]); and gastrointestinal system (nausea [2.1% on MIRAPEX tablets vs 0.4% on placebo]).
- Adverse-event Incidence in Controlled Clinical Studies in Early Parkinson's Disease: Table 4 lists treatment-emergent adverse events that occurred in the double-blind, placebo-controlled studies in early Parkinson's disease that were reported by ≥1% of patients treated with MIRAPEX tablets and were numerically more frequent than in the placebo group. In these studies, patients did not receive concomitant levodopa. Adverse events were usually mild or moderate in intensity.
- The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse-event incidence rate in the population studied.
- Other events reported by 1% or more of patients with early Parkinson's disease and treated with MIRAPEX tablets but reported equally or more frequently in the placebo group were infection, accidental injury, headache, pain, tremor, back pain, syncope, postural hypotension, hypertonia, depression, abdominal pain, anxiety, dyspepsia, flatulence, diarrhea, rash, ataxia, dry mouth, extrapyramidal syndrome, leg cramps, twitching, pharyngitis, sinusitis, sweating, rhinitis, urinary tract infection, vasodilation, flu syndrome, increased saliva, tooth disease, dyspnea, increased cough, gait abnormalities, urinary frequency, vomiting, allergic reaction, hypertension, pruritus, hypokinesia, increased creatine PK, nervousness, dream abnormalities, chest pain, neck pain, paresthesia, tachycardia, vertigo, voice alteration, conjunctivitis, paralysis, accommodation abnormalities, tinnitus, diplopia, and taste perversions.
- In a fixed-dose study in early Parkinson's disease, occurrence of the following events increased in frequency as the dose increased over the range from 1.5 mg/day to 6 mg/day: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence with pramipexole at a dose of 1.5 mg/day was comparable to that reported for placebo.
- Advanced Parkinson's Disease
- In the four double-blind, placebo-controlled trials of patients with advanced Parkinson's disease, the most commonly observed adverse events (>5%) that were numerically more frequent in the group treated with MIRAPEX tablets and concomitant levodopa were postural orthostatic hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary frequency.
- Approximately 12% of 260 patients with advanced Parkinson's disease who received MIRAPEX tablets and concomitant levodopa in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared with 16% of 264 patients who received placebo and concomitant levodopa. The events most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [2.7% on MIRAPEX tablets vs 0.4% on placebo]; dyskinesia [1.9% on MIRAPEX tablets vs 0.8% on placebo]; extrapyramidal syndrome [1.5% on MIRAPEX tablets vs 4.9% on placebo]; dizziness [1.2% on MIRAPEX tablets vs 1.5% on placebo]; confusion [1.2% on MIRAPEX tablets vs 2.3% on placebo]); and cardiovascular system (postural orthostatic hypotension [2.3% on MIRAPEX tablets vs 1.1% on placebo]).
- Adverse-event Incidence in Controlled Clinical Studies in Advanced Parkinson's Disease: Table 5 lists treatment-emergent adverse events that occurred in the double-blind, placebo-controlled studies in advanced Parkinson's disease that were reported by ≥1% of patients treated with MIRAPEX tablets and were numerically more frequent than in the placebo group. In these studies, MIRAPEX tablets or placebo was administered to patients who were also receiving concomitant levodopa. Adverse events were usually mild or moderate in intensity.
- The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse-events incidence rate in the population studied.
- Other events reported by 1% or more of patients with advanced Parkinson's disease and treated with MIRAPEX tablets but reported equally or more frequently in the placebo group were nausea, pain, infection, headache, depression, tremor, hypokinesia, anorexia, back pain, dyspepsia, flatulence, ataxia, flu syndrome, sinusitis, diarrhea, myalgia, abdominal pain, anxiety, rash, paresthesia, hypertension, increased saliva, tooth disorder, apathy, hypotension, sweating, vasodilation, vomiting, increased cough, nervousness, pruritus, hypesthesia, neck pain, syncope, arthralgia, dysphagia, palpitations, pharyngitis, vertigo, leg cramps, conjunctivitis, and lacrimation disorders.
- MIRAPEX tablets for treatment of RLS have been evaluated for safety in 889 patients, including 427 treated for over six months and 75 for over one year.
- The overall safety assessment focuses on the results of three double-blind, placebo-controlled trials, in which 575 patients with RLS were treated with MIRAPEX tablets for up to 12 weeks. The most commonly observed adverse events with MIRAPEX tablets in the treatment of RLS (observed in >5% of pramipexole-treated patients and at a rate at least twice that observed in placebo-treated patients) were nausea and somnolence. Occurrences of nausea and somnolence in clinical trials were generally mild and transient.
- Approximately 7% of 575 patients treated with MIRAPEX tablets during the double-blind periods of three placebo-controlled trials discontinued treatment due to adverse events compared to 5% of 223 patients who received placebo. The adverse event most commonly causing discontinuation of treatment was nausea (1%).
- Table 6 lists treatment-emergent events that occurred in three double-blind, placebo-controlled studies in RLS patients that were reported by ≥2% of patients treated with MIRAPEX tablets and were numerically more frequent than in the placebo group.
- The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse-event incidence rate in the population studied.
- Other events reported by 2% or more of RLS patients treated with MIRAPEX tablets but reported equally or more frequently in the placebo group, were: vomiting, nasopharyngitis, back pain, pain in extremity, dizziness, and insomnia.
- Table 7 summarizes data for adverse events that appeared to be dose related in the 12-week fixed dose study.
- General
- Adverse Events: Relationship to Age, Gender, and Race
- Among the treatment-emergent adverse events in patients treated with MIRAPEX tablets, hallucination appeared to exhibit a positive relationship to age in patients with Parkinson’s disease. Although no gender-related differences were observed in Parkinson’s disease patients, nausea and fatigue, both generally transient, were more frequently reported by female than male RLS patients. Less than 4% of patients enrolled were non-Caucasian: therefore, an evaluation of adverse events related to race is not possible.
- Laboratory Tests
- During the development of MIRAPEX tablets, no systematic abnormalities on routine laboratory testing were noted. Therefore, no specific guidance is offered regarding routine monitoring; the practitioner retains responsibility for determining how best to monitor the patient in his or her care.
- Other Adverse Events Observed During Phase 2 and 3 Clinical Trials
- MIRAPEX tablets have been administered to 1620 Parkinson’s disease patients and to 889 RLS patients in Phase 2 and 3 clinical trials. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing; similar types of events were grouped into a smaller number of standardized categories using MedDRA dictionary terminology. These categories are used in the listing below. Adverse events which are not listed above but occurred on at least two occasions (one occasion if the event was serious) in the 2509 individuals exposed to MIRAPEX tablets are listed below. The reported events below are included without regard to determination of a causal relationship to MIRAPEX tablets.
Anemia, iron deficiency anemia, leukocytosis, leukopenia, lymphadenitis, lymphadenopathy, thrombocythaemia, thrombocytopenia
Angina pectoris, supraventricular arrhythmia, atrial fibrillation, first degree atrioventricular block, second degree atrioventricular block, bradycardia, bundle branch block, cardiac arrest, cardiac failure, congestive cardiac failure, cardiomegaly, coronary artery occlusion, cyanosis, extrasystoles, left ventricular failure, myocardial infarction, nodal arrhythmia, sinus arrhythmia, sinus bradycardia, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, ventricular fibrillation, ventricular extrasystoles, ventricular hypertrophy
Atrial septal defect, congenital foot malformation, spine malformation
Deafness, ear pain, hearing impaired, hypoacusis, motion sickness, vestibular ataxia
Goiter, hyperthyroidism, hypothyroidism
Amaurosis fugax, blepharitis, blepharospasm, cataract, dacryostenosis acquired, dry eye, eye hemorrhage, eye irritation, eye pain, eyelid edema, eyelid ptosis, glaucoma, keratitis, macular degeneration, myopia, photophobia, retinal detachment, retinal vascular disorder, scotoma, vision blurred, visual acuity reduced, vitreous floaters
Abdominal discomfort, abdominal distension, aphthous stomatitis, ascites, cheilitis, colitis, ulcerative colitis, duodenal ulcer, duodenal ulcer hemorrhage, enteritis, eructation, fecal incontinence, gastric ulcer, gastric ulcer hemorrhage, gastritis, gastrointestinal hemorrhage, gastroesophageal reflux disease, gingivitis, haematemesis, haematochezia, hemorrhoids, hiatus hernia, hyperchlorhydria, ileus, inguinal hernia, intestinal obstruction, irritable bowel syndrome, esophageal spasm, esophageal stenosis, esophagitis, pancreatitis, periodontitis, rectal hemorrhage, reflux esophagitis, tongue edema, tongue ulceration, toothache, umbilical hernia
Chest discomfort, chills, death, drug withdrawal syndrome, face edema, feeling cold, feeling hot, feeling jittery, gait disturbance, impaired healing, influenza-like illness, irritability, localized edema, edema, pitting edema, thirst
Biliary colic, cholecystitis, cholecystitis chronic, cholelithiasis
Drug hypersensitivity
Abscess, acute tonsillitis, appendicitis, bronchiolitis, bronchitis, bronchopneumonia, cellulitis, cystitis, dental caries, diverticulitis, ear infection, eye infection, folliculitis, fungal infection, furuncle, gangrene, gastroenteritis, gingival infection, herpes simplex, herpes zoster, hordeolum, intervertebral discitis, laryngitis, lobar pneumonia, nail infection, onychomycosis, oral candidiasis, orchitis, osteomyelitis, otitis externa, otitis media, paronychia, pyelonephritis, pyoderma, sepsis, skin infection, tonsillitis, tooth abscess, tooth infection, upper respiratory tract infection, urethritis, vaginal candidiasis, vaginal infection, viral infection, wound infection
Accidental falls, drug toxicity, epicondylitis, road traffic accident, sunburn, tendon rupture
Cachexia, decreased appetite, dehydration, diabetes mellitus, fluid retention, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia, hyperuricemia, hypocalcemia, hypoglycemia, hypokalemia, hyponatremia, hypovitaminosis, increased appetite, metabolic alkalosis
Bone pain, fasciitis, flank pain, intervertebral disc disorder, intervertebral disc protrusion, joint effusion, joint stiffness, joint swelling, monarthritis, muscle rigidity, muscle spasms, musculoskeletal stiffness, myopathy, myositis, nuchal rigidity, osteoarthritis, osteonecrosis, osteoporosis, polymyalgia, rheumatoid arthritis, shoulder pain, spinal osteoarthritis, tendonitis, tenosynovitis
Abdominal neoplasm, adenocarcinoma, adenoma benign, basal cell carcinoma, bladder cancer, breast cancer, breast neoplasm, chronic lymphocytic leukemia, colon cancer, colorectal cancer, endometrial cancer, gallbladder cancer, gastric cancer, gastrointestinal neoplasm, hemangioma, hepatic neoplasm, hepatic neoplasm malignant, lip and/or oral cavity cancer, lung neoplasm malignant, lung cancer metastatic, lymphoma, malignant melanoma, melanocytic naevus, metastases to lung, multiple myeloma, oral neoplasm benign, neoplasm, neoplasm malignant, neoplasm prostate, neoplasm skin, neuroma, ovarian cancer, prostate cancer, prostatic adenoma, pseudo lymphoma, renal neoplasm, skin cancer, skin papilloma, squamous cell carcinoma, thyroid neoplasm, uterine leiomyoma
Ageusia, akinesia, anticholinergic syndrome, aphasia, balance disorder, brain edema, carotid artery occlusion, carpal tunnel syndrome, cerebral artery embolism, cerebral hemorrhage, cerebral infarction, cerebral ischemia, chorea, cognitive disorder, coma, convulsion, coordination abnormal, dementia, depressed level of consciousness, disturbance in attention, dizziness postural, dysarthria, dysgraphia, facial palsy, grand mal convulsion, hemiplegia, hyperaesthesia, hyperkinesia, hyperreflexia, hyporeflexia, hypotonia, lethargy, loss of consciousness, memory impairment, migraine, muscle contractions involuntary, narcolepsy, neuralgia, neuropathy, nystagmus, parosmia, psychomotor hyperactivity, sciatica, sedation, sensory disturbance, sleep phase rhythm disturbance, sleep talking, stupor, vasovagal syncope, tension headache
Affect lability, aggression, agitation, bradyphrenia, bruxism, suicide, delirium, delusional disorder persecutory type, disorientation, dissociation, emotional distress, euphoric mood, hallucination auditory, hallucination visual, initial insomnia, libido increased, mania, middle insomnia, mood altered, nightmare, obsessive thoughts, obsessive-compulsive disorder, panic reaction, parasomnia, personality disorder, psychotic disorder, restlessness, sleep walking, suicidal ideation
Chromaturia, dysuria, glycosuria, hematuria, urgency, nephrolithiasis, neurogenic bladder, nocturia, oliguria, pollakiuria, proteinuria, renal artery stenosis, renal colic, renal cyst, renal failure, renal impairment, urinary retention
Amenorrhea, breast pain, dysmenorrhea, epididymitis, gynaecomastia, menopausal symptoms, menorrhagia, metrorrhagia, ovarian cyst, priapism, prostatitis, sexual dysfunction, uterine hemorrhage, vaginal discharge, vaginal hemorrhage
Apnea, aspiration, asthma, choking, chronic obstructive pulmonary disease, dry throat, dysphonia, exertional dyspnea, epistaxis, haemoptysis, hiccups, hyperventilation, increased bronchial secretion, laryngospasm, nasal dryness, nasal polyps, obstructive airways disorder, pharyngolaryngeal pain, pleurisy, aspiration pneumonia, pneumothorax, postnasal drip, productive cough, pulmonary embolism, pulmonary edema, respiratory alkalosis, respiratory distress, respiratory failure, respiratory tract congestion, allergic rhinitis, rhinorrhea, sinus congestion, sleep apnoea syndrome, sneezing, snoring, tachypnea, wheezing
Acne, alopecia, cold sweat, dermal cyst, dermatitis, dermatitis bullous, dermatitis contact, dry skin, ecchymosis, eczema, erythema, hyperkeratosis, livedo reticularis, night sweats, periorbital edema, petechiae, photosensitivity allergic reaction, psoriasis, purpura, rash erythematous, rash maculo-papular, rash papular, rosacea, seborrhea, seborrheic dermatitis, skin burning sensation, skin discoloration, skin exfoliation, skin hyperpigmentation, skin hypertrophy, skin irritation, skin nodule, skin odor abnormal, skin ulcer, urticaria
Aneurysm, angiopathy, arteriosclerosis, circulatory collapse, deep vein thrombosis, embolism, hematoma, hot flush, hypertensive crisis, lymphoedema, pallor, phlebitis, Raynaud’s phenomenon, shock, thrombophlebitis, thrombosis, varicose vein.
## Postmarketing Experience
- In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified during post-approval use of MIRAPEX tablets, primarily in Parkinson’s disease patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to pramipexole tablets. Similar types of reactions were grouped into a smaller number of standardized categories using the MedDRA terminology: abnormal behavior, abnormal dreams, accidents (including fall), blackouts, compulsive shopping, fatigue, hallucinations (all kinds), headache, hypotension (including postural hypotension), syndrome of inappropriate antidiuretic hormone secretion (SIADH), increased eating (including binge eating, compulsive eating, and hyperphagia), libido disorders (including increased and decreased libido, and hypersexuality), pathological gambling, pruritus, syncope, vomiting, and weight increase.
# Drug Interactions
- Dopamine Antagonists
- Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of MIRAPEX tablets.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. MIRAPEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day (5 times the maximum recommended human dose (MRHD) for Parkinson’s disease of 4.5 mg/day on a body surface area (mg/m2) basis). Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis (gestation days 7 through 16) resulted in a high incidence of total resorption of embryos. The plasma AUC in rats at this dose was 4 times the AUC in humans at the MRHD. These findings are thought to be due to the prolactin-lowering effect of pramipexole, since prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not rabbits or humans). Because of pregnancy disruption and early embryonic loss in these studies, the teratogenic potential of pramipexole could not be adequately evaluated. There was no evidence of adverse effects on embryo-fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis (plasma AUC was 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately equivalent to the MRHD on a mg/m2 basis) or greater during the latter part of pregnancy and throughout lactation.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pramipexole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pramipexole during labor and delivery.
### Nursing Mothers
Studies have shown that pramipexole treatment resulted in an inhibition of prolactin secretion in humans and rats.
- A single-dose, radio-labeled study showed that drug-related material was present in rat milk at concentrations three to six times higher than those in plasma at equivalent time points. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MIRAPEX, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- Safety and effectiveness of MIRAPEX in pediatric patients has not been established.
### Geriatic Use
- Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours.
- In clinical studies with Parkinson’s disease patients, 38.7% of patients were older than 65 years. There were no apparent differences in efficacy or safety between older and younger patients, except that the relative risk of hallucination associated with the use of MIRAPEX tablets was increased in the elderly.
- In clinical studies with RLS patients, 22% of patients were at least 65 years old. There were no apparent differences in efficacy or safety between older and younger patients.
### Gender
There is no FDA guidance on the use of Pramipexole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pramipexole with respect to specific racial populations.
### Renal Impairment
- The elimination of pramipexole is dependent on renal function. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis. Caution should be exercised when administering MIRAPEX tablets to patients with renal disease.
### Hepatic Impairment
There is no FDA guidance on the use of Pramipexole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pramipexole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pramipexole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Pramipexole in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Pramipexole in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable although pulse rate increased to between 100 and 120 beats/minute. No other adverse events were reported related to the increased dose.
### Management
- There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Pramipexole in the drug label.
# Pharmacology
## Mechanism of Action
- Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.
- Parkinson’s Disease
- The precise mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in Parkinson’s disease is unknown.
- Restless Legs Syndrome (RLS)
- The precise mechanism of action of MIRAPEX tablets as a treatment for RLS is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron Emission Tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS.
## Structure
- MIRAPEX tablets contain pramipexole, a nonergot dopamine agonist. The chemical name of pramipexole dihydrochloride is (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate. Its empirical formula is C10 H17 N3 S · 2HCl · H2O, and its molecular weight is 302.26.
- The structural formula is:
- Pramipexole dihydrochloride is a white to off-white powder substance. Melting occurs in the range of 296°C to 301°C, with decomposition. Pramipexole dihydrochloride is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane.
- MIRAPEX tablets, for oral administration, contain 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, or 1.5 mg of pramipexole dihydrochloride monohydrate. Inactive ingredients consist of mannitol, corn starch, colloidal silicon dioxide, povidone, and magnesium stearate.
## Pharmacodynamics
- The effect of pramipexole on the QT interval of the ECG was investigated in a clinical study in 60 healthy male and female volunteers. All subjects initiated treatment with 0.375 mg extended release pramipexole tablets administered once daily, and were up-titrated every 3 days to 2.25 mg and 4.5 mg daily. No dose- or exposure-related effect on mean QT intervals was observed; however the study did not have a valid assessment of assay sensitivity. The effect of pramipexole on QTc intervals at higher exposures achieved either due to drug interactions (e.g., with cimetidine), renal impairment, or at higher doses has not been systematically evaluated.
- Although mean values remained within normal reference ranges throughout the study, supine systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate for subjects treated with pramipexole generally increased during the rapid up-titration phase, by 10 mmHg, 7 mmHg, and 10 bpm higher than placebo, respectively. Higher SBP, DBP, and pulse rates compared to placebo were maintained until the pramipexole doses were tapered; values on the last day of tapering were generally similar to baseline values. Such effects have not been observed in clinical studies with Parkinson’s disease patients, who were titrated according to labeled recommendations.
## Pharmacokinetics
- Pramipexole displays linear pharmacokinetics over the clinical dosage range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers. Steady-state concentrations are achieved within 2 days of dosing.
- Absorption
- Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism. Food does not affect the extent of pramipexole absorption, although the time of maximum plasma concentration (Tmax) is increased by about 1 hour when the drug is taken with a meal.
- Distribution
- Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV]=20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2.
- Metabolism
- Pramipexole is metabolized only to a negligible extent (<10%). No specific active metabolite has been identified in human plasma or urine.
- Elimination
- Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min (CV=25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system.
- Pharmacokinetics in Specific Populations
- Because therapy with MIRAPEX tablets is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, race, or age is not necessary. However, renal insufficiency, which can cause a large decrease in the ability to eliminate pramipexole, may necessitate dosage adjustment.
- Gender
- Pramipexole clearance is about 30% lower in women than in men, but this difference can be accounted for by differences in body weight. There is no difference in half-life between males and females.
- Age
- Pramipexole clearance decreases with age as the half-life and clearance are about 40% longer and 30% lower, respectively, in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). This difference is most likely due to the reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance.
- Race
- No racial differences in metabolism and elimination have been identified.
- Parkinson's Disease Patients
- A cross-study comparison of data suggests that the clearance of pramipexole may be reduced by about 30% in Parkinson's disease patients compared with healthy elderly volunteers. The reason for this difference appears to be reduced renal function in Parkinson's disease patients, which may be related to their poorer general health. The pharmacokinetics of pramipexole were comparable between early and advanced Parkinson's disease patients.
- Restless Legs Syndrome Patients
- A cross-study comparison of data suggests that the pharmacokinetic profile of pramipexole administered once daily in RLS patients is similar to the pharmacokinetic profile of pramipexole in healthy volunteers.
- Hepatic Impairment
- The influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination.
- Renal Impairment
- Clearance of pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers. In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance.
- Drug Interactions
- Carbidopa/levodopa: Carbidopa/levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (N=10). Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa Cmax by about 40% and a decrease in Tmax from 2.5 to 0.5 hours.
- Selegiline: In healthy volunteers (N=11), selegiline did not influence the pharmacokinetics of pramipexole.
- Amantadine: Population pharmacokinetic analyses suggest that amantadine may slightly decrease the oral clearance of pramipexole.
- Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12).
- Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12).
- Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. Other known organic cation transport substrates and/or inhibitors (e.g., cisplatin and procainamide) may also decrease the clearance of pramipexole.
- CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 µM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the clinical dose of 4.5 mg/day (1.5 mg TID).
## Nonclinical Toxicology
- Two-year carcinogenicity studies with pramipexole have been conducted in mice and rats. Pramipexole was administered in the diet to mice at doses up to 10 mg/kg/day (or approximately 10 times the maximum recommended human dose (MRHD) for Parkinson’s disease of 4.5 mg/day on a mg/m2 basis). Pramipexole was administered in the diet to rats at doses up to 8 mg/kg/day. These doses were associated with plasma AUCs up to approximately 12 times that in humans at the MRHD. No significant increases in tumors occurred in either species.
- Pramipexole was not mutagenic or clastogenic in a battery of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) assays.
- In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m2 basis), prolonged estrus cycles and inhibited implantation. These effects were associated with reductions in serum levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.
- Retinal Pathology in Rats
- Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study with pramipexole. These findings were first observed during week 76 and were dose-dependent in animals receiving 2 or 8 mg/kg/day (plasma AUCs equal to 2.5 and 12.5 times that in humans at the MRHD). In a similar study of pigmented rats with 2 years exposure to pramipexole at 2 or 8 mg/kg/day, retinal degeneration was not observed. Animals given drug had thinning in the outer nuclear layer of the retina that was only slightly greater (by morphometric analysis) than that seen in control rats.
- Investigative studies demonstrated that pramipexole reduced the rate of disk shedding from the photoreceptor rod cells of the retina in albino rats, which was associated with enhanced sensitivity to the damaging effects of light. In a comparative study, degeneration and loss of photoreceptor cells occurred in albino rats after 13 weeks of treatment with 25 mg/kg/day of pramipexole (54 times the MRHD on a mg/m2 basis) and constant light (100 lux) but not in pigmented rats exposed to the same dose and higher light intensities (500 lux). Thus, the retina of albino rats is considered to be uniquely sensitive to the damaging effects of pramipexole and light. Similar changes in the retina did not occur in a 2-year carcinogenicity study in albino mice treated with 0.3, 2, or 10 mg/kg/day (0.3, 2.2 and 11 times the MRHD on a mg/m2 basis). Evaluation of the retinas of monkeys given 0.1, 0.5, or 2.0 mg/kg/day of pramipexole (0.4, 2.2, and 8.6 times the MRHD on a mg/m2 basis) for 12 months and minipigs given 0.3, 1, or 5 mg/kg/day of pramipexole for 13 weeks also detected no changes.
- The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.
- Fibro-osseous Proliferative Lesions in Mice
- An increased incidence of fibro-osseous proliferative lesions occurred in the femurs of female mice treated for 2 years with 0.3, 2.0, or 10 mg/kg/day (0.3, 2.2, and 11 times the MRHD on a mg/m2 basis). Similar lesions were not observed in male mice or rats and monkeys of either sex that were treated chronically with pramipexole. The significance of this lesion to humans is not known.
# Clinical Studies
- The effectiveness of MIRAPEX tablets in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of seven randomized, controlled trials. Three were conducted in patients with early Parkinson's disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson's disease who were receiving concomitant levodopa. Among these seven studies, three studies provide the most persuasive evidence of pramipexole's effectiveness in the management of patients with Parkinson's disease who were and were not receiving concomitant levodopa. Two of these three trials enrolled patients with early Parkinson's disease (not receiving levodopa), and one enrolled patients with advanced Parkinson's disease who were receiving maximally tolerated doses of levodopa.
- In all studies, the Unified Parkinson's Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV).
- Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. It is designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.
- Studies in Patients with Early Parkinson's Disease
- Patients (N=599) in the two studies of early Parkinson's disease had a mean disease duration of 2 years, limited or no prior exposure to levodopa (generally none in the preceding 6 months), and were not experiencing the "on-off" phenomenon and dyskinesia characteristic of later stages of the disease.
- One of the two early Parkinson's disease studies (N=335) was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6-month maintenance period. Patients could be on selegiline, anticholinergics, or both, but could not be on levodopa products or amantadine. Patients were randomized to MIRAPEX tablets or placebo. Patients treated with MIRAPEX tablets had a starting daily dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) total score was 1.9 in the group receiving MIRAPEX tablets and -0.4 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.0 in the group receiving MIRAPEX tablets and -0.8 in the placebo group, a difference that was also statistically significant. A statistically significant difference between groups in favor of MIRAPEX tablets was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day).
- The second early Parkinson's disease study (N=264) was a double-blind, placebo-controlled, parallel trial consisting of a 6-week dose-escalation period and a 4-week maintenance period. Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but could not be on levodopa products. Patients were randomized to 1 of 4 fixed doses of MIRAPEX tablets (1.5 mg, 3.0 mg, 4.5 mg, or 6.0 mg per day) or placebo. At the end of the 4-week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with MIRAPEX tablets, regardless of assigned dose group, and 0.3 in placebo-treated patients. The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with MIRAPEX tablets and 0.6 in placebo-treated patients. No dose-response relationship was demonstrated. The between-treatment differences on both parts of the UPDRS were statistically significant in favor of MIRAPEX tablets for all doses.
- No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race. Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs.
- Studies in Patients with Advanced Parkinson's Disease
- In the advanced Parkinson's disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of "on" and "off" time.
- Patients in the advanced Parkinson's disease study (N=360) had a mean disease duration of 9 years, had been exposed to levodopa for long periods of time (mean 8 years), used concomitant levodopa during the trial, and had "on-off" periods.
- The advanced Parkinson's disease study was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6-month maintenance period. Patients were all treated with concomitant levodopa products and could additionally be on concomitant selegiline, anticholinergics, amantadine, or any combination. Patients treated with MIRAPEX tablets had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At selected times during the 6-month maintenance period, patients were asked to record the amount of "off," "on," or "on with dyskinesia" time per day for several sequential days. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with MIRAPEX tablets and 0.5 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with MIRAPEX tablets and 2.8 in the placebo group, a difference that was statistically significant. A statistically significant difference between groups in favor of MIRAPEX tablets was seen at week 3 of the UPDRS part II (maximum dose 1.5 mg/day) and at week 2 of the UPDRS part III (maximum dose 0.75 mg/day). Dosage reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with MIRAPEX tablets versus 54% of placebo patients. On average, the levodopa dose was reduced 27%.
- The mean number of "off" hours per day during baseline was 6 hours for both treatment groups. Throughout the trial, patients treated with MIRAPEX tablets had a mean of 4 "off" hours per day, while placebo-treated patients continued to experience 6 "off" hours per day.
- No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.
- The efficacy of MIRAPEX tablets in the treatment of RLS was evaluated in a multinational drug development program consisting of 4 randomized, double-blind, placebo-controlled trials. This program included approximately 1000 patients with moderate to severe RLS; patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, and anemia) were excluded. All patients were administered MIRAPEX tablets (0.125 mg, 0.25 mg, 0.5 mg, or 0.75 mg) or placebo once daily 2-3 hours before going to bed. Across the 4 studies, the mean duration of RLS was 4.6 years (range of 0 to 56 years), mean age was approximately 55 years (range of 18 to 81 years), and approximately 66.6% were women.
- Key diagnostic criteria for RLS are: an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant leg sensations; symptoms begin or worsen during periods of rest or inactivity such as lying or sitting; symptoms are partially or totally relieved by movement such as walking or stretching at least as long as the activity continues; and symptoms are worse or occur only in the evening or night. Difficulty falling asleep may frequently be associated with symptoms of RLS.
- The two outcome measures used to assess the effect of treatment were the International RLS Rating Scale (IRLS Scale) and a Clinical Global Impression - Improvement (CGI-I) assessment. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I is designed to assess clinical progress (global improvement) on a 7-point scale.
- In Study 1, fixed doses of MIRAPEX tablets were compared to placebo in a study of 12 weeks duration. A total of 344 patients were randomized equally to the 4 treatment groups. Patients treated with MIRAPEX tablets (n=254) had a starting dose of 0.125 mg/day and were titrated to one of the three randomized doses (0.25, 0.5, 0.75 mg/day) in the first three weeks of the study. The mean improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the MIRAPEX tablets treatment groups compared to placebo are summarized in Table 8. All treatment groups reached statistically significant superiority compared to placebo for both endpoints. There was no clear evidence of a dose-response across the 3 randomized dose groups.
- Study 2 was a randomized-withdrawal study, designed to demonstrate the sustained efficacy of pramipexole for treatment of RLS after a period of six months. RLS patients who responded to MIRAPEX tablets treatment in a preceding 6-month open-label treatment phase (defined as having a CGI-I rating of “very much improved” or “much improved” compared to baseline and an IRLS score of 15 or below) were randomized to receive either continued active treatment (n=78) or placebo (n=69) for 12 weeks. The primary endpoint of this study was time to treatment failure, defined as any worsening on the CGI-I score along with an IRLS Scale total score above 15.
- In patients who had responded to 6-month open label treatment with MIRAPEX tablets, the administration of placebo led to a rapid decline in their overall conditions and return of their RLS symptoms. At the end of the 12-week observation period, 85% of patients treated with placebo had failed treatment, compared to 21% treated with blinded pramipexole, a difference that was highly statistically significant. The majority of treatment failures occurred within 10 days of randomization. For the patients randomized, the distribution of doses was: 7 on 0.125 mg, 44 on 0.25 mg, 47 on 0.5 mg, and 49 on 0.75 mg.
- Study 3 was a 6-week study, comparing a flexible dose of MIRAPEX tablets to placebo. In this study, 345 patients were randomized in a 2:1 ratio to MIRAPEX tablets or placebo. The mean improvement from baseline on the IRLS Scale total score was -12 for MIRAPEX-treated patients and -6 for placebo-treated patients. The percentage of CGI-I responders was 63% for MIRAPEX-treated patients and 32% for placebo-treated patients. The between-group differences were statistically significant for both outcome measures. For the patients randomized to MIRAPEX tablets, the distribution of achieved doses was: 35 on 0.125 mg, 51 on 0.25 mg, 65 on 0.5 mg, and 69 on 0.75 mg.
- Study 4 was a 3-week study, comparing 4 fixed doses of MIRAPEX tablets, 0.125 mg, 0.25 mg, 0.5 mg, and 0.75 mg, to placebo. Approximately 20 patients were randomized to each of the 5 dose groups. The mean improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the MIRAPEX tablets treatment groups compared to placebo are summarized in Table 9. In this study, the 0.125 mg dose group was not significantly different from placebo. On average, the 0.5 mg dose group performed better than the 0.25 mg dose group, but there was no difference between the 0.5 mg and 0.75 mg dose groups.
- No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.
# How Supplied
- MIRAPEX tablets are available as follows:
- 0.125 mg: white, round, tablet with "BI" on one side and "83" on the reverse side.
- Bottles of 90 NDC 0597-0183-90
- 0.25 mg: white, oval, scored tablet with "BI BI" on one side and "84 84" on the reverse side.
- Bottles of 90 NDC 0597-0184-90
- Unit dose packages of 100 NDC 0597-0184-61
- 0.5 mg: white, oval, scored tablet with "BI BI" on one side and "85 85" on the reverse side.
- Bottles of 90 NDC 0597-0185-90
- Unit dose packages of 100 NDC 0597-0185-61
- 0.75 mg: white, oval, debossed tablet with "BI” on one side and "101" on the reverse side.
- Bottles of 90 NDC 0597-0101-90
- 1 mg: white, round, scored tablet with "BI BI" on one side and "90 90" on the reverse side.
- Bottles of 90 NDC 0597-0190-90
- Unit dose packages of 100 NDC 0597-0190-61
- 1.5 mg: white, round, scored tablet with "BI BI" on one side and "91 91" on the reverse side.
- Bottles of 90 NDC 0597-0191-90
- Unit dose packages of 100 NDC 0597-0191-61
- Storage
- Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).
- Protect from light.
- Store in a safe place out of the reach of children.
## Storage
There is limited information regarding Pramipexole Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Dosing Instructions
- Instruct patients to take MIRAPEX tablets only as prescribed. If a dose is missed, advise patients not to double their next dose.
- MIRAPEX tablets can be taken with or without food. If patients develop nausea, they should be advised that taking MIRAPEX tablets with food may reduce the occurrence of nausea.
- Pramipexole is the active ingredient that is in both MIRAPEX tablets and extended-release pramipexole tablets. Ensure that patients do not take both extended-release pramipexole and MIRAPEX.
- Sedating Effects
- Patients should be alerted to the potential sedating effects associated with MIRAPEX tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with MIRAPEX tablets to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., conversations or eating) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with MIRAPEX tablets and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine).
- Impulse Control Symptoms Including Compulsive Behaviors
- Patients and their caregivers should be alerted to the possibility that they may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges, binge eating and/or other intense urges and the inability to control these urges while taking MIRAPEX.
- Hallucinations
- Patients should be informed that hallucinations can occur and that the elderly are at a higher risk than younger patients with Parkinson's disease. In clinical trials, patients with RLS treated with pramipexole rarely reported hallucinations.
- Postural (Orthostatic) Hypotension
- Advise patients that they may develop orthostatic hypotension, with or without symptoms such as dizziness, nausea, fainting or blackouts, and sometimes, sweating. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with MIRAPEX tablets.
- Pregnancy
- Because the teratogenic potential of pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, advise women to notify their physicians if they become pregnant or intend to become pregnant during therapy.
- Nursing Mothers
- Because of the possibility that pramipexole may be excreted in breast milk, advise women to notify their physicians if they intend to breast-feed or are breast-feeding an infant.
# Precautions with Alcohol
- Alcohol-Pramipexole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MIRAPEX®[1]
# Look-Alike Drug Names
- Mirapex® — Hiprex®[2]
- Mirapex® — Miralax®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Pramipexole | |
dacb4ebadf8b1fad3c262292aed4e65f01d81b73 | wikidoc | Pramlintide | Pramlintide
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# Black Box Warning
# Overview
Pramlintide is an antidiabetic that is FDA approved for the treatment of patients with type 1 or type 2 diabetes who use mealtime insulin therapy and who have failed to achieve desired glucose] control despite optimal insulin therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, anorexia, nausea, vomiting, hypersensitivity reaction, dizziness, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- SYMLIN is indicated as an adjunctive treatment in patients with type 1 or type 2 diabetes who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy.
- Pramlintide acetate is supplied as a sterile injection in the following dosage forms:
- 1.5 mL disposable multidose pramlintide acetatePen ® 60 pen-injector containing 1000 mcg/mL pramlintide (as acetate).
- 2.7 mL disposable multidose pramlintide acetatePen ® 120 pen-injector containing 1000 mcg/mL pramlintide (as acetate).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pramlintide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pramlintide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pramlintide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pramlintide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pramlintide in pediatric patients.
# Contraindications
- pramlintide acetate is contraindicated in patients with any of the following: serious hypersensitivity reaction to pramlintide acetate or to any of its product components.
- Hypoglycemia unawareness.
- Confirmed gastroparesis.
# Warnings
- Patients may experience erythema, edema, or pruritus at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than pramlintide acetate, such as irritants in a skin cleansing agent or improper injection technique.
- Proper patient selection is critical to the safe and effective use of pramlintide acetate. Before initiating pramlintide acetate, the patient's HbA1c, recent blood glucose monitoring data, history of insulin-induced hypoglycemia, current insulin regimen, and body weight should be reviewed. Pramlintide acetate therapy should only be considered in patients with type 1 diabetes or patients with type 2 diabetes using mealtime insulin who fulfill the following criteria:
- Have failed to achieve adequate glycemic control despite individualized insulin management.
- Are receiving ongoing care under the guidance of a healthcare professional skilled in the use of insulin and supported by the services of diabetes educator(s).
- Patients meeting any of the following criteria should NOT be considered for SYMLIN therapy:
- Poor compliance with current insulin regimen.
- Poor compliance with prescribed self blood glucose monitoring.
- Have a HbA1c >9%.
- Recurrent severe hypoglycemia requiring assistance during the past 6 months.
- Presence of hypoglycemia unawareness.
- Confirmed diagnosis of gastroparesis.
- Require the use of drugs that stimulate gastrointestinal motility.
- Pediatric patients.
- SYMLIN should be prescribed with caution to persons with visual or dexterity impairment.
- Pramlintide acetate alone does not cause hypoglycemia. However, pramlintide acetate is indicated to be coadministered with mealtime insulin therapy, and in this setting there is an increased risk of severe hypoglycemia, particularly in patients with type 1 diabetes. If severe hypoglycemia associated with pramlintide acetate occurs, it is usually seen within the first 2 to 3 hours following a pramlintide acetate injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries or death may occur. Therefore, when introducing pramlintide acetate therapy, appropriate precautions need to be taken to avoid increasing the risk for severe hypoglycemia.
- These precautions include frequent monitoring of pre- and post-meal glucose combined with an initial 50% reduction in doses of mealtime insulin.
- Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes; diabetic neuropathy; use of medications such as beta-blockers, clonidine, guanethidine, or reserpine; or intensified glycemic control.
- The addition of any anti-diabetic medication, such as pramlintide acetate, to an existing regimen of one or more anti-diabetic medications (e.g., sulfonylurea), or other medications that can increase the risk of hypoglycemia may necessitate further insulin dose adjustments and particularly close monitoring of blood glucose.
- pramlintide acetatePen should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.
- Mixing pramlintide acetate and insulin can alter the pharmacokinetics of both products which may result in inadequate glucose control or hypoglycemia. Therefore, pramlintide acetate and insulin must always be administered as separate injections and should never be mixed.
- Pramlintide acetate slows gastric emptying, which may delay the absorption of concomitantly administered oral medications. Administer the concomitant oral medication at least 1 hour prior to pramlintide acetate injection or 2 hours after pramlintide acetate injection if the rapid onset or threshold concentration of the concomitant medication is a critical determinant of its effectiveness (such as with analgesics, antibiotics, and oral contraceptives).
- Pramlintide acetate slows gastric emptying. Pramlintide acetate is not recommended for patients taking other medications that alter gastrointestinal motility.
- Local allergy.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reactions (excluding hypoglycemia, which is discussed separately below) commonly associated with pramlintide acetate when coadministered with a fixed dose of insulin in the 26- to 52-week, placebo-controlled trials in patients with type 1 diabetes and patients with type 2 diabetes on mealtime insulin are presented in Table 1 and Table 2, respectively.
- Most adverse reactions were gastrointestinal in nature. The incidence of nausea is higher at the beginning of pramlintide acetate treatment and decreases with time in most patients. Gradual titration of the pramlintide acetate dose minimizes the incidence and severity of nausea.
- Coadministration of pramlintide acetate with mealtime insulin increases the risk of severe hypoglycemia, particularly in patients with type 1 diabetes.
- Two definitions of severe hypoglycemia were used in the pramlintide acetate clinical trials. Patient-ascertained severe hypoglycemia was defined as an episode of hypoglycemia requiring the assistance of another individual (including help administering oral carbohydrate) or requiring the administration of glucagon, intravenous glucose, or other medical intervention.
- Medically-assisted severe hypoglycemia was defined as an episode of hypoglycemia that was classified as a serious event by the investigator or that required glucagon, intravenous glucose, hospitalization, paramedic assistance or an emergency room visit. The incidence of severe hypoglycemia during the pramlintide acetate clinical development program is summarized in Table 3 and Table 4.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of pramlintide acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Injection site reactions
- Pancreatitis
# Drug Interactions
- The pharmacokinetic parameters of pramlintide are altered when pramlintide acetate is mixed in the same syringe with regular, NPH, and 70/30 premixed formulations of recombinant human insulin. pramlintide acetate and insulin must not be mixed and must be administered as separate injections.
- Pramlintide acetate has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset or threshold concentration of a concomitant orally administered medication is a critical determinant of effectiveness (such as with analgesics, antibiotics, and oral contraceptives), the medication should be administered at least 1 hour prior to pramlintide acetate injection or 2 hours after pramlintide acetate injection.
- Due to its effects on gastric emptying, pramlintide acetate should not be considered for patients taking medications that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) or medications that slow the intestinal absorption of nutrients (e.g., alpha-glucosidase inhibitors). Patients using these medications have not been studied in pramlintide acetate clinical trials.
- The following are examples of medications that may increase the susceptibility to hypoglycemia when administered with pramlintide acetate: oral anti-diabetic products, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, propoxyphene, salicylates, somatostatin analogs, and sulfonamide antibiotics. Pramlintide acetate and these drugs should be coadministered with caution.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- No adequate and well-controlled studies have been conducted in pregnant women. Studies in perfused human placenta indicate that pramlintide acetate has low potential to cross the maternal/fetal placental barrier. Embryofetal toxicity studies with pramlintide acetate have been performed in rats and rabbits.
- Increases in congenital abnormalities (neural tube defect, cleft palate, exencephaly) were observed in fetuses of rats treated during organogenesis with 0.3 and 1.0 mg/kg/day (10 and 47 times the exposure resulting from the human dose of 360 mcg/day based on area under the plasma concentration curve , respectively). Administration of doses up to 0.3 mg/kg/day pramlintide acetate (9 times the human dose of 360 mcg/day based on AUC) to pregnant rabbits had no adverse effects in embryo fetal development; however, animal reproduction studies are not always predictive of human response. pramlintide acetate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pramlintide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pramlintide during labor and delivery.
### Nursing Mothers
- It is unknown whether pramlintide acetate is excreted in human milk. Many drugs, including peptides, are excreted in human milk. Therefore, pramlintide acetate should be administered to nursing women only if it is determined by the healthcare professional that the potential benefit outweighs the potential risk to the infant.
### Pediatric Use
- Safety and effectiveness of SYMLIN in pediatric patients have not been established.
### Geriatic Use
- Pramlintide acetate has been studied in patients ranging in age from 15 to 84 years of age, including 769 patients ≥65 to 75 years of age and 87 patients ≥75 years of age. No consistent differences in the efficacy and safety of pramlintide acetate have been observed in older patients, but greater sensitivity in some older individuals cannot be ruled out.
- As is recommended for all patients, pramlintide acetate and insulin regimens should be carefully managed to minimize the risk of severe hypoglycemia.
### Gender
- No consistent differences in the efficacy and safety of pramlintide acetate have been observed between men and women in pramlintide acetate clinical trials (n=2799 for male and n=2085 for female).
### Race
- No consistent differences in the efficacy and safety of pramlintide acetate have been observed among patients of differing race/ethnicity in pramlintide acetate clinical trials (n=4257 for Caucasian, n=229 for black, n=337 for Hispanic or Latino, and n=61 for Asian and one or more races) although the smaller sample sizes for non-Caucasians, particularly Asians, limit conclusions.
### Renal Impairment
- The dosing requirements for pramlintide acetate are not altered in patients with mild (creatinine clearance 60-89 mL/min), moderate (ClCr 30-59 mL/min) or severe renal impairment (ClCr 15-29 mL/min). pramlintide acetate has not been studied in patients with end-stage renal disease
### Hepatic Impairment
- pramlintide acetate use has not been studied in patients with hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pramlintide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pramlintide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
- Monitor glucoses frequently and individualize subsequent insulin dose adjustments.
- Monitor blood glucoses frequently, including pre- and post-meals and at bedtime, particularly when initiating pramlintide acetate or increasing the pramlintide acetate dose.
# IV Compatibility
There is limited information regarding IV Compatibility of Pramlintide in the drug label.
# Overdosage
- Single 10 mg doses of pramlintide acetate (83 times the maximum recommended dose of 120 mcg for patients with type 2 diabetes) were administered to 3 healthy volunteers.
- All 3 individuals reported severe nausea associated with vomiting, diarrhea, vasodilatation, and dizziness. No hypoglycemia was reported. Pramlintide has a short half-life (approximately 48 minutes in healthy individuals). Initiate supportive measures in the case of overdose.
# Pharmacology
There is limited information regarding Pramlintide Pharmacology in the drug label.
## Mechanism of Action
- Pramlintide is an analog of human amylin. Amylin is colocated with insulin in secretory granules and cosecreted with insulin by pancreatic beta cells in response to food intake. Amylin and insulin show similar fasting and postprandial patterns in healthy individuals (Figure 1).
- In patients with type 1 and type 2 diabetes, there is reduced secretion from pancreatic beta cells of both insulin and amylin in response to food.
- Amylin affects the rate of postprandial glucose appearance through a variety of mechanisms, as determined by nonclinical studies. Amylin slows gastric emptying (i.e., the rate at which food is released from the stomach to the small intestine) without altering the overall absorption of nutrients. - In addition, amylin suppresses glucagon secretion (not normalized by insulin alone), which leads to suppression of endogenous glucose output from the liver. Amylin also regulates food intake due to centrally-mediated modulation of appetite.
- In human studies, pramlintide, acting as an amylin analog, slows gastric emptying, reduces the postprandial rise in plasma glucagon, and modulates satiety leading to decreased caloric intake.
## Structure
- Pramlintide acetate injection is an anti-diabetic medication for use in patients with diabetes treated with insulin. Pramlintide is a synthetic analog of human amylin, a naturally occurring neuroendocrine hormone synthesized by pancreatic beta cells that contributes to glucose control during the postprandial period. Pramlintide is provided as an acetate salt of the synthetic 37-amino acid polypeptide, which differs in amino acid sequence from human amylin by replacement with proline at positions 25 (alanine), 28 (serine), and 29 (serine).
Pramlintide acetate is a white powder that has a molecular formula of C171H267N51O53S2- × C2H4O2 (3≤ × ≤8); the molecular weight is 3949.4. Pramlintide acetate is soluble in water.
- Pramlintide acetate is formulated as a clear, isotonic, sterile solution for subcutaneous administration. The disposable multidose pramlintide acetatePen® pen-injector contains 1000 mcg/mL of pramlintide (as acetate). The formulation contains 2.25 mg/mL of metacresol as a preservative, D-mannitol as a tonicity modifier, acetic acid, sodium acetate as pH modifiers, and water for injection. Pramlintide acetate has a pH of approximately 4.0.
## Pharmacodynamics
- In clinical studies in patients with type 1 diabetes and patients with type 2 diabetes using mealtime insulin, pramlintide acetate reduced mean postprandial glucose concentrations, reduced glucose fluctuations, and reduced food intake.
- In a randomized, single-blind, placebo-controlled, crossover study, 19 subjects with type 2 diabetes using insulin lispro, 19 subjects with type 1 diabetes using regular human insulin, and 21 subjects with type 1 diabetes using insulin lispro underwent mixed-meal tests. Pramlintide acetate administered subcutaneously immediately prior to a meal reduced plasma glucose concentrations following the meal when used with mealtime insulin (rapid-acting insulin analogs or regular human insulin) (Figure 2). When rapid-acting insulin analogs were used, plasma glucose concentrations tended to rise during the interval between 150 minutes following pramlintide acetate injection and the next meal
- While pramlintide acetate reduces postprandial glucose, clinical studies employing a controlled hypoglycemic challenge have demonstrated that pramlintide acetate does not alter the counter-regulatory hormonal response to insulin-induced hypoglycemia. Likewise, in pramlintide acetate-treated patients, the perception of hypoglycemic symptoms was not altered with plasma glucose concentrations as low as 45 mg/dL. In a separate clinical trial pramlintide also reduced the 24-hour glucose fluctuations based upon 24-hour glucose monitoring.
- A single, subcutaneous dose of 30 mcg of pramlintide acetate to patients with type 1 diabetes and 120 mcg of pramlintide acetate to patients with type 2 diabetes administered 1 hour prior to an unlimited buffet meal was associated with reductions in total caloric intake (placebo-subtracted mean changes of ~21% and 23%, respectively), which occurred without decreases in meal duration.
## Pharmacokinetics
- The absolute bioavailability of pramlintide following a single subcutaneous dose of pramlintide acetate is approximately 30% to 40%. Subcutaneous administration of different doses of pramlintide acetate into the abdominal area or thigh of healthy individuals showed a linear, dose-dependent increase in maximum plasma concentrations (Cmax) and overall exposure (AUC) (Table 5).
- Table 5: Mean Pharmacokinetic Parameters Following Administration of Single Subcutaneous Doses of pramlintide acetate
- Injection of pramlintide acetate into the arm in obese patients with type 1 or type 2 diabetes showed higher overall exposure (20%-36%) with greater variability (% CV for AUC: 73%-106%), compared with exposure after injection of pramlintide acetate into the abdominal area or thigh.
- Relative bioavailability of pramlintide was not significantly different between obese and non-obese patients and based on BMI or skin fold thickness. Injections administered with 6.0-mm and 12.7-mm needles yielded similar bioavailability.
- Pramlintide acetate does not extensively bind to red blood cells or albumin (approximately 40% of the drug is unbound in plasma).
- In healthy individuals, the half-life of pramlintide is approximately 48 minutes. The primary metabolite, Des-lys1 pramlintide (2-37 pramlintide), is biologically active in vitro. Overall exposure (AUC) to pramlintide is relatively constant with repeat dosing of pramlintide acetate, indicating no bioaccumulation.
- No studies have been conducted in patients with end-stage renal disease. In a single-dose pharmacokinetic study in patients with type 1 diabetes, 60 mcg of pramlintide acetate was administered to 4 patients with normal renal function (ClCr >90 mL/min), 9 patients with mild renal impairment (ClCr 60-89 mL/min), 5 patients with moderate renal impairment (ClCr 30-59 mL/min) and 3 patients with severe renal impairment (ClCr 15-29 mL/min). No statistically significant differences were noted in total (AUC0-∞) and peak (Cmax) exposure of pramlintide for mild, moderate, and severe renal impairment categories in comparison to patients with normal renal function; although, inter-patient variability in pharmacokinetic parameters was high.
- Pharmacokinetic studies have not been conducted in patients with hepatic impairment.
- Pharmacokinetic studies have not been conducted in the geriatric population.
- The efficacy and safety of pramlintide acetate have not been established in the pediatric population. The use of SYMLIN is not recommended in pediatric patients due to the risk of severe hypoglycemia.
- No study has been conducted to evaluate the effect of gender on pramlintide pharmacokinetics.
- No study has been conducted to evaluate the effect of ethnicity on pramlintide pharmacokinetics.
- Pharmacokinetic profiles of pramlintide and insulins after coadministration of 30 mcg pramlintide acetate with different insulins (regular, NPH, and 70/30 premixed formulations of recombinant human insulin) as one subcutaneous injection, premixed in one syringe, were compared to those observed after the coadministration of pramlintide acetate and different insulins given as separate subcutaneous injections. The effects of premixing on pramlintide pharmacokinetics varied across the different insulin products with a maximum decrease of 40% in pramlintide Cmax and a maximum increase of 36% in pramlintide AUC0-∞. Similarly, effects of premixing on insulin pharmacokinetics varied across different insulin products with a maximum increase of 15% in insulin Cmax and up to a 20% increase in insulin AUC0-600min. Always administer SYMLIN and insulin as separate injections and never mix.
- When 1000 mg acetaminophen was given within 0, 1, and 2 hours after a 120 mcg pramlintide acetate injection in patients with type 2 diabetes (n=24), acetaminophen Cmax decreased by 29%, 23%, and 20%, respectively compared to placebo. The time to maximum plasma concentration or Tmax increased by 72, 48, and 48 minutes, respectively. pramlintide acetate did not significantly affect acetaminophen Tmax or Cmax when acetaminophen was administered 1 to 2 hours before pramlintide acetate injection. pramlintide acetate did not affect acetaminophen AUC regardless of the time of acetaminophen administration in relation to pramlintide acetate injection.
- When a single dose of a combination oral contraceptive product, containing 30 mcg ethinyl estradiol and 300 mcg norgestrel, was administered 15 minutes after pramlintide acetate injection (90 mcg dose) in healthy female subjects, there was no statistically significant change in the Cmax and AUC of ethinyl estradiol. However, the norgestrel Cmax was reduced by about 30% and Tmax was delayed by 45 minutes; there was no effect on norgestrel AUC. The clinical relevance of this change is unknown.
- The effect of concomitant administration of pramlintide acetate and ampicillin was evaluated in healthy volunteers. The administration of a single oral 500 mg dose of ampicillin 15 minutes after a single dose of pramlintide acetate (90 mcg) did not alter the Cmax or AUC for ampicillin. However, the Tmax for ampicillin was delayed by approximately 60 minutes.
## Nonclinical Toxicology
- A two-year carcinogenicity study was conducted in CD-1 mice with doses of 0.2, 0.5, and 1.2 mg/kg/day of pramlintide acetate (32, 67, and 159 times the exposure resulting from the human dose of 360 mcg/day based on area under the plasma concentration curve or AUC, respectively). No drug-induced tumors were observed. A two-year carcinogenicity study was conducted in Sprague-Dawley rats with doses of 0.04, 0.2, and 0.5 mg/kg/day of pramlintide acetate (3, 9, and 25 times the exposure resulting from the human dose of 360 mcg/day based on AUC, respectively). No drug-induced tumors were observed in any organ.
- Pramlintide acetate was not mutagenic in the Ames test and did not increase chromosomal aberration in the human lymphocytes assay. Pramlintide acetate was not clastogenic in the in vivo mouse micronucleus test or in the chromosomal aberration assay utilizing Chinese hamster ovary cells.
- Administration of 0.3, 1, or 3 mg/kg/day of pramlintide acetate (8, 17, and 82 times the exposure resulting from the human dose of 360 mcg/day of mcg based on body surface area) had no significant effects on fertility in male or female rats. The highest dose of 3 mg/kg/day resulted in dystocia in 8/12 female rats secondary to significant decreases in serum calcium levels.
# Clinical Studies
- A total of 2333 patients with type 1 diabetes and 1852 patients with type 2 diabetes received pramlintide acetate in controlled clinical trials.
- The efficacy and safety of pramlintide acetate were evaluated in 3 (26-52-week), randomized, double-blind, placebo-controlled trials in patients with type 1 diabetes. In these studies, insulin adjustments were minimized in order to isolate the pramlintide acetate effect with insulin adjustments allowed, at the investigator's discretion, when excessive hypoglycemia was encountered. Patients participating in these 3 trials had a mean age of 40 years, a mean duration of diabetes of 17 years, and a mean body mass index of 25.9 kg/m2.
- Table 6 summarizes the 6-month results for those patients assigned to the 30 or 60 mcg dose of pramlintide acetate or placebo.
- In both studies, from a mean baseline body weight of 96.7 kg, and 85.6 kg, respectively, after randomization there were corresponding mean reductions of –1.4 kg, and –1.6 kg in the pramlintide acetate treatment group compared to mean increases of +0.3 kg, and +0.1 kg in the placebo treatment group.
# How Supplied
- pramlintide acetate Injection is available in the following package sizes:
- Pramlintide acetatePen ® 60 pen-injector, containing 1000 mcg/mL pramlintide (as acetate)
- Two 1.5 mL disposable multidose pen-injectors (NDC 0310-6615-02)
- Pramlintide acetatePen ® 120 pen-injector, containing 1000 mcg/mL pramlintide (as acetate)
- Two 2.7 mL disposable multidose pen-injectors (NDC 0310-6627-02)
## Storage
- Pramlintide acetate pen-injectors not in use: Refrigerate (2°C to 8°C; 36°F to 46°F), and protect from light. Do not freeze. Do not use if product has been frozen. Unused pramlintide acetate (opened or unopened) should not be used after the expiration (EXP) date printed on the carton and the label.
- Pramlintide acetate pen-injectors in use: After first use, refrigerate or keep at a temperature not greater than 86°F (30°C) for 30 days. Use within 30 days, whether or not refrigerated.
- Storage conditions are summarized in Table 9.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Discuss the risk and consequences of hypoglycemia and approaches to minimize its occurrence. Inform patients about the importance of self-management practices including glucose monitoring and timing of dosing. In addition, reinforce the importance of adherence to meal planning, physical activity, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.
- Advise patients that they should never share a SymlinPen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens.
- Inform patients that SYMLpramlintide acetateIN and insulin should always be administered as separate injections and never be mixed.
- Show patients how to administer SYMLIN using the pen-injector. Advise patients to use a new needle for each injection.
- Inform patients of the potential risks and advantages of SYMLIN therapy. Advise women with diabetes to inform their healthcare professional if they are pregnant or contemplating pregnancy. Instruct patients on the proper injection technique and proper storage of SYMLIN. Instruct patients on handling of special situations such as intercurrent conditions (illness or stress), an inadequate or omitted insulin dose, inadvertent administration of increased insulin or SYMLIN dose, inadequate food intake or missed meals. Refer patients to the SYMLIN Medication Guide and Patient Instructions for Use for additional information.
# Precautions with Alcohol
- Alcohol-Pramlintide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SYMLINPEN ®
# Look-Alike Drug Names
There is limited information regarding Pramlintide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Pramlintide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
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# Black Box Warning
# Overview
Pramlintide is an antidiabetic that is FDA approved for the treatment of patients with type 1 or type 2 diabetes who use mealtime insulin therapy and who have failed to achieve desired glucose] control despite optimal insulin therapy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, anorexia, nausea, vomiting, hypersensitivity reaction, dizziness, headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- SYMLIN is indicated as an adjunctive treatment in patients with type 1 or type 2 diabetes who use mealtime insulin therapy and who have failed to achieve desired glucose control despite optimal insulin therapy.
- Pramlintide acetate is supplied as a sterile injection in the following dosage forms:
- 1.5 mL disposable multidose pramlintide acetatePen ® 60 pen-injector containing 1000 mcg/mL pramlintide (as acetate).
- 2.7 mL disposable multidose pramlintide acetatePen ® 120 pen-injector containing 1000 mcg/mL pramlintide (as acetate).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pramlintide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pramlintide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pramlintide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pramlintide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pramlintide in pediatric patients.
# Contraindications
- pramlintide acetate is contraindicated in patients with any of the following: serious hypersensitivity reaction to pramlintide acetate or to any of its product components.
- Hypoglycemia unawareness.
- Confirmed gastroparesis.
# Warnings
- Patients may experience erythema, edema, or pruritus at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than pramlintide acetate, such as irritants in a skin cleansing agent or improper injection technique.
- Proper patient selection is critical to the safe and effective use of pramlintide acetate. Before initiating pramlintide acetate, the patient's HbA1c, recent blood glucose monitoring data, history of insulin-induced hypoglycemia, current insulin regimen, and body weight should be reviewed. Pramlintide acetate therapy should only be considered in patients with type 1 diabetes or patients with type 2 diabetes using mealtime insulin who fulfill the following criteria:
- Have failed to achieve adequate glycemic control despite individualized insulin management.
- Are receiving ongoing care under the guidance of a healthcare professional skilled in the use of insulin and supported by the services of diabetes educator(s).
- Patients meeting any of the following criteria should NOT be considered for SYMLIN therapy:
- Poor compliance with current insulin regimen.
- Poor compliance with prescribed self blood glucose monitoring.
- Have a HbA1c >9%.
- Recurrent severe hypoglycemia requiring assistance during the past 6 months.
- Presence of hypoglycemia unawareness.
- Confirmed diagnosis of gastroparesis.
- Require the use of drugs that stimulate gastrointestinal motility.
- Pediatric patients.
- SYMLIN should be prescribed with caution to persons with visual or dexterity impairment.
- Pramlintide acetate alone does not cause hypoglycemia. However, pramlintide acetate is indicated to be coadministered with mealtime insulin therapy, and in this setting there is an increased risk of severe hypoglycemia, particularly in patients with type 1 diabetes. If severe hypoglycemia associated with pramlintide acetate occurs, it is usually seen within the first 2 to 3 hours following a pramlintide acetate injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries or death may occur. Therefore, when introducing pramlintide acetate therapy, appropriate precautions need to be taken to avoid increasing the risk for severe hypoglycemia.
- These precautions include frequent monitoring of pre- and post-meal glucose combined with an initial 50% reduction in doses of mealtime insulin.
- Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes; diabetic neuropathy; use of medications such as beta-blockers, clonidine, guanethidine, or reserpine; or intensified glycemic control.
- The addition of any anti-diabetic medication, such as pramlintide acetate, to an existing regimen of one or more anti-diabetic medications (e.g., sulfonylurea), or other medications that can increase the risk of hypoglycemia may necessitate further insulin dose adjustments and particularly close monitoring of blood glucose.
- pramlintide acetatePen should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.
- Mixing pramlintide acetate and insulin can alter the pharmacokinetics of both products which may result in inadequate glucose control or hypoglycemia. Therefore, pramlintide acetate and insulin must always be administered as separate injections and should never be mixed.
- Pramlintide acetate slows gastric emptying, which may delay the absorption of concomitantly administered oral medications. Administer the concomitant oral medication at least 1 hour prior to pramlintide acetate injection or 2 hours after pramlintide acetate injection if the rapid onset or threshold concentration of the concomitant medication is a critical determinant of its effectiveness (such as with analgesics, antibiotics, and oral contraceptives).
- Pramlintide acetate slows gastric emptying. Pramlintide acetate is not recommended for patients taking other medications that alter gastrointestinal motility.
- Local allergy.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reactions (excluding hypoglycemia, which is discussed separately below) commonly associated with pramlintide acetate when coadministered with a fixed dose of insulin in the 26- to 52-week, placebo-controlled trials in patients with type 1 diabetes and patients with type 2 diabetes on mealtime insulin are presented in Table 1 and Table 2, respectively.
- Most adverse reactions were gastrointestinal in nature. The incidence of nausea is higher at the beginning of pramlintide acetate treatment and decreases with time in most patients. Gradual titration of the pramlintide acetate dose minimizes the incidence and severity of nausea.
- Coadministration of pramlintide acetate with mealtime insulin increases the risk of severe hypoglycemia, particularly in patients with type 1 diabetes.
- Two definitions of severe hypoglycemia were used in the pramlintide acetate clinical trials. Patient-ascertained severe hypoglycemia was defined as an episode of hypoglycemia requiring the assistance of another individual (including help administering oral carbohydrate) or requiring the administration of glucagon, intravenous glucose, or other medical intervention.
- Medically-assisted severe hypoglycemia was defined as an episode of hypoglycemia that was classified as a serious event by the investigator or that required glucagon, intravenous glucose, hospitalization, paramedic assistance or an emergency room visit. The incidence of severe hypoglycemia during the pramlintide acetate clinical development program is summarized in Table 3 and Table 4.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of pramlintide acetate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Injection site reactions
- Pancreatitis
# Drug Interactions
- The pharmacokinetic parameters of pramlintide are altered when pramlintide acetate is mixed in the same syringe with regular, NPH, and 70/30 premixed formulations of recombinant human insulin. pramlintide acetate and insulin must not be mixed and must be administered as separate injections.
- Pramlintide acetate has the potential to delay the absorption of concomitantly administered oral medications. When the rapid onset or threshold concentration of a concomitant orally administered medication is a critical determinant of effectiveness (such as with analgesics, antibiotics, and oral contraceptives), the medication should be administered at least 1 hour prior to pramlintide acetate injection or 2 hours after pramlintide acetate injection.
- Due to its effects on gastric emptying, pramlintide acetate should not be considered for patients taking medications that alter gastrointestinal motility (e.g., anticholinergic agents such as atropine) or medications that slow the intestinal absorption of nutrients (e.g., alpha-glucosidase inhibitors). Patients using these medications have not been studied in pramlintide acetate clinical trials.
- The following are examples of medications that may increase the susceptibility to hypoglycemia when administered with pramlintide acetate: oral anti-diabetic products, angiotensin converting enzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, propoxyphene, salicylates, somatostatin analogs, and sulfonamide antibiotics. Pramlintide acetate and these drugs should be coadministered with caution.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- No adequate and well-controlled studies have been conducted in pregnant women. Studies in perfused human placenta indicate that pramlintide acetate has low potential to cross the maternal/fetal placental barrier. Embryofetal toxicity studies with pramlintide acetate have been performed in rats and rabbits.
- Increases in congenital abnormalities (neural tube defect, cleft palate, exencephaly) were observed in fetuses of rats treated during organogenesis with 0.3 and 1.0 mg/kg/day (10 and 47 times the exposure resulting from the human dose of 360 mcg/day based on area under the plasma concentration curve [AUC], respectively). Administration of doses up to 0.3 mg/kg/day pramlintide acetate (9 times the human dose of 360 mcg/day based on AUC) to pregnant rabbits had no adverse effects in embryo fetal development; however, animal reproduction studies are not always predictive of human response. pramlintide acetate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pramlintide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pramlintide during labor and delivery.
### Nursing Mothers
- It is unknown whether pramlintide acetate is excreted in human milk. Many drugs, including peptides, are excreted in human milk. Therefore, pramlintide acetate should be administered to nursing women only if it is determined by the healthcare professional that the potential benefit outweighs the potential risk to the infant.
### Pediatric Use
- Safety and effectiveness of SYMLIN in pediatric patients have not been established.
### Geriatic Use
- Pramlintide acetate has been studied in patients ranging in age from 15 to 84 years of age, including 769 patients ≥65 to 75 years of age and 87 patients ≥75 years of age. No consistent differences in the efficacy and safety of pramlintide acetate have been observed in older patients, but greater sensitivity in some older individuals cannot be ruled out.
- As is recommended for all patients, pramlintide acetate and insulin regimens should be carefully managed to minimize the risk of severe hypoglycemia.
### Gender
- No consistent differences in the efficacy and safety of pramlintide acetate have been observed between men and women in pramlintide acetate clinical trials (n=2799 for male and n=2085 for female).
### Race
- No consistent differences in the efficacy and safety of pramlintide acetate have been observed among patients of differing race/ethnicity in pramlintide acetate clinical trials (n=4257 for Caucasian, n=229 for black, n=337 for Hispanic or Latino, and n=61 for Asian and one or more races) although the smaller sample sizes for non-Caucasians, particularly Asians, limit conclusions.
### Renal Impairment
- The dosing requirements for pramlintide acetate are not altered in patients with mild (creatinine clearance [ClCr] 60-89 mL/min), moderate (ClCr 30-59 mL/min) or severe renal impairment (ClCr 15-29 mL/min). pramlintide acetate has not been studied in patients with end-stage renal disease
### Hepatic Impairment
- pramlintide acetate use has not been studied in patients with hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pramlintide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pramlintide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
- Monitor glucoses frequently and individualize subsequent insulin dose adjustments.
- Monitor blood glucoses frequently, including pre- and post-meals and at bedtime, particularly when initiating pramlintide acetate or increasing the pramlintide acetate dose.
# IV Compatibility
There is limited information regarding IV Compatibility of Pramlintide in the drug label.
# Overdosage
- Single 10 mg doses of pramlintide acetate (83 times the maximum recommended dose of 120 mcg for patients with type 2 diabetes) were administered to 3 healthy volunteers.
- All 3 individuals reported severe nausea associated with vomiting, diarrhea, vasodilatation, and dizziness. No hypoglycemia was reported. Pramlintide has a short half-life (approximately 48 minutes in healthy individuals). Initiate supportive measures in the case of overdose.
# Pharmacology
There is limited information regarding Pramlintide Pharmacology in the drug label.
## Mechanism of Action
- Pramlintide is an analog of human amylin. Amylin is colocated with insulin in secretory granules and cosecreted with insulin by pancreatic beta cells in response to food intake. Amylin and insulin show similar fasting and postprandial patterns in healthy individuals (Figure 1).
- In patients with type 1 and type 2 diabetes, there is reduced secretion from pancreatic beta cells of both insulin and amylin in response to food.
- Amylin affects the rate of postprandial glucose appearance through a variety of mechanisms, as determined by nonclinical studies. Amylin slows gastric emptying (i.e., the rate at which food is released from the stomach to the small intestine) without altering the overall absorption of nutrients. * In addition, amylin suppresses glucagon secretion (not normalized by insulin alone), which leads to suppression of endogenous glucose output from the liver. Amylin also regulates food intake due to centrally-mediated modulation of appetite.
- In human studies, pramlintide, acting as an amylin analog, slows gastric emptying, reduces the postprandial rise in plasma glucagon, and modulates satiety leading to decreased caloric intake.
## Structure
- Pramlintide acetate injection is an anti-diabetic medication for use in patients with diabetes treated with insulin. Pramlintide is a synthetic analog of human amylin, a naturally occurring neuroendocrine hormone synthesized by pancreatic beta cells that contributes to glucose control during the postprandial period. Pramlintide is provided as an acetate salt of the synthetic 37-amino acid polypeptide, which differs in amino acid sequence from human amylin by replacement with proline at positions 25 (alanine), 28 (serine), and 29 (serine).
Pramlintide acetate is a white powder that has a molecular formula of C171H267N51O53S2• × C2H4O2 (3≤ × ≤8); the molecular weight is 3949.4. Pramlintide acetate is soluble in water.
- Pramlintide acetate is formulated as a clear, isotonic, sterile solution for subcutaneous administration. The disposable multidose pramlintide acetatePen® pen-injector contains 1000 mcg/mL of pramlintide (as acetate). The formulation contains 2.25 mg/mL of metacresol as a preservative, D-mannitol as a tonicity modifier, acetic acid, sodium acetate as pH modifiers, and water for injection. Pramlintide acetate has a pH of approximately 4.0.
## Pharmacodynamics
- In clinical studies in patients with type 1 diabetes and patients with type 2 diabetes using mealtime insulin, pramlintide acetate reduced mean postprandial glucose concentrations, reduced glucose fluctuations, and reduced food intake.
- In a randomized, single-blind, placebo-controlled, crossover study, 19 subjects with type 2 diabetes using insulin lispro, 19 subjects with type 1 diabetes using regular human insulin, and 21 subjects with type 1 diabetes using insulin lispro underwent mixed-meal tests. Pramlintide acetate administered subcutaneously immediately prior to a meal reduced plasma glucose concentrations following the meal when used with mealtime insulin (rapid-acting insulin analogs or regular human insulin) (Figure 2). When rapid-acting insulin analogs were used, plasma glucose concentrations tended to rise during the interval between 150 minutes following pramlintide acetate injection and the next meal
- While pramlintide acetate reduces postprandial glucose, clinical studies employing a controlled hypoglycemic challenge have demonstrated that pramlintide acetate does not alter the counter-regulatory hormonal response to insulin-induced hypoglycemia. Likewise, in pramlintide acetate-treated patients, the perception of hypoglycemic symptoms was not altered with plasma glucose concentrations as low as 45 mg/dL. In a separate clinical trial pramlintide also reduced the 24-hour glucose fluctuations based upon 24-hour glucose monitoring.
- A single, subcutaneous dose of 30 mcg of pramlintide acetate to patients with type 1 diabetes and 120 mcg of pramlintide acetate to patients with type 2 diabetes administered 1 hour prior to an unlimited buffet meal was associated with reductions in total caloric intake (placebo-subtracted mean changes of ~21% and 23%, respectively), which occurred without decreases in meal duration.
## Pharmacokinetics
- The absolute bioavailability of pramlintide following a single subcutaneous dose of pramlintide acetate is approximately 30% to 40%. Subcutaneous administration of different doses of pramlintide acetate into the abdominal area or thigh of healthy individuals showed a linear, dose-dependent increase in maximum plasma concentrations (Cmax) and overall exposure (AUC) (Table 5).
- Table 5: Mean Pharmacokinetic Parameters Following Administration of Single Subcutaneous Doses of pramlintide acetate
- Injection of pramlintide acetate into the arm in obese patients with type 1 or type 2 diabetes showed higher overall exposure (20%-36%) with greater variability (% CV for AUC: 73%-106%), compared with exposure after injection of pramlintide acetate into the abdominal area or thigh.
- Relative bioavailability of pramlintide was not significantly different between obese and non-obese patients and based on BMI or skin fold thickness. Injections administered with 6.0-mm and 12.7-mm needles yielded similar bioavailability.
- Pramlintide acetate does not extensively bind to red blood cells or albumin (approximately 40% of the drug is unbound in plasma).
- In healthy individuals, the half-life of pramlintide is approximately 48 minutes. The primary metabolite, Des-lys1 pramlintide (2-37 pramlintide), is biologically active in vitro. Overall exposure (AUC) to pramlintide is relatively constant with repeat dosing of pramlintide acetate, indicating no bioaccumulation.
- No studies have been conducted in patients with end-stage renal disease. In a single-dose pharmacokinetic study in patients with type 1 diabetes, 60 mcg of pramlintide acetate was administered to 4 patients with normal renal function (ClCr >90 mL/min), 9 patients with mild renal impairment (ClCr 60-89 mL/min), 5 patients with moderate renal impairment (ClCr 30-59 mL/min) and 3 patients with severe renal impairment (ClCr 15-29 mL/min). No statistically significant differences were noted in total (AUC0-∞) and peak (Cmax) exposure of pramlintide for mild, moderate, and severe renal impairment categories in comparison to patients with normal renal function; although, inter-patient variability in pharmacokinetic parameters was high.
- Pharmacokinetic studies have not been conducted in patients with hepatic impairment.
- Pharmacokinetic studies have not been conducted in the geriatric population.
- The efficacy and safety of pramlintide acetate have not been established in the pediatric population. The use of SYMLIN is not recommended in pediatric patients due to the risk of severe hypoglycemia.
- No study has been conducted to evaluate the effect of gender on pramlintide pharmacokinetics.
- No study has been conducted to evaluate the effect of ethnicity on pramlintide pharmacokinetics.
- Pharmacokinetic profiles of pramlintide and insulins after coadministration of 30 mcg pramlintide acetate with different insulins (regular, NPH, and 70/30 premixed formulations of recombinant human insulin) as one subcutaneous injection, premixed in one syringe, were compared to those observed after the coadministration of pramlintide acetate and different insulins given as separate subcutaneous injections. The effects of premixing on pramlintide pharmacokinetics varied across the different insulin products with a maximum decrease of 40% in pramlintide Cmax and a maximum increase of 36% in pramlintide AUC0-∞. Similarly, effects of premixing on insulin pharmacokinetics varied across different insulin products with a maximum increase of 15% in insulin Cmax and up to a 20% increase in insulin AUC0-600min. Always administer SYMLIN and insulin as separate injections and never mix.
- When 1000 mg acetaminophen was given within 0, 1, and 2 hours after a 120 mcg pramlintide acetate injection in patients with type 2 diabetes (n=24), acetaminophen Cmax decreased by 29%, 23%, and 20%, respectively compared to placebo. The time to maximum plasma concentration or Tmax increased by 72, 48, and 48 minutes, respectively. pramlintide acetate did not significantly affect acetaminophen Tmax or Cmax when acetaminophen was administered 1 to 2 hours before pramlintide acetate injection. pramlintide acetate did not affect acetaminophen AUC regardless of the time of acetaminophen administration in relation to pramlintide acetate injection.
- When a single dose of a combination oral contraceptive product, containing 30 mcg ethinyl estradiol and 300 mcg norgestrel, was administered 15 minutes after pramlintide acetate injection (90 mcg dose) in healthy female subjects, there was no statistically significant change in the Cmax and AUC of ethinyl estradiol. However, the norgestrel Cmax was reduced by about 30% and Tmax was delayed by 45 minutes; there was no effect on norgestrel AUC. The clinical relevance of this change is unknown.
- The effect of concomitant administration of pramlintide acetate and ampicillin was evaluated in healthy volunteers. The administration of a single oral 500 mg dose of ampicillin 15 minutes after a single dose of pramlintide acetate (90 mcg) did not alter the Cmax or AUC for ampicillin. However, the Tmax for ampicillin was delayed by approximately 60 minutes.
## Nonclinical Toxicology
- A two-year carcinogenicity study was conducted in CD-1 mice with doses of 0.2, 0.5, and 1.2 mg/kg/day of pramlintide acetate (32, 67, and 159 times the exposure resulting from the human dose of 360 mcg/day based on area under the plasma concentration curve or AUC, respectively). No drug-induced tumors were observed. A two-year carcinogenicity study was conducted in Sprague-Dawley rats with doses of 0.04, 0.2, and 0.5 mg/kg/day of pramlintide acetate (3, 9, and 25 times the exposure resulting from the human dose of 360 mcg/day based on AUC, respectively). No drug-induced tumors were observed in any organ.
- Pramlintide acetate was not mutagenic in the Ames test and did not increase chromosomal aberration in the human lymphocytes assay. Pramlintide acetate was not clastogenic in the in vivo mouse micronucleus test or in the chromosomal aberration assay utilizing Chinese hamster ovary cells.
- Administration of 0.3, 1, or 3 mg/kg/day of pramlintide acetate (8, 17, and 82 times the exposure resulting from the human dose of 360 mcg/day of mcg based on body surface area) had no significant effects on fertility in male or female rats. The highest dose of 3 mg/kg/day resulted in dystocia in 8/12 female rats secondary to significant decreases in serum calcium levels.
# Clinical Studies
- A total of 2333 patients with type 1 diabetes and 1852 patients with type 2 diabetes received pramlintide acetate in controlled clinical trials.
- The efficacy and safety of pramlintide acetate were evaluated in 3 (26-52-week), randomized, double-blind, placebo-controlled trials in patients with type 1 diabetes. In these studies, insulin adjustments were minimized in order to isolate the pramlintide acetate effect with insulin adjustments allowed, at the investigator's discretion, when excessive hypoglycemia was encountered. Patients participating in these 3 trials had a mean age of 40 years, a mean duration of diabetes of 17 years, and a mean body mass index of 25.9 kg/m2.
- Table 6 summarizes the 6-month results for those patients assigned to the 30 or 60 mcg dose of pramlintide acetate or placebo.
- In both studies, from a mean baseline body weight of 96.7 kg, and 85.6 kg, respectively, after randomization there were corresponding mean reductions of –1.4 kg, and –1.6 kg in the pramlintide acetate treatment group compared to mean increases of +0.3 kg, and +0.1 kg in the placebo treatment group.
# How Supplied
- pramlintide acetate Injection is available in the following package sizes:
- Pramlintide acetatePen ® 60 pen-injector, containing 1000 mcg/mL pramlintide (as acetate)
- Two 1.5 mL disposable multidose pen-injectors (NDC 0310-6615-02)
- Pramlintide acetatePen ® 120 pen-injector, containing 1000 mcg/mL pramlintide (as acetate)
- Two 2.7 mL disposable multidose pen-injectors (NDC 0310-6627-02)
## Storage
- Pramlintide acetate pen-injectors not in use: Refrigerate (2°C to 8°C; 36°F to 46°F), and protect from light. Do not freeze. Do not use if product has been frozen. Unused pramlintide acetate (opened or unopened) should not be used after the expiration (EXP) date printed on the carton and the label.
- Pramlintide acetate pen-injectors in use: After first use, refrigerate or keep at a temperature not greater than 86°F (30°C) for 30 days. Use within 30 days, whether or not refrigerated.
- Storage conditions are summarized in Table 9.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Discuss the risk and consequences of hypoglycemia and approaches to minimize its occurrence. Inform patients about the importance of self-management practices including glucose monitoring and timing of dosing. In addition, reinforce the importance of adherence to meal planning, physical activity, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.
- Advise patients that they should never share a SymlinPen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens.
- Inform patients that SYMLpramlintide acetateIN and insulin should always be administered as separate injections and never be mixed.
- Show patients how to administer SYMLIN using the pen-injector. Advise patients to use a new needle for each injection.
- Inform patients of the potential risks and advantages of SYMLIN therapy. Advise women with diabetes to inform their healthcare professional if they are pregnant or contemplating pregnancy. Instruct patients on the proper injection technique and proper storage of SYMLIN. Instruct patients on handling of special situations such as intercurrent conditions (illness or stress), an inadequate or omitted insulin dose, inadvertent administration of increased insulin or SYMLIN dose, inadequate food intake or missed meals. Refer patients to the SYMLIN Medication Guide and Patient Instructions for Use for additional information.
# Precautions with Alcohol
- Alcohol-Pramlintide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SYMLINPEN ®[1]
# Look-Alike Drug Names
There is limited information regarding Pramlintide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Pramlintide | |
69b24f275e82214ee5755129b3f59aa469b6c997 | wikidoc | Repaglinide | Repaglinide
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# Overview
Repaglinide is an antidiabetic agent that is FDA approved for the {{{indicationType}}} of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia, diarrhea, arthralgia, headache, sinusitis, and upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Starting Dose
- For patients not previously treated or whose HbA1c is < 8%, the starting dose should be 0.5 mg with each meal. For patients previously treated with blood glucose-lowering drugs and whose HbA1c is ≥ 8%, the initial dose is 1 or 2 mg with each meal preprandially.
- Dose Adjustment
- Dosing adjustments should be determined by blood glucose response, usually fasting blood glucose. Postprandial glucose levels testing may be clinically helpful in patients whose pre-meal blood glucose levels are satisfactory but whose overall glycemic control (HbA1c) is inadequate. The preprandial dose should be doubled up to 4 mg with each meal until satisfactory blood glucose response is achieved. At least one week should elapse to assess response after each dose adjustment.
- The recommended dose range is 0.5 mg to 4 mg taken with meals. PRANDIN may be dosed preprandially 2, 3, or 4 times a day in response to changes in the patient’s meal pattern. The maximum recommended daily dose is 16 mg.
- Patient Management
- Long-term efficacy should be monitored by measurement of HbA1c levels approximately every 3 months. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia or hyperglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy including hypoglycemia. When hypoglycemia occurs in patients taking a combination of PRANDIN and a thiazolidinedione or PRANDIN and metformin, the dose of PRANDIN should be reduced.
- Patients Receiving Other Oral Hypoglycemic Agents
- When PRANDIN is used to replace therapy with other oral hypoglycemic agents, PRANDIN may be started on the day after the final dose is given. Patients should then be observed carefully for hypoglycemia due to potential overlapping of drug effects. When transferred from longer half-life sulfonylurea agents (e.g., chlorpropamide) to repaglinide, close monitoring may be indicated for up to one week or longer.
- Combination Therapy
- If PRANDIN monotherapy does not result in adequate glycemic control, metformin or a thiazolidinedione may be added. If metformin or thiazolidinedione monotherapy does not provide adequate control, PRANDIN may be added. The starting dose and dose adjustments for PRANDIN combination therapy is the same as for PRANDIN monotherapy. The dose of each drug should be carefully adjusted to determine the minimal dose required to achieve the desired pharmacologic effect. Failure to do so could result in an increase in the incidence of hypoglycemic episodes. Appropriate monitoring of FPG and HbA1c measurements should be used to ensure that the patient is not subjected to excessive drug exposure or increased probability of secondary drug failure.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Repaglinide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Repaglinide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Repaglinide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Repaglinide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Repaglinide in pediatric patients.
# Contraindications
- Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
- Type 1 diabetes.
- Co-administration of gemfibrozil.
- Known hypersensitivity to the drug or its inactive ingredients.
# Warnings
### Precautions
- General:
- PRANDIN is not indicated for use in combination with NPH-insulin.
- Macrovascular Outcomes:
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with PRANDIN or any other anti-diabetic drug.
- Hypoglycemia
- All oral blood glucose-lowering drugs including repaglinide are capable of producing hypoglycemia. Proper patient selection, dosage, and instructions to the patients are important to avoid hypoglycemic episodes. Hepatic insufficiency may cause elevated repaglinide blood levels and may diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemia. Elderly, debilitated, or malnourished patients, and those with adrenal, pituitary, hepatic, or severe renal insufficiency may be particularly susceptible to the hypoglycemic action of glucose-lowering drugs.
- Hypoglycemia may be difficult to recognize in the elderly and in people taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.
- The frequency of hypoglycemia is greater in patients with type 2 diabetes who have not been previously treated with oral blood glucose-lowering drugs (naïve) or whose HbA1c is less than 8%. PRANDIN should be administered with meals to lessen the risk of hypoglycemia.
- Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of glycemic control may occur. At such times, it may be necessary to discontinue PRANDIN and administer insulin. The effectiveness of any hypoglycemic drug in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when the drug is first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.
# Adverse Reactions
## Clinical Trials Experience
- PRANDIN has been administered to 2931 individuals during clinical trials. Approximately 1500 of these individuals with type 2 diabetes have been treated for at least 3 months, 1000 for at least 6 months, and 800 for at least 1 year. The majority of these individuals (1228) received PRANDIN in one of five 1-year, active-controlled trials. The comparator drugs in these 1-year trials were oral sulfonylurea drugs (SU) including glyburide and glipizide. Over one year, 13% of PRANDIN patients were discontinued due to adverse events, as were 14% of SU patients. The most common adverse events leading to withdrawal were hyperglycemia, hypoglycemia, and related symptoms. Mild or moderate hypoglycemia occurred in 16% of PRANDIN patients, 20% of glyburide patients, and 19% of glipizide patients.
- The table below lists common adverse events for PRANDIN patients compared to both placebo (in trials 12 to 24 weeks duration) and to glyburide and glipizide in one year trials. The adverse event profile of PRANDIN was generally comparable to that for sulfonylurea drugs (SU).
- Cardiovascular Events
- In one-year trials comparing PRANDIN to sulfonylurea drugs, the incidence of angina was comparable (1.8%) for both treatments, with an incidence of chest pain of 1.8% for PRANDIN and 1.0% for sulfonylureas. The incidence of other selected cardiovascular events (hypertension, abnormal EKG, myocardial infarction, arrhythmias, and palpitations) was ≤ 1% and not different between PRANDIN and the comparator drugs.
- The incidence of total serious cardiovascular adverse events, including ischemia, was higher for repaglinide (4%) than for sulfonylurea drugs (3%) in controlled comparator clinical trials. In 1-year controlled trials, PRANDIN treatment was not associated with excess mortality when compared to the rates observed with other oral hypoglycemic agent therapies.
- Seven controlled clinical trials included PRANDIN combination therapy with NPH-insulin (n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH-insulin or PRANDIN plus metformin) (n=120). There were six serious adverse events of myocardial ischemia in patients treated with PRANDIN plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study.
- Infrequent Adverse Events (<1% of Patients)
- Less common adverse clinical or laboratory events observed in clinical trials included elevated liver enzymes, thrombocytopenia, leukopenia, and anaphylactoid reactions.
- Although no causal relationship with repaglinide has been established, postmarketing experience includes reports of the following rare adverse events: alopecia, hemolytic anemia, pancreatitis, Stevens-Johnson Syndrome, and severe hepatic dysfunction including jaundice and hepatitis.
- Combination Therapy with Thiazolidinediones
- During 24-week treatment clinical trials of PRANDIN-rosiglitazone or PRANDIN-pioglitazone combination therapy (a total of 250 patients in combination therapy), hypoglycemia (blood glucose < 50 mg/dL) occurred in 7% of combination therapy patients in comparison to 7% for PRANDIN monotherapy, and 2% for thiazolidinedione monotherapy.
- Peripheral edema was reported in 12 out of 250 PRANDIN-thiazolidinedione combination therapy patients and 3 out of 124 thiazolidinedione monotherapy patients, with no cases reported in these trials for PRANDIN monotherapy. When corrected for dropout rates of the treatment groups, the percentage of patients having events of peripheral edema per 24 weeks of treatment were 5% for PRANDIN-thiazolidinedione combination therapy, and 4% for thiazolidinedione monotherapy. There were reports in 2 of 250 patients (0.8%) treated with PRANDIN-thiazolidinedione therapy of episodes of edema with congestive heart failure. Both patients had a prior history of coronary artery disease and recovered after treatment with diuretic agents. No comparable cases in the monotherapy treatment groups were reported.
- Mean change in weight from baseline was +4.9 kg for PRANDIN-thiazolidinedione therapy. There were no patients on PRANDIN-thiazolidinedione combination therapy who had elevations of liver transaminases (defined as 3 times the upper limit of normal levels).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Repaglinide in the drug label.
# Drug Interactions
- In vitro data indicate that PRANDIN is metabolized by cytochrome P450 enzymes 2C8 and 3A4. Consequently, repaglinide metabolism may be altered by drugs which influence these cytochrome P450 enzyme systems via induction and inhibition. Caution should therefore be used in patients who are on PRANDIN and taking inhibitors and/or inducers of CYP2C8 and CYP3A4. The effect may be very significant if both enzymes are inhibited at the same time resulting in a substantial increase in repaglinide plasma concentrations. Drugs that are known to inhibit CYP3A4 include antifungal agents like ketoconazole, itraconazole, and antibacterial agents like erythromycin. Drugs that are known to inhibit CYP2C8 include agents like trimethoprim, gemfibrozil and montelukast. Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine.
- Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1). Drugs that inhibit OATP1B1 (e.g. cyclosporine) may likewise have the potential to increase plasma concentrations of repaglinide.
- In vivo data from a study that evaluated the co-administration of a cytochrome P450 enzyme 3A4 inhibitor, clarithromycin, with PRANDIN resulted in a clinically significant increase in repaglinide plasma levels. In addition, an increase in repaglinide plasma levels was observed in studies that evaluated the co-administration of PRANDIN with trimethoprim and PRANDIN with deferasirox, both cytochrome P-450 enzyme 2C8 inhibitors. These increases in repaglinide plasma levels may necessitate a PRANDIN dose adjustment.
- Gemfibrozil significantly increased PRANDIN exposure. Therefore, patients should not take PRANDIN with gemfibrozil.
- The hypoglycemic action of oral blood glucose-lowering agents may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, cyclosporine, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving oral blood glucose-lowering agents, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving oral blood glucose-lowering agents, the patient should be observed closely for loss of glycemic control.
- Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When these drugs are administered to a patient receiving oral blood glucose-lowering agents, the patient should be observed for loss of glycemic control. When these drugs are withdrawn from a patient receiving oral blood glucose-lowering agents, the patient should be observed closely for hypoglycemia.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratogenic Effects
- Safety in pregnant women has not been established. Repaglinide was not teratogenic in rats or rabbits at doses 40 times (rats) and approximately 0.8 times (rabbit) clinical exposure (on a mg/m2 basis) throughout pregnancy. Because animal reproduction studies are not always predictive of human response, PRANDIN should be used during pregnancy only if it is clearly needed.
- Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
- Nonteratogenic Effects
- Offspring of rat dams exposed to repaglinide at 15 times clinical exposure on a mg/m2 basis during days 17 to 22 of gestation and during lactation developed nonteratogenic skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. This effect was not seen at doses up to 2.5 times clinical exposure (on a mg/m2 basis) on days 1 to 22 of pregnancy or at higher doses given during days 1 to 16 of pregnancy. Relevant human exposure has not occurred to date and therefore the safety of PRANDIN administration throughout pregnancy or lactation cannot be established.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Repaglinide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Repaglinide during labor and delivery.
### Nursing Mothers
- In rat reproduction studies, measurable levels of repaglinide were detected in the breast milk of the dams and lowered blood glucose levels were observed in the pups. Cross fostering studies indicated that skeletal changes could be induced in control pups nursed by treated dams, although this occurred to a lesser degree than those pups treated in utero. Although it is not known whether repaglinide is excreted in human milk some oral agents are known to be excreted by this route. Because the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, a decision should be made as to whether PRANDIN should be discontinued in nursing mothers, or if mothers should discontinue nursing. If PRANDIN is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
### Pediatric Use
- No studies have been performed in pediatric patients.
### Geriatic Use
- In repaglinide clinical studies of 24 weeks or greater duration, 415 patients were over 65 years of age. In one-year, active-controlled trials, no differences were seen in effectiveness or adverse events between these subjects and those less than 65 other than the expected age-related increase in cardiovascular events observed for PRANDIN and comparator drugs. There was no increase in frequency or severity of hypoglycemia in older subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals to PRANDIN therapy cannot be ruled out.
### Gender
There is no FDA guidance on the use of Repaglinide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Repaglinide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Repaglinide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Repaglinide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Repaglinide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Repaglinide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Repaglinide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Repaglinide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In a clinical trial, patients received increasing doses of PRANDIN up to 80 mg a day for 14 days. There were few adverse effects other than those associated with the intended effect of lowering blood glucose. Hypoglycemia did not occur when meals were given with these high doses.
### Management
- Hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring may continue until the physician is assured that the patient is out of danger. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery. There is no evidence that repaglinide is dialyzable using hemodialysis.
- Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Repaglinide in the drug label.
# Pharmacology
## Mechanism of Action
- Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (ß) cells in the pancreatic islets. Insulin release is glucose-dependent and diminishes at low glucose concentrations.
- Repaglinide closes ATP-dependent potassium channels in the ß-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the ß-cell, which leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion. The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle.
## Structure
- PRANDIN® (repaglinide) is an oral blood glucose-lowering drug of the meglitinide class used in the management of type 2 diabetes mellitus (also known as non-insulin dependent diabetes mellitus or NIDDM). Repaglinide, S(+)2-ethoxy-4(2((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2-oxoethyl) benzoic acid, is chemically unrelated to the oral sulfonylurea insulin secretagogues.
- The structural formula is as shown below:
- Repaglinide is a white to off-white powder with molecular formula C27 H36 N2 O4 and a molecular weight of 452.6. PRANDIN tablets contain 0.5 mg, 1 mg, or 2 mg of repaglinide. In addition each tablet contains the following inactive ingredients: calcium hydrogen phosphate (anhydrous), microcrystalline cellulose, maize starch, polacrilin potassium, povidone, glycerol (85%), magnesium stearate, meglumine, and poloxamer. The 1 mg and 2 mg tablets contain iron oxides (yellow and red, respectively) as coloring agents.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Repaglinide in the drug label.
## Pharmacokinetics
- Absorption: After oral administration, repaglinide is rapidly and completely absorbed from the gastrointestinal tract. After single and multiple oral doses in healthy subjects or in patients, peak plasma drug levels (Cmax) occur within 1 hour (Tmax). Repaglinide is rapidly eliminated from the blood stream with a half-life of approximately 1 hour. The mean absolute bioavailability is 56%. When repaglinide was given with food, the mean Tmax was not changed, but the mean Cmax and AUC (area under the time/plasma concentration curve) were decreased 20% and 12.4%, respectively.
- Distribution: After intravenous (IV) dosing in healthy subjects, the volume of distribution at steady state (Vss) was 31 L, and the total body clearance (CL) was 38 L/h. Protein binding and binding to human serum albumin was greater than 98%.
- Metabolism: Repaglinide is completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid after either an IV or oral dose. The major metabolites are an oxidized dicarboxylic acid (M2), the aromatic amine (M1), and the acyl glucuronide (M7). The cytochrome P-450 enzyme system, specifically 2C8 and 3A4, have been shown to be involved in the N-dealkylation of repaglinide to M2 and the further oxidation to M1. Metabolites do not contribute to the glucose-lowering effect of repaglinide.
- Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1).
- Excretion: Within 96 hours after dosing with 14C-repaglinide as a single, oral dose, approximately 90% of the radiolabel was recovered in the feces and approximately 8% in the urine. Only 0.1% of the dose is cleared in the urine as parent compound. The major metabolite (M2) accounted for 60% of the administered dose. Less than 2% of parent drug was recovered in feces.
- Pharmacokinetic Parameters: The pharmacokinetic parameters of repaglinide obtained from a single-dose, crossover study in healthy subjects and from a multiple-dose, parallel, dose-proportionality (0.5, 1, 2 and 4 mg) study in patients with type 2 diabetes are summarized in the following table:
- These data indicate that repaglinide did not accumulate in serum. Clearance of oral repaglinide did not change over the 0.5 - 4 mg dose range, indicating a linear relationship between dose and plasma drug levels.
- Variability of Exposure: Repaglinide AUC after multiple doses of 0.25 to 4 mg with each meal varies over a wide range. The intra-individual and inter-individual coefficients of variation were 36% and 69%, respectively. AUC over the therapeutic dose range included 69 to 1005 ng/mL*hr, but AUC exposure up to 5417 ng/mL*hr was reached in dose escalation studies without apparent adverse consequences.
- Special Populations
- Geriatric: Healthy volunteers were treated with a regimen of 2 mg taken before each of 3 meals. There were no significant differences in repaglinide pharmacokinetics between the group of patients <<65 years of age and a comparably sized group of patients ≥65 years of age.
- Pediatric: No studies have been performed in pediatric patients.
- Gender: A comparison of pharmacokinetics in males and females showed the AUC over the 0.5 mg to 4 mg dose range to be 15% to 70% higher in females with type 2 diabetes. This difference was not reflected in the frequency of hypoglycemic episodes (male: 16%; female: 17%) or other adverse events. With respect to gender, no change in general dosage recommendation is indicated since dosage for each patient should be individualized to achieve optimal clinical response.
- Race: No pharmacokinetic studies to assess the effects of race have been performed, but in a U.S. 1-year study in patients with type 2 diabetes, the blood glucose-lowering effect was comparable between Caucasians (n=297) and African-Americans (n=33). In a U.S. dose-response study, there was no apparent difference in exposure (AUC) between Caucasians (n=74) and Hispanics (n=33).
- Drug-Drug Interactions
- Drug interaction studies performed in healthy volunteers show that PRANDIN had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline, or warfarin. Co-administration of cimetidine with PRANDIN did not significantly alter the absorption and disposition of repaglinide.
- Additionally, the following drugs were studied in healthy volunteers with co-administration of PRANDIN. Listed below are the results:
- CYP2C8 and CYP3A4 Inhibitors/Inducer
- Gemfibrozil and Itraconazole: Co-administration of gemfibrozil (600 mg) and a single dose of 0.25 mg PRANDIN (after 3 days of twice-daily 600 mg gemfibrozil) resulted in an 8.1-fold higher repaglinide AUC and prolonged repaglinide half-life from 1.3 to 3.7 hr. Co-administration with itraconazole and a single dose of 0.25 mg PRANDIN (on the third day of a regimen of 200 mg initial dose, twice-daily 100 mg itraconazole) resulted in a 1.4-fold higher repaglinide AUC. Co-administration of both gemfibrozil and itraconazole with PRANDIN resulted in a 19-fold higher repaglinide AUC and prolonged repaglinide half-life to 6.1 hr. Plasma repaglinide concentration at 7 h increased 28.6-fold with gemfibrozil co-administration and 70.4-fold with the gemfibrozil-itraconazole combination.
- Fenofibrate: Co-administration of 200 mg fenofibrate with a single dose of 0.25 mg repaglinide (after 5 days of once daily fenofibrate 200 mg) resulted in unchanged AUC and Cmax values for both drugs.
- Ketoconazole: Co-administration of 200 mg ketoconazole and a single dose of 2 mg PRANDIN (after 4 days of once daily ketoconazole 200 mg) resulted in a 15% and 16% increase in repaglinide AUC and Cmax, respectively. The increases were from 20.2 ng/mL to 23.5 ng/mL for Cmax and from 38.9 ng/mL*hr to 44.9 ng/mL*hr for AUC.
- Trimethoprim: Co-administration of 160 mg trimethoprim and a single dose of 0.25 mg PRANDIN (after 2 days of twice daily and one dose on the third day of trimethoprim 160 mg) resulted in a 61% and 41% increase in repaglinide AUC and Cmax, respectively. The increase in AUC was from 5.9 ng/mL*hr to 9.6 ng/mL*hr and the increase in Cmax was from 4.7 ng/mL to 6.6 ng/mL.
- Cyclosporine: Co-administration of 100 mg cyclosporine with a single dose of 0.25 mg repaglinide (after two 100 mg doses of cyclosporine twelve hours apart) increased the repaglinide (0.25 mg) Cmax 1.8-fold and the AUC 2.5-fold in an interaction study with healthy volunteers.
- Rifampin: Co-administration of 600 mg rifampin and a single dose of 4 mg PRANDIN (after 6 days of once daily rifampin 600 mg) resulted in a 32% and 26% decrease in repaglinide AUC and Cmax, respectively. The decreases were from 40.4 ng/mL to 29.7 ng/mL for Cmax and from 56.8 ng/mL*hr to 38.7 ng/mL*hr for AUC.
- In another study, co-administration of 600 mg rifampin and a single dose of 4 mg PRANDIN (after 6 days of once daily rifampin 600 mg) resulted in a 48% and 17% decrease in repaglinide median AUC and median Cmax respectively. The median decreases were from 54 ng/mL*hr to 28 ng/mL*hr for AUC and from 35 ng/mL to 29 ng/mL for Cmax. PRANDIN administered by itself (after 7 days of once daily rifampin 600 mg) resulted in an 80% and 79% decrease in repaglinide median AUC and Cmax respectively. The decreases were from 54 ng/mL*hr to 11 ng/mL*hr for AUC and from 35 ng/mL to 7.5 ng/mL for Cmax.
- Levonorgestrel & Ethinyl Estradiol: Co-administration of a combination tablet of 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol administered once daily for 21 days with 2 mg PRANDIN administered three times daily (days 1-4) and a single dose on Day 5 resulted in 20% increases in repaglinide, levonorgestrel, and ethinyl estradiol Cmax. The increase in repaglinide Cmax was from 40.5 ng/mL to 47.4 ng/mL. Ethinyl estradiol AUC parameters were increased by 20%, while repaglinide and levonorgestrel AUC values remained unchanged.
- Simvastatin: Co-administration of 20 mg simvastatin and a single dose of 2 mg PRANDIN (after 4 days of once daily simvastatin 20 mg and three times daily PRANDIN 2 mg) resulted in a 26% increase in repaglinide Cmax from 23.6 ng/mL to 29.7 ng/mL. AUC was unchanged.
- Nifedipine: Co-administration of 10 mg nifedipine with a single dose of 2 mg PRANDIN (after 4 days of three times daily nifedipine 10 mg and three times daily PRANDIN 2 mg) resulted in unchanged AUC and Cmax values for both drugs.
- Clarithromycin: Co-administration of 250 mg clarithromycin and a single dose of 0.25 mg PRANDIN (after 4 days of twice daily clarithromycin 250 mg) resulted in a 40% and 67% increase in repaglinide AUC and Cmax, respectively. The increase in AUC was from 5.3 ng/mL*hr to 7.5 ng/mL*hr and the increase in Cmax was from 4.4 ng/mL to 7.3 ng/mL.
- Deferasirox: Co-administration of deferasirox (30 mg/kg/day for 4 days) and repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to 2.3-fold of control and an increase in Cmax of 62%.
- Renal Insufficiency: Single-dose and steady-state pharmacokinetics of repaglinide were compared between patients with type 2 diabetes and normal renal function (CrCl > 80 mL/min), mild to moderate renal function impairment (CrCl = 40 – 80 mL/min), and severe renal function impairment (CrCl = 20 – 40 mL/min). Both AUC and Cmax of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 ng/mL*hr vs 57.2 ng/mL*hr and 37.5 ng/mL vs 37.7 ng/mL, respectively.) Patients with severely reduced renal function had elevated mean AUC and Cmax values (98.0 ng/mL*hr and 50.7 ng/mL, respectively), but this study showed only a weak correlation between repaglinide levels and creatinine clearance. Initial dose adjustment does not appear to be necessary for patients with mild to moderate renal dysfunction. However, patients with type 2 diabetes who have severe renal function impairment should initiate PRANDIN therapy with the 0.5 mg dose – subsequently, patients should be carefully titrated. Studies were not conducted in patients with creatinine clearances below 20 mL/min or patients with renal failure requiring hemodialysis.
- Hepatic Insufficiency: A single-dose, open-label study was conducted in 12 healthy subjects and 12 patients with chronic liver disease (CLD) classified by Child-Pugh scale and caffeine clearance. Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations of both total and unbound repaglinide than healthy subjects (AUChealthy: 91.6 ng/mL*hr; AUCCLD patients: 368.9 ng/mL*hr; Cmax, healthy: 46.7 ng/mL; Cmax, CLD patients: 105.4 ng/mL). AUC was statistically correlated with caffeine clearance. No difference in glucose profiles was observed across patient groups. Patients with impaired liver function may be exposed to higher concentrations of repaglinide and its associated metabolites than would patients with normal liver function receiving usual doses. Therefore, PRANDIN should be used cautiously in patients with impaired liver function. Longer intervals between dose adjustments should be utilized to allow full assessment of response.
## Nonclinical Toxicology
- Long-term carcinogenicity studies were performed for 104 weeks at doses up to and including 120 mg/kg body weight/day (rats) and 500 mg/kg body weight/day (mice) or approximately 60 and 125 times clinical exposure, respectively, on a mg/m2 basis. No evidence of carcinogenicity was found in mice or female rats. In male rats, there was an increased incidence of benign adenomas of the thyroid and liver. The relevance of these findings to humans is unclear. The no-effect doses for these observations in male rats were 30 mg/kg body weight/day for thyroid tumors and 60 mg/kg body weight/day for liver tumors, which are over 15 and 30 times, respectively, clinical exposure on a mg/m2 basis.
- Repaglinide was non-genotoxic in a battery of in vivo and in vitro studies: Bacterial mutagenesis (Ames test), in vitro forward cell mutation assay in V79 cells (HGPRT), in vitro chromosomal aberration assay in human lymphocytes, unscheduled and replicating DNA synthesis in rat liver, and in vivo mouse and rat micronucleus tests.
- Fertility of male and female rats was unaffected by repaglinide administration at doses up to 80 mg/kg body weight/day (females) and 300 mg/kg body weight/day (males); over 40 times clinical exposure on a mg/m2 basis.
# Clinical Studies
- Monotherapy Trials
- A four-week, double-blind, placebo-controlled dose-response trial was conducted in 138 patients with type 2 diabetes using doses ranging from 0.25 to 4 mg taken with each of three meals. PRANDIN therapy resulted in dose-proportional glucose lowering over the full dose range. Plasma insulin levels increased after meals and reverted toward baseline before the next meal. Most of the fasting blood glucose-lowering effect was demonstrated within 1-2 weeks.
- In a double-blind, placebo-controlled, 3-month dose titration study, PRANDIN or placebo doses for each patient were increased weekly from 0.25 mg through 0.5, 1, and 2 mg, to a maximum of 4 mg, until a fasting plasma glucose (FPG) level <<160 mg/dL was achieved or the maximum dose reached. The dose that achieved the targeted control or the maximum dose was continued to end of study. FPG and 2-hour post-prandial glucose (PPG) increased in patients receiving placebo and decreased in patients treated with repaglinide. Differences between the repaglinide- and placebo-treated groups were -61 mg/dL (FPG) and -104 mg/dL (PPG). The between-group change in HbA1c, which reflects long-term glycemic control, was 1.7% units.
- Another double-blind, placebo-controlled trial was carried out in 362 patients treated for 24 weeks. The efficacy of 1 and 4 mg preprandial doses was demonstrated by lowering of fasting blood glucose and by HbA1c at the end of the study. HbA1c for the PRANDIN- treated groups (1 and 4 mg groups combined) at the end of the study was decreased compared to the placebo-treated group in previously naïve patients and in patients previously treated with oral hypoglycemic agents by 2.1% units and 1.7% units, respectively. In this fixed-dose trial, patients who were naïve to oral hypoglycemic agent therapy and patients in relatively good glycemic control at baseline (HbA1c below 8%) showed greater blood glucose-lowering including a higher frequency of hypoglycemia. Patients who were previously treated and who had baseline HbA1c ≥ 8% reported hypoglycemia at the same rate as patients randomized to placebo. There was no average gain in body weight when patients previously treated with oral hypoglycemic agents were switched to PRANDIN. The average weight gain in patients treated with PRANDIN and not previously treated with sulfonylurea drugs was 3.3%.
- The dosing of PRANDIN relative to meal-related insulin release was studied in three trials including 58 patients. Glycemic control was maintained during a period in which the meal and dosing pattern was varied (2, 3 or 4 meals per day; before meals x 2, 3, or 4) compared with a period of 3 regular meals and 3 doses per day (before meals x 3). It was also shown that PRANDIN can be administered at the start of a meal, 15 minutes before, or 30 minutes before the meal with the same blood glucose-lowering effect.
- PRANDIN was compared to other insulin secretagogues in 1-year controlled trials to demonstrate comparability of efficacy and safety. Hypoglycemia was reported in 16% of 1228 PRANDIN patients, 20% of 417 glyburide patients, and 19% of 81 glipizide patients. Of PRANDIN-treated patients with symptomatic hypoglycemia, none developed coma or required hospitalization.
- Combination Trials
- PRANDIN was studied in combination with metformin in 83 patients not satisfactorily controlled on exercise, diet, and metformin alone. PRANDIN dosage was titrated for 4 to 8 weeks, followed by a 3-month maintenance period. Combination therapy with PRANDIN and metformin resulted in significantly greater improvement in glycemic control as compared to repaglinide or metformin monotherapy. HbA1c was improved by 1% unit and FPG decreased by an additional 35 mg/dL. In this study where metformin dosage was kept constant, the combination therapy of PRANDIN and metformin showed dose-sparing effects with respect to PRANDIN. The greater efficacy response of the combination group was achieved at a lower daily repaglinide dosage than in the PRANDIN monotherapy group (see Table).
- A combination therapy regimen of PRANDIN and pioglitazone was compared to monotherapy with either agent alone in a 24-week trial that enrolled 246 patients previously treated with sulfonylurea or metformin monotherapy (HbA1c > 7.0%). Numbers of patients treated were: PRANDIN (N = 61), pioglitazone (N = 62), combination (N = 123). PRANDIN dosage was titrated during the first 12 weeks, followed by a 12-week maintenance period. Combination therapy resulted in significantly greater improvement in glycemic control as compared to monotherapy (figure below). The changes from baseline for completers in FPG (mg/dL) and HbA1c (%), respectively were: -39.8 and -0.1 for PRANDIN, -35.3 and -0.1 for pioglitazone and -92.4 and -1.9 for the combination. In this study where pioglitazone dosage was kept constant, the combination therapy group showed dose-sparing effects with respect to PRANDIN (see figure legend). The greater efficacy response of the combination group was achieved at a lower daily repaglinide dosage than in the PRANDIN monotherapy group. Mean weight increases associated with combination, PRANDIN and pioglitazone therapy were 5.5 kg, 0.3 kg, and 2.0 kg respectively.
- HbA1c values by study week for patients who completed study (combination, N = 101; PRANDIN, N = 35, pioglitazone, N = 26).
- Subjects with FPG above 270 mg/dL were withdrawn from the study.
- Pioglitazone dose: fixed at 30 mg/day; PRANDIN median final dose: 6 mg/day for combination and 10 mg/day for monotherapy.
- A combination therapy regimen of PRANDIN and rosiglitazone was compared to monotherapy with either agent alone in a 24-week trial that enrolled 252 patients previously treated with sulfonylurea or metformin (HbA1c > 7.0%). Combination therapy resulted in significantly greater improvement in glycemic control as compared to monotherapy (table below). The glycemic effects of the combination therapy were dose-sparing with respect to both total daily PRANDIN dosage and total daily rosiglitazone dosage (see table legend). A greater efficacy response of the combination therapy group was achieved with half the median daily dose of PRANDIN and rosiglitazone, as compared to the respective monotherapy groups. Mean weight change associated with combination therapy was greater than that of PRANDIN monotherapy.
# How Supplied
- PRANDIN (repaglinide) tablets are supplied as unscored, biconvex tablets available in 0.5 mg (white), 1 mg (yellow) and 2 mg (peach) strengths. Tablets are embossed with the Novo Nordisk (Apis) bull symbol and colored to indicate strength.
- Do not store above 25° C (77° F).
- Protect from moisture. Keep bottles tightly closed.
- Dispense in tight containers with safety closures.
## Storage
There is limited information regarding Repaglinide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of the potential risks and advantages of PRANDIN and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose and HbA1c. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development and concomitant administration of other glucose-lowering drugs should be explained to patients and responsible family members. Primary and secondary failure should also be explained.
- Patients should be instructed to take PRANDIN before meals (2, 3, or 4 times a day preprandially). Doses are usually taken within 15 minutes of the meal but time may vary from immediately preceding the meal to as long as 30 minutes before the meal. Patients who skip a meal (or add an extra meal) should be instructed to skip (or add) a dose for that meal.
# Precautions with Alcohol
- Alcohol-Repaglinide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PRANDIN®
# Look-Alike Drug Names
- Prandin® — Avandia®
# Drug Shortage Status
# Price | Repaglinide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Repaglinide is an antidiabetic agent that is FDA approved for the {{{indicationType}}} of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia, diarrhea, arthralgia, headache, sinusitis, and upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Starting Dose
- For patients not previously treated or whose HbA1c is < 8%, the starting dose should be 0.5 mg with each meal. For patients previously treated with blood glucose-lowering drugs and whose HbA1c is ≥ 8%, the initial dose is 1 or 2 mg with each meal preprandially.
- Dose Adjustment
- Dosing adjustments should be determined by blood glucose response, usually fasting blood glucose. Postprandial glucose levels testing may be clinically helpful in patients whose pre-meal blood glucose levels are satisfactory but whose overall glycemic control (HbA1c) is inadequate. The preprandial dose should be doubled up to 4 mg with each meal until satisfactory blood glucose response is achieved. At least one week should elapse to assess response after each dose adjustment.
- The recommended dose range is 0.5 mg to 4 mg taken with meals. PRANDIN may be dosed preprandially 2, 3, or 4 times a day in response to changes in the patient’s meal pattern. The maximum recommended daily dose is 16 mg.
- Patient Management
- Long-term efficacy should be monitored by measurement of HbA1c levels approximately every 3 months. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia or hyperglycemia. Patients who do not adhere to their prescribed dietary and drug regimen are more prone to exhibit unsatisfactory response to therapy including hypoglycemia. When hypoglycemia occurs in patients taking a combination of PRANDIN and a thiazolidinedione or PRANDIN and metformin, the dose of PRANDIN should be reduced.
- Patients Receiving Other Oral Hypoglycemic Agents
- When PRANDIN is used to replace therapy with other oral hypoglycemic agents, PRANDIN may be started on the day after the final dose is given. Patients should then be observed carefully for hypoglycemia due to potential overlapping of drug effects. When transferred from longer half-life sulfonylurea agents (e.g., chlorpropamide) to repaglinide, close monitoring may be indicated for up to one week or longer.
- Combination Therapy
- If PRANDIN monotherapy does not result in adequate glycemic control, metformin or a thiazolidinedione may be added. If metformin or thiazolidinedione monotherapy does not provide adequate control, PRANDIN may be added. The starting dose and dose adjustments for PRANDIN combination therapy is the same as for PRANDIN monotherapy. The dose of each drug should be carefully adjusted to determine the minimal dose required to achieve the desired pharmacologic effect. Failure to do so could result in an increase in the incidence of hypoglycemic episodes. Appropriate monitoring of FPG and HbA1c measurements should be used to ensure that the patient is not subjected to excessive drug exposure or increased probability of secondary drug failure.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Repaglinide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Repaglinide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Repaglinide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Repaglinide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Repaglinide in pediatric patients.
# Contraindications
- Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
- Type 1 diabetes.
- Co-administration of gemfibrozil.
- Known hypersensitivity to the drug or its inactive ingredients.
# Warnings
### Precautions
- General:
- PRANDIN is not indicated for use in combination with NPH-insulin.
- Macrovascular Outcomes:
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with PRANDIN or any other anti-diabetic drug.
- Hypoglycemia
- All oral blood glucose-lowering drugs including repaglinide are capable of producing hypoglycemia. Proper patient selection, dosage, and instructions to the patients are important to avoid hypoglycemic episodes. Hepatic insufficiency may cause elevated repaglinide blood levels and may diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemia. Elderly, debilitated, or malnourished patients, and those with adrenal, pituitary, hepatic, or severe renal insufficiency may be particularly susceptible to the hypoglycemic action of glucose-lowering drugs.
- Hypoglycemia may be difficult to recognize in the elderly and in people taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.
- The frequency of hypoglycemia is greater in patients with type 2 diabetes who have not been previously treated with oral blood glucose-lowering drugs (naïve) or whose HbA1c is less than 8%. PRANDIN should be administered with meals to lessen the risk of hypoglycemia.
- Loss of Control of Blood Glucose: When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of glycemic control may occur. At such times, it may be necessary to discontinue PRANDIN and administer insulin. The effectiveness of any hypoglycemic drug in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when the drug is first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.
# Adverse Reactions
## Clinical Trials Experience
- PRANDIN has been administered to 2931 individuals during clinical trials. Approximately 1500 of these individuals with type 2 diabetes have been treated for at least 3 months, 1000 for at least 6 months, and 800 for at least 1 year. The majority of these individuals (1228) received PRANDIN in one of five 1-year, active-controlled trials. The comparator drugs in these 1-year trials were oral sulfonylurea drugs (SU) including glyburide and glipizide. Over one year, 13% of PRANDIN patients were discontinued due to adverse events, as were 14% of SU patients. The most common adverse events leading to withdrawal were hyperglycemia, hypoglycemia, and related symptoms. Mild or moderate hypoglycemia occurred in 16% of PRANDIN patients, 20% of glyburide patients, and 19% of glipizide patients.
- The table below lists common adverse events for PRANDIN patients compared to both placebo (in trials 12 to 24 weeks duration) and to glyburide and glipizide in one year trials. The adverse event profile of PRANDIN was generally comparable to that for sulfonylurea drugs (SU).
- Cardiovascular Events
- In one-year trials comparing PRANDIN to sulfonylurea drugs, the incidence of angina was comparable (1.8%) for both treatments, with an incidence of chest pain of 1.8% for PRANDIN and 1.0% for sulfonylureas. The incidence of other selected cardiovascular events (hypertension, abnormal EKG, myocardial infarction, arrhythmias, and palpitations) was ≤ 1% and not different between PRANDIN and the comparator drugs.
- The incidence of total serious cardiovascular adverse events, including ischemia, was higher for repaglinide (4%) than for sulfonylurea drugs (3%) in controlled comparator clinical trials. In 1-year controlled trials, PRANDIN treatment was not associated with excess mortality when compared to the rates observed with other oral hypoglycemic agent therapies.
- Seven controlled clinical trials included PRANDIN combination therapy with NPH-insulin (n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH-insulin or PRANDIN plus metformin) (n=120). There were six serious adverse events of myocardial ischemia in patients treated with PRANDIN plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study.
- Infrequent Adverse Events (<1% of Patients)
- Less common adverse clinical or laboratory events observed in clinical trials included elevated liver enzymes, thrombocytopenia, leukopenia, and anaphylactoid reactions.
- Although no causal relationship with repaglinide has been established, postmarketing experience includes reports of the following rare adverse events: alopecia, hemolytic anemia, pancreatitis, Stevens-Johnson Syndrome, and severe hepatic dysfunction including jaundice and hepatitis.
- Combination Therapy with Thiazolidinediones
- During 24-week treatment clinical trials of PRANDIN-rosiglitazone or PRANDIN-pioglitazone combination therapy (a total of 250 patients in combination therapy), hypoglycemia (blood glucose < 50 mg/dL) occurred in 7% of combination therapy patients in comparison to 7% for PRANDIN monotherapy, and 2% for thiazolidinedione monotherapy.
- Peripheral edema was reported in 12 out of 250 PRANDIN-thiazolidinedione combination therapy patients and 3 out of 124 thiazolidinedione monotherapy patients, with no cases reported in these trials for PRANDIN monotherapy. When corrected for dropout rates of the treatment groups, the percentage of patients having events of peripheral edema per 24 weeks of treatment were 5% for PRANDIN-thiazolidinedione combination therapy, and 4% for thiazolidinedione monotherapy. There were reports in 2 of 250 patients (0.8%) treated with PRANDIN-thiazolidinedione therapy of episodes of edema with congestive heart failure. Both patients had a prior history of coronary artery disease and recovered after treatment with diuretic agents. No comparable cases in the monotherapy treatment groups were reported.
- Mean change in weight from baseline was +4.9 kg for PRANDIN-thiazolidinedione therapy. There were no patients on PRANDIN-thiazolidinedione combination therapy who had elevations of liver transaminases (defined as 3 times the upper limit of normal levels).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Repaglinide in the drug label.
# Drug Interactions
- In vitro data indicate that PRANDIN is metabolized by cytochrome P450 enzymes 2C8 and 3A4. Consequently, repaglinide metabolism may be altered by drugs which influence these cytochrome P450 enzyme systems via induction and inhibition. Caution should therefore be used in patients who are on PRANDIN and taking inhibitors and/or inducers of CYP2C8 and CYP3A4. The effect may be very significant if both enzymes are inhibited at the same time resulting in a substantial increase in repaglinide plasma concentrations. Drugs that are known to inhibit CYP3A4 include antifungal agents like ketoconazole, itraconazole, and antibacterial agents like erythromycin. Drugs that are known to inhibit CYP2C8 include agents like trimethoprim, gemfibrozil and montelukast. Drugs that induce the CYP3A4 and/or 2C8 enzyme systems include rifampin, barbiturates, and carbamezapine.
- Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1). Drugs that inhibit OATP1B1 (e.g. cyclosporine) may likewise have the potential to increase plasma concentrations of repaglinide.
- In vivo data from a study that evaluated the co-administration of a cytochrome P450 enzyme 3A4 inhibitor, clarithromycin, with PRANDIN resulted in a clinically significant increase in repaglinide plasma levels. In addition, an increase in repaglinide plasma levels was observed in studies that evaluated the co-administration of PRANDIN with trimethoprim and PRANDIN with deferasirox, both cytochrome P-450 enzyme 2C8 inhibitors. These increases in repaglinide plasma levels may necessitate a PRANDIN dose adjustment.
- Gemfibrozil significantly increased PRANDIN exposure. Therefore, patients should not take PRANDIN with gemfibrozil.
- The hypoglycemic action of oral blood glucose-lowering agents may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, cyclosporine, chloramphenicol, coumarins, probenecid, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving oral blood glucose-lowering agents, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving oral blood glucose-lowering agents, the patient should be observed closely for loss of glycemic control.
- Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When these drugs are administered to a patient receiving oral blood glucose-lowering agents, the patient should be observed for loss of glycemic control. When these drugs are withdrawn from a patient receiving oral blood glucose-lowering agents, the patient should be observed closely for hypoglycemia.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Teratogenic Effects
- Safety in pregnant women has not been established. Repaglinide was not teratogenic in rats or rabbits at doses 40 times (rats) and approximately 0.8 times (rabbit) clinical exposure (on a mg/m2 basis) throughout pregnancy. Because animal reproduction studies are not always predictive of human response, PRANDIN should be used during pregnancy only if it is clearly needed.
- Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
- Nonteratogenic Effects
- Offspring of rat dams exposed to repaglinide at 15 times clinical exposure on a mg/m2 basis during days 17 to 22 of gestation and during lactation developed nonteratogenic skeletal deformities consisting of shortening, thickening, and bending of the humerus during the postnatal period. This effect was not seen at doses up to 2.5 times clinical exposure (on a mg/m2 basis) on days 1 to 22 of pregnancy or at higher doses given during days 1 to 16 of pregnancy. Relevant human exposure has not occurred to date and therefore the safety of PRANDIN administration throughout pregnancy or lactation cannot be established.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Repaglinide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Repaglinide during labor and delivery.
### Nursing Mothers
- In rat reproduction studies, measurable levels of repaglinide were detected in the breast milk of the dams and lowered blood glucose levels were observed in the pups. Cross fostering studies indicated that skeletal changes could be induced in control pups nursed by treated dams, although this occurred to a lesser degree than those pups treated in utero. Although it is not known whether repaglinide is excreted in human milk some oral agents are known to be excreted by this route. Because the potential for hypoglycemia in nursing infants may exist, and because of the effects on nursing animals, a decision should be made as to whether PRANDIN should be discontinued in nursing mothers, or if mothers should discontinue nursing. If PRANDIN is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
### Pediatric Use
- No studies have been performed in pediatric patients.
### Geriatic Use
- In repaglinide clinical studies of 24 weeks or greater duration, 415 patients were over 65 years of age. In one-year, active-controlled trials, no differences were seen in effectiveness or adverse events between these subjects and those less than 65 other than the expected age-related increase in cardiovascular events observed for PRANDIN and comparator drugs. There was no increase in frequency or severity of hypoglycemia in older subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals to PRANDIN therapy cannot be ruled out.
### Gender
There is no FDA guidance on the use of Repaglinide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Repaglinide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Repaglinide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Repaglinide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Repaglinide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Repaglinide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Repaglinide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Repaglinide in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- In a clinical trial, patients received increasing doses of PRANDIN up to 80 mg a day for 14 days. There were few adverse effects other than those associated with the intended effect of lowering blood glucose. Hypoglycemia did not occur when meals were given with these high doses.
### Management
- Hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring may continue until the physician is assured that the patient is out of danger. Patients should be closely monitored for a minimum of 24 to 48 hours, since hypoglycemia may recur after apparent clinical recovery. There is no evidence that repaglinide is dialyzable using hemodialysis.
- Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Repaglinide in the drug label.
# Pharmacology
## Mechanism of Action
- Repaglinide lowers blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent upon functioning beta (ß) cells in the pancreatic islets. Insulin release is glucose-dependent and diminishes at low glucose concentrations.
- Repaglinide closes ATP-dependent potassium channels in the ß-cell membrane by binding at characterizable sites. This potassium channel blockade depolarizes the ß-cell, which leads to an opening of calcium channels. The resulting increased calcium influx induces insulin secretion. The ion channel mechanism is highly tissue selective with low affinity for heart and skeletal muscle.
## Structure
- PRANDIN® (repaglinide) is an oral blood glucose-lowering drug of the meglitinide class used in the management of type 2 diabetes mellitus (also known as non-insulin dependent diabetes mellitus or NIDDM). Repaglinide, S(+)2-ethoxy-4(2((3-methyl-1-(2-(1-piperidinyl) phenyl)-butyl) amino)-2-oxoethyl) benzoic acid, is chemically unrelated to the oral sulfonylurea insulin secretagogues.
- The structural formula is as shown below:
- Repaglinide is a white to off-white powder with molecular formula C27 H36 N2 O4 and a molecular weight of 452.6. PRANDIN tablets contain 0.5 mg, 1 mg, or 2 mg of repaglinide. In addition each tablet contains the following inactive ingredients: calcium hydrogen phosphate (anhydrous), microcrystalline cellulose, maize starch, polacrilin potassium, povidone, glycerol (85%), magnesium stearate, meglumine, and poloxamer. The 1 mg and 2 mg tablets contain iron oxides (yellow and red, respectively) as coloring agents.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Repaglinide in the drug label.
## Pharmacokinetics
- Absorption: After oral administration, repaglinide is rapidly and completely absorbed from the gastrointestinal tract. After single and multiple oral doses in healthy subjects or in patients, peak plasma drug levels (Cmax) occur within 1 hour (Tmax). Repaglinide is rapidly eliminated from the blood stream with a half-life of approximately 1 hour. The mean absolute bioavailability is 56%. When repaglinide was given with food, the mean Tmax was not changed, but the mean Cmax and AUC (area under the time/plasma concentration curve) were decreased 20% and 12.4%, respectively.
- Distribution: After intravenous (IV) dosing in healthy subjects, the volume of distribution at steady state (Vss) was 31 L, and the total body clearance (CL) was 38 L/h. Protein binding and binding to human serum albumin was greater than 98%.
- Metabolism: Repaglinide is completely metabolized by oxidative biotransformation and direct conjugation with glucuronic acid after either an IV or oral dose. The major metabolites are an oxidized dicarboxylic acid (M2), the aromatic amine (M1), and the acyl glucuronide (M7). The cytochrome P-450 enzyme system, specifically 2C8 and 3A4, have been shown to be involved in the N-dealkylation of repaglinide to M2 and the further oxidation to M1. Metabolites do not contribute to the glucose-lowering effect of repaglinide.
- Repaglinide appears to be a substrate for active hepatic uptake transporter (organic anion transporting protein OATP1B1).
- Excretion: Within 96 hours after dosing with 14C-repaglinide as a single, oral dose, approximately 90% of the radiolabel was recovered in the feces and approximately 8% in the urine. Only 0.1% of the dose is cleared in the urine as parent compound. The major metabolite (M2) accounted for 60% of the administered dose. Less than 2% of parent drug was recovered in feces.
- Pharmacokinetic Parameters: The pharmacokinetic parameters of repaglinide obtained from a single-dose, crossover study in healthy subjects and from a multiple-dose, parallel, dose-proportionality (0.5, 1, 2 and 4 mg) study in patients with type 2 diabetes are summarized in the following table:
- These data indicate that repaglinide did not accumulate in serum. Clearance of oral repaglinide did not change over the 0.5 - 4 mg dose range, indicating a linear relationship between dose and plasma drug levels.
- Variability of Exposure: Repaglinide AUC after multiple doses of 0.25 to 4 mg with each meal varies over a wide range. The intra-individual and inter-individual coefficients of variation were 36% and 69%, respectively. AUC over the therapeutic dose range included 69 to 1005 ng/mL*hr, but AUC exposure up to 5417 ng/mL*hr was reached in dose escalation studies without apparent adverse consequences.
- Special Populations
- Geriatric: Healthy volunteers were treated with a regimen of 2 mg taken before each of 3 meals. There were no significant differences in repaglinide pharmacokinetics between the group of patients <<65 years of age and a comparably sized group of patients ≥65 years of age.
- Pediatric: No studies have been performed in pediatric patients.
- Gender: A comparison of pharmacokinetics in males and females showed the AUC over the 0.5 mg to 4 mg dose range to be 15% to 70% higher in females with type 2 diabetes. This difference was not reflected in the frequency of hypoglycemic episodes (male: 16%; female: 17%) or other adverse events. With respect to gender, no change in general dosage recommendation is indicated since dosage for each patient should be individualized to achieve optimal clinical response.
- Race: No pharmacokinetic studies to assess the effects of race have been performed, but in a U.S. 1-year study in patients with type 2 diabetes, the blood glucose-lowering effect was comparable between Caucasians (n=297) and African-Americans (n=33). In a U.S. dose-response study, there was no apparent difference in exposure (AUC) between Caucasians (n=74) and Hispanics (n=33).
- Drug-Drug Interactions
- Drug interaction studies performed in healthy volunteers show that PRANDIN had no clinically relevant effect on the pharmacokinetic properties of digoxin, theophylline, or warfarin. Co-administration of cimetidine with PRANDIN did not significantly alter the absorption and disposition of repaglinide.
- Additionally, the following drugs were studied in healthy volunteers with co-administration of PRANDIN. Listed below are the results:
- CYP2C8 and CYP3A4 Inhibitors/Inducer
- Gemfibrozil and Itraconazole: Co-administration of gemfibrozil (600 mg) and a single dose of 0.25 mg PRANDIN (after 3 days of twice-daily 600 mg gemfibrozil) resulted in an 8.1-fold higher repaglinide AUC and prolonged repaglinide half-life from 1.3 to 3.7 hr. Co-administration with itraconazole and a single dose of 0.25 mg PRANDIN (on the third day of a regimen of 200 mg initial dose, twice-daily 100 mg itraconazole) resulted in a 1.4-fold higher repaglinide AUC. Co-administration of both gemfibrozil and itraconazole with PRANDIN resulted in a 19-fold higher repaglinide AUC and prolonged repaglinide half-life to 6.1 hr. Plasma repaglinide concentration at 7 h increased 28.6-fold with gemfibrozil co-administration and 70.4-fold with the gemfibrozil-itraconazole combination.
- Fenofibrate: Co-administration of 200 mg fenofibrate with a single dose of 0.25 mg repaglinide (after 5 days of once daily fenofibrate 200 mg) resulted in unchanged AUC and Cmax values for both drugs.
- Ketoconazole: Co-administration of 200 mg ketoconazole and a single dose of 2 mg PRANDIN (after 4 days of once daily ketoconazole 200 mg) resulted in a 15% and 16% increase in repaglinide AUC and Cmax, respectively. The increases were from 20.2 ng/mL to 23.5 ng/mL for Cmax and from 38.9 ng/mL*hr to 44.9 ng/mL*hr for AUC.
- Trimethoprim: Co-administration of 160 mg trimethoprim and a single dose of 0.25 mg PRANDIN (after 2 days of twice daily and one dose on the third day of trimethoprim 160 mg) resulted in a 61% and 41% increase in repaglinide AUC and Cmax, respectively. The increase in AUC was from 5.9 ng/mL*hr to 9.6 ng/mL*hr and the increase in Cmax was from 4.7 ng/mL to 6.6 ng/mL.
- Cyclosporine: Co-administration of 100 mg cyclosporine with a single dose of 0.25 mg repaglinide (after two 100 mg doses of cyclosporine twelve hours apart) increased the repaglinide (0.25 mg) Cmax 1.8-fold and the AUC 2.5-fold in an interaction study with healthy volunteers.
- Rifampin: Co-administration of 600 mg rifampin and a single dose of 4 mg PRANDIN (after 6 days of once daily rifampin 600 mg) resulted in a 32% and 26% decrease in repaglinide AUC and Cmax, respectively. The decreases were from 40.4 ng/mL to 29.7 ng/mL for Cmax and from 56.8 ng/mL*hr to 38.7 ng/mL*hr for AUC.
- In another study, co-administration of 600 mg rifampin and a single dose of 4 mg PRANDIN (after 6 days of once daily rifampin 600 mg) resulted in a 48% and 17% decrease in repaglinide median AUC and median Cmax respectively. The median decreases were from 54 ng/mL*hr to 28 ng/mL*hr for AUC and from 35 ng/mL to 29 ng/mL for Cmax. PRANDIN administered by itself (after 7 days of once daily rifampin 600 mg) resulted in an 80% and 79% decrease in repaglinide median AUC and Cmax respectively. The decreases were from 54 ng/mL*hr to 11 ng/mL*hr for AUC and from 35 ng/mL to 7.5 ng/mL for Cmax.
- Levonorgestrel & Ethinyl Estradiol: Co-administration of a combination tablet of 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol administered once daily for 21 days with 2 mg PRANDIN administered three times daily (days 1-4) and a single dose on Day 5 resulted in 20% increases in repaglinide, levonorgestrel, and ethinyl estradiol Cmax. The increase in repaglinide Cmax was from 40.5 ng/mL to 47.4 ng/mL. Ethinyl estradiol AUC parameters were increased by 20%, while repaglinide and levonorgestrel AUC values remained unchanged.
- Simvastatin: Co-administration of 20 mg simvastatin and a single dose of 2 mg PRANDIN (after 4 days of once daily simvastatin 20 mg and three times daily PRANDIN 2 mg) resulted in a 26% increase in repaglinide Cmax from 23.6 ng/mL to 29.7 ng/mL. AUC was unchanged.
- Nifedipine: Co-administration of 10 mg nifedipine with a single dose of 2 mg PRANDIN (after 4 days of three times daily nifedipine 10 mg and three times daily PRANDIN 2 mg) resulted in unchanged AUC and Cmax values for both drugs.
- Clarithromycin: Co-administration of 250 mg clarithromycin and a single dose of 0.25 mg PRANDIN (after 4 days of twice daily clarithromycin 250 mg) resulted in a 40% and 67% increase in repaglinide AUC and Cmax, respectively. The increase in AUC was from 5.3 ng/mL*hr to 7.5 ng/mL*hr and the increase in Cmax was from 4.4 ng/mL to 7.3 ng/mL.
- Deferasirox: Co-administration of deferasirox (30 mg/kg/day for 4 days) and repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to 2.3-fold of control and an increase in Cmax of 62%.
- Renal Insufficiency: Single-dose and steady-state pharmacokinetics of repaglinide were compared between patients with type 2 diabetes and normal renal function (CrCl > 80 mL/min), mild to moderate renal function impairment (CrCl = 40 – 80 mL/min), and severe renal function impairment (CrCl = 20 – 40 mL/min). Both AUC and Cmax of repaglinide were similar in patients with normal and mild to moderately impaired renal function (mean values 56.7 ng/mL*hr vs 57.2 ng/mL*hr and 37.5 ng/mL vs 37.7 ng/mL, respectively.) Patients with severely reduced renal function had elevated mean AUC and Cmax values (98.0 ng/mL*hr and 50.7 ng/mL, respectively), but this study showed only a weak correlation between repaglinide levels and creatinine clearance. Initial dose adjustment does not appear to be necessary for patients with mild to moderate renal dysfunction. However, patients with type 2 diabetes who have severe renal function impairment should initiate PRANDIN therapy with the 0.5 mg dose – subsequently, patients should be carefully titrated. Studies were not conducted in patients with creatinine clearances below 20 mL/min or patients with renal failure requiring hemodialysis.
- Hepatic Insufficiency: A single-dose, open-label study was conducted in 12 healthy subjects and 12 patients with chronic liver disease (CLD) classified by Child-Pugh scale and caffeine clearance. Patients with moderate to severe impairment of liver function had higher and more prolonged serum concentrations of both total and unbound repaglinide than healthy subjects (AUChealthy: 91.6 ng/mL*hr; AUCCLD patients: 368.9 ng/mL*hr; Cmax, healthy: 46.7 ng/mL; Cmax, CLD patients: 105.4 ng/mL). AUC was statistically correlated with caffeine clearance. No difference in glucose profiles was observed across patient groups. Patients with impaired liver function may be exposed to higher concentrations of repaglinide and its associated metabolites than would patients with normal liver function receiving usual doses. Therefore, PRANDIN should be used cautiously in patients with impaired liver function. Longer intervals between dose adjustments should be utilized to allow full assessment of response.
## Nonclinical Toxicology
- Long-term carcinogenicity studies were performed for 104 weeks at doses up to and including 120 mg/kg body weight/day (rats) and 500 mg/kg body weight/day (mice) or approximately 60 and 125 times clinical exposure, respectively, on a mg/m2 basis. No evidence of carcinogenicity was found in mice or female rats. In male rats, there was an increased incidence of benign adenomas of the thyroid and liver. The relevance of these findings to humans is unclear. The no-effect doses for these observations in male rats were 30 mg/kg body weight/day for thyroid tumors and 60 mg/kg body weight/day for liver tumors, which are over 15 and 30 times, respectively, clinical exposure on a mg/m2 basis.
- Repaglinide was non-genotoxic in a battery of in vivo and in vitro studies: Bacterial mutagenesis (Ames test), in vitro forward cell mutation assay in V79 cells (HGPRT), in vitro chromosomal aberration assay in human lymphocytes, unscheduled and replicating DNA synthesis in rat liver, and in vivo mouse and rat micronucleus tests.
- Fertility of male and female rats was unaffected by repaglinide administration at doses up to 80 mg/kg body weight/day (females) and 300 mg/kg body weight/day (males); over 40 times clinical exposure on a mg/m2 basis.
# Clinical Studies
- Monotherapy Trials
- A four-week, double-blind, placebo-controlled dose-response trial was conducted in 138 patients with type 2 diabetes using doses ranging from 0.25 to 4 mg taken with each of three meals. PRANDIN therapy resulted in dose-proportional glucose lowering over the full dose range. Plasma insulin levels increased after meals and reverted toward baseline before the next meal. Most of the fasting blood glucose-lowering effect was demonstrated within 1-2 weeks.
- In a double-blind, placebo-controlled, 3-month dose titration study, PRANDIN or placebo doses for each patient were increased weekly from 0.25 mg through 0.5, 1, and 2 mg, to a maximum of 4 mg, until a fasting plasma glucose (FPG) level <<160 mg/dL was achieved or the maximum dose reached. The dose that achieved the targeted control or the maximum dose was continued to end of study. FPG and 2-hour post-prandial glucose (PPG) increased in patients receiving placebo and decreased in patients treated with repaglinide. Differences between the repaglinide- and placebo-treated groups were -61 mg/dL (FPG) and -104 mg/dL (PPG). The between-group change in HbA1c, which reflects long-term glycemic control, was 1.7% units.
- Another double-blind, placebo-controlled trial was carried out in 362 patients treated for 24 weeks. The efficacy of 1 and 4 mg preprandial doses was demonstrated by lowering of fasting blood glucose and by HbA1c at the end of the study. HbA1c for the PRANDIN- treated groups (1 and 4 mg groups combined) at the end of the study was decreased compared to the placebo-treated group in previously naïve patients and in patients previously treated with oral hypoglycemic agents by 2.1% units and 1.7% units, respectively. In this fixed-dose trial, patients who were naïve to oral hypoglycemic agent therapy and patients in relatively good glycemic control at baseline (HbA1c below 8%) showed greater blood glucose-lowering including a higher frequency of hypoglycemia. Patients who were previously treated and who had baseline HbA1c ≥ 8% reported hypoglycemia at the same rate as patients randomized to placebo. There was no average gain in body weight when patients previously treated with oral hypoglycemic agents were switched to PRANDIN. The average weight gain in patients treated with PRANDIN and not previously treated with sulfonylurea drugs was 3.3%.
- The dosing of PRANDIN relative to meal-related insulin release was studied in three trials including 58 patients. Glycemic control was maintained during a period in which the meal and dosing pattern was varied (2, 3 or 4 meals per day; before meals x 2, 3, or 4) compared with a period of 3 regular meals and 3 doses per day (before meals x 3). It was also shown that PRANDIN can be administered at the start of a meal, 15 minutes before, or 30 minutes before the meal with the same blood glucose-lowering effect.
- PRANDIN was compared to other insulin secretagogues in 1-year controlled trials to demonstrate comparability of efficacy and safety. Hypoglycemia was reported in 16% of 1228 PRANDIN patients, 20% of 417 glyburide patients, and 19% of 81 glipizide patients. Of PRANDIN-treated patients with symptomatic hypoglycemia, none developed coma or required hospitalization.
- Combination Trials
- PRANDIN was studied in combination with metformin in 83 patients not satisfactorily controlled on exercise, diet, and metformin alone. PRANDIN dosage was titrated for 4 to 8 weeks, followed by a 3-month maintenance period. Combination therapy with PRANDIN and metformin resulted in significantly greater improvement in glycemic control as compared to repaglinide or metformin monotherapy. HbA1c was improved by 1% unit and FPG decreased by an additional 35 mg/dL. In this study where metformin dosage was kept constant, the combination therapy of PRANDIN and metformin showed dose-sparing effects with respect to PRANDIN. The greater efficacy response of the combination group was achieved at a lower daily repaglinide dosage than in the PRANDIN monotherapy group (see Table).
- A combination therapy regimen of PRANDIN and pioglitazone was compared to monotherapy with either agent alone in a 24-week trial that enrolled 246 patients previously treated with sulfonylurea or metformin monotherapy (HbA1c > 7.0%). Numbers of patients treated were: PRANDIN (N = 61), pioglitazone (N = 62), combination (N = 123). PRANDIN dosage was titrated during the first 12 weeks, followed by a 12-week maintenance period. Combination therapy resulted in significantly greater improvement in glycemic control as compared to monotherapy (figure below). The changes from baseline for completers in FPG (mg/dL) and HbA1c (%), respectively were: -39.8 and -0.1 for PRANDIN, -35.3 and -0.1 for pioglitazone and -92.4 and -1.9 for the combination. In this study where pioglitazone dosage was kept constant, the combination therapy group showed dose-sparing effects with respect to PRANDIN (see figure legend). The greater efficacy response of the combination group was achieved at a lower daily repaglinide dosage than in the PRANDIN monotherapy group. Mean weight increases associated with combination, PRANDIN and pioglitazone therapy were 5.5 kg, 0.3 kg, and 2.0 kg respectively.
- HbA1c values by study week for patients who completed study (combination, N = 101; PRANDIN, N = 35, pioglitazone, N = 26).
- Subjects with FPG above 270 mg/dL were withdrawn from the study.
- Pioglitazone dose: fixed at 30 mg/day; PRANDIN median final dose: 6 mg/day for combination and 10 mg/day for monotherapy.
- A combination therapy regimen of PRANDIN and rosiglitazone was compared to monotherapy with either agent alone in a 24-week trial that enrolled 252 patients previously treated with sulfonylurea or metformin (HbA1c > 7.0%). Combination therapy resulted in significantly greater improvement in glycemic control as compared to monotherapy (table below). The glycemic effects of the combination therapy were dose-sparing with respect to both total daily PRANDIN dosage and total daily rosiglitazone dosage (see table legend). A greater efficacy response of the combination therapy group was achieved with half the median daily dose of PRANDIN and rosiglitazone, as compared to the respective monotherapy groups. Mean weight change associated with combination therapy was greater than that of PRANDIN monotherapy.
# How Supplied
- PRANDIN (repaglinide) tablets are supplied as unscored, biconvex tablets available in 0.5 mg (white), 1 mg (yellow) and 2 mg (peach) strengths. Tablets are embossed with the Novo Nordisk (Apis) bull symbol and colored to indicate strength.
- Do not store above 25° C (77° F).
- Protect from moisture. Keep bottles tightly closed.
- Dispense in tight containers with safety closures.
## Storage
There is limited information regarding Repaglinide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of the potential risks and advantages of PRANDIN and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose and HbA1c. The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development and concomitant administration of other glucose-lowering drugs should be explained to patients and responsible family members. Primary and secondary failure should also be explained.
- Patients should be instructed to take PRANDIN before meals (2, 3, or 4 times a day preprandially). Doses are usually taken within 15 minutes of the meal but time may vary from immediately preceding the meal to as long as 30 minutes before the meal. Patients who skip a meal (or add an extra meal) should be instructed to skip (or add) a dose for that meal.
# Precautions with Alcohol
- Alcohol-Repaglinide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PRANDIN®[1]
# Look-Alike Drug Names
- Prandin® — Avandia®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Prandin | |
544a9170091805e8cef87003375db6dd0cdc277f | wikidoc | Pravadoline | Pravadoline
Pravadoline (WIN 48098) is an antiinflammatory and analgesic drug, related in structure to NSAIDs such as indometacin. It was developed in the 1980s as a new antiinflammatory and prostaglandin synthesis inhibitor, acting through inhibition of the enzyme cyclooxygenase.
However pravadoline was found to exhibit unexpectedly strong analgesic effects, which appeared at doses ten times smaller than the effective anti-inflammatory dose and so could not be explained by its action as a COX inhibitor. These effects were not blocked by opioid antagonists such as naloxone, and it was eventually discovered that pravadoline represented the first compound from a novel class of cannabinoid agonists, the aminoalkylindoles.
Pravadoline was never developed for use as an analgesic, partly due to toxicity concerns (although these were later shown to be a result of the salt form that the drug had been prepared in rather than from the pravadoline itself), however the discovery of cannabinoid activity in this structurally novel family of drugs led to the discovery of several new cannabinoid agonists, including the drug WIN 55,212-2 which is now widely used in scientific research. | Pravadoline
Pravadoline (WIN 48098) is an antiinflammatory and analgesic drug, related in structure to NSAIDs such as indometacin. It was developed in the 1980s as a new antiinflammatory and prostaglandin synthesis inhibitor, acting through inhibition of the enzyme cyclooxygenase.
However pravadoline was found to exhibit unexpectedly strong analgesic effects, which appeared at doses ten times smaller than the effective anti-inflammatory dose and so could not be explained by its action as a COX inhibitor. These effects were not blocked by opioid antagonists such as naloxone,[1] and it was eventually discovered that pravadoline represented the first compound from a novel class of cannabinoid agonists, the aminoalkylindoles.[2]
Pravadoline was never developed for use as an analgesic, partly due to toxicity concerns (although these were later shown to be a result of the salt form that the drug had been prepared in rather than from the pravadoline itself),[3] however the discovery of cannabinoid activity in this structurally novel family of drugs led to the discovery of several new cannabinoid agonists, including the drug WIN 55,212-2 which is now widely used in scientific research.[4][5]
Template:Pharma-stub | https://www.wikidoc.org/index.php/Pravadoline | |
406e58be519d6d62c138fc0b96de4b765be10cf2 | wikidoc | Pravastatin | Pravastatin
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# Overview
Pravastatin is a HMG-CoA reductase inhibitor that is FDA approved for the treatment of hypercholesterolemia and prevention of cardiovascular disease. Common adverse reactions include rash, diarrhea, nausea, vomiting, musculoskeletal pain, headache, cough, rhinitis and upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Indication
- Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
### Prevention of Cardiovascular Disease
- Indication
- In hypercholesterolemic patients without clinically evident coronary heart disease (CHD), pravastatin sodium tablets USP are indicated to:
- Reduce the risk of myocardial infarction (MI).
- Reduce the risk of undergoing myocardial revascularization procedures.
- Reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes.
General Dosing Information
- The patient should be placed on a standard cholesterol-lowering diet before receiving pravastatin sodium tablets and should continue on this diet during treatment with pravastatin sodium tablets.
- Recommended starting dosage: 40 mg PO qd.
- If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended.
- In patients with significant renal impairment,
- Starting dosage: 10 mg PO qd. Pravastatin sodium tablets can be administered orally as a single dose at any time of the day, with or without food.
- Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines.
### Concomitant Lipid-Altering Therapy
Dosing information
- Pravastatin sodium tablets may be used with bile acid resins. When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol) and pravastatin, pravastatin sodium tablets should be given either 1 hour or more before or at least 4 hours following the resin.
### Dosage in Patients Taking Cyclosporine
Dosing information
- In patients taking immunosuppressive drugs such as cyclosporine concomitantly with pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and titration to higher doses should be done with caution.
- Most patients treated with this combination received a maximum pravastatin sodium dose of 20 mg/day.
- In patients taking cyclosporine: less than 20 mg PO qd.
### Dosage in Patients Taking Clarithromycin
Dosing information
- In patients taking clarithromycin: less than 40 mg PO qd .
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Pravastatin in adult patients.
### Non–Guideline-Supported Use
### Indications
- Acute coronary syndrome
- Atrial fibrillation
- Coronary artery bypass graft
- Heart failure
- Kidney disease
- Radiographic contrast agent nephropathy
- Nephrotic syndrome
- Percutaneous coronary intervention
- Restenotic lesion of coronary artery
- Transient ischemic attack
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Hypercholesterolemia
Dosing information
- Children (Ages 8 to 13 Years, Inclusive)
- Recommended dose: 20 mg PO qd in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population.
- Adolescents (Ages 14 to 18 Years)
- Recommended starting dose: 40 mg PO qd in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population.
- Children and adolescents treated with pravastatin should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Pravastatin in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Pravastatin in pediatric patients.
# Contraindications
## Hypersensitivity
- Hypersensitivity to any component of this medication.
## Liver
- Active liver disease or unexplained, persistent elevations of serum transaminases.
## Pregnancy
- Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they are contraindicated during pregnancy and in nursing mothers. PRAVASTATIN SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus.
## Nursing Mothers
- A small amount of pravastatin is excreted in human breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require pravastatin sodium treatment should not breast-feed their infants.
# Warnings
## Skeletal Muscle
- Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
- Uncomplicated myalgia has also been reported in pravastatin-treated patients. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal (ULN), was rare (65), uncontrolled hypothyroidism, and renal impairment.
- There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum CPK, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation and improvement with immunosuppressive agents.
- All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing pravastatin sodium.
- Pravastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Pravastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
- The risk of myopathy during treatment with statins is increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or fibrates. However, neither myopathy nor significant increases in CPK levels have been observed in 3 reports involving a total of 100 post-transplant patients (24 renal and 76 cardiac) treated for up to 2 years concurrently with pravastatin 10 to 40 mg and cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies. Further, in clinical trials involving small numbers of patients who were treated concurrently with pravastatin and niacin, there were no reports of myopathy. Also, myopathy was not reported in a trial of combination pravastatin (40 mg/day) and gemfibrozil (1200 mg/day), although 4 of 75 patients on the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. There was a trend toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared with the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. The use of fibrates alone may occasionally be associated with myopathy. The benefit of further alterations in lipid levels by the combined use of pravastatin sodiumwith fibrates should be carefully weighed against the potential risks of this combination.
- Cases of myopathy, including rhabdomyolysis, have been reported with pravastatin coadministered with colchicine, and caution should be exercised when prescribing pravastatin with colchicine.
## Liver
- Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. In placebo-controlled clinical trials subjects were exposed to pravastatin or placebo. In an analysis of serum transaminase values (ALT, AST), incidences of marked abnormalities were compared between the pravastatin and placebo treatment groups; a marked abnormality was defined as a post-treatment test value greater than 3 times the upper limit of normal for subjects with pretreatment values less than or equal to the upper limit of normal, or 4 times the pretreatment value for subjects with pretreatment values greater than the upper limit of normal but less than 1.5 times the upper limit of normal. Marked abnormalities of ALT or AST occurred with similar low frequency (≤1.2%) in both treatment groups. Overall, clinical trial experience showed that liver function test abnormalities observed during pravastatin therapy were usually asymptomatic, not associated with cholestasis, and did not appear to be related to treatment duration. In a 320-patient placebo-controlled clinical trial, subjects with chronic (>6 months) stable liver disease, due primarily to hepatitis C or nonalcoholic fatty liver disease, were treated with 80 mg pravastatin or placebo for up to 9 months. The primary safety endpoint was the proportion of subjects with at least one ALT ≥2 times the upper limit of normal for those with normal ALT (≤ the upper limit of normal) at baseline or a doubling of the baseline ALT for those with elevated ALT (> the upper limit of normal) at baseline. By Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the prespecified safety ALT endpoint compared to 20 out of 160 (12.5%) subjects receiving placebo. Conclusions regarding liver safety are limited since the study was not large enough to establish similarity between groups (with 95% confidence) in the rates of ALT elevation.
- It is recommended that liver function tests be performed prior to the initiation of therapy and when clinically indicated.
- Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of pravastatin. Caution should be exercised when pravastatin is administered to patients who have a recent (<6 months) history of liver disease, have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol.
- There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with pravastatin sodium, promptly interrupt therapy. If an alternate etiology is not found do not restart pravastatin sodium.
## Endocrine Function
- Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials with pravastatin in males and post-menopausal females were inconsistent with regard to possible effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone response to human chorionic gonadotropin was significantly reduced (p<0.004) after 16 weeks of treatment with 40 mg of pravastatin. However, the percentage of patients showing a ≥50% rise in plasma testosterone after human chorionic gonadotropin stimulation did not change significantly after therapy in these patients. The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if a statin or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may diminish the levels or activity of steroid hormones.
- In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were treated with pravastatin (20 mg in the children aged 8 to 13 years and 40 mg in the adolescents aged 14 to 18 years) for 2 years, there were no detectable differences seen in any of the endocrine parameters (ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol or testosterone ) relative to placebo. There were no detectable differences seen in height and weight changes, testicular volume changes, or Tanner score relative to placebo
# Adverse Reactions
## Clinical Trials Experience
Short-Term Controlled Trials
- In the pravastatin sodium placebo-controlled clinical trials database of 1313 patients (age range 20 to 76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2% Others) with a median treatment duration of 14 weeks, 3.3% of patients on pravastatin sodium and 1.2% patients on placebo discontinued due to adverse events regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: liver function test increased, nausea, anxiety/depression, and dizziness.
- All adverse clinical events (regardless of causality) reported in ≥2% of pravastatin-treated patients in placebo-controlled trials of up to 8 months duration are identified in Table 1:
- The safety and tolerability of pravastatin sodium at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of pravastatin sodium at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN compared to 0 out of 115 patients taking 40 mg of pravastatin.
## Long-Term Controlled Morbidity and Mortality Trials
- In the pravastatin sodium placebo-controlled clinical trials database of 21,483 patients (age range 24 to 75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians, 0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of patients on pravastatin sodium and 9.3% patients on placebo discontinued due to adverse events regardless of causality.
- Adverse event data were pooled from several double-blind, placebo-controlled trials (e.g., West of Scotland Coronary Prevention Study ; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study ; Pravastatin, Lipids and Atherosclerosis in the Carotids study ; Regression Growth Evaluation Statin Study ; and Kuopio Atherosclerosis Prevention Study ) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin group was comparable to that of the placebo group. Patients were exposed to pravastatin for a mean of 4.0 to 5.1 years in, among other trials, WOS, and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these trials represent 47,613 patient-years of exposure to pravastatin. All clinical adverse events (regardless of causality) occurring in ≥2% of patients treated with pravastatin in these studies are identified in Table 2.
- In addition to the events listed above in the long-term trials table, events of probable, possible, or uncertain relationship to study drug that occurred in < 2% of pravastatin-treated patients in the long-term trials included the following:
- Dermatologic: scalp hair abnormality (including alopecia), urticaria.
- Endocrine/Metabolic: sexual dysfunction, libido change.
- General: flushing.
- Immunologic: allergy, edema head/neck.
- Musculoskeletal: muscle weakness.
- Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral neuropathy).
- Special Senses: taste disturbance.
## Laboratory Test Abnormalities
- Increases in ALT, AST values and CPK have been observed.
- Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins.
## Pediatric Patients
- In a 2-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH (n=214; age range 8 to 18.5 years, 53% female, 95% Caucasians, <1% Blacks, 3% Asians, 1% Other), the safety and tolerability profile of pravastatin was generally similar to that of placebo.
## Postmarketing Experience
- In addition to the events reported above, as with other drugs in this class, the following events have been reported rarely during postmarketing experience with pravastatin sodium, regardless of causality assessment:
- Musculoskeletal: myopathy, rhabdomyolysis.
- There have been rare reports of immune-mediated necrotizing myopathy associated with statin use .
- Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy.
- There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
- Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme (including Stevens-Johnson syndrome).
- Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, fatal and non-fatal hepatic failure.
- Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails).
- Renal: urinary abnormality (including dysuria, frequency, nocturia).
- Respiratory: dyspnea.
- Reproductive: gynecomastia.
- Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities.
# Drug Interactions
## Cyclosporine
- The risk of myopathy/rhabdomyolysis is increased with concomitant administration of cyclosporine. Limit pravastatin to 20 mg once daily for concomitant use with cyclosporine.
## Clarithromycin
- The risk of myopathy/rhabdomyolysis is increased with concomitant administration of clarithromycin. Limit pravastatin to 40 mg once daily for concomitant use with clarithromycin.
## Colchicine
- The risk of myopathy/rhabdomyolysis is increased with concomitant administration of colchicine.
## Gemfibrozil
- Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of pravastatin sodium with gemfibrozil should be avoided .
## Other Fibrates
- Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, pravastatin sodium should be administered with caution when used concomitantly with other fibrates.
## Niacin
- The risk of skeletal muscle effects may be enhanced when pravastatin is used in combination with niacin; a reduction in pravastatin sodium dosage should be considered in this setting.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Safety in pregnant women has not been established. Available data in women inadvertently taking pravastatin while pregnant do not suggest any adverse clinical events. However, there are no adequate and well-controlled studies in pregnant women. Therefore, it is not known whether pravastatin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Pravastatin should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus and patients have been informed of the potential hazards.
- Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review2 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with pravastatin sodium during pregnancy , treatment should be immediately discontinued as soon as pregnancy is recognized. Pravastatin sodium should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards.
- Pravastatin was neither embryolethal nor teratogenic in rats at doses up to 1000 mg/kg daily or in rabbits at doses of up to 50 mg/kg daily. These doses resulted in 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day maximum recommended human dose (MRHD) based on surface area (mg/m2).
- In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and skeletal anomalies were observed at 100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m2).
- In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through lactation day 21 (weaning) increased mortality of offspring and developmental delays were observed at 100 mg/kg/day systemic exposure, 12 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m2).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pravastatin in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Pravastatin during labor and delivery.
### Nursing Mothers
- A small amount of pravastatin is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants, women taking pravastatin sodium should not nurse.
- Pravastatin crosses the placenta and is found in fetal tissue at 30% maternal plasma levels following a single 20 mg/kg dose given to pregnant rats on gestation day 18. Similar studies in lactating rats indicate secretion of pravastatin into breast milk at 0.2 to 6.5 times higher levels than maternal plasma at exposures equivalent to 2 times human exposure at the MRHD.
### Pediatric Use
- The safety and effectiveness of pravastatin sodium in children and adolescents from 8 to 18 years of age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that of patients treated with placebo with influenza and headache commonly reported in both treatment groups.Doses greater than 40 mg have not been studied in this population. Children and adolescent females of childbearing potential should be counseled on appropriate contraceptive methods while on pravastatin therapy.
- Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted.
### Geriatic Use
- The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the elderly was similar to that in the overall population. Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients.
- Mean pravastatin AUCs are slightly (25% to 50%) higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and half-life (t½) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly.
- Since advanced age (≥65 years) is a predisposing factor for myopathy, pravastatin sodium should be prescribed with caution in the elderly.
### Gender
- There is no FDA guidance on the use of Pravastatin with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Pravastatin with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Pravastatin in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Pravastatin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Pravastatin in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Pravastatin in patients who are immunocompromised.
### Homozygous Familial Hypercholesterolemia
- Pravastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. In this group of patients, it has been reported that statins are less effective because the patients lack functional LDL receptors.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Pravastatin contains no information regarding drug monitoring.
# IV Compatibility
- There is limited information regarding IV Compatibility of Pravastatin in the drug label.
# Overdosage
- To date, there has been limited experience with overdosage of pravastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required.
# Pharmacology
## Mechanism of Action
- Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces VLDL and TG and increases HDL-C.
## Structure
- Pravastatin sodium tablets USP are one of a class of lipid-lowering compounds, the statins, which reduce cholesterol biosynthesis. These agents are competitive inhibitors of HMG-CoA reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate.
- Pravastatin sodium USP is designated chemically as 1-Naphthalene-heptanoic acid, 1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium salt, ]-.
Structural formula:
C23H35NaO7 MW 446.52
- Pravastatin sodium USP is an odorless, white to yellowish white, hygroscpic powder. It is a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7. It is freely soluble in water and methanol, soluble in alcohol, very slightly soluble in acetonitrile and practically insoluble in ether, ethyl acetate and chloroform.
## Pharmacodynamics
### General
Absorption: Pravastatin sodium is administered orally in the active form. In studies in man, peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals.
- Pravastatin plasma concentrations, including area under the concentration-time curve (AUC), Cmax, and steady-state minimum (Cmin), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose.
- The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin Cmax and AUC following a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively.
- Steady-state AUCs, Cmax, and Cmin plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin sodium tablets.
Distribution: Approximately 50% of the circulating drug is bound to plasma proteins.
Metabolism: The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66).
Excretion: Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation).
Following single dose oral administration of 14C-pravastatin, the radioactive elimination t½ for pravastatin is 1.8 hours in humans.
### Specific Populations
Renal Impairment: A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and Cmax values, respectively, and a 0.61 hour shorter t½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945).
Hepatic Impairment: In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects.
Geriatric: In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old). In both studies, Cmax, Tmax, and t½ values were similar in older and younger subjects.
Pediatric: After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8 to 11 years, N=14) and adolescents (12 to 16 years, N=10), respectively. The corresponding values for Cmax were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability.
### Drug-Drug Interactions
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Pravastatin in the drug label.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m2) and at approximately 4 times the HD, based on AUC.
- In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors.
- No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.
- In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance.
## Animal Toxicology and/or Pharmacology
### CNS Toxicity
- CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at approximately 59 times the HD of 80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other drugs in this class.
- A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.
- When administered to juvenile rats (postnatal days 4 through 80 at 5 to 45 mg/kg/day), no drug related changes were observed at 5 mg/kg/day. At 15 and 45 mg/kg/day, altered body-weight gain was observed during the dosing and 52-day recovery periods as well as slight thinning of the corpus callosum at the end of the recovery period. This finding was not evident in rats examined at the completion of the dosing period and was not associated with any inflammatory or degenerative changes in the brain. The biological relevance of the corpus callosum finding is uncertain due to the absence of any other microscopic changes in the brain or peripheral nervous tissue and because it occurred at the end of the recovery period. Neurobehavioral changes (enhanced acoustic startle responses and increased errors in water-maze learning) combined with evidence of generalized toxicity were noted at 45 mg/kg/day during the later part of the recovery period. Serum pravastatin levels at 15 mg/kg/day are approximately ≥1 times (AUC) the maximum pediatric dose of 40 mg. No thinning of the corpus callosum was observed in rats dosed with pravastatin (≥250 mg/kg/day) beginning PND 35 for 3 months suggesting increased sensitivity in younger rats. PND 35 in a rat is approximately equivalent to an 8- to 12-year-old human child. Juvenile male rats given 90 times (AUC) the 40 mg dose had decreased fertility (20%) with sperm abnormalities compared to controls.
# Clinical Studies
## Prevention of Coronary Heart Disease
- In the Pravastatin Primary Prevention Study (WOS),3 the effect of pravastatin sodium on fatal and nonfatal CHD was assessed in 6595 men 45 to 64 years of age, without a previous MI, and with LDL-C levels between 156 to 254 mg/dL (4 to 6.7 mmol/L). In this randomized, double-blind, placebo-controlled study, patients were treated with standard care, including dietary advice, and either pravastatin sodium 40 mg daily (N=3302) or placebo (N=3293) and followed for a median duration of 4.8 years. Median (25th, 75th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7), −27.7 (−36, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively.
- Pravastatin sodium significantly reduced the rate of first coronary events (either CHD death or nonfatal MI) by 31% (248 events in the placebo group versus 174 events in the pravastatin sodium group , p=0.0001 ). The risk reduction with pravastatin sodium was similar and significant throughout the entire range of baseline LDL cholesterol levels. This reduction was also similar and significant across the age range studied with a 40% risk reduction for patients younger than 55 years and a 27% risk reduction for patients 55 years and older. The Pravastatin Primary Prevention Study included only men, and therefore it is not clear to what extent these data can be extrapolated to a similar population of female patients.
- Pravastatin sodium also significantly decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty ) by 37% (80 vs 51 patients, p=0.009) and coronary angiography by 31% (128 vs 90, p=0.007). Cardiovascular deaths were decreased by 32% (73 vs 50, p=0.03) and there was no increase in death from non-cardiovascular causes.
## Secondary Prevention of Cardiovascular Events
- In the PLAC I6 study, the effect of pravastatin therapy on coronary atherosclerosis was assessed by coronary angiography in patients with coronary disease and moderate hypercholesterolemia (baseline LDL-C range: 130 to 190 mg/dL). In this double-blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at 3 years in 264 patients. Although the difference between pravastatin and placebo for the primary endpoint (per-patient change in mean coronary artery diameter) and 1 of 2 secondary endpoints (change in percent lumen diameter stenosis) did not reach statistical significance, for the secondary endpoint of change in minimum lumen diameter, statistically significant slowing of disease was seen in the pravastatin treatment group (p=0.02).
- In the REGRESS7 study, the effect of pravastatin on coronary atherosclerosis was assessed by coronary angiography in 885 patients with angina pectoris, angiographically documented coronary artery disease, and hypercholesterolemia (baseline total cholesterol range: 160 to 310 mg/dL). In this double-blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at 2 years in 653 patients (323 treated with pravastatin). Progression of coronary atherosclerosis was significantly slowed in the pravastatin group as assessed by changes in mean segment diameter (p=0.037) and minimum obstruction diameter (p=0.001).
- Analysis of pooled events from PLAC I, PLAC II8, REGRESS, and KAPS9 studies (combined N=1891) showed that treatment with pravastatin was associated with a statistically significant reduction in the composite event rate of fatal and nonfatal MI (46 events or 6.4% for placebo versus 21 events or 2.4% for pravastatin, p=0.001). The predominant effect of pravastatin was to reduce the rate of nonfatal MI.
## Primary Hypercholesterolemia (Fredrickson Types IIa and IIb)
- Pravastatin sodium is highly effective in reducing Total-C, LDL-C, and TG in patients with heterozygous familial, presumed familial combined, and non-familial (non-FH) forms of primary hypercholesterolemia, and mixed dyslipidemia. A therapeutic response is seen within 1 week, and the maximum response usually is achieved within 4 weeks. This response is maintained during extended periods of therapy. In addition, pravastatin sodium is effective in reducing the risk of acute coronary events in hypercholesterolemic patients with and without previous MI.
- A single daily dose is as effective as the same total daily dose given twice a day. In multicenter, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin in daily doses ranging from 10 to 40 mg consistently and significantly decreased Total-C, LDL-C, TG, and Total-C/HDL-C and LDL-C/HDL-C ratios (see Table 5).
- In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin at a daily dose of 80 mg (N=277) significantly decreased Total-C, LDL-C, and TG. The 25th and 75th percentile changes from baseline in LDL-C for pravastatin 80 mg were −43% and −30%. The efficacy results of the individual studies were consistent with the pooled data (see Table 5).
- Treatment with pravastatin sodium modestly decreased VLDL-C and pravastatin sodium across all doses produced variable increases in HDL-C (see Table 5).
- In another clinical trial, patients treated with pravastatin in combination with cholestyramine (70% of patients were taking cholestyramine 20 or 24 g per day) had reductions equal to or greater than 50% in LDL-C. Furthermore, pravastatin attenuated cholestyramine-induced increases in TG levels (which are themselves of uncertain clinical significance).
## Hypertriglyceridemia (Fredrickson Type IV)
- The response to pravastatin in patients with Type IV hyperlipidemia (baseline TG >200 mg/dL and LDL-C <160 mg/dL) was evaluated in a subset of 429 patients. For pravastatin-treated subjects, the median (min, max) baseline TG level was 246 (200.5, 349.5) mg/dL (see Table 6.)
## Dysbetalipoproteinemia (Fredrickson Type III)
The response to pravastatin in two double-blind crossover studies of 46 patients with genotype E2/E2 and Fredrickson Type III dysbetalipoproteinemia is shown in Table 7.
## Pediatric Clinical Study
- A double-blind, placebo-controlled study in 214 patients (100 boys and 114 girls) with heterozygous familial hypercholesterolemia (HeFH), aged 8 to 18 years was conducted for 2 years. The children (aged 8 to 13 years) were randomized to placebo (N=63) or 20 mg of pravastatin daily (N=65) and the adolescents (aged 14 to 18 years) were randomized to placebo (N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C level >95th percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercholesterolemia. The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL in the pravastatin (range: 151 to 405 mg/dL) and placebo (range: 154 to 375 mg/dL) groups, respectively.
- Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both children and adolescents (see Table 8). The effect of pravastatin treatment in the 2 age groups was similar.
- The mean achieved LDL-C was 186 mg/dL (range: 67 to 363 mg/dL) in the pravastatin group compared to 236 mg/dL (range: 105 to 438 mg/dL) in the placebo group.
- The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in children. The long-term efficacy of pravastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
# How Supplied
- Pravastatin sodium tablets USP are supplied as:
- 10 mg tablets: Yellow colored, circular shaped tablets having flat surface, with “G5” debossed on one surface and “10” debossed on the other surface. They are supplied in bottles of 90 (NDC 68462-195-90) and bottles of 500 (NDC 68462-195-05). Bottles contain a desiccant canister.
- 20 mg tablets: Yellow rounded-rectangular tablets having biconvex surface, with “G5” debossed on one surface and “20” debossed on the other surface. They are supplied in bottles of 90 (NDC 68462-196-90) and bottles of 500 (NDC 68462-196-05). Bottles contain a desiccant canister.
- 40 mg tablets: Green rounded-rectangular tablets having biconvex surface, with “G5” debossed on one surface and “40” debossed on the other surface. They are supplied in bottles of 90 (NDC 68462-197-90) and bottles of 500 (NDC 68462-197-05). Bottles contain a desiccant canister.
- 80 mg tablets: Yellow oval tablets having biconvex surface, with “G5” debossed on one surface and “80” debossed on the other surface. They are supplied in bottles of 90 (NDC 68462-198-90) and bottles of 500 (NDC 68462-198-05). Bottles contain a desiccant canister.
## Storage
- Store at 20o to 25oC (68o to 77oF); excursions permitted to 15° to 30°C (59° to 86°F).
- Keep tightly closed (protect from moisture). Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever .
It is recommended that liver enzyme tests be performed before the initiation of pravastatin sodium, and thereafter when clinically indicated. All patients treated with pravastatin sodium should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice .
Manufactured by:
Glenmark Generics Ltd.
Colvale-Bardez, Goa 403 513, India
Manufactured for:
Glenmark logo
Glenmark Generics Inc., USA
Mahwah, NJ 07430
Questions? 1 (888)721-7115
www.glenmarkgenerics.com
May 2014
# Precautions with Alcohol
Caution should be exercised when pravastatin is administered to patients who have a recent (<6 months) history of liver disease, have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol.
# Brand Names
Pravachol
# Look-Alike Drug Names
pravastatin - pitavastatin
Pravachol - prasugrel
# Drug Shortage Status
# Price | Pravastatin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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# Overview
Pravastatin is a HMG-CoA reductase inhibitor that is FDA approved for the treatment of hypercholesterolemia and prevention of cardiovascular disease. Common adverse reactions include rash, diarrhea, nausea, vomiting, musculoskeletal pain, headache, cough, rhinitis and upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Indication
- Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate.
### Prevention of Cardiovascular Disease
- Indication
- In hypercholesterolemic patients without clinically evident coronary heart disease (CHD), pravastatin sodium tablets USP are indicated to:
- Reduce the risk of myocardial infarction (MI).
- Reduce the risk of undergoing myocardial revascularization procedures.
- Reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes.
General Dosing Information
- The patient should be placed on a standard cholesterol-lowering diet before receiving pravastatin sodium tablets and should continue on this diet during treatment with pravastatin sodium tablets.
- Recommended starting dosage: 40 mg PO qd.
- If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended.
- In patients with significant renal impairment,
- Starting dosage: 10 mg PO qd. Pravastatin sodium tablets can be administered orally as a single dose at any time of the day, with or without food.
- Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines.
### Concomitant Lipid-Altering Therapy
Dosing information
- Pravastatin sodium tablets may be used with bile acid resins. When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol) and pravastatin, pravastatin sodium tablets should be given either 1 hour or more before or at least 4 hours following the resin.
### Dosage in Patients Taking Cyclosporine
Dosing information
- In patients taking immunosuppressive drugs such as cyclosporine concomitantly with pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and titration to higher doses should be done with caution.
- Most patients treated with this combination received a maximum pravastatin sodium dose of 20 mg/day.
- In patients taking cyclosporine: less than 20 mg PO qd.
### Dosage in Patients Taking Clarithromycin
Dosing information
- In patients taking clarithromycin: less than 40 mg PO qd .
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Pravastatin in adult patients.
### Non–Guideline-Supported Use
### Indications
- Acute coronary syndrome
- Atrial fibrillation
- Coronary artery bypass graft
- Heart failure
- Kidney disease
- Radiographic contrast agent nephropathy
- Nephrotic syndrome
- Percutaneous coronary intervention
- Restenotic lesion of coronary artery
- Transient ischemic attack
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
### Hypercholesterolemia
Dosing information
- Children (Ages 8 to 13 Years, Inclusive)
- Recommended dose: 20 mg PO qd in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population.
- Adolescents (Ages 14 to 18 Years)
- Recommended starting dose: 40 mg PO qd in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population.
- Children and adolescents treated with pravastatin should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Pravastatin in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Pravastatin in pediatric patients.
# Contraindications
## Hypersensitivity
- Hypersensitivity to any component of this medication.
## Liver
- Active liver disease or unexplained, persistent elevations of serum transaminases.
## Pregnancy
- Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they are contraindicated during pregnancy and in nursing mothers. PRAVASTATIN SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus.
## Nursing Mothers
- A small amount of pravastatin is excreted in human breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require pravastatin sodium treatment should not breast-feed their infants.
# Warnings
## Skeletal Muscle
- Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
- Uncomplicated myalgia has also been reported in pravastatin-treated patients. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal (ULN), was rare (<0.1%) in pravastatin clinical trials. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Predisposing factors include advanced age (>65), uncontrolled hypothyroidism, and renal impairment.
- There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum CPK, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation and improvement with immunosuppressive agents.
- All patients should be advised to promptly report to their physician unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing pravastatin sodium.
- Pravastatin therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected. Pravastatin therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy.
- The risk of myopathy during treatment with statins is increased with concurrent therapy with either erythromycin, cyclosporine, niacin, or fibrates. However, neither myopathy nor significant increases in CPK levels have been observed in 3 reports involving a total of 100 post-transplant patients (24 renal and 76 cardiac) treated for up to 2 years concurrently with pravastatin 10 to 40 mg and cyclosporine. Some of these patients also received other concomitant immunosuppressive therapies. Further, in clinical trials involving small numbers of patients who were treated concurrently with pravastatin and niacin, there were no reports of myopathy. Also, myopathy was not reported in a trial of combination pravastatin (40 mg/day) and gemfibrozil (1200 mg/day), although 4 of 75 patients on the combination showed marked CPK elevations versus 1 of 73 patients receiving placebo. There was a trend toward more frequent CPK elevations and patient withdrawals due to musculoskeletal symptoms in the group receiving combined treatment as compared with the groups receiving placebo, gemfibrozil, or pravastatin monotherapy. The use of fibrates alone may occasionally be associated with myopathy. The benefit of further alterations in lipid levels by the combined use of pravastatin sodiumwith fibrates should be carefully weighed against the potential risks of this combination.
- Cases of myopathy, including rhabdomyolysis, have been reported with pravastatin coadministered with colchicine, and caution should be exercised when prescribing pravastatin with colchicine.
## Liver
- Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. In placebo-controlled clinical trials subjects were exposed to pravastatin or placebo. In an analysis of serum transaminase values (ALT, AST), incidences of marked abnormalities were compared between the pravastatin and placebo treatment groups; a marked abnormality was defined as a post-treatment test value greater than 3 times the upper limit of normal for subjects with pretreatment values less than or equal to the upper limit of normal, or 4 times the pretreatment value for subjects with pretreatment values greater than the upper limit of normal but less than 1.5 times the upper limit of normal. Marked abnormalities of ALT or AST occurred with similar low frequency (≤1.2%) in both treatment groups. Overall, clinical trial experience showed that liver function test abnormalities observed during pravastatin therapy were usually asymptomatic, not associated with cholestasis, and did not appear to be related to treatment duration. In a 320-patient placebo-controlled clinical trial, subjects with chronic (>6 months) stable liver disease, due primarily to hepatitis C or nonalcoholic fatty liver disease, were treated with 80 mg pravastatin or placebo for up to 9 months. The primary safety endpoint was the proportion of subjects with at least one ALT ≥2 times the upper limit of normal for those with normal ALT (≤ the upper limit of normal) at baseline or a doubling of the baseline ALT for those with elevated ALT (> the upper limit of normal) at baseline. By Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the prespecified safety ALT endpoint compared to 20 out of 160 (12.5%) subjects receiving placebo. Conclusions regarding liver safety are limited since the study was not large enough to establish similarity between groups (with 95% confidence) in the rates of ALT elevation.
- It is recommended that liver function tests be performed prior to the initiation of therapy and when clinically indicated.
- Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of pravastatin. Caution should be exercised when pravastatin is administered to patients who have a recent (<6 months) history of liver disease, have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol.
- There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with pravastatin sodium, promptly interrupt therapy. If an alternate etiology is not found do not restart pravastatin sodium.
## Endocrine Function
- Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials with pravastatin in males and post-menopausal females were inconsistent with regard to possible effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone response to human chorionic gonadotropin was significantly reduced (p<0.004) after 16 weeks of treatment with 40 mg of pravastatin. However, the percentage of patients showing a ≥50% rise in plasma testosterone after human chorionic gonadotropin stimulation did not change significantly after therapy in these patients. The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if a statin or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may diminish the levels or activity of steroid hormones.
- In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were treated with pravastatin (20 mg in the children aged 8 to 13 years and 40 mg in the adolescents aged 14 to 18 years) for 2 years, there were no detectable differences seen in any of the endocrine parameters (ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol [girls] or testosterone [boys]) relative to placebo. There were no detectable differences seen in height and weight changes, testicular volume changes, or Tanner score relative to placebo
# Adverse Reactions
## Clinical Trials Experience
Short-Term Controlled Trials
- In the pravastatin sodium placebo-controlled clinical trials database of 1313 patients (age range 20 to 76 years, 32.4% women, 93.5% Caucasians, 5% Blacks, 0.9% Hispanics, 0.4% Asians, 0.2% Others) with a median treatment duration of 14 weeks, 3.3% of patients on pravastatin sodium and 1.2% patients on placebo discontinued due to adverse events regardless of causality. The most common adverse reactions that led to treatment discontinuation and occurred at an incidence greater than placebo were: liver function test increased, nausea, anxiety/depression, and dizziness.
- All adverse clinical events (regardless of causality) reported in ≥2% of pravastatin-treated patients in placebo-controlled trials of up to 8 months duration are identified in Table 1:
- The safety and tolerability of pravastatin sodium at a dose of 80 mg in 2 controlled trials with a mean exposure of 8.6 months was similar to that of pravastatin sodium at lower doses except that 4 out of 464 patients taking 80 mg of pravastatin had a single elevation of CK >10 times ULN compared to 0 out of 115 patients taking 40 mg of pravastatin.
## Long-Term Controlled Morbidity and Mortality Trials
- In the pravastatin sodium placebo-controlled clinical trials database of 21,483 patients (age range 24 to 75 years, 10.3% women, 52.3% Caucasians, 0.8% Blacks, 0.5% Hispanics, 0.1% Asians, 0.1% Others, 46.1% Not Recorded) with a median treatment duration of 261 weeks, 8.1% of patients on pravastatin sodium and 9.3% patients on placebo discontinued due to adverse events regardless of causality.
- Adverse event data were pooled from several double-blind, placebo-controlled trials (e.g., West of Scotland Coronary Prevention Study [WOS]; Pravastatin Limitation of Atherosclerosis in the Coronary Arteries study [PLAC I]; Pravastatin, Lipids and Atherosclerosis in the Carotids study [PLAC II]; Regression Growth Evaluation Statin Study [REGRESS]; and Kuopio Atherosclerosis Prevention Study [KAPS]) involving a total of 10,764 patients treated with pravastatin 40 mg and 10,719 patients treated with placebo. The safety and tolerability profile in the pravastatin group was comparable to that of the placebo group. Patients were exposed to pravastatin for a mean of 4.0 to 5.1 years in, among other trials, WOS, and 1.9 to 2.9 years in PLAC I, PLAC II, KAPS, and REGRESS. In these long-term trials, the most common reasons for discontinuation were mild, non-specific gastrointestinal complaints. Collectively, these trials represent 47,613 patient-years of exposure to pravastatin. All clinical adverse events (regardless of causality) occurring in ≥2% of patients treated with pravastatin in these studies are identified in Table 2.
- In addition to the events listed above in the long-term trials table, events of probable, possible, or uncertain relationship to study drug that occurred in < 2% of pravastatin-treated patients in the long-term trials included the following:
- Dermatologic: scalp hair abnormality (including alopecia), urticaria.
- Endocrine/Metabolic: sexual dysfunction, libido change.
- General: flushing.
- Immunologic: allergy, edema head/neck.
- Musculoskeletal: muscle weakness.
- Nervous System: vertigo, insomnia, memory impairment, neuropathy (including peripheral neuropathy).
- Special Senses: taste disturbance.
## Laboratory Test Abnormalities
- Increases in ALT, AST values and CPK have been observed.
- Transient, asymptomatic eosinophilia has been reported. Eosinophil counts usually returned to normal despite continued therapy. Anemia, thrombocytopenia, and leukopenia have been reported with statins.
## Pediatric Patients
- In a 2-year, double-blind, placebo-controlled study involving 100 boys and 114 girls with HeFH (n=214; age range 8 to 18.5 years, 53% female, 95% Caucasians, <1% Blacks, 3% Asians, 1% Other), the safety and tolerability profile of pravastatin was generally similar to that of placebo.
## Postmarketing Experience
- In addition to the events reported above, as with other drugs in this class, the following events have been reported rarely during postmarketing experience with pravastatin sodium, regardless of causality assessment:
- Musculoskeletal: myopathy, rhabdomyolysis.
- There have been rare reports of immune-mediated necrotizing myopathy associated with statin use .
- Nervous System: dysfunction of certain cranial nerves (including alteration of taste, impairment of extraocular movement, facial paresis), peripheral nerve palsy.
- There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
- Hypersensitivity: anaphylaxis, angioedema, lupus erythematosus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, hemolytic anemia, positive ANA, ESR increase, arthritis, arthralgia, asthenia, photosensitivity, chills, malaise, toxic epidermal necrolysis, erythema multiforme (including Stevens-Johnson syndrome).
- Gastrointestinal: abdominal pain, constipation, pancreatitis, hepatitis (including chronic active hepatitis), cholestatic jaundice, fatty change in liver, cirrhosis, fulminant hepatic necrosis, hepatoma, fatal and non-fatal hepatic failure.
- Dermatologic: a variety of skin changes (e.g., nodules, discoloration, dryness of mucous membranes, changes to hair/nails).
- Renal: urinary abnormality (including dysuria, frequency, nocturia).
- Respiratory: dyspnea.
- Reproductive: gynecomastia.
- Laboratory Abnormalities: liver function test abnormalities, thyroid function abnormalities.
# Drug Interactions
## Cyclosporine
- The risk of myopathy/rhabdomyolysis is increased with concomitant administration of cyclosporine. Limit pravastatin to 20 mg once daily for concomitant use with cyclosporine.
## Clarithromycin
- The risk of myopathy/rhabdomyolysis is increased with concomitant administration of clarithromycin. Limit pravastatin to 40 mg once daily for concomitant use with clarithromycin.
## Colchicine
- The risk of myopathy/rhabdomyolysis is increased with concomitant administration of colchicine.
## Gemfibrozil
- Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of pravastatin sodium with gemfibrozil should be avoided [see Warnings and Precautions (5.1)].
## Other Fibrates
- Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, pravastatin sodium should be administered with caution when used concomitantly with other fibrates.
## Niacin
- The risk of skeletal muscle effects may be enhanced when pravastatin is used in combination with niacin; a reduction in pravastatin sodium dosage should be considered in this setting.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): X
- Safety in pregnant women has not been established. Available data in women inadvertently taking pravastatin while pregnant do not suggest any adverse clinical events. However, there are no adequate and well-controlled studies in pregnant women. Therefore, it is not known whether pravastatin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Pravastatin should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus and patients have been informed of the potential hazards.
- Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review2 of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3- to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified. As safety in pregnant women has not been established and there is no apparent benefit to therapy with pravastatin sodium during pregnancy [see Contraindications (4.3)], treatment should be immediately discontinued as soon as pregnancy is recognized. Pravastatin sodium should be administered to women of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards.
- Pravastatin was neither embryolethal nor teratogenic in rats at doses up to 1000 mg/kg daily or in rabbits at doses of up to 50 mg/kg daily. These doses resulted in 10 times (rabbit) or 120 times (rat) the human exposure at 80 mg/day maximum recommended human dose (MRHD) based on surface area (mg/m2).
- In pregnant rats given oral gavage doses of 4, 20, 100, 500, and 1000 mg/kg/day from gestation days 7 through 17 (organogenesis) increased mortality of offspring and skeletal anomalies were observed at 100 mg/kg/day systemic exposure, 10 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m2).
- In pregnant rats given oral gavage doses of 10, 100, and 1000 mg/kg/day from gestation day 17 through lactation day 21 (weaning) increased mortality of offspring and developmental delays were observed at 100 mg/kg/day systemic exposure, 12 times the human exposure at 80 mg/day MRHD based on body surface area (mg/m2).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pravastatin in women who are pregnant.
### Labor and Delivery
- There is no FDA guidance on use of Pravastatin during labor and delivery.
### Nursing Mothers
- A small amount of pravastatin is excreted in human breast milk. Because of the potential for serious adverse reactions in nursing infants, women taking pravastatin sodium should not nurse.
- Pravastatin crosses the placenta and is found in fetal tissue at 30% maternal plasma levels following a single 20 mg/kg dose given to pregnant rats on gestation day 18. Similar studies in lactating rats indicate secretion of pravastatin into breast milk at 0.2 to 6.5 times higher levels than maternal plasma at exposures equivalent to 2 times human exposure at the MRHD.
### Pediatric Use
- The safety and effectiveness of pravastatin sodium in children and adolescents from 8 to 18 years of age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that of patients treated with placebo with influenza and headache commonly reported in both treatment groups.Doses greater than 40 mg have not been studied in this population. Children and adolescent females of childbearing potential should be counseled on appropriate contraceptive methods while on pravastatin therapy.
- Double-blind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted.
### Geriatic Use
- The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the elderly was similar to that in the overall population. Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients.
- Mean pravastatin AUCs are slightly (25% to 50%) higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and half-life (t½) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly.
- Since advanced age (≥65 years) is a predisposing factor for myopathy, pravastatin sodium should be prescribed with caution in the elderly.
### Gender
- There is no FDA guidance on the use of Pravastatin with respect to specific gender populations.
### Race
- There is no FDA guidance on the use of Pravastatin with respect to specific racial populations.
### Renal Impairment
- There is no FDA guidance on the use of Pravastatin in patients with renal impairment.
### Hepatic Impairment
- There is no FDA guidance on the use of Pravastatin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- There is no FDA guidance on the use of Pravastatin in women of reproductive potentials and males.
### Immunocompromised Patients
- There is no FDA guidance one the use of Pravastatin in patients who are immunocompromised.
### Homozygous Familial Hypercholesterolemia
- Pravastatin has not been evaluated in patients with rare homozygous familial hypercholesterolemia. In this group of patients, it has been reported that statins are less effective because the patients lack functional LDL receptors.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- FDA Package Insert for Pravastatin contains no information regarding drug monitoring.
# IV Compatibility
- There is limited information regarding IV Compatibility of Pravastatin in the drug label.
# Overdosage
- To date, there has been limited experience with overdosage of pravastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required.
# Pharmacology
## Mechanism of Action
- Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces VLDL and TG and increases HDL-C.
## Structure
- Pravastatin sodium tablets USP are one of a class of lipid-lowering compounds, the statins, which reduce cholesterol biosynthesis. These agents are competitive inhibitors of HMG-CoA reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate.
- Pravastatin sodium USP is designated chemically as 1-Naphthalene-heptanoic acid, 1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium salt, [1S[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-.
Structural formula:
C23H35NaO7 MW 446.52
- Pravastatin sodium USP is an odorless, white to yellowish white, hygroscpic powder. It is a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7. It is freely soluble in water and methanol, soluble in alcohol, very slightly soluble in acetonitrile and practically insoluble in ether, ethyl acetate and chloroform.
## Pharmacodynamics
### General
Absorption: Pravastatin sodium is administered orally in the active form. In studies in man, peak plasma pravastatin concentrations occurred 1 to 1.5 hours upon oral administration. Based on urinary recovery of total radiolabeled drug, the average oral absorption of pravastatin is 34% and absolute bioavailability is 17%. While the presence of food in the gastrointestinal tract reduces systemic bioavailability, the lipid-lowering effects of the drug are similar whether taken with or 1 hour prior to meals.
- Pravastatin plasma concentrations, including area under the concentration-time curve (AUC), Cmax, and steady-state minimum (Cmin), are directly proportional to administered dose. Systemic bioavailability of pravastatin administered following a bedtime dose was decreased 60% compared to that following an AM dose. Despite this decrease in systemic bioavailability, the efficacy of pravastatin administered once daily in the evening, although not statistically significant, was marginally more effective than that after a morning dose.
- The coefficient of variation (CV), based on between-subject variability, was 50% to 60% for AUC. The geometric means of pravastatin Cmax and AUC following a 20 mg dose in the fasted state were 26.5 ng/mL and 59.8 ng*hr/mL, respectively.
- Steady-state AUCs, Cmax, and Cmin plasma concentrations showed no evidence of pravastatin accumulation following once or twice daily administration of pravastatin sodium tablets.
Distribution: Approximately 50% of the circulating drug is bound to plasma proteins.
Metabolism: The major biotransformation pathways for pravastatin are: (a) isomerization to 6-epi pravastatin and the 3α-hydroxyisomer of pravastatin (SQ 31,906) and (b) enzymatic ring hydroxylation to SQ 31,945. The 3α-hydroxyisomeric metabolite (SQ 31,906) has 1/10 to 1/40 the HMG-CoA reductase inhibitory activity of the parent compound. Pravastatin undergoes extensive first-pass extraction in the liver (extraction ratio 0.66).
Excretion: Approximately 20% of a radiolabeled oral dose is excreted in urine and 70% in the feces. After intravenous administration of radiolabeled pravastatin to normal volunteers, approximately 47% of total body clearance was via renal excretion and 53% by non-renal routes (i.e., biliary excretion and biotransformation).
Following single dose oral administration of 14C-pravastatin, the radioactive elimination t½ for pravastatin is 1.8 hours in humans.
### Specific Populations
Renal Impairment: A single 20 mg oral dose of pravastatin was administered to 24 patients with varying degrees of renal impairment (as determined by creatinine clearance). No effect was observed on the pharmacokinetics of pravastatin or its 3α-hydroxy isomeric metabolite (SQ 31,906). Compared to healthy subjects with normal renal function, patients with severe renal impairment had 69% and 37% higher mean AUC and Cmax values, respectively, and a 0.61 hour shorter t½ for the inactive enzymatic ring hydroxylation metabolite (SQ 31,945).
Hepatic Impairment: In a study comparing the kinetics of pravastatin in patients with biopsy confirmed cirrhosis (N=7) and normal subjects (N=7), the mean AUC varied 18-fold in cirrhotic patients and 5-fold in healthy subjects. Similarly, the peak pravastatin values varied 47-fold for cirrhotic patients compared to 6-fold for healthy subjects.
Geriatric: In a single oral dose study using pravastatin 20 mg, the mean AUC for pravastatin was approximately 27% greater and the mean cumulative urinary excretion (CUE) approximately 19% lower in elderly men (65 to 75 years old) compared with younger men (19 to 31 years old). In a similar study conducted in women, the mean AUC for pravastatin was approximately 46% higher and the mean CUE approximately 18% lower in elderly women (65 to 78 years old) compared with younger women (18 to 38 years old). In both studies, Cmax, Tmax, and t½ values were similar in older and younger subjects.
Pediatric: After 2 weeks of once-daily 20 mg oral pravastatin administration, the geometric means of AUC were 80.7 (CV 44%) and 44.8 (CV 89%) ng*hr/mL for children (8 to 11 years, N=14) and adolescents (12 to 16 years, N=10), respectively. The corresponding values for Cmax were 42.4 (CV 54%) and 18.6 ng/mL (CV 100%) for children and adolescents, respectively. No conclusion can be made based on these findings due to the small number of samples and large variability.
### Drug-Drug Interactions
## Pharmacokinetics
- There is limited information regarding Pharmacokinetics of Pravastatin in the drug label.
## Nonclinical Toxicology
## Carcinogenesis, Mutagenesis, Impairment of Fertility
- In a 2-year study in rats fed pravastatin at doses of 10, 30, or 100 mg/kg body weight, there was an increased incidence of hepatocellular carcinomas in males at the highest dose (p<0.01). These effects in rats were observed at approximately 12 times the human dose (HD) of 80 mg based on body surface area (mg/m2) and at approximately 4 times the HD, based on AUC.
- In a 2-year study in mice fed pravastatin at doses of 250 and 500 mg/kg/day, there was an increased incidence of hepatocellular carcinomas in males and females at both 250 and 500 mg/kg/day (p<0.0001). At these doses, lung adenomas in females were increased (p=0.013). These effects in mice were observed at approximately 15 times (250 mg/kg/day) and 23 times (500 mg/kg/day) the HD of 80 mg, based on AUC. In another 2-year study in mice with doses up to 100 mg/kg/day (producing drug exposures approximately 2 times the HD of 80 mg, based on AUC), there were no drug-induced tumors.
- No evidence of mutagenicity was observed in vitro, with or without rat-liver metabolic activation, in the following studies: microbial mutagen tests, using mutant strains of Salmonella typhimurium or Escherichia coli; a forward mutation assay in L5178Y TK +/− mouse lymphoma cells; a chromosomal aberration test in hamster cells; and a gene conversion assay using Saccharomyces cerevisiae. In addition, there was no evidence of mutagenicity in either a dominant lethal test in mice or a micronucleus test in mice.
- In a fertility study in adult rats with daily doses up to 500 mg/kg, pravastatin did not produce any adverse effects on fertility or general reproductive performance.
## Animal Toxicology and/or Pharmacology
### CNS Toxicity
- CNS vascular lesions, characterized by perivascular hemorrhage and edema and mononuclear cell infiltration of perivascular spaces, were seen in dogs treated with pravastatin at a dose of 25 mg/kg/day. These effects in dogs were observed at approximately 59 times the HD of 80 mg/day, based on AUC. Similar CNS vascular lesions have been observed with several other drugs in this class.
- A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose (as measured by total enzyme inhibitory activity). This same drug also produced vestibulocochlear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14 weeks at 180 mg/kg/day, a dose which resulted in a mean plasma drug level similar to that seen with the 60 mg/kg/day dose.
- When administered to juvenile rats (postnatal days [PND] 4 through 80 at 5 to 45 mg/kg/day), no drug related changes were observed at 5 mg/kg/day. At 15 and 45 mg/kg/day, altered body-weight gain was observed during the dosing and 52-day recovery periods as well as slight thinning of the corpus callosum at the end of the recovery period. This finding was not evident in rats examined at the completion of the dosing period and was not associated with any inflammatory or degenerative changes in the brain. The biological relevance of the corpus callosum finding is uncertain due to the absence of any other microscopic changes in the brain or peripheral nervous tissue and because it occurred at the end of the recovery period. Neurobehavioral changes (enhanced acoustic startle responses and increased errors in water-maze learning) combined with evidence of generalized toxicity were noted at 45 mg/kg/day during the later part of the recovery period. Serum pravastatin levels at 15 mg/kg/day are approximately ≥1 times (AUC) the maximum pediatric dose of 40 mg. No thinning of the corpus callosum was observed in rats dosed with pravastatin (≥250 mg/kg/day) beginning PND 35 for 3 months suggesting increased sensitivity in younger rats. PND 35 in a rat is approximately equivalent to an 8- to 12-year-old human child. Juvenile male rats given 90 times (AUC) the 40 mg dose had decreased fertility (20%) with sperm abnormalities compared to controls.
# Clinical Studies
## Prevention of Coronary Heart Disease
- In the Pravastatin Primary Prevention Study (WOS),3 the effect of pravastatin sodium on fatal and nonfatal CHD was assessed in 6595 men 45 to 64 years of age, without a previous MI, and with LDL-C levels between 156 to 254 mg/dL (4 to 6.7 mmol/L). In this randomized, double-blind, placebo-controlled study, patients were treated with standard care, including dietary advice, and either pravastatin sodium 40 mg daily (N=3302) or placebo (N=3293) and followed for a median duration of 4.8 years. Median (25th, 75th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7), −27.7 (−36, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively.
- Pravastatin sodium significantly reduced the rate of first coronary events (either CHD death or nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus 174 events in the pravastatin sodium group [CHD death=31, nonfatal MI=143], p=0.0001 [see figure below]). The risk reduction with pravastatin sodium was similar and significant throughout the entire range of baseline LDL cholesterol levels. This reduction was also similar and significant across the age range studied with a 40% risk reduction for patients younger than 55 years and a 27% risk reduction for patients 55 years and older. The Pravastatin Primary Prevention Study included only men, and therefore it is not clear to what extent these data can be extrapolated to a similar population of female patients.
- Pravastatin sodium also significantly decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients, p=0.009) and coronary angiography by 31% (128 vs 90, p=0.007). Cardiovascular deaths were decreased by 32% (73 vs 50, p=0.03) and there was no increase in death from non-cardiovascular causes.
## Secondary Prevention of Cardiovascular Events
- In the PLAC I6 study, the effect of pravastatin therapy on coronary atherosclerosis was assessed by coronary angiography in patients with coronary disease and moderate hypercholesterolemia (baseline LDL-C range: 130 to 190 mg/dL). In this double-blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at 3 years in 264 patients. Although the difference between pravastatin and placebo for the primary endpoint (per-patient change in mean coronary artery diameter) and 1 of 2 secondary endpoints (change in percent lumen diameter stenosis) did not reach statistical significance, for the secondary endpoint of change in minimum lumen diameter, statistically significant slowing of disease was seen in the pravastatin treatment group (p=0.02).
- In the REGRESS7 study, the effect of pravastatin on coronary atherosclerosis was assessed by coronary angiography in 885 patients with angina pectoris, angiographically documented coronary artery disease, and hypercholesterolemia (baseline total cholesterol range: 160 to 310 mg/dL). In this double-blind, multicenter, controlled clinical trial, angiograms were evaluated at baseline and at 2 years in 653 patients (323 treated with pravastatin). Progression of coronary atherosclerosis was significantly slowed in the pravastatin group as assessed by changes in mean segment diameter (p=0.037) and minimum obstruction diameter (p=0.001).
- Analysis of pooled events from PLAC I, PLAC II8, REGRESS, and KAPS9 studies (combined N=1891) showed that treatment with pravastatin was associated with a statistically significant reduction in the composite event rate of fatal and nonfatal MI (46 events or 6.4% for placebo versus 21 events or 2.4% for pravastatin, p=0.001). The predominant effect of pravastatin was to reduce the rate of nonfatal MI.
## Primary Hypercholesterolemia (Fredrickson Types IIa and IIb)
- Pravastatin sodium is highly effective in reducing Total-C, LDL-C, and TG in patients with heterozygous familial, presumed familial combined, and non-familial (non-FH) forms of primary hypercholesterolemia, and mixed dyslipidemia. A therapeutic response is seen within 1 week, and the maximum response usually is achieved within 4 weeks. This response is maintained during extended periods of therapy. In addition, pravastatin sodium is effective in reducing the risk of acute coronary events in hypercholesterolemic patients with and without previous MI.
- A single daily dose is as effective as the same total daily dose given twice a day. In multicenter, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin in daily doses ranging from 10 to 40 mg consistently and significantly decreased Total-C, LDL-C, TG, and Total-C/HDL-C and LDL-C/HDL-C ratios (see Table 5).
- In a pooled analysis of 2 multicenter, double-blind, placebo-controlled studies of patients with primary hypercholesterolemia, treatment with pravastatin at a daily dose of 80 mg (N=277) significantly decreased Total-C, LDL-C, and TG. The 25th and 75th percentile changes from baseline in LDL-C for pravastatin 80 mg were −43% and −30%. The efficacy results of the individual studies were consistent with the pooled data (see Table 5).
- Treatment with pravastatin sodium modestly decreased VLDL-C and pravastatin sodium across all doses produced variable increases in HDL-C (see Table 5).
- In another clinical trial, patients treated with pravastatin in combination with cholestyramine (70% of patients were taking cholestyramine 20 or 24 g per day) had reductions equal to or greater than 50% in LDL-C. Furthermore, pravastatin attenuated cholestyramine-induced increases in TG levels (which are themselves of uncertain clinical significance).
## Hypertriglyceridemia (Fredrickson Type IV)
- The response to pravastatin in patients with Type IV hyperlipidemia (baseline TG >200 mg/dL and LDL-C <160 mg/dL) was evaluated in a subset of 429 patients. For pravastatin-treated subjects, the median (min, max) baseline TG level was 246 (200.5, 349.5) mg/dL (see Table 6.)
## Dysbetalipoproteinemia (Fredrickson Type III)
The response to pravastatin in two double-blind crossover studies of 46 patients with genotype E2/E2 and Fredrickson Type III dysbetalipoproteinemia is shown in Table 7.
## Pediatric Clinical Study
- A double-blind, placebo-controlled study in 214 patients (100 boys and 114 girls) with heterozygous familial hypercholesterolemia (HeFH), aged 8 to 18 years was conducted for 2 years. The children (aged 8 to 13 years) were randomized to placebo (N=63) or 20 mg of pravastatin daily (N=65) and the adolescents (aged 14 to 18 years) were randomized to placebo (N=45) or 40 mg of pravastatin daily (N=41). Inclusion in the study required an LDL-C level >95th percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercholesterolemia. The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL in the pravastatin (range: 151 to 405 mg/dL) and placebo (range: 154 to 375 mg/dL) groups, respectively.
- Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both children and adolescents (see Table 8). The effect of pravastatin treatment in the 2 age groups was similar.
- The mean achieved LDL-C was 186 mg/dL (range: 67 to 363 mg/dL) in the pravastatin group compared to 236 mg/dL (range: 105 to 438 mg/dL) in the placebo group.
- The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in children. The long-term efficacy of pravastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
# How Supplied
- Pravastatin sodium tablets USP are supplied as:
- 10 mg tablets: Yellow colored, circular shaped tablets having flat surface, with “G5” debossed on one surface and “10” debossed on the other surface. They are supplied in bottles of 90 (NDC 68462-195-90) and bottles of 500 (NDC 68462-195-05). Bottles contain a desiccant canister.
- 20 mg tablets: Yellow rounded-rectangular tablets having biconvex surface, with “G5” debossed on one surface and “20” debossed on the other surface. They are supplied in bottles of 90 (NDC 68462-196-90) and bottles of 500 (NDC 68462-196-05). Bottles contain a desiccant canister.
- 40 mg tablets: Green rounded-rectangular tablets having biconvex surface, with “G5” debossed on one surface and “40” debossed on the other surface. They are supplied in bottles of 90 (NDC 68462-197-90) and bottles of 500 (NDC 68462-197-05). Bottles contain a desiccant canister.
- 80 mg tablets: Yellow oval tablets having biconvex surface, with “G5” debossed on one surface and “80” debossed on the other surface. They are supplied in bottles of 90 (NDC 68462-198-90) and bottles of 500 (NDC 68462-198-05). Bottles contain a desiccant canister.
## Storage
- Store at 20o to 25oC (68o to 77oF); excursions permitted to 15° to 30°C (59° to 86°F).
- Keep tightly closed (protect from moisture). Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever [see Warnings and Precautions (5.1)].
It is recommended that liver enzyme tests be performed before the initiation of pravastatin sodium, and thereafter when clinically indicated. All patients treated with pravastatin sodium should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.2)].
Manufactured by:
Glenmark Generics Ltd.
Colvale-Bardez, Goa 403 513, India
Manufactured for:
Glenmark logo
Glenmark Generics Inc., USA
Mahwah, NJ 07430
Questions? 1 (888)721-7115
www.glenmarkgenerics.com
May 2014
# Precautions with Alcohol
Caution should be exercised when pravastatin is administered to patients who have a recent (<6 months) history of liver disease, have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol.
# Brand Names
Pravachol
# Look-Alike Drug Names
pravastatin - pitavastatin
Pravachol - prasugrel[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Pravastatin | |
ac845f897c266c209a59656c13a5098928beebb0 | wikidoc | Pre-medical | Pre-medical
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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# Overview
Pre-medical (often shortened to pre-med) is a term used to describe a track an undergraduate student in the United States pursues prior to becoming a medical student. It refers to the activities that prepare an undergraduate student for medical school, such as pre-med coursework, volunteer activities, clinical experience, research, and the application process.
### Pre-Med Timeline
Typical pre-med students will structure their coursework in their first year at college to accommodate the required courses. After, typically, a semester, many pursue extracurricular activities that demonstrate a commitment to medicine. Once junior year arrives, students typically register for and take the MCAT, the required standardized exam that medical schools use to identify qualified candidates. Once taken, students apply to various schools using the automated AMCAS system, or using a non-AMCAS-using school's own application. The application process consists of a review of coursework, activities, work experience, and a personal statement. Applicants can expect to hear from schools within several weeks, at which point they may receive "secondary applications". These applications are generated by each individual school. They contain essay questions that the applicant must answer. A qualified applicant can expect to receive an invitation to interview at certain schools. Such an invitation is generally considered an accomplishment with regards to the amount of time and work one puts into building his candidacy. Upon completion of the interview, the application process is considered "complete," and applicants can then wait for letters from schools.
## Coursework
The Association of American Medical Colleges has created standard required courses that every pre-med student must take. Each school is allowed to place its own further requirements.
The pre-medical coursework is offered at many American colleges and universities; however, it is considered to be a "track" that follows a certain curriculum. Most pre-medical students major in the natural sciences, such as biology, chemistry, or physics, though this is not a requirement. Approximately 25% of matriculants major in a field other than the natural and physical sciences, such as anthropology, philosophy, or other humanities.
The typical courses that must be taken to meet the pre-medical requirement are:
- General Chemistry 1 & 2 (with laboratories)
- General Biology 1 & 2 (with laboratories) (some schools allow zoology in place of second semester)
- Organic Chemistry 1 & 2 (with laboratories) (some schools allow biochemistry in place of second semester)
- General Physics 1 & 2 (with laboratories)
- One or two semesters of math, usually Calculus 1 and either Calculus 2 or a statistics course
- English and Writing
Pre-medical students may be advised or required to take upper level biology and chemistry electives, such as cellular biology, physical chemistry, biochemistry, genetics, etc. Specific requirements for these courses vary by institution.
Schools may also have requirements for non-science classes. Some schools require a certain number of general humanities credits, while others have specific requirements for courses in English, Psychology, or other disciplines.
## Other Countries
In Australia, a number of universities offer a three or four year Bachelor of Medical Science or Biomedical Science degree, which is similar in content and aim to pre-med courses in the US, as the majority of graduates attempt to gain entry to a graduate medical school. | Pre-medical
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Pre-medical (often shortened to pre-med) is a term used to describe a track an undergraduate student in the United States pursues prior to becoming a medical student. It refers to the activities that prepare an undergraduate student for medical school, such as pre-med coursework, volunteer activities, clinical experience, research, and the application process.
### Pre-Med Timeline
Typical pre-med students will structure their coursework in their first year at college to accommodate the required courses. After, typically, a semester, many pursue extracurricular activities that demonstrate a commitment to medicine. Once junior year arrives, students typically register for and take the MCAT, the required standardized exam that medical schools use to identify qualified candidates. Once taken, students apply to various schools using the automated AMCAS system, or using a non-AMCAS-using school's own application. The application process consists of a review of coursework, activities, work experience, and a personal statement. Applicants can expect to hear from schools within several weeks, at which point they may receive "secondary applications". These applications are generated by each individual school. They contain essay questions that the applicant must answer. A qualified applicant can expect to receive an invitation to interview at certain schools. Such an invitation is generally considered an accomplishment with regards to the amount of time and work one puts into building his candidacy. Upon completion of the interview, the application process is considered "complete," and applicants can then wait for letters from schools.
## Coursework
The Association of American Medical Colleges has created standard required courses that every pre-med student must take. Each school is allowed to place its own further requirements.
The pre-medical coursework is offered at many American colleges and universities; however, it is considered to be a "track" that follows a certain curriculum. Most pre-medical students major in the natural sciences, such as biology, chemistry, or physics, though this is not a requirement. Approximately 25% of matriculants major in a field other than the natural and physical sciences, such as anthropology, philosophy, or other humanities.[1]
The typical courses that must be taken to meet the pre-medical requirement are:
- General Chemistry 1 & 2 (with laboratories)
- General Biology 1 & 2 (with laboratories) (some schools allow zoology in place of second semester)
- Organic Chemistry 1 & 2 (with laboratories) (some schools allow biochemistry in place of second semester)
- General Physics 1 & 2 (with laboratories)
- One or two semesters of math, usually Calculus 1 and either Calculus 2 or a statistics course
- English and Writing
Pre-medical students may be advised or required to take upper level biology and chemistry electives, such as cellular biology, physical chemistry, biochemistry, genetics, etc. Specific requirements for these courses vary by institution.
Schools may also have requirements for non-science classes. Some schools require a certain number of general humanities credits, while others have specific requirements for courses in English, Psychology, or other disciplines.
## Other Countries
In Australia, a number of universities offer a three or four year Bachelor of Medical Science or Biomedical Science degree, which is similar in content and aim to pre-med courses in the US, as the majority of graduates attempt to gain entry to a graduate medical school. | https://www.wikidoc.org/index.php/Pre-medical | |
ba9a4635ed41ba4c397f7d0b4bdde926dd99b7a7 | wikidoc | Prediabetes | Prediabetes
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Prediabetes is the state in which blood glucose levels are above normal but have not reached that of diabetes. This state is also referred to as borderline diabetes, impaired glucose tolerance (IGT), and/or impaired fasting glucose (IFG). These are associated with insulin resistance and are risk factors for the development of type 2 diabetes mellitus. In addition, obesity, family history of type 2 diabetes mellitus, and certain ethnic groups are also at high-risk. Those in this stratum (IGT or IFG) are at increased risk of cardiovascular disease. Of the two, impaired glucose tolerance better predicts cardiovascular disease and mortality.
Diabetes mellitus (DM) is a group of metabolic diseases that are characterized by hyperglycemia and defects in insulin production in the pancreas and/or impaired tolerance to insulin effects. DM is a leading cause of morbidity and mortality. Because the disease can be insidious, the diagnosis is often delayed. Effects of the disease can be macrovascular, as seen in the cardiovascular system/arthrosclerosis, or microvascular, as seen with retinopathy, nephropathy, and neuropathy.
# Epidemiology
About one third of Americans have prediabetes.
# Signs and symptoms
Prediabetes typically has no signs or symptoms. patients should monitor for signs and symptoms of type 2 diabetes mellitus. These include the following:
- Constant hunger
- Unexplained weight loss
- Weight gain
- Flu-like symptoms, including weakness and fatigue
- Blurred vision
- Slow healing of cuts or bruises
- Tingling or loss of feeling in hands or feet
- Recurring gum or skin infections
- Recurring vaginal or bladder infections
# Genetics
As the human genome is further explored, it is likely that multiple genetic anomalies at different loci will be found that confer varying degrees of predisposition to type 2 diabetes. Type 2 DM, which is the condition for which prediabetes is a precursor, has 90-100% concordance in twins; there is no HLA association.
# Pathophysiology
Normal glucose homeostasis is controlled by three interrelated processes. There is gluconeogenesis (glucose production that occurs in the liver), uptake and utilization of glucose by the peripheral tissues of the body, and insulin secretion by the pancreatic islet cells. What triggers the production and release of insulin from the pancreas is the presence of glucose in the body. The main function of insulin is to increase the rate of transport of glucose into certain cells of the body, such as striated muscles, fibroblasts, and fat cells. It is also necessary for transport of amino acids, glycogen formation in the liver and skeletal muscles, triglyceride formation from glucose, nucleic acid synthesis, and protein synthesis.
Insulin enters cells by first binding to target insulin receptors. DM and some of those with prediabetes have impaired glucose tolerance—in these individuals, blood glucose rises to abnormally high levels. This may be from a lack of pancreatic enzyme release or failure of target tissues to respond to the insulin present or both.
# Diagnosis
Prediabetes can be diagnosed in different ways. Each, however, must be confirmed with repeat testing on separate days. The diagnosis of IFG is done after an 8 hour fast; the plasma glucose level must be greater than 99 but less than 126. In order to diagnose IGT, the plasma glucose level must be greater than 139 but less than 200 two hours after an OGTT (oral glucose tolerance test), which is an oral load of 75 grams of glucose. A random glucose level over 140 at any time can result in the diagnosis of prediabetes.
A meta-analysis of the accuracy of the fasting plasma glucose for current prediabetes found:
- Sensitivity = 25%
- Specificity = 94%
A meta-analysis of the accuracy of the glycosylated hemoglobin for current prediabetes found:
- Sensitivity = 50%
- Specificity = 80%
# Screening
## USPSTF Recommendations
This recommendation applies to adults aged 40 to 70 years who are seen in primary care settings and do not have obvious symptoms of diabetes. Persons who have a family history of diabetes, have a history of gestational diabetes or polycystic ovarian syndrome, or are members of certain racial/ethnic groups (that is, African Americans, American Indians or Alaskan Natives, Asian Americans, Hispanics or Latinos, or Native Hawaiians or Pacific Islanders) may be at increased risk for diabetes at a younger age or at a lower body mass index. Clinicians should consider screening earlier in persons with 1 or more of these characteristics.
# Treatment and management
The goals are to delay the onset of type 2 diabetes, preserving the function of the beta cells, and preventing or delaying the microvascular and cardiovascular complications. Obesity is an extremely important environmental influence, therefore, exercise, weight loss, and drug therapies have been studied. It has been found that lifestyle modification/intervention provides the greatest benefit in preventing the progression into type 2 diabetes. Receiving a diagnosis of prediabetes may increase patient engagement with improving health behavior and healthy lifestyle.
The U.S. Preventive Services Task Force's systematic review of screening for diabetes found:
- Screening for diabetes did not improve mortality rates after 10 years of follow-up, but treatment of IFG or IGT was associated with a moderate benefit in delaying progression to diabetes.
The Community Preventive Services Task Force's systematic review of lifestyle modifications to prevent diabetes in patients with prediabetes:
- Programs based on Diabetes Prevention Program study or the Finnish Diabetes Prevention Study which were more intensive and had more direct interaction than many other programs resulted in more weight loss and lower incidence of diabetes.
The "Let's Prevent Diabetes" Trial also found benefit from a lifestyle and eating educational program to prevent diabetes.
The ADA clinical practice guidelines recommend modest weight loss (5-10% body weight, moderate-intensity exercise (30 minutes daily), and smoking cessation.
## Diabetes Prevention Program
The Diabetes Prevention Program (DPP) is a CDC recognized lifestyle intervention program designed for diagnosed prediabetic patients as an attempt to prevent or delay the progression of the disease to type 2 diabetes.
A meta-analysis by the Cochrane Collaboration found favorable effects on preventing cardiovascular outcomes of the DPP compared to alternatives including metformin. An previous meta-analysis by the Cochrane found benefit from counseling for diet and exercise.
In a 2015 randomized control trial comparing a YMCA Diabetes Prevention program to standard care, 12-month weight loss was 2.3 kilograms more for the DPP arm than for standard care participants. Additionally, persons attending 9 or more lessons had a 5.3-kilogram greater weight loss than did those with standard care alone.
The Diabetes Prevention Program (DPP) randomized controlled trial, comparing intensive lifestyle intervention with masked Metformin and placebo among patients at high risk for diabetes, showed the following relative risk reductions in incidence of diabetes compared to placebo:
- Lifestyle modification: 58%
- Metformin: 31%
- Lifestyle compared to Metformin: 39%
Intensive weight loss and lifestyle intervention, if sustained, can substantially improve glucose tolerance and prevent progression from IGT to type 2 diabetes, and has the potential to cut the incidence of diabetes in half. In the Diabetes Prevention Program (DPP) study, there was found to be a 16% reduction in diabetes risk for every kilogram of weight loss. Reducing weight by 7% through a low-fat diet and performing 150 minutes of exercise a week is the goal.
At long-term follow-up, behavior changes may persist at 10 years, and at 15-year follow-up study suggests that long-term lifestyle modification is superior to Metformin, with a 27% reduced diabetes incidence with lifestyle intervention vs. 18% reduced diabetes incidence with Metformin intervention. However, metformin may be superior for weight loss.
A structured decision aid may increase patients intentions to start lifestyle interventions.
Peer coaches may not add to the DPP.
## Metformin
Metformin can be considered in patients for whom lifestyle therapy has failed or is not sustainable and who are at high-risk for developing type 2 diabetes. However, metformin does not add to "intensive diet and exercise did not reduce or delay the risk of T2DM" according to a systematic review by the Cochrane Collaboration.
## Vitamin D
Vitamin D has been investigated but was not beneficial
# Cure
There currently is no cure. Prevention and delay of the disease are key. There are studies being conducted, but no cure has yet to be found. However as per Ayurveda Diabetes can be cured with the help of Pranayam and Yogasanas.
# Prognosis
The progression to type 2 diabetes mellitus is not inevitable for those with prediabetes. The progression into DM from prediabetes (IFG or IGT) is approximately 25% over three to five years
# Epidemiology
Studies conducted from 1988-1994 indicated that at that time, 33.8% of the US population 40-74 years of age had IFG, 15.4% had IGT, and 40.1% had prediabetes (IFG, IGT, or both). Eighteen million people (6.3% of the population) had type 2 diabetes in 2002. | Prediabetes
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Prediabetes is the state in which blood glucose levels are above normal but have not reached that of diabetes. This state is also referred to as borderline diabetes, impaired glucose tolerance (IGT), and/or impaired fasting glucose (IFG). These are associated with insulin resistance and are risk factors for the development of type 2 diabetes mellitus. In addition, obesity, family history of type 2 diabetes mellitus, and certain ethnic groups are also at high-risk. Those in this stratum (IGT or IFG) are at increased risk of cardiovascular disease. Of the two, impaired glucose tolerance better predicts cardiovascular disease and mortality. [1] [2][3]
Diabetes mellitus (DM) is a group of metabolic diseases that are characterized by hyperglycemia and defects in insulin production in the pancreas and/or impaired tolerance to insulin effects. DM is a leading cause of morbidity and mortality. Because the disease can be insidious, the diagnosis is often delayed. Effects of the disease can be macrovascular, as seen in the cardiovascular system/arthrosclerosis, or microvascular, as seen with retinopathy, nephropathy, and neuropathy. [4]
# Epidemiology
About one third of Americans have prediabetes.[5][6]
# Signs and symptoms
Prediabetes typically has no signs or symptoms. patients should monitor for signs and symptoms of type 2 diabetes mellitus. These include the following:
- Constant hunger
- Unexplained weight loss
- Weight gain
- Flu-like symptoms, including weakness and fatigue
- Blurred vision
- Slow healing of cuts or bruises
- Tingling or loss of feeling in hands or feet
- Recurring gum or skin infections
- Recurring vaginal or bladder infections[7]
# Genetics
As the human genome is further explored, it is likely that multiple genetic anomalies at different loci will be found that confer varying degrees of predisposition to type 2 diabetes. [8] Type 2 DM, which is the condition for which prediabetes is a precursor, has 90-100% concordance in twins; there is no HLA association.[9]
# Pathophysiology
Normal glucose homeostasis is controlled by three interrelated processes. There is gluconeogenesis (glucose production that occurs in the liver), uptake and utilization of glucose by the peripheral tissues of the body, and insulin secretion by the pancreatic islet cells. What triggers the production and release of insulin from the pancreas is the presence of glucose in the body. The main function of insulin is to increase the rate of transport of glucose into certain cells of the body, such as striated muscles, fibroblasts, and fat cells. It is also necessary for transport of amino acids, glycogen formation in the liver and skeletal muscles, triglyceride formation from glucose, nucleic acid synthesis, and protein synthesis.
Insulin enters cells by first binding to target insulin receptors. DM and some of those with prediabetes have impaired glucose tolerance—in these individuals, blood glucose rises to abnormally high levels. This may be from a lack of pancreatic enzyme release or failure of target tissues to respond to the insulin present or both. [10]
# Diagnosis
Prediabetes can be diagnosed in different ways. Each, however, must be confirmed with repeat testing on separate days. The diagnosis of IFG is done after an 8 hour fast; the plasma glucose level must be greater than 99 but less than 126. In order to diagnose IGT, the plasma glucose level must be greater than 139 but less than 200 two hours after an OGTT (oral glucose tolerance test), which is an oral load of 75 grams of glucose. A random glucose level over 140 at any time can result in the diagnosis of prediabetes.[11]
A meta-analysis of the accuracy of the fasting plasma glucose for current prediabetes found:
[12]
- Sensitivity = 25%
- Specificity = 94%
A meta-analysis of the accuracy of the glycosylated hemoglobin for current prediabetes found:
[12]
- Sensitivity = 50%
- Specificity = 80%
# Screening
## USPSTF Recommendations
This recommendation applies to adults aged 40 to 70 years who are seen in primary care settings and do not have obvious symptoms of diabetes. Persons who have a family history of diabetes, have a history of gestational diabetes or polycystic ovarian syndrome, or are members of certain racial/ethnic groups (that is, African Americans, American Indians or Alaskan Natives, Asian Americans, Hispanics or Latinos, or Native Hawaiians or Pacific Islanders) may be at increased risk for diabetes at a younger age or at a lower body mass index. Clinicians should consider screening earlier in persons with 1 or more of these characteristics. [13]
# Treatment and management
The goals are to delay the onset of type 2 diabetes, preserving the function of the beta cells, and preventing or delaying the microvascular and cardiovascular complications. Obesity is an extremely important environmental influence, therefore, exercise, weight loss, and drug therapies have been studied. It has been found that lifestyle modification/intervention provides the greatest benefit in preventing the progression into type 2 diabetes. [14] Receiving a diagnosis of prediabetes may increase patient engagement with improving health behavior and healthy lifestyle.[15]
The U.S. Preventive Services Task Force's systematic review of screening for diabetes found:
- Screening for diabetes did not improve mortality rates after 10 years of follow-up, but treatment of IFG or IGT was associated with a moderate benefit in delaying progression to diabetes.[16]
The Community Preventive Services Task Force's systematic review of lifestyle modifications to prevent diabetes in patients with prediabetes[17]:
- Programs based on Diabetes Prevention Program study or the Finnish Diabetes Prevention Study which were more intensive and had more direct interaction than many other programs resulted in more weight loss and lower incidence of diabetes.
The "Let's Prevent Diabetes" Trial also found benefit from a lifestyle and eating educational program to prevent diabetes.[18]
The ADA clinical practice guidelines [2] recommend modest weight loss (5-10% body weight, moderate-intensity exercise (30 minutes daily), and smoking cessation.
## Diabetes Prevention Program
The Diabetes Prevention Program (DPP) is a CDC recognized lifestyle intervention program designed for diagnosed prediabetic patients as an attempt to prevent or delay the progression of the disease to type 2 diabetes.
A meta-analysis by the Cochrane Collaboration found favorable effects on preventing cardiovascular outcomes of the DPP compared to alternatives including metformin[19]. An previous meta-analysis by the Cochrane found benefit from counseling for diet and exercise[20].
In a 2015 randomized control trial comparing a YMCA Diabetes Prevention program to standard care, 12-month weight loss was 2.3 kilograms more for the DPP arm than for standard care participants. Additionally, persons attending 9 or more lessons had a 5.3-kilogram greater weight loss than did those with standard care alone. [21]
The Diabetes Prevention Program (DPP) randomized controlled trial, comparing intensive lifestyle intervention with masked Metformin and placebo among patients at high risk for diabetes, showed the following relative risk reductions in incidence of diabetes compared to placebo:[22]
- Lifestyle modification: 58%
- Metformin: 31%
- Lifestyle compared to Metformin: 39%
Intensive weight loss and lifestyle intervention, if sustained, can substantially improve glucose tolerance and prevent progression from IGT to type 2 diabetes, and has the potential to cut the incidence of diabetes in half[21]. In the Diabetes Prevention Program (DPP)[3] study, there was found to be a 16% reduction in diabetes risk for every kilogram of weight loss. Reducing weight by 7% through a low-fat diet and performing 150 minutes of exercise a week is the goal.
At long-term follow-up, behavior changes may persist at 10 years[23], and at 15-year follow-up study suggests that long-term lifestyle modification is superior to Metformin, with a 27% reduced diabetes incidence with lifestyle intervention vs. 18% reduced diabetes incidence with Metformin intervention[22]. However, metformin may be superior for weight loss[24].
A structured decision aid may increase patients intentions to start lifestyle interventions[25].
Peer coaches may not add to the DPP[26].
## Metformin
Metformin can be considered in patients for whom lifestyle therapy has failed or is not sustainable and who are at high-risk for developing type 2 diabetes.[27] However, metformin does not add to "intensive diet and exercise did not reduce or delay the risk of T2DM" according to a systematic review by the Cochrane Collaboration[19].
## Vitamin D
Vitamin D has been investigated but was not beneficial[28]
.
# Cure
There currently is no cure. Prevention and delay of the disease are key. There are studies being conducted, but no cure has yet to be found. However as per Ayurveda Diabetes can be cured with the help of Pranayam and Yogasanas.
# Prognosis
The progression to type 2 diabetes mellitus is not inevitable for those with prediabetes. The progression into DM from prediabetes (IFG or IGT) is approximately 25% over three to five years [29]
# Epidemiology
Studies conducted from 1988-1994 indicated that at that time, 33.8% of the US population 40-74 years of age had IFG, 15.4% had IGT, and 40.1% had prediabetes (IFG, IGT, or both). Eighteen million people (6.3% of the population) had type 2 diabetes in 2002.[30] | https://www.wikidoc.org/index.php/Prediabetes | |
55ed9b09402bca84cc4afe59e3827a980a167fe3 | wikidoc | Preferences | Preferences
# Overview
The preferences dialog allows you to personalize some aspects of a MediaWiki wiki. They will apply only when you are logged in. The default wiki sysop admin login name is: WikiSysop.
Some MediaWiki projects form a family in the sense that one logs in into the family as a whole, and that common preference settings apply. Notably this is the case for the more than 1000 Wikia projects. On Wikimedia projects logging in and setting preferences are currently done separately on each wiki. You may find it convenient to specify the same preferences on each wiki that you use, but this is not necessary. See also Single signon transition.
# User data
- Your e-mail: You may optionally register your e-mail address (it will not be shown publicly on the site). This will enable you to reset your password by clicking the "Mail me a new password" box on the log in screen, if you forget it. Additionally, it will enable other registered users to send e-mail to you from the "E-mail this user" link on your user page unless you've checked the disable box (see below).
- Disable e-mail from other users: If you check this, users will not be able to send you e-mail by way of the "E-mail this user" feature.
## Your nickname
Although your username is not necessarily your real name and could therefore be called a nickname, the term "nickname" is used here for a name you may optionally specify, different from your username, for when you enter your signature with ~~~ or ~~~~.
(If you use the edit toolbar for signing, remember that it gives two dashes before the four tildes.)
### Raw signatures
However, there is even more versatility. You can use any text as your nickname.
From MediaWiki 1.5 the behaviour of signatures has changed. In older versions of MediaWiki, wiki and HTML markup could be entered in signatures, even without "Raw signatures" being checked. So entering "]] | [[User talk:Name|Talk" as your signature would have also included a link to your talk page in your signature, producing an effect similar to: "Name | Talk". This is now no longer the case.
If "Raw signatures (without automatic link)" is unchecked, then
- The software enters "]" after your nickname text.
- Any characters in your nickname that would otherwise constitute Wiki markup and HTML markup are escaped as HTML character entities. A nickname of "]] | ] | [[User talk:Name|Talk", which is probably not what you want.
If "Raw signatures" is checked, then
- Nothing is added to the text that you specify. What you specify is what is used between the two dashes and the timestamp.
- Wiki markup and HTML markup are not escaped, allowing you to include links, font tags, images, and templates in your signature.
### Invalid raw signatures
You may find the following message displayed in your user preferences:
This means you are using invalid HTML markup on your signature. Some possible causes with their corresponding solutions:
### Using images and templates in signatures
Note that changes in the images and templates are retroactive, which on one hand may be confusing, but on the other hand, to rectify annoying signatures, may be convenient. To avoid retroactivity, use a new image or template name. Do not create a signature template in the article or template namespace: instead use a subpage of your own userpage such as sig, and link it with "{{User:Name/sig}}".
In the case of a common signature on several projects, as in Wikicities, remember that templates are project-specific. Thus, if a signature contains a template call, to make it work in all projects, a template is needed in each (these may be copies, but the content can also be different for each project). Note also that links may lead to a different page, depending on the project in which you put the signature, even if you use interwiki link style. For example, India:User talk:John leads to the page User talk:John on India, except from the India project, where it leads to India:User talk:John in the India namespace. Therefore you may want to use external link style, or make a redirect such that the final target of the link is always the same.
### Signature content
Check the rules of your project (for example, for the English Wikipedia see w:Wikipedia:Sign your posts on talk pages) and note that:
- using another nickname than your username is confusing (the page history shows your username, not your nickname)
- if you show your username as an image, or with letters replaced by special characters, even if the name is still readable, searching a talk page for your username will fail
- excessive signatures may clutter talk pages
- drawing excessive attention to yourself may create the impression that you find yourself more important than other people
## Password
To change your password, enter your old password, the new password, and the new password a second time. (If you're merely changing the other preferences, you do not need to enter your password.)
- Remember password across sessions. Enabling this feature will place an HTTP cookie in your browser's cache, which will allow MediaWiki to recognize you each time you visit the page. You will not have to log in each time you visit.
If you want to use remember my password you have to change your password if it was generated by Mediawiki and emailed to you. This is a security feature but very often causes trouble for new users.
## Interface language
One can specify an interface language. If that is different from the default language of the wiki, it causes the default messages of the specified other language to appear, not those in the MediaWiki namespace. If MediaWiki:Sidebar in a project contains literal labels, these are in effect for all interface languages.
Note that some contain internal links, with the name of a page in the interface language project but without the corresponding prefix; therefore these links in general do not work, unless redirects are made.
Note that using English as interface language in RTL projects shows "This is a minor edit" and "Watch this page" on the edit page with tick boxes reversed: the tick boxes do not belong to the nearest but to the other text.
Note that using Spanish as interface language in version up than 1.4.0 shows no Edit toolbar when editing articles (Mozilla browser, firefox as well).
# QuickBar settings
File:Prefs help - quickbar.png
This selection only works in the Classic and Cologne Blue skins (see below). In Monobook there is a left panel anyway; in Nostalgia there is none.
This is the list of links to the various special pages. You may optionally have it appear at the right or left side of each page. There's no option yet to have it appear at the top or bottom of the page.
The "fixed" quickbar will appear at the top corner of the page, while the "floating" quickbar will appear at the top corner of the browser window instead of scrolling with the article text. Floating quickbars may not float correctly on old or mobile browsers.
The QuickBar must be enabled to allow you access to some features such as moving (renaming) a page, and in the case of Classic, also to arrive at the Special Pages, unless you type the URL.
From MediaWiki 1.5 This has been removed in 1.5
# Skin
Skin
O Classic
O Nostalgia
O Cologne Blue
O MonoBook
O MySkin
A MediaWiki skin is a style of page display. There are differences in the HTML code the system produces (but probably not in the page body), and also different style sheets are used.
The default is the MonoBook skin; what was called Standard is here in the preferences called Classic (not to be confused with the even older Nostalgia), but the system uses "wikistandard" in the naming of css files.
Links at the edges of the page are in different positions. Some links are not present in every skin. In Nostalgia some links are in a drop-down menu instead of directly visible.
Cologne Blue has a fixed font size unless one specifies in the browser "ignore font sizes specified in the webpage"; even then the line height is fixed; therefore this skin is hardly suitable for a large font.
In MonoBook the width of the panel on the left is dependent on the font size. Therefore, with a large font, the width of the main part of the page is smaller than with other skins.
For Classic with a quickbar and a large font a CSS setting to reduce the size of the quickbar text may be necessary. This depends on the project, specifically on the length of the longest word in the quickbar. If that does not fit in the designated width, there are complications depending on the browser. In Internet Explorer the quickbar overlaps the main text and a vertical line which is intended to separate the two, crosses the main text. In some other browsers the problem does not arise if the quickbar is on the right.
Since there is word wrapping but no wrapping within a word, the longest word and not the longest full label is the criterion:
- "contributions" - English and French Wikipedia and Meta - short, large font is possible
- "Beobachtungsliste" - German Wikipedia - long - large font is hardly useable
- "Foutenrapportage" - Dutch Wikipedia - ditto
- "Gebruikersbydraes" - Afrikaans - ditto
To use the full width of the screen for the main text, use Classic without quickbar or Nostalgia. The drawback is that links are missing to the special pages and your user page, respectively.
Screenshots:
- Image:Colognebluess.png
- Image:Nostalgiass.png
- Image:Standardss.png
See also Help:User style, and for developments and discussions, Skins.
# Rendering math
MediaWiki allows you to enter mathematical equations as TeX code. These options let you control how that code is rendered into PNG images.
- Always render PNG: Always make a PNG image from the TeX code.
- HTML if very simple or else PNG: If the TeX code is very simple, like "x = 3", render it as HTML. For more complex code, render as PNG.
- HTML if possible or else PNG: This option tries really hard to use HTML, but if it's too complicated, then it renders it as PNG. This option does not show a^{b^c} correctly! It shows the c at base level, which is not just a matter of being ugly, but it makes formulas wrong!. A workaround is to add "\,\!": a^{b^{\,\!2+2}}. With the current settings you get a^{b^c} and a^{b^{\,\!c}}
- Leave it as TeX: Don't convert the TeX code, just show it. This is primarily for text-based browsers like Lynx.
- Recommended for modern browsers. If you use a web browser that was released in the past year or so, use this option.
- MathML if possible (experimental)
# Files
(Prior to version 1.5, this is under "Recent changes and stub display".)
One can specify a limit on the size of images on image description pages.
The large limit 10000x10000 means that one gets the full image.
With a slow connection it is not practical to have to load a large image just to read image info. Also, it may be practical if a large image at first is made to fit on the screen, in the case that the browser does not do that itself. If the image has been reduced there is a link to the full image.
From MediaWiki 1.5 the default thumbnail width can be set in the preferences; this can be overridden by an image width specified in the image tag; the latter is typically not advisable, in order to respect the users' preferences.
# Date format
The following is rendered depending on preferences:
With your current preference setting on this project the seven are rendered as follows:
- 2001 January 15
- January 15, 2001
- 15 January 2001
- January 15
- 15 January
By default the rendering is as usual for links, except that in the first case the syntax for a single link gives two links. However, one can specify as preference that all full date formats are rendered the same, in the 1st, 2nd, 3rd, or 4th way. (Note that format ] is the shortest of these five.) If the 1st or 2nd way is selected, the 5th and 6th line are not affected.
If the 3rd or 4th way is selected, the 5th and 6th line are rendered accordingly, without the year.
For years in the range 1-1000, in the two cases on the first line the year has to be padded with zeros:
gives:
- 11 January 15
- January 15, 11
- 15 January 11
For years B.C.:
gives:
- 12 BC January 15
- January 15, 12 BC
- 15 January 12 BC
The setting also affects what wikitext the signature of the user produces. Since dates in signatures are not linked, this determines how the date is rendered for everybody, and this can not be changed retroactively, except by editing the pages with the signature.
Note that using this date formatting feature in section headers complicates section linking: a link to a section with a variable date format has to be set in a fixed date format, which works only for users for whom the formats match. Thus, if you want to be able to use links like w:November_2004#November_1.2C_2004, in the calendar at the upper right of the month pages on Wikipedia, or links elsewhere to the section about a particular day (if they also use the default format), you cannot use the date formatting feature.
For chronological table sorting the format ] is required. Another special property of this format is that it also gives seconds, in Recent Changes, User Contributions, etc.: "HH:mm:SS", or with the date: "YYYY-MM-DDTHH:mm:SS".
See also m:Dynamic dates and w:en:Wikipedia:Manual of Style (dates and numbers)#Dates.
## Screenshots
- Date-preferences-Screenshot
# Time zone
- Time diff. This is the number of hours to be added or subtracted from UTC to find your time zone. This time zone is used when calculating displayed page update timestamps, and may become temporarily incorrect from time to time if you observe daylight saving time -- don't forget to update it to match your local time, because the Wiki doesn't know where you are or precisely when you celebrate DST. (Also, the server's clock may be slightly offset from reality, much as Wikipedia articles may be.) A scattering of typical (and possibly incorrect!) time diff values are below. If yours isn't listed, try this link or add and subtract a few hours as needed.
- -10 (DST -9) Hawaii, western Aleutians (Hawaii-Aleutian Standard Time)
-9 (DST -8) All of Alaska, except for western Aleutians (Alaska Standard Time)
-8 (DST -7) California; Washington; almost all of Oregon, Nevada, and British Columbia (Pacific Standard Time)
-7 (DST -6) Colorado, Arizona (no DST except for Navajo Nation), Alberta (Mountain Standard Time)
-6 (DST -5) Chicago, most of Mexico, Central America, Saskatchewan (Central Standard Time)
-5 (DST -4) New York, Toronto, Quebec (Eastern Standard Time)
-4 (DST -3) Canada's Maritime Provinces, plus most of Labrador
-3.5 (DST -2.5) Newfoundland
-3 (DST -2) Brasilia, Buenos Aires, Montevideo, most of Greenland
-2 (DST -1) Mid-Atlantic
-1 (DST 0) Azores, Cape Verde Islands
0 (DST 1) United Kingdom, Republic of Ireland, mainland Portugal, Iceland (no DST), Casablanca, Monrovia (no DST)
1 (DST 2) most of Europe, West Central Africa (no DST)
2 (DST 3) Istanbul, Bucharest, Kiev, Cairo, Johannesburg (no DST), Finland, Jerusalem
3 (DST 4) Moscow, Kuwait, Baghdad, Tehran, Nairobi (no DST)
4 Abu Dhabi, Baku
4.5 Kabul
5 Islamabad
5.5 India
5.75 Nepal
6 Sri Lanka, etc.
6.5 Rangoon
7 Bangkok, Hanoi, Jakarta
8 People's Republic of China, Taiwan, Western Australia, Ulaan Bataar, Singapore, Manila
9 Japan, Seoul
9.5 (DST 10.5) South Australia and Northern Territory (no DST)
10 (DST 11) Queensland (no DST), New South Wales, Victoria, Tasmania, Guam (no DST), Vladivostok
11 Magadan (DST 12), Solomon Islands, New Caledonia
12 Pago Pago, New Zealand (DST 13)
- -10 (DST -9) Hawaii, western Aleutians (Hawaii-Aleutian Standard Time)
- -9 (DST -8) All of Alaska, except for western Aleutians (Alaska Standard Time)
- -8 (DST -7) California; Washington; almost all of Oregon, Nevada, and British Columbia (Pacific Standard Time)
- -7 (DST -6) Colorado, Arizona (no DST except for Navajo Nation), Alberta (Mountain Standard Time)
- -6 (DST -5) Chicago, most of Mexico, Central America, Saskatchewan (Central Standard Time)
- -5 (DST -4) New York, Toronto, Quebec (Eastern Standard Time)
- -4 (DST -3) Canada's Maritime Provinces, plus most of Labrador
- -3.5 (DST -2.5) Newfoundland
- -3 (DST -2) Brasilia, Buenos Aires, Montevideo, most of Greenland
- -2 (DST -1) Mid-Atlantic
- -1 (DST 0) Azores, Cape Verde Islands
- 0 (DST 1) United Kingdom, Republic of Ireland, mainland Portugal, Iceland (no DST), Casablanca, Monrovia (no DST)
- 1 (DST 2) most of Europe, West Central Africa (no DST)
- 2 (DST 3) Istanbul, Bucharest, Kiev, Cairo, Johannesburg (no DST), Finland, Jerusalem
- 3 (DST 4) Moscow, Kuwait, Baghdad, Tehran, Nairobi (no DST)
- 4 Abu Dhabi, Baku
- 4.5 Kabul
- 5 Islamabad
- 5.5 India
- 5.75 Nepal
- 6 Sri Lanka, etc.
- 6.5 Rangoon
- 7 Bangkok, Hanoi, Jakarta
- 8 People's Republic of China, Taiwan, Western Australia, Ulaan Bataar, Singapore, Manila
- 9 Japan, Seoul
- 9.5 (DST 10.5) South Australia and Northern Territory (no DST)
- 10 (DST 11) Queensland (no DST), New South Wales, Victoria, Tasmania, Guam (no DST), Vladivostok
- 11 Magadan (DST 12), Solomon Islands, New Caledonia
- 12 Pago Pago, New Zealand (DST 13)
The time is displayed in local time, according to the set preferences, in:
- Recent changes
- Related changes
- Page history, Image history
- User contributions
- Special:Newpages
- "This page was last modified" at the bottom of pages
- Special:Imagelist
The UTC time is applicable:
- In the signing of Talk pages
- In the Upload log
- In referring to non-localized events, including things that happen on the wiki.
Keep this in mind when copying an excerpt from Recent Changes, a revision history listing, etc. to a Talk page. Convert manually to UTC or temporarily set the preferences to a zero offset before producing the revision history etc. to be copied.
# Editing
- Rows, Columns. Here you can set up your preferred dimensions for the textbox used for editing page text.
- Enable section editing via links. An edit link will appear to the right of each sub-heading to allow editing of that subsection only.
- Enable section editing by right-clicking on section titles (JavaScript). In compatible browsers, if this option is checked, a right-click on the section title will bring up the edit box for that section only.
- Edit pages on double click (JavaScript). In compatible browsers, if this option is checked, a double click anywhere on the page will bring up the edit box for the entire contents of the page.
- Edit box has full width. If this box is checked, the edit box (when you click "Edit this page") will be the width of the browser window, minus the quickbar width.
- Show edit toolbar. In compatible browsers, a toolbar with editing buttons can be displayed.
- Show preview on first edit - when pressing the edit button or otherwise following a link to an edit page, show not only the edit box but also the rendered page, just like after pressing "Show preview". This is especially useful when viewing a template, because even just viewing, not editing, typically requires both.
- Show preview before edit box. If you select this option, the preview will be displayed above the edit box when you click the "Show preview" button while editing a page.
- Add pages I create to my watchlist. If this option is selected, any page you create will automatically be added to your watchlist.
- Add pages you edit to your watchlist. If this option is selected, any pages that you modify will be automatically added to your watchlist.
- Mark all edits minor by default. This option automatically selects the "This is a minor edit" checkbox when you edit pages.
- Use external editor by default. (New to 1.5) Changes editing from online version to external program. See Help:External editors.
- Use external diff by default. (New to 1.5) Changes diffing from online version to external program. See Help:External editors.
- Prompt me when entering a blank edit summary. If selected, the editor will display a warning message when no edit summary is added to the edit summary box, after the "Save page" button is pressed.
# Recent changes and stub display
- Number of titles on recent changes: You may select the number of changes which will be shown by default on the Recent Changes and Watchlist page. Once on those pages, links are provided for other options.
- Hide minor edits in recent changes. Registered users may choose to mark edits as being minor (meaning fixes too trivial for trusting users to check up on). It applies to Recent Changes and Enhanced Recent Changes, but not to the Watchlist. It also affects Related changes, but currently in an odd way: if the last edit of a page linking to the current page was minor, then neither that nor the last major change is shown.
- Enhanced recent changes (not for all browsers). Group recent changes per day by article, display the titles of the changed articles in order from new to old latest change, or in the case of hiding minor edits, latest major change. This feature applies also to Related Changes, but not to the watchlist.
- Threshold for stub display: see Stub feature.
# Search result settings
- Hits to show per page: You may choose the number of results returned on each page of search results.
- Lines to show per hit is somewhat cryptic; specifying a number n means: "do not show any context if the search term occurs beyond line n in the page"; here a paragraph, as well as the blank line between two paragraphs, each count as one "line"; line breaks in the source, even when not affecting the lay-out of the page (and even when not directly visible in the edit box of the article), affect the line count. Setting the parameter to 5000 or more gives context for every occurrence.
- Characters of context per line: the number of characters of context per occurrence; however, the context is anyway restricted to the "line" (see above) it occurs in. To get the whole line, put a large number like 5000.
- Search in these namespaces by default: shows a list of all namespaces (not the same in all projects; for older MediaWiki versions, which do not have Special:Version, this is also a useful indicator what version is used; for even older versions that do not have this item in the preferences, see the list after performing a search), allowing one to select which ones are searched by default; see also Namespaces searched.
# Misc settings
- Show hoverbox over wiki links. This option determines whether a link title is put in the HTML code. The result depends on the browser: putting the mouse pointer over a link often displays this title in a hover box. However, some browsers show the URL anyway, so a link title may be superfluous. If enabled, the link title is the page name in the case of an internal link, the page name with prefix in the case of an interwiki link, and the URL in the case of an external link.
- Underline links. Normally, link text will be underlined. Optionally, you may request that links not be underlined, although your browser may not respect this setting. Normally links that are not underlined can still be recognized by color. However, one can then not distinguish between two consecutive words being a single link or two links, without pointing at the words with the cursor. For an old discussion of changing the default here, see m:Link style vote. For further choices of style of links in general and/or types of links one can use CSS (site-wide for all skins, site-wide per skin, user-specific per skin, or web-wide, user-specific)
- Format broken links like this. An internal link to a non-existing pages is automatically a link to the edit page. By default the link label of ] and ] is "b", just like for links to existing pages. Alternatively the link label is a question mark inserted after "b", like this: A red link?. The appearance of the link is further determined by the style specified for css selectors "a.new" and "a.new:hover" (the example on the preferences page wrongly uses class="internal" for the question mark). Internal links to pages which do not yet exist currently appear on your browser like this one. Normally, this is underlined and in red. With the trailing question mark link one can then not distinguish between a single word being linked or a phrase of more than one word, without pointing at the question mark with the cursor. Also, remember that the question mark does not mean that the information is uncertain.
- Justify paragraphs. If set, article paragraphs will be formatted to avoid jagged line endings. If unset, the paragraphs will be formatted as-is.
- Auto-number headings. This adds hierarchical outline-style numbering to headers in articles.
- Edit pages on double click. If this box is checked, you can double-click on a page to edit it. This option requires JavaScript to be enabled in your browser.
- Enable section editing via links. Shows or hides the links on section titles.
- Enable section editing by right-clicking on section titles (JavaScript). Note that in the case of a header with a link (which may occur, although it is not recommended in some projects) this disables opening the link in a new window through right-clicking (an alternative way such as shift-clicking may work). Also other right-clicking functions, such as "Properties", are disabled.
- Show table of contents (for articles with more than 3 headings)
- Disable page caching. This turns off page caching. This is useful if you're experiencing problems of seeing outdated versions of pages, but this comes at a cost of longer loading times.
- Enable "jump to" accessibility links - Provides or hides the two links "Jump to: navigation, search" at the top of each page, to the navigation bar and the search box.
# Notes
If you want to change your username, it is recommended that you do this retroactively in the sense that your previous user contributions are recorded under the new name. Users and sysops cannot do this, one can ask a bureaucrat to do so. Signatures are not changed and therefore will no longer match page histories of the talk pages concerned. However, you can edit signatures manually. Also other occurrences of your name on talk pages are not retroactively changed. The deletion log and the upload log are not altered.
Account deletion is not possible.
You cannot indicate personal information (such as your real name) here, but you may do so on a page named after your username in the User: namespace. (That's available as a link on the line which says "You are logged in as user WhatsYourName" above the preferences panel. Feel free to start your own page with anything you want to say about yourself on it.)
# Browser preferences
Browsers usually also allow you to specify preferences, e.g. font size and font type. The standard skin is compatible with your browser setting of font size and font type. The Cologne Blue skin has most text in a fixed font size, ignoring your browser setting. Some browsers, e.g. IE, allow you to specify that font size specified in the web page is ignored. In that case the font size in Cologne Blue is as specified in the browser, but with the line height not adjusted accordingly. Therefore a large font gives a messy result.
# Providing your own CSS
Cascading Style Sheets are used to configure MediaWiki's visual appearance. You can specify your own CSS definitions and overwrite the default settings. See Help:User style. | Preferences
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The preferences dialog allows you to personalize some aspects of a MediaWiki wiki. They will apply only when you are logged in. The default wiki sysop admin login name is: WikiSysop.
Some MediaWiki projects form a family in the sense that one logs in into the family as a whole, and that common preference settings apply. Notably this is the case for the more than 1000 Wikia projects. On Wikimedia projects logging in and setting preferences are currently done separately on each wiki. You may find it convenient to specify the same preferences on each wiki that you use, but this is not necessary. See also Single signon transition.
# User data
- Your e-mail: You may optionally register your e-mail address (it will not be shown publicly on the site). This will enable you to reset your password by clicking the "Mail me a new password" box on the log in screen, if you forget it. Additionally, it will enable other registered users to send e-mail to you from the "E-mail this user" link on your user page unless you've checked the disable box (see below).
- Disable e-mail from other users: If you check this, users will not be able to send you e-mail by way of the "E-mail this user" feature.
## Your nickname
Although your username is not necessarily your real name and could therefore be called a nickname, the term "nickname" is used here for a name you may optionally specify, different from your username, for when you enter your signature with ~~~ or ~~~~.
(If you use the edit toolbar for signing, remember that it gives two dashes before the four tildes.)
### Raw signatures
However, there is even more versatility. You can use any text as your nickname.
From MediaWiki 1.5 the behaviour of signatures has changed. In older versions of MediaWiki, wiki and HTML markup could be entered in signatures, even without "Raw signatures" being checked. So entering "]] | [[User talk:Name|Talk" as your signature would have also included a link to your talk page in your signature, producing an effect similar to: "Name | Talk". This is now no longer the case.
If "Raw signatures (without automatic link)" is unchecked, then
- The software enters "[[User:Name|" in front of, and "]]" after your nickname text.
- Any characters in your nickname that would otherwise constitute Wiki markup and HTML markup are escaped as HTML character entities. A nickname of "]] | [[User talk:Name|Talk" will thus produce a signature of "]] | [[User talk:Name|Talk", which is probably not what you want.
If "Raw signatures" is checked, then
- Nothing is added to the text that you specify. What you specify is what is used between the two dashes and the timestamp.
- Wiki markup and HTML markup are not escaped, allowing you to include links, font tags, images, and templates in your signature.
### Invalid raw signatures
You may find the following message displayed in your user preferences:
This means you are using invalid HTML markup on your signature. Some possible causes with their corresponding solutions:
### Using images and templates in signatures
Note that changes in the images and templates are retroactive, which on one hand may be confusing, but on the other hand, to rectify annoying signatures, may be convenient. To avoid retroactivity, use a new image or template name. Do not create a signature template in the article or template namespace: instead use a subpage of your own userpage such as sig, and link it with "{{User:Name/sig}}".
In the case of a common signature on several projects, as in Wikicities, remember that templates are project-specific. Thus, if a signature contains a template call, to make it work in all projects, a template is needed in each (these may be copies, but the content can also be different for each project). Note also that links may lead to a different page, depending on the project in which you put the signature, even if you use interwiki link style. For example, India:User talk:John leads to the page User talk:John on India, except from the India project, where it leads to India:User talk:John in the India namespace. Therefore you may want to use external link style, or make a redirect such that the final target of the link is always the same.
### Signature content
Check the rules of your project (for example, for the English Wikipedia see w:Wikipedia:Sign your posts on talk pages) and note that:
- using another nickname than your username is confusing (the page history shows your username, not your nickname)
- if you show your username as an image, or with letters replaced by special characters, even if the name is still readable, searching a talk page for your username will fail
- excessive signatures may clutter talk pages
- drawing excessive attention to yourself may create the impression that you find yourself more important than other people
## Password
To change your password, enter your old password, the new password, and the new password a second time. (If you're merely changing the other preferences, you do not need to enter your password.)
- Remember password across sessions. Enabling this feature will place an HTTP cookie in your browser's cache, which will allow MediaWiki to recognize you each time you visit the page. You will not have to log in each time you visit.
If you want to use remember my password you have to change your password if it was generated by Mediawiki and emailed to you. This is a security feature but very often causes trouble for new users.
## Interface language
One can specify an interface language. If that is different from the default language of the wiki, it causes the default messages of the specified other language to appear, not those in the MediaWiki namespace. If MediaWiki:Sidebar in a project contains literal labels, these are in effect for all interface languages.
Note that some contain internal links, with the name of a page in the interface language project but without the corresponding prefix; therefore these links in general do not work, unless redirects are made.
Note that using English as interface language in RTL projects shows "This is a minor edit" and "Watch this page" on the edit page with tick boxes reversed: the tick boxes do not belong to the nearest but to the other text.
Note that using Spanish as interface language in version up than 1.4.0 shows no Edit toolbar when editing articles (Mozilla browser, firefox as well).
# QuickBar settings
File:Prefs help - quickbar.png
This selection only works in the Classic and Cologne Blue skins (see below). In Monobook there is a left panel anyway; in Nostalgia there is none.
This is the list of links to the various special pages. You may optionally have it appear at the right or left side of each page. There's no option yet to have it appear at the top or bottom of the page.
The "fixed" quickbar will appear at the top corner of the page, while the "floating" quickbar will appear at the top corner of the browser window instead of scrolling with the article text. Floating quickbars may not float correctly on old or mobile browsers.
The QuickBar must be enabled to allow you access to some features such as moving (renaming) a page, and in the case of Classic, also to arrive at the Special Pages, unless you type the URL.
From MediaWiki 1.5 This has been removed in 1.5
# Skin
Skin
O Classic
O Nostalgia
O Cologne Blue
O MonoBook
O MySkin
A MediaWiki skin is a style of page display. There are differences in the HTML code the system produces (but probably not in the page body), and also different style sheets are used.
The default is the MonoBook skin; what was called Standard is here in the preferences called Classic (not to be confused with the even older Nostalgia), but the system uses "wikistandard" in the naming of css files.
Links at the edges of the page are in different positions. Some links are not present in every skin. In Nostalgia some links are in a drop-down menu instead of directly visible.
Cologne Blue has a fixed font size unless one specifies in the browser "ignore font sizes specified in the webpage"; even then the line height is fixed; therefore this skin is hardly suitable for a large font.
In MonoBook the width of the panel on the left is dependent on the font size. Therefore, with a large font, the width of the main part of the page is smaller than with other skins.
For Classic with a quickbar and a large font a CSS setting to reduce the size of the quickbar text may be necessary. This depends on the project, specifically on the length of the longest word in the quickbar. If that does not fit in the designated width, there are complications depending on the browser. In Internet Explorer the quickbar overlaps the main text and a vertical line which is intended to separate the two, crosses the main text. In some other browsers the problem does not arise if the quickbar is on the right.
Since there is word wrapping but no wrapping within a word, the longest word and not the longest full label is the criterion:
- "contributions" - English and French Wikipedia and Meta - short, large font is possible
- "Beobachtungsliste" - German Wikipedia - long - large font is hardly useable
- "Foutenrapportage" - Dutch Wikipedia - ditto
- "Gebruikersbydraes" - Afrikaans - ditto
To use the full width of the screen for the main text, use Classic without quickbar or Nostalgia. The drawback is that links are missing to the special pages and your user page, respectively.
Screenshots:
- Image:Colognebluess.png
- Image:Nostalgiass.png
- Image:Standardss.png
See also Help:User style, and for developments and discussions, Skins.
# Rendering math
MediaWiki allows you to enter mathematical equations as TeX code. These options let you control how that code is rendered into PNG images.
- Always render PNG: Always make a PNG image from the TeX code.
- HTML if very simple or else PNG: If the TeX code is very simple, like "x = 3", render it as HTML. For more complex code, render as PNG.
- HTML if possible or else PNG: This option tries really hard to use HTML, but if it's too complicated, then it renders it as PNG. This option does not show a^{b^c} correctly! It shows the c at base level, which is not just a matter of being ugly, but it makes formulas wrong!. A workaround is to add "\,\!": a^{b^{\,\!2+2}}. With the current settings you get <math>a^{b^c}</math> and <math>a^{b^{\,\!c}}</math>
- Leave it as TeX: Don't convert the TeX code, just show it. This is primarily for text-based browsers like Lynx.
- Recommended for modern browsers. If you use a web browser that was released in the past year or so, use this option.
- MathML if possible (experimental)
# Files
(Prior to version 1.5, this is under "Recent changes and stub display".)
One can specify a limit on the size of images on image description pages.
The large limit 10000x10000 means that one gets the full image.
With a slow connection it is not practical to have to load a large image just to read image info. Also, it may be practical if a large image at first is made to fit on the screen, in the case that the browser does not do that itself. If the image has been reduced there is a link to the full image.
From MediaWiki 1.5 the default thumbnail width can be set in the preferences; this can be overridden by an image width specified in the image tag; the latter is typically not advisable, in order to respect the users' preferences.
# Date format
The following is rendered depending on preferences:
With your current preference setting on this project the seven are rendered as follows:
- 2001-01-15 (2001-01-15)
- 2001 January 15
- January 15, 2001
- 15 January 2001
- January 15
- 15 January
By default the rendering is as usual for links, except that in the first case the syntax for a single link gives two links. However, one can specify as preference that all full date formats are rendered the same, in the 1st, 2nd, 3rd, or 4th way. (Note that format [[YYYY-MM-DD]] is the shortest of these five.) If the 1st or 2nd way is selected, the 5th and 6th line are not affected.
If the 3rd or 4th way is selected, the 5th and 6th line are rendered accordingly, without the year.
For years in the range 1-1000, in the two cases on the first line the year has to be padded with zeros:
gives:
- 0011-01-15 (0011-01-15)
- 11 January 15
- January 15, 11
- 15 January 11
For years B.C.:
gives:
- -0011-01-15 (-0011-01-15)
- 12 BC January 15
- January 15, 12 BC
- 15 January 12 BC
The setting also affects what wikitext the signature of the user produces. Since dates in signatures are not linked, this determines how the date is rendered for everybody, and this can not be changed retroactively, except by editing the pages with the signature.
Note that using this date formatting feature in section headers complicates section linking: a link to a section with a variable date format has to be set in a fixed date format, which works only for users for whom the formats match. Thus, if you want to be able to use links like w:November_2004#November_1.2C_2004, in the calendar at the upper right of the month pages on Wikipedia, or links elsewhere to the section about a particular day (if they also use the default format), you cannot use the date formatting feature.
For chronological table sorting the format [[YYYY-MM-DD]] is required. Another special property of this format is that it also gives seconds, in Recent Changes, User Contributions, etc.: "HH:mm:SS", or with the date: "YYYY-MM-DDTHH:mm:SS".
See also m:Dynamic dates and w:en:Wikipedia:Manual of Style (dates and numbers)#Dates.
## Screenshots
- Date-preferences-Screenshot
# Time zone
- Time diff. This is the number of hours to be added or subtracted from UTC to find your time zone. This time zone is used when calculating displayed page update timestamps, and may become temporarily incorrect from time to time if you observe daylight saving time -- don't forget to update it to match your local time, because the Wiki doesn't know where you are or precisely when you celebrate DST. (Also, the server's clock may be slightly offset from reality, much as Wikipedia articles may be.) A scattering of typical (and possibly incorrect!) time diff values are below. If yours isn't listed, try this link or add and subtract a few hours as needed.
- -10 (DST -9) Hawaii, western Aleutians (Hawaii-Aleutian Standard Time)
-9 (DST -8) All of Alaska, except for western Aleutians (Alaska Standard Time)
-8 (DST -7) California; Washington; almost all of Oregon, Nevada, and British Columbia (Pacific Standard Time)
-7 (DST -6) Colorado, Arizona (no DST except for Navajo Nation), Alberta (Mountain Standard Time)
-6 (DST -5) Chicago, most of Mexico, Central America, Saskatchewan (Central Standard Time)
-5 (DST -4) New York, Toronto, Quebec (Eastern Standard Time)
-4 (DST -3) Canada's Maritime Provinces, plus most of Labrador
-3.5 (DST -2.5) Newfoundland
-3 (DST -2) Brasilia, Buenos Aires, Montevideo, most of Greenland
-2 (DST -1) Mid-Atlantic
-1 (DST 0) Azores, Cape Verde Islands
0 (DST 1) United Kingdom, Republic of Ireland, mainland Portugal, Iceland (no DST), Casablanca, Monrovia (no DST)
1 (DST 2) most of Europe, West Central Africa (no DST)
2 (DST 3) Istanbul, Bucharest, Kiev, Cairo, Johannesburg (no DST), Finland, Jerusalem
3 (DST 4) Moscow, Kuwait, Baghdad, Tehran, Nairobi (no DST)
4 Abu Dhabi, Baku
4.5 Kabul
5 Islamabad
5.5 India
5.75 Nepal
6 Sri Lanka, etc.
6.5 Rangoon
7 Bangkok, Hanoi, Jakarta
8 People's Republic of China, Taiwan, Western Australia, Ulaan Bataar, Singapore, Manila
9 Japan, Seoul
9.5 (DST 10.5) South Australia and Northern Territory (no DST)
10 (DST 11) Queensland (no DST), New South Wales, Victoria, Tasmania, Guam (no DST), Vladivostok
11 Magadan (DST 12), Solomon Islands, New Caledonia
12 Pago Pago, New Zealand (DST 13)
- -10 (DST -9) Hawaii, western Aleutians (Hawaii-Aleutian Standard Time)
- -9 (DST -8) All of Alaska, except for western Aleutians (Alaska Standard Time)
- -8 (DST -7) California; Washington; almost all of Oregon, Nevada, and British Columbia (Pacific Standard Time)
- -7 (DST -6) Colorado, Arizona (no DST except for Navajo Nation), Alberta (Mountain Standard Time)
- -6 (DST -5) Chicago, most of Mexico, Central America, Saskatchewan (Central Standard Time)
- -5 (DST -4) New York, Toronto, Quebec (Eastern Standard Time)
- -4 (DST -3) Canada's Maritime Provinces, plus most of Labrador
- -3.5 (DST -2.5) Newfoundland
- -3 (DST -2) Brasilia, Buenos Aires, Montevideo, most of Greenland
- -2 (DST -1) Mid-Atlantic
- -1 (DST 0) Azores, Cape Verde Islands
- 0 (DST 1) United Kingdom, Republic of Ireland, mainland Portugal, Iceland (no DST), Casablanca, Monrovia (no DST)
- 1 (DST 2) most of Europe, West Central Africa (no DST)
- 2 (DST 3) Istanbul, Bucharest, Kiev, Cairo, Johannesburg (no DST), Finland, Jerusalem
- 3 (DST 4) Moscow, Kuwait, Baghdad, Tehran, Nairobi (no DST)
- 4 Abu Dhabi, Baku
- 4.5 Kabul
- 5 Islamabad
- 5.5 India
- 5.75 Nepal
- 6 Sri Lanka, etc.
- 6.5 Rangoon
- 7 Bangkok, Hanoi, Jakarta
- 8 People's Republic of China, Taiwan, Western Australia, Ulaan Bataar, Singapore, Manila
- 9 Japan, Seoul
- 9.5 (DST 10.5) South Australia and Northern Territory (no DST)
- 10 (DST 11) Queensland (no DST), New South Wales, Victoria, Tasmania, Guam (no DST), Vladivostok
- 11 Magadan (DST 12), Solomon Islands, New Caledonia
- 12 Pago Pago, New Zealand (DST 13)
The time is displayed in local time, according to the set preferences, in:
- Recent changes
- Related changes
- Page history, Image history
- User contributions
- Special:Newpages
- "This page was last modified" at the bottom of pages
- Special:Imagelist
The UTC time is applicable:
- In the signing of Talk pages
- In the Upload log
- In referring to non-localized events, including things that happen on the wiki.
Keep this in mind when copying an excerpt from Recent Changes, a revision history listing, etc. to a Talk page. Convert manually to UTC or temporarily set the preferences to a zero offset before producing the revision history etc. to be copied.
# Editing
- Rows, Columns. Here you can set up your preferred dimensions for the textbox used for editing page text.
- Enable section editing via [edit] links. An edit link will appear to the right of each sub-heading to allow editing of that subsection only.
- Enable section editing by right-clicking on section titles (JavaScript). In compatible browsers, if this option is checked, a right-click on the section title will bring up the edit box for that section only.
- Edit pages on double click (JavaScript). In compatible browsers, if this option is checked, a double click anywhere on the page will bring up the edit box for the entire contents of the page.
- Edit box has full width. If this box is checked, the edit box (when you click "Edit this page") will be the width of the browser window, minus the quickbar width.
- Show edit toolbar. In compatible browsers, a toolbar with editing buttons can be displayed.
- Show preview on first edit - when pressing the edit button or otherwise following a link to an edit page, show not only the edit box but also the rendered page, just like after pressing "Show preview". This is especially useful when viewing a template, because even just viewing, not editing, typically requires both.
- Show preview before edit box. If you select this option, the preview will be displayed above the edit box when you click the "Show preview" button while editing a page.
- Add pages I create to my watchlist. If this option is selected, any page you create will automatically be added to your watchlist.
- Add pages you edit to your watchlist. If this option is selected, any pages that you modify will be automatically added to your watchlist.
- Mark all edits minor by default. This option automatically selects the "This is a minor edit" checkbox when you edit pages.
- Use external editor by default. (New to 1.5) Changes editing from online version to external program. See Help:External editors.
- Use external diff by default. (New to 1.5) Changes diffing from online version to external program. See Help:External editors.
- Prompt me when entering a blank edit summary. If selected, the editor will display a warning message when no edit summary is added to the edit summary box, after the "Save page" button is pressed.
# Recent changes and stub display
- Number of titles on recent changes: You may select the number of changes which will be shown by default on the Recent Changes and Watchlist page. Once on those pages, links are provided for other options.
- Hide minor edits in recent changes. Registered users may choose to mark edits as being minor (meaning fixes too trivial for trusting users to check up on). It applies to Recent Changes and Enhanced Recent Changes, but not to the Watchlist. It also affects Related changes, but currently in an odd way: if the last edit of a page linking to the current page was minor, then neither that nor the last major change is shown.
- Enhanced recent changes (not for all browsers). Group recent changes per day by article, display the titles of the changed articles in order from new to old latest change, or in the case of hiding minor edits, latest major change. This feature applies also to Related Changes, but not to the watchlist.
- Threshold for stub display: see Stub feature.
# Search result settings
- Hits to show per page: You may choose the number of results returned on each page of search results.
- Lines to show per hit is somewhat cryptic; specifying a number n means: "do not show any context if the search term occurs beyond line n in the page"; here a paragraph, as well as the blank line between two paragraphs, each count as one "line"; line breaks in the source, even when not affecting the lay-out of the page (and even when not directly visible in the edit box of the article), affect the line count. Setting the parameter to 5000 or more gives context for every occurrence.
- Characters of context per line: the number of characters of context per occurrence; however, the context is anyway restricted to the "line" (see above) it occurs in. To get the whole line, put a large number like 5000.
- Search in these namespaces by default: shows a list of all namespaces (not the same in all projects; for older MediaWiki versions, which do not have Special:Version, this is also a useful indicator what version is used; for even older versions that do not have this item in the preferences, see the list after performing a search), allowing one to select which ones are searched by default; see also Namespaces searched.
# Misc settings
- Show hoverbox over wiki links. This option determines whether a link title is put in the HTML code. The result depends on the browser: putting the mouse pointer over a link often displays this title in a hover box. However, some browsers show the URL anyway, so a link title may be superfluous. If enabled, the link title is the page name in the case of an internal link, the page name with prefix in the case of an interwiki link, and the URL in the case of an external link.
- Underline links. Normally, link text will be underlined. Optionally, you may request that links not be underlined, although your browser may not respect this setting. Normally links that are not underlined can still be recognized by color. However, one can then not distinguish between two consecutive words being a single link or two links, without pointing at the words with the cursor. For an old discussion of changing the default here, see m:Link style vote. For further choices of style of links in general and/or types of links one can use CSS (site-wide for all skins, site-wide per skin, user-specific per skin, or web-wide, user-specific)
- Format broken links like this. An internal link to a non-existing pages is automatically a link to the edit page. By default the link label of [[b]] and [[a|b]] is "b", just like for links to existing pages. Alternatively the link label is a question mark inserted after "b", like this: A red link?. The appearance of the link is further determined by the style specified for css selectors "a.new" and "a.new:hover" (the example on the preferences page wrongly uses class="internal" for the question mark). Internal links to pages which do not yet exist currently appear on your browser like this one. Normally, this is underlined and in red. With the trailing question mark link one can then not distinguish between a single word being linked or a phrase of more than one word, without pointing at the question mark with the cursor. Also, remember that the question mark does not mean that the information is uncertain.
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ce451125fee249df0764b06eb8ff8efa56656338 | wikidoc | Price index | Price index
A price index is a numerical time series measure designed to help compare how the prices of some class of goods and/or services, taken as a whole, differ between time periods or geographical locations. In the latter case, these are known as purchasing power parity measures. The class of goods can be quite broad; in a consumer price index, for instance, the class of goods is roughly "things bought by a typical urban consumer". As an example of a narrower index, the United States Bureau of Labor Statistics has a price index for "steel mill products". Sometimes an index will be very specific, as in the US Energy Information Administration index entitled "Gasoline - All Grades".
By design, a price index reduces all the distinct prices for the class of goods in question to a single number. On one hand, doing this has the potential to cut through the noise and make it easy to see the big picture. On the other hand, it has the risk of hiding potentially important details; for instance, a price index can potentially increase even though a sizable minority of the prices are actually decreasing. The usefulness of a price index may therefore depend on both the nature of the particular dataset and the intended use of the index.
Price indexes have several potential uses. For particularly broad indexes, the index can be said to measure the economy's price level, and the extent to which there is inflation. This information is useful to central banks as they plan out monetary policy. A broad index can also be used to estimate changes in the cost of living. This can be useful in, for example, contract negotiation; one party, for instance, may be more willing to accept a certain salary if it's scheduled to automatically increase as costs go up. Price indices can also be used to help measure other economic statistics such as Gross Domestic Product.
More narrow price indexes can help producers with business plans and pricing. Sometimes they can also be useful to help guide investment.
Some notable price indexes include:
- Consumer price index
- Producer price index
- Personal consumption expenditures price index
# Introductory treatment
## Unweighted price average
Perhaps the simplest way to get a general sense of the price of a class of goods would be to take the (arithmetic) average of the price of each good. For example, let's say the class of goods under consideration is apples. Here are some Seattle-area apple prices from Aug 18, 2007:
- Granny Smith: $0.72 each
- Red Delicious: $0.75 each
- Fuji: $0.50 each
- Gala (large): $0.75 each
- Breaburn: $0.90 each
Then one measure of the general price apples, taken as a whole, is
The average is $0.72 each.
When the price changes, you can compute the new value of the index by taking the average of the new prices. If p_{granny mith} is the new price of Granny Smith, etc., then the value of the index becomes
Note that approach has meets one of the most basic criteria you might like a price index to have: If the price of all the goods in the class goes up, then so does the price index.
## Fixed basket indexes
It's perhaps plausible that people would eat about the same amount of each type of apple. For other classes of goods, however, this is not necessarily the case. For instance, consider the class "fruit". If we limit our attention to just applies and bananas, then it may be the case that we tend to eat twice as many apples as bananas. (Okay, this is probably backwards, but stick with it for now.) As such, the price of apples is, in some sense, more important than the price of bananas.
One way to proceed, then, is to think not in terms of prices directly, but in terms of a fixed "basket" of goods, i.e. a list of specific quantities of specific goods. Here our basket would be "two apples and one banana". One can construct a price index from such a basket by simply calculating how much that basket would cost to buy at different points in time. For instance, the following shows the value of our apples-and-banana basket as hypothetical prices change through time:
- 2000: apples are $1, bananas are $0.50, index is 2*$1 + $0.50 = $2.50
- 2001: apples are $1.10, bananas are $0.50, index is 2*$1.10 + $0.50 = $2.70
- 2002: apples are $1.20, bananas are $0.30, index is $2*$1.20 + $0.30 = $2.70
- 2003: apples are $1.20, bananas are $0.40, index is $2*$1.20 + $0.40 = $2.80
Note that the 2001 and 2002 index values are the same, even though the individual prices are different.
As a whimsical example of a fixed-basket price index, the financial services firm PNC maintains a Christmas Price Index, which uses, for its basket, the list of goods enumerated in the Christmas song The Twelve Days of Christmas: three French hens, two turtledoves, a partridge in a pear tree, and so on. The price of this basket is evaluated yearly.
For a more serious example: In 1780 the Massachusetts state legislature, worried about inflation created a fixed-basket price index in order to help them track inflation and make sure soldiers' pay was increased to keep up with it. The basket they chose was 5 bushels of corn, 68 and 4/7 pounds of beef, 10 pounds of sheep's wool and 16 pounds of sole leather.
## Normalizing index numbers
Note that sometimes the values of these baskets are normalized so they are reported not in dollars but rather in percentage terms. The most common way to do this is to take one year of the index as the "base" year and make that index value equal to 100. You then express every other year as a percentage of that base year. In our example above, let's take 2000 as our base year. The value of our index will be 100. The price
- 2000: original index value was $2.50; $2.50/$2.50 = 100%, so our new index value is 100
- 2001: original index value was $2.70; $2.70/$2.50 = 108%, so our new index value is 108
- 2002: same as 2001; our new values is 108
- 2003: original value was $2.80; $2.80/$2.50 = 112%, so our new value is 112
When an index has been normalized in this manner, then the sole meaning of the number 108, for instance, is that the index is 8% higher than it was in year 2000. There is no price or quantity or anything else in the economy signified by the number 108.
## Trouble with fixed basket indexes
Though fixed basket indexes are easy to work with, most classes of goods for which people want to make an index can't be modeled by an unchanging basket. Let's consider, for example, the class of goods "things bought by a typical urban consumer". (This is our quick summary of what a consumer price index is about.) Can this class be represented by a single, fixed basket of goods? There are at least two problems with this idea:
First, over time, the typical urban consumer will start buying certain new things, and stop buying certain old things. For example, at one point there was no such thing as a microwave oven, and yet now microwaves are very much something that a typical urban consumer might buy. If you proposed a fixed basket without a microwave, then it would be a misleading representation of what urban consumers tend to buy now. If you proposed a fixed basket with a microwave, however, then it would be a misleading representation of what urban consumers would have bought before.
Second, even if the typical consumer doesn't buy any new goods, or stop buying any old ones, the proportion spent on different goods may well change. For instance, as any area gets wealthier, people might buy fewer groceries and more prepared food. Alternatively, if people switch from physically demanding jobs to office work, spending on gym memberships may raise, as people find their exercise off the job, rather than on.
Another more technical problem is that a fixed basket approach may suffer from substitution bias. For example, in a consumer price index, substitution bias would occur if consumers stopped buying apples and only bought oranges because the cost of apples had risen and oranges were good substitutes. A price index based on a fixed basket of goods would overstate price change since it would reflect the rising cost of apples even though they were substituted out of the real world market basket. Instead of using a fixed market basket, some price indices attempt to reflect a cost of living concept. In a cost of living index, the standard of living for an initial period is gauged. The price index reflects the change in the amount of money required to maintain that standard of living in later periods. The cost of living index shows the change in the amount of money required to attain a certain level of utility.
The above suggests that a fixed basket won't do for a consumer price index.
An example of another place where a fixed basket may not work is a broad-spectrum commodity price index, such as the Dow Jones-AIG Commodity Index. To simplify a little, the point of such an index is to give a broad overview of how commodity prices are moving. ...
## Variable baskets
The above suggests that many indexes should be constructed based not on a single fixed basket but rather different (but related) baskets at different times. For example, let's say that the popularity of bananas increases fivefold between in 2004. It might not make sense, then, to use our original apples-and-banana basket (see above) to compute an index value for 2004. It might make more sense to start using a new basket, perhaps consisting of 2 apples and 10 bananas, in 2004.
Now we've established that fixed basket indexes have their problems, but they do do one thing right, which is to, as they say, compare apples to apples. That is, it doesn't seem unreasonable to say that, when the very same thing (in this case, a particular basket of goods) costs different amounts at different times, then this is because prices have changed.
With varying baskets, in contrast, we arguably have a case of apples and oranges. It's not obvious that we're comparing the same things any longer. So we should be wary. Indeed, let's consider what would happen if we compared baskets in this way: we'll compare baskets by comparing how much last year's basket cost at last year's prices to what this year's basket costs at this year's prices.
For instance, from our earlier example, we have that, in 2003, the 2003 basket cost $2.80.
Let's forget about the idea of the popularity of bananas increasing fivefold. Instead, let's say that people got hungrier overall between 2003 and 2004, so that the basket goes from 2 apples and 1 banana to 4 apples and 2 bananas. Let's say that prices stay the same. This means the 2004 basket at 2004 prices costs $2.80 - 2 + 1 $0.80 = $6.20.
For comparison, let's say that the basket stayed the same between 2003 and 2004 but the prices doubled. Then the 2004 basket at 2004 prices costs 2 - $2.40 + 1 - $0.80 = $6.20.
What we see is that, using this method, if price doubles, then the basket price doubles. But if the quantities double, then the basket price also doubles. What this means is that we haven't found a very good way of measuring measuring price change; it mixes up price change with quantity change.
The primary ways forward here are either calculating several short indexes for different baskets and then merging those indexes into one through a technique called "linking" or "chaining"; or turning to a more sophisticated price index formula; or both.
### Laspeyres
One way to approximate the price change between the two periods when the basket changes would be to pretend that there wasn't actually basket change. That is, instead of calculating the index with the second basket, we'll use the second prices, but the first basket.
Thus for 2003 our index will still be
and for 2004 out index (still based on the 2003 basket) will be
Since we're comparing apples to apples again, then we are back to measuring what you might call price changes; we've controlled for quantity changes.
Now if we're only comparing two time periods, this is silly; we've forgotten about the second basket!
Let's apply this through time, though. One thought is that, in reality, the quantity of each basket item isn't going to change all that much from year to year. This means that, approximately speaking, we can use the first year's basket as a proxy for the second years basket, and the above approach will give us a reasonable estimate of the change from one year to the next. For instance, if we compare 2003 and 2004 using the 2003 basket, then there could be worse things to do than use the 2003 basket. The ratio of the 2004 index over the 2003 index will give us a sense of by what factor prices have increased from 2003 to 2004.
Now let's suppose we pick a new basket every year, to reflect change in buying habits. Well then the 2004 and 2005 baskets will be different, but we'll guess that, in practice, they won't be too different. Therefore we can get an approximation of the change from 2004 to 2005 by using the 2004 basket and ignoring the 2005 basket. The same will be true between 2005 and 2006, or 2006 and 2007. Thus we have an estimate of how much each year has increased relative to the year prior.
But we can combine these numbers into a general price index. Let's let the value of the index at 2004 be the price of the 2004 basket at 2004 prices. Well we've calculated an estimate of by how much 2005 prices exceed 2004 prices. So if we multiply the 2004 index number by the 2005 factor, we can get a new index number for 2005. We also have calculated an estimate of by how much 2006 prices exceed 2005 prices. So if we multiply the 2005 prices by the that factor, then we'll get a number we can use for the 2006 index value. And so on.
Now two notes here. First, there are other ways to average different times together. What we've examined here is called the Laspeyres index, but there are other ways to answer the question "by what factor have prices increased"?
Second, governments often chain their indexes less often. In part, this is due to practical considerations.
# History of early price indices
No clear consensus has emerged on who created the first price index. The earliest reported research in this area came from Englishman Rice Vaughan who examined price level change in his 1675 book A Discourse of Coin and Coinage. Vaughan wanted to separate the inflationary impact of the influx of precious metals brought by Spain from the New World from the effect due to currency debasement. Vaughan compared labor statutes from his own time to similar statutes dating back to Edward III. These statutes set wages for certain tasks and provided a good record of the change in wage levels. Rice reasoned that the market for basic labor did not fluctuate much with time and that a basic laborers salary would probably buy the same amount of goods in different time periods, so that a laborer's salary acted as a basket of goods. Vaughan's analysis indicated that price levels in England had risen six to eight fold over the preceding century.
While Vaughan can be considered a forerunner of price index research, his analysis did not actually involve calculating an index. In 1707 Vaughan's fellow Englishman William Fleetwood probably created the first true price index. An Oxford student asked Fleetwood to help show how prices had changed. The student stood to lose his fellowship since a fifteenth century stipulation barred students with annual incomes over five pounds from receiving a fellowship. Fleetwood, who already had an interest in price change, had collected a large amount of price data going back hundreds of years. Fleetwood proposed an index consisting of averaged price relatives and used his methods to show that the value of five pounds had changed greatly over the course of 260 years. He argued on behalf of the Oxford students and published his findings anonymously in a volume entitled Chronicon Preciosum.
# Formal calculation
Given a set C of goods and services, the total market value of transactions in C in some period t would be
where
If, across two periods t_0 and t_n, the same quantities of each good or service were sold, but under different prices, then
and
would be a reasonable measure of the price of the set in one period relative to that in the other, and would provide an index measuring relative prices overall, weighted by quantities sold.
Of course, for any practical purpose, quantities purchased are rarely if ever identical across any two periods. As such, this is not a very practical index formula.
One might be tempted to modify the formula slightly to
This new index, however, doesn't do anything to distinguish growth or reduction in quantities sold from price changes. To see that this is so, consider what happens if all the prices double between t_0 and t_n while quantities stay the same: P will double. Now consider what happens if all the quantities double between t_0 and t_n while all the prices stay the same: P will double. In either case the change in P is identical. As such, P is as much a quantity index as it is a price index.
Various indices have been constructed in an attempt to compensate for this difficulty.
## Paasche and Laspeyres price indices
The two most basic formulas used to calculate price indices are the Paasche index (after the German economist Hermann Paasche) and the Laspeyres index (after the German economist
Etienne Laspeyres).
The Paasche index is computed as
while the Laspeyres index is computed as
where P is the change in price level, t_0 is the base period (usually the first year), and t_n the period for which the index is computed.
Note that the only difference in the formulas is that the former uses period n quantities, whereas the latter uses base period (period 0) quantities.
When applied to bundles of individual consumers, a Laspeyres index of 1 would state that an agent in the current period can afford to buy the same bundle as he consumed in the previous period, given that income has not changed; a Paasche index of 1 would state that an agent could have consumed the same bundle in the base period as she is consuming in the current period, given that income has not changed.
Hence, one may think of the Paasche index as the inflation rate when taking the numeraire as the bundle of goods using previous prices but current quantities. Similarly, the Laspeyres index can be thought of as the inflation rate when the numeraire is given by the bundle of goods using current prices and current quantities.
The Laspeyres index systematically overstates inflation, while the Paasche index understates it, because the indices do not account for the fact that consumers typically react to price changes by changing the quantities that they buy. For example, if prices go up for good c, then ceteris paribus, quantities of that good should go down.
## Fisher index and Marshall-Edgeworth index
A third index, the Marshall-Edgeworth index (named for economists Alfred Marshall and Francis Ysidro Edgeworth), tries to overcome these problems of under- and overstatement by using the arithmethic means of the quantities:
A fourth, the Fisher index (after the American economist Irving Fisher), is calculated as the geometric mean of P_P and P_L:
However, there is no guarantee with either the Marshall-Edgeworth index or the Fisher index that the overstatement and understatement will thus exactly one cancel the other.
While these indices were introduced to provide overall measurement of relative prices, there is ultimately no way of measuring the imperfections of any of these indices (Paasche, Laspeyres, Fisher, or Marshall-Edgeworth) against reality.
## Practical measurement considerations
### Relative ease of calculating the Laspeyres index
As can be seen from the definitions above, if one already has price and quantity data (or, alternatively, price and expenditure data) for the base period, then calculating the Laspeyres index for a new period requires only new price data. In contrast, calculating many other indexes (e.g., the Paasche index) for a new period requires both new price data and new quantity data (or, alternatively, both new price data and new expenditure data) for each new period. Collecting only new price data is often easier than collecting both new price data and new quantity data, so calculating the Laspeyres index for a new period tends to require less time and effort than calculating these other indexes for a new period.
### Calculating indices from expenditure data
Sometimes, especially for aggregate data, expenditure data is more readily available than quantity data. For these cases, we can formulate the indices in terms of relative prices and base year expenditures, rather than quantities.
Here is a reformulation for the Laspeyres index:
Let E_{c,t_0} be the total expenditure on good c in the base period, then (by definition) we have
E_{c,t_0} = p_{c,t_0}\cdot q_{c,t_0}
and therefore also
\frac{E_{c,t_0}}{p_{c,t_0}} = q_{c,t_0}.
We can substitute these values into our Laspeyres formula as follows:
P_L
=\frac{\sum (p_{c,t_n}\cdot q_{c,t_0})}{\sum (p_{c,t_0}\cdot q_{c,t_0})}
=\frac{\sum (p_{c,t_n}\cdot \frac{E_{c,t_0}}{p_{c,t_0}})}{\sum E_{c,t_0}}
=\frac{\sum (\frac{p_{c,t_n}}{p_{c,t_0}} \cdot E_{c,t_0})}{\sum E_{c,t_0}}
A similar transformation can be made for any index.
## Chained vs non-chained calculations
So far, in our discussion, we have always had our price indices relative to some fixed base period. An alternative is to take the base period for each time period to be the immediately preceding time period. This can be done with any of the above indexes, but here's an example with the Laspeyres index, where t_n is the period for which we wish to calculate the index and t_0 is a reference period that anchors the value of the series:
P_{t_n}=
\frac{\sum (p_{c,t_1}\cdot q_{c,t_0})}{\sum (p_{c,t_0}\cdot q_{c,t_0})}
\times
\frac{\sum (p_{c,t_2}\cdot q_{c,t_1})}{\sum (p_{c,t_1}\cdot q_{c,t_1})}
\times
\cdots
\times
\frac{\sum (p_{c,t_n}\cdot q_{c,t_{n-1}})}{\sum (p_{c,t_{n-1}}\cdot q_{c,t_{n-1}})}
Each term
answers the question "by what factor have prices increased between period t_{n-1} and period t_n". When you multiply these all together, you get the answer to the question "by what factor have prices increased since period t_0.
Nonetheless, note that, when chain indexes are in use, the numbers cannot be said to be "in period t_0" prices.
# Index number theory
Price index formulas can be evaluated in terms of their mathematical properties per se. Several different tests of such properties have been proposed in index number theory literature. W.E. Diewert summarized past research in a list of nine such tests for a price index I(P_{t_0}, P_{t_m}, Q_{t_0}, Q_{t_m}), where P_0 and P_n are vectors giving prices for a base period and a reference period while Q_{t_0} and Q_{t_m} give quantities for these periods.
- Identity test:
I(p_{t_m},p_{t_m},\alpha \cdot q_{t_m},\beta\cdot q_{t_n})=1~~\forall (\alpha ,\beta )\in (0,\infty )^2
The identity test basically means that if prices remain the same and quantities remain in the same proportion to each other (each quantity of an item is multiplied by the same factor of either \alpha, for the first period, or \beta, for the later period) then the index value will be one.
- Proportionality test:
I(p_{t_m},\alpha \cdot p_{t_m},q_{t_m},q_{t_n})=\alpha \cdot I(p_{t_m},p_{t_n},q_{t_m},q_{t_n})
If each price in the original period increases by a factor α then the index should increase by the factor α.
- Invariance to changes in scale test:
I(\alpha \cdot p_{t_m},\alpha \cdot p_{t_n},\beta \cdot q_{t_m}, \gamma \cdot q_{t_n})=I(p_{t_m},p_{t_n},q_{t_m},q_{t_n})~~\forall (\alpha,\beta,\gamma)\in(0,\infty )^3
The price index should not change if the prices in both periods are increased by a factor and the quantities in both periods are increased by another factor. In other words, the magnitude of the values of quantities and prices should not affect the price index.
- Commensurability test:
The index should not be affected by the choice of units used to measure prices and quantities.
- Symmetric treatment of time (or, in parity measures, symmetric treatment of place):
I(p_{t_n},p_{t_m},q_{t_n},q_{t_m})=\frac{1}{I(p_{t_m},p_{t_n},q_{t_m},q_{t_n})}
Reversing the order of the time periods should produce a reciprocal index value. If the index is calculated from the most recent time period to the earlier time period, it should be the reciprocal of the index found going from the earlier period to the more recent.
- Symmetric treatment of commodities:
All commodities should have a symmetric effect on the index. Different permutations of the same set of vectors should not change the index.
- Monotonicity test:
I(p_{t_m},p_{t_n},q_{t_m},q_{t_n}) \le I(p_{t_m},p_{t_r},q_{t_m},q_{t_r})~~\Leftarrow~~p_{t_n} \le p_{t_r}
A price index for lower later prices should be lower than a price index with higher later period prices.
- Mean value test:
The overall price relative implied by the price index should be between the smallest and largest price relatives for all commodities.
- Circularity test:
I(p_{t_m},p_{t_n},q_{t_m},q_{t_n}) \cdot I(p_{t_n},p_{t_r},q_{t_n},q_{t_r})=I(p_{t_m},p_{t_r},q_{t_m},q_{t_r})~~\Leftarrow~~t_m \le t_n \le t_r
Given three ordered periods t_m, t_n, t_r, the price index for periods t_m and t_n times the price index for periods t_n and t_r should be equivalent to the price index for periods t_m and t_r.
# Quality change
Price indexes often capture changes in price and quantities for goods and services, but they often fail to account for improvements in the quality of goods and services. Statistical agencies generally use "matched-model" price indexes, where one model of a particular good is priced at the same store at regular time intervals. The matched-model method becomes problematic when statistical agencies try to use this method on goods and services with rapid turnover in quality features. For instance, computers rapidly improve and a specific model may quickly become obsolete. Statisticians constructing matched-model price indexes must decide how to compare the price of the obsolete item originally used in the index with the new and improved item that replaces it. Statistical agencies use several different methods to make such price comparisons.
The problem discussed above can be represented as attempting how to bridge the gap between the price for the old item in time t, P(M)_{t}, with the price of the new item in the later time period, P(N)_{t+1}.
The "overlap method" uses prices collected for both items in both time periods, t and t+1. The price relative {P(N)_{t+1}}/{P(N)_{t}} is used.
The "direct comparison method" assumes that the difference in the price of the two items is not due to quality change, so the entire price difference is used in the index. P(N)_{t+1}/P(M)_t is used as the price relative.
The "link-to-show-no-change" assumes the opposite of the direct comparison method; it assumes that the entire difference between the two items is do to the change in quality. The price relative based on link-to-show-no-change is 1.
The "deletion method" simply leaves the price relative for the changing item out of the price index. This is equivalent to using the average of other price relatives in the index as the price relative for the changing item. Similarly, "class mean" imputation uses the average price relative for items with similar characteristics (physical, geographic, economic, etc.)to M and N. | Price index
A price index is a numerical time series measure designed to help compare how the prices of some class of goods and/or services, taken as a whole, differ between time periods or geographical locations. In the latter case, these are known as purchasing power parity measures. The class of goods can be quite broad; in a consumer price index, for instance, the class of goods is roughly "things bought by a typical urban consumer". As an example of a narrower index, the United States Bureau of Labor Statistics has a price index for "steel mill products". Sometimes an index will be very specific, as in the US Energy Information Administration index entitled "Gasoline - All Grades".
By design, a price index reduces all the distinct prices for the class of goods in question to a single number. On one hand, doing this has the potential to cut through the noise and make it easy to see the big picture. On the other hand, it has the risk of hiding potentially important details; for instance, a price index can potentially increase even though a sizable minority of the prices are actually decreasing. The usefulness of a price index may therefore depend on both the nature of the particular dataset and the intended use of the index.
Price indexes have several potential uses. For particularly broad indexes, the index can be said to measure the economy's price level, and the extent to which there is inflation. This information is useful to central banks as they plan out monetary policy. A broad index can also be used to estimate changes in the cost of living. This can be useful in, for example, contract negotiation; one party, for instance, may be more willing to accept a certain salary if it's scheduled to automatically increase as costs go up. Price indices can also be used to help measure other economic statistics such as Gross Domestic Product.
More narrow price indexes can help producers with business plans and pricing. Sometimes they can also be useful to help guide investment.
Some notable price indexes include:
- Consumer price index
- Producer price index
- Personal consumption expenditures price index
# Introductory treatment
## Unweighted price average
Perhaps the simplest way to get a general sense of the price of a class of goods would be to take the (arithmetic) average of the price of each good. For example, let's say the class of goods under consideration is apples. Here are some Seattle-area apple prices from Aug 18, 2007:[1]
- Granny Smith: $0.72 each
- Red Delicious: $0.75 each
- Fuji: $0.50 each
- Gala (large): $0.75 each
- Breaburn: $0.90 each
Then one measure of the general price apples, taken as a whole, is
The average is $0.72 each.
When the price changes, you can compute the new value of the index by taking the average of the new prices. If <math>p_{granny mith}</math> is the new price of Granny Smith, etc., then the value of the index becomes
Note that approach has meets one of the most basic criteria you might like a price index to have: If the price of all the goods in the class goes up, then so does the price index.
## Fixed basket indexes
It's perhaps plausible that people would eat about the same amount of each type of apple. For other classes of goods, however, this is not necessarily the case. For instance, consider the class "fruit". If we limit our attention to just applies and bananas, then it may be the case that we tend to eat twice as many apples as bananas. (Okay, this is probably backwards, but stick with it for now.) As such, the price of apples is, in some sense, more important than the price of bananas.
One way to proceed, then, is to think not in terms of prices directly, but in terms of a fixed "basket" of goods, i.e. a list of specific quantities of specific goods. Here our basket would be "two apples and one banana". One can construct a price index from such a basket by simply calculating how much that basket would cost to buy at different points in time. For instance, the following shows the value of our apples-and-banana basket as hypothetical prices change through time:
- 2000: apples are $1, bananas are $0.50, index is 2*$1 + $0.50 = $2.50
- 2001: apples are $1.10, bananas are $0.50, index is 2*$1.10 + $0.50 = $2.70
- 2002: apples are $1.20, bananas are $0.30, index is $2*$1.20 + $0.30 = $2.70
- 2003: apples are $1.20, bananas are $0.40, index is $2*$1.20 + $0.40 = $2.80
Note that the 2001 and 2002 index values are the same, even though the individual prices are different.
As a whimsical example of a fixed-basket price index, the financial services firm PNC maintains a Christmas Price Index, which uses, for its basket, the list of goods enumerated in the Christmas song The Twelve Days of Christmas: three French hens, two turtledoves, a partridge in a pear tree, and so on. The price of this basket is evaluated yearly.[2]
For a more serious example: In 1780 the Massachusetts state legislature, worried about inflation created a fixed-basket price index in order to help them track inflation and make sure soldiers' pay was increased to keep up with it. The basket they chose was 5 bushels of corn, 68 and 4/7 pounds of beef, 10 pounds of sheep's wool and 16 pounds of sole leather.[3]
## Normalizing index numbers
Note that sometimes the values of these baskets are normalized so they are reported not in dollars but rather in percentage terms. The most common way to do this is to take one year of the index as the "base" year and make that index value equal to 100. You then express every other year as a percentage of that base year. In our example above, let's take 2000 as our base year. The value of our index will be 100. The price
- 2000: original index value was $2.50; $2.50/$2.50 = 100%, so our new index value is 100
- 2001: original index value was $2.70; $2.70/$2.50 = 108%, so our new index value is 108
- 2002: same as 2001; our new values is 108
- 2003: original value was $2.80; $2.80/$2.50 = 112%, so our new value is 112
When an index has been normalized in this manner, then the sole meaning of the number 108, for instance, is that the index is 8% higher than it was in year 2000. There is no price or quantity or anything else in the economy signified by the number 108.
## Trouble with fixed basket indexes
Though fixed basket indexes are easy to work with, most classes of goods for which people want to make an index can't be modeled by an unchanging basket. Let's consider, for example, the class of goods "things bought by a typical urban consumer". (This is our quick summary of what a consumer price index is about.) Can this class be represented by a single, fixed basket of goods? There are at least two problems with this idea:
First, over time, the typical urban consumer will start buying certain new things, and stop buying certain old things. For example, at one point there was no such thing as a microwave oven, and yet now microwaves are very much something that a typical urban consumer might buy. If you proposed a fixed basket without a microwave, then it would be a misleading representation of what urban consumers tend to buy now. If you proposed a fixed basket with a microwave, however, then it would be a misleading representation of what urban consumers would have bought before.
Second, even if the typical consumer doesn't buy any new goods, or stop buying any old ones, the proportion spent on different goods may well change. For instance, as any area gets wealthier, people might buy fewer groceries and more prepared food. Alternatively, if people switch from physically demanding jobs to office work, spending on gym memberships may raise, as people find their exercise off the job, rather than on.
Another more technical problem is that a fixed basket approach may suffer from substitution bias. For example, in a consumer price index, substitution bias would occur if consumers stopped buying apples and only bought oranges because the cost of apples had risen and oranges were good substitutes. A price index based on a fixed basket of goods would overstate price change since it would reflect the rising cost of apples even though they were substituted out of the real world market basket. Instead of using a fixed market basket, some price indices attempt to reflect a cost of living concept. In a cost of living index, the standard of living for an initial period is gauged. The price index reflects the change in the amount of money required to maintain that standard of living in later periods. The cost of living index shows the change in the amount of money required to attain a certain level of utility.
The above suggests that a fixed basket won't do for a consumer price index.
An example of another place where a fixed basket may not work is a broad-spectrum commodity price index, such as the Dow Jones-AIG Commodity Index. To simplify a little, the point of such an index is to give a broad overview of how commodity prices are moving. ...
## Variable baskets
The above suggests that many indexes should be constructed based not on a single fixed basket but rather different (but related) baskets at different times. For example, let's say that the popularity of bananas increases fivefold between in 2004. It might not make sense, then, to use our original apples-and-banana basket (see above) to compute an index value for 2004. It might make more sense to start using a new basket, perhaps consisting of 2 apples and 10 bananas, in 2004.
Now we've established that fixed basket indexes have their problems, but they do do one thing right, which is to, as they say, compare apples to apples. That is, it doesn't seem unreasonable to say that, when the very same thing (in this case, a particular basket of goods) costs different amounts at different times, then this is because prices have changed.
With varying baskets, in contrast, we arguably have a case of apples and oranges. It's not obvious that we're comparing the same things any longer. So we should be wary. Indeed, let's consider what would happen if we compared baskets in this way: we'll compare baskets by comparing how much last year's basket cost at last year's prices to what this year's basket costs at this year's prices.
For instance, from our earlier example, we have that, in 2003, the 2003 basket cost $2.80.
Let's forget about the idea of the popularity of bananas increasing fivefold. Instead, let's say that people got hungrier overall between 2003 and 2004, so that the basket goes from 2 apples and 1 banana to 4 apples and 2 bananas. Let's say that prices stay the same. This means the 2004 basket at 2004 prices costs $2.80 * 2 + 1 $0.80 = $6.20.
For comparison, let's say that the basket stayed the same between 2003 and 2004 but the prices doubled. Then the 2004 basket at 2004 prices costs 2 * $2.40 + 1 * $0.80 = $6.20.
What we see is that, using this method, if price doubles, then the basket price doubles. But if the quantities double, then the basket price also doubles. What this means is that we haven't found a very good way of measuring measuring price change; it mixes up price change with quantity change.
The primary ways forward here are either calculating several short indexes for different baskets and then merging those indexes into one through a technique called "linking" or "chaining"; or turning to a more sophisticated price index formula; or both.
### Laspeyres
One way to approximate the price change between the two periods when the basket changes would be to pretend that there wasn't actually basket change. That is, instead of calculating the index with the second basket, we'll use the second prices, but the first basket.
Thus for 2003 our index will still be
and for 2004 out index (still based on the 2003 basket) will be
Since we're comparing apples to apples again, then we are back to measuring what you might call price changes; we've controlled for quantity changes.
Now if we're only comparing two time periods, this is silly; we've forgotten about the second basket!
Let's apply this through time, though. One thought is that, in reality, the quantity of each basket item isn't going to change all that much from year to year. This means that, approximately speaking, we can use the first year's basket as a proxy for the second years basket, and the above approach will give us a reasonable estimate of the change from one year to the next. For instance, if we compare 2003 and 2004 using the 2003 basket, then there could be worse things to do than use the 2003 basket. The ratio of the 2004 index over the 2003 index will give us a sense of by what factor prices have increased from 2003 to 2004.
Now let's suppose we pick a new basket every year, to reflect change in buying habits. Well then the 2004 and 2005 baskets will be different, but we'll guess that, in practice, they won't be too different. Therefore we can get an approximation of the change from 2004 to 2005 by using the 2004 basket and ignoring the 2005 basket. The same will be true between 2005 and 2006, or 2006 and 2007. Thus we have an estimate of how much each year has increased relative to the year prior.
But we can combine these numbers into a general price index. Let's let the value of the index at 2004 be the price of the 2004 basket at 2004 prices. Well we've calculated an estimate of by how much 2005 prices exceed 2004 prices. So if we multiply the 2004 index number by the 2005 factor, we can get a new index number for 2005. We also have calculated an estimate of by how much 2006 prices exceed 2005 prices. So if we multiply the 2005 prices by the that factor, then we'll get a number we can use for the 2006 index value. And so on.
...
Now two notes here. First, there are other ways to average different times together. What we've examined here is called the Laspeyres index, but there are other ways to answer the question "by what factor have prices increased"?
Second, governments often chain their indexes less often. In part, this is due to practical considerations.
# History of early price indices
No clear consensus has emerged on who created the first price index. The earliest reported research in this area came from Englishman Rice Vaughan who examined price level change in his 1675 book A Discourse of Coin and Coinage. Vaughan wanted to separate the inflationary impact of the influx of precious metals brought by Spain from the New World from the effect due to currency debasement. Vaughan compared labor statutes from his own time to similar statutes dating back to Edward III. These statutes set wages for certain tasks and provided a good record of the change in wage levels. Rice reasoned that the market for basic labor did not fluctuate much with time and that a basic laborers salary would probably buy the same amount of goods in different time periods, so that a laborer's salary acted as a basket of goods. Vaughan's analysis indicated that price levels in England had risen six to eight fold over the preceding century.[4]
While Vaughan can be considered a forerunner of price index research, his analysis did not actually involve calculating an index.[5] In 1707 Vaughan's fellow Englishman William Fleetwood probably created the first true price index. An Oxford student asked Fleetwood to help show how prices had changed. The student stood to lose his fellowship since a fifteenth century stipulation barred students with annual incomes over five pounds from receiving a fellowship. Fleetwood, who already had an interest in price change, had collected a large amount of price data going back hundreds of years. Fleetwood proposed an index consisting of averaged price relatives and used his methods to show that the value of five pounds had changed greatly over the course of 260 years. He argued on behalf of the Oxford students and published his findings anonymously in a volume entitled Chronicon Preciosum.[6]
# Formal calculation
Given a set <math>C</math> of goods and services, the total market value of transactions in <math>C</math> in some period <math>t</math> would be
where
If, across two periods <math>t_0</math> and <math>t_n</math>, the same quantities of each good or service were sold, but under different prices, then
and
would be a reasonable measure of the price of the set in one period relative to that in the other, and would provide an index measuring relative prices overall, weighted by quantities sold.
Of course, for any practical purpose, quantities purchased are rarely if ever identical across any two periods. As such, this is not a very practical index formula.
One might be tempted to modify the formula slightly to
This new index, however, doesn't do anything to distinguish growth or reduction in quantities sold from price changes. To see that this is so, consider what happens if all the prices double between <math>t_0</math> and <math>t_n</math> while quantities stay the same: <math>P</math> will double. Now consider what happens if all the quantities double between <math>t_0</math> and <math>t_n</math> while all the prices stay the same: <math>P</math> will double. In either case the change in <math>P</math> is identical. As such, <math>P</math> is as much a quantity index as it is a price index.
Various indices have been constructed in an attempt to compensate for this difficulty.
## Paasche and Laspeyres price indices
The two most basic formulas used to calculate price indices are the Paasche index (after the German economist Hermann Paasche) and the Laspeyres index (after the German economist
Etienne Laspeyres).
The Paasche index is computed as
while the Laspeyres index is computed as
where <math>P</math> is the change in price level, <math>t_0</math> is the base period (usually the first year), and <math>t_n</math> the period for which the index is computed.
Note that the only difference in the formulas is that the former uses period n quantities, whereas the latter uses base period (period 0) quantities.
When applied to bundles of individual consumers, a Laspeyres index of 1 would state that an agent in the current period can afford to buy the same bundle as he consumed in the previous period, given that income has not changed; a Paasche index of 1 would state that an agent could have consumed the same bundle in the base period as she is consuming in the current period, given that income has not changed.
Hence, one may think of the Paasche index as the inflation rate when taking the numeraire as the bundle of goods using previous prices but current quantities. Similarly, the Laspeyres index can be thought of as the inflation rate when the numeraire is given by the bundle of goods using current prices and current quantities.
The Laspeyres index systematically overstates inflation, while the Paasche index understates it, because the indices do not account for the fact that consumers typically react to price changes by changing the quantities that they buy. For example, if prices go up for good c, then ceteris paribus, quantities of that good should go down.
## Fisher index and Marshall-Edgeworth index
A third index, the Marshall-Edgeworth index (named for economists Alfred Marshall and Francis Ysidro Edgeworth), tries to overcome these problems of under- and overstatement by using the arithmethic means of the quantities:
A fourth, the Fisher index (after the American economist Irving Fisher), is calculated as the geometric mean of <math>P_P</math> and <math>P_L</math>:
However, there is no guarantee with either the Marshall-Edgeworth index or the Fisher index that the overstatement and understatement will thus exactly one cancel the other.
While these indices were introduced to provide overall measurement of relative prices, there is ultimately no way of measuring the imperfections of any of these indices (Paasche, Laspeyres, Fisher, or Marshall-Edgeworth) against reality.
## Practical measurement considerations
### Relative ease of calculating the Laspeyres index
As can be seen from the definitions above, if one already has price and quantity data (or, alternatively, price and expenditure data) for the base period, then calculating the Laspeyres index for a new period requires only new price data. In contrast, calculating many other indexes (e.g., the Paasche index) for a new period requires both new price data and new quantity data (or, alternatively, both new price data and new expenditure data) for each new period. Collecting only new price data is often easier than collecting both new price data and new quantity data, so calculating the Laspeyres index for a new period tends to require less time and effort than calculating these other indexes for a new period.[7]
### Calculating indices from expenditure data
Sometimes, especially for aggregate data, expenditure data is more readily available than quantity data.[8] For these cases, we can formulate the indices in terms of relative prices and base year expenditures, rather than quantities.
Here is a reformulation for the Laspeyres index:
Let <math>E_{c,t_0}</math> be the total expenditure on good c in the base period, then (by definition) we have
<math>E_{c,t_0} = p_{c,t_0}\cdot q_{c,t_0}</math>
and therefore also
<math>\frac{E_{c,t_0}}{p_{c,t_0}} = q_{c,t_0}</math>.
We can substitute these values into our Laspeyres formula as follows:
P_L
=\frac{\sum (p_{c,t_n}\cdot q_{c,t_0})}{\sum (p_{c,t_0}\cdot q_{c,t_0})}
=\frac{\sum (p_{c,t_n}\cdot \frac{E_{c,t_0}}{p_{c,t_0}})}{\sum E_{c,t_0}}
=\frac{\sum (\frac{p_{c,t_n}}{p_{c,t_0}} \cdot E_{c,t_0})}{\sum E_{c,t_0}}
</math>
A similar transformation can be made for any index.
## Chained vs non-chained calculations
So far, in our discussion, we have always had our price indices relative to some fixed base period. An alternative is to take the base period for each time period to be the immediately preceding time period. This can be done with any of the above indexes, but here's an example with the Laspeyres index, where <math>t_n</math> is the period for which we wish to calculate the index and <math>t_0</math> is a reference period that anchors the value of the series:
P_{t_n}=
\frac{\sum (p_{c,t_1}\cdot q_{c,t_0})}{\sum (p_{c,t_0}\cdot q_{c,t_0})}
\times
\frac{\sum (p_{c,t_2}\cdot q_{c,t_1})}{\sum (p_{c,t_1}\cdot q_{c,t_1})}
\times
\cdots
\times
\frac{\sum (p_{c,t_n}\cdot q_{c,t_{n-1}})}{\sum (p_{c,t_{n-1}}\cdot q_{c,t_{n-1}})}
</math>
Each term
answers the question "by what factor have prices increased between period <math>t_{n-1}</math> and period <math>t_n</math>". When you multiply these all together, you get the answer to the question "by what factor have prices increased since period <math>t_0</math>.
Nonetheless, note that, when chain indexes are in use, the numbers cannot be said to be "in period <math>t_0</math>" prices.
# Index number theory
Price index formulas can be evaluated in terms of their mathematical properties per se. Several different tests of such properties have been proposed in index number theory literature. W.E. Diewert summarized past research in a list of nine such tests for a price index <math>I(P_{t_0}, P_{t_m}, Q_{t_0}, Q_{t_m})</math>, where <math>P_0</math> and <math>P_n</math> are vectors giving prices for a base period and a reference period while <math>Q_{t_0}</math> and <math>Q_{t_m}</math> give quantities for these periods.[9]
- Identity test:
<math>I(p_{t_m},p_{t_m},\alpha \cdot q_{t_m},\beta\cdot q_{t_n})=1~~\forall (\alpha ,\beta )\in (0,\infty )^2</math>
The identity test basically means that if prices remain the same and quantities remain in the same proportion to each other (each quantity of an item is multiplied by the same factor of either <math>\alpha</math>, for the first period, or <math>\beta</math>, for the later period) then the index value will be one.
- Proportionality test:
<math>I(p_{t_m},\alpha \cdot p_{t_m},q_{t_m},q_{t_n})=\alpha \cdot I(p_{t_m},p_{t_n},q_{t_m},q_{t_n})</math>
If each price in the original period increases by a factor α then the index should increase by the factor α.
- Invariance to changes in scale test:
<math>I(\alpha \cdot p_{t_m},\alpha \cdot p_{t_n},\beta \cdot q_{t_m}, \gamma \cdot q_{t_n})=I(p_{t_m},p_{t_n},q_{t_m},q_{t_n})~~\forall (\alpha,\beta,\gamma)\in(0,\infty )^3</math>
The price index should not change if the prices in both periods are increased by a factor and the quantities in both periods are increased by another factor. In other words, the magnitude of the values of quantities and prices should not affect the price index.
- Commensurability test:
The index should not be affected by the choice of units used to measure prices and quantities.
- Symmetric treatment of time (or, in parity measures, symmetric treatment of place):
<math>I(p_{t_n},p_{t_m},q_{t_n},q_{t_m})=\frac{1}{I(p_{t_m},p_{t_n},q_{t_m},q_{t_n})}</math>
Reversing the order of the time periods should produce a reciprocal index value. If the index is calculated from the most recent time period to the earlier time period, it should be the reciprocal of the index found going from the earlier period to the more recent.
- Symmetric treatment of commodities:
All commodities should have a symmetric effect on the index. Different permutations of the same set of vectors should not change the index.
- Monotonicity test:
<math>I(p_{t_m},p_{t_n},q_{t_m},q_{t_n}) \le I(p_{t_m},p_{t_r},q_{t_m},q_{t_r})~~\Leftarrow~~p_{t_n} \le p_{t_r}</math>
A price index for lower later prices should be lower than a price index with higher later period prices.
- Mean value test:
The overall price relative implied by the price index should be between the smallest and largest price relatives for all commodities.
- Circularity test:
<math>I(p_{t_m},p_{t_n},q_{t_m},q_{t_n}) \cdot I(p_{t_n},p_{t_r},q_{t_n},q_{t_r})=I(p_{t_m},p_{t_r},q_{t_m},q_{t_r})~~\Leftarrow~~t_m \le t_n \le t_r</math>
Given three ordered periods <math>t_m</math>, <math>t_n</math>, <math>t_r</math>, the price index for periods <math>t_m</math> and <math>t_n</math> times the price index for periods <math>t_n</math> and <math>t_r</math> should be equivalent to the price index for periods <math>t_m</math> and <math>t_r</math>.
# Quality change
Price indexes often capture changes in price and quantities for goods and services, but they often fail to account for improvements in the quality of goods and services. Statistical agencies generally use "matched-model" price indexes, where one model of a particular good is priced at the same store at regular time intervals. The matched-model method becomes problematic when statistical agencies try to use this method on goods and services with rapid turnover in quality features. For instance, computers rapidly improve and a specific model may quickly become obsolete. Statisticians constructing matched-model price indexes must decide how to compare the price of the obsolete item originally used in the index with the new and improved item that replaces it. Statistical agencies use several different methods to make such price comparisons.[10]
The problem discussed above can be represented as attempting how to bridge the gap between the price for the old item in time t, <math>P(M)_{t}</math>, with the price of the new item in the later time period, <math>P(N)_{t+1}</math>.[11]
The "overlap method" uses prices collected for both items in both time periods, t and t+1. The price relative <math>{P(N)_{t+1}}</math>/<math>{P(N)_{t}}</math> is used.
The "direct comparison method" assumes that the difference in the price of the two items is not due to quality change, so the entire price difference is used in the index. <math>P(N)_{t+1}</math>/<math>P(M)_t</math> is used as the price relative.
The "link-to-show-no-change" assumes the opposite of the direct comparison method; it assumes that the entire difference between the two items is do to the change in quality. The price relative based on link-to-show-no-change is 1.[12]
The "deletion method" simply leaves the price relative for the changing item out of the price index. This is equivalent to using the average of other price relatives in the index as the price relative for the changing item. Similarly, "class mean" imputation uses the average price relative for items with similar characteristics (physical, geographic, economic, etc.)to M and N.[13] | https://www.wikidoc.org/index.php/Price_index | |
684aa8a06b48fe10c1e0d919bdeaf9d7fc4a7a5e | wikidoc | Rifapentine | Rifapentine
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# Overview
Rifapentine is an antimycobacterial drug that is FDA approved for the treatment of active pulmonary tuberculosis and latent tuberculosis. Common adverse reactions include anemia, lymphopenia, neutropenia, increased ALT, arthralgia, conjunctivitis, headache, vomiting, nausea, diarrhea, rash, pruritus, anorexia and lymphadenopathy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Active Pulmonary Tuberculosis
- PRIFTIN® (rifapentine) is indicated in adults and children 12 years and older for the treatment of active pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis. PRIFTIN must always be used in combination with one or more antituberculosis (anti-TB) drugs to which the isolate is susceptible.
Limitations of Use
- Do not use PRIFTIN monotherapy in either the initial or the continuation phases of active antituberculous treatment.
- PRIFTIN should not be used once-weekly in the continuation phase regimen in combination with isoniazid (INH) in HIV-infected patients with active pulmonary tuberculosis because of a higher rate of failure and/or relapse with rifampin (RIF)-resistant organisms.
- PRIFTIN has not been studied as part of the initial phase treatment regimen in HIV- infected patients with active pulmonary tuberculosis.
Latent Tuberculosis Infection
- PRIFTIN is indicated in adults and children 2 years and older for the treatment of latent tuberculosis infection caused by Mycobacterium tuberculosis in patients at high risk of progression to tuberculosis disease (including those in close contact with active tuberculosis patients, recent conversion to a positive tuberculin skin test, HIV-infected patients, or those with pulmonary fibrosis on radiograph).
Limitations of Use
- Active tuberculosis disease should be ruled out before initiating treatment for latent tuberculosis infection.
- PRIFTIN must always be used in combination with isoniazid as a 12-week once-weekly regimen for the treatment of latent tuberculosis infection.
- PRIFTIN in combination with isoniazid is not recommended for Individuals presumed to be exposed to rifamycin- or - isoniazid resistant M. tuberculosis.
# Dosage
Dosage in Active Pulmonary Tuberculosis
- PRIFTIN is only recommended for the treatment of active pulmonary tuberculosis caused by drug-susceptible organisms as part of regimens consisting of a 2 month initial phase followed by a 4 month continuation phase.
- PRIFTIN should not be used in the treatment of active pulmonary tuberculosis caused by rifampin-resistant strains.
- Initial phase (2 Months): PRIFTIN should be administered at a dose of 600 mg twice weekly for two months as directly observed therapy (DOT), with an interval of no less than 3 consecutive days (72 hours) between doses, in combination with other anti- tuberculosis drugs as part of an appropriate regimen which includes daily companion drugs such as isoniazid (INH), ethambutol (EMB) and pyrazinamide (PZA).
- Continuation phase (4 Months): Following the initial phase (2 months), continuation phase (4 months) treatment consists of PRIFTIN 600 mg once-weekly for 4 months in combination with isoniazid or another appropriate anti- tuberculosis agent for susceptible organisms administered as directly observed therapy.
Dosage in Latent Tuberculosis Infection
- PRIFTIN should be administered once-weekly in combination with isoniazid for 12 weeks as directly observed therapy.
- Adults and children 12 years and older: The recommended dose of PRIFTIN should be determined based on weight of the patient up to a maximum of 900 mg once-weekly (see TABLE 1). The recommended dose of isoniazid is 15 mg/kg (rounded to the nearest 50 mg or 100mg) up to a maximum of 900 mg once-weekly for 12 weeks.
- Children 2–11 years: The recommended dose of PRIFTIN should be determined based on weight of the patient up to a maximum of 900 mg once- weekly (see TABLE 1). The recommended dose of isoniazid is 25 mg/kg (rounded to the nearest 50 mg or 100mg) up to a maximum of 900 mg once-weekly for 12 weeks.
# DOSAGE FORMS AND STRENGTHS
- PRIFTIN is supplied as 150 mg round normal convex dark-pink film-coated tablets debossed "Priftin" on top and "150" on the bottom.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Rifapentine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifapentine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Rifapentine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Rifapentine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifapentine in pediatric patients.
# Contraindications
Hypersensitivity
- PRIFTIN is contraindicated in patients with a history of hypersensitivity to rifamycins.
# Warnings
Hepatotoxicity
- Elevations of liver transaminases may occur in patients receiving PRIFTIN. Patients on PRIFTIN should be monitored for symptoms of liver injury.
- Patients with abnormal liver tests and/or liver disease or patients initiating treatment for active pulmonary tuberculosis should only be given PRIFTIN in cases of necessity and under strict medical supervision. In such patients, obtain serum transaminase levels prior to therapy and every 2–4 weeks while on therapy. Discontinue PRIFTIN if evidence of liver injury occurs.
Hypersensitivity and Related Reactions
- Hypersensitivity reactions may occur in patients receiving PRIFTIN. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). There have been reports of anaphylaxis.
- Monitor patients receiving PRIFTIN therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue PRIFTIN.
Relapse in the Treatment of Active Pulmonary Tuberculosis
- PRIFTIN has not been evaluated as part of the initial phase treatment regimen in HIV-infected patients with active pulmonary TB.
- Do not use PRIFTIN as a once-weekly continuation phase regimen in HIV-infected patients with active pulmonary tuberculosis because of a higher rate of failure and/or relapse with rifampin-resistant organisms.
- Higher relapse rates may occur in patients with cavitary pulmonary lesions and/or positive sputum cultures after the initial phase of active tuberculosis treatment and in patients with evidence of bilateral pulmonary disease. Monitor for signs and symptoms of TB relapse in these patients.
- Poor adherence to therapy is associated with high relapse rate. Emphasize the importance of compliance with therapy.
Drug Interactions
- Rifapentine is an inducer of CYP450 enzymes. Concomitant use of rifapentine with other drugs metabolized by these enzymes, such as protease inhibitors, certain reverse transcriptase inhibitors, and hormonal contraception may cause a significant decrease in plasma concentrations and loss of therapeutic effect.
Discoloration of Body Fluids
- PRIFTIN may produce a red-orange discoloration of body tissues and/or fluids (e.g., skin, teeth, tongue, urine, feces, saliva, sputum, tears, sweat, and cerebrospinal fluid). Contact lenses or dentures may become permanently stained.
Clostridium difficile-Associated Diarrhea
- Clostridium difficile-associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including PRIFTIN, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, discontinue antibacterial use not directed against C. difficile if possible. Institute appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation as clinically indicated.
Porphyria
- Porphyria has been reported in patients receiving rifampin, attributed to induction of delta amino levulinic acid synthetase. Because PRIFTIN may have similar enzyme induction properties, avoid the use of PRIFTIN in patients with porphyria.
# Adverse Reactions
## Clinical Trials Experience
- The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
- Hepatotoxicity
- Hypersensitivity
- Discoloration of Body Fluids
- Clostridium difficile-Associated Diarrhea
- Porphyria
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Active Pulmonary Tuberculosis
- PRIFTIN was studied in a randomized, open label, active-controlled trial of HIV-negative patients with active pulmonary tuberculosis. The population consisted of primarily of male subjects with a mean age of 37 ± 11 years. In the initial 2 month phase of treatment, 361 patients received PRIFTIN 600 mg twice a week in combination with daily isoniazid, pyrazinamide, and ethambutol and 361 subjects received rifampin in combination with isoniazid, pyrazinamide and ethambutol all administered daily. Ethambutol was discontinued when drug susceptibly testing was known. During the 4 month continuation phase, 317 patients in the PRIFTIN group continued to receive PRIFTIN 600 mg dosed once-weekly with isoniazid and 304 patients in the rifampin group received twice weekly rifampin and isoniazid. Both treatment groups received pyridoxine (Vitamin B6) over the 6 month treatment period.
- Because PRIFTIN was administered as part of a combination regimen, the adverse reaction profile reflects the entire regimen.
- Twenty-two deaths occurred in the study, eleven in the rifampin combination therapy group and eleven in the PRIFTIN combination therapy group. 18/361 (5%) rifampin combination therapy patients discontinued the study due to an adverse reaction compared to 11/361 (3%) PRIFTIN combination therapy patients. Three patients (two rifampin combination therapy patients and one PRIFTIN combination therapy patient) were discontinued in the initial phase due to hepatotoxicity. Concomitant medications for all three patients included isoniazid, pyrazinamide, ethambutol, and pyridoxine. All three recovered without sequelae.
- Five patients had adverse reactions associated with PRIFTIN overdose. These reactions included hematuria, neutropenia, hyperglycemia, ALT increased, hyperuricemia, pruritus, and arthritis.
- Table 2 presents selected treatment-emergent adverse reactions associated with the treatment regimens which occurred in at least 1% of patients during treatment and post-treatment through the first three months of follow-up.
- The following selected treatment-emergent adverse reactions were reported in less than 1% of the PRIFTIN combination therapy patients during treatment and post-treatment through the first three months of follow-up.
- Blood and Lymphatics: lymphocytosis, hematoma, purpura, thrombosis.
- Cardiovascular: syncope, tachycardia, palpitation, orthostatic hypotension, pericarditis.
- Metabolic & Nutritional: BUN increased, alkaline phosphatase increased.
- Gastrointestinal: gastritis, esophagitis, pancreatitis, salivary gland enlargement.
- General: asthenia, facial edema.
- Hepatobiliary: bilirubinemia, hepatomegaly, jaundice.
- Infectious Disease: infection fungal.
- Musculoskeletal: myalgia, myositis.
- Neurologic: somnolence, dysphonia.
- Pregnancy, Puerperium and Perinatal conditions: abortion
- Psychiatric: anxiety, confusion
- Reproductive Disorders: vaginitis, vaginal hemorrhage, leukorrhea.
- Respiratory: dyspnea, pneumonitis, pulmonary fibrosis, asthma, bronchospasm, laryngeal edema, laryngitis.
- Skin: urticaria, skin discoloration,
- In another randomized, open-label trial, 1075 HIV non-infected and infected patients with active pulmonary tuberculosis who had completed an initial 2 month phase of treatment with 4 drugs were randomly assigned to receive either PRIFTIN 600 mg and isoniazid once weekly or rifampin and isoniazid twice weekly for the 4 month continuation phase. 502 HIV non-infected and 36 HIV-infected patients were randomized to receive the PRIFTIN regimen and 502 HIV-noninfected and 35 HIV-infected patients were randomized to receive the rifampin regimen.
- The death rate was 6.5% for the PRIFTIN combination regimen compared to 6.7% for the rifampin combination regimen.
Latent Tuberculosis Infection
Main Study
- PRIFTIN in combination with isoniazid given once-weekly for 3 months (3RPT/INH) was compared to isoniazid given once daily for 9 months (9INH) in an open-label, randomized trial in patients with a positive tuberculin skin test, and at high risk for progression from latent tuberculosis infection to active tuberculosis disease. PRIFTIN was dosed by weight, and isoniazid mg/kg dose was determined according to age to a maximum of 900 mg each.
- A total of 4040 patients received at least one dose of the 3RPT/INH regimen, including 348 children 2–17 years of age and 105 HIV-infected individuals. A total of 3759 received at least one dose of the 9INH regimen, including 342 children 2 years–17 years of age and 95 HIV-infected individuals.
- Patients were followed for 33 months from the time of enrollment. Treatment-emergent adverse reactions were defined as those occurring during treatment and 60 days after the last dose of treatment. 161 (4%) 3RPT/INH subjects had a rifamycin hypersensitivity reaction, defined as either: a) one of the following: hypotension, urticaria, angioedema, acute bronchospasm, or conjunctivitis occurring in relation to study drug or b) at least four of the following symptoms occurring in relation to the study drug, with at least one symptom being CTCAE Grade 2 or higher: weakness, fatigue, nausea, vomiting, headache, fever, aches, sweats, dizziness, shortness of breath, flushing or chills. No specific definition was used for isoniazid hypersensitivity; 18 (0.5%) 9INH subjects were classified as having a hypersensitivity reaction. Hepatotoxicity was defined as AST≥3× upper limit of normal in the presence of specific signs and symptoms of hepatitis, or AST>5× upper limit of normal regardless of signs or symptoms. 113 (3%) 9INH subjects and 24 (0.6%) 3RPT/INH subjects developed hepatotoxicity.
- 196 subjects (4.9%) in the 3RPT/INH arm discontinued treatment due to a treatment related adverse reaction patients and 142 (3.8%) in the 9INH arm discontinued treatment due to a treatment related adverse reaction. In the 3RPT/INH group, the most frequent treatment related adverse reaction resulting in treatment discontinuation was hypersensitivity reaction, occurring in 120 (3%) patients. In the 9INH group, the most frequent treatment related adverse reaction resulting in treatment discontinuation was hepatotoxicity, occurring in 76 (2%) patients.
- Seventy one deaths occurred, 31/4040, 0.77% in the 3RPT/INH group and 40/3759 (1.06%) in the 9INH group) during the 33 month study period. During the treatment emergent period, 11 deaths occurred, 4 in the 3RPT/INH group and 7 in the 9INH group. None of the reported deaths were considered related to treatment with study drugs or were attributed to tuberculosis disease.
- Table 3 presents select adverse reactions that occurred during the treatment emergent period in the main study in LTBI patients treated with 3RPT/INH or 9INH at a frequency greater than 0.5%.
Pediatric Substudy
- Six-hundred and ninety children 2 years–17 years of age received at least one dose of study drugs in the main study. An additional 342 children 2 years–17 years of age received at least one dose in the pediatric extension study (total 1032 children; 539 received 3RPT/INH and 493 received 9INH).
- No children in either treatment arm developed hepatotoxicity. Using the same definition for rifamycin hypersensitivity reaction as in the main study, 7 (1.3%) of children in the 3RPT/INH group experienced a rifamycin hypersensitivity reaction. Adverse reactions in children 2 years–11 years of age and 12 years–17 years of age were similar.
HIV Substudy
- Two-hundred HIV-infected patients with latent tuberculosis infection received at least one dose of study drugs in the main study and an additional 193 patients received at least one dose in the extension study (total of 393; 207 received 3RPT/INH and 186 received 9INH). Compared to the HIV-negative patients enrolled in the main study, a higher proportion of HIV-infected patients in each treatment arm experienced a treatment emergent adverse reaction, including a higher incidence of hepatotoxicity. Hepatotoxicity occurred in 3/207 (1.5%) patients in the 3RPT/INH arm and in 14/186 (7.5%) in the 9INH arm. Rifamycin hypersensitivity occurred in only one HIV-infected patient.
- Eleven deaths occurred during the 33 month follow up period (6/207 in the 3RPT/INH group and 5/186 in the 9INH group) including one death in the 9INH arm during the treatment emergent period. None of the reported deaths were considered related to treatment with study drugs or tuberculosis disease.
- Selected treatment-emergent adverse reactions reported during treatment and 60 days post-treatment in less 0.5% of the 3RPT/INH combination-therapy group in the main study are presented below by body system.
- Eye Disorders: conjunctivitis.
- Blood and Lymphatic System Disorders: leukopenia, anemia, lymphadenopathy, neutropenia.
- Gastrointestinal Disorders: nausea, diarrhea, vomiting, abdominal pain, constipation, dry mouth, dyspepsia, esophageal irritation, gastritis, pancreatitis.
- General Disorders and Administration Site Conditions: fatigue, pyrexia, asthenia, chest pain, chills, feeling jittery.
- Infections and Infestations: pharyngitis, viral infection, vulvovaginal candidiasis.
- Metabolism and Nutrition Disorders: hyperglycemia, gout, hyperkalemia, decreased appetite, hyperlipidemia.
- Musculoskeletal and Connective Tissue Disorders: arthralgia, myalgia, back pain, rhabdomyolysis.
- Nervous system Disorders: dizziness, convulsion, paresthesia, headache, neuropathy peripheral, syncope.
- Psychiatric Disorders: depression, anxiety, disorientation, suicidal ideation.
- Renal and Urinary Disorders: azotemia.
- Reproductive System and Breast Disorders: vulvovaginal pruritus.
- Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnea, oropharyngeal pain, asthma, bronchial hyperactivity, epistaxis.
- Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, urticaria.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Rifapentine in the drug label.
# Drug Interactions
Protease Inhibitors and Reverse Transcriptase Inhibitors
- Rifapentine is an inducer of CYP450 enzymes. Concomitant use of PRIFTIN with other drugs metabolized by these enzymes, such as protease inhibitors and certain reverse transcriptase inhibitors, may cause a significant decrease in plasma concentrations and loss of therapeutic effect of the protease inhibitor or reverse transcriptase inhibitor.
Fixed Dose Combination of Efavirenz, Emtricitabine and Tenofovir
- Once-weekly co-administration of 900 mg PRIFTIN with the antiretroviral fixed dose combination of efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxyl fumarate 300mg in HIV- infected patients did not result in any substantial change in steady state exposures of efavirenz, emtricitabine, and tenofovir. No clinically significant change in CD4 cell counts or viral loads were noted.
Hormonal Contraceptives
- PRIFTIN may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to change to non-hormonal methods of birth control.
Cytochrome P450 3A4 and 2C8/9
- Rifapentine is an inducer of cytochromes P4503A4 and P4502C8/9. Therefore, PRIFTIN may increase the metabolism of other coadministered drugs that are metabolized by these enzymes. Induction of enzyme activities by PRIFTIN occurred within 4 days after the first dose. Enzyme activities returned to baseline levels 14 days after discontinuing PRIFTIN.
- Rifampin has been reported to accelerate the metabolism and may reduce the activity of the following drugs; hence, PRIFTIN may also increase the metabolism and decrease the activity of these drugs. Dosage adjustments of the drugs in Table 4 or of other drugs metabolized by cytochrome P4503A4 or P4502C8/9 may be necessary if they are given concurrently with PRIFTIN.
Other Interactions
- The conversion of PRIFTIN to 25-desacetyl rifapentine is mediated by an esterase enzyme. There is minimal potential for PRIFTIN metabolism to be inhibited or induced by another drug, based upon the characteristics of the esterase enzymes.
- Since PRIFTIN is highly bound to albumin, drug displacement interactions may also occur.
Interactions with Laboratory Tests
- Therapeutic concentrations of rifampin have been shown to inhibit standard microbiological assays for serum folate and Vitamin B12. Similar drug-laboratory interactions should be considered for PRIFTIN; thus, alternative assay methods should be considered.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C:
Risk Summary
- There are no adequate and well controlled trials of PRIFTIN in pregnant women; however, there are limited pregnancy outcome data reported from women enrolled in clinical trials of various PRIFTIN treatment regimens for active tuberculosis and latent tuberculosis infection. The reported rate of spontaneous abortion following PRIFTIN exposure did not represent an increase over the background rate of spontaneous abortion reported in the general population. Further interpretation of these data is limited by the quality of clinical trial adverse event reporting. In animal reproduction and developmental toxicity studies, rifapentine produced fetal harm and was teratogenic at doses less than and similar to the recommended human dose. Because animal studies are not always predictive of human response, PRIFTIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rifapentine in women who are pregnant.
### Labor and Delivery
- When administered during the last few weeks of pregnancy, rifampin, another rifamycin product, may increase the risk for maternal postpartum hemorrhage and bleeding in the exposed neonate. Monitor prothrombin time of pregnant women and neonates, who are exposed to PRIFTIN during the last few weeks of pregnancy. Treatment with Vitamin K may be indicated.
### Nursing Mothers
- It is not known whether PRIFTIN is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Since PRIFTIN may produce a red-orange discoloration of body fluids, there is a potential for discoloration of breast milk.
- A slight increase in rat pup mortality was observed during lactation when dams were dosed late in gestation through lactation.
### Pediatric Use
- The safety and effectiveness of PRIFTIN in the treatment of active pulmonary tuberculosis have not been established in pediatric patients under the age of 12.
- The safety and effectiveness of PRIFTIN in combination with isoniazid once-weekly regimen has been evaluated in pediatric patients (2–17 years of age) for the treatment of latent tuberculosis infection. In clinical studies, the safety profile in children was similar to that observed in adult patients.
- In a pharmacokinetic study conducted in 2 year to 11 year-old pediatric patients with latent tuberculosis infection, PRIFTIN was administered once-weekly based on weight (15mg/kg to 30 mg/Kg, up to a maximum of 900 mg). Exposures (AUC) in children 2 years–11 years with latent tuberculosis infection were higher (average 31%) than those observed in adults receiving PRIFTIN 900mg once-weekly
### Geriatic Use
- Clinical studies with PRIFTIN did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In a pharmacokinetic study with PRIFTIN, no substantial differences in the pharmacokinetics of rifapentine and 25-desacetyl metabolite were observed in the elderly compared to younger adults.
### Gender
There is no FDA guidance on the use of Rifapentine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rifapentine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rifapentine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rifapentine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rifapentine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rifapentine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- There is limited information regarding Monitoring of Rifapentine in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Rifapentine in the drug label.
# Overdosage
- While there is no experience with the treatment of acute overdose with PRIFTIN, clinical experience with rifamycins suggests that gastric lavage to evacuate gastric contents (within a few hours of overdose), followed by instillation of an activated charcoal slurry into the stomach, may help adsorb any remaining drug from the gastrointestinal tract.
- Rifapentine and 25-desacetyl rifapentine are 97.7% and 93.2% plasma protein bound, respectively. Rifapentine and related compounds excreted in urine account for only 17% of the administered dose, therefore, neither hemodialysis nor forced diuresis is expected to enhance the systemic elimination of unchanged rifapentine from the body of a patient with PRIFTIN overdose.
# Pharmacology
## Mechanism of Action
- Rifapentine, a cyclopentyl rifamycin, inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis but does not affect mammalian cells at concentrations that are active against these bacteria. At therapeutic levels, rifapentine inhibits RNA transcription by preventing the initiation of RNA chain formation. It forms a stable complex with bacterial DNA-dependent RNA polymerase, leading to repression of RNA synthesis and cell death. Rifapentine and its 25-desacetyl metabolite accumulate in human monocyte-derived macrophages and are bactericidal to both intracellular and extracellular M. tuberculosis bacilli.
## Structure
- PRIFTIN (rifapentine) for oral administration contains 150 mg of the active ingredient rifapentine per tablet.
- The 150 mg tablets also contain, as inactive ingredients: calcium stearate, disodium EDTA, FD&C Blue No. 2 aluminum lake, hydroxypropyl cellulose, hypromellose USP, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, propylene glycol, sodium ascorbate, sodium lauryl sulfate, sodium starch glycolate, synthetic red iron oxide, and titanium dioxide.
- Rifapentine is a rifamycin derivative antimicrobial and has a similar profile of microbiological activity to rifampicin. The molecular weight is 877.04.
- The molecular formula is C47H64N4O12.
- The chemical name for rifapentine is rifamycin, 3-methyl]]-or 3-rifamycin or 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8--2,7-(epoxypentadecatrienimino)naphthofuran-1,11(2H)-dione 21-acetate. It has the following structure:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Rifapentin in the drug label.
## Pharmacokinetics
- When oral doses of PRIFTIN were administered once daily or once every 72 hours to healthy volunteers for 10 days, single dose AUC (0–∞) of rifapentine was similar to its steady-state AUCss (0–24h) or AUCss (0–72h) values, suggesting no significant auto-induction effect on steady-state pharmacokinetics of rifapentine. Steady-state conditions were achieved by day 10 following daily administration of PRIFTIN 600 mg. No plasma accumulation of rifapentine and 25-desacetyl rifapentine (active metabolite) is expected after once weekly administration of PRIFTIN.
- The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine on day 10 following oral administration of 600 mg PRIFTIN every 72 hours to healthy volunteers are described in Table 5.
- The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine following single-dose oral administration of 900 mg PRIFTIN in combination with 900 mg isoniazid in fed conditions are described in Table 6.
Absorption
- The absolute bioavailability of PRIFTIN has not been determined. The relative bioavailability (with an oral solution as a reference) of PRIFTIN after a single 600 mg dose to healthy adult volunteers was 70%. The maximum concentrations were achieved from 5 hours to 6 hours after administration of the 600 mg PRIFTIN dose.
- The administration of PRIFTIN with a high fat meal increased rifapentine Cmax and AUC by 40% to 50% over that observed when PRIFTIN was administered under fasting conditions.
- The administration of PRIFTIN (900 mg single dose) and isoniazid (900 mg single dose) with a low fat, high carbohydrate breakfast, led to a 47% and 51% increase in rifapentine Cmax and AUC, respectively. In contrast, the ingestion of the same meal decreased isoniazid Cmax and AUC by 46% and of 23%, respectively.
Distribution
- In a population pharmacokinetic analysis in 351 tuberculosis patients who received 600 mg PRIFTIN in combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent volume of distribution was 70.2 ± 9.1 L. In healthy volunteers, rifapentine and 25-desacetyl rifapentine were 97.7% and 93.2% bound to plasma proteins, respectively. Rifapentine was mainly bound to albumin. Similar extent of protein binding was observed in healthy volunteers, asymptomatic HIV-infected subjects and hepatically impaired subjects.
Metabolism/Excretion
- Following a single 600 mg oral dose of radiolabeled rifapentine to healthy volunteers (n=4), 87% of the total 14C rifapentine was recovered in the urine (17%) and feces (70%). Greater than 80% of the total 14C rifapentine dose was excreted from the body within 7 days. Rifapentine was hydrolyzed by an esterase enzyme to form a microbiologically active 25-desacetyl rifapentine. Rifapentine and 25-desacetyl rifapentine accounted for 99% of the total radioactivity in plasma. Plasma AUC(0–∞) and Cmax values of the 25-desacetyl rifapentine metabolite were one-half and one-third those of the rifapentine, respectively. Based upon relative in vitro activities and AUC(0–∞) values, rifapentine and 25-desacetyl rifapentine potentially contributes 62% and 38% to the clinical activities against M. tuberculosis, respectively.
Specific Populations
Gender: In a population pharmacokinetics analysis of sparse blood samples obtained from 351 tuberculosis patients who received 600 mg PRIFTIN in combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent oral clearance of PRIFTIN for males and females was 2.51 ± 0.14 L/h and 1.69 ± 0.41 L/h, respectively. The clinical significance of the difference in the estimated apparent oral clearance is not known.
Elderly: Following oral administration of a single 600 mg dose of PRIFTIN to elderly (65 years and older) male healthy volunteers (n=14), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were similar to that observed for young (18 to 45 years) healthy male volunteers (n=20).
Pediatric: In a pharmacokinetic study in pediatric patients (age 2 to 12 years), a single oral dose of 150 mg PRIFTIN was administered to those weighing less than 30 kg (n=11) and a single oral dose of 300 mg was administered to those weighing greater than30kg (n=12). The mean estimates of AUC and Cmax were approximately 30% to 50% lower in these pediatric patients than those observed in healthy adults administered single oral doses of 600 mg and 900 mg.
A study compared the pharmacokinetics of rifapentine in pediatric patients (age 2 years to 11 years) with latent tuberculosis infection (n=80) receiving PRIFTIN once weekly based on weight (15 mg/kg–30 mg/kg, up to a maximum of 900 mg, see TABLE 1) to that of adults (n=77) receiving PRIFTIN 900 mg once weekly. Children who could not swallow whole tablets were administered crushed tablets mixed in soft food. Overall, the geometric mean AUC of rifapentine in this age group was 31% higher compared to adult patients receiving 900 mg PRIFTIN once weekly (720 versus 551 mcg*h/mL). The geometric mean AUC of rifapentine was 60% higher in children administered whole tablets (884 versus 551 mcg*h/mL) and 19% higher in children administered crushed tablets (656 versus 551 mcg*h/mL), as compared to exposures in adults. Pediatric patients administered crushed PRIFTIN tablets had 26% lower rifapentine exposures compared to those pediatric patients who were given whole tablets.
Population pharmacokinetic analysis showed that rifapentine clearance adjusted to body weight decreased with increasing age of pediatric patients (2–18 years).
In another pharmacokinetics study of PRIFTIN in healthy adolescents (age 12 to 15 years), 600 mg PRIFTIN was administered to those weighing ≥45 kg (n=10) and 450 mg was administered to those weighing less than 45 kg (n=2). The pharmacokinetics of rifapentine were similar to those observed in healthy adults.
Renal Impaired Patients: The pharmacokinetics of rifapentine have not been evaluated in renal impaired patients. Although only about 17% of an administered dose is excreted via the kidneys, the clinical significance of impaired renal function on the disposition of rifapentine and its 25-desacetyl metabolite is not known.
Hepatic Impaired Patients: Following oral administration of a single 600 mg dose of PRIFTIN to mild to severe hepatic impaired patients (n=15), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were similar in patients with various degrees of hepatic impairment and to that observed in another study for healthy volunteers (n=12).
Asymptomatic HIV-Infected Volunteers: Following oral administration of a single 600 mg dose of PRIFTIN to asymptomatic HIV-infected volunteers (n=15) under fasting conditions, mean Cmax and AUC(0–∞) of rifapentine were lower (20%–32%) than that observed in other studies in healthy volunteers (n=55). In a cross-study comparison, mean Cmax and AUC values of the 25-desacetyl rifapentine, when compared to healthy volunteers were higher (6%–21%) in one study (n=20), but lower (15%–16%) in a different study (n=40). The clinical significance of this observation is not known. Food (850 total calories: 33 g protein, 55 g fat, and 58 g carbohydrate) increases the mean AUC and Cmax of rifapentine observed under fasting conditions in asymptomatic HIV-infected volunteers by about 51% and 53%, respectively.
Drug-Drug Interactions:
Isoniazid: Co-administration of PRIFTIN (900 mg single dose) and isoniazid (900 mg single dose), in fasted condition, did not result in any significant change in the exposure of rifapentine and isoniazid compared to when administered alone in fasted condition.
Rifapentine is an inducer of cytochrome P4503A4 and 2C8/9. Therefore, it may increase the metabolism and decrease the activity of other co-administered drugs that are metabolized by these enzymes. Dosage adjustments of the co-administered drugs may be necessary if they are given concurrently with PRIFTIN .
Indinavir: In a study in which 600 mg PRIFTIN was administered twice weekly for 14 days followed by PRIFTIN twice weekly plus 800 mg indinavir 3 times a day for an additional 14 days, indinavir Cmax decreased by 55% while AUC reduced by 70%. Clearance of indinavir increased by 3-fold in the presence of PRIFTIN while half-life did not change. But when indinavir was administered for 14 days followed by co-administration with PRIFTIN for an additional 14 days, indinavir did not affect the pharmacokinetics of rifapentine.
Fixed dose combination of efavirenz, emtricitabine and tenofovir: Once-weekly co-administration of 900 mg PRIFTIN with the antiretroviral fixed dose combination of efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxyl fumarate 300mg in HIV- infected patients did not result in any substantial change in steady state exposures of efavirenz, emtricitabine, and tenofovir (Table7). A 15% decrease in efavirenz Cmin and AUC and a 13% decrease in tenofovir Cmin were observed with repeated weekly doses of PRIFTIN (Table 7). No clinically significant change in CD4 cell counts or viral loads were noted.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Hepatocellular carcinomas were increased in male NMRI mice (Harlan Winklemann) which were treated orally with rifapentine for two years at or above doses of 5 mg/kg/day (0.04 times the recommended human dose based on body surface area conversions). In a two year rat study, there was an increase in nasal cavity adenomas in Wistar rats treated orally with rifapentine at 40 mg/kg/day (0.6 times human dose based on body surface area conversions).
- Rifapentine was negative in the following genotoxicity tests: in vitro gene mutation assay in bacteria (Ames test); in vitro point mutation test in Aspergillus nidulans; in vitro gene conversion assay in Saccharomyces cerevisiae; host-mediated (mouse) gene conversion assay with Saccharomyces cerevisiae; in vitro Chinese hamster ovary cell/hypoxanthineguanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay; in vitro chromosomal aberration assay utilizing rat lymphocytes; and in vivo mouse bone marrow micronucleus assay.
- The 25-desacetyl metabolite of rifapentine was positive in the in vitro mammalian chromosome aberration test in V79 Chinese Hamster cells, but was negative in the in vitro gene mutation assay in bacteria (Ames test), the in vitro Chinese hamster ovary cell/hypoxanthine-guanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay, and the in vivo mouse bone marrow micronucleus assay. Fertility and reproductive performance were not affected by oral administration of rifapentine to male and female rats at doses of up to 20 mg/kg/day (one-third of the human dose based on body surface area conversions).
# Clinical Studies
Active Pulmonary Tuberculosis
- PRIFTIN was studied in two randomized, open-label controlled clinical trials in the treatment of active pulmonary tuberculosis.
- The first trial was an open-label, prospective, parallel group, active controlled trial in HIV-negative patients with active pulmonary tuberculosis. The population mostly comprised Black (approximately 60%) or multiracial (approximately 31%) patients. Treatment groups were comparable for age and sex and consisted primarily of male subjects with a mean age of 37 ± 11 years. In the initial 2 month phase of treatment, 361 patients received PRIFTIN 600 mg twice a week in combination with daily isoniazid, pyrazinamide, and ethambutol and 361 subjects received rifampin600 mg in combination with isoniazid, pyrazinamide and ethambutol all administered daily. The doses of the companion drugs were the same in both treatment groups during the initial phase: isoniazid 300 mg, pyrazinamide 2000 mg, and ethambutol 1200 mg. For patients weighing less than 50 kg, the doses of rifampin (450 mg), pyrazinamide (1500 mg) and ethambutol (800 mg) were reduced. Ethambutol was discontinued when isoniazid and rifampin susceptibility testing results were confirmed. During the 4 month continuation phase, 317 patients in the PRIFTIN group continued to receive PRIFTIN 600 mg dosed once-weekly with isoniazid 300 mg and 304 patients in the rifampin group received twice weekly rifampin and isoniazid 900 mg. For patients weighing less than 50 kg, the doses of rifampin (450 mg) and isoniazid (600 mg) were reduced. Both treatment groups received pyridoxine (Vitamin B6) over the 6 month treatment period. Treatment was directly observed. 65/361 (18%) of patients in the PRIFTIN group and 34/361 (9%) in the rifampin group received overdoses of one or more of the administered study medications during the initial or continuation phase of treatment. Seven of these patients had adverse reactions reported with the overdose (5 in the PRIFTIN group and 2 in the rifampin group).
- Table 8 below contains assessments of sputum conversion at end of treatment (6 months) and relapse rates at the end of follow-up (24 months).
- Risk of relapse was greater in the group treated with the PRIFTIN combination. Higher relapse rates were associated with a lower rate of compliance as well as a failure to convert sputum cultures at the end of the initial 2 month treatment phase. Relapse rates were also higher for males in both regimens. Relapse in the PRIFTIN group was not associated with development of mono-resistance to rifampin.
- The second trial was randomized, open-label performed in 1075 HIV-negative and positive patients with active pulmonary tuberculosis. Patients with culture-positive, drug-susceptible pulmonary tuberculosis who had completed the initial 2-month phase of treatment with 4 drugs (rifampin, isoniazid, pyrazinamide, and either ethambutol or streptomycin) under direct observation were randomly assigned to receive either PRIFTIN 600 mg and isoniazid 15 mg/kg (max 900 mg) once-weekly or rifampin 10 mg/kg (max 600 mg) and isoniazid 15 mg/kg (max 900 mg) twice weekly for the 4 month continuation phase. Study drugs were given under direct observation therapy in both groups.
- In the PRIFTIN group, 502 HIV-negative and 36 HIV-positive patients were randomized and in the rifampin group 502 HIV-negative and 35 HIV-positive patients were randomized to treatment. Enrollment of HIV-infected patients was stopped when 4 of 36 patients in the PRIFTIN combination group relapsed with isolates that were rifampin resistant.
- Table 9 below contains assessments of sputum conversion at the end of treatment (6 months total: 2 months of initial and 4 months of randomized continuation treatment) and relapse rates at the end of follow-up (24 months) in all HIV-negative patients randomized to treatment. Positive culture was based on either one sputum sample with >10 colonies on solid media OR at least 2 positive sputum samples on liquid or solid media. However, only one sputum sample was collected at each visit in a majority of patients.
- In HIV-negative patients, higher relapse rates were seen in patients with a positive sputum culture at 2 months (i.e., at the time of study randomization), cavitation on chest x-ray, and bilateral pulmonary involvement.
- Sixty-one HIV-positive patients were assessed for relapse. The rates of relapse were 16.7% (5/30) in the PRIFTIN group and 9.7% (3/31) in the rifampin group. In HIV-positive patients, 4 of the 5 relapses in the PRIFTIN combination group involved M. tuberculosis strains with rifampin monoresistance. No relapse strain in the twice weekly rifampin / isoniazid group acquired drug resistance.
- The death rate among all study participants did not differ between the two treatment groups.
Latent Tuberculosis Infection
- A multi-center, prospective, open-label, randomized, active-controlled trial compared the effectiveness of 12 weekly doses of PRIFTIN in combination with isoniazid (3RPT/INH arm) administered by directly observed therapy to 9 months of self-administered daily isoniazid (9INH arm). The trial enrolled patients two years of age or older with positive tuberculin skin test and at high risk for progression to tuberculosis disease. Enrolled patients included those having close contact with a patient with active tuberculosis disease, recent (within two years) conversion to a positive tuberculin skin test, HIV-infection, or fibrosis on chest radiograph. PRIFTIN was dosed by weight, for a maximum of 900 mg weekly. Isoniazid mg/kg dose was determined by age, for a maximum of 900 mg weekly in the 3RPT/INH arm and 300 mg daily in the 9INH arm.
- The outcome measure was the development of active tuberculosis disease, defined as culture confirmed tuberculosis in adults and culture-confirmed or clinical tuberculosis in children less than 18 years of age, at 33 months after trial enrollment. Patients who were found after enrollment to be ineligible because they had active tuberculosis disease, were contacts of a source case with culture-negative or drug-resistant tuberculosis disease cases or no information regarding susceptibility of M. tuberculosis, and young children lacking a positive TST on initial and repeat testing were excluded from the analysis.
- Active tuberculosis disease developed in 5 of 3074 randomized patients in the 3RPT/INH group (0.16%) versus 10 of 3074 patients in 9INH group (0.32%), for a difference in cumulative rates of 0.17%, 95% CI (-0.43, 0.09) (Table 10).
- The proportion of patients completing treatment was 81.2% in the 3RPT/INH group and 68.3% in the 9INH group for a difference (3RPT/INH-9INH) of 12.8% 95% CI (10.7, 15.0).
- In the 9INH treatment group, two of the thirteen culture-confirmed cases were found to be isoniazid -monoresistant. In the 3RPT/INH treatment group, one of the seven cases was rifampin -resistant, isoniazid -susceptible M. bovis infection.
Pediatric Sub-study
- Enrollment of children was extended after the overall target number of patients was attained in the main study. Data from both the main study and the extension were pooled resulting in an eligible population for analysis of 375 children in the 3RPT/INH arm and 367 in the 9INH arm.
- One child in the 9INH group developed tuberculosis (1/367, cumulative rate 0.32%) versus zero tuberculosis cases in the 3RPT/INH group (0/375) at 33 months post-enrollment. The proportion of patients completing treatment in the 3RPT/INH and the 9INH groups was 87.5% and 79.6% respectively for a difference of 7.9%, 95% CI (2.5, 13.2).
HIV Sub-study
- Enrollment of HIV-positive patients was extended after the overall target number of patients was attained in the main study. Data from both the main study and the extension were pooled resulting in an eligible population for analysis of 206 patients in the 3RPT/INH group and 193 in the 9INH group. Tuberculosis disease developed in 2/206 patients in the 3RPT/INH group (cumulative rate, 1.01%) and in 6/193 patients in the 9INH group (cumulative rate, 3.45%). The proportion of patients completing treatment in the 3RPT/INH and 9INH groups was 88.8% and 63.7%, respectively for a difference of 25.1%, 95% CI (16.8, 32.9).
# How Supplied
- PRIFTIN is supplied as 150 mg round normal convex dark-pink film-coated tablets debossed "Priftin" on top and "150" on the bottom, packaged in aluminum formable foil blister strips inserted into an aluminum foil laminated pouch.
- Carton of 32 tablets (4 strips of 8 tablets) NDC 0088-2100-32
- Carton of 24 tablets (3 strips of 8 tablets) NDC 0088-2100-24
## Storage
- Store at 25°C (77°F); excursions permitted 15–30°C (59–86°F) (see USP Controlled Room Temperature). Protect from excessive heat and humidity.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Treatment Adherence
- Emphasize the importance of compliance with the full course of therapy, and the importance of not missing any doses of PRIFTIN or companion medications in the treatment of active pulmonary tuberculosis or the treatment of latent tuberculosis infection.
Hypersensitivity Reactions
- Inform patients that PRIFTIN may cause hypersensitivity reactions. Signs and symptoms of this reaction may include a flu-like illness, hypotension, urticaria, angioedema, bronchospasm, conjunctivitis, thrombocytopenia or neutropenia. Anaphylaxis may also occur.
- Inform patients of signs and symptoms of hypersensitivity reactions and advise them to stop the medication and contact their healthcare provider if they experience any of these symptoms.
Hepatitis
- Instruct patients to stop the medication and notify their physician promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, and pain or swelling of the joints .
Drug Interactions
- Rifapentine may increase the metabolism and decrease the activity of other drugs that are metabolized by the P4503A4 and 2C8/9 pathways. Dosage adjustments of the co-administered drugs may be necessary. Advise patients to discuss with their physician any other medications they are taking before starting treatment with PRIFTIN.
- Concomitant use of PRIFTIN with protease inhibitors or reverse transcriptase inhibitors may cause a significant decrease in plasma concentrations and loss of therapeutic effect of the protease inhibitor or reverse transcriptase inhibitor.
- Rifapentine may reduce the effectiveness of hormonal contraceptives. Advise patients using oral, transdermal patch, or other systemic hormonal contraceptives to change to non-hormonal methods of birth control.
Discoloration of Body Fluids
- Inform the patient that PRIFTIN produces a reddish coloration of the urine, sweat, sputum, tears, and breast milk. Contact lenses or dentures may be permanently stained.
Administration with Food
- Advise patients to take PRIFTIN with food.
Nursing Mothers
- Advise nursing mothers that breastfeeding is not recommended with PRIFTIN use
# Precautions with Alcohol
Alcohol-Rifapentin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PRIFTIN ®
# Look-Alike Drug Names
There is limited information regarding Rifapentine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Rifapentine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Overview
Rifapentine is an antimycobacterial drug that is FDA approved for the treatment of active pulmonary tuberculosis and latent tuberculosis. Common adverse reactions include anemia, lymphopenia, neutropenia, increased ALT, arthralgia, conjunctivitis, headache, vomiting, nausea, diarrhea, rash, pruritus, anorexia and lymphadenopathy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Active Pulmonary Tuberculosis
- PRIFTIN® (rifapentine) is indicated in adults and children 12 years and older for the treatment of active pulmonary tuberculosis (TB) caused by Mycobacterium tuberculosis. PRIFTIN must always be used in combination with one or more antituberculosis (anti-TB) drugs to which the isolate is susceptible.
Limitations of Use
- Do not use PRIFTIN monotherapy in either the initial or the continuation phases of active antituberculous treatment.
- PRIFTIN should not be used once-weekly in the continuation phase regimen in combination with isoniazid (INH) in HIV-infected patients with active pulmonary tuberculosis because of a higher rate of failure and/or relapse with rifampin (RIF)-resistant organisms.
- PRIFTIN has not been studied as part of the initial phase treatment regimen in HIV- infected patients with active pulmonary tuberculosis.
Latent Tuberculosis Infection
- PRIFTIN is indicated in adults and children 2 years and older for the treatment of latent tuberculosis infection caused by Mycobacterium tuberculosis in patients at high risk of progression to tuberculosis disease (including those in close contact with active tuberculosis patients, recent conversion to a positive tuberculin skin test, HIV-infected patients, or those with pulmonary fibrosis on radiograph).
Limitations of Use
- Active tuberculosis disease should be ruled out before initiating treatment for latent tuberculosis infection.
- PRIFTIN must always be used in combination with isoniazid as a 12-week once-weekly regimen for the treatment of latent tuberculosis infection.
- PRIFTIN in combination with isoniazid is not recommended for Individuals presumed to be exposed to rifamycin- or - isoniazid resistant M. tuberculosis.
# Dosage
Dosage in Active Pulmonary Tuberculosis
- PRIFTIN is only recommended for the treatment of active pulmonary tuberculosis caused by drug-susceptible organisms as part of regimens consisting of a 2 month initial phase followed by a 4 month continuation phase.
- PRIFTIN should not be used in the treatment of active pulmonary tuberculosis caused by rifampin-resistant strains.
- Initial phase (2 Months): PRIFTIN should be administered at a dose of 600 mg twice weekly for two months as directly observed therapy (DOT), with an interval of no less than 3 consecutive days (72 hours) between doses, in combination with other anti- tuberculosis drugs as part of an appropriate regimen which includes daily companion drugs such as isoniazid (INH), ethambutol (EMB) and pyrazinamide (PZA).
- Continuation phase (4 Months): Following the initial phase (2 months), continuation phase (4 months) treatment consists of PRIFTIN 600 mg once-weekly for 4 months in combination with isoniazid or another appropriate anti- tuberculosis agent for susceptible organisms administered as directly observed therapy.
Dosage in Latent Tuberculosis Infection
- PRIFTIN should be administered once-weekly in combination with isoniazid for 12 weeks as directly observed therapy.
- Adults and children 12 years and older: The recommended dose of PRIFTIN should be determined based on weight of the patient up to a maximum of 900 mg once-weekly (see TABLE 1). The recommended dose of isoniazid is 15 mg/kg (rounded to the nearest 50 mg or 100mg) up to a maximum of 900 mg once-weekly for 12 weeks.
- Children 2–11 years: The recommended dose of PRIFTIN should be determined based on weight of the patient up to a maximum of 900 mg once- weekly (see TABLE 1). The recommended dose of isoniazid is 25 mg/kg (rounded to the nearest 50 mg or 100mg) up to a maximum of 900 mg once-weekly for 12 weeks.
# DOSAGE FORMS AND STRENGTHS
- PRIFTIN is supplied as 150 mg round normal convex dark-pink film-coated tablets debossed "Priftin" on top and "150" on the bottom.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Rifapentine in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifapentine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Rifapentine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Rifapentine in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Rifapentine in pediatric patients.
# Contraindications
Hypersensitivity
- PRIFTIN is contraindicated in patients with a history of hypersensitivity to rifamycins.
# Warnings
Hepatotoxicity
- Elevations of liver transaminases may occur in patients receiving PRIFTIN. Patients on PRIFTIN should be monitored for symptoms of liver injury.
- Patients with abnormal liver tests and/or liver disease or patients initiating treatment for active pulmonary tuberculosis should only be given PRIFTIN in cases of necessity and under strict medical supervision. In such patients, obtain serum transaminase levels prior to therapy and every 2–4 weeks while on therapy. Discontinue PRIFTIN if evidence of liver injury occurs.
Hypersensitivity and Related Reactions
- Hypersensitivity reactions may occur in patients receiving PRIFTIN. Signs and symptoms of these reactions may include hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, neutropenia or flu-like syndrome (weakness, fatigue, muscle pain, nausea, vomiting, headache, fever, chills, aches, rash, itching, sweats, dizziness, shortness of breath, chest pain, cough, syncope, palpitations). There have been reports of anaphylaxis.
- Monitor patients receiving PRIFTIN therapy for signs and/or symptoms of hypersensitivity reactions. If these symptoms occur, administer supportive measures and discontinue PRIFTIN.
Relapse in the Treatment of Active Pulmonary Tuberculosis
- PRIFTIN has not been evaluated as part of the initial phase treatment regimen in HIV-infected patients with active pulmonary TB.
- Do not use PRIFTIN as a once-weekly continuation phase regimen in HIV-infected patients with active pulmonary tuberculosis because of a higher rate of failure and/or relapse with rifampin-resistant organisms.
- Higher relapse rates may occur in patients with cavitary pulmonary lesions and/or positive sputum cultures after the initial phase of active tuberculosis treatment and in patients with evidence of bilateral pulmonary disease. Monitor for signs and symptoms of TB relapse in these patients.
- Poor adherence to therapy is associated with high relapse rate. Emphasize the importance of compliance with therapy.
Drug Interactions
- Rifapentine is an inducer of CYP450 enzymes. Concomitant use of rifapentine with other drugs metabolized by these enzymes, such as protease inhibitors, certain reverse transcriptase inhibitors, and hormonal contraception may cause a significant decrease in plasma concentrations and loss of therapeutic effect.
Discoloration of Body Fluids
- PRIFTIN may produce a red-orange discoloration of body tissues and/or fluids (e.g., skin, teeth, tongue, urine, feces, saliva, sputum, tears, sweat, and cerebrospinal fluid). Contact lenses or dentures may become permanently stained.
Clostridium difficile-Associated Diarrhea
- Clostridium difficile-associated diarrhea (CDAD) has been reported with the use of nearly all systemic antibacterial agents, including PRIFTIN, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon and may permit overgrowth of C. difficile.
- C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, discontinue antibacterial use not directed against C. difficile if possible. Institute appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation as clinically indicated.
Porphyria
- Porphyria has been reported in patients receiving rifampin, attributed to induction of delta amino levulinic acid synthetase. Because PRIFTIN may have similar enzyme induction properties, avoid the use of PRIFTIN in patients with porphyria.
# Adverse Reactions
## Clinical Trials Experience
- The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:
- Hepatotoxicity
- Hypersensitivity
- Discoloration of Body Fluids
- Clostridium difficile-Associated Diarrhea
- Porphyria
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Active Pulmonary Tuberculosis
- PRIFTIN was studied in a randomized, open label, active-controlled trial of HIV-negative patients with active pulmonary tuberculosis. The population consisted of primarily of male subjects with a mean age of 37 ± 11 years. In the initial 2 month phase of treatment, 361 patients received PRIFTIN 600 mg twice a week in combination with daily isoniazid, pyrazinamide, and ethambutol and 361 subjects received rifampin in combination with isoniazid, pyrazinamide and ethambutol all administered daily. Ethambutol was discontinued when drug susceptibly testing was known. During the 4 month continuation phase, 317 patients in the PRIFTIN group continued to receive PRIFTIN 600 mg dosed once-weekly with isoniazid and 304 patients in the rifampin group received twice weekly rifampin and isoniazid. Both treatment groups received pyridoxine (Vitamin B6) over the 6 month treatment period.
- Because PRIFTIN was administered as part of a combination regimen, the adverse reaction profile reflects the entire regimen.
- Twenty-two deaths occurred in the study, eleven in the rifampin combination therapy group and eleven in the PRIFTIN combination therapy group. 18/361 (5%) rifampin combination therapy patients discontinued the study due to an adverse reaction compared to 11/361 (3%) PRIFTIN combination therapy patients. Three patients (two rifampin combination therapy patients and one PRIFTIN combination therapy patient) were discontinued in the initial phase due to hepatotoxicity. Concomitant medications for all three patients included isoniazid, pyrazinamide, ethambutol, and pyridoxine. All three recovered without sequelae.
- Five patients had adverse reactions associated with PRIFTIN overdose. These reactions included hematuria, neutropenia, hyperglycemia, ALT increased, hyperuricemia, pruritus, and arthritis.
- Table 2 presents selected treatment-emergent adverse reactions associated with the treatment regimens which occurred in at least 1% of patients during treatment and post-treatment through the first three months of follow-up.
- The following selected treatment-emergent adverse reactions were reported in less than 1% of the PRIFTIN combination therapy patients during treatment and post-treatment through the first three months of follow-up.
- Blood and Lymphatics: lymphocytosis, hematoma, purpura, thrombosis.
- Cardiovascular: syncope, tachycardia, palpitation, orthostatic hypotension, pericarditis.
- Metabolic & Nutritional: BUN increased, alkaline phosphatase increased.
- Gastrointestinal: gastritis, esophagitis, pancreatitis, salivary gland enlargement.
- General: asthenia, facial edema.
- Hepatobiliary: bilirubinemia, hepatomegaly, jaundice.
- Infectious Disease: infection fungal.
- Musculoskeletal: myalgia, myositis.
- Neurologic: somnolence, dysphonia.
- Pregnancy, Puerperium and Perinatal conditions: abortion
- Psychiatric: anxiety, confusion
- Reproductive Disorders: vaginitis, vaginal hemorrhage, leukorrhea.
- Respiratory: dyspnea, pneumonitis, pulmonary fibrosis, asthma, bronchospasm, laryngeal edema, laryngitis.
- Skin: urticaria, skin discoloration,
- In another randomized, open-label trial, 1075 HIV non-infected and infected patients with active pulmonary tuberculosis who had completed an initial 2 month phase of treatment with 4 drugs were randomly assigned to receive either PRIFTIN 600 mg and isoniazid once weekly or rifampin and isoniazid twice weekly for the 4 month continuation phase. 502 HIV non-infected and 36 HIV-infected patients were randomized to receive the PRIFTIN regimen and 502 HIV-noninfected and 35 HIV-infected patients were randomized to receive the rifampin regimen.
- The death rate was 6.5% for the PRIFTIN combination regimen compared to 6.7% for the rifampin combination regimen.
Latent Tuberculosis Infection
Main Study
- PRIFTIN in combination with isoniazid given once-weekly for 3 months (3RPT/INH) was compared to isoniazid given once daily for 9 months (9INH) in an open-label, randomized trial in patients with a positive tuberculin skin test, and at high risk for progression from latent tuberculosis infection to active tuberculosis disease. PRIFTIN was dosed by weight, and isoniazid mg/kg dose was determined according to age to a maximum of 900 mg each.
- A total of 4040 patients received at least one dose of the 3RPT/INH regimen, including 348 children 2–17 years of age and 105 HIV-infected individuals. A total of 3759 received at least one dose of the 9INH regimen, including 342 children 2 years–17 years of age and 95 HIV-infected individuals.
- Patients were followed for 33 months from the time of enrollment. Treatment-emergent adverse reactions were defined as those occurring during treatment and 60 days after the last dose of treatment. 161 (4%) 3RPT/INH subjects had a rifamycin hypersensitivity reaction, defined as either: a) one of the following: hypotension, urticaria, angioedema, acute bronchospasm, or conjunctivitis occurring in relation to study drug or b) at least four of the following symptoms occurring in relation to the study drug, with at least one symptom being CTCAE Grade 2 or higher: weakness, fatigue, nausea, vomiting, headache, fever, aches, sweats, dizziness, shortness of breath, flushing or chills. No specific definition was used for isoniazid hypersensitivity; 18 (0.5%) 9INH subjects were classified as having a hypersensitivity reaction. Hepatotoxicity was defined as AST≥3× upper limit of normal in the presence of specific signs and symptoms of hepatitis, or AST>5× upper limit of normal regardless of signs or symptoms. 113 (3%) 9INH subjects and 24 (0.6%) 3RPT/INH subjects developed hepatotoxicity.
- 196 subjects (4.9%) in the 3RPT/INH arm discontinued treatment due to a treatment related adverse reaction patients and 142 (3.8%) in the 9INH arm discontinued treatment due to a treatment related adverse reaction. In the 3RPT/INH group, the most frequent treatment related adverse reaction resulting in treatment discontinuation was hypersensitivity reaction, occurring in 120 (3%) patients. In the 9INH group, the most frequent treatment related adverse reaction resulting in treatment discontinuation was hepatotoxicity, occurring in 76 (2%) patients.
- Seventy one deaths occurred, 31/4040, 0.77% in the 3RPT/INH group and 40/3759 (1.06%) in the 9INH group) during the 33 month study period. During the treatment emergent period, 11 deaths occurred, 4 in the 3RPT/INH group and 7 in the 9INH group. None of the reported deaths were considered related to treatment with study drugs or were attributed to tuberculosis disease.
- Table 3 presents select adverse reactions that occurred during the treatment emergent period in the main study in LTBI patients treated with 3RPT/INH or 9INH at a frequency greater than 0.5%.
Pediatric Substudy
- Six-hundred and ninety children 2 years–17 years of age received at least one dose of study drugs in the main study. An additional 342 children 2 years–17 years of age received at least one dose in the pediatric extension study (total 1032 children; 539 received 3RPT/INH and 493 received 9INH).
- No children in either treatment arm developed hepatotoxicity. Using the same definition for rifamycin hypersensitivity reaction as in the main study, 7 (1.3%) of children in the 3RPT/INH group experienced a rifamycin hypersensitivity reaction. Adverse reactions in children 2 years–11 years of age and 12 years–17 years of age were similar.
HIV Substudy
- Two-hundred HIV-infected patients with latent tuberculosis infection received at least one dose of study drugs in the main study and an additional 193 patients received at least one dose in the extension study (total of 393; 207 received 3RPT/INH and 186 received 9INH). Compared to the HIV-negative patients enrolled in the main study, a higher proportion of HIV-infected patients in each treatment arm experienced a treatment emergent adverse reaction, including a higher incidence of hepatotoxicity. Hepatotoxicity occurred in 3/207 (1.5%) patients in the 3RPT/INH arm and in 14/186 (7.5%) in the 9INH arm. Rifamycin hypersensitivity occurred in only one HIV-infected patient.
- Eleven deaths occurred during the 33 month follow up period (6/207 in the 3RPT/INH group and 5/186 in the 9INH group) including one death in the 9INH arm during the treatment emergent period. None of the reported deaths were considered related to treatment with study drugs or tuberculosis disease.
- Selected treatment-emergent adverse reactions reported during treatment and 60 days post-treatment in less 0.5% of the 3RPT/INH combination-therapy group in the main study are presented below by body system.
- Eye Disorders: conjunctivitis.
- Blood and Lymphatic System Disorders: leukopenia, anemia, lymphadenopathy, neutropenia.
- Gastrointestinal Disorders: nausea, diarrhea, vomiting, abdominal pain, constipation, dry mouth, dyspepsia, esophageal irritation, gastritis, pancreatitis.
- General Disorders and Administration Site Conditions: fatigue, pyrexia, asthenia, chest pain, chills, feeling jittery.
- Infections and Infestations: pharyngitis, viral infection, vulvovaginal candidiasis.
- Metabolism and Nutrition Disorders: hyperglycemia, gout, hyperkalemia, decreased appetite, hyperlipidemia.
- Musculoskeletal and Connective Tissue Disorders: arthralgia, myalgia, back pain, rhabdomyolysis.
- Nervous system Disorders: dizziness, convulsion, paresthesia, headache, neuropathy peripheral, syncope.
- Psychiatric Disorders: depression, anxiety, disorientation, suicidal ideation.
- Renal and Urinary Disorders: azotemia.
- Reproductive System and Breast Disorders: vulvovaginal pruritus.
- Respiratory, Thoracic and Mediastinal Disorders: cough, dyspnea, oropharyngeal pain, asthma, bronchial hyperactivity, epistaxis.
- Skin and Subcutaneous Tissue Disorders: rash, hyperhidrosis, pruritus, urticaria.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Rifapentine in the drug label.
# Drug Interactions
Protease Inhibitors and Reverse Transcriptase Inhibitors
- Rifapentine is an inducer of CYP450 enzymes. Concomitant use of PRIFTIN with other drugs metabolized by these enzymes, such as protease inhibitors and certain reverse transcriptase inhibitors, may cause a significant decrease in plasma concentrations and loss of therapeutic effect of the protease inhibitor or reverse transcriptase inhibitor.
Fixed Dose Combination of Efavirenz, Emtricitabine and Tenofovir
- Once-weekly co-administration of 900 mg PRIFTIN with the antiretroviral fixed dose combination of efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxyl fumarate 300mg in HIV- infected patients did not result in any substantial change in steady state exposures of efavirenz, emtricitabine, and tenofovir. No clinically significant change in CD4 cell counts or viral loads were noted.
Hormonal Contraceptives
- PRIFTIN may reduce the effectiveness of hormonal contraceptives. Therefore, patients using oral, transdermal patch, or other systemic hormonal contraceptives should be advised to change to non-hormonal methods of birth control.
Cytochrome P450 3A4 and 2C8/9
- Rifapentine is an inducer of cytochromes P4503A4 and P4502C8/9. Therefore, PRIFTIN may increase the metabolism of other coadministered drugs that are metabolized by these enzymes. Induction of enzyme activities by PRIFTIN occurred within 4 days after the first dose. Enzyme activities returned to baseline levels 14 days after discontinuing PRIFTIN.
- Rifampin has been reported to accelerate the metabolism and may reduce the activity of the following drugs; hence, PRIFTIN may also increase the metabolism and decrease the activity of these drugs. Dosage adjustments of the drugs in Table 4 or of other drugs metabolized by cytochrome P4503A4 or P4502C8/9 may be necessary if they are given concurrently with PRIFTIN.
Other Interactions
- The conversion of PRIFTIN to 25-desacetyl rifapentine is mediated by an esterase enzyme. There is minimal potential for PRIFTIN metabolism to be inhibited or induced by another drug, based upon the characteristics of the esterase enzymes.
- Since PRIFTIN is highly bound to albumin, drug displacement interactions may also occur.
Interactions with Laboratory Tests
- Therapeutic concentrations of rifampin have been shown to inhibit standard microbiological assays for serum folate and Vitamin B12. Similar drug-laboratory interactions should be considered for PRIFTIN; thus, alternative assay methods should be considered.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C:
Risk Summary
- There are no adequate and well controlled trials of PRIFTIN in pregnant women; however, there are limited pregnancy outcome data reported from women enrolled in clinical trials of various PRIFTIN treatment regimens for active tuberculosis and latent tuberculosis infection. The reported rate of spontaneous abortion following PRIFTIN exposure did not represent an increase over the background rate of spontaneous abortion reported in the general population. Further interpretation of these data is limited by the quality of clinical trial adverse event reporting. In animal reproduction and developmental toxicity studies, rifapentine produced fetal harm and was teratogenic at doses less than and similar to the recommended human dose. Because animal studies are not always predictive of human response, PRIFTIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rifapentine in women who are pregnant.
### Labor and Delivery
- When administered during the last few weeks of pregnancy, rifampin, another rifamycin product, may increase the risk for maternal postpartum hemorrhage and bleeding in the exposed neonate. Monitor prothrombin time of pregnant women and neonates, who are exposed to PRIFTIN during the last few weeks of pregnancy. Treatment with Vitamin K may be indicated.
### Nursing Mothers
- It is not known whether PRIFTIN is present in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Since PRIFTIN may produce a red-orange discoloration of body fluids, there is a potential for discoloration of breast milk.
- A slight increase in rat pup mortality was observed during lactation when dams were dosed late in gestation through lactation.
### Pediatric Use
- The safety and effectiveness of PRIFTIN in the treatment of active pulmonary tuberculosis have not been established in pediatric patients under the age of 12.
- The safety and effectiveness of PRIFTIN in combination with isoniazid once-weekly regimen has been evaluated in pediatric patients (2–17 years of age) for the treatment of latent tuberculosis infection. In clinical studies, the safety profile in children was similar to that observed in adult patients.
- In a pharmacokinetic study conducted in 2 year to 11 year-old pediatric patients with latent tuberculosis infection, PRIFTIN was administered once-weekly based on weight (15mg/kg to 30 mg/Kg, up to a maximum of 900 mg). Exposures (AUC) in children 2 years–11 years with latent tuberculosis infection were higher (average 31%) than those observed in adults receiving PRIFTIN 900mg once-weekly
### Geriatic Use
- Clinical studies with PRIFTIN did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In a pharmacokinetic study with PRIFTIN, no substantial differences in the pharmacokinetics of rifapentine and 25-desacetyl metabolite were observed in the elderly compared to younger adults.
### Gender
There is no FDA guidance on the use of Rifapentine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rifapentine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rifapentine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rifapentine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rifapentine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rifapentine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- There is limited information regarding Monitoring of Rifapentine in the drug label.
# IV Compatibility
- There is limited information regarding IV Compatibility of Rifapentine in the drug label.
# Overdosage
- While there is no experience with the treatment of acute overdose with PRIFTIN, clinical experience with rifamycins suggests that gastric lavage to evacuate gastric contents (within a few hours of overdose), followed by instillation of an activated charcoal slurry into the stomach, may help adsorb any remaining drug from the gastrointestinal tract.
- Rifapentine and 25-desacetyl rifapentine are 97.7% and 93.2% plasma protein bound, respectively. Rifapentine and related compounds excreted in urine account for only 17% of the administered dose, therefore, neither hemodialysis nor forced diuresis is expected to enhance the systemic elimination of unchanged rifapentine from the body of a patient with PRIFTIN overdose.
# Pharmacology
## Mechanism of Action
- Rifapentine, a cyclopentyl rifamycin, inhibits DNA-dependent RNA polymerase in susceptible strains of Mycobacterium tuberculosis but does not affect mammalian cells at concentrations that are active against these bacteria. At therapeutic levels, rifapentine inhibits RNA transcription by preventing the initiation of RNA chain formation. It forms a stable complex with bacterial DNA-dependent RNA polymerase, leading to repression of RNA synthesis and cell death. Rifapentine and its 25-desacetyl metabolite accumulate in human monocyte-derived macrophages and are bactericidal to both intracellular and extracellular M. tuberculosis bacilli.
## Structure
- PRIFTIN (rifapentine) for oral administration contains 150 mg of the active ingredient rifapentine per tablet.
- The 150 mg tablets also contain, as inactive ingredients: calcium stearate, disodium EDTA, FD&C Blue No. 2 aluminum lake, hydroxypropyl cellulose, hypromellose USP, microcrystalline cellulose, polyethylene glycol, pregelatinized starch, propylene glycol, sodium ascorbate, sodium lauryl sulfate, sodium starch glycolate, synthetic red iron oxide, and titanium dioxide.
- Rifapentine is a rifamycin derivative antimicrobial and has a similar profile of microbiological activity to rifampicin. The molecular weight is 877.04.
- The molecular formula is C47H64N4O12.
- The chemical name for rifapentine is rifamycin, 3-[[(4-cyclopentyl-1-piperazinyl)imino]methyl]]-or 3-[N-(4-Cyclopentyl-1-piperazinyl)formimidoyl]rifamycin or 5,6,9,17,19,21-hexahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[N-(4-cyclopentyl-l-piperazinyl)-formimidoyl]-2,7-(epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-1,11(2H)-dione 21-acetate. It has the following structure:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Rifapentin in the drug label.
## Pharmacokinetics
- When oral doses of PRIFTIN were administered once daily or once every 72 hours to healthy volunteers for 10 days, single dose AUC (0–∞) of rifapentine was similar to its steady-state AUCss (0–24h) or AUCss (0–72h) values, suggesting no significant auto-induction effect on steady-state pharmacokinetics of rifapentine. Steady-state conditions were achieved by day 10 following daily administration of PRIFTIN 600 mg. No plasma accumulation of rifapentine and 25-desacetyl rifapentine (active metabolite) is expected after once weekly administration of PRIFTIN.
- The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine on day 10 following oral administration of 600 mg PRIFTIN every 72 hours to healthy volunteers are described in Table 5.
- The pharmacokinetic parameters of rifapentine and 25-desacetyl rifapentine following single-dose oral administration of 900 mg PRIFTIN in combination with 900 mg isoniazid in fed conditions are described in Table 6.
Absorption
- The absolute bioavailability of PRIFTIN has not been determined. The relative bioavailability (with an oral solution as a reference) of PRIFTIN after a single 600 mg dose to healthy adult volunteers was 70%. The maximum concentrations were achieved from 5 hours to 6 hours after administration of the 600 mg PRIFTIN dose.
- The administration of PRIFTIN with a high fat meal increased rifapentine Cmax and AUC by 40% to 50% over that observed when PRIFTIN was administered under fasting conditions.
- The administration of PRIFTIN (900 mg single dose) and isoniazid (900 mg single dose) with a low fat, high carbohydrate breakfast, led to a 47% and 51% increase in rifapentine Cmax and AUC, respectively. In contrast, the ingestion of the same meal decreased isoniazid Cmax and AUC by 46% and of 23%, respectively.
Distribution
- In a population pharmacokinetic analysis in 351 tuberculosis patients who received 600 mg PRIFTIN in combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent volume of distribution was 70.2 ± 9.1 L. In healthy volunteers, rifapentine and 25-desacetyl rifapentine were 97.7% and 93.2% bound to plasma proteins, respectively. Rifapentine was mainly bound to albumin. Similar extent of protein binding was observed in healthy volunteers, asymptomatic HIV-infected subjects and hepatically impaired subjects.
Metabolism/Excretion
- Following a single 600 mg oral dose of radiolabeled rifapentine to healthy volunteers (n=4), 87% of the total 14C rifapentine was recovered in the urine (17%) and feces (70%). Greater than 80% of the total 14C rifapentine dose was excreted from the body within 7 days. Rifapentine was hydrolyzed by an esterase enzyme to form a microbiologically active 25-desacetyl rifapentine. Rifapentine and 25-desacetyl rifapentine accounted for 99% of the total radioactivity in plasma. Plasma AUC(0–∞) and Cmax values of the 25-desacetyl rifapentine metabolite were one-half and one-third those of the rifapentine, respectively. Based upon relative in vitro activities and AUC(0–∞) values, rifapentine and 25-desacetyl rifapentine potentially contributes 62% and 38% to the clinical activities against M. tuberculosis, respectively.
Specific Populations
Gender: In a population pharmacokinetics analysis of sparse blood samples obtained from 351 tuberculosis patients who received 600 mg PRIFTIN in combination with isoniazid, pyrazinamide and ethambutol, the estimated apparent oral clearance of PRIFTIN for males and females was 2.51 ± 0.14 L/h and 1.69 ± 0.41 L/h, respectively. The clinical significance of the difference in the estimated apparent oral clearance is not known.
Elderly: Following oral administration of a single 600 mg dose of PRIFTIN to elderly (65 years and older) male healthy volunteers (n=14), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were similar to that observed for young (18 to 45 years) healthy male volunteers (n=20).
Pediatric: In a pharmacokinetic study in pediatric patients (age 2 to 12 years), a single oral dose of 150 mg PRIFTIN was administered to those weighing less than 30 kg (n=11) and a single oral dose of 300 mg was administered to those weighing greater than30kg (n=12). The mean estimates of AUC and Cmax were approximately 30% to 50% lower in these pediatric patients than those observed in healthy adults administered single oral doses of 600 mg and 900 mg.
A study compared the pharmacokinetics of rifapentine in pediatric patients (age 2 years to 11 years) with latent tuberculosis infection (n=80) receiving PRIFTIN once weekly based on weight (15 mg/kg–30 mg/kg, up to a maximum of 900 mg, see TABLE 1) to that of adults (n=77) receiving PRIFTIN 900 mg once weekly. Children who could not swallow whole tablets were administered crushed tablets mixed in soft food. Overall, the geometric mean AUC of rifapentine in this age group was 31% higher compared to adult patients receiving 900 mg PRIFTIN once weekly (720 versus 551 mcg*h/mL). The geometric mean AUC of rifapentine was 60% higher in children administered whole tablets (884 versus 551 mcg*h/mL) and 19% higher in children administered crushed tablets (656 versus 551 mcg*h/mL), as compared to exposures in adults. Pediatric patients administered crushed PRIFTIN tablets had 26% lower rifapentine exposures compared to those pediatric patients who were given whole tablets.
Population pharmacokinetic analysis showed that rifapentine clearance adjusted to body weight decreased with increasing age of pediatric patients (2–18 years).
In another pharmacokinetics study of PRIFTIN in healthy adolescents (age 12 to 15 years), 600 mg PRIFTIN was administered to those weighing ≥45 kg (n=10) and 450 mg was administered to those weighing less than 45 kg (n=2). The pharmacokinetics of rifapentine were similar to those observed in healthy adults.
Renal Impaired Patients: The pharmacokinetics of rifapentine have not been evaluated in renal impaired patients. Although only about 17% of an administered dose is excreted via the kidneys, the clinical significance of impaired renal function on the disposition of rifapentine and its 25-desacetyl metabolite is not known.
Hepatic Impaired Patients: Following oral administration of a single 600 mg dose of PRIFTIN to mild to severe hepatic impaired patients (n=15), the pharmacokinetics of rifapentine and 25-desacetyl metabolite were similar in patients with various degrees of hepatic impairment and to that observed in another study for healthy volunteers (n=12).
Asymptomatic HIV-Infected Volunteers: Following oral administration of a single 600 mg dose of PRIFTIN to asymptomatic HIV-infected volunteers (n=15) under fasting conditions, mean Cmax and AUC(0–∞) of rifapentine were lower (20%–32%) than that observed in other studies in healthy volunteers (n=55). In a cross-study comparison, mean Cmax and AUC values of the 25-desacetyl rifapentine, when compared to healthy volunteers were higher (6%–21%) in one study (n=20), but lower (15%–16%) in a different study (n=40). The clinical significance of this observation is not known. Food (850 total calories: 33 g protein, 55 g fat, and 58 g carbohydrate) increases the mean AUC and Cmax of rifapentine observed under fasting conditions in asymptomatic HIV-infected volunteers by about 51% and 53%, respectively.
Drug-Drug Interactions:
Isoniazid: Co-administration of PRIFTIN (900 mg single dose) and isoniazid (900 mg single dose), in fasted condition, did not result in any significant change in the exposure of rifapentine and isoniazid compared to when administered alone in fasted condition.
Rifapentine is an inducer of cytochrome P4503A4 and 2C8/9. Therefore, it may increase the metabolism and decrease the activity of other co-administered drugs that are metabolized by these enzymes. Dosage adjustments of the co-administered drugs may be necessary if they are given concurrently with PRIFTIN [see DRUG INTERACTIONS (7.4)].
Indinavir: In a study in which 600 mg PRIFTIN was administered twice weekly for 14 days followed by PRIFTIN twice weekly plus 800 mg indinavir 3 times a day for an additional 14 days, indinavir Cmax decreased by 55% while AUC reduced by 70%. Clearance of indinavir increased by 3-fold in the presence of PRIFTIN while half-life did not change. But when indinavir was administered for 14 days followed by co-administration with PRIFTIN for an additional 14 days, indinavir did not affect the pharmacokinetics of rifapentine.
Fixed dose combination of efavirenz, emtricitabine and tenofovir: Once-weekly co-administration of 900 mg PRIFTIN with the antiretroviral fixed dose combination of efavirenz 600 mg, emtricitabine 200 mg and tenofovir disoproxyl fumarate 300mg in HIV- infected patients did not result in any substantial change in steady state exposures of efavirenz, emtricitabine, and tenofovir (Table7). A 15% decrease in efavirenz Cmin and AUC and a 13% decrease in tenofovir Cmin were observed with repeated weekly doses of PRIFTIN (Table 7). No clinically significant change in CD4 cell counts or viral loads were noted.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Hepatocellular carcinomas were increased in male NMRI mice (Harlan Winklemann) which were treated orally with rifapentine for two years at or above doses of 5 mg/kg/day (0.04 times the recommended human dose based on body surface area conversions). In a two year rat study, there was an increase in nasal cavity adenomas in Wistar rats treated orally with rifapentine at 40 mg/kg/day (0.6 times human dose based on body surface area conversions).
- Rifapentine was negative in the following genotoxicity tests: in vitro gene mutation assay in bacteria (Ames test); in vitro point mutation test in Aspergillus nidulans; in vitro gene conversion assay in Saccharomyces cerevisiae; host-mediated (mouse) gene conversion assay with Saccharomyces cerevisiae; in vitro Chinese hamster ovary cell/hypoxanthineguanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay; in vitro chromosomal aberration assay utilizing rat lymphocytes; and in vivo mouse bone marrow micronucleus assay.
- The 25-desacetyl metabolite of rifapentine was positive in the in vitro mammalian chromosome aberration test in V79 Chinese Hamster cells, but was negative in the in vitro gene mutation assay in bacteria (Ames test), the in vitro Chinese hamster ovary cell/hypoxanthine-guanine-phosphoribosyl transferase (CHO/HGPRT) forward mutation assay, and the in vivo mouse bone marrow micronucleus assay. Fertility and reproductive performance were not affected by oral administration of rifapentine to male and female rats at doses of up to 20 mg/kg/day (one-third of the human dose based on body surface area conversions).
# Clinical Studies
Active Pulmonary Tuberculosis
- PRIFTIN was studied in two randomized, open-label controlled clinical trials in the treatment of active pulmonary tuberculosis.
- The first trial was an open-label, prospective, parallel group, active controlled trial in HIV-negative patients with active pulmonary tuberculosis. The population mostly comprised Black (approximately 60%) or multiracial (approximately 31%) patients. Treatment groups were comparable for age and sex and consisted primarily of male subjects with a mean age of 37 ± 11 years. In the initial 2 month phase of treatment, 361 patients received PRIFTIN 600 mg twice a week in combination with daily isoniazid, pyrazinamide, and ethambutol and 361 subjects received rifampin600 mg in combination with isoniazid, pyrazinamide and ethambutol all administered daily. The doses of the companion drugs were the same in both treatment groups during the initial phase: isoniazid 300 mg, pyrazinamide 2000 mg, and ethambutol 1200 mg. For patients weighing less than 50 kg, the doses of rifampin (450 mg), pyrazinamide (1500 mg) and ethambutol (800 mg) were reduced. Ethambutol was discontinued when isoniazid and rifampin susceptibility testing results were confirmed. During the 4 month continuation phase, 317 patients in the PRIFTIN group continued to receive PRIFTIN 600 mg dosed once-weekly with isoniazid 300 mg and 304 patients in the rifampin group received twice weekly rifampin and isoniazid 900 mg. For patients weighing less than 50 kg, the doses of rifampin (450 mg) and isoniazid (600 mg) were reduced. Both treatment groups received pyridoxine (Vitamin B6) over the 6 month treatment period. Treatment was directly observed. 65/361 (18%) of patients in the PRIFTIN group and 34/361 (9%) in the rifampin group received overdoses of one or more of the administered study medications during the initial or continuation phase of treatment. Seven of these patients had adverse reactions reported with the overdose (5 in the PRIFTIN group and 2 in the rifampin group).
- Table 8 below contains assessments of sputum conversion at end of treatment (6 months) and relapse rates at the end of follow-up (24 months).
- Risk of relapse was greater in the group treated with the PRIFTIN combination. Higher relapse rates were associated with a lower rate of compliance as well as a failure to convert sputum cultures at the end of the initial 2 month treatment phase. Relapse rates were also higher for males in both regimens. Relapse in the PRIFTIN group was not associated with development of mono-resistance to rifampin.
- The second trial was randomized, open-label performed in 1075 HIV-negative and positive patients with active pulmonary tuberculosis. Patients with culture-positive, drug-susceptible pulmonary tuberculosis who had completed the initial 2-month phase of treatment with 4 drugs (rifampin, isoniazid, pyrazinamide, and either ethambutol or streptomycin) under direct observation were randomly assigned to receive either PRIFTIN 600 mg and isoniazid 15 mg/kg (max 900 mg) once-weekly or rifampin 10 mg/kg (max 600 mg) and isoniazid 15 mg/kg (max 900 mg) twice weekly for the 4 month continuation phase. Study drugs were given under direct observation therapy in both groups.
- In the PRIFTIN group, 502 HIV-negative and 36 HIV-positive patients were randomized and in the rifampin group 502 HIV-negative and 35 HIV-positive patients were randomized to treatment. Enrollment of HIV-infected patients was stopped when 4 of 36 patients in the PRIFTIN combination group relapsed with isolates that were rifampin resistant.
- Table 9 below contains assessments of sputum conversion at the end of treatment (6 months total: 2 months of initial and 4 months of randomized continuation treatment) and relapse rates at the end of follow-up (24 months) in all HIV-negative patients randomized to treatment. Positive culture was based on either one sputum sample with >10 colonies on solid media OR at least 2 positive sputum samples on liquid or solid media. However, only one sputum sample was collected at each visit in a majority of patients.
- In HIV-negative patients, higher relapse rates were seen in patients with a positive sputum culture at 2 months (i.e., at the time of study randomization), cavitation on chest x-ray, and bilateral pulmonary involvement.
- Sixty-one HIV-positive patients were assessed for relapse. The rates of relapse were 16.7% (5/30) in the PRIFTIN group and 9.7% (3/31) in the rifampin group. In HIV-positive patients, 4 of the 5 relapses in the PRIFTIN combination group involved M. tuberculosis strains with rifampin monoresistance. No relapse strain in the twice weekly rifampin / isoniazid group acquired drug resistance.
- The death rate among all study participants did not differ between the two treatment groups.
Latent Tuberculosis Infection
- A multi-center, prospective, open-label, randomized, active-controlled trial compared the effectiveness of 12 weekly doses of PRIFTIN in combination with isoniazid (3RPT/INH arm) administered by directly observed therapy to 9 months of self-administered daily isoniazid (9INH arm). The trial enrolled patients two years of age or older with positive tuberculin skin test and at high risk for progression to tuberculosis disease. Enrolled patients included those having close contact with a patient with active tuberculosis disease, recent (within two years) conversion to a positive tuberculin skin test, HIV-infection, or fibrosis on chest radiograph. PRIFTIN was dosed by weight, for a maximum of 900 mg weekly. Isoniazid mg/kg dose was determined by age, for a maximum of 900 mg weekly in the 3RPT/INH arm and 300 mg daily in the 9INH arm.
- The outcome measure was the development of active tuberculosis disease, defined as culture confirmed tuberculosis in adults and culture-confirmed or clinical tuberculosis in children less than 18 years of age, at 33 months after trial enrollment. Patients who were found after enrollment to be ineligible because they had active tuberculosis disease, were contacts of a source case with culture-negative or drug-resistant tuberculosis disease cases or no information regarding susceptibility of M. tuberculosis, and young children lacking a positive TST on initial and repeat testing were excluded from the analysis.
- Active tuberculosis disease developed in 5 of 3074 randomized patients in the 3RPT/INH group (0.16%) versus 10 of 3074 patients in 9INH group (0.32%), for a difference in cumulative rates of 0.17%, 95% CI (-0.43, 0.09) (Table 10).
- The proportion of patients completing treatment was 81.2% in the 3RPT/INH group and 68.3% in the 9INH group for a difference (3RPT/INH-9INH) of 12.8% 95% CI (10.7, 15.0).
- In the 9INH treatment group, two of the thirteen culture-confirmed cases were found to be isoniazid -monoresistant. In the 3RPT/INH treatment group, one of the seven cases was rifampin -resistant, isoniazid -susceptible M. bovis infection.
Pediatric Sub-study
- Enrollment of children was extended after the overall target number of patients was attained in the main study. Data from both the main study and the extension were pooled resulting in an eligible population for analysis of 375 children in the 3RPT/INH arm and 367 in the 9INH arm.
- One child in the 9INH group developed tuberculosis (1/367, cumulative rate 0.32%) versus zero tuberculosis cases in the 3RPT/INH group (0/375) at 33 months post-enrollment. The proportion of patients completing treatment in the 3RPT/INH and the 9INH groups was 87.5% and 79.6% respectively for a difference of 7.9%, 95% CI (2.5, 13.2).
HIV Sub-study
- Enrollment of HIV-positive patients was extended after the overall target number of patients was attained in the main study. Data from both the main study and the extension were pooled resulting in an eligible population for analysis of 206 patients in the 3RPT/INH group and 193 in the 9INH group. Tuberculosis disease developed in 2/206 patients in the 3RPT/INH group (cumulative rate, 1.01%) and in 6/193 patients in the 9INH group (cumulative rate, 3.45%). The proportion of patients completing treatment in the 3RPT/INH and 9INH groups was 88.8% and 63.7%, respectively for a difference of 25.1%, 95% CI (16.8, 32.9).
# How Supplied
- PRIFTIN is supplied as 150 mg round normal convex dark-pink film-coated tablets debossed "Priftin" on top and "150" on the bottom, packaged in aluminum formable foil blister strips inserted into an aluminum foil laminated pouch.
- Carton of 32 tablets (4 strips of 8 tablets) NDC 0088-2100-32
- Carton of 24 tablets (3 strips of 8 tablets) NDC 0088-2100-24
## Storage
- Store at 25°C (77°F); excursions permitted 15–30°C (59–86°F) (see USP Controlled Room Temperature). Protect from excessive heat and humidity.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Treatment Adherence
- Emphasize the importance of compliance with the full course of therapy, and the importance of not missing any doses of PRIFTIN or companion medications in the treatment of active pulmonary tuberculosis or the treatment of latent tuberculosis infection.
Hypersensitivity Reactions
- Inform patients that PRIFTIN may cause hypersensitivity reactions. Signs and symptoms of this reaction may include a flu-like illness, hypotension, urticaria, angioedema, bronchospasm, conjunctivitis, thrombocytopenia or neutropenia. Anaphylaxis may also occur.
- Inform patients of signs and symptoms of hypersensitivity reactions and advise them to stop the medication and contact their healthcare provider if they experience any of these symptoms.
Hepatitis
- Instruct patients to stop the medication and notify their physician promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, and pain or swelling of the joints [see WARNINGS AND PRECAUTIONS (5.1)].
Drug Interactions
- Rifapentine may increase the metabolism and decrease the activity of other drugs that are metabolized by the P4503A4 and 2C8/9 pathways. Dosage adjustments of the co-administered drugs may be necessary. Advise patients to discuss with their physician any other medications they are taking before starting treatment with PRIFTIN.
- Concomitant use of PRIFTIN with protease inhibitors or reverse transcriptase inhibitors may cause a significant decrease in plasma concentrations and loss of therapeutic effect of the protease inhibitor or reverse transcriptase inhibitor.
- Rifapentine may reduce the effectiveness of hormonal contraceptives. Advise patients using oral, transdermal patch, or other systemic hormonal contraceptives to change to non-hormonal methods of birth control. [see DRUG INTERACTIONS (7.3)]
Discoloration of Body Fluids
- Inform the patient that PRIFTIN produces a reddish coloration of the urine, sweat, sputum, tears, and breast milk. Contact lenses or dentures may be permanently stained.
Administration with Food
- Advise patients to take PRIFTIN with food.
Nursing Mothers
- Advise nursing mothers that breastfeeding is not recommended with PRIFTIN use
# Precautions with Alcohol
Alcohol-Rifapentin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- PRIFTIN ®[1]
# Look-Alike Drug Names
There is limited information regarding Rifapentine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Priftin | |
e70442153ee09fe4c55dd1ded572335fbe794a74 | wikidoc | Prison loaf | Prison loaf
Prison loaf, sometimes called Food loaf, Nutriloaf, Confinement Loaf or Special Management Meal, is a food item sometimes used in prisons as a deterrent to misbehavior. It is similar to meatloaf in texture, but has vegetarian or vegan ingredients which are baked into a solid loaf-like form. In some institutions it has no fixed recipe but is simply the regular prison meal (including drink), blended and baked into a loaf. Prison loaf is typically intended to be exceedingly bland in taste, perhaps even unpleasant, but meets all basic human nutritional needs. Prison wardens use the food as a means of punishment for ill-behaving prisoners, who may be punished by being provided with no other form of meal for prolonged periods of time as a means of breaking the prisoners' spirits and encouraging them to change their behavior.
Although prison loaf has been employed in many United States prisons, its use is somewhat controversial. The standards of the American Correctional Association, which accredits prisons, discourage the use of food as a disciplinary measure, but adherence to the organizations' food standards is voluntary. Denying inmates food as punishment has been found to be unconstitutional by the United States Supreme Court, but because the loaf is generally nutritionally complete, it is sometimes justified as a "dietary adjustment" rather than a denial of proper meals.
# References in popular culture
- The 1988 Frank Zappa album Broadway the Hard Way makes reference to Confinement Loaf. | Prison loaf
Prison loaf, sometimes called Food loaf, Nutriloaf, Confinement Loaf or Special Management Meal, is a food item sometimes used in prisons as a deterrent to misbehavior. It is similar to meatloaf in texture, but has vegetarian or vegan ingredients which are baked into a solid loaf-like form. In some institutions it has no fixed recipe but is simply the regular prison meal (including drink), blended and baked into a loaf. Prison loaf is typically intended to be exceedingly bland in taste, perhaps even unpleasant, but meets all basic human nutritional needs. Prison wardens use the food as a means of punishment for ill-behaving prisoners, who may be punished by being provided with no other form of meal for prolonged periods of time as a means of breaking the prisoners' spirits and encouraging them to change their behavior.
Although prison loaf has been employed in many United States prisons, its use is somewhat controversial. The standards of the American Correctional Association, which accredits prisons, discourage the use of food as a disciplinary measure, but adherence to the organizations' food standards is voluntary.[1] Denying inmates food as punishment has been found to be unconstitutional by the United States Supreme Court, but because the loaf is generally nutritionally complete, it is sometimes justified as a "dietary adjustment" rather than a denial of proper meals.[citation needed]
# References in popular culture
- The 1988 Frank Zappa album Broadway the Hard Way makes reference to Confinement Loaf.
# External links
- Loaf Without Parole - Slate.com article, 12/23/2002. Contains a recipe for "the Loaf".
- 'Food Loaf' Helps Stop Food Fights In Jails - KIROTV.com, 2/3/2007. | https://www.wikidoc.org/index.php/Prison_loaf | |
501ba85c0bf03bc37307012e4d4c2b81f7910e4c | wikidoc | Pro-oxidant | Pro-oxidant
Pro-oxidants are chemicals that induce oxidative stress, either through creating reactive oxygen species or inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues, for example an overdose of the analgesic paracetamol (acetaminophen) can cause fatal damage to the liver, partly through its production of reactive oxygen species.
Some substances can act as either antioxidants, or pro-oxidants, depending on the specific set of conditions. Some of the conditions that are important include the concentration of the chemical and if oxygen or transition metals are present. While thermodynamically very favored, reduction of molecular oxygen or peroxide to superoxide or hydroxyl radical is fortunately spin forbidden. This greatly reduces the rates of these reactions, thus allowing aerobic life to exist. As a result, the reduction of oxygen typically involves either the initial formation of singlet oxygen, or spin-orbit coupling through a reduction of a transition-series metal such as manganese, iron, or copper. This reduced metal then transfers the single electron to molecular oxygen or peroxide.
# Metals
Transition metals can act as pro-oxidants. E.g., chronic manganism is a classic "pro-oxidant" disease . Another disease associated with the chronic presence of a pro-oxidant transition-series metal is hemochromatosis, associated with elevated iron levels. Similarly, Wilson's disease is associated with elevated tissue levels of copper. Such syndromes tend to be associated with a common sympomology. This typically-includes various combinations of psychosis, dyskinesia (including Parkinsonian-like symptomology), pigmentary abnormalities, fibrosis, deafness, diabetes, and arthritis. . Thus, all are occasional symptoms of (e.g) hemochromatosis, another name for which is "bronze diabetes". Interestingly, the pro-oxidant herbicide paraquat, Wilson's disease, and striatal iron have similarly been linked to human Parkinsonism. Paraquat also produces parkinsonian-like symptoms in rodents.
# Fibrosis
Fibrosis or scar formation is another pro-oxidant-related symptom. E.g., interocular copper or vitreous chalcosis is associated with severe vitreous fibrosis, as is interocular iron. Liver cirrhosis is also a major symptom of Wilson's disease. The pulmonary fibrosis produced by paraquat and the antitumor agent bleomycin is also thought to be induced by the pro-oxidant properties of these agents. It may be that oxidative stress produced by such agents mimics a normal physiological signal for fibroblast conversion to myofibroblasts.
# Pro-oxidant vitamins
Vitamins that are reducing agents can be pro-oxidants. Vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide, however, it can also reduce metal ions which leads to the generation of free radicals through the fenton reaction.
The relative importance of the antioxidant and pro-oxidant activities of antioxidant vitamins are an area of current research, but vitamin C, for example, appears to have a mostly antioxidant action in the body. However, less data is available for other dietary antioxidants, such as polyphenol antioxidants, zinc, and vitamin E.
# Uric acid
The pro-oxidant properties of reductants can also have clinical consequences. For example, in humans, uric acid accounts for roughly half the antioxidant ability of plasma. In fact, uric acid may have substituted for ascorbate in human evolution .
However, like ascorbate, uric acid can also mediate the production of active oxygen species and thus act as a prooxidant. This was first proposed to play a role in the etiology of the Lesch-Nyhan Syndrome (associated with choreoathetoid dyskinesia) and in hyperuricemic syndrome in dalmatian dogs. The latter responds to treatment with the antioxidant drug orgotein, a pharmaceutical form of superoxide dismutase. Interestingly, such animals are also typically "bronzed".
High uric acid levels are also encountered in atherosclerosis, metabolic syndrome, and in stroke. The issue is whether hyperuricemia is a protective response to oxidative stress in such diseases or whether it is a primary cause . Thus, some researchers think urate-induced oxidative stress is causative in stroke , while others suggest the exact opposite, that urate is neuroprotective by means of its antioxidant properties . Similarly, evidence relates metabolic syndrome to the pro-oxidant properties of urate secondary to fructose-induced hyperuricemia .
# Homocystinuria
In humans, elevated homocysteine levels are associated with an increased incidence of atherosclerosis and may play a role in Alzheimers. Homocysteine is a powerful reducing agent and like most such agents can induce oxidative stress. This has been proposed to play a role in the etiology of such diseases.
# Anticancer Drugs
Several important anticancer agents both bind to DNA and generate reactive oxygen species. These include adriamycin and other anthracyclines, bleomycin, and cisplatin. These agents may show specific toxicity towards cancer cells because of the low level of antioxidant defenses found in tumors. | Pro-oxidant
Pro-oxidants are chemicals that induce oxidative stress, either through creating reactive oxygen species or inhibiting antioxidant systems.[1] The oxidative stress produced by these chemicals can damage cells and tissues, for example an overdose of the analgesic paracetamol (acetaminophen) can cause fatal damage to the liver, partly through its production of reactive oxygen species.[2][3]
Some substances can act as either antioxidants, or pro-oxidants, depending on the specific set of conditions.[4] Some of the conditions that are important include the concentration of the chemical and if oxygen or transition metals are present. While thermodynamically very favored, reduction of molecular oxygen or peroxide to superoxide or hydroxyl radical is fortunately spin forbidden. This greatly reduces the rates of these reactions, thus allowing aerobic life to exist. As a result, the reduction of oxygen typically involves either the initial formation of singlet oxygen, or spin-orbit coupling through a reduction of a transition-series metal such as manganese, iron, or copper. This reduced metal then transfers the single electron to molecular oxygen or peroxide.
# Metals
Transition metals can act as pro-oxidants. E.g., chronic manganism is a classic "pro-oxidant" disease [1]. Another disease associated with the chronic presence of a pro-oxidant transition-series metal is hemochromatosis, associated with elevated iron levels. Similarly, Wilson's disease is associated with elevated tissue levels of copper. Such syndromes tend to be associated with a common sympomology. This typically-includes various combinations of psychosis, dyskinesia (including Parkinsonian-like symptomology), pigmentary abnormalities, fibrosis, deafness, diabetes, and arthritis. [2]. Thus, all are occasional symptoms of (e.g) hemochromatosis, another name for which is "bronze diabetes". Interestingly, the pro-oxidant herbicide paraquat, Wilson's disease, and striatal iron have similarly been linked to human Parkinsonism. Paraquat also produces parkinsonian-like symptoms in rodents.
# Fibrosis
Fibrosis or scar formation is another pro-oxidant-related symptom. E.g., interocular copper or vitreous chalcosis is associated with severe vitreous fibrosis, as is interocular iron. Liver cirrhosis is also a major symptom of Wilson's disease. The pulmonary fibrosis produced by paraquat and the antitumor agent bleomycin is also thought to be induced by the pro-oxidant properties of these agents. It may be that oxidative stress produced by such agents mimics a normal physiological signal for fibroblast conversion to myofibroblasts.
# Pro-oxidant vitamins
Vitamins that are reducing agents can be pro-oxidants. Vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide,[5] however, it can also reduce metal ions which leads to the generation of free radicals through the fenton reaction.[6][7]
The relative importance of the antioxidant and pro-oxidant activities of antioxidant vitamins are an area of current research, but vitamin C, for example, appears to have a mostly antioxidant action in the body.[8][6] However, less data is available for other dietary antioxidants, such as polyphenol antioxidants,[9] zinc,[10] and vitamin E.[11]
# Uric acid
The pro-oxidant properties of reductants can also have clinical consequences. For example, in humans, uric acid accounts for roughly half the antioxidant ability of plasma. In fact, uric acid may have substituted for ascorbate in human evolution [3].
However, like ascorbate, uric acid can also mediate the production of active oxygen species and thus act as a prooxidant. This was first proposed to play a role in the etiology of the Lesch-Nyhan Syndrome (associated with choreoathetoid dyskinesia) and in hyperuricemic syndrome in dalmatian dogs. The latter responds to treatment with the antioxidant drug orgotein, a pharmaceutical form of superoxide dismutase. Interestingly, such animals are also typically "bronzed".
High uric acid levels are also encountered in atherosclerosis, metabolic syndrome, and in stroke. The issue is whether hyperuricemia is a protective response to oxidative stress in such diseases or whether it is a primary cause [4]. Thus, some researchers think urate-induced oxidative stress is causative in stroke [5], while others suggest the exact opposite, that urate is neuroprotective by means of its antioxidant properties [6]. Similarly, evidence relates metabolic syndrome to the pro-oxidant properties of urate secondary to fructose-induced hyperuricemia [7].
# Homocystinuria
In humans, elevated homocysteine levels are associated with an increased incidence of atherosclerosis and may play a role in Alzheimers. Homocysteine is a powerful reducing agent and like most such agents can induce oxidative stress. This has been proposed to play a role in the etiology of such diseases. [8] [9][10][11]
# Anticancer Drugs
Several important anticancer agents both bind to DNA and generate reactive oxygen species. These include adriamycin and other anthracyclines, bleomycin, and cisplatin. These agents may show specific toxicity towards cancer cells because of the low level of antioxidant defenses found in tumors. | https://www.wikidoc.org/index.php/Pro-oxidant | |
6728059a59826787561e0e05090e56025e6f377c | wikidoc | Probability | Probability
Probability is the likelihood that something is the case or will happen. Probability theory is used extensively in areas such as statistics, mathematics, science and philosophy to draw conclusions about the likelihood of potential events and the underlying mechanics of complex systems.
# Interpretations
The word probability does not have a consistent direct definition. However, it can be consistently defined as a mathematical object satisfying a coherent set of axioms (see Template:Harvtxt). Actually, there are two broad categories of probability interpretations: Frequentists talk about probabilities only when dealing with well defined random experiments. The relative frequency of occurrence of an experiment's outcome, when repeating the experiment, is a measure of the probability of that random event. Bayesians, however, assign probabilities to any statement whatsoever, even when no random process is involved, as a way to represent its subjective plausibility.
# History
The scientific study of probability is a modern development. Gambling shows that there has been an interest in quantifying the ideas of probability for millennia, but exact mathematical descriptions of use in those problems only arose much later.
According to Richard Jeffrey, "Before the middle of the seventeenth century, the term 'probable' (Latin probabilis) meant approvable, and was applied in that sense, univocally, to opinion and to action. A probable action or opinion was one such as sensible people would undertake or hold, in the circumstances."
Aside from some elementary considerations made by Girolamo Cardano in the 16th century, the doctrine of probabilities dates to the correspondence of Pierre de Fermat and Blaise Pascal (1654). Christiaan Huygens (1657) gave the earliest known scientific treatment of the subject. Jakob Bernoulli's Ars Conjectandi (posthumous, 1713) and Abraham de Moivre's Doctrine of Chances (1718) treated the subject as a branch of mathematics. See Ian Hacking's The Emergence of Probability for a history of the early development of the very concept of mathematical probability.
The theory of errors may be traced back to Roger Cotes's Opera Miscellanea (posthumous, 1722), but a memoir prepared by Thomas Simpson in 1755 (printed 1756) first applied the theory to the discussion of errors of observation. The reprint (1757) of this memoir lays down the axioms that positive and negative errors are equally probable, and that there are certain assignable limits within which all errors may be supposed to fall; continuous errors are discussed and a probability curve is given.
Pierre-Simon Laplace (1774) made the first attempt to deduce a rule for the combination of observations from the principles of the theory of probabilities. He represented the law of probability of errors by a curve y = \phi(x), x being any error and y its probability, and laid down three properties of this curve:
- it is symmetric as to the y-axis;
- the x-axis is an asymptote, the probability of the error \infty being 0;
- the area enclosed is 1, it being certain that an error exists.
He deduced a formula for the mean of three observations. He also gave (1781) a formula for the law of facility of error (a term due to Lagrange, 1774), but one which led to unmanageable equations. Daniel Bernoulli (1778) introduced the principle of the maximum product of the probabilities of a system of concurrent errors.
The method of least squares is due to Adrien-Marie Legendre (1805), who introduced it in his Nouvelles méthodes pour la détermination des orbites des comètes (New Methods for Determining the Orbits of Comets). In ignorance of Legendre's contribution, an Irish-American writer, Robert Adrain, editor of "The Analyst" (1808), first deduced the law of facility of error,
c and h being constants depending on precision of observation. He gave two proofs, the second being essentially the same as John Herschel's (1850). Gauss gave the first proof which seems to have been known in Europe (the third after Adrain's) in 1809. Further proofs were given by Laplace (1810, 1812), Gauss (1823), James Ivory (1825, 1826), Hagen (1837), Friedrich Bessel (1838), W. F. Donkin (1844, 1856), and Morgan Crofton (1870). Other contributors were Ellis (1844), De Morgan (1864), Glaisher (1872), and Giovanni Schiaparelli (1875). Peters's (1856) formula for r, the probable error of a single observation, is well known.
In the nineteenth century authors on the general theory included Laplace, Sylvestre Lacroix (1816), Littrow (1833), Adolphe Quetelet (1853), Richard Dedekind (1860), Helmert (1872), Hermann Laurent (1873), Liagre, Didion, and Karl Pearson. Augustus De Morgan and George Boole improved the exposition of the theory.
On the geometric side (see integral geometry) contributors to The Educational Times were influential (Miller, Crofton, McColl, Wolstenholme, Watson, and Artemas Martin).
# Theory
Like other theories, the theory of probability is a representation of probabilistic concepts in formal terms—that is, in terms that can be considered separately from their meaning. These formal terms are manipulated by the rules of mathematics and logic, and any results are then interpreted or translated back into the problem domain.
In probability theory, a probability is represented by a real number in the range from 0 to 1. An impossible event has a probability of 0, and a certain event has a probability of 1. (However, other events may also have probabilities 0 or 1: events with probability 0 are not necessarily impossible, and those with probability 1 are not necessarily certain. For examples, see Almost surely.)
There are other methods for quantifying uncertainty,
such as the Dempster-Shafer theory and possibility theory,
but those are essentially different and not compatible with the laws of probability as they are usually understood.
# Applications
Two major applications of probability theory in everyday life are in risk assessment and in trade on commodity markets. Governments typically apply probabilistic methods in environmental regulation where it is called "pathway analysis", often measuring well-being using methods that are stochastic in nature, and choosing projects to undertake based on statistical analyses of their probable effect on the population as a whole. It is not correct to say that statistics are involved in the modelling itself, as typically the assessments of risk are one-time and thus require more fundamental probability models, e.g. "the probability of another 9/11". A law of small numbers tends to apply to all such choices and perception of the effect of such choices, which makes probability measures a political matter.
A good example is the effect of the perceived probability of any widespread Middle East conflict on oil prices - which have ripple effects in the economy as a whole. An assessment by a commodity trader that a war is more likely vs. less likely sends prices up or down, and signals other traders of that opinion. Accordingly, the probabilities are not assessed independently nor necessarily very rationally. The theory of behavioral finance emerged to describe the effect of such groupthink on pricing, on policy, and on peace and conflict.
It can reasonably be said that the discovery of rigorous methods to assess and combine probability assessments has had a profound effect on modern society. Accordingly, it may be of some importance to most citizens to understand how odds and probability assessments are made, and how they contribute to reputations and to decisions, especially in a democracy.
Another significant application of probability theory in everyday life is reliability. Many consumer products, such as automobiles and consumer electronics, utilize reliability theory in the design of the product in order to reduce the probability of failure. The probability of failure is also closely associated with the product's warranty.
It could be said that there is no such thing as probability. It could also be said that probability is a measure of our degree of uncertainty, or that is, the extent of our ignorance in a given situation. Consequently, there might be a probability of 1 in 52 that the top card in a deck of cards is the Jack of diamonds. However, if one looks at the top card and replaces it, then the probability is either 100% or zero percent, and the correct choice can be accurately made by the viewer. Modern physics provides important examples of deterministic situations where only probabilistic description is feasible due to incomplete information and complexity of a system as well as examples of truly random phenomena.
In a deterministic universe, based on Newtonian concepts, there is no probability if all conditions are known. In the case of a roulette wheel, if the force of the hand and the period of that force are known, then the number on which the ball will stop would be a certainty. Of course, this also assumes knowledge of inertia and friction of the wheel, weight, smoothness and roundness of the ball, variations in hand speed during the turning and so forth. A probabilistic description can thus be more useful than Newtonian mechanics for analysing the pattern of outcomes of repeated rolls of roulette wheel. Physicists face the same situation in kinetic theory of gases, where the system while deterministic in principle, is so complex (with the number of molecules typically the order of magnitude of Avogadro constant 6\cdot 10^{23}) that only statistical description of its properties is feasible.
A revolutionary discovery of 20th century physics was the random character of all physical processes that occur at microscopic scales and are governed by the laws of quantum mechanics. The wave function itself evolves deterministically as long as no observation is made, but, according to the prevailing Copenhagen interpretation, the randomness of the wave function collapse when an observation is made, is fundamental. This means that probability theory is required to describe nature. Some scientists spoke of expulsion from Paradise. Others never came to terms with the loss of determinism. Albert Einstein famously remarked in a letter to Max Born: Jedenfalls bin ich überzeugt, daß der Alte nicht würfelt. (I am convinced that God does not play dice). Although alternative viewpoints exist, such as that of quantum decoherence being the cause of an apparent random collapse, at present there is a firm consensus among the physicists that probability theory is necessary to describe quantum phenomena. | Probability
Template:Certainty
Probability is the likelihood that something is the case or will happen. Probability theory is used extensively in areas such as statistics, mathematics, science and philosophy to draw conclusions about the likelihood of potential events and the underlying mechanics of complex systems.
# Interpretations
The word probability does not have a consistent direct definition. However, it can be consistently defined as a mathematical object satisfying a coherent set of axioms (see Template:Harvtxt). Actually, there are two broad categories of probability interpretations: Frequentists talk about probabilities only when dealing with well defined random experiments. The relative frequency of occurrence of an experiment's outcome, when repeating the experiment, is a measure of the probability of that random event. Bayesians, however, assign probabilities to any statement whatsoever, even when no random process is involved, as a way to represent its subjective plausibility.
# History
The scientific study of probability is a modern development. Gambling shows that there has been an interest in quantifying the ideas of probability for millennia, but exact mathematical descriptions of use in those problems only arose much later.
According to Richard Jeffrey, "Before the middle of the seventeenth century, the term 'probable' (Latin probabilis) meant approvable, and was applied in that sense, univocally, to opinion and to action. A probable action or opinion was one such as sensible people would undertake or hold, in the circumstances."[1]
Aside from some elementary considerations made by Girolamo Cardano in the 16th century, the doctrine of probabilities dates to the correspondence of Pierre de Fermat and Blaise Pascal (1654). Christiaan Huygens (1657) gave the earliest known scientific treatment of the subject. Jakob Bernoulli's Ars Conjectandi (posthumous, 1713) and Abraham de Moivre's Doctrine of Chances (1718) treated the subject as a branch of mathematics. See Ian Hacking's The Emergence of Probability for a history of the early development of the very concept of mathematical probability.
The theory of errors may be traced back to Roger Cotes's Opera Miscellanea (posthumous, 1722), but a memoir prepared by Thomas Simpson in 1755 (printed 1756) first applied the theory to the discussion of errors of observation. The reprint (1757) of this memoir lays down the axioms that positive and negative errors are equally probable, and that there are certain assignable limits within which all errors may be supposed to fall; continuous errors are discussed and a probability curve is given.
Pierre-Simon Laplace (1774) made the first attempt to deduce a rule for the combination of observations from the principles of the theory of probabilities. He represented the law of probability of errors by a curve <math>y = \phi(x)</math>, <math>x</math> being any error and <math>y</math> its probability, and laid down three properties of this curve:
- it is symmetric as to the <math>y</math>-axis;
- the <math>x</math>-axis is an asymptote, the probability of the error <math>\infty</math> being 0;
- the area enclosed is 1, it being certain that an error exists.
He deduced a formula for the mean of three observations. He also gave (1781) a formula for the law of facility of error (a term due to Lagrange, 1774), but one which led to unmanageable equations. Daniel Bernoulli (1778) introduced the principle of the maximum product of the probabilities of a system of concurrent errors.
The method of least squares is due to Adrien-Marie Legendre (1805), who introduced it in his Nouvelles méthodes pour la détermination des orbites des comètes (New Methods for Determining the Orbits of Comets). In ignorance of Legendre's contribution, an Irish-American writer, Robert Adrain, editor of "The Analyst" (1808), first deduced the law of facility of error,
<math>c</math> and <math>h</math> being constants depending on precision of observation. He gave two proofs, the second being essentially the same as John Herschel's (1850). Gauss gave the first proof which seems to have been known in Europe (the third after Adrain's) in 1809. Further proofs were given by Laplace (1810, 1812), Gauss (1823), James Ivory (1825, 1826), Hagen (1837), Friedrich Bessel (1838), W. F. Donkin (1844, 1856), and Morgan Crofton (1870). Other contributors were Ellis (1844), De Morgan (1864), Glaisher (1872), and Giovanni Schiaparelli (1875). Peters's (1856) formula for <math>r</math>, the probable error of a single observation, is well known.
In the nineteenth century authors on the general theory included Laplace, Sylvestre Lacroix (1816), Littrow (1833), Adolphe Quetelet (1853), Richard Dedekind (1860), Helmert (1872), Hermann Laurent (1873), Liagre, Didion, and Karl Pearson. Augustus De Morgan and George Boole improved the exposition of the theory.
On the geometric side (see integral geometry) contributors to The Educational Times were influential (Miller, Crofton, McColl, Wolstenholme, Watson, and Artemas Martin).
# Theory
Like other theories, the theory of probability is a representation of probabilistic concepts in formal terms—that is, in terms that can be considered separately from their meaning. These formal terms are manipulated by the rules of mathematics and logic, and any results are then interpreted or translated back into the problem domain.
In probability theory, a probability is represented by a real number in the range from 0 to 1. An impossible event has a probability of 0, and a certain event has a probability of 1. (However, other events may also have probabilities 0 or 1: events with probability 0 are not necessarily impossible, and those with probability 1 are not necessarily certain. For examples, see Almost surely.)
There are other methods for quantifying uncertainty,
such as the Dempster-Shafer theory and possibility theory,
but those are essentially different and not compatible with the laws of probability as they are usually understood.
# Applications
Two major applications of probability theory in everyday life are in risk assessment and in trade on commodity markets. Governments typically apply probabilistic methods in environmental regulation where it is called "pathway analysis", often measuring well-being using methods that are stochastic in nature, and choosing projects to undertake based on statistical analyses of their probable effect on the population as a whole. It is not correct to say that statistics are involved in the modelling itself, as typically the assessments of risk are one-time and thus require more fundamental probability models, e.g. "the probability of another 9/11". A law of small numbers tends to apply to all such choices and perception of the effect of such choices, which makes probability measures a political matter.
A good example is the effect of the perceived probability of any widespread Middle East conflict on oil prices - which have ripple effects in the economy as a whole. An assessment by a commodity trader that a war is more likely vs. less likely sends prices up or down, and signals other traders of that opinion. Accordingly, the probabilities are not assessed independently nor necessarily very rationally. The theory of behavioral finance emerged to describe the effect of such groupthink on pricing, on policy, and on peace and conflict.
It can reasonably be said that the discovery of rigorous methods to assess and combine probability assessments has had a profound effect on modern society. Accordingly, it may be of some importance to most citizens to understand how odds and probability assessments are made, and how they contribute to reputations and to decisions, especially in a democracy.
Another significant application of probability theory in everyday life is reliability. Many consumer products, such as automobiles and consumer electronics, utilize reliability theory in the design of the product in order to reduce the probability of failure. The probability of failure is also closely associated with the product's warranty.
It could be said that there is no such thing as probability. It could also be said that probability is a measure of our degree of uncertainty, or that is, the extent of our ignorance in a given situation. Consequently, there might be a probability of 1 in 52 that the top card in a deck of cards is the Jack of diamonds. However, if one looks at the top card and replaces it, then the probability is either 100% or zero percent, and the correct choice can be accurately made by the viewer. Modern physics provides important examples of deterministic situations where only probabilistic description is feasible due to incomplete information and complexity of a system as well as examples of truly random phenomena.
In a deterministic universe, based on Newtonian concepts, there is no probability if all conditions are known. In the case of a roulette wheel, if the force of the hand and the period of that force are known, then the number on which the ball will stop would be a certainty. Of course, this also assumes knowledge of inertia and friction of the wheel, weight, smoothness and roundness of the ball, variations in hand speed during the turning and so forth. A probabilistic description can thus be more useful than Newtonian mechanics for analysing the pattern of outcomes of repeated rolls of roulette wheel. Physicists face the same situation in kinetic theory of gases, where the system while deterministic in principle, is so complex (with the number of molecules typically the order of magnitude of Avogadro constant <math>6\cdot 10^{23}</math>) that only statistical description of its properties is feasible.
A revolutionary discovery of 20th century physics was the random character of all physical processes that occur at microscopic scales and are governed by the laws of quantum mechanics. The wave function itself evolves deterministically as long as no observation is made, but, according to the prevailing Copenhagen interpretation, the randomness of the wave function collapse when an observation is made, is fundamental. This means that probability theory is required to describe nature. Some scientists spoke of expulsion from Paradise.[citation needed] Others never came to terms with the loss of determinism. Albert Einstein famously remarked in a letter to Max Born: Jedenfalls bin ich überzeugt, daß der Alte nicht würfelt. (I am convinced that God does not play dice). Although alternative viewpoints exist, such as that of quantum decoherence being the cause of an apparent random collapse, at present there is a firm consensus among the physicists that probability theory is necessary to describe quantum phenomena. | https://www.wikidoc.org/index.php/Probabilities | |
2278fa80c7ad9a3ceffaa3d52af200c8bf6bf940 | wikidoc | Progestagen | Progestagen
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Progestagens (also spelled progestogens or gestagens) are hormones which produce effects similar to progesterone, the only natural progestagen. All other progestogens are synthetic and are often referred to as progestins.
All progestagens have antiestrogenic (counteracting the effects of estrogens on the body) and antigonadotropic (inhibiting the production of sex steroids by gonads) properties.
Progestogens differ in their potency (affinity for progesterone receptors) and side effects. Such side effects may be androgenic (medroxyprogesterone and most C19 progestagens), antiandrogenic (cyproterone acetate), estrogenic, glucocorticoid (some C21 progestogens) or antimineralocorticoid (progesterone).
# Uses
## Birth control
- Progestogens are used alone in progestogen only pills, or with an estrogen in combined oral contraceptive pills, a contraceptive patch, and a contraceptive vaginal ring.
Medroxyprogesterone acetate (Depo-Provera) and norethindrone enantate (Noristerat) are used by depot injection.
Etonogestrol is released by subcutaneous implants (Implanon). Norplant and Jadelle implants release levonorgestrel.
Levonorgestrel is released by the intrauterine system IUS (Mirena).
- Progestogens are used alone in progestogen only pills, or with an estrogen in combined oral contraceptive pills, a contraceptive patch, and a contraceptive vaginal ring.
- Medroxyprogesterone acetate (Depo-Provera) and norethindrone enantate (Noristerat) are used by depot injection.
- Etonogestrol is released by subcutaneous implants (Implanon). Norplant and Jadelle implants release levonorgestrel.
- Levonorgestrel is released by the intrauterine system IUS (Mirena).
## Antiandrogen
Cyproterone is an antiandrogen.
## Progestogen withdrawal bleeding
In a normal menstrual cycle, a sudden drop in progesterone levels triggers menstruation. Norethindrone acetate (brand name Aygestin) and medroxyprogesterone acetate (brand name Provera) may be used to artificially induce progestogen withdrawal bleeding. | Progestagen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Progestagens (also spelled progestogens or gestagens) are hormones which produce effects similar to progesterone, the only natural progestagen. All other progestogens are synthetic and are often referred to as progestins.
All progestagens have antiestrogenic (counteracting the effects of estrogens on the body) and antigonadotropic (inhibiting the production of sex steroids by gonads) properties.
Progestogens differ in their potency (affinity for progesterone receptors) and side effects. Such side effects may be androgenic (medroxyprogesterone and most C19 progestagens), antiandrogenic (cyproterone acetate), estrogenic, glucocorticoid (some C21 progestogens) or antimineralocorticoid (progesterone).
# Uses
## Birth control
- Progestogens are used alone in progestogen only pills, or with an estrogen in combined oral contraceptive pills, a contraceptive patch, and a contraceptive vaginal ring.
Medroxyprogesterone acetate (Depo-Provera) and norethindrone enantate (Noristerat) are used by depot injection.
Etonogestrol is released by subcutaneous implants (Implanon). Norplant and Jadelle implants release levonorgestrel.
Levonorgestrel is released by the intrauterine system IUS (Mirena).
- Progestogens are used alone in progestogen only pills, or with an estrogen in combined oral contraceptive pills, a contraceptive patch, and a contraceptive vaginal ring.
- Medroxyprogesterone acetate (Depo-Provera) and norethindrone enantate (Noristerat) are used by depot injection.
- Etonogestrol is released by subcutaneous implants (Implanon). Norplant and Jadelle implants release levonorgestrel.
- Levonorgestrel is released by the intrauterine system IUS (Mirena).
## Antiandrogen
Cyproterone is an antiandrogen.
## Progestogen withdrawal bleeding
In a normal menstrual cycle, a sudden drop in progesterone levels triggers menstruation. Norethindrone acetate (brand name Aygestin) and medroxyprogesterone acetate (brand name Provera) may be used to artificially induce progestogen withdrawal bleeding.
# External links
- The Million Women Study
- The Women's HOPE Study (PubMed Abstract)
- HERS Study (JAMA Abstract)
Template:Sex hormones
Template:SIB
da:Gestagen
de:Gestagen
lt:Gestagenai
nl:Progestageen
no:Progestagen
sv:Gestagener
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Progestagen | |
c063949ed03cbed57d4b3fdab2b3ba836c2c8e6b | wikidoc | Progesterex | Progesterex
Progesterex is a fictitious date rape drug. It is part of a hoax that began to circulate in 1999 via e-mail on the internet. No actual drug by this name or even with these properties exists, and no such incident has ever been documented or confirmed.
Typical contents of the e-mail hoax are as follows, although different versions tend to turn up over time:
"A woman at a nightclub called _______ on Saturday night was taken by 5 men, who according to hospital and police reports, gang raped her before dumping her. Unable to remember the events of the evening, tests later confirmed the repeat rapes along with traces of Rohypnol in her blood and Progesterex, essentially a small sterilization pill. The drug is now being used by rapists at parties to rape AND sterilize their victims. Progesterex is available to vets to sterilize large animals. Progesterex is being used together with Rohypnol, the date rape drug. As with Rohypnol, all they have to do is drop it into the girl's drink. The girl can't remember a thing the next morning, of all that had taken place the night before. Progesterex, which dissolves in drinks just as easily, is such that the victim doesn't conceive from the rape and the rapist needn't worry about having a paternity test identifying him months later. The drug's effects ARE NOT TEMPORARY - Progesterex was designed to sterilize horses. Any female who takes it WILL NEVER BE ABLE TO CONCEIVE.. The weasels can get this drug from anyone who is in the vet school or any university. It's that easy, and Progesterex is about to break out big on campuses everywhere. Believe it or not, there are even sites on the Internet telling people how to use it. Please forward this to everyone you know, especially girls. Be careful when you're out and don't leave your drink unattended. Please make the effort to forward this on to all you know... Guys, please inform all your female friends and relatives."
A version of this hoax has also recently made the rounds via bulletins on MySpace.com (July 2006). It made it to Bebo in September-October 2006.
A version of this hoax has been seen on Facebook, in the form of a group named "Heads Up Ladies", and sports the same story as listed above.
According to the Spanish language website VSAntirus.com at least two versions in Spanish have made the rounds since 2001 as well.
Furthermore, no sterilization pill for horses exists. Sterilization is done via gelding of stallions. Mares are usually left unaltered.
In addition to this vet students do not have access to drugs. Drugs can only be prescribed by a qualified, registered veterinarian (Member of the Royal Collage of Veterinary Surgeons - MRCVS - in UK).
On 18 April 2006 UK Member of Parliament Lynne Featherstone submitted a Written Question to the Home Secretary on whether the Home Office had calculated the number of date rape incidences that had been connected with Progesterex. Home Office Minister Paul Goggins replied that the drug did not exist. | Progesterex
Progesterex is a fictitious date rape drug. It is part of a hoax that began to circulate in 1999 via e-mail on the internet. No actual drug by this name or even with these properties exists, and no such incident has ever been documented or confirmed.
Typical contents of the e-mail hoax are as follows, although different versions tend to turn up over time:
"A woman at a nightclub called _______ on Saturday night was taken by 5 men, who according to hospital and police reports, gang raped her before dumping her. Unable to remember the events of the evening, tests later confirmed the repeat rapes along with traces of Rohypnol in her blood and Progesterex, essentially a small sterilization pill. The drug is now being used by rapists at parties to rape AND sterilize their victims. Progesterex is available to vets to sterilize large animals. Progesterex is being used together with Rohypnol, the date rape drug. As with Rohypnol, all they have to do is drop it into the girl's drink. The girl can't remember a thing the next morning, of all that had taken place the night before. Progesterex, which dissolves in drinks just as easily, is such that the victim doesn't conceive from the rape and the rapist needn't worry about having a paternity test identifying him months later. The drug's effects ARE NOT TEMPORARY - Progesterex was designed to sterilize horses. Any female who takes it WILL NEVER BE ABLE TO CONCEIVE.. The weasels can get this drug from anyone who is in the vet school or any university. It's that easy, and Progesterex is about to break out big on campuses everywhere. Believe it or not, there are even sites on the Internet telling people how to use it. Please forward this to everyone you know, especially girls. Be careful when you're out and don't leave your drink unattended. Please make the effort to forward this on to all you know... Guys, please inform all your female friends and relatives."
A version of this hoax has also recently made the rounds via bulletins on MySpace.com (July 2006). It made it to Bebo in September-October 2006.
A version of this hoax has been seen on Facebook, in the form of a group named "Heads Up Ladies", and sports the same story as listed above.
According to the Spanish language website VSAntirus.com at least two versions in Spanish have made the rounds since 2001 as well.
Furthermore, no sterilization pill for horses exists. Sterilization is done via gelding of stallions. Mares are usually left unaltered.
In addition to this vet students do not have access to drugs. Drugs can only be prescribed by a qualified, registered veterinarian (Member of the Royal Collage of Veterinary Surgeons - MRCVS - in UK).
On 18 April 2006 UK Member of Parliament Lynne Featherstone submitted a Written Question to the Home Secretary on whether the Home Office had calculated the number of date rape incidences that had been connected with Progesterex. Home Office Minister Paul Goggins replied that the drug did not exist. [1] [2]
# External links
- Urbanlegends.about.com article on the Progesterex Urban Legend
- Snopes.com article on the Progesterex Urban Legend
- GoAskAlice!: "Progesterex": Horse and Human Sterilizer, date rape drug, or Urban Legend?
- Hoax: Progesterex. La droga de los violadores
da:Progesterex
el:Προγκεστερέξ
sv:Progesterex | https://www.wikidoc.org/index.php/Progesterex | |
0c12d3695b069acb316b8907371860589f43be30 | wikidoc | Project 4.1 | Project 4.1
Project 4.1 was the designation for a medical study conducted by the United States of those residents of the Marshall Islands exposed to radioactive fallout from the March 1, 1954 Castle Bravo nuclear test at Bikini Atoll, which had an unexpectedly large yield. The official title of the study was "Study of Response of Human Beings Exposed to Significant Beta and Gamma radiation due to Fall-Out from High Yield Weapons." Government and mainstream historical sources point to the study being organized on March 6 or March 7, 1954, six days after the Bravo shot.
# Project 4.1
The purpose of the project, as a 1982 Defense Nuclear Agency report explained, was both medical as well as for research purposes:
The purposes of were to (1) evaluate the severity of radiation injury to the human beings exposed, (2) provide for all necessary medical care, and (3) conduct a scientific study of radiation injuries to human beings.
As a Department of Energy Committee writing on the human radiation experiments wrote, "It appears to have been almost immediately apparent to the AEC and the Joint Task Force running the Castle series that research on radiation effects could be done in conjunction with the medical treatment of the exposed populations." The DOE report also concluded that "The dual purpose of what is now a DOE medical program has led to a view by the Marshallese that they were being used as 'guinea pigs' in a 'radiation experiment.'"
Organizations involved in the project included the Naval Medical Research Institute, the Naval Radiological Defense Laboratory, Patrol Squadron 29, the Naval Air Station, Kwajalein, Los Alamos National Laboratory, the Applied Fisheries Laboratory at the University of Washington, and Hanford Atomic Power Operations. Three U.S. Navy ships were used in the project: USS Nicholas, USS Renshaw, and USS Philip. The primary study of the Marshallese was terminated around 75 days after the time of exposure. In July 1954 a meeting at the Division of Biology at the U.S. Atomic Energy Commission decided to complete 6- and 12-month followup exposure studies, some of which were later written up as addendums to Project 4.1.
Some Marshallese have alleged that the exposure of the Marshallese was premeditated. In 1972, Micronesian Representative Ataji Balos charged at the Congress of Micronesia that the exposure during Bravo was purposeful so that the AEC could develop medical capabilities for treating those exposed to fallout during nuclear war, and charged that the Marshallese were chosen because of their marginal status in the world at large. According to a U.S. internal transcription of Balos' talk, Balos alleged that "The U.S. chose to make guinea pigs out of our people because they are not white but some brown natives in some remote Pacific islands. Medical treatment that Rongelapese and Utrikese have been receiving is also highly questionable." The AEC issued a staff comment denying these charges.
In 1994, a 1953 Castle Bravo program prospectus was found which included reference to Project 4.1 apparently written before the Bravo shot had occurred. The U.S. government responded that someone had gone back into the project list after the Bravo test to insert Project 4.1; thus the acts were not premeditated. All other U.S. documents point to Project 4.1 having been established after the Bravo test—most sources point to its having been organized on March 7, 1954. The final Project 4.1 report began in its preface with the statement that "Operation CASTLE did not include a biomedical program" (it mentions this in discussing the ad hoc nature by which the project personnel were assembled). All official and mainstream historical accounts of the Bravo test indicate that its high level of fallout was a result of a miscalculation in relation to its design and was not deliberate (see the Castle Bravo article for more information on the accident).
Barton C. Hacker, the official historian of U.S. nuclear testing exposures (who is, in the end, very critical of the U.S. handling of the Bravo incident), characterized the controversy in the following way:
In March 1954, the AEC had quickly decided that learning how the Marshallese victims of Castle Bravo responsed to their accidental exposure could be of immense medical and military value. Immediate action centered on seeing them evacuated and decontaminated, then cared for medically. But studies of their exposures and aftereffects also began. That effort became project 4.1 in the Castle experimental program. This unfortunate choice of terminology may help explain later charges that the AEC had deliberately exposed the Marshallese to observe the effects. Like the American radium dial painters of the 1920s and the Japanese of Hiroshima and Nagasaki in 1945, the Marshallese of 1954 inadvertently were to provide otherwise unobtainable data on the human consequences of high radiation exposures. Findings from project 4.1 soon began to appear in print.
Controversy continues however, fed by the legacy of mistrust sown by American nuclear testing in the Marshall Islands, which involved relocating hundreds of people and rendering several atolls uninhabitable. While most sources do not think that the exposure was intentional, there is no dispute that the United States did carefully study the exposed Marshallese, but never obtained informed consent from the study subjects (a difficult matter given language and cultural differences). This study of the Marshallese was in some cases beneficial for their treatment, and in other cases not. In these ways, the study of the exposed Marshallese reflects the same ethical lapses as were undertaken in other aspects of the secret human radiation experiments conducted by the Atomic Energy Commission in the 1940s and 1950s, which came to light only after the end of the Cold War.
According to the Final Project 4.1 report, the Bravo test exposed 239 Marshallese on the Utirik, Rongelap, and Ailinginae Atolls to significant level of radiation, and 28 Americans stationed on the Rongerik Atoll were also exposed. Those on the Rongelap Atoll were the most seriously affected, receiving approximately 175 rads of radiation before they were evacuated. Those on Ailinginae received 69 rads, those on Utirik received 14 rads, and the Americans on Rongerik received an average dose of 78 rads. Most of those exposed did not immediately show signs of radiation sickness, though within a few days other effects of significant radiation exposure manifested: loss of hair and significant skin damage, including "raw, weeping lesions", among the Rongelap and Ailinginae groups. The legions healed quickly, however, consistent with radiation exposure. The report abstract concluded that "estimates of total body burden indicate that there is no long term hazard." Additional follow-up checks on the Marshallese studied in Project 4.1 were conducted at regular intervals afterwards every year since 1954. Though the Marshallese experienced far milder immediate effects than the Japanese fishermen exposed to Bravo fallout on the fishing boat Daigo Fukuryū Maru, the long-term effects were more pronounced. For the first decade after the test, the effects were ambiguous and statistically difficult to correlate to radiation exposure: miscarriages and stillbirths among exposed Rongelap women doubled in the first five years after the accident, but then returned to normal; some developmental difficulties and impaired growth appeared in children, but in no clear-cut pattern. In the decades that followed, though, the effects were undeniable. Children began to suffer disproportionately from thyroid cancer (due to exposure to radioiodines), and almost a third of those exposed developed neoplasms by 1974.
The results of the original Project 4.1 were published by the study's authors in professional medical journals, such as the Journal of the American Medical Association.
# Notes
- ↑ Jump up to: 1.0 1.1 Edwin J. Martin and Richard H. Rowland, "Castle Series, 1951", Defense Nuclear Agency Report DNA 6035F (1 April 1982), p. 186 and 188. Available online at .
- ↑ Jump up to: 2.0 2.1 Final Report of the Advisory Committee on Human Radiation Experiments, Chapter 12, Part 3: "The Marshallese". Available online at .
- ↑ See the "Introduction" of E.P. Cronkite, C.L. Dunham, David Griffin, S.D. McPherson, Kent T. Woodward, Twelve-Month Postexposure Survey on Marshallese Exposed to Fallout Radiation (Upton, NY: Brookhaven National Laboratory, August 1955). Available online at .
- ↑ See entry under 25 Jan 1972 at /. Quote is from unclassified telegram DISTAD Palau to SECSTATE Wash. DC, 27 Jan 72, Document 48025, CIC, available online at .
- ↑ See the chronologies at both the Department of Energy Marshall Islands Chronology and Republic of the Marshall Islands Embassy.
- ↑ Jump up to: 6.0 6.1 E.P. Cronkite, V.P. Bond, L.E. Browning, W.H. Chapman, S.H. Cohn, R.A. Conard, C.L. Dunham, R.S. Farr, W.S. Hall, R. Sharp, N.R. Shulman, Study of Response of Human Beings Accidentally Exposed to Significant Fallout Radiation, Operation CASTLE—Final Report Project 4.1, Naval Medical Research Institute, Naval Radiological Defense Laboratory, Defense Atomic Support Agency, Oak Ridge National Laboratory, Report #WT-923 (October 1954). Online at .
- ↑ Jump up to: 7.0 7.1 Barton C. Hacker, Elements of controversy: the Atomic Energy Commission and radiation safety in nuclear weapons testing, 1947-1974 (Berkeley, CA: University of California Press, 1994): pp. 226-228.
- ↑ For example, Cronkite, et al, "Response of Human Beings Accidentally Exposed to Significant Fall-out Radiation," JAMA 159 (1 October 1955): 430-434. | Project 4.1
Project 4.1 was the designation for a medical study conducted by the United States of those residents of the Marshall Islands exposed to radioactive fallout from the March 1, 1954 Castle Bravo nuclear test at Bikini Atoll, which had an unexpectedly large yield. The official title of the study was "Study of Response of Human Beings Exposed to Significant Beta and Gamma radiation due to Fall-Out from High Yield Weapons." Government and mainstream historical sources point to the study being organized on March 6 or March 7, 1954, six days after the Bravo shot.
# Project 4.1
The purpose of the project, as a 1982 Defense Nuclear Agency report explained, was both medical as well as for research purposes:
The purposes of [Project 4.1] were to (1) evaluate the severity of radiation injury to the human beings exposed, (2) provide for all necessary medical care, and (3) conduct a scientific study of radiation injuries to human beings.[1]
As a Department of Energy Committee writing on the human radiation experiments wrote, "It appears to have been almost immediately apparent to the AEC and the Joint Task Force running the Castle series that research on radiation effects could be done in conjunction with the medical treatment of the exposed populations."[2] The DOE report also concluded that "The dual purpose of what is now a DOE medical program has led to a view by the Marshallese that they were being used as 'guinea pigs' in a 'radiation experiment.'"[2]
Organizations involved in the project included the Naval Medical Research Institute, the Naval Radiological Defense Laboratory, Patrol Squadron 29, the Naval Air Station, Kwajalein, Los Alamos National Laboratory, the Applied Fisheries Laboratory at the University of Washington, and Hanford Atomic Power Operations. Three U.S. Navy ships were used in the project: USS Nicholas, USS Renshaw, and USS Philip.[1] The primary study of the Marshallese was terminated around 75 days after the time of exposure. In July 1954 a meeting at the Division of Biology at the U.S. Atomic Energy Commission decided to complete 6- and 12-month followup exposure studies, some of which were later written up as addendums to Project 4.1.[3]
Some Marshallese have alleged that the exposure of the Marshallese was premeditated. In 1972, Micronesian Representative Ataji Balos charged at the Congress of Micronesia that the exposure during Bravo was purposeful so that the AEC could develop medical capabilities for treating those exposed to fallout during nuclear war, and charged that the Marshallese were chosen because of their marginal status in the world at large. According to a U.S. internal transcription of Balos' talk, Balos alleged that "The U.S. chose to make guinea pigs out of our people because they are not white but some brown natives in some remote Pacific islands. Medical treatment that Rongelapese and Utrikese have been receiving is also highly questionable."[4] The AEC issued a staff comment denying these charges.
In 1994, a 1953 Castle Bravo program prospectus was found which included reference to Project 4.1 apparently written before the Bravo shot had occurred. The U.S. government responded that someone had gone back into the project list after the Bravo test to insert Project 4.1; thus the acts were not premeditated. All other U.S. documents point to Project 4.1 having been established after the Bravo test—most sources point to its having been organized on March 7, 1954.[5] The final Project 4.1 report began in its preface with the statement that "Operation CASTLE did not include a biomedical program" (it mentions this in discussing the ad hoc nature by which the project personnel were assembled).[6] All official and mainstream historical accounts of the Bravo test indicate that its high level of fallout was a result of a miscalculation in relation to its design and was not deliberate (see the Castle Bravo article for more information on the accident).
Barton C. Hacker, the official historian of U.S. nuclear testing exposures (who is, in the end, very critical of the U.S. handling of the Bravo incident), characterized the controversy in the following way:
In March 1954, the AEC had quickly decided that learning how the Marshallese victims of Castle Bravo responsed to their accidental exposure could be of immense medical and military value. Immediate action centered on seeing them evacuated and decontaminated, then cared for medically. But studies of their exposures and aftereffects also began. That effort became project 4.1 in the Castle experimental program. This unfortunate choice of terminology may help explain later charges that the AEC had deliberately exposed the Marshallese to observe the effects. Like the American radium dial painters of the 1920s and the Japanese of Hiroshima and Nagasaki in 1945, the Marshallese of 1954 inadvertently were to provide otherwise unobtainable data on the human consequences of high radiation exposures. Findings from project 4.1 soon began to appear in print.[7]
Controversy continues however, fed by the legacy of mistrust sown by American nuclear testing in the Marshall Islands, which involved relocating hundreds of people and rendering several atolls uninhabitable. While most sources do not think that the exposure was intentional, there is no dispute that the United States did carefully study the exposed Marshallese, but never obtained informed consent from the study subjects (a difficult matter given language and cultural differences). This study of the Marshallese was in some cases beneficial for their treatment, and in other cases not. In these ways, the study of the exposed Marshallese reflects the same ethical lapses as were undertaken in other aspects of the secret human radiation experiments conducted by the Atomic Energy Commission in the 1940s and 1950s, which came to light only after the end of the Cold War.
According to the Final Project 4.1 report, the Bravo test exposed 239 Marshallese on the Utirik, Rongelap, and Ailinginae Atolls to significant level of radiation, and 28 Americans stationed on the Rongerik Atoll were also exposed. Those on the Rongelap Atoll were the most seriously affected, receiving approximately 175 rads of radiation before they were evacuated. Those on Ailinginae received 69 rads, those on Utirik received 14 rads, and the Americans on Rongerik received an average dose of 78 rads. Most of those exposed did not immediately show signs of radiation sickness, though within a few days other effects of significant radiation exposure manifested: loss of hair and significant skin damage, including "raw, weeping lesions", among the Rongelap and Ailinginae groups. The legions healed quickly, however, consistent with radiation exposure. The report abstract concluded that "estimates of total body burden indicate that there is no long term hazard."[6] Additional follow-up checks on the Marshallese studied in Project 4.1 were conducted at regular intervals afterwards every year since 1954. Though the Marshallese experienced far milder immediate effects than the Japanese fishermen exposed to Bravo fallout on the fishing boat Daigo Fukuryū Maru, the long-term effects were more pronounced. For the first decade after the test, the effects were ambiguous and statistically difficult to correlate to radiation exposure: miscarriages and stillbirths among exposed Rongelap women doubled in the first five years after the accident, but then returned to normal; some developmental difficulties and impaired growth appeared in children, but in no clear-cut pattern. In the decades that followed, though, the effects were undeniable. Children began to suffer disproportionately from thyroid cancer (due to exposure to radioiodines), and almost a third of those exposed developed neoplasms by 1974.[7]
The results of the original Project 4.1 were published by the study's authors in professional medical journals, such as the Journal of the American Medical Association.[8]
# Notes
- ↑ Jump up to: 1.0 1.1 Edwin J. Martin and Richard H. Rowland, "Castle Series, 1951", Defense Nuclear Agency Report DNA 6035F (1 April 1982), p. 186 and 188. Available online at http://worf.eh.doe.gov/data/ihp1c/0858_a.pdf.
- ↑ Jump up to: 2.0 2.1 Final Report of the Advisory Committee on Human Radiation Experiments, Chapter 12, Part 3: "The Marshallese". Available online at http://www.eh.doe.gov/ohre/roadmap/achre/chap12_3.html.
- ↑ See the "Introduction" of E.P. Cronkite, C.L. Dunham, David Griffin, S.D. McPherson, Kent T. Woodward, Twelve-Month Postexposure Survey on Marshallese Exposed to Fallout Radiation (Upton, NY: Brookhaven National Laboratory, August 1955). Available online at http://worf.eh.doe.gov/data/ihp1a/1013_.pdf.
- ↑ See entry under 25 Jan 1972 at http://worf.eh.doe.gov/ihp/chron/. Quote is from unclassified telegram DISTAD Palau to SECSTATE Wash. DC, 27 Jan 72, Document 48025, CIC, available online at http://worf.eh.doe.gov/ihp/chron/G15.PDF.
- ↑ See the chronologies at both the Department of Energy Marshall Islands Chronology and Republic of the Marshall Islands Embassy.
- ↑ Jump up to: 6.0 6.1 E.P. Cronkite, V.P. Bond, L.E. Browning, W.H. Chapman, S.H. Cohn, R.A. Conard, C.L. Dunham, R.S. Farr, W.S. Hall, R. Sharp, N.R. Shulman, Study of Response of Human Beings Accidentally Exposed to Significant Fallout Radiation, Operation CASTLE—Final Report Project 4.1, Naval Medical Research Institute, Naval Radiological Defense Laboratory, Defense Atomic Support Agency, Oak Ridge National Laboratory, Report #WT-923 (October 1954). Online at http://worf.eh.doe.gov/data/ihp2/2776_.pdf.
- ↑ Jump up to: 7.0 7.1 Barton C. Hacker, Elements of controversy: the Atomic Energy Commission and radiation safety in nuclear weapons testing, 1947-1974 (Berkeley, CA: University of California Press, 1994): pp. 226-228.
- ↑ For example, Cronkite, et al, "Response of Human Beings Accidentally Exposed to Significant Fall-out Radiation," JAMA 159 (1 October 1955): 430-434. | https://www.wikidoc.org/index.php/Project_4.1 | |
3b9c844e395174df00123ff7cd93c85a9094aea0 | wikidoc | Trypanosome | Trypanosome
# Overview
Trypanosomes are a group of kinetoplastid protozoa distinguished by having only a single flagellum. All members are exclusively parasitic, found primarily in insects. A few genera have life-cycles involving a secondary host, which may be a vertebrate or a plant. These include several species that cause major diseases in humans.
The most notable trypanosomal diseases are trypanosomiasis (African Sleeping Sickness and South American Chagas Disease); these are caused by species of Trypanosoma. Leishmaniasis is a trypanosomal disease caused by species of Leishmania.
A variety of different forms appear in the life-cycles of trypanosomes, distinguished mainly by the position of the flagellum:
All trypanosomes have at least amastigote and promastigote stages. Trypanosoma appears in all five forms, with the trypanosomal stage occurring in the vertebrate host. Trypanosoma brucei sub-species have two forms in the bloodstream of a vertebrate host, the rapidly dividing long-slender form and the non-dividing short stumpy form. The short stumpy parasites are adapted for uptake into the tsetse fly vector, and are non-proliferative in comparison with the slender forms.
Unique to Trypansoma brucei is the expression of a variable surface glycoprotein (VSG) coat on the cell surface, which undergoes constant variation in order to evade the humoral immune system and host antibodies. It is thought that recombination from a repertoire of >1000 VSG genes is responsible for the vast diversity of the parasite, and its effectiveness in immune evasion. | Trypanosome
# Overview
Trypanosomes are a group of kinetoplastid protozoa distinguished by having only a single flagellum. All members are exclusively parasitic, found primarily in insects. A few genera have life-cycles involving a secondary host, which may be a vertebrate or a plant. These include several species that cause major diseases in humans.
The most notable trypanosomal diseases are trypanosomiasis (African Sleeping Sickness and South American Chagas Disease); these are caused by species of Trypanosoma. Leishmaniasis is a trypanosomal disease caused by species of Leishmania.
A variety of different forms appear in the life-cycles of trypanosomes, distinguished mainly by the position of the flagellum:
All trypanosomes have at least amastigote and promastigote stages. Trypanosoma appears in all five forms, with the trypanosomal stage occurring in the vertebrate host. Trypanosoma brucei sub-species have two forms in the bloodstream of a vertebrate host, the rapidly dividing long-slender form and the non-dividing short stumpy form. The short stumpy parasites are adapted for uptake into the tsetse fly vector, and are non-proliferative in comparison with the slender forms.
Unique to Trypansoma brucei is the expression of a variable surface glycoprotein (VSG) coat on the cell surface, which undergoes constant variation in order to evade the humoral immune system and host antibodies. It is thought that recombination from a repertoire of >1000 VSG genes is responsible for the vast diversity of the parasite, and its effectiveness in immune evasion.
Template:Jb1
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Promastigote | |
b4d8ff527104c887968251bc744d6971d3db6c06 | wikidoc | Propafenone | Propafenone
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Propafenone is an antiarrhythmic that is FDA approved for the {{{indicationType}}} of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease, recurrent paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients without structural heart disease, and life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include chest pain, edema, palpitations, constipation, nausea, taste alteration, vomiting, dizziness, anxiety, dyspnea, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The dose of Rythmol must be individually titrated on the basis of response and tolerance.
- Initiate therapy with Rythmol 150 mg given every 8 hours (450 mg/day).
- Dosage may be increased at a minimum of 3 to 4 day intervals to 225 mg every 8 hours (675 mg/day).
- If additional therapeutic effect is needed, the dose of Rythmol may be increased to 300 mg every 8 hours (900 mg/day). The usefulness and safety of dosages exceeding 900 mg per day have not been established.
- In patients with hepatic impairment or those with significant widening of the QRS complex or second- or third-degree AV block, consider reducing the dose.
- As with other antiarrhythmic agents, in the elderly or in ventricular arrhythmia patients with marked previous myocardial damage, the dose of Rythmol should be increased more gradually during the initial phase of treatment.
- The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with the simultaneous administration of propafenone may significantly increase the concentration of propafenone and thereby increase the risk of proa
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Propafenone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness of propafenone in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Propafenone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Propafenone in pediatric patients.
# Contraindications
- Heart failure
- Cardiogenic shock
- Sinoatrial, atrioventricular, and intraventricular disorders of impulse generation or conduction (e.g., sick sinus syndrome, AV block) in the absence of an artificial pacemaker
- Brugada Syndrome
- Bradycardia
- Marked hypotension
- Bronchospastic disorders or severe obstructive pulmonary disease
- Marked electrolyte imbalance
# Warnings
- Proarrhythmic Effects
- Propafenone has caused new or worsened arrhythmias. Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole, and torsade de pointes. It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval. It is therefore essential that each patient given Rythmol be evaluated electrocardiographically prior to and during therapy to determine whether the response to Rythmol supports continued treatment. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret.
- In a US uncontrolled, open-label, multicenter trial in subjects with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these subjects experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the trial. However, in 4 of the 9 subjects, the ventricular tachycardia was of atrial origin. Six of the 9 subjects that developed ventricular arrhythmias did so within 14 days of onset of therapy. About 2.3% (11/474) of all subjects had a recurrence of SVT during the trial which could have been a change in the subjects’ arrhythmia behavior or could represent a proarrhythmic event. Case reports in patients treated with propafenone for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), VT, VF, torsade de pointes, asystole, and death.
- Overall in clinical trials with Rythmol (which included subjects treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all subjects had new or worsened ventricular arrhythmia possibly representing a proarrhythmic event (0.7% was an increase in PVCs; 4.0% a worsening, or new appearance, of VT or VF). Of the subjects who had worsening of VT (4%), 92% had a history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had a prior myocardial infarction. The incidence of proarrhythmia in subjects with less serious or benign arrhythmias, which include subjects with an increase in frequency of PVCs, was 1.6%. Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST trial suggests that an increased risk of proarrythmia is present throughout treatment.
- In a trial of sustained-release propafenone (Rythmol SR®), there were too few deaths to assess the long-term risk to patients. There were 5 deaths, 3 in the pooled group for Rythmol SR (0.8%) and 2 in the placebo group (1.6%). In the overall database of 8 trials of Rythmol SR and immediate-release Rythmol, the mortality rate was 2.5% per year on propafenone and 4.0% per year on placebo. Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.
- Unmasking Brugada Syndrome
- Brugada Syndrome may be unmasked after exposure to Rythmol. Perform an ECG after initiation of Rythmol, and discontinue the drug if changes are suggestive of Brugada Syndrome.
- Use With Drugs That Prolong the QT Interval and Antiarrhythmic Agents
- The use of Rythmol in conjunction with other drugs that prolong the QT interval has not been extensively studied. Such drugs may include many antiarrhythmics, some phenothiazines, tricyclic antidepressants, and oral macrolides. Withhold Class IA and III antiarrhythmic agents for at least 5 half-lives prior to dosing with Rythmol. Avoid the use of propafenone with Class IA and III antiarrhythmic agents (including quinidine and amiodarone). There is only limited experience with the concomitant use of Class IB or IC antiarrhythmics.
- Drug Interactions: Simultaneous Use With Inhibitors of Cytochrome P450 Isoenzymes 2D6 and 3A4
- Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes. Approximately 6% of Caucasians in the US population are naturally deficient in CYP2D6 activity and to a somewhat lesser extent in other demographic groups. Drugs that inhibit these CYP pathways (such as desipramine, paroxetine, ritonavir, sertraline for CYP2D6; ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone.
- Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of Rythmol with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.
- Use in Patients With a History of Heart Failure
- Propafenone exerts a negative inotropic activity on the myocardium as well as beta-blockade effects and may provoke overt heart failure.
- In clinical trial experience with Rythmol, new or worsened congestive heart failure (CHF) has been reported in 3.7% of subjects with ventricular arrhythmia; of those 0.9% were considered probably or definitely related to propafenone HCl. Of the subjects with CHF probably related to propafenone, 80% had pre-existing heart failure and 85% had coronary artery disease. CHF attributable to propafenone HCl developed rarely (<0.2%) in ventricular arrhythmia subjects who had no previous history of CHF. CHF occurred in 1.9% of subjects studied with PAF or PSVT.
- In a US trial of Rythmol SR in subjects with symptomatic AF, heart failure was reported in 4 (1.0%) subjects receiving Rythmol SR (all doses), compared with 1 (0.8%) subject receiving placebo.
- Conduction Disturbances
- Propafenone slows atrioventricular conduction and may also cause dose-related first-degree AV block. Average PR interval prolongation and increases in QRS duration are also dose-related. Do not give propafenone to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker.
- The incidence of first-degree, second-degree, and third-degree AV block observed in 2,127 subjects with ventricular arrhythmia was 2.5%, 0.6%, and 0.2%, respectively. Development of second- or third-degree AV block requires a reduction in dosage or discontinuation of propafenone HCl. Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in subjects receiving propafenone. Bradycardia has also been reported (1.5%). Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone.
- In a US trial in 523 subjects with a history of symptomatic AF treated with Rythmol SR, sinus bradycardia (rate <50 beats/min) was reported with the same frequency with Rythmol SR and placebo.
- Effects on Pacemaker Threshold
- Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators. During and after therapy, monitor and re-program these devices accordingly.
- Agranulocytosis
- Agranulocytosis has been reported in patients receiving propafenone. Generally, the agranulocytosis occurred within the first 2 months of propafenone therapy and upon discontinuation of therapy; the white count usually normalized by 14 days. Unexplained fever or decrease in white cell count, particularly during the initial 3 months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia. Instruct patients to report promptly any signs of infection such as fever, sore throat, or chills.
- Use in Patients With Hepatic Dysfunction
- Propafenone is highly metabolized by the liver. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared with 3% to 40% in patients with normal liver function. In 8 subjects with moderate to severe liver disease, the mean half-life was approximately 9 hours. Increased bioavailability of propafenone in these patients may result in excessive accumulation. Carefully monitor patients with impaired hepatic function for excessive pharmacological effects.
- Use in Patients With Renal Dysfunction
- Approximately 50% of propafenone metabolites are excreted in the urine following administration of Rythmol.
- In patients with impaired renal function, monitor for signs of overdosage.
- Use in Patients With Myasthenia Gravis
- Exacerbation of myasthenia gravis has been reported during propafenone therapy.
- Elevated ANA Titers
- Positive ANA titers have been reported in patients receiving propafenone. They have been reversible upon cessation of treatment and may disappear even in the face of continued propafenone therapy. These laboratory findings were usually not associated with clinical symptoms, but there is one published case of drug-induced lupus erythematosis (positive rechallenge); it resolved completely upon discontinuation of therapy. Carefully evaluate patients who develop an abnormal ANA test and, if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.
- Impaired Spermatogenesis
- Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs, and rabbits after high-dose intravenous administration of propafenone. Evaluation of the effects of short-term administration of Rythmol on spermatogenesis in 11 normal subjects suggested that propafenone produced a reversible, short-term drop (within normal range) in sperm count.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reactions associated with Rythmol occur most frequently in the gastrointestinal, cardiovascular, and central nervous systems. About 20% of subjects treated with Rythmol have discontinued treatment because of adverse reactions.
- Adverse reactions reported for >1.5% of 474 subjects with SVT who received Rythmol in US clinical trials are presented in Table 1 by incidence and percent discontinuation, reported to the nearest percent.
- In controlled trials in subjects with ventricular arrhythmia, the most common reactions reported for Rythmol and more frequent than on placebo were unusual taste, dizziness, first degree AV block, intraventricular conduction delay, nausea and/or vomiting, and constipation. Headache was relatively common also, but was not increased compared with placebo. Other reactions reported more frequently than on placebo or comparator and not already reported elsewhere included anxiety, angina, second-degree AV block, bundle branch block, loss of balance, congestive heart failure, and dyspepsia.
- Adverse reactions reported for ≥1% of 2,127 subjects with ventricular arrhythmia who received propafenone in US clinical trials were evaluated by daily dose. The most common adverse reactions appeared dose-related (but note that most subjects spent more time at the larger doses), especially dizziness, nausea and/or vomiting, unusual taste, constipation, and blurred vision. Some less common reactions may also have been dose-related such as first-degree AV block, congestive heart failure, dyspepsia, and weakness. Other adverse reactions included rash, syncope, chest pain, abdominal pain, ataxia, and hypotension.In addition, the following adverse reactions were reported less frequently than 1% either in clinical trials or in marketing experience. Causality and relationship to propafenone therapy cannot necessarily be judged from these events.
- In addition, the following adverse reactions were reported less frequently than 1% either in clinical trials or in marketing experience. Causality and relationship to propafenone therapy cannot necessarily be judged from these events.
Atrial flutter, AV dissociation, cardiac arrest, flushing, hot flashes, sick sinus syndrome, sinus pause or arrest, supraventricular tachycardia.
Cholestasis , elevated liver enzymes (alkaline phosphatase, serum transaminases), gastroenteritis, hepatitis.
Agranulocytosis, anemia, bruising, granulocytopenia, leukopenia, purpura, thrombocytopenia.
Abnormal dreams, abnormal speech, abnormal vision, confusion, depression, memory loss, numbness, paresthesias, psychosis/mania, seizures (0.3%), tinnitus, unusual smell sensation, vertigo.
Alopecia, eye irritation, impotence, increased glucose, positive ANA (0.7%), muscle cramps, muscle weakness, nephrotic syndrome, pain, pruritus.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of Rythmol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
A number of patients with liver abnormalities associated with propafenone therapy have been reported in postmarketing experience. Some appeared due to hepatocellular injury, some were cholestatic, and some showed a mixed picture. Some of these reports were simply discovered through clinical chemistries, others because of clinical symptoms including fulminant hepatitis and death. One case was rechallenged with a positive outcome.
Increased bleeding time.
Apnea, coma.
Lupus erythematosis.
Hyponatremia/inappropriate ADH secretion, kidney failure.
# Drug Interactions
- CYP2D6 and CYP3A4 Inhibitors
- Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, or sertraline) and CYP3A4 (such as ketoconazole, ritonavir, saquinavir, erythromycin, or grapefruit juice) can be expected to cause increased plasma levels of propafenone. The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with administration of propafenone may increase the risk of adverse reactions, including proarrhythmia. Therefore, simultaneous use of Rythmol with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided.
- Amiodarone: Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended.
- Cimetidine: Concomitant administration of propafenone immediate-release tablets and cimetidine in 12 healthy subjects resulted in a 20% increase in steady-state plasma concentrations of propafenone.
- Fluoxetine: Concomitant administration of propafenone and fluoxetine in extensive metabolizers increased the S-propafenone Cmax and AUC by 39% and 50%, respectively, and the R propafenone Cmax and AUC by 71% and 50%, respectively.
- Quinidine: Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers. Concomitant administration of quinidine (50 mg 3 times daily) with 150 mg immediate-release propafenone 3 times daily decreased the clearance of propafenone by 60% in extensive metabolizers, making them slow metabolizers. Steady-state plasma concentrations more than doubled for propafenone, and decreased 50% for 5-OH-propafenone. A 100-mg dose of quinidine tripled steady-state concentrations of propafenone. Avoid concomitant use of propafenone and quinidine.
- Rifampin: Concomitant administration of rifampin and propafenone in extensive metabolizers decreased the plasma concentrations of propafenone by 67% with a corresponding decrease of 5-OH-propafenone by 65%. The concentrations of norpropafenone increased by 30%. In slow metabolizers, there was a 50% decrease in propafenone plasma concentrations and an increase in the AUC and Cmax of norpropafenone by 74% and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients: Both the AUC and Cmax of propafenone decreased by 84%, with a corresponding decrease in AUC and Cmaxof 5-OH‑propafenone by 69% and 57%, respectively.
- Digoxin
- Concomitant use of propafenone and digoxin increased steady-state serum digoxin exposure (AUC) in patients by 60% to 270%, and decreased the clearance of digoxin by 31% to 67%. Monitor plasma digoxin levels of patients receiving propafenone and adjust digoxin dosage as needed.
- Warfarin
- The concomitant administration of propafenone and warfarin increased warfarin plasma concentrations at steady state by 39% in healthy volunteers and prolonged the prothrombin time (PT) in patients taking warfarin. Adjust the warfarin dose as needed by monitoring INR (international normalized ratio).
- Orlistat
- Orlistat may limit the fraction of propafenone available for absorption. In postmarketing reports, abrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events including convulsions, atrioventricular block, and acute circulatory failure.
- Beta-Antagonists
- Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at steady state by 113%. In 4 patients, administration of metoprolol with propafenone increased the metoprolol plasma concentrations at steady state by 100% to 400%. The pharmacokinetics of propafenone was not affected by the coadministration of either propranolol or metoprolol. In clinical trials using propafenone immediate-release tablets, subjects who were receiving beta-blockers concurrently did not experience an increased incidence of side effects.
- Lidocaine
- No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. Rythmol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Teratogenic Effects: Propafenone has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg/kg day (about 3 times the maximum recommended human dose on a mg/m2 basis) and 600 mg/kg/day (about 6 times the MRHD on a mg/m2 basis), respectively. Although maternally tolerated doses (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m2 basis) produced no evidence of embryotoxicity in rats; post-implantation loss was elevated in all rabbit treatment groups (doses as low as 15 mg/kg/day, about 1/3 the MRHD on a mg/m2 basis).
- Non-teratogenic Effects: In a study in which female rats received daily oral doses of propafenone from mid-gestation through weaning of their offspring, doses as low as 90 mg/kg/day (equivalent to the MRHD on a mg/m2 basis) produced increases in maternal deaths. Doses of 360 or more mg/kg/day (4 or more times the MRHD on a mg/m2 basis) resulted in reductions in neonatal survival, body weight gain, and physiological development.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Propafenone in women who are pregnant.
### Labor and Delivery
- It is not known whether the use of propafenone during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetrical intervention.
### Nursing Mothers
- Propafenone is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from propafenone, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of propafenone in pediatric patients have not been established.
### Geriatic Use
- Clinical trials of Rythmol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Propafenone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Propafenone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Propafenone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Propafenone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Propafenone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Propafenone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators. During and after therapy, monitor and re-program these devices accordingly.
- Carefully monitor patients with impaired hepatic function for excessive pharmacological effects.
- In patients with impaired renal function, monitor for signs of overdosage.
- Monitor plasma digoxin levels of patients receiving propafenone and adjust digoxin dosage as needed.
- The concomitant administration of propafenone and warfarin increased warfarin plasma concentrations at steady state by 39% in healthy volunteers and prolonged the prothrombin time (PT) in patients taking warfarin. Adjust the warfarin dose as needed by monitoring INR (international normalized ratio).
# IV Compatibility
There is limited information regarding IV Compatibility of Propafenone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The symptoms of overdosage may include hypotension, somnolence, bradycardia, intra-atrial and intraventricular conduction disturbances, and rarely, convulsions and high-grade ventricular arrhythmias.
### Management
- Defibrillation, as well as infusion of dopamine and isoproterenol have been effective in controlling abnormal rhythm and blood pressure. Convulsions have been alleviated with intravenous diazepam. General supportive measures such as mechanical respiratory assistance and external cardiac massage may be necessary.
- The hemodialysis of propafenone in patients with an overdose is expected to be of limited value in the removal of propafenone as a result of both its high protein binding (>95%) and large volume of distribution.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Propafenone in the drug label.
# Pharmacology
## Mechanism of Action
- Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocardial membranes. The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity.
- Studies in anesthetized dogs and isolated organ preparations show that propafenone has beta-sympatholytic activity at about 1/50 the potency of propranolol. Clinical studies employing isoproterenol challenge and exercise testing after single doses of propafenone indicate a beta-adrenergic blocking potency (per mg) about 1/40 that of propranolol in man. In clinical trials, resting heart rate decreases of about 8% were noted at the higher end of the therapeutic plasma concentration range. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by calcium, but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. Moreover, propafenone inhibits a variety of cardiac potassium currents in in vitro studies (i.e., the transient outward, the delayed rectifier, and the inward rectifier current). Propafenone has local anesthetic activity approximately equal to procaine. Compared with propafenone, the main metabolite, 5-hydroxypropafenone, has similar sodium and calcium channel activity, but about 10 times less beta-blocking activity (N-depropylpropafenone has weaker sodium channel activity but equivalent affinity for beta-receptors).
## Structure
- Rythmol (propafenone hydrochloride) is an antiarrhythmic drug supplied in scored, film-coated tablets of 150 and 225 mg for oral administration. Propafenone has some structural similarities to beta-blocking agents.
- Chemically, propafenone hydrochloride (HCl) is 2’--3-phenylpropiophenone hydrochloride, with a molecular weight of 377.92. The molecular formula is C21H27NO3HCl. The structural formula of propafenone HCl is given below:
- Propafenone HCl occurs as colorless crystals or white crystalline powder with a very bitter taste. It is slightly soluble in water (20°C), chloroform and ethanol. The following inactive ingredients are contained in the tablet: corn starch, hypromellose, magnesium stearate, polyethylene glycol, polysorbate, povidone, propylene glycol, sodium starch glycolate, and titanium dioxide.
## Pharmacodynamics
- Electrophysiology: Electrophysiology trials in subjects with ventricular tachycardia have shown that propafenone prolongs atrioventricular conduction while having little or no effect on sinus node function. Both atrioventricular nodal conduction time (AH interval) and His-Purkinje conduction time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are prolonged. In patients with Wolff-Parkinson-White syndrome, Rythmol reduces conduction and increases the effective refractory period of the accessory pathway in both directions.
- Electrocardiograms: Propafenone slows prolongs the PR and QRS intervals. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval.
- In any individual patient, the above ECG changes cannot be readily used to predict either efficacy or plasma concentration.
- Rythmol causes a dose-related and concentration-related decrease in the rate of single and multiple premature ventricular contractions (PVCs) and can suppress recurrence of ventricular tachycardia. Based on the percent of patients attaining substantial (80% to 90%) suppression of ventricular ectopic activity, it appears that trough plasma levels of 0.2 to 1.5 mcg/mL can provide good suppression, with higher concentrations giving a greater rate of good response.
- When 600 mg/day propafenone was administered to subjects with paroxysmal atrial tachyarrhythmias, mean heart rate during arrhythmia decreased 14 beats/min and 37 beats/min for subjects with paroxysmal atrial fibrillation/flutter (PAF) and subjects with paroxysmal supraventricular tachycardia (PSVT), respectively.
- Hemodynamics: Trials in humans have shown that propafenone HCl exerts a negative inotropic effect on the myocardium. Cardiac catheterization trials in subjects with moderately impaired ventricular function (mean C.I. = 2.61 L/min/m2) utilizing intravenous propafenone infusions (loading dose of 2 mg/kg over 10 min followed by 2 mg/min for 30 min) that gave mean plasma concentrations of 3.0 mcg/mL (a dose that produces plasma levels of propafenone greater than recommended oral dosing) showed significant increases in pulmonary capillary wedge pressure, systemic and pulmonary vascular resistances, and depression of cardiac output and cardiac index.
## Pharmacokinetics
- Absorption/Bioavailability: Propafenone HCl is nearly completely absorbed after oral administration with peak plasma levels occurring approximately 3.5 hours after administration in most individuals. Propafenone exhibits extensive saturable presystemic biotransformation (first-pass effect) resulting in a dose dependent and dosage form dependent absolute bioavailability; e.g., a 150-mg tablet had absolute bioavailability of 3.4%, while a 300-mg tablet had absolute bioavailability of 10.6%. A 300-mg solution which was rapidly absorbed had absolute bioavailability of 21.4%. At still larger doses, above those recommended, bioavailability increases still further.
Propafenone HCl follows a nonlinear pharmacokinetic disposition presumably because of saturation of first-pass hepatic metabolism as the liver is exposed to higher concentrations of propafenone and shows a very high degree of interindividual variability. For example, for an increase in daily dose from 300 to 900 mg/day there is a 10-fold increase in steady-state plasma concentration. The top 25% of subjects given 337.5 mg/day, however, had a mean concentration of propafenone larger than the bottom 25%, and about equal to the second 25%, of subjects given a dose of 900 mg. Although food increased peak blood level and bioavailability in a single-dose trial, during multiple-dose administration of propafenone to healthy volunteers, food did not change bioavailability significantly.
- Distribution: Following intravenous administration of propafenone, plasma levels decline in a bi-phasic manner consistent with a 2-compartment pharmacokinetic model. The average distribution half-life corresponding to the first phase was about 5 minutes. The volume of the central compartment was about 88 liters (1.1 L/kg) and the total volume of distribution about 252 liters.
- In serum, propafenone is greater than 95% bound to proteins within the concentration range of 0.5 to 2 mcg/mL.
- Metabolism: There are 2 genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life from 2 to 10 hours. These patients metabolize propafenone into 2 active metabolites: 5-hydroxypropafenone which is formed by CYP2D6 and N-depropylpropafenone (norpropafenone) which is formed by both CYP3A4 and CYP1A2.
- In less than 10% of patients, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed. In these patients, the estimated propafenone elimination half-life ranges from 10 to 32 hours. Decreased ability to form the 5-hydroxy metabolite of propafenone is associated with a diminished ability to metabolize debrisoquine and a variety of other drugs (such as encainide, metoprolol, and dextromethorphan) whose metabolism is mediated by the CYP2D6 isozyme. In these patients, the N-depropylpropafenone metabolite occurs in quantities comparable to the levels occurring in extensive metabolizers.
- There are significant differences in plasma concentrations of propafenone in slow and extensive metabolizers, the former achieving concentrations 1.5 to 2.0 times those of the extensive metabolizers at daily doses of 675 to 900 mg/day. At low doses the differences are greater, with slow metabolizers attaining concentrations more than 5 times that of extensive metabolizers. Because the difference decreases at high doses and is mitigated by the lack of the active 5-hydroxy metabolite in the slow metabolizers, and because steady-state conditions are achieved after 4 to 5 days of dosing in all patients, the recommended dosing regimen is the same for all patients. The greater variability in blood levels require that the drug be titrated carefully in patients with close attention paid to clinical and ECG evidence of toxicity.
- Stereochemistry: Rythmol is a racemic mixture. The R- and S-enantiomers of propafenone display stereoselective disposition characteristics. In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5-hydroxylation pathway (CYP2D6). This results in a higher ratio of S-propafenone to R-propafenone at steady state. Both enantiomers have equivalent potency to block sodium channels; however, the S-enantiomer is a more potent beta-antagonist than the R-enantiomer. Following administration of Rythmol immediate-release tablets, the S/R ratio for the area under the plasma concentration-time curve was about 1.7. In addition, no difference in the average values of the S/R ratios is evident between genotypes or over time.
- Special Populations:Hepatic Impairment: Decreased liver function increases the bioavailability of propafenone. Absolute bioavailability of Rythmol immediate-release tablets is inversely related to indocyanine green clearance, reaching 60% to 70% at clearances of 7 mL/min and below. Protein binding decreases to about 88% in patients with severe hepatic dysfunction. The clearance of propafenone is reduced and the elimination half-life increased in patients with significant hepatic dysfunction.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day, about twice the maximum recommended human oral daily dose on a mg/m2 basis) and rats (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m2 basis) provided no evidence of a carcinogenic potential for propafenone HCl.
- Propafenone HCl tested negative for mutagenicity in the Ames (salmonella) test and in the in vivo mouse dominant lethal test. It tested negative for clastogenicity in the human lymphocyte chromosome aberration assay in vitro and in rat and Chinese hamster micronucleus tests, and other in vivo tests for chromosomal aberrations in rat bone marrow and Chinese hamster bone marrow and spermatogonia.
- Propafenone HCl, administered intravenously to rabbits, dogs, and monkeys, has been shown to decrease spermatogenesis. These effects were reversible, were not found following oral dosing of propafenone HCl, were seen at lethal or near lethal dose levels, and were not seen in rats treated either orally or intravenously. Treatment of male rabbits for 10 weeks prior to mating at an oral dose of 120 mg/kg/day (about 2.4 times the MRHD on a mg/m2 basis) or an intravenous dose of 3.5 mg/kg/day (a spermatogenesis-impairing dose) did not result in evidence of impaired fertility. Nor was there evidence of impaired fertility when propafenone HCl was administered orally to male and female rats at dose levels up to 270 mg/kg/day (about 3 times the MRHD on a mg/m2 basis).
- Animal Toxicology and/or Pharmacology
- Renal changes have been observed in the rat following 6 months of oral administration of propafenone HCl at doses of 180 and 360 mg/kg/day (about 2 and 4 times, respectively, the MRHD on a mg/m2 basis). Both inflammatory and non-inflammatory changes in the renal tubules, with accompanying interstitial nephritis, were observed. These changes were reversible, as they were not found in rats allowed to recover for 6 weeks. Fatty degenerative changes of the liver were found in rats following longer durations of administration of propafenone HCl at a dose of 270 mg/kg/day (about 3 times the MRHD on a mg/m2 basis). There were no renal or hepatic changes at 90 mg/kg/day (equivalent to the MRHD on a mg/m2 basis).
# Clinical Studies
- In 2 randomized, crossover, placebo-controlled, double-blind trials of 60 to 90 days’ duration in subjects with paroxysmal supraventricular arrhythmias (paroxysmal atrial fibrillation/flutter , or paroxysmal supraventricular tachycardia ), propafenone reduced the rate of both arrhythmias, as shown in Table 3.
- The patient population in the above trials was 50% male with a mean age of 57.3 years. Fifty percent of the subjects had a diagnosis of PAF and 50% had PSVT. Eighty percent of the subjects received 600 mg/day propafenone. No subject died in the above 2 trials.
- In US long-term safety trials, 474 subjects (mean age: 57.4 + 14.5 years) with supraventricular arrhythmias were treated up to 5 years (mean: 14.4 months) with propafenone. Fourteen of the subjects died. When this mortality rate was compared with the rate in a similar patient population (n = 194 subjects; mean age: 43.0 + 16.8 years) studied in an arrhythmia clinic, there was no age-adjusted difference in mortality. This comparison was not, however, a randomized trial and the 95% confidence interval around the comparison was large, such that neither a significant adverse or favorable effect could be ruled out.
# How Supplied
- Rythmol Tablets are supplied as white, biconvex, scored, round, film-coated tablets containing either 150 mg or 225 mg of propafenone hydrochloride and embossed (on the same side) with GS and TF5 for the 150-mg tablet, and GS and F1X for the 225-mg tablet, in the following package sizes:
- Storage: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Dispense in a tight, light-resistant container.
## Storage
There is limited information regarding Propafenone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to notify their healthcare providers of any change in over-the-counter, prescription, and supplement use. The healthcare provider should assess the patients’ medication history including all over-the-counter, prescription, and herbal/natural preparations for those that may affect the pharmacodynamics or kinetics of Rythmol.
- Patients should also check with their healthcare providers prior to taking a new over-the-counter medicine.
- If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, vomiting, or loss of appetite or thirst, these conditions should be immediately reported to their healthcare provider.
- Patients should be instructed NOT to double the next dose if a dose is missed. The next dose should be taken at the usual time.
# Precautions with Alcohol
- Alcohol-Propafenone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Rythmol®
# Look-Alike Drug Names
- N/A
# Drug Shortage Status
# Price | Propafenone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi
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# Black Box Warning
# Overview
Propafenone is an antiarrhythmic that is FDA approved for the {{{indicationType}}} of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease, recurrent paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients without structural heart disease, and life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include chest pain, edema, palpitations, constipation, nausea, taste alteration, vomiting, dizziness, anxiety, dyspnea, and fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The dose of Rythmol must be individually titrated on the basis of response and tolerance.
- Initiate therapy with Rythmol 150 mg given every 8 hours (450 mg/day).
- Dosage may be increased at a minimum of 3 to 4 day intervals to 225 mg every 8 hours (675 mg/day).
- If additional therapeutic effect is needed, the dose of Rythmol may be increased to 300 mg every 8 hours (900 mg/day). The usefulness and safety of dosages exceeding 900 mg per day have not been established.
- In patients with hepatic impairment or those with significant widening of the QRS complex or second- or third-degree AV block, consider reducing the dose.
- As with other antiarrhythmic agents, in the elderly or in ventricular arrhythmia patients with marked previous myocardial damage, the dose of Rythmol should be increased more gradually during the initial phase of treatment.
- The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with the simultaneous administration of propafenone may significantly increase the concentration of propafenone and thereby increase the risk of proa
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Propafenone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- The safety and effectiveness of propafenone in pediatric patients have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Propafenone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Propafenone in pediatric patients.
# Contraindications
- Heart failure
- Cardiogenic shock
- Sinoatrial, atrioventricular, and intraventricular disorders of impulse generation or conduction (e.g., sick sinus syndrome, AV block) in the absence of an artificial pacemaker
- Brugada Syndrome
- Bradycardia
- Marked hypotension
- Bronchospastic disorders or severe obstructive pulmonary disease
- Marked electrolyte imbalance
# Warnings
- Proarrhythmic Effects
- Propafenone has caused new or worsened arrhythmias. Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole, and torsade de pointes. It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval. It is therefore essential that each patient given Rythmol be evaluated electrocardiographically prior to and during therapy to determine whether the response to Rythmol supports continued treatment. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret.
- In a US uncontrolled, open-label, multicenter trial in subjects with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these subjects experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the trial. However, in 4 of the 9 subjects, the ventricular tachycardia was of atrial origin. Six of the 9 subjects that developed ventricular arrhythmias did so within 14 days of onset of therapy. About 2.3% (11/474) of all subjects had a recurrence of SVT during the trial which could have been a change in the subjects’ arrhythmia behavior or could represent a proarrhythmic event. Case reports in patients treated with propafenone for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), VT, VF, torsade de pointes, asystole, and death.
- Overall in clinical trials with Rythmol (which included subjects treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all subjects had new or worsened ventricular arrhythmia possibly representing a proarrhythmic event (0.7% was an increase in PVCs; 4.0% a worsening, or new appearance, of VT or VF). Of the subjects who had worsening of VT (4%), 92% had a history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had a prior myocardial infarction. The incidence of proarrhythmia in subjects with less serious or benign arrhythmias, which include subjects with an increase in frequency of PVCs, was 1.6%. Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST trial suggests that an increased risk of proarrythmia is present throughout treatment.
- In a trial of sustained-release propafenone (Rythmol SR®), there were too few deaths to assess the long-term risk to patients. There were 5 deaths, 3 in the pooled group for Rythmol SR (0.8%) and 2 in the placebo group (1.6%). In the overall database of 8 trials of Rythmol SR and immediate-release Rythmol, the mortality rate was 2.5% per year on propafenone and 4.0% per year on placebo. Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.
- Unmasking Brugada Syndrome
- Brugada Syndrome may be unmasked after exposure to Rythmol. Perform an ECG after initiation of Rythmol, and discontinue the drug if changes are suggestive of Brugada Syndrome.
- Use With Drugs That Prolong the QT Interval and Antiarrhythmic Agents
- The use of Rythmol in conjunction with other drugs that prolong the QT interval has not been extensively studied. Such drugs may include many antiarrhythmics, some phenothiazines, tricyclic antidepressants, and oral macrolides. Withhold Class IA and III antiarrhythmic agents for at least 5 half-lives prior to dosing with Rythmol. Avoid the use of propafenone with Class IA and III antiarrhythmic agents (including quinidine and amiodarone). There is only limited experience with the concomitant use of Class IB or IC antiarrhythmics.
- Drug Interactions: Simultaneous Use With Inhibitors of Cytochrome P450 Isoenzymes 2D6 and 3A4
- Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes. Approximately 6% of Caucasians in the US population are naturally deficient in CYP2D6 activity and to a somewhat lesser extent in other demographic groups. Drugs that inhibit these CYP pathways (such as desipramine, paroxetine, ritonavir, sertraline for CYP2D6; ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone.
- Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of Rythmol with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.
- Use in Patients With a History of Heart Failure
- Propafenone exerts a negative inotropic activity on the myocardium as well as beta-blockade effects and may provoke overt heart failure.
- In clinical trial experience with Rythmol, new or worsened congestive heart failure (CHF) has been reported in 3.7% of subjects with ventricular arrhythmia; of those 0.9% were considered probably or definitely related to propafenone HCl. Of the subjects with CHF probably related to propafenone, 80% had pre-existing heart failure and 85% had coronary artery disease. CHF attributable to propafenone HCl developed rarely (<0.2%) in ventricular arrhythmia subjects who had no previous history of CHF. CHF occurred in 1.9% of subjects studied with PAF or PSVT.
- In a US trial of Rythmol SR in subjects with symptomatic AF, heart failure was reported in 4 (1.0%) subjects receiving Rythmol SR (all doses), compared with 1 (0.8%) subject receiving placebo.
- Conduction Disturbances
- Propafenone slows atrioventricular conduction and may also cause dose-related first-degree AV block. Average PR interval prolongation and increases in QRS duration are also dose-related. Do not give propafenone to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker.
- The incidence of first-degree, second-degree, and third-degree AV block observed in 2,127 subjects with ventricular arrhythmia was 2.5%, 0.6%, and 0.2%, respectively. Development of second- or third-degree AV block requires a reduction in dosage or discontinuation of propafenone HCl. Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in subjects receiving propafenone. Bradycardia has also been reported (1.5%). Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone.
- In a US trial in 523 subjects with a history of symptomatic AF treated with Rythmol SR, sinus bradycardia (rate <50 beats/min) was reported with the same frequency with Rythmol SR and placebo.
- Effects on Pacemaker Threshold
- Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators. During and after therapy, monitor and re-program these devices accordingly.
- Agranulocytosis
- Agranulocytosis has been reported in patients receiving propafenone. Generally, the agranulocytosis occurred within the first 2 months of propafenone therapy and upon discontinuation of therapy; the white count usually normalized by 14 days. Unexplained fever or decrease in white cell count, particularly during the initial 3 months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia. Instruct patients to report promptly any signs of infection such as fever, sore throat, or chills.
- Use in Patients With Hepatic Dysfunction
- Propafenone is highly metabolized by the liver. Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared with 3% to 40% in patients with normal liver function. In 8 subjects with moderate to severe liver disease, the mean half-life was approximately 9 hours. Increased bioavailability of propafenone in these patients may result in excessive accumulation. Carefully monitor patients with impaired hepatic function for excessive pharmacological effects.
- Use in Patients With Renal Dysfunction
- Approximately 50% of propafenone metabolites are excreted in the urine following administration of Rythmol.
- In patients with impaired renal function, monitor for signs of overdosage.
- Use in Patients With Myasthenia Gravis
- Exacerbation of myasthenia gravis has been reported during propafenone therapy.
- Elevated ANA Titers
- Positive ANA titers have been reported in patients receiving propafenone. They have been reversible upon cessation of treatment and may disappear even in the face of continued propafenone therapy. These laboratory findings were usually not associated with clinical symptoms, but there is one published case of drug-induced lupus erythematosis (positive rechallenge); it resolved completely upon discontinuation of therapy. Carefully evaluate patients who develop an abnormal ANA test and, if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.
- Impaired Spermatogenesis
- Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs, and rabbits after high-dose intravenous administration of propafenone. Evaluation of the effects of short-term administration of Rythmol on spermatogenesis in 11 normal subjects suggested that propafenone produced a reversible, short-term drop (within normal range) in sperm count.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reactions associated with Rythmol occur most frequently in the gastrointestinal, cardiovascular, and central nervous systems. About 20% of subjects treated with Rythmol have discontinued treatment because of adverse reactions.
- Adverse reactions reported for >1.5% of 474 subjects with SVT who received Rythmol in US clinical trials are presented in Table 1 by incidence and percent discontinuation, reported to the nearest percent.
- In controlled trials in subjects with ventricular arrhythmia, the most common reactions reported for Rythmol and more frequent than on placebo were unusual taste, dizziness, first degree AV block, intraventricular conduction delay, nausea and/or vomiting, and constipation. Headache was relatively common also, but was not increased compared with placebo. Other reactions reported more frequently than on placebo or comparator and not already reported elsewhere included anxiety, angina, second-degree AV block, bundle branch block, loss of balance, congestive heart failure, and dyspepsia.
- Adverse reactions reported for ≥1% of 2,127 subjects with ventricular arrhythmia who received propafenone in US clinical trials were evaluated by daily dose. The most common adverse reactions appeared dose-related (but note that most subjects spent more time at the larger doses), especially dizziness, nausea and/or vomiting, unusual taste, constipation, and blurred vision. Some less common reactions may also have been dose-related such as first-degree AV block, congestive heart failure, dyspepsia, and weakness. Other adverse reactions included rash, syncope, chest pain, abdominal pain, ataxia, and hypotension.In addition, the following adverse reactions were reported less frequently than 1% either in clinical trials or in marketing experience. Causality and relationship to propafenone therapy cannot necessarily be judged from these events.
- In addition, the following adverse reactions were reported less frequently than 1% either in clinical trials or in marketing experience. Causality and relationship to propafenone therapy cannot necessarily be judged from these events.
Atrial flutter, AV dissociation, cardiac arrest, flushing, hot flashes, sick sinus syndrome, sinus pause or arrest, supraventricular tachycardia.
Cholestasis , elevated liver enzymes (alkaline phosphatase, serum transaminases), gastroenteritis, hepatitis.
Agranulocytosis, anemia, bruising, granulocytopenia, leukopenia, purpura, thrombocytopenia.
Abnormal dreams, abnormal speech, abnormal vision, confusion, depression, memory loss, numbness, paresthesias, psychosis/mania, seizures (0.3%), tinnitus, unusual smell sensation, vertigo.
Alopecia, eye irritation, impotence, increased glucose, positive ANA (0.7%), muscle cramps, muscle weakness, nephrotic syndrome, pain, pruritus.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of Rythmol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
A number of patients with liver abnormalities associated with propafenone therapy have been reported in postmarketing experience. Some appeared due to hepatocellular injury, some were cholestatic, and some showed a mixed picture. Some of these reports were simply discovered through clinical chemistries, others because of clinical symptoms including fulminant hepatitis and death. One case was rechallenged with a positive outcome.
Increased bleeding time.
Apnea, coma.
Lupus erythematosis.
Hyponatremia/inappropriate ADH secretion, kidney failure.
# Drug Interactions
- CYP2D6 and CYP3A4 Inhibitors
- Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, or sertraline) and CYP3A4 (such as ketoconazole, ritonavir, saquinavir, erythromycin, or grapefruit juice) can be expected to cause increased plasma levels of propafenone. The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with administration of propafenone may increase the risk of adverse reactions, including proarrhythmia. Therefore, simultaneous use of Rythmol with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided.
- Amiodarone: Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended.
- Cimetidine: Concomitant administration of propafenone immediate-release tablets and cimetidine in 12 healthy subjects resulted in a 20% increase in steady-state plasma concentrations of propafenone.
- Fluoxetine: Concomitant administration of propafenone and fluoxetine in extensive metabolizers increased the S-propafenone Cmax and AUC by 39% and 50%, respectively, and the R propafenone Cmax and AUC by 71% and 50%, respectively.
- Quinidine: Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers. Concomitant administration of quinidine (50 mg 3 times daily) with 150 mg immediate-release propafenone 3 times daily decreased the clearance of propafenone by 60% in extensive metabolizers, making them slow metabolizers. Steady-state plasma concentrations more than doubled for propafenone, and decreased 50% for 5-OH-propafenone. A 100-mg dose of quinidine tripled steady-state concentrations of propafenone. Avoid concomitant use of propafenone and quinidine.
- Rifampin: Concomitant administration of rifampin and propafenone in extensive metabolizers decreased the plasma concentrations of propafenone by 67% with a corresponding decrease of 5-OH-propafenone by 65%. The concentrations of norpropafenone increased by 30%. In slow metabolizers, there was a 50% decrease in propafenone plasma concentrations and an increase in the AUC and Cmax of norpropafenone by 74% and 20%, respectively. Urinary excretion of propafenone and its metabolites decreased significantly. Similar results were noted in elderly patients: Both the AUC and Cmax of propafenone decreased by 84%, with a corresponding decrease in AUC and Cmaxof 5-OH‑propafenone by 69% and 57%, respectively.
- Digoxin
- Concomitant use of propafenone and digoxin increased steady-state serum digoxin exposure (AUC) in patients by 60% to 270%, and decreased the clearance of digoxin by 31% to 67%. Monitor plasma digoxin levels of patients receiving propafenone and adjust digoxin dosage as needed.
- Warfarin
- The concomitant administration of propafenone and warfarin increased warfarin plasma concentrations at steady state by 39% in healthy volunteers and prolonged the prothrombin time (PT) in patients taking warfarin. Adjust the warfarin dose as needed by monitoring INR (international normalized ratio).
- Orlistat
- Orlistat may limit the fraction of propafenone available for absorption. In postmarketing reports, abrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events including convulsions, atrioventricular block, and acute circulatory failure.
- Beta-Antagonists
- Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at steady state by 113%. In 4 patients, administration of metoprolol with propafenone increased the metoprolol plasma concentrations at steady state by 100% to 400%. The pharmacokinetics of propafenone was not affected by the coadministration of either propranolol or metoprolol. In clinical trials using propafenone immediate-release tablets, subjects who were receiving beta-blockers concurrently did not experience an increased incidence of side effects.
- Lidocaine
- No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients. However, concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. Rythmol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Teratogenic Effects: Propafenone has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg/kg day (about 3 times the maximum recommended human dose [MRHD] on a mg/m2 basis) and 600 mg/kg/day (about 6 times the MRHD on a mg/m2 basis), respectively. Although maternally tolerated doses (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m2 basis) produced no evidence of embryotoxicity in rats; post-implantation loss was elevated in all rabbit treatment groups (doses as low as 15 mg/kg/day, about 1/3 the MRHD on a mg/m2 basis).
- Non-teratogenic Effects: In a study in which female rats received daily oral doses of propafenone from mid-gestation through weaning of their offspring, doses as low as 90 mg/kg/day (equivalent to the MRHD on a mg/m2 basis) produced increases in maternal deaths. Doses of 360 or more mg/kg/day (4 or more times the MRHD on a mg/m2 basis) resulted in reductions in neonatal survival, body weight gain, and physiological development.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Propafenone in women who are pregnant.
### Labor and Delivery
- It is not known whether the use of propafenone during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetrical intervention.
### Nursing Mothers
- Propafenone is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from propafenone, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of propafenone in pediatric patients have not been established.
### Geriatic Use
- Clinical trials of Rythmol did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Propafenone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Propafenone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Propafenone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Propafenone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Propafenone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Propafenone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators. During and after therapy, monitor and re-program these devices accordingly.
- Carefully monitor patients with impaired hepatic function for excessive pharmacological effects.
- In patients with impaired renal function, monitor for signs of overdosage.
- Monitor plasma digoxin levels of patients receiving propafenone and adjust digoxin dosage as needed.
- The concomitant administration of propafenone and warfarin increased warfarin plasma concentrations at steady state by 39% in healthy volunteers and prolonged the prothrombin time (PT) in patients taking warfarin. Adjust the warfarin dose as needed by monitoring INR (international normalized ratio).
# IV Compatibility
There is limited information regarding IV Compatibility of Propafenone in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- The symptoms of overdosage may include hypotension, somnolence, bradycardia, intra-atrial and intraventricular conduction disturbances, and rarely, convulsions and high-grade ventricular arrhythmias.
### Management
- Defibrillation, as well as infusion of dopamine and isoproterenol have been effective in controlling abnormal rhythm and blood pressure. Convulsions have been alleviated with intravenous diazepam. General supportive measures such as mechanical respiratory assistance and external cardiac massage may be necessary.
- The hemodialysis of propafenone in patients with an overdose is expected to be of limited value in the removal of propafenone as a result of both its high protein binding (>95%) and large volume of distribution.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Propafenone in the drug label.
# Pharmacology
## Mechanism of Action
- Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects, and a direct stabilizing action on myocardial membranes. The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity.
- Studies in anesthetized dogs and isolated organ preparations show that propafenone has beta-sympatholytic activity at about 1/50 the potency of propranolol. Clinical studies employing isoproterenol challenge and exercise testing after single doses of propafenone indicate a beta-adrenergic blocking potency (per mg) about 1/40 that of propranolol in man. In clinical trials, resting heart rate decreases of about 8% were noted at the higher end of the therapeutic plasma concentration range. At very high concentrations in vitro, propafenone can inhibit the slow inward current carried by calcium, but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. Moreover, propafenone inhibits a variety of cardiac potassium currents in in vitro studies (i.e., the transient outward, the delayed rectifier, and the inward rectifier current). Propafenone has local anesthetic activity approximately equal to procaine. Compared with propafenone, the main metabolite, 5-hydroxypropafenone, has similar sodium and calcium channel activity, but about 10 times less beta-blocking activity (N-depropylpropafenone has weaker sodium channel activity but equivalent affinity for beta-receptors).
## Structure
- Rythmol (propafenone hydrochloride) is an antiarrhythmic drug supplied in scored, film-coated tablets of 150 and 225 mg for oral administration. Propafenone has some structural similarities to beta-blocking agents.
- Chemically, propafenone hydrochloride (HCl) is 2’-[2-hydroxy-3-(propylamino)-propoxy]-3-phenylpropiophenone hydrochloride, with a molecular weight of 377.92. The molecular formula is C21H27NO3•HCl. The structural formula of propafenone HCl is given below:
- Propafenone HCl occurs as colorless crystals or white crystalline powder with a very bitter taste. It is slightly soluble in water (20°C), chloroform and ethanol. The following inactive ingredients are contained in the tablet: corn starch, hypromellose, magnesium stearate, polyethylene glycol, polysorbate, povidone, propylene glycol, sodium starch glycolate, and titanium dioxide.
## Pharmacodynamics
- Electrophysiology: Electrophysiology trials in subjects with ventricular tachycardia have shown that propafenone prolongs atrioventricular conduction while having little or no effect on sinus node function. Both atrioventricular nodal conduction time (AH interval) and His-Purkinje conduction time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are prolonged. In patients with Wolff-Parkinson-White syndrome, Rythmol reduces conduction and increases the effective refractory period of the accessory pathway in both directions.
- Electrocardiograms: Propafenone slows prolongs the PR and QRS intervals. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval.
- In any individual patient, the above ECG changes cannot be readily used to predict either efficacy or plasma concentration.
- Rythmol causes a dose-related and concentration-related decrease in the rate of single and multiple premature ventricular contractions (PVCs) and can suppress recurrence of ventricular tachycardia. Based on the percent of patients attaining substantial (80% to 90%) suppression of ventricular ectopic activity, it appears that trough plasma levels of 0.2 to 1.5 mcg/mL can provide good suppression, with higher concentrations giving a greater rate of good response.
- When 600 mg/day propafenone was administered to subjects with paroxysmal atrial tachyarrhythmias, mean heart rate during arrhythmia decreased 14 beats/min and 37 beats/min for subjects with paroxysmal atrial fibrillation/flutter (PAF) and subjects with paroxysmal supraventricular tachycardia (PSVT), respectively.
- Hemodynamics: Trials in humans have shown that propafenone HCl exerts a negative inotropic effect on the myocardium. Cardiac catheterization trials in subjects with moderately impaired ventricular function (mean C.I. = 2.61 L/min/m2) utilizing intravenous propafenone infusions (loading dose of 2 mg/kg over 10 min followed by 2 mg/min for 30 min) that gave mean plasma concentrations of 3.0 mcg/mL (a dose that produces plasma levels of propafenone greater than recommended oral dosing) showed significant increases in pulmonary capillary wedge pressure, systemic and pulmonary vascular resistances, and depression of cardiac output and cardiac index.
## Pharmacokinetics
- Absorption/Bioavailability: Propafenone HCl is nearly completely absorbed after oral administration with peak plasma levels occurring approximately 3.5 hours after administration in most individuals. Propafenone exhibits extensive saturable presystemic biotransformation (first-pass effect) resulting in a dose dependent and dosage form dependent absolute bioavailability; e.g., a 150-mg tablet had absolute bioavailability of 3.4%, while a 300-mg tablet had absolute bioavailability of 10.6%. A 300-mg solution which was rapidly absorbed had absolute bioavailability of 21.4%. At still larger doses, above those recommended, bioavailability increases still further.
Propafenone HCl follows a nonlinear pharmacokinetic disposition presumably because of saturation of first-pass hepatic metabolism as the liver is exposed to higher concentrations of propafenone and shows a very high degree of interindividual variability. For example, for an increase in daily dose from 300 to 900 mg/day there is a 10-fold increase in steady-state plasma concentration. The top 25% of subjects given 337.5 mg/day, however, had a mean concentration of propafenone larger than the bottom 25%, and about equal to the second 25%, of subjects given a dose of 900 mg. Although food increased peak blood level and bioavailability in a single-dose trial, during multiple-dose administration of propafenone to healthy volunteers, food did not change bioavailability significantly.
- Distribution: Following intravenous administration of propafenone, plasma levels decline in a bi-phasic manner consistent with a 2-compartment pharmacokinetic model. The average distribution half-life corresponding to the first phase was about 5 minutes. The volume of the central compartment was about 88 liters (1.1 L/kg) and the total volume of distribution about 252 liters.
- In serum, propafenone is greater than 95% bound to proteins within the concentration range of 0.5 to 2 mcg/mL.
- Metabolism: There are 2 genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life from 2 to 10 hours. These patients metabolize propafenone into 2 active metabolites: 5-hydroxypropafenone which is formed by CYP2D6 and N-depropylpropafenone (norpropafenone) which is formed by both CYP3A4 and CYP1A2.
- In less than 10% of patients, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed. In these patients, the estimated propafenone elimination half-life ranges from 10 to 32 hours. Decreased ability to form the 5-hydroxy metabolite of propafenone is associated with a diminished ability to metabolize debrisoquine and a variety of other drugs (such as encainide, metoprolol, and dextromethorphan) whose metabolism is mediated by the CYP2D6 isozyme. In these patients, the N-depropylpropafenone metabolite occurs in quantities comparable to the levels occurring in extensive metabolizers.
- There are significant differences in plasma concentrations of propafenone in slow and extensive metabolizers, the former achieving concentrations 1.5 to 2.0 times those of the extensive metabolizers at daily doses of 675 to 900 mg/day. At low doses the differences are greater, with slow metabolizers attaining concentrations more than 5 times that of extensive metabolizers. Because the difference decreases at high doses and is mitigated by the lack of the active 5-hydroxy metabolite in the slow metabolizers, and because steady-state conditions are achieved after 4 to 5 days of dosing in all patients, the recommended dosing regimen is the same for all patients. The greater variability in blood levels require that the drug be titrated carefully in patients with close attention paid to clinical and ECG evidence of toxicity.
- Stereochemistry: Rythmol is a racemic mixture. The R- and S-enantiomers of propafenone display stereoselective disposition characteristics. In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5-hydroxylation pathway (CYP2D6). This results in a higher ratio of S-propafenone to R-propafenone at steady state. Both enantiomers have equivalent potency to block sodium channels; however, the S-enantiomer is a more potent beta-antagonist than the R-enantiomer. Following administration of Rythmol immediate-release tablets, the S/R ratio for the area under the plasma concentration-time curve was about 1.7. In addition, no difference in the average values of the S/R ratios is evident between genotypes or over time.
- Special Populations:Hepatic Impairment: Decreased liver function increases the bioavailability of propafenone. Absolute bioavailability of Rythmol immediate-release tablets is inversely related to indocyanine green clearance, reaching 60% to 70% at clearances of 7 mL/min and below. Protein binding decreases to about 88% in patients with severe hepatic dysfunction. The clearance of propafenone is reduced and the elimination half-life increased in patients with significant hepatic dysfunction.
## Nonclinical Toxicology
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day, about twice the maximum recommended human oral daily dose [MRHD] on a mg/m2 basis) and rats (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m2 basis) provided no evidence of a carcinogenic potential for propafenone HCl.
- Propafenone HCl tested negative for mutagenicity in the Ames (salmonella) test and in the in vivo mouse dominant lethal test. It tested negative for clastogenicity in the human lymphocyte chromosome aberration assay in vitro and in rat and Chinese hamster micronucleus tests, and other in vivo tests for chromosomal aberrations in rat bone marrow and Chinese hamster bone marrow and spermatogonia.
- Propafenone HCl, administered intravenously to rabbits, dogs, and monkeys, has been shown to decrease spermatogenesis. These effects were reversible, were not found following oral dosing of propafenone HCl, were seen at lethal or near lethal dose levels, and were not seen in rats treated either orally or intravenously. Treatment of male rabbits for 10 weeks prior to mating at an oral dose of 120 mg/kg/day (about 2.4 times the MRHD on a mg/m2 basis) or an intravenous dose of 3.5 mg/kg/day (a spermatogenesis-impairing dose) did not result in evidence of impaired fertility. Nor was there evidence of impaired fertility when propafenone HCl was administered orally to male and female rats at dose levels up to 270 mg/kg/day (about 3 times the MRHD on a mg/m2 basis).
- Animal Toxicology and/or Pharmacology
- Renal changes have been observed in the rat following 6 months of oral administration of propafenone HCl at doses of 180 and 360 mg/kg/day (about 2 and 4 times, respectively, the MRHD on a mg/m2 basis). Both inflammatory and non-inflammatory changes in the renal tubules, with accompanying interstitial nephritis, were observed. These changes were reversible, as they were not found in rats allowed to recover for 6 weeks. Fatty degenerative changes of the liver were found in rats following longer durations of administration of propafenone HCl at a dose of 270 mg/kg/day (about 3 times the MRHD on a mg/m2 basis). There were no renal or hepatic changes at 90 mg/kg/day (equivalent to the MRHD on a mg/m2 basis).
# Clinical Studies
- In 2 randomized, crossover, placebo-controlled, double-blind trials of 60 to 90 days’ duration in subjects with paroxysmal supraventricular arrhythmias (paroxysmal atrial fibrillation/flutter [PAF], or paroxysmal supraventricular tachycardia [PSVT]), propafenone reduced the rate of both arrhythmias, as shown in Table 3.
- The patient population in the above trials was 50% male with a mean age of 57.3 years. Fifty percent of the subjects had a diagnosis of PAF and 50% had PSVT. Eighty percent of the subjects received 600 mg/day propafenone. No subject died in the above 2 trials.
- In US long-term safety trials, 474 subjects (mean age: 57.4 + 14.5 years) with supraventricular arrhythmias [195 with PAF, 274 with PSVT and 5 with both PAF and PSVT] were treated up to 5 years (mean: 14.4 months) with propafenone. Fourteen of the subjects died. When this mortality rate was compared with the rate in a similar patient population (n = 194 subjects; mean age: 43.0 + 16.8 years) studied in an arrhythmia clinic, there was no age-adjusted difference in mortality. This comparison was not, however, a randomized trial and the 95% confidence interval around the comparison was large, such that neither a significant adverse or favorable effect could be ruled out.
# How Supplied
- Rythmol Tablets are supplied as white, biconvex, scored, round, film-coated tablets containing either 150 mg or 225 mg of propafenone hydrochloride and embossed (on the same side) with GS and TF5 for the 150-mg tablet, and GS and F1X for the 225-mg tablet, in the following package sizes:
- Storage: Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Dispense in a tight, light-resistant container.
## Storage
There is limited information regarding Propafenone Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to notify their healthcare providers of any change in over-the-counter, prescription, and supplement use. The healthcare provider should assess the patients’ medication history including all over-the-counter, prescription, and herbal/natural preparations for those that may affect the pharmacodynamics or kinetics of Rythmol.
- Patients should also check with their healthcare providers prior to taking a new over-the-counter medicine.
- If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, vomiting, or loss of appetite or thirst, these conditions should be immediately reported to their healthcare provider.
- Patients should be instructed NOT to double the next dose if a dose is missed. The next dose should be taken at the usual time.
# Precautions with Alcohol
- Alcohol-Propafenone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Rythmol®[1]
# Look-Alike Drug Names
- N/A[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Propafenone | |
9bce029e3c19a7957249dfdb7c289ad079c15220 | wikidoc | Prophylaxis | Prophylaxis
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
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# Overview
Prophylaxis (Greek "προφυλάσσω" to guard or prevent beforehand) is any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease. Roughly, prophylactic measures are divided between primary prophylaxis (to prevent the development of a disease) and secondary prophylaxis (whereby the disease has already developed and the patient is protected against worsening of this process).
# Specific examples
Influenza vaccines are prophylactic.
Antibiotics are sometimes used prophylactically: For example, during the 2001 anthrax attacks scare in the United States, patients who were believed to be exposed were given ciprofloxacin. Similarly, the use of antibiotic ointments on burns and other wounds is prophylactic.
Tricyclic antidepressants (TCAs) may, with caution, be an example of a chronic migraine preventative (see Amitriptyline and migraines' prevention by medicine).
Antimalarials such as chloroquine are used both in treatment and as prophylaxis by visitors to countries where malaria is endemic to prevent the development of the parasitic plasmodium which cause malaria.
Condoms are sometimes referred to as "prophylactics" because of their use to prevent pregnancy and the transmission of sexually transmitted diseases.
Low molecular weight heparin is used as a prophylaxis in hospital patients, as they are at risk for several forms of thrombosis due to their immobilization.
Professional cleaning of the teeth is dental prophylaxis.
Daily and moderate physical exercise in various forms can be called prophylactic because it can maintain or improve one's health. Cycling for transport appears to very significantly improve health by reducing risk of heart diseases, various cancers, muscular- and skeletal diseases and overall mortality
Prophylaxis may be administered as vaccine. Prophylactic vaccines include: PEP, nPEP, PREP, or nPREP. PEP stands for post-exposure prophylaxis used in an occupational setting. nPEP is non-occupational post-exposure prophylaxis. nPEP may be used in a recreational setting e.g. during intercourse if the condom breaks and one partner is HIV-positive, nPEP will help to decrease the probability of spread of infection of HIV. PREP is often used in occupational settings e.g. in hospital staff to prevent the spread of HIV or Hepatitis C from patient to staff. nPREP is a measure taken before exposure but in a non-occupational setting (non-occupational Pre-exposure prophylaxis) e.g. injection drug users may seek nPREP vaccinations.
# Related Chapters
- Pre-exposure prophylaxis
- Post-exposure prophylaxis | Prophylaxis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Prophylaxis (Greek "προφυλάσσω" to guard or prevent beforehand) is any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease. Roughly, prophylactic measures are divided between primary prophylaxis (to prevent the development of a disease) and secondary prophylaxis (whereby the disease has already developed and the patient is protected against worsening of this process).
# Specific examples
Influenza vaccines are prophylactic.[1]
Antibiotics are sometimes used prophylactically: For example, during the 2001 anthrax attacks scare in the United States, patients who were believed to be exposed were given ciprofloxacin. Similarly, the use of antibiotic ointments on burns and other wounds is prophylactic.
Tricyclic antidepressants (TCAs) may, with caution, be an example of a chronic migraine preventative (see Amitriptyline and migraines' prevention by medicine).
Antimalarials such as chloroquine are used both in treatment and as prophylaxis by visitors to countries where malaria is endemic to prevent the development of the parasitic plasmodium which cause malaria.
Condoms are sometimes referred to as "prophylactics" because of their use to prevent pregnancy and the transmission of sexually transmitted diseases.
Low molecular weight heparin is used as a prophylaxis in hospital patients, as they are at risk for several forms of thrombosis due to their immobilization.
Professional cleaning of the teeth is dental prophylaxis.
Daily and moderate physical exercise in various forms can be called prophylactic because it can maintain or improve one's health. Cycling for transport appears to very significantly improve health by reducing risk of heart diseases, various cancers, muscular- and skeletal diseases and overall mortality
[2].
Prophylaxis may be administered as vaccine. Prophylactic vaccines include: PEP, nPEP, PREP, or nPREP. PEP stands for post-exposure prophylaxis used in an occupational setting. nPEP is non-occupational post-exposure prophylaxis. nPEP may be used in a recreational setting e.g. during intercourse if the condom breaks and one partner is HIV-positive, nPEP will help to decrease the probability of spread of infection of HIV. PREP is often used in occupational settings e.g. in hospital staff to prevent the spread of HIV or Hepatitis C from patient to staff. nPREP is a measure taken before exposure but in a non-occupational setting (non-occupational Pre-exposure prophylaxis) e.g. injection drug users may seek nPREP vaccinations.
# Related Chapters
- Pre-exposure prophylaxis
- Post-exposure prophylaxis | https://www.wikidoc.org/index.php/Prophylactic | |
34dd0a4fea6f9500cdfa926dc8299179416e7531 | wikidoc | Protein 4.2 | Protein 4.2
Erythrocyte membrane protein band 4.2 is a protein that in humans is encoded by the EPB42 gene.
Protein 4.2 is a cytoskeleton protein found in red blood cells.
Erythrocyte membrane protein band 4.2 is an ATP-binding protein which may regulate the association of band 3 with ankyrin. It probably has a role in erythrocyte shape and mechanical property regulation. Mutations in the EPB42 gene are associated with recessive spherocytic elliptocytosis and recessively transmitted hereditary hemolytic anemia. | Protein 4.2
Erythrocyte membrane protein band 4.2 is a protein that in humans is encoded by the EPB42 gene.[1][2]
Protein 4.2 is a cytoskeleton protein found in red blood cells.
Erythrocyte membrane protein band 4.2 is an ATP-binding protein which may regulate the association of band 3 with ankyrin. It probably has a role in erythrocyte shape and mechanical property regulation. Mutations in the EPB42 gene are associated with recessive spherocytic elliptocytosis and recessively transmitted hereditary hemolytic anemia.[2] | https://www.wikidoc.org/index.php/Protein_4.2 | |
d58d7055907cf070a0cd70a1f9ca9afc2f79b4ab | wikidoc | Proteopathy | Proteopathy
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Proteopathy (Proteo- ; -pathy ; proteopathies pl.; proteopathic adj.). Proteopathy is the abnormal accumulation and toxicity of proteins in certain disease states. The proteopathies (sometimes referred to as "proteinopathies") comprise more than 30 diseases that affect a variety of organs and tissues, including Alzheimer's disease, Parkinson's disease, type 2 diabetes, amyloidosis, selective hyperproteolytic diseases (e.g. critical illness myopathies or tumor cachexia), and a wide range of other disorders (see Table).
The proteopathies also are called protein conformational diseases, because a change in the 3-dimensional folding (conformation) of a protein increases the tendency of the protein to misfold and polymerize into aggregates that are resistant to clearance, and can become pathogenic. Because of the common structure of the polypeptide backbone, all proteins have the potential to misfold under some conditions.
Only certain proteins are linked to proteopathy, possibly due to instability or other structural features of the monomeric protein that increase the probability of misconformation, which in nearly all instances involves an increase in beta-sheet secondary structure. Potential risk factors for proteopathic diseases augment the tendency of vulnerable proteins to self-assemble. They include destabilizing changes in the primary amino acid sequence of the protein, post-translational modifications (such as hyperphosphorylation), changes in temperature or pH, an increase in production of a protein, or a decrease in its clearance. Advancing age frequently is a risk factor.
In some proteopathies, abnormal assembly can be templated on an exogenous protein, typically a misfolded form of the same protein. In this way, the disease state can be induced in a susceptible host by the introduction of diseased tissue extract from an afflicted donor. The best known form of such infectious (or transmissible) proteopathy is prion disease, which can be transmitted by exposure of a host organism to purified prion protein in a disease-causing conformation. There is now evidence that other proteopathies are inducible by a similar mechanism, including AA amyloidosis, apolipoprotein AII amyloidosis, and Aβ amyloidosis. In all of these instances, an aberrant form of the protein itself appears to be the pathogenic agent. | Proteopathy
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Proteopathy (Proteo- [pref. protein]; -pathy [suff. disease]; proteopathies pl.; proteopathic adj.). Proteopathy is the abnormal accumulation and toxicity of proteins in certain disease states.[1] The proteopathies (sometimes referred to as "proteinopathies") comprise more than 30 diseases that affect a variety of organs and tissues, including Alzheimer's disease, Parkinson's disease, type 2 diabetes, amyloidosis, selective hyperproteolytic diseases (e.g. critical illness myopathies or tumor cachexia), and a wide range of other disorders (see Table).[2][3][4][5][6][7]
The proteopathies also are called protein conformational diseases,[6] because a change in the 3-dimensional folding (conformation) of a protein increases the tendency of the protein to misfold and polymerize into aggregates that are resistant to clearance, and can become pathogenic. Because of the common structure of the polypeptide backbone, all proteins have the potential to misfold under some conditions.[8]
Only certain proteins are linked to proteopathy, possibly due to instability or other structural features of the monomeric protein that increase the probability of misconformation,[6][8] which in nearly all instances involves an increase in beta-sheet secondary structure.[8][6][9] Potential risk factors for proteopathic diseases augment the tendency of vulnerable proteins to self-assemble. They include destabilizing changes in the primary amino acid sequence of the protein, post-translational modifications (such as hyperphosphorylation), changes in temperature or pH, an increase in production of a protein, or a decrease in its clearance.[6][8][1] Advancing age frequently is a risk factor.[1]
In some proteopathies, abnormal assembly can be templated on an exogenous protein, typically a misfolded form of the same protein.[10][11] In this way, the disease state can be induced in a susceptible host by the introduction of diseased tissue extract from an afflicted donor. The best known form of such infectious (or transmissible) proteopathy is prion disease, which can be transmitted by exposure of a host organism to purified prion protein in a disease-causing conformation.[12][13] There is now evidence that other proteopathies are inducible by a similar mechanism, including AA amyloidosis, apolipoprotein AII amyloidosis, and Aβ amyloidosis.[11][14] In all of these instances, an aberrant form of the protein itself appears to be the pathogenic agent. | https://www.wikidoc.org/index.php/Proteopathy | |
22575f1f0e1b82b7db88b76b382d8cf75acb2d5f | wikidoc | Proterozoic | Proterozoic
The Proterozoic (Template:PronEng) is a geological eon representing a period before the first abundant complex life on Earth. The Proterozoic Eon extended from 2500 Ma to 542.0 ± 1.0 Ma (million years ago), and is the most recent part of the old, informally named ‘Precambrian’ time.
The Proterozoic consists of 3 geologic eras, from oldest to youngest:
- Paleoproterozoic
- Mesoproterozoic
- Neoproterozoic
The well-identified events were:
- The transition to an oxygenated atmosphere during the Mesoproterozoic.
- Several glaciations, including the hypothesized Snowball Earth during the Cryogenian period in the late Neoproterozoic.
- The Ediacaran Period (635 to 542 Ma) which is characterized by the evolution of abundant soft-bodied multicellular organisms.
# The Proterozoic record
The geologic record of the Proterozoic is much better than that for the preceding Archean. In contrast to the deep-water deposits of the Archean, the Proterozoic features many strata that were laid down in extensive shallow epicontinental seas; furthermore, many of these rocks are less metamorphosed than Archean-age ones, and plenty are unaltered. Study of these rocks show that the eon featured massive, rapid continental accretion (unique to the Proterozoic), supercontinent cycles, and wholly-modern orogenic activity.
The first known glaciations occurred during the Proterozoic, one began shortly after the beginning of the eon, while there were at least four during the Neoproterozoic, climaxing with the Snowball Earth of the Varangian glaciation.
# The build-up of oxygen
One of the most important events of the Proterozoic was the gathering up of oxygen in the Earth's atmosphere. Though oxygen was undoubtedly released by photosynthesis well back in Archean times, it could not build up to any significant degree until chemical sinks — unoxidized sulfur and iron — had been filled; until roughly 2.3 billion years ago, oxygen was probably only 1% to 2% of its current level. Banded iron formations, which provide most of the world's iron ore, were also a prominent chemical sink; most accumulation ceased after 1.9 billion years ago, either due to an increase in oxygen or a more thorough mixing of the oceanic water column.
Red beds, which are colored by hematite, indicate an increase in atmospheric oxygen after 2 billion years ago; they are not found in older rocks. The oxygen build-up was probably due to two factors: a filling of the chemical sinks, and an increase in carbon burial, which sequestered organic compounds that would have otherwise been oxidized by the atmosphere.
# Paleogeography
The Mackenzie dike swarm in Canada's Canadian Shield is the largest known dike swarm on Earth, and was a source for significant massive flood basalt eruptions throughout the Proterozoic period. The source for the Mackenzie dike swarm is thought to have been a mantle plume center called the Mackenzie hotspot.
# Proterozoic life
The first advanced single-celled and multi-cellular life roughly coincides with the start of the accumulation of free oxygen; this may have been due to an increase in the oxidized nitrates that eukaryotes use, as opposed to cyanobacteria. It was also during the Proterozoic that the first symbiotic relationships between mitochondria (for nearly all eukaryotes) and chloroplasts (for plants and some protists only) and their hosts evolved.
The blossoming of eukaryotes such as acritarchs did not preclude the expansion of cyanobacteria; in fact, stromatolites reached their greatest abundance and diversity during the Proterozoic, peaking roughly 1.2 billion years ago.
Classically, the boundary between the Proterozoic and the Phanerozoic eons was set at the base of the Cambrian period when the first fossils of animals known as trilobites and archeocyathids appeared. In the second half of the 20th century, a number of fossil forms have been found in Proterozoic rocks, but the upper boundary of the Proterozoic has remained fixed at the base of the Cambrian, which is currently placed at 542 Ma. | Proterozoic
Template:Proterozoic Infobox
The Proterozoic (Template:PronEng) is a geological eon representing a period before the first abundant complex life on Earth. The Proterozoic Eon extended from 2500 Ma to 542.0 ± 1.0 Ma (million years ago), and is the most recent part of the old, informally named ‘Precambrian’ time.
The Proterozoic consists of 3 geologic eras, from oldest to youngest:
- Paleoproterozoic
- Mesoproterozoic
- Neoproterozoic
The well-identified events were:
- The transition to an oxygenated atmosphere during the Mesoproterozoic.
- Several glaciations, including the hypothesized Snowball Earth during the Cryogenian period in the late Neoproterozoic.
- The Ediacaran Period (635 to 542 Ma) which is characterized by the evolution of abundant soft-bodied multicellular organisms.
# The Proterozoic record
The geologic record of the Proterozoic is much better than that for the preceding Archean. In contrast to the deep-water deposits of the Archean, the Proterozoic features many strata that were laid down in extensive shallow epicontinental seas; furthermore, many of these rocks are less metamorphosed than Archean-age ones, and plenty are unaltered.[1] Study of these rocks show that the eon featured massive, rapid continental accretion (unique to the Proterozoic), supercontinent cycles, and wholly-modern orogenic activity.[2]
The first known glaciations occurred during the Proterozoic, one began shortly after the beginning of the eon, while there were at least four during the Neoproterozoic, climaxing with the Snowball Earth of the Varangian glaciation.[3]
# The build-up of oxygen
One of the most important events of the Proterozoic was the gathering up of oxygen in the Earth's atmosphere. Though oxygen was undoubtedly released by photosynthesis well back in Archean times, it could not build up to any significant degree until chemical sinks — unoxidized sulfur and iron — had been filled; until roughly 2.3 billion years ago, oxygen was probably only 1% to 2% of its current level.[4] Banded iron formations, which provide most of the world's iron ore, were also a prominent chemical sink; most accumulation ceased after 1.9 billion years ago, either due to an increase in oxygen or a more thorough mixing of the oceanic water column.[5]
Red beds, which are colored by hematite, indicate an increase in atmospheric oxygen after 2 billion years ago; they are not found in older rocks.[5] The oxygen build-up was probably due to two factors: a filling of the chemical sinks, and an increase in carbon burial, which sequestered organic compounds that would have otherwise been oxidized by the atmosphere.[6]
# Paleogeography
The Mackenzie dike swarm in Canada's Canadian Shield is the largest known dike swarm on Earth, and was a source for significant massive flood basalt eruptions throughout the Proterozoic period. The source for the Mackenzie dike swarm is thought to have been a mantle plume center called the Mackenzie hotspot.[7]
Template:Sectstub
# Proterozoic life
The first advanced single-celled and multi-cellular life roughly coincides with the start of the accumulation of free oxygen; this may have been due to an increase in the oxidized nitrates that eukaryotes use, as opposed to cyanobacteria.[6] It was also during the Proterozoic that the first symbiotic relationships between mitochondria (for nearly all eukaryotes) and chloroplasts (for plants and some protists only) and their hosts evolved.[8]
The blossoming of eukaryotes such as acritarchs did not preclude the expansion of cyanobacteria; in fact, stromatolites reached their greatest abundance and diversity during the Proterozoic, peaking roughly 1.2 billion years ago.[9]
Classically, the boundary between the Proterozoic and the Phanerozoic eons was set at the base of the Cambrian period when the first fossils of animals known as trilobites and archeocyathids appeared. In the second half of the 20th century, a number of fossil forms have been found in Proterozoic rocks, but the upper boundary of the Proterozoic has remained fixed at the base of the Cambrian, which is currently placed at 542 Ma. | https://www.wikidoc.org/index.php/Proterozoic | |
8ee6eb04aa7017b2bad3fe10cbdabe5546c8a019 | wikidoc | Prototheria | Prototheria
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Prototheria (Template:PronEng, from Greek prōtos, first, + thēr, wild animal) is a taxonomic group, or taxon, to which the order Monotremata belongs. It is conventionally ranked as a subclass within the mammals.
Most of the animals in this group are extinct. The egg-laying monotremes are known from fossils of the Cretaceous and Cenozoic periods; they are represented today by the platypus and several species of echidna.
The names Prototheria, Metatheria and Eutheria (meaning "first beasts", "changed beasts", and "true beasts") refer to the three mammalian groupings which have living representatives. Each of the three may be defined as a putative clade comprising a living crown-group (respectively the Monotremata, Marsupialia and Placentalia) plus any fossil species which are more closely related to that crown-group than to any other animals.
The threefold division of living mammals into monotremes, marsupials and placentals was already well established when Thomas Huxley proposed the names Metatheria and Eutheria to incorporate the two latter groups in 1880. Initially treated as subclasses, Metatheria and Eutheria are by convention now grouped as infraclasses of the subclass Theria, and in more recent proposals have been demoted further (to cohorts or even magnorders), as cladistic reappraisals of the relationships between living and fossil mammals have suggested that the Theria itself should be reduced in rank.
Prototheria, on the other hand, was generally recognised as a subclass until quite recently, on the basis of an hypothesis which defined the group by two supposed synapomorphies: (1) formation of the side wall of the braincase from a bone called the anterior lamina, contrasting with the alisphenoid in therians; and (2) a linear alignment of molar cusps, contrasting with a triangular arrangement in therians. These characters appeared to unite monotremes with a range of Mesozoic fossil orders (Morganucodonta, Triconodonta, Docodonta and Multituberculata) in a broader clade for which the name Prototheria was retained, and of which monotremes were thought to be only the last surviving branch (Benton 2005: 300, 306).
The evidence which was held to support this grouping is now universally discounted. In the first place, examination of embryos has revealed that the development of the braincase wall is essentially identical in therians and in 'prototherians': the anterior lamina simply fuses with the alisphenoid in therians, and therefore the 'prototherian' condition of the braincase wall is primitive for all mammals while the therian condition can be derived from it. Additionally, the linear alignment of molar cusps is also primitive for all mammals. Therefore, neither of these states can supply a uniquely shared derived character which would support a 'prototherian' grouping of orders in contradistinction to Theria (Kemp 1983).
In a further reappraisal, the molars of embryonic and fossil monotremes (living monotreme adults are toothless) appear to demonstrate an ancestral pattern of cusps which is similar to the triangular arrangement observed in therians. Some peculiarities of this dentition support an alternative grouping of monotremes with certain recently-discovered fossil forms into a proposed new clade known as the Australosphenida, and also suggest that the triangular array of cusps may have evolved independently in australosphenidans and therians (Luo et al. 2001, 2002).
The Australosphenida hypothesis remains controversial, and some taxonomists (e.g. McKenna & Bell 1997) prefer to maintain the name Prototheria as a fitting contrast to the other group of living mammals, the Theria. In theory, the Prototheria is taxonomically redundant, since Monotremata is currently the only order which can still be confidently included, but its retention might be justified if new fossil evidence, or a re-examination of known fossils, enables extinct relatives of the monotremes to be identified and placed within a wider grouping.
# Notes
- ↑ Marsupialia and Eutheria/Placentalia appear as cohorts in McKenna & Bell 1997 and in Benton 2005, with Theria ranked as a supercohort or an infralegion, respectively. | Prototheria
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Prototheria (Template:PronEng, from Greek prōtos, first, + thēr, wild animal) is a taxonomic group, or taxon, to which the order Monotremata belongs. It is conventionally ranked as a subclass within the mammals.
Most of the animals in this group are extinct. The egg-laying monotremes are known from fossils of the Cretaceous and Cenozoic periods; they are represented today by the platypus and several species of echidna.
The names Prototheria, Metatheria and Eutheria (meaning "first beasts", "changed beasts", and "true beasts") refer to the three mammalian groupings which have living representatives. Each of the three may be defined as a putative clade comprising a living crown-group (respectively the Monotremata, Marsupialia and Placentalia) plus any fossil species which are more closely related to that crown-group than to any other animals.
The threefold division of living mammals into monotremes, marsupials and placentals was already well established when Thomas Huxley proposed the names Metatheria and Eutheria to incorporate the two latter groups in 1880. Initially treated as subclasses, Metatheria and Eutheria are by convention now grouped as infraclasses of the subclass Theria, and in more recent proposals have been demoted further (to cohorts or even magnorders), as cladistic reappraisals of the relationships between living and fossil mammals have suggested that the Theria itself should be reduced in rank.[1]
Prototheria, on the other hand, was generally recognised as a subclass until quite recently, on the basis of an hypothesis which defined the group by two supposed synapomorphies: (1) formation of the side wall of the braincase from a bone called the anterior lamina, contrasting with the alisphenoid in therians; and (2) a linear alignment of molar cusps, contrasting with a triangular arrangement in therians. These characters appeared to unite monotremes with a range of Mesozoic fossil orders (Morganucodonta, Triconodonta, Docodonta and Multituberculata) in a broader clade for which the name Prototheria was retained, and of which monotremes were thought to be only the last surviving branch (Benton 2005: 300, 306).
The evidence which was held to support this grouping is now universally discounted. In the first place, examination of embryos has revealed that the development of the braincase wall is essentially identical in therians and in 'prototherians': the anterior lamina simply fuses with the alisphenoid in therians, and therefore the 'prototherian' condition of the braincase wall is primitive for all mammals while the therian condition can be derived from it. Additionally, the linear alignment of molar cusps is also primitive for all mammals. Therefore, neither of these states can supply a uniquely shared derived character which would support a 'prototherian' grouping of orders in contradistinction to Theria (Kemp 1983).
In a further reappraisal, the molars of embryonic and fossil monotremes (living monotreme adults are toothless) appear to demonstrate an ancestral pattern of cusps which is similar to the triangular arrangement observed in therians. Some peculiarities of this dentition support an alternative grouping of monotremes with certain recently-discovered fossil forms into a proposed new clade known as the Australosphenida, and also suggest that the triangular array of cusps may have evolved independently in australosphenidans and therians (Luo et al. 2001, 2002).
The Australosphenida hypothesis remains controversial, and some taxonomists (e.g. McKenna & Bell 1997) prefer to maintain the name Prototheria as a fitting contrast to the other group of living mammals, the Theria. In theory, the Prototheria is taxonomically redundant, since Monotremata is currently the only order which can still be confidently included, but its retention might be justified if new fossil evidence, or a re-examination of known fossils, enables extinct relatives of the monotremes to be identified and placed within a wider grouping.
# Notes
- ↑ Marsupialia and Eutheria/Placentalia appear as cohorts in McKenna & Bell 1997 and in Benton 2005, with Theria ranked as a supercohort or an infralegion, respectively. | https://www.wikidoc.org/index.php/Prototheria | |
266ab255b199c456ccb7d201ccf2dd0259898a99 | wikidoc | Providencia | Providencia
# Overview
Providencia is a Gram negative, motile bacterium of the family Enterobacteriaceae. Some strains (P. stuartii, for example) are opportunistic pathogens in humans and can cause urinary tract infections, particularly in patients with long-term indwelling urinary catheters or extensive severe burns. Other strains (for example P. burhodogranariea and P. sneebia) are found in the haemolymph of Drosophila melanogaster fruit flies.
Some strains are sensitive to ampicillin.
# Organism
Providencia stuartii is the most common Providencia species capable of causing human infections. Providencia stuartii is an opportunistic pathogen seen in patients with severe burns or long-term indwelling urinary catheters. This puts elderly individuals at a greater risk for P. stuartii infections. In animals P. stuartii infections can cause neonatal diarrhea due to P. stuartii infection in dairy cows. In humans, P. stuartii can be isolated from urine (most common), stool, and blood, as well as from sputum, skin, and wound cultures. P. stuartii septicemia is primarily of urinary origin. It is the most common cause of purple urine bag syndrome. Upon physical examination, P stuartii bloodstream infection is associated with fever, tachycardia, and hypotension.
Providencia rettgeri (commonly P. rettgeri), is a Gram negative bacterium that is commonly found in both water and land environments. P. rettgeri can be incubated at 37 °C in nutrient agar or nutrient broth. It was first discovered in 1904 after a waterfowl epidemic.Hadley, Phillip (1908). The colon-typhoid intermediates as causative agents of disease in birds: The paratyphoid bacteria. RarebooksCLub. pp. 174–180. ISBN 1236439406..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} Strains of the species have also been isolated from nematodes.
# Pathogenicity
Providencia rettgeri can cause a number of opportunistic infections in humans and can be found in the human gut. It is a major cause of traveller's diarrhea. Strains of P. rettgeri have also been found to cause urinary tract infections and eye infections.
# Diagnosis and Testing
P. rettgeri can be identified by its motility and its ability to produce acid from mannitol. It does not produce gas from glucose and does not ferment lactose. It also does not produce hydrogen sulfide or acid from xylose.
# Gallery
- Providencia alcalifaciens bacteria cultured on a blood agar plate (BAP). From Public Health Image Library (PHIL).
## Antimicrobial Regimen
- Providencia
- 1. Complicated uti/bacteremia/acute prostatitis
- Preferred regimen (1): Ciprofloxacin 500-750 mg PO q12h or 400 mg IV q8-12h
- Preferred regimen (2): Levofloxacin 500 mg IV/PO q24h
- Preferred regimen (3): Piperacillin-Tazobactam 3.375 mg IV q6h
- Preferred regimen (4): Ceftriaxone 1-2 g IV q24h (donot use if ESBL suspected or critically ill)
- Preferred regimen (5): Meropenem 1 g IV q8h (consider if critically ill or ESBL suspected)
- Preferred regimen (6): Amikacin 7.5 mg/kg IV q12h
- Preferred regimen (7): Gentamicin
- Preferred regimen (8): Tobramycin acceptable if susceptible but many species are resistant
- Note (1): Duration of treatment for (UTI) is 7 days common or 3-5 days after defervescence or control/elimination of complicating factors (e.g.,removal of foreign material catheter).
- Note (2): Duration of treatment for (bacteremia) is 10-14 days or 3-5 days after defervescence or control/elimination of complicating factors.
- Note (3): Duration for acute prostatitis (2 weeks), shorter than chronic prostatitis (4-6 weeks).
- Alternative regimen: TMP-SMX DS PO q12h for 10-14 days or TMP 5-10 mg/kg/day IV q6h | Providencia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Providencia is a Gram negative, motile bacterium of the family Enterobacteriaceae. Some strains (P. stuartii, for example) are opportunistic pathogens in humans and can cause urinary tract infections, particularly in patients with long-term indwelling urinary catheters or extensive severe burns. Other strains (for example P. burhodogranariea and P. sneebia) are found in the haemolymph of Drosophila melanogaster fruit flies.
Some strains are sensitive to ampicillin.
# Organism
Providencia stuartii is the most common Providencia species capable of causing human infections. Providencia stuartii is an opportunistic pathogen seen in patients with severe burns or long-term indwelling urinary catheters. This puts elderly individuals at a greater risk for P. stuartii infections. In animals P. stuartii infections can cause neonatal diarrhea due to P. stuartii infection in dairy cows. In humans, P. stuartii can be isolated from urine (most common), stool, and blood, as well as from sputum, skin, and wound cultures. P. stuartii septicemia is primarily of urinary origin. It is the most common cause of purple urine bag syndrome.[1] Upon physical examination, P stuartii bloodstream infection is associated with fever, tachycardia, and hypotension.
Providencia rettgeri (commonly P. rettgeri), is a Gram negative bacterium that is commonly found in both water and land environments. P. rettgeri can be incubated at 37 °C in nutrient agar or nutrient broth. It was first discovered in 1904 after a waterfowl epidemic.Hadley, Phillip (1908). The colon-typhoid intermediates as causative agents of disease in birds: The paratyphoid bacteria. RarebooksCLub. pp. 174–180. ISBN 1236439406..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} Strains of the species have also been isolated from nematodes.[2]
# Pathogenicity
Providencia rettgeri can cause a number of opportunistic infections in humans and can be found in the human gut. It is a major cause of traveller's diarrhea.[3] Strains of P. rettgeri have also been found to cause urinary tract infections[4] and eye infections.[5]
# Diagnosis and Testing
P. rettgeri can be identified by its motility and its ability to produce acid from mannitol. It does not produce gas from glucose and does not ferment lactose. It also does not produce hydrogen sulfide or acid from xylose.
# Gallery
- Providencia alcalifaciens bacteria cultured on a blood agar plate (BAP). From Public Health Image Library (PHIL). [6]
## Antimicrobial Regimen
- Providencia[7]
- 1. Complicated uti/bacteremia/acute prostatitis
- Preferred regimen (1): Ciprofloxacin 500-750 mg PO q12h or 400 mg IV q8-12h
- Preferred regimen (2): Levofloxacin 500 mg IV/PO q24h
- Preferred regimen (3): Piperacillin-Tazobactam 3.375 mg IV q6h
- Preferred regimen (4): Ceftriaxone 1-2 g IV q24h (donot use if ESBL suspected or critically ill)
- Preferred regimen (5): Meropenem 1 g IV q8h (consider if critically ill or ESBL suspected)
- Preferred regimen (6): Amikacin 7.5 mg/kg IV q12h
- Preferred regimen (7): Gentamicin
- Preferred regimen (8): Tobramycin acceptable if susceptible but many species are resistant
- Note (1): Duration of treatment for (UTI) is 7 days common or 3-5 days after defervescence or control/elimination of complicating factors (e.g.,removal of foreign material catheter).
- Note (2): Duration of treatment for (bacteremia) is 10-14 days or 3-5 days after defervescence or control/elimination of complicating factors.
- Note (3): Duration for acute prostatitis (2 weeks), shorter than chronic prostatitis (4-6 weeks).
- Alternative regimen: TMP-SMX DS PO q12h for 10-14 days or TMP 5-10 mg/kg/day IV q6h | https://www.wikidoc.org/index.php/Providencia | |
00d7c8639561a711e188f66e465759efd7ce391f | wikidoc | Pseudopolyp | Pseudopolyp
# Overview
Pseudopolyps are projecting mass of scar tissue, that develops from granulation tissue during the healing phase in repeated cycle of ulceration (especially in inflammatory bowel disease). Inflammatory tissue without malignant potential, pseudopolyps may, according to Joffe (1977), represent either regenerating mucosal islands between areas of ulceration, oedematous polypoid tags or granulation tissue covered by epithelium. There are reported casese when localized giant pseudopolyposis resulted in intestinal obstruction.
Residual mucosal islands between ulcerated and denuded areas of mucosa may have a polypoid appearance and are referred to as pseudopolyps. Polyposis syndromes, such as familial adenomatous polyposis, could give rise to a similar appearance on imaging, although the clinical presentation would differ from that of inflammatory pseudopolyposis.
Numerous, confluent ulcerations with bulging of the edematous residual mucosa determine a cobblestone appearance at endoscopy. | Pseudopolyp
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Pseudopolyps are projecting mass of scar tissue, that develops from granulation tissue during the healing phase in repeated cycle of ulceration (especially in inflammatory bowel disease). Inflammatory tissue without malignant potential,[1] pseudopolyps may, according to Joffe (1977), represent either regenerating mucosal islands between areas of ulceration, oedematous polypoid tags or granulation tissue covered by epithelium. There are reported casese when localized giant pseudopolyposis resulted in intestinal obstruction. [2]
Residual mucosal islands between ulcerated and denuded areas of mucosa may have a polypoid appearance and are referred to as pseudopolyps.[3] Polyposis syndromes, such as familial adenomatous polyposis, could give rise to a similar appearance on imaging, although the clinical presentation would differ from that of inflammatory pseudopolyposis.[4]
Numerous, confluent ulcerations with bulging of the edematous residual mucosa determine a cobblestone appearance at endoscopy.[5] [6] | https://www.wikidoc.org/index.php/Pseudopolyp | |
5d13a53c450d1bdecd8365b9202d1fa7226aba5a | wikidoc | Psychopathy | Psychopathy
# Overview
Psychopathy is a psychological construct that describes chronic immoral and antisocial behavior. The term is often used interchangeably with sociopathy. Psychopathy has been the most studied of any personality disorder. Today the term can legitimately be used in two ways. One is in the legal sense, "psychopathic personality disorder" under the Mental Health Act 1983 of the UK. The other use is as a severe form of the antisocial or dissocial personality disorder as exclusively defined by the Psychopathy Checklist-Revised (PCL-R). The term "psychopathy" is often confused with psychotic disorders. It is estimated that approximately one percent of the general population are psychopaths. They are overrepresented in prison systems, politics, law enforcement agencies, law firms, and in the media.
The psychopath is defined by a continual seeking of instant gratification in criminal, sexual, or aggressive impulses. It is frequently co-morbid with other psychological disorders (particularly narcissistic personality disorder). The psychopath differs slightly from the sociopath, and even more so from an individual with antisocial personality disorder. Nevertheless, the three are frequently used interchangeably. While nearly all psychopaths have antisocial personality disorder, only some individuals with antisocial personality disorder are psychopaths. Many psychologists believe that psychopathy falls on a spectrum of disorders ranging from narcissistic personality disorder on the low end, malignant narcissism in the middle, and psychopathy on the high end. An almost all-pervasive misconception is that psychopaths are doomed to a life of violence and crime. It is possible for psychopaths to become successful in many lines of work, while many also become lazy underachievers. Psychopathy is frequently mistaken with other similar personality disorders, such as dissocial personality disorder, narcissistic personality disorder, and schizoid personality disorder (as well as others).
# History
Interest in the psychopathic personality pattern goes back to colonial times. In those times, a person with a mental illness such as psychopathy would be reasoned as a subject of demonic possession. It also goes back to Theophrastus . In 1801, Philippe Pinel described patients who were mentally unimpaired but nonetheless engaged in impulsive and self-defeating acts. He saw them as la folie raisonnante ("insane without delirium") meaning that they fully understood the irrationality of their behavior but continued with it anyway. Pinel was one of the last to study psychopathic personalities without including a moral judgment in his diagnosis. By the turn of the century, Henry Maudsley had begun writing about the moral imbecile, and was arguing that such individuals could not be rehabilitated by the correctional system.
Maudsley included the psychopath's immunity to the reformational effects of punishment, owing to their refusal to anticipate further failure, and punishment. In 1904, Emil Kraepelin described four types of personalities similar to the antisocial personality disorder. By 1915 he had identified them as defective in either effect or volition, dividing the types further into categories only some of which correspond to the current descriptions of antisocial.
The Mask of Sanity by Hervey Cleckley, M.D., first published in 1941, is considered a seminal work and the most influential clinical description of psychopathy in the 20th century. The basic elements of psychopathy outlined by Cleckley are still relevant today. The title refers to the normal "mask" that conceals the mental disorder of the psychopathic person in Cleckley's conceptualization.
Otto Kernberg believed that psychopathy should fall under a spectrum of pathological narcissism, that ranged from narcissitic personality on the low end, malignant narcissism in the middle, and psychopathy at the high end. Because of the psychopaths inability to internalize superego precursors, they are unable to learn from past mistakes, and are completely devoid of a conscience. This trait in conjunction with an inability to control criminal, sexual and aggressive desires, leads to the psychopath to constantly engage in antisocial behaviors. Psychopathy (in its extreme form) does not necessarily lead itself to criminal and violent behavior (although such tendencies are likely). Instead, psychopaths high in social cognition may be able to redirect their aggressive and sexual desires in a more positive manner. Psychopaths (and others on the pathological narcissism scale) low in social cognition are more prone to violence against others, failure in occupational settings, and problems maintaining relationships. All psychopaths differ in their impulse control abilities, and overall desires. Psychopaths high in the pathological narcissism scale are more equipped to succeed, but pathological narcissism does not in any way guarantee success. Those that fall into the category of psychopath are vulnerable to a life of crime, poverty, and extremely poor interpersonal relationships.
Psychopathy in its extreme form offers very few benefits. Such benefits include lack of anxiety/nervousness, the ability to lead and control others without concerns of failure, and the ability to stay calm in extremely difficult situations. These benefits mixed in with pathological narcissism and high levels of social cognition may lead to the psychopath becoming an extremely effective leader. Again, this occurs only in rare circumstances.
# Hare and psychopathy
In contemporary research, psychopathy has been most frequently operationalized by Dr. Robert D. Hare’s Psychopathy Checklist-Revised (PCL-R). The checklist assesses both interpersonal and affective components as well as lifestyle and antisocial deficits. However, the research results cannot be easily extrapolated to the clinical diagnoses of dissocial personality disorder or antisocial personality disorder. A sample research finding is that between 50 percent and 80 percent of prisoners in England and Wales meet the diagnostic criteria of dissocial personality disorder, but only 15 percent would be predicted to be psychopathic as measured by the PCL-R. Therefore, the findings drawn from psychopathy research have not yet been shown to be relevant as an aid to diagnosis and treatment of dissocial or antisocial personality disorders.
## Hare's items
The following findings are for research purposes only, and are not used in clinical diagnosis. These items cover the affective, interpersonal, and behavioral features. Each item is rated on a score from zero to two. The sum total determines the extent of a person's psychopathy.
Factor1: Aggressive narcissism
- Glibness / superficial charm
- Grandiose sense of self-worth
- Pathological lying
- Cunning / manipulative
- Lack of remorse or guilt
- Shallow
- Callous / lack of empathy
- Failure to accept responsibility for own actions
Factor2: Socially deviant lifestyle
- Need for stimulation / proneness to boredom
- Parasitic lifestyle
- Poor behavioral control
- Lack of realistic, long-term goals
- Impulsivity
- Irresponsibility
- Juvenile delinquency
- Early behavior problems
- Revocation of conditional release
Traits not correlated with either factor
- Many short-term marital relationships
- Promiscuous sexual behavior
- Criminal versatility
In practice, mental health professional rarely treat psychopathic personality disorders as they are considered untreatable and no interventions have proved to be effective.In England and Wales the diagnosis of dissocial personality disorder is grounds for detention in secure psychiatric hospitals under the Mental Health Act if they have committed serious crimes, but since such individuals are disruptive for other patients and not responsive to treatment this alternative to prison is not often used.
Because an individual's scores may have important consequences for his or her future, the potential for harm if the test is used or administered incorrectly is considerable. The test should only be considered valid if administered by a suitably qualified and experienced clinician under controlled conditions.
Hare wants the Diagnostic and Statistical Manual of Mental Disorders to list psychopathy as a unique disorder, saying that psychopathy has no precise equivalent in either the DSM-IV-TR, where it is most strongly correlated with the diagnosis of antisocial personality disorder, or the ICD-10, which has a partly similar condition called dissocial personality disorder. Both organisations view the terms as synonymous. But only a minority of what Hare and his followers would diagnose as psychopaths who are in institutions are violent offenders. The manipulative skills of some of the others are valued for providing audacious leadership. It is argued that psychopathy is adaptive in a highly competitive environment, because it gets results for both the individual and the corporations or, often small political sects that they represent. However, these individuals will often cause long-term harm, both to their co-workers and the organization as a whole, due their manipulative, deceitful, abusive, and often fraudulent behaviour.
Hare describes people he calls psychopaths as "intraspecies predators who use charm, manipulation, intimidation, sex and violence to control others and to satisfy their own selfish needs. Lacking in conscience and empathy, they take what they want and do as they please, violating social norms and expectations without guilt or remorse". "What is missing, in other words, are the very qualities that allow a human being to live in social harmony."
## PCL-R Factors
Early factor analysis of the PCL-R indicated that it consisted of two factors. Factor 1 capture traits dealing with the interpersonal and affective deficits of psychopathy (e.g. shallow affect, superficial charm, manipulativeness, lack of empathy) whereas Factor 2 dealt with symptoms relating to antisocial behaviour (e.g. criminal versatility, impulsiveness, irresponsibility, poor behaviour controls, juvenile delinquency). The two factors have been found by those following this theory to display different correlates. Factor 1 has been correlated with narcissistic personality disorder, low anxiety, low empathy , low stress reaction and low suicide risk but high scores on scales of achievement and well-being. In contrast, Factor 2 was found to be related to antisocial personality disorder, social deviance, sensation seeking, low socio-economic status and high risk of suicide . The two factors are nonetheless highly correlated and there are strong indications that they do result from a single underlying disorder. However, research has failed to replicate the two-factor model in female samples.
Recent statistical analysis using confirmatory factor analysis by Cooke and Michie indicated a three-factor structure, with those items from factor 2 strictly relating to antisocial behaviour (criminal versatility, juvenile delinquency, revocation of conditional release, early behavioural problems and poor behavioural controls) removed from the final model. The remain items divided into three factors: Arrogant and Deceitful Interpersonal Style, Deficient Affective Experience and Impulsive and Irresponsible Behavioural Style . In the most recent edition of the PCL-R, Hare adds a fourth antisocial behaviour factor, consisting of those Factor 2 items excluded in the previous model . Again, these models are presumed to be hierarchical with a single unified psychopathy disorder underlying the distinct but correlated factors.
### Diagnostic criteria and PCL-R assessment
Hare's PCL-R has allowed for a differentiation between individuals with psychopathy and antisocial personality disorder (APD).
In contemporary research and clinical psychiatric practice, the American Psychiatric Association use the DSM and European doctors use the ICD-10 and will use the term antisocial personality disorder. Psychopathy is most commonly assessed by those who subscribe to a separate idea of psychopathy with the PCL-R, which is a clinical rating scale with 20 items. Each of the items in the PCL-R is scored on a three-point (0, 1, 2) scale according to two factors. PCL-R Factor 2 is associated with reactive anger, anxiety, increased risk of suicide, criminality, and impulsive violence. PCL-R Factor 1, in contrast, is associated with extroversion and positive affect. Factor 1, the so-called core personality traits of psychopathy, may even be beneficial for the psychopath (in terms of nondeviant social functioning). A psychopath will score high on both factors, whereas someone with APD will score high only on Factor 2.
Both case history and a semi-structured interview are used in the analysis.
# Legal definition (Sexual predators)
Psychopathy has quite separate legal and judicial definitions that should not be confused with the medical definition. The American Psychiatric Association is vigorously opposing any non-medical or legal definition of what purports to be a medical condition "without regard for scientific and clinical knowledge". Various states and nations have at various times enacted laws specific to dealing with psychopaths. In the United States approximately twenty states currently have provisions for the involuntary civil commitment for sex offenders or sexual predators, under Sexually violent predator acts, avoiding the use of the term "psychopath". These statutes and provisions are controversial and are being reviewed by the U.S. Supreme Court as a violation of a person's Fourteenth Amendment rights. (See Foucha v. Louisiana for an example.)
- Washington State Legislature defines a "Psychopathic personality" to mean "the existence in any person of such hereditary, congenital or acquired condition affecting the emotional or volitional rather than the intellectual field and manifested by anomalies of such character as to render satisfactory social adjustment of such person difficult or impossible". The same statute defines the "sexual psychopath" as "any person who is affected in a form of psychoneurosis or in a form of psychopathic personality, which form predisposes such person to the commission of sexual offenses in a degree constituting him a menace to the health or safety of others" for prison sentencing purposes in the Sentencing Reform Act of 1981.
- California enacted a psychopathic offender law in 1939, since greatly outmodeled and revised. that defined a psychopath solely in terms of offenders with a predisposition "to the commission of sexual offenses against children." A 1941 law attempted to further clarify this to the point where anyone examined and found to be psychopathic was to be committed to a state hospital and anyone else was to be sentenced by the courts. However, these laws were enacted years before the American Psychiatric Association began publishing the Diagnostic and Statistical Manual of Mental Disorders which is used today for diagnosis and does not include "psychopathic offender". Hence, these laws are of historical interest only.
- In the United Kingdom, "Psychopathic Disorder" is legally defined in the Mental Health Act (UK) as, "a persistent disorder or disability of mind (whether or not including significant impairment of intelligence) which results in abnormally aggressive or seriously irresponsible conduct on the part of the person concerned."
According to Jay Ziskin any diagnosis that does not appear in DSM III is not a formal diagnoses for legal uses, as shown in a quote from Coping with Psychiatric and Psychological Testimony Vol II by Jay Ziskin which is a book for attorneys to shoot down psychiatric testimony in the United States.
One should note whether the report contains a formal diagnosis......Those that do not are weakened......One can usually spot a formal diagnosis by the presence of a code number, usually a three-digit number, sometimes with additional digits ... although in some cases, psychiatrists will state what turns out to be a formal diagnosis without using the code numbers. Where there is a formal diagnosis, one should check to see if it is one of those listed in the diagnostic and statistical manual (DSM-III). .......the lawyer ... should check the manual for the elements required for making that diagnosis and then check to see if the report describes those elements.....If there is a diagnosis, but it is not from DSM-III, this is a matter to be questioned as there is only one official diagnositic classification system and it is DSM-III.
# Subtypes of psychopathy
## The Primary–Secondary distinction
Primary psychopathy was defined by those following this theory as the root disorder in patients diagnosed with it, whereas secondary psychopathy was defined as an aspect of another psychiatric disorder or social circumstances. Today, primary psychopaths are considered to have mostly Factor 1 traits from the PCL-R (arrogance, callousness, manipulativeness, lying) whereas secondary psychopaths have a majority of Factor 2 traits (impulsivity, boredom proneness, irresponsibility, lack of long-term goals).Secondary psychopaths show normal to above-normal physiological responses to (perceived) potential threats. Their crimes tend to be unplanned and impulsive with little thought of the consequences. Including to those using this theory, this type have hot tempers and are prone to reactive aggression. They experience normal to above-normal levels of anxiety but are nevertheless highly stimulus seeking and have trouble tolerating boredom. Their lifestyle may lead to depression and even suicide.
Mealey uses the term "primary psychopathy" to differentiate between psychopathy that is biological in origin and "secondary psychopathy" that results from a combination of genetic and environmental influences. Lykken prefers sociopathy to describe the latter.
Sellbom and Ben-Porath (2005) describe the distinction:
This distinction closely resembles the distinction between instrumental and impulsive/reactive crime/violence in the field of criminology.
Joseph P. Newman et al, who use this concept of psychopathy, have validated David T. Lykken's conceptualization of psychopathy subtypes in relation to Gray's behavioral activation system and behavioral inhibition system. Newman et al. found measures of primary psychopathy to be negatively correlated with Gray's behavioral inhibition system, a construct intended to measure behavioral inhibition from cues of punishment or nonreward. In contrast, measures of secondary psychopathy to be positively correlated with Gray's behavioral activation system, a construct intended to measure sensitivity to cues of behavioral approach.
# Relationship to other terms
## Relationship to sociopathy
The difference between sociopathy and psychopathy, according to Hare, may "reflect the user's views on the origins and determinates of the disorder."
David T. Lykken proposes that psychopathy and sociopathy are two distinct kinds of antisocial personality disorder. He holds that psychopaths are born with temperamental differences such as impulsivity, cortical underarousal, and fearlessness that lead them to risk-seeking behavior and an inability to internalize social norms. Sociopaths, on the other hand, he believes to have relatively normal temperaments; their personality disorder being more an effect of negative sociological factors like parental neglect, delinquent peers, poverty, and extremely low or extremely high intelligence. Both personality disorders are, of course, the result of an interaction between genetic predispositions and environmental factors, but psychopathy leans towards the hereditary whereas sociopathy tends towards the environmental.
## Relationship to Antisocial personality disorder
The criteria for the Antisocial Personality Disorder were derived from the Research Diagnositic Criteria developed by Spitzer, Endicott and Robbins (1978). There was concern in the development of DSM-IV that there was too much emphasis on research data and not enough on the more traditional psychopathic traits such as a lack of empathy, superficial charm, and inflated self appraisal. Field trial data indicated that some of these traits of psychopathy derived from the Psychopathy Checklist developed by Hare et al., 1992, were difficult to assess reliably and thus were not included. Lack of remorse is an example. The antisocial person may express genuine or false guilt or remorse and/or offer excuses and rationalizations. However, a history of criminal acts in itself suggests little remorse or guilt.
The American Psychiatric Association removed the word "psychopathy" or "psychopathic", and started using the term "Antisocial Personality" to cover the disorder in DSM-II.
The World Health Organization's stance in its ICD-10 refers to psychopathy, sociopathy, antisocial personality, asocial personality, and amoral personality as synonyms for dissocial personality disorder. Further, the DSM was meant as a diagnostic guide, and the term psychopath best fit the criteria met for antisocial personality disorder.
# Research findings
The prototypical psychopath has deficits or deviances in several areas: interpersonal relationships, emotion, and self-control. Psychopaths lack a sense of guilt or remorse for any harm they may have caused others, instead rationalizing the behavior, blaming someone else, or denying it outright. Psychopaths also lack empathy towards others in general, resulting in tactlessness, insensitivity, and contemptuousness. All of this belies their tendency to make a good, likable first impression. Psychopaths have a superficial charm about them, enabled by a willingness to say anything without concern for accuracy or truth.
This extends into their pathological lying and willingness to con and manipulate others for personal gain or amusement. The prototypical psychopath's emotions are described as a shallow affect, meaning their overall way of relating is characterized by mere displays of friendliness and other emotion for personal gain; the displayed emotion need not correlate with felt emotion, in other words.
Shallow affect also describes the psychopath's tendency for genuine emotion to be short lived and egocentric with an overall cold demeanor. Their behavior is impulsive and irresponsible, often failing to keep a job or defaulting on debts.
Most research studies of psychopaths have taken place among prison populations. This remains a limitation on its applicability to a general population.
It has been shown that punishment and behavior modification techniques do not improve the behavior of what Hare and other followers of this theory call a psychopath. They have been regularly observed to respond to both by becoming more cunning and hiding their behavior better. It has been suggested by them that traditional therapeutic approaches actually make psychopaths if not worse, then far more adept at manipulating others and concealing their behavior. They are generally considered to be not only incurable but also untreatable.
Psychopaths also have a markedly distorted sense of the potential consequences of their actions, not only for others, but also for themselves. They do not, for example, deeply recognize the risk of being caught, disbelieved or injured as a result of their behaviour.
## Relation to sex offenders
No clinical definition of psychopathy indicates that psychopaths are especially prone to commit sexually-oriented murders, and scientific studies do not suggest that a large proportion of psychopaths have committed these crimes. Although some claim a large proportion of such offenders have been classified as psychopathic, this evidence comes from single, unrepeated research study using the Rorschach Inkblot Test, an invalid test for psychopathy and for sex offenders, references not considering psychopathy , and studies concerning sexual homicide, a somewhat different population that the general class of sex offenders. and not from meta studies combining repeatable results.
## Childhood precursors
Psychopathy is not normally diagnosed in children or adolescents, and some jurisdictions explicitly forbid diagnosing psychopathy and similar personality disorders in minors. Psychopathic tendencies can sometimes be recognized in childhood or early adolescence and, if recognised, are diagnosed as conduct disorder. It must be stressed that not all children diagnosed with conduct disorder grow up to be psychopaths, or even disordered at all, but these childhood signs are found in significantly higher proportions in psychopaths than in the general population. Conduct disorder, as well as a related disorder, Oppositional Defiant Disorder, can sometimes develop into adult psychopathy. However, conduct disorder "fails to capture the emotional, cognitive and interpersonality traits - egocentricity, lack of remorse, empathy or guilt - that are so important in the diagnosis of psychopathy."
Children showing strong psychopathic precursors often appear immune to punishment; nothing seems to modify their undesirable behavior. Consequently parents usually give up, and the behavior worsens.
The following childhood indicators are to be seen not as to the type of behavior, but as to its relentless and unvarying occurrence. Not all must be present concurrently, but at least a number of them need to be present over a period of years:
- An extended period of bedwetting past the preschool years that is not due to any medical problem.
- Cruelty to animals beyond an angry outburst.
- Firesetting and other vandalism. Not to be confused with playing with matches, which is not uncommon for preschoolers. This is the deliberate setting of destructive fires with utter disregard for the property and lives of others.
- Lying, often without discernible objectives, extending beyond a child's normal impulse not to be punished. Lies that are so extensive that it is often impossible to know lies from truth.
- Theft and truancy.
- Aggression to peers, not necessarily physical, which can include getting others into trouble or a campaign of psychological torment.
The three indicators—bedwetting, cruelty to animals and firestarting, known as the MacDonald triad—were first described by J.M. MacDonald as indicators of psychopathy. The relevance of these indicators to serial murder etiology has since been called into question, and they are considered irrelevant to psychopathy.
The question of whether young children with early indicators of psychopathy respond poorly to intervention compared to conduct disordered children without these traits has only recently been examined in controlled clinical research. The empirical findings from this research have been consistent with broader anecdotal evidence, pointing to poor treatment outcomes.
## Discrete vs. continuous dimension
As part of the larger debate on whether personality disorders are distinct from normal personality or extremes on various dimensions of normal personality is the debate on whether psychopathy represents something "qualitatively different" from normal personality or a "continuous dimension" shading from normality into severely psychopathic. Early taxonometric analysis from Harris and colleagues indicated that a discrete category may underlie psychopathy, however this was only found for the behavioural Factor 2 items, indicating that this analysis may be related to Anti-social Personality Disorder rather than psychopathy per se. Marcus, John, and Edens more recently performed a series of statistical analysis on previously attained PCL–R and PPI scores and concluded that psychopathy may best be conceptualized as having a "dimensional latent structure" like depression.
In contrast, the PCL–R sets a score of 30 out of 40 for North American male inmates as its cut-off point for a diagnosis of psychopathy, however this is an abitrary cut-off and should not be taken to reflect any sort of underlying structure for the disorder.
## Perceptual/emotional recognition deficits
In a 2002 study, David Kosson and Yana Suchy, et al. asked psychopathic inmates to name the emotion expressed on each of 30 faces; compared to controls, psychopaths had a significantly lower rate of accuracy in recognizing disgusted facial affect but a higher rate of accuracy in recognizing anger. Additionally, when "conditions designed to minimize the involvement of left-hemispheric mechanisms" (i.e. sadness) were used, psychopaths had more difficulty accurately identifying emotions. This study did not replicate Blaire, et al. (1997)'s findings that psychopaths are specifically less sensitive to nonverbal cues of fear or distress.
In a 2002 experiment, Blair, Mitchell, et al. used the Vocal Affect Recognition Test to measure psychopaths' recognition of the emotional intonation given to connotatively neutral words. Psychopaths tended to make more recognition errors than controls with a particularly high rate of error for sad and fearful vocal affect.
A 2004 experiment tested the hypothesis of overselective attention in psychopaths using two forms of the Stroop color-word and picture-word tasks: with color/picture and word separated and with color/picture and word together. They found that in the separated Stroop tasks, psychopaths performed significantly worse than controls; however, on standard Stroop tasks, psychopaths performed equally well as controls.
When split into low-anxious and high-anxious groups, low-anxious psychopaths and low-anxious controls showed less interference on the separated Stroop tasks than their high-anxious counterparts; for low-anxious psychopaths, interference was very nearly zero. They conclude that the inability to integrate contextual cues depends on the cues' relationship to "the deliberately attended, goal-relevant information." | Psychopathy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]
# Overview
Psychopathy is a psychological construct that describes chronic immoral and antisocial behavior.[1] The term is often used interchangeably with sociopathy[2]. Psychopathy has been the most studied of any personality disorder. Today the term can legitimately be used in two ways. One is in the legal sense, "psychopathic personality disorder" under the Mental Health Act 1983 of the UK. The other use is as a severe form of the antisocial or dissocial personality disorder as exclusively defined by the Psychopathy Checklist-Revised (PCL-R).[3] The term "psychopathy" is often confused with psychotic disorders. It is estimated that approximately one percent of the general population are psychopaths. They are overrepresented in prison systems, politics, law enforcement agencies, law firms, and in the media.[4][5][6]
The psychopath is defined by a continual seeking of instant gratification in criminal, sexual, or aggressive impulses. It is frequently co-morbid with other psychological disorders (particularly narcissistic personality disorder). The psychopath differs slightly from the sociopath, and even more so from an individual with antisocial personality disorder. Nevertheless, the three are frequently used interchangeably. While nearly all psychopaths have antisocial personality disorder, only some individuals with antisocial personality disorder are psychopaths. Many psychologists believe that psychopathy falls on a spectrum of disorders ranging from narcissistic personality disorder on the low end, malignant narcissism in the middle, and psychopathy on the high end. An almost all-pervasive misconception is that psychopaths are doomed to a life of violence and crime. It is possible for psychopaths to become successful in many lines of work, while many also become lazy underachievers. Psychopathy is frequently mistaken with other similar personality disorders, such as dissocial personality disorder, narcissistic personality disorder, and schizoid personality disorder (as well as others).
# History
Template:Expand
Interest in the psychopathic personality pattern goes back to colonial times. In those times, a person with a mental illness such as psychopathy would be reasoned as a subject of demonic possession. It also goes back to Theophrastus [7]. In 1801, Philippe Pinel described patients who were mentally unimpaired but nonetheless engaged in impulsive and self-defeating acts. He saw them as la folie raisonnante ("insane without delirium") meaning that they fully understood the irrationality of their behavior but continued with it anyway. Pinel was one of the last to study psychopathic personalities without including a moral judgment in his diagnosis. By the turn of the century, Henry Maudsley had begun writing about the moral imbecile, and was arguing that such individuals could not be rehabilitated by the correctional system.[8]
Maudsley included the psychopath's immunity to the reformational effects of punishment, owing to their refusal to anticipate further failure, and punishment. In 1904, Emil Kraepelin described four types of personalities similar to the antisocial personality disorder. By 1915 he had identified them as defective in either effect or volition, dividing the types further into categories only some of which correspond to the current descriptions of antisocial.[9]
The Mask of Sanity by Hervey Cleckley, M.D., first published in 1941, is considered a seminal work and the most influential clinical description of psychopathy in the 20th century. The basic elements of psychopathy outlined by Cleckley are still relevant today.[10] The title refers to the normal "mask" that conceals the mental disorder of the psychopathic person in Cleckley's conceptualization.[11]
Otto Kernberg believed that psychopathy should fall under a spectrum of pathological narcissism, that ranged from narcissitic personality on the low end, malignant narcissism in the middle, and psychopathy at the high end.[12] Because of the psychopaths inability to internalize superego precursors, they are unable to learn from past mistakes, and are completely devoid of a conscience. This trait in conjunction with an inability to control criminal, sexual and aggressive desires, leads to the psychopath to constantly engage in antisocial behaviors. Psychopathy (in its extreme form) does not necessarily lead itself to criminal and violent behavior (although such tendencies are likely). Instead, psychopaths high in social cognition may be able to redirect their aggressive and sexual desires in a more positive manner. Psychopaths (and others on the pathological narcissism scale) low in social cognition are more prone to violence against others, failure in occupational settings, and problems maintaining relationships. All psychopaths differ in their impulse control abilities, and overall desires. Psychopaths high in the pathological narcissism scale are more equipped to succeed, but pathological narcissism does not in any way guarantee success. Those that fall into the category of psychopath are vulnerable to a life of crime, poverty, and extremely poor interpersonal relationships.[citation needed]
Psychopathy in its extreme form offers very few benefits. Such benefits include lack of anxiety/nervousness, the ability to lead and control others without concerns of failure, and the ability to stay calm in extremely difficult situations. These benefits mixed in with pathological narcissism and high levels of social cognition may lead to the psychopath becoming an extremely effective leader. Again, this occurs only in rare circumstances.[citation needed]
# Hare and psychopathy
In contemporary research, psychopathy has been most frequently operationalized by Dr. Robert D. Hare’s Psychopathy Checklist-Revised (PCL-R). The checklist assesses both interpersonal and affective components as well as lifestyle and antisocial deficits. However, the research results cannot be easily extrapolated to the clinical diagnoses of dissocial personality disorder or antisocial personality disorder. A sample research finding is that between 50 percent and 80 percent of prisoners in England and Wales meet the diagnostic criteria of dissocial personality disorder, but only 15 percent would be predicted to be psychopathic as measured by the PCL-R. Therefore, the findings drawn from psychopathy research have not yet been shown to be relevant as an aid to diagnosis and treatment of dissocial or antisocial personality disorders.[13]
## Hare's items
The following findings are for research purposes only, and are not used in clinical diagnosis. These items cover the affective, interpersonal, and behavioral features. Each item is rated on a score from zero to two. The sum total determines the extent of a person's psychopathy.[3]
Factor1: Aggressive narcissism
- Glibness / superficial charm
- Grandiose sense of self-worth
- Pathological lying
- Cunning / manipulative
- Lack of remorse or guilt
- Shallow
- Callous / lack of empathy
- Failure to accept responsibility for own actions
Factor2: Socially deviant lifestyle
- Need for stimulation / proneness to boredom
- Parasitic lifestyle
- Poor behavioral control
- Lack of realistic, long-term goals
- Impulsivity
- Irresponsibility
- Juvenile delinquency
- Early behavior problems
- Revocation of conditional release
Traits not correlated with either factor
- Many short-term marital relationships
- Promiscuous sexual behavior
- Criminal versatility
In practice, mental health professional rarely treat psychopathic personality disorders as they are considered untreatable and no interventions have proved to be effective.[14]In England and Wales the diagnosis of dissocial personality disorder is grounds for detention in secure psychiatric hospitals under the Mental Health Act if they have committed serious crimes, but since such individuals are disruptive for other patients and not responsive to treatment this alternative to prison is not often used.[15]
Because an individual's scores may have important consequences for his or her future, the potential for harm if the test is used or administered incorrectly is considerable. The test should only be considered valid if administered by a suitably qualified and experienced clinician under controlled conditions. [16][17]
Hare wants the Diagnostic and Statistical Manual of Mental Disorders to list psychopathy as a unique disorder, saying that psychopathy has no precise equivalent[16] in either the DSM-IV-TR, where it is most strongly correlated with the diagnosis of antisocial personality disorder, or the ICD-10, which has a partly similar condition called dissocial personality disorder. Both organisations view the terms as synonymous. But only a minority of what Hare and his followers would diagnose as psychopaths who are in institutions are violent offenders.[18][19] The manipulative skills of some of the others are valued for providing audacious leadership.[20] It is argued that psychopathy is adaptive in a highly competitive environment, because it gets results for both the individual and the corporations[21][22][23] or, often small political sects that they represent.[24] However, these individuals will often cause long-term harm, both to their co-workers and the organization as a whole, due their manipulative, deceitful, abusive, and often fraudulent behaviour.[25]
Hare describes people he calls psychopaths as "intraspecies predators[26][27] who use charm, manipulation, intimidation, sex and violence[28][29][30] to control others and to satisfy their own selfish needs. Lacking in conscience and empathy, they take what they want and do as they please, violating social norms and expectations without guilt or remorse".[17] "What is missing, in other words, are the very qualities that allow a human being to live in social harmony."[31]
## PCL-R Factors
Early factor analysis of the PCL-R indicated that it consisted of two factors. [32] Factor 1 capture traits dealing with the interpersonal and affective deficits of psychopathy (e.g. shallow affect, superficial charm, manipulativeness, lack of empathy) whereas Factor 2 dealt with symptoms relating to antisocial behaviour (e.g. criminal versatility, impulsiveness, irresponsibility, poor behaviour controls, juvenile delinquency).[32] The two factors have been found by those following this theory to display different correlates. Factor 1 has been correlated with narcissistic personality disorder[32], low anxiety[32], low empathy [33], low stress reaction [34] and low suicide risk[34] but high scores on scales of achievement[34] and well-being[34]. In contrast, Factor 2 was found to be related to antisocial personality disorder[32], social deviance[32], sensation seeking[32], low socio-economic status [32] and high risk of suicide [34]. The two factors are nonetheless highly correlated[32] and there are strong indications that they do result from a single underlying disorder.[35] However, research has failed to replicate the two-factor model in female samples. [36]
Recent statistical analysis using confirmatory factor analysis by Cooke and Michie [37] indicated a three-factor structure, with those items from factor 2 strictly relating to antisocial behaviour (criminal versatility, juvenile delinquency, revocation of conditional release, early behavioural problems and poor behavioural controls) removed from the final model. The remain items divided into three factors: Arrogant and Deceitful Interpersonal Style, Deficient Affective Experience and Impulsive and Irresponsible Behavioural Style [37]. In the most recent edition of the PCL-R, Hare adds a fourth antisocial behaviour factor, consisting of those Factor 2 items excluded in the previous model [38]. Again, these models are presumed to be hierarchical with a single unified psychopathy disorder underlying the distinct but correlated factors.[39]
### Diagnostic criteria and PCL-R assessment
Hare's PCL-R has allowed for a differentiation between individuals with psychopathy and antisocial personality disorder (APD).
In contemporary research and clinical psychiatric practice, the American Psychiatric Association use the DSM and European doctors use the ICD-10 and will use the term antisocial personality disorder. Psychopathy is most commonly assessed by those who subscribe to a separate idea of psychopathy with the PCL-R, [40] which is a clinical rating scale with 20 items. Each of the items in the PCL-R is scored on a three-point (0, 1, 2) scale according to two factors. PCL-R Factor 2 is associated with reactive anger, anxiety, increased risk of suicide, criminality, and impulsive violence. PCL-R Factor 1, in contrast, is associated with extroversion and positive affect. Factor 1, the so-called core personality traits of psychopathy, may even be beneficial for the psychopath (in terms of nondeviant social functioning). A psychopath will score high on both factors, whereas someone with APD will score high only on Factor 2.[41]
Both case history and a semi-structured interview are used in the analysis.
# Legal definition (Sexual predators)
Psychopathy has quite separate legal and judicial definitions that should not be confused with the medical definition. The American Psychiatric Association is vigorously opposing any non-medical or legal definition of what purports to be a medical condition "without regard for scientific and clinical knowledge".[42] Various states and nations have at various times enacted laws specific to dealing with psychopaths. In the United States approximately twenty states currently have provisions for the involuntary civil commitment for sex offenders or sexual predators, under Sexually violent predator acts, avoiding the use of the term "psychopath". These statutes and provisions are controversial and are being reviewed by the U.S. Supreme Court as a violation of a person's Fourteenth Amendment rights.[43] (See Foucha v. Louisiana for an example.[44])
- Washington State Legislature [45] defines a "Psychopathic personality" to mean "the existence in any person of such hereditary, congenital or acquired condition affecting the emotional or volitional rather than the intellectual field and manifested by anomalies of such character as to render satisfactory social adjustment of such person difficult or impossible".[43] The same statute defines the "sexual psychopath" as "any person who is affected in a form of psychoneurosis or in a form of psychopathic personality, which form predisposes such person to the commission of sexual offenses in a degree constituting him a menace to the health or safety of others" for prison sentencing purposes in the Sentencing Reform Act of 1981.[45]
- California enacted a psychopathic offender law in 1939, since greatly outmodeled and revised. [46] that defined a psychopath solely in terms of offenders with a predisposition "to the commission of sexual offenses against children." A 1941 law[47] attempted to further clarify this to the point where anyone examined and found to be psychopathic was to be committed to a state hospital and anyone else was to be sentenced by the courts. However, these laws were enacted years before the American Psychiatric Association began publishing the Diagnostic and Statistical Manual of Mental Disorders which is used today for diagnosis and does not include "psychopathic offender". Hence, these laws are of historical interest only.
- In the United Kingdom, "Psychopathic Disorder" is legally defined in the Mental Health Act (UK)[48] as, "a persistent disorder or disability of mind (whether or not including significant impairment of intelligence) which results in abnormally aggressive or seriously irresponsible conduct on the part of the person concerned."
According to Jay Ziskin any diagnosis that does not appear in DSM III is not a formal diagnoses for legal uses, as shown in a quote from Coping with Psychiatric and Psychological Testimony Vol II by Jay Ziskin which is a book for attorneys to shoot down psychiatric testimony in the United States.
One should note whether the report contains a formal diagnosis......Those that do not are weakened......One can usually spot a formal diagnosis by the presence of a code number, usually a three-digit number, sometimes with additional digits ... although in some cases, psychiatrists will state what turns out to be a formal diagnosis without using the code numbers. Where there is a formal diagnosis, one should check to see if it is one of those listed in the diagnostic and statistical manual (DSM-III). .......the lawyer ... should check the manual for the elements required for making that diagnosis and then check to see if the report describes those elements.....If there is a diagnosis, but it is not from DSM-III, this is a matter to be questioned as there is only one official diagnositic classification system and it is DSM-III.[49]
# Subtypes of psychopathy
## The Primary–Secondary distinction
Primary psychopathy was defined by those following this theory as the root disorder in patients diagnosed with it, whereas secondary psychopathy was defined as an aspect of another psychiatric disorder or social circumstances.[50] Today, primary psychopaths are considered to have mostly Factor 1 traits from the PCL-R (arrogance, callousness, manipulativeness, lying) whereas secondary psychopaths have a majority of Factor 2 traits (impulsivity, boredom proneness, irresponsibility, lack of long-term goals).[51]Secondary psychopaths show normal to above-normal physiological responses to (perceived) potential threats. Their crimes tend to be unplanned and impulsive with little thought of the consequences.[52] Including to those using this theory, this type have hot tempers and are prone to reactive aggression. They experience normal to above-normal levels of anxiety but are nevertheless highly stimulus seeking and have trouble tolerating boredom. Their lifestyle may lead to depression and even suicide.
Mealey uses the term "primary psychopathy" to differentiate between psychopathy that is biological in origin and "secondary psychopathy" that results from a combination of genetic and environmental influences.[53] Lykken prefers sociopathy to describe the latter.
Sellbom and Ben-Porath (2005) describe the distinction:
This distinction closely resembles the distinction between instrumental and impulsive/reactive crime/violence in the field of criminology.
Joseph P. Newman et al, who use this concept of psychopathy, have validated David T. Lykken's conceptualization of psychopathy subtypes in relation to Gray's behavioral activation system and behavioral inhibition system.[55] Newman et al. found measures of primary psychopathy to be negatively correlated with Gray's behavioral inhibition system, a construct intended to measure behavioral inhibition from cues of punishment or nonreward.[55] In contrast, measures of secondary psychopathy to be positively correlated with Gray's behavioral activation system, a construct intended to measure sensitivity to cues of behavioral approach.[55]
# Relationship to other terms
## Relationship to sociopathy
The difference between sociopathy and psychopathy, according to Hare, may "reflect the user's views on the origins and determinates of the disorder."[56]
David T. Lykken proposes that psychopathy and sociopathy are two distinct kinds of antisocial personality disorder. He holds that psychopaths are born with temperamental differences such as impulsivity, cortical underarousal, and fearlessness that lead them to risk-seeking behavior and an inability to internalize social norms. Sociopaths, on the other hand, he believes to have relatively normal temperaments; their personality disorder being more an effect of negative sociological factors like parental neglect, delinquent peers, poverty, and extremely low or extremely high intelligence. Both personality disorders are, of course, the result of an interaction between genetic predispositions and environmental factors, but psychopathy leans towards the hereditary whereas sociopathy tends towards the environmental.[51]
## Relationship to Antisocial personality disorder
The criteria for the Antisocial Personality Disorder were derived from the Research Diagnositic Criteria developed by Spitzer, Endicott and Robbins (1978). There was concern in the development of DSM-IV that there was too much emphasis on research data and not enough on the more traditional psychopathic traits such as a lack of empathy, superficial charm, and inflated self appraisal. Field trial data indicated that some of these traits of psychopathy derived from the Psychopathy Checklist developed by Hare et al., 1992, were difficult to assess reliably and thus were not included. Lack of remorse is an example. The antisocial person may express genuine or false guilt or remorse and/or offer excuses and rationalizations. However, a history of criminal acts in itself suggests little remorse or guilt.[57]
The American Psychiatric Association removed the word "psychopathy" or "psychopathic", and started using the term "Antisocial Personality" to cover the disorder in DSM-II.[58]
The World Health Organization's stance in its ICD-10 refers to psychopathy, sociopathy, antisocial personality, asocial personality, and amoral personality as synonyms for dissocial personality disorder. Further, the DSM was meant as a diagnostic guide, and the term psychopath best fit the criteria met for antisocial personality disorder.
# Research findings
The prototypical psychopath has deficits or deviances in several areas: interpersonal relationships, emotion, and self-control. Psychopaths lack a sense of guilt or remorse for any harm they may have caused others, instead rationalizing the behavior, blaming someone else, or denying it outright.[59] Psychopaths also lack empathy towards others in general, resulting in tactlessness, insensitivity, and contemptuousness. All of this belies their tendency to make a good, likable first impression. Psychopaths have a superficial charm about them, enabled by a willingness to say anything without concern for accuracy or truth.
This extends into their pathological lying and willingness to con and manipulate others for personal gain or amusement. The prototypical psychopath's emotions are described as a shallow affect, meaning their overall way of relating is characterized by mere displays of friendliness and other emotion for personal gain; the displayed emotion need not correlate with felt emotion, in other words.
Shallow affect also describes the psychopath's tendency for genuine emotion to be short lived and egocentric with an overall cold demeanor. Their behavior is impulsive and irresponsible, often failing to keep a job or defaulting on debts.[59]
Most research studies of psychopaths have taken place among prison populations. This remains a limitation on its applicability to a general population.
It has been shown that punishment and behavior modification techniques do not improve the behavior of what Hare and other followers of this theory call a psychopath. They have been regularly observed to respond to both by becoming more cunning and hiding their behavior better. It has been suggested by them that traditional therapeutic approaches actually make psychopaths if not worse, then far more adept at manipulating others and concealing their behavior. They are generally considered to be not only incurable but also untreatable.[60]
Psychopaths also have a markedly distorted sense of the potential consequences of their actions, not only for others, but also for themselves. They do not, for example, deeply recognize the risk of being caught, disbelieved or injured as a result of their behaviour.[61]
## Relation to sex offenders
No clinical definition of psychopathy indicates that psychopaths are especially prone to commit sexually-oriented murders, and scientific studies do not suggest that a large proportion of psychopaths have committed these crimes.[62] Although some claim a large proportion of such offenders have been classified as psychopathic, this evidence comes from single, unrepeated research study using the Rorschach Inkblot Test, an invalid test for psychopathy and for sex offenders[63], references not considering psychopathy [64], and studies concerning sexual homicide, a somewhat different population that the general class of sex offenders. and not from meta studies combining repeatable results.
## Childhood precursors
Psychopathy is not normally diagnosed in children or adolescents, and some jurisdictions explicitly forbid diagnosing psychopathy and similar personality disorders in minors. Psychopathic tendencies can sometimes be recognized in childhood or early adolescence and, if recognised, are diagnosed as conduct disorder. It must be stressed that not all children diagnosed with conduct disorder grow up to be psychopaths, or even disordered at all, but these childhood signs are found in significantly higher proportions in psychopaths than in the general population. Conduct disorder, as well as a related disorder, Oppositional Defiant Disorder, can sometimes develop into adult psychopathy. However, conduct disorder "fails to capture the emotional, cognitive and interpersonality traits - egocentricity, lack of remorse, empathy or guilt - that are so important in the diagnosis of psychopathy."[65]
Children showing strong psychopathic precursors often appear immune to punishment; nothing seems to modify their undesirable behavior. Consequently parents usually give up, and the behavior worsens.[66]
The following childhood indicators are to be seen not as to the type of behavior, but as to its relentless and unvarying occurrence. Not all must be present concurrently, but at least a number of them need to be present over a period of years[citation needed]:
- An extended period of bedwetting past the preschool years that is not due to any medical problem.
- Cruelty to animals beyond an angry outburst.
- Firesetting and other vandalism. Not to be confused with playing with matches, which is not uncommon for preschoolers. This is the deliberate setting of destructive fires with utter disregard for the property and lives of others.
- Lying, often without discernible objectives, extending beyond a child's normal impulse not to be punished. Lies that are so extensive that it is often impossible to know lies from truth.
- Theft and truancy.
- Aggression to peers, not necessarily physical, which can include getting others into trouble or a campaign of psychological torment.
The three indicators—bedwetting, cruelty to animals and firestarting, known as the MacDonald triad—were first described by J.M. MacDonald as indicators of psychopathy.[67] The relevance of these indicators to serial murder etiology has since been called into question, and they are considered irrelevant to psychopathy.
The question of whether young children with early indicators of psychopathy respond poorly to intervention compared to conduct disordered children without these traits has only recently been examined in controlled clinical research. The empirical findings from this research have been consistent with broader anecdotal evidence, pointing to poor treatment outcomes.[68]
## Discrete vs. continuous dimension
As part of the larger debate on whether personality disorders are distinct from normal personality or extremes on various dimensions of normal personality is the debate on whether psychopathy represents something "qualitatively different" from normal personality or a "continuous dimension" shading from normality into severely psychopathic. Early taxonometric analysis from Harris and colleagues[69] indicated that a discrete category may underlie psychopathy, however this was only found for the behavioural Factor 2 items, indicating that this analysis may be related to Anti-social Personality Disorder rather than psychopathy per se. Marcus, John, and Edens more recently performed a series of statistical analysis on previously attained PCL–R and PPI scores and concluded that psychopathy may best be conceptualized as having a "dimensional latent structure" like depression.[70]
In contrast, the PCL–R sets a score of 30 out of 40 for North American male inmates as its cut-off point for a diagnosis of psychopathy, however this is an abitrary cut-off and should not be taken to reflect any sort of underlying structure for the disorder.
## Perceptual/emotional recognition deficits
In a 2002 study, David Kosson and Yana Suchy, et al. asked psychopathic inmates to name the emotion expressed on each of 30 faces; compared to controls, psychopaths had a significantly lower rate of accuracy in recognizing disgusted facial affect but a higher rate of accuracy in recognizing anger. Additionally, when "conditions designed to minimize the involvement of left-hemispheric mechanisms" (i.e. sadness) were used, psychopaths had more difficulty accurately identifying emotions. This study did not replicate Blaire, et al. (1997)'s findings that psychopaths are specifically less sensitive to nonverbal cues of fear or distress.[71]
In a 2002 experiment, Blair, Mitchell, et al. used the Vocal Affect Recognition Test to measure psychopaths' recognition of the emotional intonation given to connotatively neutral words. Psychopaths tended to make more recognition errors than controls with a particularly high rate of error for sad and fearful vocal affect.[72]
A 2004 experiment tested the hypothesis of overselective attention in psychopaths using two forms of the Stroop color-word and picture-word tasks: with color/picture and word separated and with color/picture and word together. They found that in the separated Stroop tasks, psychopaths performed significantly worse than controls; however, on standard Stroop tasks, psychopaths performed equally well as controls.
When split into low-anxious and high-anxious groups, low-anxious psychopaths and low-anxious controls showed less interference on the separated Stroop tasks than their high-anxious counterparts; for low-anxious psychopaths, interference was very nearly zero. They conclude that the inability to integrate contextual cues depends on the cues' relationship to "the deliberately attended, goal-relevant information."[73] | https://www.wikidoc.org/index.php/Psychopathy | |
85f6ba0be0ddba3e1e20f449697a27c127835c73 | wikidoc | Webbed neck | Webbed neck
A webbed neck, or pterygium colli deformity, is a congenital skin fold that runs along the sides of the neck down to the shoulders.
There are many variants.
# Associated conditions
It is a feature of Turner syndrome and Noonan syndrome, as well as the rarer Klippel-Feil syndrome.
# Presentation
On babies, webbed neck may look like loose folds of skin on the neck. As the child grows, the skin may stretch out to look like there is little or no neck. | Webbed neck
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
A webbed neck, or pterygium colli deformity, is a congenital skin fold that runs along the sides of the neck down to the shoulders.
There are many variants.
# Associated conditions
It is a feature of Turner syndrome[1] and Noonan syndrome,[2] as well as the rarer Klippel-Feil syndrome.[3]
# Presentation
On babies, webbed neck may look like loose folds of skin on the neck. As the child grows, the skin may stretch out to look like there is little or no neck. | https://www.wikidoc.org/index.php/Pterigium_Colli | |
6f9ae33df9f82822970f8563cc072c94e2bf3f41 | wikidoc | Puddle sign | Puddle sign
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
In gastroenterology, the puddle sign is a physical examination maneuver that can be used to detect the presence of ascites.
It is useful for detecting small amounts of ascites -- as small as 120 mL; shifting dullness and bulging flanks typically require 500 mL.
In relation to auscultatory percussion, the puddle sign is more specific, but less sensitive. | Puddle sign
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
In gastroenterology, the puddle sign is a physical examination maneuver that can be used to detect the presence of ascites.
It is useful for detecting small amounts of ascites -- as small as 120 mL; shifting dullness and bulging flanks typically require 500 mL.[1]
In relation to auscultatory percussion, the puddle sign is more specific, but less sensitive.[2] | https://www.wikidoc.org/index.php/Puddle_sign | |
0f965d352b2bd29e11e12e8b0e72fd9b7e92bd01 | wikidoc | Pulse Polio | Pulse Polio
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Pulse Polio is an immunization campaign established by the government of India in 1994 to eradicate poliomyelitis (polio) in India by vaccinating annually all children under age five against poliovirus.
Every child receives a dose of Oral Polio Vaccine (OPV), a live, attenuated virus which colonises the gastrointestinal tract. This virus competitively inhibits the wild, disease-causing poliovirus. Not only does this prevent pernicious infection in the host, it precludes transmission of the wild poliovirus to other hosts. Since poliovirus cannot survive outside a host for more than two weeks, theoretically it would be eradicated, resulting in the eradication of poliomyelitis.
The campaign proved to be successful, and the incidence of poliomyelitis in India has decreased dramatically: India recorded 4,791 cases of polio in 1994; 2,489 in 1997; 1,600 in 2002; 225 in 2003; and 135 in 2004. Nevertheless, critics charge that the campaign has seriously encroached on other essential public health services at times when health care resources were minimal.
# Sources
- Staff writer. "India vaccinates nearly 80 million children." Onlypunjab.com 28 February 2005: Health News.
PULSE stands for "Post-resuscitation and Initial Utility in Life saving Efforts" | Pulse Polio
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Pulse Polio is an immunization campaign established by the government of India in 1994 to eradicate poliomyelitis (polio) in India by vaccinating annually all children under age five against poliovirus.
Every child receives a dose of Oral Polio Vaccine (OPV), a live, attenuated virus which colonises the gastrointestinal tract. This virus competitively inhibits the wild, disease-causing poliovirus. Not only does this prevent pernicious infection in the host, it precludes transmission of the wild poliovirus to other hosts. Since poliovirus cannot survive outside a host for more than two weeks, theoretically it would be eradicated, resulting in the eradication of poliomyelitis.
The campaign proved to be successful, and the incidence of poliomyelitis in India has decreased dramatically: India recorded 4,791 cases of polio in 1994; 2,489 in 1997; 1,600 in 2002; 225 in 2003; and 135 in 2004. Nevertheless, critics charge that the campaign has seriously encroached on other essential public health services at times when health care resources were minimal.
# Sources
- Staff writer. "India vaccinates nearly 80 million children." Onlypunjab.com 28 February 2005: Health News.
PULSE stands for "Post-resuscitation and Initial Utility in Life saving Efforts" | https://www.wikidoc.org/index.php/Pulse_Polio | |
e8502240f77020b4de3f9bb58b4c02e2f153bf22 | wikidoc | Punctuation | Punctuation
# Overview
Writing is quite different from speaking. During speaking you can add expressions to what you say. Expressions mean what you do with your voice, or with your hands and face, while you are talking. You can make your voice go up or down; you can make it loud or soft, you can pause, hesitate or repeat things. But in writing, there are no voices or faces or hands to give expressions.
Written words are just flat on the page. To bring them to life, you need punctuation marks:
Full stop . Question mark ? Exclamation mark ! Comma , Colon : Semicolon ; Dash - Brackets ( )
# Full stop (period or dot)
Whether a sentence is short or long, it needs a full stop at the end. Full stops come at the end of complete sentences. You can put as much information into one long sentence as you can put into several short ones. Good writing is a mixture of short, medium, and long sentences.
- Example:
The management of the patient with acute decompensated heart failure depends upon whether the patient has acute decompensated systolic heart failure or acute decompensated diastolic heart failure.
- The management of the patient with acute decompensated heart failure depends upon whether the patient has acute decompensated systolic heart failure or acute decompensated diastolic heart failure.
# Question mark ?
There are sentences which ask you something. Questions, as you would expect, end with a question mark, and like all sentences they begin with a capital letter.
- Example:
Is the patient symptomatic?
- Is the patient symptomatic?
# Exclamation mark !
Exclamation mark is used for sentences which have expressions, such as anger, surprise, urgency, amusement or annoyance in them. An urgent or angry command can have an exclamation mark. Commands can be very short, sometimes as short as one word.
- Example:
Thank you!
- Thank you!
# Comma ,
The job of the comma is to make sentences-particularly longer sentences-easier to read. When you are reading aloud, commas usually mark a slight pause, or change of voice.
Often when you name someone, or something, you need a description as well. Do not forget to put space after comma.
- Example:
Oxygen improves the patient's status if hypoxemia is present, and the goal is to keep the oxygen saturation above 90%.
- Oxygen improves the patient's status if hypoxemia is present, and the goal is to keep the oxygen saturation above 90%.
A comma is useful between the name and the description.
- Example:
Dr. Rene Laennec, described bronchitis for the first time.
- Dr. Rene Laennec, described bronchitis for the first time.
Commas are also useful to show the joints in a sentence: for example, where a phrase or clause has been added, or two sentences made into one.
- Example:
Following transmission, the agent inoculates the tracheobronchial epithelium.
- Following transmission, the agent inoculates the tracheobronchial epithelium.
Commas are particularly important when the sentence has an extra part stuck in the middle. When this happens there should be a comma before and after the extra part.
- Example:
During a streptococcal infection, activated antigen-presenting cells such as macrophages, present the bacterial antigen to helper T cells.
- During a streptococcal infection, activated antigen-presenting cells such as macrophages, present the bacterial antigen to helper T cells.
# Semicolon ;
A semicolon marks a bigger break than a comma but does not replace a full stop. Unlike a comma, a semicolon can go between two sentences.
Use a semicolon if the sentences are alike, or belong together. Unlike full stops, semicolons can come in the middle of sentences. Use them only when you want a strong break between two parts of your sentence.
- Example:
The most recent classification according to the left ventricular ejection fraction; heart failure with reduced ejection fraction vs heart failure with preserved ejection fraction, is widely used.
- The most recent classification according to the left ventricular ejection fraction; heart failure with reduced ejection fraction vs heart failure with preserved ejection fraction, is widely used.
# Colon :
Use a colon when you have a list of things coming after a heading. A colon is used before giving an example – or examples – of something.
You also use a colon between two sentences, when the first one says something, and the second one says what you mean by it. Colons are often found before instructions even if they are pictures.
- Example:
There are numerous systemic risk factors associated with thrombus formation following plaque rupture:
Smoking: Smoking increases platelet aggregation and plasma epinephrine levels.
Fibrinogen: Elevated levels of fibrinogen have been associated with thrombosis including abnormal levels of fibrinogen.
- There are numerous systemic risk factors associated with thrombus formation following plaque rupture:
Smoking: Smoking increases platelet aggregation and plasma epinephrine levels.
Fibrinogen: Elevated levels of fibrinogen have been associated with thrombosis including abnormal levels of fibrinogen.
- Smoking: Smoking increases platelet aggregation and plasma epinephrine levels.
- Fibrinogen: Elevated levels of fibrinogen have been associated with thrombosis including abnormal levels of fibrinogen.
# Brackets ( )
Brackets come in pairs, with words, phrases, or sentences inside them. Inside brackets, you put things that may be helpful, but not really necessary. Sometimes just a part of a sentence is in brackets.
- Example:
Atherosclerosis is the gradual buildup of cholesterol and fibrous tissue (collagen and smooth muscle cells) throughout the vascular tree.
- Atherosclerosis is the gradual buildup of cholesterol and fibrous tissue (collagen and smooth muscle cells) throughout the vascular tree.
# Dash -
Dashes are sometimes used to mark a big break, or interruption, in a sentence. A dash can be used like a colon. Sometimes dashes are used instead of brackets. Dashes are very useful in writing speech and they are also very useful for showing where someone is interrupted, and doesn’t finish what they’re saying.
- Example:
Pathology studies indicate that it is often mild-to-moderate, lipid-laden, inflamed plaques that are the ones most likely to rupture and cause an ST elevation MI.
- Pathology studies indicate that it is often mild-to-moderate, lipid-laden, inflamed plaques that are the ones most likely to rupture and cause an ST elevation MI.
# Start with a capital letter
When you start a new sentence, you should use a capital letter.
Proper nouns-the words which name people, places or things – also begin with a capital letter, wherever they come in a sentence.
- Always capitalize:
The first word of every new sentence or bullet
Example 1: "Heart failure" is defined as the inability of the heart to pump enough blood to meet the demands of the body.
Example 2: (Bullet)
"Headache"
The name of a disease, named after someone, but not the general disease names
Example 1: The patient is suffering from "Münchausen syndrome" but has no symptoms of "major depressive disorder".
Trade names of medications but not the generic names
Example 1: The preferred drug for the symptoms of this disease is "Tylenol", which contains "acetaminophen".
Abbreviations
Example 1: Pathogens: Chickenpox is caused by "varicella zoster virus (VZV)".
Example 2: Organizations: The "United States Preventive Task Force (USPSTF)" has established guidelines for screening various diseases.
Names of individuals, cities, countries, race or study design
Example 1: Individuals : In 1836, "Joseph Parrish" described three cases of severe lower urinary tract symptoms without the presence of a bladder stone.
Example 2: Race: Pyelonephritis is more prevalent among "Asian" population as compared to "Caucasians".
Example 3: Race: New information suggests that elements of heart failure in "African Americans" and "Caucasians" may be different.
Example 4: Countries: It is estimated that about 5.7 million adults in the "United States" have heart failure (about 2,650,000 males, and 2,650,000 females).
Example 5: Cities/States: A study conducted in "Olmsted County", 'Minnesota", showed that the incidence of heart failure (ICD9/428) has not declined during two decades, but survival after onset has increased overall, with less improvement among women and elderly persons.
Example 6: Study Design: Data from the NHLBI’s "Framingham Heart Study" indicate that heart failure (HF) incidence approaches 10 per 1,000 population after age 65.
Headings
Example 7: Headings: "Country Specific Causes"
Example 8: Headings: "Natural History, Complications and Prognosis"
- The first word of every new sentence or bullet
Example 1: "Heart failure" is defined as the inability of the heart to pump enough blood to meet the demands of the body.
Example 2: (Bullet)
"Headache"
- Example 1: "Heart failure" is defined as the inability of the heart to pump enough blood to meet the demands of the body.
- Example 2: (Bullet)
"Headache"
- "Headache"
- The name of a disease, named after someone, but not the general disease names
Example 1: The patient is suffering from "Münchausen syndrome" but has no symptoms of "major depressive disorder".
- Example 1: The patient is suffering from "Münchausen syndrome" but has no symptoms of "major depressive disorder".
- Trade names of medications but not the generic names
Example 1: The preferred drug for the symptoms of this disease is "Tylenol", which contains "acetaminophen".
- Example 1: The preferred drug for the symptoms of this disease is "Tylenol", which contains "acetaminophen".
- Abbreviations
Example 1: Pathogens: Chickenpox is caused by "varicella zoster virus (VZV)".
Example 2: Organizations: The "United States Preventive Task Force (USPSTF)" has established guidelines for screening various diseases.
- Example 1: Pathogens: Chickenpox is caused by "varicella zoster virus (VZV)".
- Example 2: Organizations: The "United States Preventive Task Force (USPSTF)" has established guidelines for screening various diseases.
- Names of individuals, cities, countries, race or study design
Example 1: Individuals : In 1836, "Joseph Parrish" described three cases of severe lower urinary tract symptoms without the presence of a bladder stone.
Example 2: Race: Pyelonephritis is more prevalent among "Asian" population as compared to "Caucasians".
Example 3: Race: New information suggests that elements of heart failure in "African Americans" and "Caucasians" may be different.
Example 4: Countries: It is estimated that about 5.7 million adults in the "United States" have heart failure (about 2,650,000 males, and 2,650,000 females).
Example 5: Cities/States: A study conducted in "Olmsted County", 'Minnesota", showed that the incidence of heart failure (ICD9/428) has not declined during two decades, but survival after onset has increased overall, with less improvement among women and elderly persons.
Example 6: Study Design: Data from the NHLBI’s "Framingham Heart Study" indicate that heart failure (HF) incidence approaches 10 per 1,000 population after age 65.
- Example 1: Individuals : In 1836, "Joseph Parrish" described three cases of severe lower urinary tract symptoms without the presence of a bladder stone.
- Example 2: Race: Pyelonephritis is more prevalent among "Asian" population as compared to "Caucasians".
- Example 3: Race: New information suggests that elements of heart failure in "African Americans" and "Caucasians" may be different.
- Example 4: Countries: It is estimated that about 5.7 million adults in the "United States" have heart failure (about 2,650,000 males, and 2,650,000 females).
- Example 5: Cities/States: A study conducted in "Olmsted County", 'Minnesota", showed that the incidence of heart failure (ICD9/428) has not declined during two decades, but survival after onset has increased overall, with less improvement among women and elderly persons.
- Example 6: Study Design: Data from the NHLBI’s "Framingham Heart Study" indicate that heart failure (HF) incidence approaches 10 per 1,000 population after age 65.
- Headings
Example 7: Headings: "Country Specific Causes"
Example 8: Headings: "Natural History, Complications and Prognosis"
- Example 7: Headings: "Country Specific Causes"
- Example 8: Headings: "Natural History, Complications and Prognosis"
- In case of any confusion, google the world and look for its utilization within a sentence.
# Apostrophe S ‘S and S’
For singular words you always show belonging by ‘s. Even if a singular word already ends in –s, you still add ‘s. If the word ends in –s because it’s plural, the apostrophe goes after it. If the word is plural but it doesn’t end in –s, then stick to ‘s. Don’t make the common mistake of putting an apostrophe wherever you see an s. Most words that end in –s are just plain plurals. The –s on the in is not for belonging, so there is NO apostrophe!
There is an odd-one-out you have to remember: its. When its means there’s something belonging to it, there’s no apostrophe. When it’s short for it is, there is an apostrophe.
- Example:
The patient's heart, Ankles' bones, Appendice's entries.
- The patient's heart, Ankles' bones, Appendice's entries.
# Bullet
Bullet points help to make what you’re saying more clear. They break up blocks of text into tidy chunks so the reader can take in what you’re saying. They present lists in a clear format so people can see, it’s a list.
When using bullets, be consistent throughout the document with the formatting (e.g. capital letters and punctuation at the start and end of each bullet). Most often, bullets should be indented by at least an inch from the left margin. Also, most lists included in academic papers must be double spaced and properly referenced. The text introducing the list of bullet points should end with a colon. The first word in each entry is normally capitalized. When the entries look like titles, they may use title capitalization.
- Example:
- The following are other risk factors:
Low socioeconomic status
Prior or current STD
New or multiple sex partners
- Low socioeconomic status
- Prior or current STD
- New or multiple sex partners
# i.e and e.g
i.e. is Latin for id est and means that is or in other words. Use i.e. before clarifying or adding to the previous statement.
- Example:
Cortex of the long bones of the body (i.e. bones of the leg, potentially resulting in bowing of the legs)
- Cortex of the long bones of the body (i.e. bones of the leg, potentially resulting in bowing of the legs)
e.g. is Latin for exempli gratia and means for example. Use e.g. before listing examples of the previous statement.
- Example:
Certain types of medications (e.g. long-term steroid use)
- Certain types of medications (e.g. long-term steroid use)
Users of American English frequently put a comma after i.e. and e.g. Note that it is not necessary to set these abbreviations in italics in normal use
# Such as and as well as
It is more professional to use such as instead of like. Also, use as well as instead of and.
- Example:
Activated antigen-presenting cells, such as macrophages.
- Activated antigen-presenting cells, such as macrophages.
# Referencing
Code for reference should be inserted at the end of sentence, after period.
- Example:
Acute or decompensated heart failure is a term used to describe exacerbated or decompensated heart failure, and refers to an episode in which a patient sustains a change in heart failure signs and symptoms that necessitates urgent therapy or hospitalization.
- Acute or decompensated heart failure is a term used to describe exacerbated or decompensated heart failure, and refers to an episode in which a patient sustains a change in heart failure signs and symptoms that necessitates urgent therapy or hospitalization.
# Test passage
## Passage 1
Coagulation necrosis, characterized by Hypereosinophilia and nuclear pyknosis followed by karyorrhexis, karyolysis, total loss of nuclei and loss of cytoplasmic cross-striations is generally first visible in the period from 4,12 hours following infarction. necrotic myocytes may retain their striations for a long time
Neutrophilic infiltration (Acute inflammation) edema and hemorrhage are also first visible at 4-12 hours but generally closer to 12 hours. the interstitium at the margin of the Infarcted area is initially infiltrated with Neutrophils, then with Lymphocytes and Macrophages, who phagocytose or eat the myocyte debris; The necrotic area is surrounded and progressively invaded by granulation tissue: which will replace the infarct with a fibrous or collagenous scar (which are typical steps in wound healing). the interstitial space or the space between cells outside of blood vessels may be infiltrated with red blood cells.
Infiltration by macrophages, lymphocytes, eosinophils, fibroblasts and capillaries begins around the periphery at 3-10 days. contraction band necrosis, characterized by hypereosinophilic transverse bands of precipitated Myofibrils in dead myocytes is usually seen at the edge of an Infarct or with reperfusion for example with Thrombolytic therapy.
## Passage 2
Acute Bronchitis may be caused by either Viral bacterial or environmental factor.
Influenza virus is the most common overall cause
-ther causes's of Acute bronchitis are mostly viruses including;
- Respiratory Syncytial Virus (rsv)
- coronavirus
- Enterovirus | Punctuation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]
# Overview
Writing is quite different from speaking. During speaking you can add expressions to what you say. Expressions mean what you do with your voice, or with your hands and face, while you are talking. You can make your voice go up or down; you can make it loud or soft, you can pause, hesitate or repeat things. But in writing, there are no voices or faces or hands to give expressions.
Written words are just flat on the page. To bring them to life, you need punctuation marks:
Full stop . Question mark ? Exclamation mark ! Comma , Colon : Semicolon ; Dash - Brackets ( )
# Full stop (period or dot)
Whether a sentence is short or long, it needs a full stop at the end. Full stops come at the end of complete sentences. You can put as much information into one long sentence as you can put into several short ones. Good writing is a mixture of short, medium, and long sentences.
- Example:
The management of the patient with acute decompensated heart failure depends upon whether the patient has acute decompensated systolic heart failure or acute decompensated diastolic heart failure.
- The management of the patient with acute decompensated heart failure depends upon whether the patient has acute decompensated systolic heart failure or acute decompensated diastolic heart failure.
# Question mark ?
There are sentences which ask you something. Questions, as you would expect, end with a question mark, and like all sentences they begin with a capital letter.
- Example:
Is the patient symptomatic?
- Is the patient symptomatic?
# Exclamation mark !
Exclamation mark is used for sentences which have expressions, such as anger, surprise, urgency, amusement or annoyance in them. An urgent or angry command can have an exclamation mark. Commands can be very short, sometimes as short as one word.
- Example:
Thank you!
- Thank you!
# Comma ,
The job of the comma is to make sentences-particularly longer sentences-easier to read. When you are reading aloud, commas usually mark a slight pause, or change of voice.
Often when you name someone, or something, you need a description as well. Do not forget to put space after comma.
- Example:
Oxygen improves the patient's status if hypoxemia is present, and the goal is to keep the oxygen saturation above 90%.
- Oxygen improves the patient's status if hypoxemia is present, and the goal is to keep the oxygen saturation above 90%.
A comma is useful between the name and the description.
- Example:
Dr. Rene Laennec, described bronchitis for the first time.
- Dr. Rene Laennec, described bronchitis for the first time.
Commas are also useful to show the joints in a sentence: for example, where a phrase or clause has been added, or two sentences made into one.
- Example:
Following transmission, the agent inoculates the tracheobronchial epithelium.
- Following transmission, the agent inoculates the tracheobronchial epithelium.
Commas are particularly important when the sentence has an extra part stuck in the middle. When this happens there should be a comma before and after the extra part.
- Example:
During a streptococcal infection, activated antigen-presenting cells such as macrophages, present the bacterial antigen to helper T cells.
- During a streptococcal infection, activated antigen-presenting cells such as macrophages, present the bacterial antigen to helper T cells.
# Semicolon ;
A semicolon marks a bigger break than a comma but does not replace a full stop. Unlike a comma, a semicolon can go between two sentences.
Use a semicolon if the sentences are alike, or belong together. Unlike full stops, semicolons can come in the middle of sentences. Use them only when you want a strong break between two parts of your sentence.
- Example:
The most recent classification according to the left ventricular ejection fraction; heart failure with reduced ejection fraction vs heart failure with preserved ejection fraction, is widely used.
- The most recent classification according to the left ventricular ejection fraction; heart failure with reduced ejection fraction vs heart failure with preserved ejection fraction, is widely used.
# Colon :
Use a colon when you have a list of things coming after a heading. A colon is used before giving an example – or examples – of something.
You also use a colon between two sentences, when the first one says something, and the second one says what you mean by it. Colons are often found before instructions even if they are pictures.
- Example:
There are numerous systemic risk factors associated with thrombus formation following plaque rupture:
Smoking: Smoking increases platelet aggregation and plasma epinephrine levels.
Fibrinogen: Elevated levels of fibrinogen have been associated with thrombosis including abnormal levels of fibrinogen.
- There are numerous systemic risk factors associated with thrombus formation following plaque rupture:
Smoking: Smoking increases platelet aggregation and plasma epinephrine levels.
Fibrinogen: Elevated levels of fibrinogen have been associated with thrombosis including abnormal levels of fibrinogen.
- Smoking: Smoking increases platelet aggregation and plasma epinephrine levels.
- Fibrinogen: Elevated levels of fibrinogen have been associated with thrombosis including abnormal levels of fibrinogen.
# Brackets ( )
Brackets come in pairs, with words, phrases, or sentences inside them. Inside brackets, you put things that may be helpful, but not really necessary. Sometimes just a part of a sentence is in brackets.
- Example:
Atherosclerosis is the gradual buildup of cholesterol and fibrous tissue (collagen and smooth muscle cells) throughout the vascular tree.
- Atherosclerosis is the gradual buildup of cholesterol and fibrous tissue (collagen and smooth muscle cells) throughout the vascular tree.
# Dash -
Dashes are sometimes used to mark a big break, or interruption, in a sentence. A dash can be used like a colon. Sometimes dashes are used instead of brackets. Dashes are very useful in writing speech and they are also very useful for showing where someone is interrupted, and doesn’t finish what they’re saying.
- Example:
Pathology studies indicate that it is often mild-to-moderate, lipid-laden, inflamed plaques that are the ones most likely to rupture and cause an ST elevation MI.
- Pathology studies indicate that it is often mild-to-moderate, lipid-laden, inflamed plaques that are the ones most likely to rupture and cause an ST elevation MI.
# Start with a capital letter
When you start a new sentence, you should use a capital letter.
Proper nouns-the words which name people, places or things – also begin with a capital letter, wherever they come in a sentence.
- Always capitalize:
The first word of every new sentence or bullet
Example 1: "Heart failure" is defined as the inability of the heart to pump enough blood to meet the demands of the body.
Example 2: (Bullet)
"Headache"
The name of a disease, named after someone, but not the general disease names
Example 1: The patient is suffering from "Münchausen syndrome" but has no symptoms of "major depressive disorder".
Trade names of medications but not the generic names
Example 1: The preferred drug for the symptoms of this disease is "Tylenol", which contains "acetaminophen".
Abbreviations
Example 1: Pathogens: Chickenpox is caused by "varicella zoster virus (VZV)".
Example 2: Organizations: The "United States Preventive Task Force (USPSTF)" has established guidelines for screening various diseases.
Names of individuals, cities, countries, race or study design
Example 1: Individuals : In 1836, "Joseph Parrish" described three cases of severe lower urinary tract symptoms without the presence of a bladder stone.
Example 2: Race: Pyelonephritis is more prevalent among "Asian" population as compared to "Caucasians".
Example 3: Race: New information suggests that elements of heart failure in "African Americans" and "Caucasians" may be different.
Example 4: Countries: It is estimated that about 5.7 million adults in the "United States" have heart failure (about 2,650,000 males, and 2,650,000 females).
Example 5: Cities/States: A study conducted in "Olmsted County", 'Minnesota", showed that the incidence of heart failure (ICD9/428) has not declined during two decades, but survival after onset has increased overall, with less improvement among women and elderly persons.
Example 6: Study Design: Data from the NHLBI’s "Framingham Heart Study" indicate that heart failure (HF) incidence approaches 10 per 1,000 population after age 65.
Headings
Example 7: Headings: "Country Specific Causes"
Example 8: Headings: "Natural History, Complications and Prognosis"
- The first word of every new sentence or bullet
Example 1: "Heart failure" is defined as the inability of the heart to pump enough blood to meet the demands of the body.
Example 2: (Bullet)
"Headache"
- Example 1: "Heart failure" is defined as the inability of the heart to pump enough blood to meet the demands of the body.
- Example 2: (Bullet)
"Headache"
- "Headache"
- The name of a disease, named after someone, but not the general disease names
Example 1: The patient is suffering from "Münchausen syndrome" but has no symptoms of "major depressive disorder".
- Example 1: The patient is suffering from "Münchausen syndrome" but has no symptoms of "major depressive disorder".
- Trade names of medications but not the generic names
Example 1: The preferred drug for the symptoms of this disease is "Tylenol", which contains "acetaminophen".
- Example 1: The preferred drug for the symptoms of this disease is "Tylenol", which contains "acetaminophen".
- Abbreviations
Example 1: Pathogens: Chickenpox is caused by "varicella zoster virus (VZV)".
Example 2: Organizations: The "United States Preventive Task Force (USPSTF)" has established guidelines for screening various diseases.
- Example 1: Pathogens: Chickenpox is caused by "varicella zoster virus (VZV)".
- Example 2: Organizations: The "United States Preventive Task Force (USPSTF)" has established guidelines for screening various diseases.
- Names of individuals, cities, countries, race or study design
Example 1: Individuals : In 1836, "Joseph Parrish" described three cases of severe lower urinary tract symptoms without the presence of a bladder stone.
Example 2: Race: Pyelonephritis is more prevalent among "Asian" population as compared to "Caucasians".
Example 3: Race: New information suggests that elements of heart failure in "African Americans" and "Caucasians" may be different.
Example 4: Countries: It is estimated that about 5.7 million adults in the "United States" have heart failure (about 2,650,000 males, and 2,650,000 females).
Example 5: Cities/States: A study conducted in "Olmsted County", 'Minnesota", showed that the incidence of heart failure (ICD9/428) has not declined during two decades, but survival after onset has increased overall, with less improvement among women and elderly persons.
Example 6: Study Design: Data from the NHLBI’s "Framingham Heart Study" indicate that heart failure (HF) incidence approaches 10 per 1,000 population after age 65.
- Example 1: Individuals : In 1836, "Joseph Parrish" described three cases of severe lower urinary tract symptoms without the presence of a bladder stone.
- Example 2: Race: Pyelonephritis is more prevalent among "Asian" population as compared to "Caucasians".
- Example 3: Race: New information suggests that elements of heart failure in "African Americans" and "Caucasians" may be different.
- Example 4: Countries: It is estimated that about 5.7 million adults in the "United States" have heart failure (about 2,650,000 males, and 2,650,000 females).
- Example 5: Cities/States: A study conducted in "Olmsted County", 'Minnesota", showed that the incidence of heart failure (ICD9/428) has not declined during two decades, but survival after onset has increased overall, with less improvement among women and elderly persons.
- Example 6: Study Design: Data from the NHLBI’s "Framingham Heart Study" indicate that heart failure (HF) incidence approaches 10 per 1,000 population after age 65.
- Headings
Example 7: Headings: "Country Specific Causes"
Example 8: Headings: "Natural History, Complications and Prognosis"
- Example 7: Headings: "Country Specific Causes"
- Example 8: Headings: "Natural History, Complications and Prognosis"
- In case of any confusion, google the world and look for its utilization within a sentence.
# Apostrophe S ‘S and S’
For singular words you always show belonging by ‘s. Even if a singular word already ends in –s, you still add ‘s. If the word ends in –s because it’s plural, the apostrophe goes after it. If the word is plural but it doesn’t end in –s, then stick to ‘s. Don’t make the common mistake of putting an apostrophe wherever you see an s. Most words that end in –s are just plain plurals. The –s on the in is not for belonging, so there is NO apostrophe!
There is an odd-one-out you have to remember: its. When its means there’s something belonging to it, there’s no apostrophe. When it’s short for it is, there is an apostrophe.
- Example:
The patient's heart, Ankles' bones, Appendice's entries.
- The patient's heart, Ankles' bones, Appendice's entries.
# Bullet
Bullet points help to make what you’re saying more clear. They break up blocks of text into tidy chunks so the reader can take in what you’re saying. They present lists in a clear format so people can see, it’s a list.
When using bullets, be consistent throughout the document with the formatting (e.g. capital letters and punctuation at the start and end of each bullet). Most often, bullets should be indented by at least an inch from the left margin. Also, most lists included in academic papers must be double spaced and properly referenced. The text introducing the list of bullet points should end with a colon. The first word in each entry is normally capitalized. When the entries look like titles, they may use title capitalization.
- Example:
- The following are other risk factors:
Low socioeconomic status
Prior or current STD
New or multiple sex partners
- Low socioeconomic status
- Prior or current STD
- New or multiple sex partners
# i.e and e.g
i.e. is Latin for id est and means that is or in other words. Use i.e. before clarifying or adding to the previous statement.
- Example:
Cortex of the long bones of the body (i.e. bones of the leg, potentially resulting in bowing of the legs)
- Cortex of the long bones of the body (i.e. bones of the leg, potentially resulting in bowing of the legs)
e.g. is Latin for exempli gratia and means for example. Use e.g. before listing examples of the previous statement.
- Example:
Certain types of medications (e.g. long-term steroid use)
- Certain types of medications (e.g. long-term steroid use)
Users of American English frequently put a comma after i.e. and e.g. Note that it is not necessary to set these abbreviations in italics in normal use
# Such as and as well as
It is more professional to use such as instead of like. Also, use as well as instead of and.
- Example:
Activated antigen-presenting cells, such as macrophages.
- Activated antigen-presenting cells, such as macrophages.
# Referencing
Code for reference should be inserted at the end of sentence, after period.
- Example:
Acute or decompensated heart failure is a term used to describe exacerbated or decompensated heart failure, and refers to an episode in which a patient sustains a change in heart failure signs and symptoms that necessitates urgent therapy or hospitalization.[1]
- Acute or decompensated heart failure is a term used to describe exacerbated or decompensated heart failure, and refers to an episode in which a patient sustains a change in heart failure signs and symptoms that necessitates urgent therapy or hospitalization.[1]
# Test passage
## Passage 1
Coagulation necrosis, characterized by Hypereosinophilia and nuclear pyknosis followed by karyorrhexis, karyolysis, total loss of nuclei and loss of cytoplasmic cross-striations is generally first visible in the period from 4,12 hours following infarction. necrotic myocytes may retain their striations for a long time
Neutrophilic infiltration (Acute inflammation) edema and hemorrhage are also first visible at 4-12 hours but generally closer to 12 hours. the interstitium at the margin of the Infarcted area is initially infiltrated with Neutrophils, then with Lymphocytes and Macrophages, who phagocytose or eat the myocyte debris; The necrotic area is surrounded and progressively invaded by granulation tissue: which will replace the infarct with a fibrous or collagenous scar (which are typical steps in wound healing). the interstitial space or the space between cells outside of blood vessels may be infiltrated with red blood cells.
Infiltration by macrophages, lymphocytes, eosinophils, fibroblasts and capillaries begins around the periphery at 3-10 days. contraction band necrosis, characterized by hypereosinophilic transverse bands of precipitated Myofibrils in dead myocytes is usually seen at the edge of an Infarct or with reperfusion for example with Thrombolytic therapy.
## Passage 2
Acute Bronchitis may be caused by either Viral bacterial or environmental factor.
Influenza virus is the most common overall cause
other causes's of Acute bronchitis are mostly viruses including;
- Respiratory Syncytial Virus (rsv)
- coronavirus
- Enterovirus | https://www.wikidoc.org/index.php/Punctuation | |
1b8563964ef341b02e369e3db062e2449e454d53 | wikidoc | Pyelectasis | Pyelectasis
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Pyelectasis is a dilation of the renal pelvis. The term is derived from the prefix pyelo- meaning "pelvis" and ectasia meaning "dilation or distension". It is a relatively common ultrasound finding and is three times more common in male fetuses. In most cases pyelectasis resolves normally, having no ill effects on the baby. The significance of pyelectasis in fetuses is not clear. It was thought to be a marker for obstruction, which in some cases it can be. In most cases it resolves spontaneously. In some studies it has been shown to appear and disappear several times throughtout the course of pregnancy. There is some discussion about what degree of pyelectasis is considered severe enough to warrant further investigation and most authorities use 6mm as the cut-off point.
Pyelectasis is considered to be a "soft marker” for Down syndrome. This, along with other factors such as age and a Triple test, may be grounds for an amniocentesis to test for Down syndrome.
Babies with unresolved pyelectasis may experience urological problems requiring surgery. | Pyelectasis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [2] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
# Overview
Pyelectasis is a dilation of the renal pelvis. The term is derived from the prefix pyelo- meaning "pelvis" and ectasia meaning "dilation or distension". It is a relatively common ultrasound finding and is three times more common in male fetuses. In most cases pyelectasis resolves normally, having no ill effects on the baby. The significance of pyelectasis in fetuses is not clear. It was thought to be a marker for obstruction, which in some cases it can be. In most cases it resolves spontaneously. In some studies it has been shown to appear and disappear several times throughtout the course of pregnancy. There is some discussion about what degree of pyelectasis is considered severe enough to warrant further investigation and most authorities use 6mm as the cut-off point.
Pyelectasis is considered to be a "soft marker” for Down syndrome. This, along with other factors such as age and a Triple test, may be grounds for an amniocentesis to test for Down syndrome.
Babies with unresolved pyelectasis may experience urological problems requiring surgery.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Pyelectasis | |
55b1247324119c73dab93fc4a8bac38db8daba08 | wikidoc | Q-switching | Q-switching
Q-switching, sometimes known as giant pulse formation, is a technique by which a laser can be made to produce a pulsed output beam. The technique allows the production of light pulses with extremely high (gigawatt) peak power, much higher than would be produced by the same laser if it were operating in a continuous wave (constant output) mode. Compared to modelocking, another technique for pulse generation with lasers, Q-switching leads to much lower pulse repetition rates, much higher pulse energies, and much longer pulse durations. Both techniques are sometimes applied at once .
Q-switching was first proposed in 1958 by Gordon Gould, and independently discovered and demonstrated in 1961 or 1962 by R.W. Hellwarth and F.J. McClung using electrically switched Kerr cell shutters in a ruby laser.
# Principle of Q-switching
Q-switching is achieved by putting some type of variable attenuator inside the laser's optical resonator. When the attenuator is functioning, light which leaves the gain medium does not return, and lasing cannot begin. This attenuation inside the cavity corresponds to a decrease in the Q factor or quality factor of the optical resonator. A high Q factor corresponds to low resonator losses per roundtrip, and vice versa. The variable attenuator is commonly called a "Q-switch", when used for this purpose.
Initially the laser medium is pumped while the Q-switch is set to prevent feedback of light into the gain medium (producing an optical resonator with low Q). This produces a population inversion, but laser operation cannot yet occur since there is no feedback from the resonator. Since the rate of stimulated emission is dependent on the amount of light entering the medium, the amount of energy stored in the gain medium increases as the medium is pumped. Due to losses from spontaneous emission and other processes, after a certain time the stored energy will reach some maximum level; the medium is said to be gain saturated. At this point, the Q-switch device is quickly changed from low to high Q, allowing feedback and the process of optical amplification by stimulated emission to begin. Because of the large amount of energy already stored in the gain medium, the intensity of light in the laser resonator builds up very quickly; this also causes the energy stored in the medium to be depleted almost as quickly. The net result is a short pulse of light output from the laser, known as a giant pulse, which may have a very high peak intensity.
There are two main types of Q-switching:
## Active Q-switching
Here, the Q-switch is an externally-controlled variable attenuator. This may be a mechanical device such as a shutter, chopper wheel or spinning mirror placed inside the cavity, or (more commonly) it may be some form of modulator such as an acousto-optic device or an electro-optic device — a Pockels cell or Kerr cell. The reduction of losses (increase of Q) is triggered by an external event, typically an electrical signal. The pulse repetition rate can therefore be externally controlled.
Modulators generally allow a faster transition from low to high Q, and provide better control. An additional advantage of modulators is that the rejected light may be coupled out of the cavity and can be used for something else. Alternatively, when the modulator is in its low-Q state, an externally-generated beam can be coupled into the cavity through the modulator. This can be used to "seed" the cavity with a beam that has desired characteristics (such as transverse mode or wavelength). When the Q is raised, lasing builds up from the initial seed, producing a Q-switched pulse that has characteristics inherited from the seed.
## Passive Q-switching
In this case, the Q-switch is a saturable absorber, a material whose transmission increases when the intensity of light exceeds some threshold. The material may be an ion-doped crystal like Cr:YAG, which is used for Q-switching of Nd:YAG lasers, a bleachable dye, or a passive semiconductor device. Initially, the loss of the absorber is high, but still low enough to permit some lasing once a large amount of energy is stored in the gain medium. As the laser power increases, it saturates the absorber, i.e., rapidly reduces the resonator loss, so that the power can increase even faster. Ideally, this brings the absorber into a state with low losses to allow efficient extraction of the stored energy by the laser pulse. After the pulse, the absorber recovers to its high-loss state before the gain recovers, so that the next pulse is delayed until the energy in the gain medium is fully replenished. The pulse repetition rate can only indirectly be controlled, e.g. by varying the laser's pump power and the amount of saturable absorber in the cavity. Direct control of the repetition rate can be achieved by using a pulsed pump source as well as passive Q-switching.
## Variants
- Jitter can be reduced by not reducing the Q by as much, so that a small amount of light can still circulate in the cavity. This provides a "seed" of light that can aid in the buildup of the next Q-switched pulse.
- Cavity dumping: The cavity end mirrors are 100% reflective, so that no output beam is produced when the Q is high. Instead, the Q-switch is used to "dump" the beam out of the cavity after a time delay. The cavity Q goes from low to high to start the laser buildup, and then goes from high to low to "dump" the beam from the cavity all at once. This produces a shorter output pulse than regular Q-switching. Electro-optic modulators are normally used for this, since they can easily be made to function as a near-perfect beam "switch" to couple the beam out of the cavity. The modulator that dumps the beam may be the same modulator that Q-switches the cavity, or a second (possibly identical) modulator. A dumped cavity is more complicated to align than simple Q-switching, and may need a control loop to choose the best time at which to dump the beam from the cavity.
- Regenerative amplification: In regenerative amplification, an optical amplifier is placed inside a Q-switched cavity. Pulses of light from another laser (the "master oscillator") are injected into the cavity by lowering the Q to allow the pulse to enter and then increasing the Q to confine the pulse to the cavity where it can be amplified by repeated passes through the gain medium. The pulse is then allowed to leave the cavity via another Q switch.
# Typical performance
A typical Q-switched laser (e.g. a Nd:YAG laser) with a resonator length of e.g. 10 cm can produce light pulses of several tens of nanoseconds duration. Even when the average power is well below 1 W, the peak power can be many kilowatts. Large-scale laser systems can produce Q-switched pulses with energies of many joules and peak powers in the gigawatt region. On the other hand, passively Q-switched microchip lasers (with very short resonators) have generated pulses with durations far below one nanosecond and pulse repetition rates from hundreds of hertz to several megahertz (MHz)
# Applications
Q-switched lasers are often used in applications which demand high laser intensities in nanosecond pulses, such metal cutting or pulsed holography. Nonlinear optics often takes advantage of the high peak powers of these lasers, offering applications such as 3D optical data storage and 3D microfabrication. However, Q-switched lasers can also be used for measurement purposes, such as for distance measurements (range finding) by measuring the time it takes for the pulse to get to some target and the reflected light to get back to the sender.
Q-switched lasers are used to remove tattoos. They are used to shatter tattoo pigment into particles that are cleared by the body's lymphatic system. Full removal takes an average of eight treatments, spaced at least a month apart, using different lasers for different colored inks. | Q-switching
Q-switching, sometimes known as giant pulse formation, is a technique by which a laser can be made to produce a pulsed output beam. The technique allows the production of light pulses with extremely high (gigawatt) peak power, much higher than would be produced by the same laser if it were operating in a continuous wave (constant output) mode. Compared to modelocking, another technique for pulse generation with lasers, Q-switching leads to much lower pulse repetition rates, much higher pulse energies, and much longer pulse durations. Both techniques are sometimes applied at once .
Q-switching was first proposed in 1958 by Gordon Gould[1], and independently discovered and demonstrated in 1961 or 1962 by R.W. Hellwarth and F.J. McClung using electrically switched Kerr cell shutters in a ruby laser.[2]
# Principle of Q-switching
Q-switching is achieved by putting some type of variable attenuator inside the laser's optical resonator. When the attenuator is functioning, light which leaves the gain medium does not return, and lasing cannot begin. This attenuation inside the cavity corresponds to a decrease in the Q factor or quality factor of the optical resonator. A high Q factor corresponds to low resonator losses per roundtrip, and vice versa. The variable attenuator is commonly called a "Q-switch", when used for this purpose.
Initially the laser medium is pumped while the Q-switch is set to prevent feedback of light into the gain medium (producing an optical resonator with low Q). This produces a population inversion, but laser operation cannot yet occur since there is no feedback from the resonator. Since the rate of stimulated emission is dependent on the amount of light entering the medium, the amount of energy stored in the gain medium increases as the medium is pumped. Due to losses from spontaneous emission and other processes, after a certain time the stored energy will reach some maximum level; the medium is said to be gain saturated. At this point, the Q-switch device is quickly changed from low to high Q, allowing feedback and the process of optical amplification by stimulated emission to begin. Because of the large amount of energy already stored in the gain medium, the intensity of light in the laser resonator builds up very quickly; this also causes the energy stored in the medium to be depleted almost as quickly. The net result is a short pulse of light output from the laser, known as a giant pulse, which may have a very high peak intensity.
There are two main types of Q-switching:
## Active Q-switching
Here, the Q-switch is an externally-controlled variable attenuator. This may be a mechanical device such as a shutter, chopper wheel or spinning mirror placed inside the cavity, or (more commonly) it may be some form of modulator such as an acousto-optic device or an electro-optic device — a Pockels cell or Kerr cell. The reduction of losses (increase of Q) is triggered by an external event, typically an electrical signal. The pulse repetition rate can therefore be externally controlled.
Modulators generally allow a faster transition from low to high Q, and provide better control. An additional advantage of modulators is that the rejected light may be coupled out of the cavity and can be used for something else. Alternatively, when the modulator is in its low-Q state, an externally-generated beam can be coupled into the cavity through the modulator. This can be used to "seed" the cavity with a beam that has desired characteristics (such as transverse mode or wavelength). When the Q is raised, lasing builds up from the initial seed, producing a Q-switched pulse that has characteristics inherited from the seed.
## Passive Q-switching
In this case, the Q-switch is a saturable absorber, a material whose transmission increases when the intensity of light exceeds some threshold. The material may be an ion-doped crystal like Cr:YAG, which is used for Q-switching of Nd:YAG lasers, a bleachable dye, or a passive semiconductor device. Initially, the loss of the absorber is high, but still low enough to permit some lasing once a large amount of energy is stored in the gain medium. As the laser power increases, it saturates the absorber, i.e., rapidly reduces the resonator loss, so that the power can increase even faster. Ideally, this brings the absorber into a state with low losses to allow efficient extraction of the stored energy by the laser pulse. After the pulse, the absorber recovers to its high-loss state before the gain recovers, so that the next pulse is delayed until the energy in the gain medium is fully replenished. The pulse repetition rate can only indirectly be controlled, e.g. by varying the laser's pump power and the amount of saturable absorber in the cavity. Direct control of the repetition rate can be achieved by using a pulsed pump source as well as passive Q-switching.
## Variants
- Jitter can be reduced by not reducing the Q by as much, so that a small amount of light can still circulate in the cavity. This provides a "seed" of light that can aid in the buildup of the next Q-switched pulse.
- Cavity dumping: The cavity end mirrors are 100% reflective, so that no output beam is produced when the Q is high. Instead, the Q-switch is used to "dump" the beam out of the cavity after a time delay. The cavity Q goes from low to high to start the laser buildup, and then goes from high to low to "dump" the beam from the cavity all at once. This produces a shorter output pulse than regular Q-switching. Electro-optic modulators are normally used for this, since they can easily be made to function as a near-perfect beam "switch" to couple the beam out of the cavity. The modulator that dumps the beam may be the same modulator that Q-switches the cavity, or a second (possibly identical) modulator. A dumped cavity is more complicated to align than simple Q-switching, and may need a control loop to choose the best time at which to dump the beam from the cavity.
- Regenerative amplification: In regenerative amplification, an optical amplifier is placed inside a Q-switched cavity. Pulses of light from another laser (the "master oscillator") are injected into the cavity by lowering the Q to allow the pulse to enter and then increasing the Q to confine the pulse to the cavity where it can be amplified by repeated passes through the gain medium. The pulse is then allowed to leave the cavity via another Q switch.
# Typical performance
A typical Q-switched laser (e.g. a Nd:YAG laser) with a resonator length of e.g. 10 cm can produce light pulses of several tens of nanoseconds duration. Even when the average power is well below 1 W, the peak power can be many kilowatts. Large-scale laser systems can produce Q-switched pulses with energies of many joules and peak powers in the gigawatt region. On the other hand, passively Q-switched microchip lasers (with very short resonators) have generated pulses with durations far below one nanosecond and pulse repetition rates from hundreds of hertz to several megahertz (MHz)
# Applications
Q-switched lasers are often used in applications which demand high laser intensities in nanosecond pulses, such metal cutting or pulsed holography. Nonlinear optics often takes advantage of the high peak powers of these lasers, offering applications such as 3D optical data storage and 3D microfabrication. However, Q-switched lasers can also be used for measurement purposes, such as for distance measurements (range finding) by measuring the time it takes for the pulse to get to some target and the reflected light to get back to the sender.
Q-switched lasers are used to remove tattoos. They are used to shatter tattoo pigment into particles that are cleared by the body's lymphatic system. Full removal takes an average of eight treatments, spaced at least a month apart, using different lasers for different colored inks. | https://www.wikidoc.org/index.php/Q-switched | |
9d43153f5ddc865d5d815ed4e0383775fdb757e1 | wikidoc | Triple test | Triple test
# Overview
The triple test, also called triple screen, the Kettering test or the Bart's test, is an investigation performed during pregnancy (usually the second trimester).
# Conditions detected
The most common abnormality the test can detect is fetal trisomy 21 (Down syndrome).
In addition to Down syndrome, the triple and quadruple tests preferentially identify fetal trisomy 18, Turner syndrome, triploidy, trisomy 16 mosaicism, fetal death, Smith-Lemli-Opitz syndrome, and steroid sulfatase deficiency.
# Values measured
The triple test measures the following three levels in the maternal serum:
- alpha-fetoprotein (AFP)
- human chorionic gonadotropin (hCG)
- unconjugated estriol (UE3)
# Interpretation
Low values for AFP and UE3 and high values for hCG and nuchal thickness suggest an increased risk of developing Down's Syndrome. High levels for AFP indicate possible neural tube defects like spina bifida. An estimated risk is calculated and adjusted for the expectant mother's age, weight and ethnicity; if she's diabetic; if she's having twins or other multiples and the gestational age of the fetus. Many of these factors affect the levels of the substances being measured and the interpretation of the results.
The test is for screening, not for diagnosis, and does not have nearly the same predictive power of amniocentesis or chorionic villus sampling. However, the screening test carries a much lower risk to the fetus, and in conjunction with the age-related risk by the patient is useful to indicate the need to proceed to the more invasive tests.
# Variations
Only two of the hormones above can be tested for. Then the test is instead called a double test. In contrast, a quad test focuses on yet another hormone in addition. Furthermore, the triple test may be combined with an ultrasound measurement of nuchal translucency.
## Double test
Only AFP and hCG are measured. However, the maternal age, weight, ethnicity etc. are still included. A double test is almost as effective as a triple test, because unconjugated estriol, the omitted hormone, is, in practice, not detected at a higher rate in people who have it, than in people without.
## Quad test
The term "quadruple test" or "quad test" is sometimes used to refer to the above three tests plus a test for dimeric inhibin A (DIA). | Triple test
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The triple test, also called triple screen, the Kettering test or the Bart's test, is an investigation performed during pregnancy (usually the second trimester).
# Conditions detected
The most common abnormality the test can detect is fetal trisomy 21 (Down syndrome).
In addition to Down syndrome, the triple and quadruple tests preferentially identify fetal trisomy 18, Turner syndrome, triploidy, trisomy 16 mosaicism, fetal death, Smith-Lemli-Opitz syndrome, and steroid sulfatase deficiency.
# Values measured
The triple test measures the following three levels in the maternal serum:
- alpha-fetoprotein (AFP)
- human chorionic gonadotropin (hCG)
- unconjugated estriol (UE3)
# Interpretation
Low values for AFP and UE3 and high values for hCG and nuchal thickness suggest an increased risk of developing Down's Syndrome. High levels for AFP indicate possible neural tube defects like spina bifida. An estimated risk is calculated and adjusted for the expectant mother's age, weight and ethnicity; if she's diabetic; if she's having twins or other multiples and the gestational age of the fetus. Many of these factors affect the levels of the substances being measured and the interpretation of the results.
The test is for screening, not for diagnosis, and does not have nearly the same predictive power of amniocentesis or chorionic villus sampling. However, the screening test carries a much lower risk to the fetus, and in conjunction with the age-related risk by the patient is useful to indicate the need to proceed to the more invasive tests.
# Variations
Only two of the hormones above can be tested for. Then the test is instead called a double test. In contrast, a quad test focuses on yet another hormone in addition. Furthermore, the triple test may be combined with an ultrasound measurement of nuchal translucency.
## Double test
Only AFP and hCG are measured. However, the maternal age, weight, ethnicity etc. are still included. A double test is almost as effective as a triple test[1], because unconjugated estriol, the omitted hormone, is, in practice, not detected at a higher rate in people who have it, than in people without[1].
## Quad test
The term "quadruple test" or "quad test" is sometimes used to refer to the above three tests plus a test for dimeric inhibin A (DIA). | https://www.wikidoc.org/index.php/Quad_screen | |
8d00a2147bf1af3a8d2c18b7989685c94c319b08 | wikidoc | QuantiFERON | QuantiFERON
QuantiFERON is the registered trademark of two tests for tuberculosis or latent tuberculosis, manufactured by Cellestis Limited, Carnegie, Victoria, Australia. These are interferon-γ release assays used in tuberculosis diagnosis.
# QuantiFERON-TB
According to the U.S. Centers for Disease Control,:
In 2001, the QuantiFERON®-TB test (QFT) was approved by the Food and Drug Administration (FDA) as an aid for detecting latent Mycobacterium tuberculosis infection (1). This test is an in vitro diagnostic aid that measures a component of cell-mediated immune reactivity to M. tuberculosis. The test is based on the quantification of interferon-gamma (IFN-γ) released from sensitized lymphocytes in whole blood incubated overnight with purified protein derivative (PPD) from M. tuberculosis and control antigens.
Tuberculin skin testing (TST) has been used for years as an aid in diagnosing latent tuberculosis infection (LTBI) and includes measurement of the delayed type hypersensitivity response 48--72 hours after intradermal injection of PPD. TST and QFT do not measure the same components of the immunologic response and are not interchangeable. Assessment of the accuracy of these tests is limited by lack of a standard for confirming LTBI.
As a diagnostic test, QFT 1) requires phlebotomy, 2) can be accomplished after a single patient visit, 3) assesses responses to multiple antigens simultaneously, and 4) does not boost anamnestic immune responses. Compared with TST, QFT results are less subject to reader bias and error. In a CDC-sponsored multicenter trial, QFT and TST results were moderately concordant (overall kappa value = 0.60). The level of concordance was adversely affected by prior bacille Calmette-Guérin (BCG) vaccination, immune reactivity to nontuberculous mycobacteria (NTM), and a prior positive TST (2). In addition to the multicenter study, two other published studies have demonstrated moderate concordance between TST and QFT (3,4). However, one of the five sites involved in the CDC study reported less agreement (5).
Limitations of QFT include the need to draw blood and process it within 12 hours after collection and limited laboratory and clinical experience with the assay. The utility of QFT in predicting the progression to active tuberculosis has not been evaluated.
# QuantiFERON-TB Gold
According to the U.S. Centers for Disease Control,
The QuantiFERON®-TB Gold test (QFT-G) is a whole-blood test for use as an aid in diagnosing Mycobacterium tuberculosis infection, including latent tuberculosis infection (LTBI) and tuberculosis (TB) disease. This test was approved by the U.S. Food and Drug Administration (FDA) in 2005.
Blood samples are mixed with antigens (substances that can produce an immune response) and controls. For QFT-G, the antigens include mixtures of synthetic peptides representing two M. tuberculosis proteins, ESAT-6 and CFP-10. After incubation of the blood with antigens for 16 to 24 hours, the amount of interferon-gamma (IFN-gamma) is measured.
If the patient is infected with M. tuberculosis, their white blood cells will release IFN-gamma in response to contact with the TB antigens. The QFT-G results are based on the amount of IFN-gamma that is released in response to the antigens.
Clinical evaluation and additional tests (such as a chest radiograph, sputum smear, and culture) are needed to confirm the diagnosis of LTBI or TB disease.
Advantages of the test are:
- Requires a single patient visit to draw a blood sample.
- Results can be available within 24 hours.
- Does not boost responses measured by subsequent tests, which can happen with tuberculin skin tests (TST).
- Is not subject to reader bias that can occur with TST.
- Is not affected by prior BCG (bacille Calmette-Guérin) vaccination.
Disadvantages and limitations of the test are:
- Blood samples must be processed within 12 hours after collection while white blood cells are still viable.
- There are limited data on the use of QFT-G in children younger than 17 years of age, among persons recently exposed to M. tuberculosis, and in immunocompromised persons (e.g., impaired immune function caused by HIV infection or acquired immunodeficiency syndrome , current treatment with immunosuppressive drugs, selected hematological disorders, specific malignancies, diabetes, silicosis, and chronic renal failure).
- Errors in collecting or transporting blood specimens or in running and interpreting the assay can decrease the accuracy of QFT-G.
- Limited data on the use of QFT-G to determine who is at risk for developing TB disease. | QuantiFERON
QuantiFERON is the registered trademark of two tests for tuberculosis or latent tuberculosis, manufactured by Cellestis Limited, Carnegie, Victoria, Australia. These are interferon-γ release assays used in tuberculosis diagnosis.
# QuantiFERON-TB
According to the U.S. Centers for Disease Control,[1]:
In 2001, the QuantiFERON®-TB test (QFT) was approved by the Food and Drug Administration (FDA) as an aid for detecting latent Mycobacterium tuberculosis infection (1). This test is an in vitro diagnostic aid that measures a component of cell-mediated immune reactivity to M. tuberculosis. The test is based on the quantification of interferon-gamma (IFN-γ) released from sensitized lymphocytes in whole blood incubated overnight with purified protein derivative (PPD) from M. tuberculosis and control antigens.
Tuberculin skin testing (TST) has been used for years as an aid in diagnosing latent tuberculosis infection (LTBI) and includes measurement of the delayed type hypersensitivity response 48--72 hours after intradermal injection of PPD. TST and QFT do not measure the same components of the immunologic response and are not interchangeable. Assessment of the accuracy of these tests is limited by lack of a standard for confirming LTBI.
As a diagnostic test, QFT 1) requires phlebotomy, 2) can be accomplished after a single patient visit, 3) assesses responses to multiple antigens simultaneously, and 4) does not boost anamnestic immune responses. Compared with TST, QFT results are less subject to reader bias and error. In a CDC-sponsored multicenter trial, QFT and TST results were moderately concordant (overall kappa value = 0.60). The level of concordance was adversely affected by prior bacille Calmette-Guérin (BCG) vaccination, immune reactivity to nontuberculous mycobacteria (NTM), and a prior positive TST (2). In addition to the multicenter study, two other published studies have demonstrated moderate concordance between TST and QFT (3,4). However, one of the five sites involved in the CDC study reported less agreement (5).
Limitations of QFT include the need to draw blood and process it within 12 hours after collection and limited laboratory and clinical experience with the assay. The utility of QFT in predicting the progression to active tuberculosis has not been evaluated.
# QuantiFERON-TB Gold
According to the U.S. Centers for Disease Control,[2]
The QuantiFERON®-TB Gold test (QFT-G) is a whole-blood test for use as an aid in diagnosing Mycobacterium tuberculosis infection, including latent tuberculosis infection (LTBI) and tuberculosis (TB) disease. This test was approved by the U.S. Food and Drug Administration (FDA) in 2005.
Blood samples are mixed with antigens (substances that can produce an immune response) and controls. For QFT-G, the antigens include mixtures of synthetic peptides representing two M. tuberculosis proteins, ESAT-6 and CFP-10. After incubation of the blood with antigens for 16 to 24 hours, the amount of interferon-gamma (IFN-gamma) is measured.
If the patient is infected with M. tuberculosis, their white blood cells will release IFN-gamma in response to contact with the TB antigens. The QFT-G results are based on the amount of IFN-gamma that is released in response to the antigens.
Clinical evaluation and additional tests (such as a chest radiograph, sputum smear, and culture) are needed to confirm the diagnosis of LTBI or TB disease.
Advantages of the test are:
- Requires a single patient visit to draw a blood sample.
- Results can be available within 24 hours.
- Does not boost responses measured by subsequent tests, which can happen with tuberculin skin tests (TST).
- Is not subject to reader bias that can occur with TST.
- Is not affected by prior BCG (bacille Calmette-Guérin) vaccination.
Disadvantages and limitations of the test are:
- Blood samples must be processed within 12 hours after collection while white blood cells are still viable.
- There are limited data on the use of QFT-G in children younger than 17 years of age, among persons recently exposed to M. tuberculosis, and in immunocompromised persons (e.g., impaired immune function caused by HIV infection or acquired immunodeficiency syndrome [AIDS], current treatment with immunosuppressive drugs, selected hematological disorders, specific malignancies, diabetes, silicosis, and chronic renal failure).
- Errors in collecting or transporting blood specimens or in running and interpreting the assay can decrease the accuracy of QFT-G.
- Limited data on the use of QFT-G to determine who is at risk for developing TB disease. | https://www.wikidoc.org/index.php/QuantiFERON | |
929477bd2aee3bdac43fec2158fe7ed6a6a527ee | wikidoc | R-spondin 1 | R-spondin 1
R-spondin-1 is a secreted protein that in humans is encoded by the Rspo1 gene, found on chromosome 1. In humans, it interacts with WNT4 in the process of female sex development. Loss of function can cause female to male sex reversal. Furthermore, it promotes canonical WNT/β catenin signaling.
# Structure
The protein has two cysteine-rich, furin-like domains and one thrombospondin type 1 domain.
# Function
## Sex Development
### Early Gonads
RSPO1 is required for the early development of gonads, regardless of sex. It has been found in mice only eleven days after fertilization. To induce cell proliferation, it acts synergistically with WNT4. They help stabilize β-catenin, which activates downstream targets. If both are deficient in XY mice, there is less expression of SRY and a reduction in the amount of SOX9. Moreover, defects in vascularization are found. These occurrences result in testicular hypoplasia. Male to female sex reversal, however, does not occur because Leydig cells remain normal. They are maintained by steroidogenic cells, now unrepressed.
### Ovaries
RSPO1 is necessary in female sex development. It augments the WNT/β catenin pathway to oppose male sex development. In critical gonadal stages, between six and nine weeks after fertilization, the ovaries upregulate it while the testes downregulate it.
## Mucositis
Oral mucosa has been identified as a target tissue for RSPO1. When administered to normal mice, it causes nuclear translocation of β-catenin to this region. Modulation of the WNT/β catenin pathway occurs through the relief of Dkk1 inhibition. This occurrence results in increased basal cellularity, thickened mucosa, and elevated epithelial cell proliferation in the tongue. RSPO1 can therefore potentially aid in the treatment of mucositis, which is characterized by inflammation of the oral cavity. This unfortunate condition often accompanies chemotherapy and radiation in cancer patients with head and neck tumors. RSPO1 has also been shown to promote gastrointestinal epithelial cell proliferation in mice. | R-spondin 1
R-spondin-1 is a secreted protein that in humans is encoded by the Rspo1 gene, found on chromosome 1.[1] In humans, it interacts with WNT4 in the process of female sex development. Loss of function can cause female to male sex reversal.[2] Furthermore, it promotes canonical WNT/β catenin signaling.[3]
# Structure
The protein has two cysteine-rich, furin-like domains and one thrombospondin type 1 domain.[1]
# Function
## Sex Development
### Early Gonads
RSPO1 is required for the early development of gonads, regardless of sex. It has been found in mice only eleven days after fertilization.[2] To induce cell proliferation, it acts synergistically with WNT4.[2] They help stabilize β-catenin, which activates downstream targets. If both are deficient in XY mice, there is less expression of SRY and a reduction in the amount of SOX9. Moreover, defects in vascularization are found. These occurrences result in testicular hypoplasia. Male to female sex reversal, however, does not occur because Leydig cells remain normal. They are maintained by steroidogenic cells, now unrepressed.[2]
### Ovaries
RSPO1 is necessary in female sex development. It augments the WNT/β catenin pathway to oppose male sex development. In critical gonadal stages, between six and nine weeks after fertilization, the ovaries upregulate it while the testes downregulate it.[4]
## Mucositis
Oral mucosa has been identified as a target tissue for RSPO1. When administered to normal mice, it causes nuclear translocation of β-catenin to this region.[3] Modulation of the WNT/β catenin pathway occurs through the relief of Dkk1 inhibition. This occurrence results in increased basal cellularity, thickened mucosa, and elevated epithelial cell proliferation in the tongue. RSPO1 can therefore potentially aid in the treatment of mucositis, which is characterized by inflammation of the oral cavity. This unfortunate condition often accompanies chemotherapy and radiation in cancer patients with head and neck tumors.[3] RSPO1 has also been shown to promote gastrointestinal epithelial cell proliferation in mice.[1] | https://www.wikidoc.org/index.php/R-spondin_1 | |
ab3b3ddf7c964ce31ac7b3f8b7b6179c185ab355 | wikidoc | R-spondin 3 | R-spondin 3
R-spondin-3 is a protein that in humans is encoded by the RSPO3 gene.
# Function
This gene encodes a member of the thrombospondin type 1 repeat supergene family. In addition, the protein contains a furin-like cysteine-rich region. Furin-like repeat domains have been found in a variety of eukaryotic proteins involved in the mechanism of signal transduction by receptor tyrosine kinases.
During embryonic development, RSPO3 is expressed in the tail bud and the posterior presomitic mesoderm of the embryo. In tissue engineering, R-spondin 3 has been used to differentiate pluripotent stem cells into paraxial mesoderm progenitors | R-spondin 3
R-spondin-3 is a protein that in humans is encoded by the RSPO3 gene.[1][2][3]
# Function
This gene encodes a member of the thrombospondin type 1 repeat supergene family. In addition, the protein contains a furin-like cysteine-rich region. Furin-like repeat domains have been found in a variety of eukaryotic proteins involved in the mechanism of signal transduction by receptor tyrosine kinases.[3]
During embryonic development, RSPO3 is expressed in the tail bud and the posterior presomitic mesoderm of the embryo. In tissue engineering, R-spondin 3 has been used to differentiate pluripotent stem cells into paraxial mesoderm progenitors[4] | https://www.wikidoc.org/index.php/R-spondin_3 | |
da3cbfe7b03084b7db32707b781a28c248314d09 | wikidoc | RARS (gene) | RARS (gene)
Arginyl-tRNA synthetase, cytoplasmic is an enzyme that in humans is encoded by the RARS gene.
Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Arginyl-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family.
# Genetics
Mutations in RARS cause hypomyelination .
# Interactions
RARS (gene) has been shown to interact with QARS. | RARS (gene)
Arginyl-tRNA synthetase, cytoplasmic is an enzyme that in humans is encoded by the RARS gene.[1][2]
Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Arginyl-tRNA synthetase belongs to the class-I aminoacyl-tRNA synthetase family.[2]
# Genetics
Mutations in RARS cause hypomyelination .[3]
# Interactions
RARS (gene) has been shown to interact with QARS.[4] | https://www.wikidoc.org/index.php/RARS_(gene) | |
30333b6b03e9cc828c6ec52adac4dde1325ca9a5 | wikidoc | RHCE (gene) | RHCE (gene)
Blood group Rh(CE) polypeptide is a protein that in humans is encoded by the RHCE gene. RHCE has also recently been designated CD240CE (cluster of differentiation 240CE).
The Rh blood group system is the second most clinically significant of the blood groups, second only to ABO. It is also the most polymorphic of the blood groups, with variations due to deletions, gene conversions, and missense mutations. The Rh blood group includes this gene which encodes both the RhC and RhE antigens on a single polypeptide and a second gene which encodes the RhD protein. The classification of Rh-positive and Rh-negative individuals is determined by the presence or absence of the highly immunogenic RhD protein on the surface of erythrocytes. Alternative splicing of this gene results in four transcript variants encoding four different isoforms.
A recent study in the population of the island of Sardinia shows the association of a noncoding variant in the RHCE gene (rs630337) with an increased erythrocyte sedimentation rate(ESR). This suggest a possible causal effect of this polymorphism on this inflammatory marker despite not found in coding region of the gene. | RHCE (gene)
Blood group Rh(CE) polypeptide is a protein that in humans is encoded by the RHCE gene.[1][2] RHCE has also recently been designated CD240CE (cluster of differentiation 240CE).
The Rh blood group system is the second most clinically significant of the blood groups, second only to ABO. It is also the most polymorphic of the blood groups, with variations due to deletions, gene conversions, and missense mutations. The Rh blood group includes this gene which encodes both the RhC and RhE antigens on a single polypeptide and a second gene which encodes the RhD protein. The classification of Rh-positive and Rh-negative individuals is determined by the presence or absence of the highly immunogenic RhD protein on the surface of erythrocytes. Alternative splicing of this gene results in four transcript variants encoding four different isoforms.[2]
A recent study in the population of the island of Sardinia shows the association of a noncoding variant in the RHCE gene (rs630337) with an increased erythrocyte sedimentation rate(ESR). This suggest a possible causal effect of this polymorphism on this inflammatory marker despite not found in coding region of the gene.[3] | https://www.wikidoc.org/index.php/RHCE_(gene) | |
4bf3b0a4bbbcda595388a7f9849461642c5afb1b | wikidoc | RICS (gene) | RICS (gene)
Rho GTPase-activating protein 32 is a protein that in humans is encoded by the RICS gene. RICS has two known isoforms, RICS that are expressed primarily at neurite growth cones, and at the post synaptic membranes, and PX-RICS which is more widely expressed in the endoplasmic reticulum, Golgi apparatus and endosomes. The only known domain of the RICS is the RhoGAP domain, whilst PX-RICS has an additional Phox homology and SH3 domain.
# Function
RICS (a.k.a. GRIT/Arhgap32) is a neuron-associated GTPase-activating protein that may regulate dendritic spine morphology and strength by modulating Rho GTPase activity.
# Isoforms
## RICS
Experiments have shown that knocking down RICS, or just knocking out its GAP or C-terminal TrkA binding site, results in abnormally extended neurites, and blocks NGF regulated outgrowth.
The GAP activity of RICS is known to be regulated by two phosphorylation sites, one controlled by CaMKII, and the other by RPTPa. When CaMKII is activated by Ca2+ entry through NMDA receptors and inactivates RICS through phosphorylation, which in turn increases the active GTP-bound forms of Cdc42 and Rac1. This would thereby induce, for example, remodeling of dendritic spines. Because it has been shown in some experiments that Cdc42 does not affect spine morphology, whilst others have shown that Rac1 does (via the PAK1, LIMK, CFL1 pathway), the most likely pathway is via Rac1. That RACS also binds to β-catenin and N-cadherins, in vivo within the PSD (which it binds to through PSD-95, and weak binding to the NR2 subunits) suggests that there may be another pathway for it modifying spine structure as well. The RPTPa controlled phosphorylation site controls the specificity of the GAP activity, through a mechanism thought to involve movement of the c-terminal region of RICS. In the phosphorylated state, RICS can affect Rac, Rho and Cdc42, but after dephosphorylation by RPTPa it can only affect Rac. A further phosphorylation site, regulated by FYN controls the binding of RPTPa to RICS.
## PX-RICS
PX-RICS is the dominant isoform expressed during nervous system development. It is known to have much lower GAP activity than RICS. Although it is more generally expressed than RICS, it is still known to inhibit neuronal elongation. Furthering the idea that it is a synaptically relevant isoform is that it is known to bind NR2B and PSD95 in vivo.
PX-RICS is known to be involved in transport of certain synaptic proteins which lack ER export signals, from the endoplasmic reticulum, to the Golgi apparatus. This has been shown for the β-catenin and N-cadherin, the later of which lacks the ER export signal, and the former which binds the later within the ER as a necessary but not sufficient part of its export process. PX-RICS was found to be a necessary component for the export of this complex to the Golgi and then onwards to the cellular membrane. PX-RICS is thought to do this by first localizing to the ER membrane---this it does by binding to GABARAP which binds ER, and through its Phox homology domain, which has a high binding affinity for Pi4P, the predominant phosphoinositide in the endoplasmic reticulum and Golgi apparatus. PX-RICS is then thought to bind a heterodimer of the 14-3-3 proteins encoded by YWHAZ and YWHAQ genes. The site were this binding occurs is a RSKSDP site in PX-RICS c-terminal, which is phosphorylated by CAMKII to encourage the binding. It has also now been shown that membrane transport of FGFR4, a N-Cadherin binding protein, is affected by PX-RICS knockdown.
# Interactions
RICS (gene) has been shown to interact with:
- BCAR1,
- CDC42,
- CRK,
- CRKL,
- FYN,
- GAB2,
- GRIN2B,
- NCK1,
- RAC1,
- RHOA,
- SHC3,
- Src, and
- TrkA.
The Mir-132 microRNA has been described as targeting the mRNA from this gene for degradation; this is thought to be important in the regulation of neuronal development. | RICS (gene)
Rho GTPase-activating protein 32 is a protein that in humans is encoded by the RICS gene.[1] RICS has two known isoforms, RICS that are expressed primarily at neurite growth cones, and at the post synaptic membranes, and PX-RICS which is more widely expressed in the endoplasmic reticulum, Golgi apparatus and endosomes.[2] The only known domain of the RICS is the RhoGAP domain, whilst PX-RICS has an additional Phox homology and SH3 domain.
# Function
RICS (a.k.a. GRIT/Arhgap32) is a neuron-associated GTPase-activating protein that may regulate dendritic spine morphology and strength by modulating Rho GTPase activity.[1][2]
# Isoforms
## RICS
Experiments have shown that knocking down RICS, or just knocking out its GAP or C-terminal TrkA binding site, results in abnormally extended neurites, and blocks NGF regulated outgrowth.[3]
The GAP activity of RICS is known to be regulated by two phosphorylation sites, one controlled by CaMKII, and the other by RPTPa. When CaMKII is activated by Ca2+ entry through NMDA receptors and inactivates RICS through phosphorylation, which in turn increases the active GTP-bound forms of Cdc42 and Rac1. This would thereby induce, for example, remodeling of dendritic spines. Because it has been shown in some experiments that Cdc42 does not affect spine morphology, whilst others have shown that Rac1 does (via the PAK1, LIMK, CFL1 pathway), the most likely pathway is via Rac1. That RACS also binds to β-catenin and N-cadherins, in vivo within the PSD (which it binds to through PSD-95, and weak binding to the NR2 subunits) suggests that there may be another pathway for it modifying spine structure as well.[2] The RPTPa controlled phosphorylation site controls the specificity of the GAP activity, through a mechanism thought to involve movement of the c-terminal region of RICS. In the phosphorylated state, RICS can affect Rac, Rho and Cdc42, but after dephosphorylation by RPTPa it can only affect Rac. A further phosphorylation site, regulated by FYN controls the binding of RPTPa to RICS.[4]
## PX-RICS
PX-RICS is the dominant isoform expressed during nervous system development. It is known to have much lower GAP activity than RICS. Although it is more generally expressed than RICS, it is still known to inhibit neuronal elongation.[5] Furthering the idea that it is a synaptically relevant isoform is that it is known to bind NR2B and PSD95 in vivo.
PX-RICS is known to be involved in transport of certain synaptic proteins which lack ER export signals, from the endoplasmic reticulum, to the Golgi apparatus. This has been shown for the β-catenin and N-cadherin, the later of which lacks the ER export signal, and the former which binds the later within the ER as a necessary but not sufficient part of its export process. PX-RICS was found to be a necessary component for the export of this complex to the Golgi and then onwards to the cellular membrane. PX-RICS is thought to do this by first localizing to the ER membrane---this it does by binding to GABARAP which binds ER, and through its Phox homology domain, which has a high binding affinity for Pi4P, the predominant phosphoinositide in the endoplasmic reticulum and Golgi apparatus. PX-RICS is then thought to bind a heterodimer of the 14-3-3 proteins encoded by YWHAZ and YWHAQ genes. The site were this binding occurs is a RSKSDP site in PX-RICS c-terminal, which is phosphorylated by CAMKII to encourage the binding.[6] It has also now been shown that membrane transport of FGFR4, a N-Cadherin binding protein, is affected by PX-RICS knockdown.[7]
# Interactions
RICS (gene) has been shown to interact with:
- BCAR1,[3][8]
- CDC42,[3][8][9]
- CRK,[8][10]
- CRKL,[3]
- FYN,[11]
- GAB2,[8]
- GRIN2B,[9]
- NCK1,[8]
- RAC1,[8][10]
- RHOA,[3][9][10]
- SHC3,[3]
- Src,[10] and
- TrkA.[3]
The Mir-132 microRNA has been described as targeting the mRNA from this gene for degradation; this is thought to be important in the regulation of neuronal development.[12] | https://www.wikidoc.org/index.php/RICS_(gene) | |
25f8d53db405168145f13bef1e943ce76b092aed | wikidoc | Radiography | Radiography
Assistant Editor-In-Chief: Anand Patel, MD
Radiography is the use of certain types of electromagnetic radiation—usually ionizing—to view objects. The use of non-ionizing radiations (visible light and ultraviolet light) to view objects should be considered as a normal “optical” method (e.g., light microscopy). The modification of an object through the use of ionizing radiation is not radiography. Depending on the nature of the object and the intended outcome it can be radiotherapy, food irradiation, or radiation processing.
# Medical and industrial radiography
Radiography is used for both medical and industrial applications; for further details please see the Medical radiography and Industrial radiography pages. If the object being examined is living (human or animal) it is regarded as medical, and all other radiography is regarded as being industrial radiographic work.
# History of radiography
Radiography started in 1895 with the discovery of X-rays (also called Roentgen rays after the man who first described their properties in rigorous detail), a type of electromagnetic radiation. Soon X-rays were used in various applications, from helping to fit shoes, to the medical uses that have persisted. X-rays were put to diagnostic use very early, before the dangers of ionizing radiation were discovered. Initially, many kinds of staff conducted radiography in hospitals, including physicists, photographers, doctors, nurses, and engineers. The medical specialty of radiology grew up over many years around the new technology. When new diagnostic tests involving X-rays were developed, it was natural for the radiographers to be trained in and to adopt this new technology. This happened first with fluoroscopy, computed tomography (1960s), mammography, ultrasound (1970s), and magnetic resonance imaging (1980s). Although a nonspecialist dictionary might define radiography quite narrowly as "taking X-ray images", this has long been only part of the work of "X-ray departments", radiographers, and radiologists.
# Equipment
Below is a very short overview. For more details please see the radiographic equipment page.
## Sources
A number of sources of X-ray photons have been used, these include sealed X-ray tubes, betatrons and linacs. For gamma photons, radioactive sources such as 192Ir have been used.
## Detectors
A range of detectors including photographic film, scintillator and semiconductor diode arrays have been used to collect images.
# Theory of X-ray attenuation
Medical usage X-ray photons are more likely to be formed by an event involving an electron, while gamma ray photons are more likely to be formed from the nucleus of an atom. In general, medical radiography is done using X-rays formed in an X-ray tube. Nuclear medicine typically involves gamma rays.
The types of electromagnetic radiation of most interest to radiography are X-ray and gamma radiation. This radiation is much more energetic than the more familiar types such as radio waves and visible light. It is this relatively high energy which makes gamma rays useful in radiography but potentially hazardous to living organisms.
The radiation is produced by X-ray tubes, high energy X-ray equipment or natural radioactive elements, such as radium and radon, and artificially produced radioactive isotopes of elements, such as cobalt-60 and iridium-192. Electromagnetic radiation consists of oscillating electric and magnetic fields, but is generally depicted as a single sinusoidal wave. While in the past radium and radon have both been used for radiography, they have fallen out of use as they are radiotoxic alpha radiation emitters which are expensive; iridium-192 and cobalt-60 are far better photon sources. For further details see commonly used gamma emitting isotopes.
Such a wave is characterised by its wavelength (the distance from a point on one cycle to the corresponding point on the next cycle) or its frequency (the number of oscillations per second). In a vacuum, all electromagnetic waves travel at the same speed, the speed of light (c). The wavelength (λ, lambda) and the frequency (f) are all related by the equation:
This is true for all electromagnetic radiation.
Electromagnetic radiation is known by various names, depending on its energy. The energy of these waves is related to the frequency and the wavelength by the relationship:
Where h is a constant known as Planck's Constant.
Gamma rays are indirectly ionizing radiation. A gamma ray passes through matter until it undergoes an interaction with an atomic particle, usually an electron. During this interaction, energy is transferred from the gamma ray to the electron, which is a directly ionizing particle. As a result of this energy transfer, the electron is liberated from the atom and proceeds to ionize matter by colliding with other electrons along its path. Other times, the passing gamma ray interferes with the orbit of the electron, and slows it, releasing energy but not becoming dislodged. The atom is not ionised, and the gamma ray continues on, although at a lower energy. This energy released is usually heat or another, weaker photon, and causes biological harm as a radiation burn. The chain reaction caused by the initial dose of radiation can continue after exposure, much like a sunburn continues to damage skin even after one is out of direct sunlight.
For the range of energies commonly used in radiography, the interaction between gamma rays and electrons occurs in two ways. One effect takes place where all the gamma ray's energy is transmitted to an entire atom. The gamma ray no longer exists and an electron emerges from the atom with kinetic (motion in relation to force) energy almost equal to the gamma energy. This effect is predominant at low gamma energies and is known as the photoelectric effect. The other major effect occurs when a gamma ray interacts with an atomic electron, freeing it from the atom and imparting to it only a fraction of the gamma ray's kinetic energy. A secondary gamma ray with less energy (hence lower frequency) also emerges from the interaction. This effect predominates at higher gamma energies and is known as the Compton effect.
In both of these effects the emergent electrons lose their kinetic energy by ionizing surrounding atoms. The density of ions so generated is a measure of the energy delivered to the material by the gamma rays.
The most common means of measuring the variations in a beam of radiation is by observing its effect on a photographic film. This effect is the same as that of light, and the more intense the radiation is, the more it darkens, or exposes, the film. Other methods are in use, such as the ionizing effect measured electronically, its ability to discharge an electrostatically charged plate or to cause certain chemicals to fluoresce as in fluoroscopy.
# Obsolete terminology
The term skiagrapher was used until about 1918 to mean radiographer. It was derived from Ancient Greek words for 'shadow' and 'writer'. | Radiography
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Assistant Editor-In-Chief: Anand Patel, MD [2]
Radiography is the use of certain types of electromagnetic radiation—usually ionizing—to view objects. The use of non-ionizing radiations (visible light and ultraviolet light) to view objects should be considered as a normal “optical” method (e.g., light microscopy). The modification of an object through the use of ionizing radiation is not radiography. Depending on the nature of the object and the intended outcome it can be radiotherapy, food irradiation, or radiation processing. [3]
# Medical and industrial radiography
Radiography is used for both medical and industrial applications; for further details please see the Medical radiography and Industrial radiography pages. If the object being examined is living (human or animal) it is regarded as medical, and all other radiography is regarded as being industrial radiographic work.
# History of radiography
Radiography started in 1895 with the discovery of X-rays (also called Roentgen rays after the man who first described their properties in rigorous detail), a type of electromagnetic radiation. Soon X-rays were used in various applications, from helping to fit shoes, to the medical uses that have persisted. X-rays were put to diagnostic use very early, before the dangers of ionizing radiation were discovered. Initially, many kinds of staff conducted radiography in hospitals, including physicists, photographers, doctors, nurses, and engineers. The medical specialty of radiology grew up over many years around the new technology. When new diagnostic tests involving X-rays were developed, it was natural for the radiographers to be trained in and to adopt this new technology. This happened first with fluoroscopy, computed tomography (1960s), mammography, ultrasound (1970s), and magnetic resonance imaging (1980s). Although a nonspecialist dictionary might define radiography quite narrowly as "taking X-ray images", this has long been only part of the work of "X-ray departments", radiographers, and radiologists.
# Equipment
Below is a very short overview. For more details please see the radiographic equipment page.
## Sources
A number of sources of X-ray photons have been used, these include sealed X-ray tubes, betatrons and linacs. For gamma photons, radioactive sources such as 192Ir have been used.
## Detectors
A range of detectors including photographic film, scintillator and semiconductor diode arrays have been used to collect images.
# Theory of X-ray attenuation
Medical usage X-ray photons are more likely to be formed by an event involving an electron, while gamma ray photons are more likely to be formed from the nucleus of an atom. In general, medical radiography is done using X-rays formed in an X-ray tube. Nuclear medicine typically involves gamma rays.
The types of electromagnetic radiation of most interest to radiography are X-ray and gamma radiation. This radiation is much more energetic than the more familiar types such as radio waves and visible light. It is this relatively high energy which makes gamma rays useful in radiography but potentially hazardous to living organisms.
The radiation is produced by X-ray tubes, high energy X-ray equipment or natural radioactive elements, such as radium and radon, and artificially produced radioactive isotopes of elements, such as cobalt-60 and iridium-192. Electromagnetic radiation consists of oscillating electric and magnetic fields, but is generally depicted as a single sinusoidal wave. While in the past radium and radon have both been used for radiography, they have fallen out of use as they are radiotoxic alpha radiation emitters which are expensive; iridium-192 and cobalt-60 are far better photon sources. For further details see commonly used gamma emitting isotopes.
Such a wave is characterised by its wavelength (the distance from a point on one cycle to the corresponding point on the next cycle) or its frequency (the number of oscillations per second). In a vacuum, all electromagnetic waves travel at the same speed, the speed of light (c). The wavelength (λ, lambda) and the frequency (f) are all related by the equation:
This is true for all electromagnetic radiation.
Electromagnetic radiation is known by various names, depending on its energy. The energy of these waves is related to the frequency and the wavelength by the relationship:
Where h is a constant known as Planck's Constant.
Gamma rays are indirectly ionizing radiation. A gamma ray passes through matter until it undergoes an interaction with an atomic particle, usually an electron. During this interaction, energy is transferred from the gamma ray to the electron, which is a directly ionizing particle. As a result of this energy transfer, the electron is liberated from the atom and proceeds to ionize matter by colliding with other electrons along its path. Other times, the passing gamma ray interferes with the orbit of the electron, and slows it, releasing energy but not becoming dislodged. The atom is not ionised, and the gamma ray continues on, although at a lower energy. This energy released is usually heat or another, weaker photon, and causes biological harm as a radiation burn. The chain reaction caused by the initial dose of radiation can continue after exposure, much like a sunburn continues to damage skin even after one is out of direct sunlight.
For the range of energies commonly used in radiography, the interaction between gamma rays and electrons occurs in two ways. One effect takes place where all the gamma ray's energy is transmitted to an entire atom. The gamma ray no longer exists and an electron emerges from the atom with kinetic (motion in relation to force) energy almost equal to the gamma energy. This effect is predominant at low gamma energies and is known as the photoelectric effect. The other major effect occurs when a gamma ray interacts with an atomic electron, freeing it from the atom and imparting to it only a fraction of the gamma ray's kinetic energy. A secondary gamma ray with less energy (hence lower frequency) also emerges from the interaction. This effect predominates at higher gamma energies and is known as the Compton effect.
In both of these effects the emergent electrons lose their kinetic energy by ionizing surrounding atoms. The density of ions so generated is a measure of the energy delivered to the material by the gamma rays.
The most common means of measuring the variations in a beam of radiation is by observing its effect on a photographic film. This effect is the same as that of light, and the more intense the radiation is, the more it darkens, or exposes, the film. Other methods are in use, such as the ionizing effect measured electronically, its ability to discharge an electrostatically charged plate or to cause certain chemicals to fluoresce as in fluoroscopy.
# Obsolete terminology
The term skiagrapher was used until about 1918 to mean radiographer. It was derived from Ancient Greek words for 'shadow' and 'writer'. | https://www.wikidoc.org/index.php/Radiograph | |
e3fcd698921f917cf7453a6a0d38ecd67b14cfcd | wikidoc | Radiophobia | Radiophobia
# Background
Radiophobia is an abnormal fear of ionizing radiation, also used in the sense of fear of X-rays. The term is used in several related senses: in reference to a neurological disorder, to a specific phobia, and (polemically, not medically) to general opposition to the use of nuclear energy.
Fear of ionizing radiation is not unnatural, since it can pose significant risks; however this fear may become abnormal and even irrational, often owing to poor information or understanding, but also as a consequence of traumatic experience.
# Radiophobia and Chernobyl
In the former Soviet Union many patients with radioactive sickness after the Chernobyl disaster were accused of radiophobia, perhaps in attempts to diminish the scale of the consequences. These claims were supported in some reports of experts from IAEA. At the same time, radiophobia (in the sense of an excessive fear of radiation) existed widely amongst the affected population, for the very reason that people believed that the government was lying and seriously understating the degree of danger. Lyubov Sirota, the author of Chernobyl Poems wrote in her poem, Radiophobia:
At the same time, medical experts investigating the psychological consequences of Chernobyl have presented evidence indicating that certain psychoneurological symptoms, manifesting themselves in fatigue, sleep disturbances, impaired memory, etc., (i.e., similar to those of chronic fatigue syndrome), appeared to have no direct correlation to the dose of radiation received, or to the level of contamination of the area of residence.
# Radiophobia as a term in the atomic energy debate
Attempts to downplay the danger of radiation by stigmatizing the opponents of nuclear plants and nuclear tests with the label of "phobiacs" took place in the USA.
Today the term "radiophobia" is polemically applied to the arguments of proponents of the LNT concept (Linear no-threshold response model for ionizing radiation) of radiation security proposed by the U.S. National Council on Radiation Protection and Measurements (NCRP) in 1949. The "no-threshold" position effectively assumes that even negligible doses of radiation may pose danger. The issue remains controversial. | Radiophobia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Radiophobia is an abnormal fear of ionizing radiation, also used in the sense of fear of X-rays. The term is used in several related senses: in reference to a neurological disorder, to a specific phobia, and (polemically, not medically) to general opposition to the use of nuclear energy.
Fear of ionizing radiation is not unnatural, since it can pose significant risks; however this fear may become abnormal and even irrational, often owing to poor information or understanding, but also as a consequence of traumatic experience.
# Radiophobia and Chernobyl
In the former Soviet Union many patients with radioactive sickness after the Chernobyl disaster were accused of radiophobia[2], perhaps in attempts to diminish the scale of the consequences. These claims were supported in some reports of experts from IAEA. At the same time, radiophobia (in the sense of an excessive fear of radiation) existed widely amongst the affected population, for the very reason that people believed that the government was lying and seriously understating the degree of danger. Lyubov Sirota, the author of Chernobyl Poems wrote in her poem, Radiophobia:
At the same time, medical experts investigating the psychological consequences of Chernobyl have presented evidence indicating that certain psychoneurological symptoms, manifesting themselves in fatigue, sleep disturbances, impaired memory, etc., (i.e., similar to those of chronic fatigue syndrome), appeared to have no direct correlation to the dose of radiation received, or to the level of contamination of the area of residence.
# Radiophobia as a term in the atomic energy debate
Attempts to downplay the danger of radiation by stigmatizing the opponents of nuclear plants and nuclear tests with the label of "phobiacs" took place in the USA[citation needed].
Today the term "radiophobia" is polemically applied to the arguments of proponents of the LNT concept (Linear no-threshold response model for ionizing radiation) of radiation security proposed by the U.S. National Council on Radiation Protection and Measurements (NCRP) in 1949. The "no-threshold" position effectively assumes that even negligible doses of radiation may pose danger. The issue remains controversial.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Radiophobia | |
044fd96a1d15b483eac79a495166fa666aa64656 | wikidoc | Rakesh Jain | Rakesh Jain
# Overview
Dr. Rakesh K. Jain is the Andrew Werk Cook Professor of Tumor Biology at Massachusetts General Hospital in the Harvard Medical School. Dr. Jain primarily researches tumor pathophysiology. His work on cancer therapies led to discovery of an alternate use of Herceptin, an anti-tumor cell pharmaceutical compound produced by Genentech, as an inhibitor for blood vessel growth necessary for tumor growth. His award-winning work on tumor biology has been recognized by a number of professional recognitions, including the following awards in 2006:
- Distinguished Service Award, Nature Biotechnology-Miami Symposium on Angiogenesis
- Outstanding Achievement Award, Society of American Asian Scientists in Cancer Research
- Robert L. Krigel Lecture, Fox Chase Cancer Center, Philadelphia
- Alpha Chi Sigma Research Award, American Institute of Chemical Engineers
- Benjamin Zweifach Distinguished Lecture, The City College, New York
Dr. Jain received his B.Tech. degree from the Indian Institutes of Technology in Chemical Engineering in 1972 and received his M.Ch.E. and Ph.D. in Chemical Engineering from the University of Delaware in 1974 and 1976, respectively. | Rakesh Jain
# Overview
Dr. Rakesh K. Jain is the Andrew Werk Cook Professor of Tumor Biology at Massachusetts General Hospital in the Harvard Medical School. Dr. Jain primarily researches tumor pathophysiology. His work on cancer therapies led to discovery of an alternate use of Herceptin, an anti-tumor cell pharmaceutical compound produced by Genentech, as an inhibitor for blood vessel growth necessary for tumor growth.[1] His award-winning work on tumor biology has been recognized by a number of professional recognitions, including the following awards in 2006:
- Distinguished Service Award, Nature Biotechnology-Miami Symposium on Angiogenesis
- Outstanding Achievement Award, Society of American Asian Scientists in Cancer Research
- Robert L. Krigel Lecture, Fox Chase Cancer Center, Philadelphia
- Alpha Chi Sigma Research Award, American Institute of Chemical Engineers
- Benjamin Zweifach Distinguished Lecture, The City College, New York
Dr. Jain received his B.Tech. degree from the Indian Institutes of Technology in Chemical Engineering in 1972 and received his M.Ch.E. and Ph.D. in Chemical Engineering from the University of Delaware in 1974 and 1976, respectively. | https://www.wikidoc.org/index.php/Rakesh_Jain | |
e1a535c777a38e2bfabf6d594fd2482145f2fca6 | wikidoc | Raltitrexed | Raltitrexed
# Overview
Raltitrexed (brand name Tomudex®) is a chemotherapy drug manufactured AstraZeneca
Company, is an antimetabolite used in chemotherapy. It is an inhibitor of thymidylate synthase.
# Uses
Used in treatment of colorectal cancer since 1998.
# Mechanism of action
Raltitrexed is chemically similar to folic acid and is in the class of chemotherapy drugs called folate antimetabolites. It works by inhibiting enzyme used in pyrimidine synthesis —thymidylate synthase (TS). Raltitrexed is fully active after polyglutamylation. Inhibition of L1210 cell growth i culture IC50 = 9 nM, is one of the strongest antimetabolite in use.
By inhibiting the formation of precursor pyrimidine nucleotides, raltitrexed prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells. | Raltitrexed
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Raltitrexed (brand name Tomudex®) is a chemotherapy drug manufactured AstraZeneca
Company, is an antimetabolite used in chemotherapy. It is an inhibitor of thymidylate synthase.
# Uses
Used in treatment of colorectal cancer since 1998.
# Mechanism of action
Raltitrexed is chemically similar to folic acid and is in the class of chemotherapy drugs called folate antimetabolites. It works by inhibiting enzyme used in pyrimidine synthesis —thymidylate synthase (TS). Raltitrexed is fully active after polyglutamylation. Inhibition of L1210 cell growth i culture IC50 = 9 nM, is one of the strongest antimetabolite in use.
By inhibiting the formation of precursor pyrimidine nucleotides, raltitrexed prevents the formation of DNA and RNA, which are required for the growth and survival of both normal cells and cancer cells.
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Raltitrexed | |
4d91416524ae0f3538da72108881d88fbfad29d5 | wikidoc | Random walk | Random walk
A random walk, sometimes denoted RW, is a mathematical formalization of a trajectory that consists of taking successive random steps. The results of random walk analysis have been applied to computer science, physics, ecology, economics and a number of other fields as a fundamental model for random processes in time. For example, the path traced by a molecule as it travels in a liquid or a gas, the search path of a foraging animal, the price of a fluctuating stock and the financial status of a gambler can all be modeled as random walks.
Specific cases or limits of random walks include the drunkard's walk and Lévy flight. Random walks are related to the diffusion models and are a fundamental topic in discussions of Markov processes. Several properties of random walks, including dispersal distributions, first-passage times and encounter rates, have been extensively studied.
Various different types of random walks are of interest. Often, random walks are assumed to be Markov, but other, more complicated walks are also of interest. Some random walks are on graphs, others on the line, in the plane, or in higher dimensions, while some random walks are on groups. Random walks also vary with regards to the time parameter. Often, the walk is indexed by the natural numbers, as in X_0,X_1,X_2,\dots. However, some walks take their steps at random times, and in that case the position X_t is defined for t\ge 0.
# One-dimensional random walk
A particularly elementary and concrete random walk is the random walk on the integers \mathbb Z, which starts at S_0=0 and at each step moves by \pm1 with equal probability. To define this walk formally, take independent random variables Z_1,Z_2,\dots, each of which is 1 with probability 1/2 and -1 with probability 1/2, and set S_n:=\sum_{j=1}^nZ_j. This sequence \{S_n\} is called the simple random walk on \mathbb Z.
This walk can be illustrated as follows. Say you flip a fair coin. If it lands on heads, you move one to the right on the number line. If it lands on tails, you move one to the left. So after five flips, you have the possibility of landing on 1, -1, 3, -3, 5, or -5. You can land on 1 by flipping three heads and two tails in any order. There are 10 possible ways of landing on 1. Similarly, there are 10 ways of landing on -1 (by flipping three tails and two heads), 5 ways of landing on 3 (by flipping four heads and one tail), 5 ways of landing on -3 (by flipping four tails and one head), 1 way of landing on 5 (by flipping five heads), and 1 way of landing on -5 (by flipping five tails). See the figure below for an illustration of this example.
What can we say about the position S_n of the walk after n steps? Of course, it is random, so we cannot calculate it. But we may say quite a bit about its distribution. It is not hard to see that the expectation E(S_n) of S_n is zero. For example, this follows by the additivity property of expectation: E(S_n)=\sum_{j=1}^n E(Z_n)=0.
A similar calculation, using the independence of the random variables Z_n, shows that E(S_n^2)=n. This hints that E|S_n|, the expected translation distance after n steps, should be of the order of \sqrt{n}. In fact,
Suppose we draw a line some distance from the origin of the walk. How many times will the random walk cross the line if permitted to continue walking forever? The following, perhaps surprising theorem is the answer: simple random walk on \mathbb Z will almost surely cross every point an infinite number of times. This result has many names: the level-crossing phenomenon, recurrence or the gambler's ruin. The reason for the last name is as follows: if you are a gambler with a finite amount of money playing a fair game against a bank with an infinite amount of money, you will surely lose. The amount of money you have will perform a random walk, and it will almost surely, at some time, reach 0 and the game will be over.
If a and b are positive integers, then the expected number of steps until a one dimensional simple random walk starting at 0 first hits b or -a is a\,b. The probability that this walk will hit b before -a steps is a \over a+b.
Some of the results mentioned above can be derived from properties of Pascal's triangle. The number of different walks of n steps where each step is +1 or -1 is clearly 2^n. For the simple random walk, each of these walks are equally likely. In order for S_n to be equal to a number k it is necessary and sufficient that the number of +1 in the walk exceeds those of -1 by k. Thus, the number of walks which satisfy S_n=k is precisely the number of ways of choosing (n+k)/2 elements from an n element set (for this to be non-zero, it is necessary that n+k be an even number), which is an entry in Pascal's triangle denoted by n \choose (n+k)/2. Therefore, the probability that S_n=k is equal to 2^{-n}{n\choose (n+k)/2}. By representing entries of Pascal's triangle in terms of factorials and using Stirling's formula, one can obtain good estimates for these probabilities for large values of n.
This relation with Pascal's triangle is easily demonstrated for small values of n. At zero turns, the only possibility will be to remain at zero. However, at one turn, you can move either to the left or the right of zero, meaning there is one chance of landing on -1 or one chance of landing on 1. At two turns, you examine the turns from before. If you had been at 1, you could move to 2 or back to zero. If you had been at -1, you could move to -2 or back to zero. So there is one chance of landing on -2, two chances of landing on zero, and one chance of landing on 2.
The central limit theorem and the law of the iterated logarithm describe important aspects of the behavior of simple random walk on \mathbb Z.
# Higher dimensions
Imagine now a drunkard walking randomly in a city. The city is realistically infinite and arranged in a square grid, and at every intersection, the drunkard chooses one of the four possible routes (including the one he came from) with equal probability. Formally, this is a random walk on the set of all points in the plane with integer coordinates. Will the drunkard ever get back to his home from the bar? It turns out that he will. This is the high dimensional equivalent of the level crossing problem discussed above. However, in dimensions 3 and above, this no longer holds. In other words, a drunk bird might forever wander the sky, never finding its nest. The formal terms to describe this phenomenon is that a random walk in dimensions 1 and 2 is recurrent, while in dimension 3 and above it is transient. This was proven by Pólya in 1921, and is discussed in a section of Markov Chains available online.
The trajectory of a random walk is the collection of sites it visited, considered as a set with disregard to when the walk arrived at the point. In one dimension, the trajectory is simply all points between the minimum height the walk achieved and the maximum (both are, on average, on the order of √n). In higher dimensions the set has interesting geometric properties. In fact, one gets a discrete fractal, that is a set which exhibits stochastic self-similarity on large scales, but on small scales one can observe "jugginess" resulting from the grid on which the walk is performed. The two books of Lawler referenced below are a good source on this topic.
# Random walk on graphs
Assume now that our city is no longer a perfect square grid. When our drunkard reaches a certain junction he picks between the various available roads with equal probability. Thus, if the junction has seven exits the drunkard will go to each one with probability one seventh. This is a random walk on a graph. Will our drunkard reach his home? It turns out that under rather mild conditions, the answer is still yes. For example, if the lengths of all the blocks are between a and b (where a and b are any two finite positive numbers), then the drunkard will, almost surely, reach his home. Notice that we do not assume that the graph is planar, i.e. the city may contain tunnels and bridges. One way to prove this result is using the connection to electrical networks. Take a map of the city and place a one ohm resistor on every block. Now measure the "resistance between a point and infinity". In other words, choose some number R and take all the points in the electrical network with distance bigger than R from our point and wire them together. This is now a finite electrical network and we may measure the resistance from our point to the wired points. Take R to infinity. The limit is called the resistance between a point and infinity. It turns out that the following is true (an elementary proof can be found in the book by Doyle and Snell):
Theorem: a graph is transient if and only if the resistance between a point and infinity is finite. It is not important which point is chosen if the graph is connected.
In other words, in a transient system, one only needs to overcome a finite resistance to get to infinity from any point. In a recurrent system, the resistance from any point to infinity is infinite.
This characterization of recurrence and transience is very useful, and specifically it allows us to analyze the case of a city drawn in the plane with the distances bounded.
A random walk on a graph is a very special case of a Markov chain. Unlike a general Markov chain, random walk on a graph enjoys a property called time symmetry or reversibility. Roughly speaking, this property, also called the principle of detailed balance, means that the probabilities to traverse a given path in one direction or in the other have a very simple connection between them (if the graph is regular, they are just equal). This property has important consequences.
Starting in the 1980s, much research has gone into connecting properties of the graph to random walks. In addition to the electrical network connection described above, there are important connections to isoperimetric inequalities, see more here, functional inequalities such as Sobolev and Poincaré inequalities and properties of solutions of Laplace's equation. A significant portion of this research was focused on Cayley graphs of finitely generated groups. For example, the proof of Dave Bayer and Persi Diaconis that 7 riffle shuffles are enough to mix a pack of cards (see more details under shuffle) is in effect a result about random walk on the group Sn, and the proof uses the group structure in an essential way. In many cases these discrete results carry over to, or are derived from Manifolds and Lie groups.
A good reference for random walk on graphs is the online book by Aldous and Fill. For groups see the book of Woess.
If the graph itself is random, this topic is called "random walk in random environment" — see the book of Hughes.
# Relation to Brownian motion
Brownian motion is the scaling limit of random walk in dimension 1. This means that if you take a random walk with very small steps you get an approximation to Brownian motion. To be more precise, if the step size is ε, one needs to take a walk of length L/ε² to approximate a Brownian motion of length L. As the step size tends to 0 (and the number of steps increased comparatively) random walk converges to Brownian motion in an appropriate sense. Formally, if B is the space of all paths of length L with the maximum topology, and if M is the space of measure over B with the norm topology, then the convergence is in the space M. Similarly, Brownian motion in several dimensions is the scaling limit of random walk in the same number of dimensions. Note that Brownian motion in the present article refers to the mathematical definition of the term, rather than the actual physical phenomenon of a minute particle diffusing in a fluid.
A random walk is a discrete fractal, but Brownian motion is a true fractal, and there is a connection between the two. For example, take a random walk until it hits a circle of radius r times the step length. The average number of steps it performs is r². This fact is the discrete version of the fact that Brownian motion is a fractal of Hausdorff dimension 2
In two dimensions, the average number of points the same random walk has on the boundary of its trajectory is r^{4/3}. This corresponds to the fact that the boundary of the trajectory of Brownian motion is a fractal of dimension 4/3, a fact predicted by Mandelbrot using simulations but proved only in 2000 (Science, 2000).
Brownian motion enjoys many symmetries random walk does not. For example, Brownian motion is invariant to rotations, but random walk is not, since the underlying grid is not (random walk is invariant to rotations by 90 degrees, but Brownian motion is invariant to rotations by, for example, 17 degrees too). This means that in many cases, problems on random walk are easier to solve by translating them to Brownian motion, solving the problem there, and then translating back. On the other hand, some problems are easier to solve with random walks due to its discrete nature.
Random walk and Brownian motion can be coupled, namely manifested on the same probability space in a dependent way that forces them to be quite close. The simplest such coupling is the Skorokhod embedding, but other, more precise couplings exist as well.
The convergence of a random walk toward the Brownian motion is controlled by the central limit theorem. For a particle in a known fixed position at t=0, the theorem tells us that after a large number of independent steps in the random walk, the walker's position is distributed according to a normal distribution of total variance:
This corresponds to the Green function of the diffusion equation that controls the Brownian motion, which demonstrates that, after a large number of steps, the random walk converges toward a Brownian motion.
In 3D, the variance corresponding to the Green's function of the diffusion equation is:
By equalizing this quantity with the variance associated to the position of the random walker, one obtains the equivalent diffusion coefficient to be considered for the asymptotic Brownian motion toward which the random walk converges after a large number of steps:
Remark: the two expressions of the variance above correspond to the distribution associated to the vector \vec R that links the two ends of the random walk, in 3D. The variance associated to each component R_x, R_y or R_z is only one third of this value (still in 3D).
# Self-interacting random walks
There are a number of interesting models of random paths in which each step depends on the past in a complicated manner. All are more difficult to analyze than the usual random walk — some notoriously so. For example
- The self-avoiding walk. See the Madras and Slade book.
- The loop-erased random walk. See the two books of Lawler.
- The reinforced random walk. See the review by Robin Pemantle.
- The exploration process.
# Applications
The following are the applications of random walk:
- In economics, the "random walk hypothesis" is used to model shares prices and other factors. Empirical studies found some deviations from this theoretical model, especially in short term and long term correlations. See share prices.
- In population genetics, random walk describes the statistical properties of genetic drift
- In physics, random walks are used as simplified models of physical Brownian motion and the random movement of molecules in liquids and gases. See for example diffusion-limited aggregation.
- In mathematical ecology, random walks are used to describe individual animal movements, to empirically support processes of biodiffusion, and occasionally to model population dynamics.
- Also in physics, random walks and some of the self interacting walks play a role in quantum field theory.
- In polymer physics, random walk describes an ideal chain. It is the simplest model to study polymers.
- In other fields of mathematics, random walk is used to calculate solutions to Laplace's equation, to estimate the harmonic measure, and for various constructions in analysis and combinatorics.
- In computer science, random walks are used to estimate the size of the Web. In the World Wide Web conference-2006, bar-yossef et.al. published their findings and algorithms for the same. (This was awarded the best paper for the year 2006).
In all these cases, random walk is often substituted for Brownian motion.
- In brain research, random walks and reinforced random walks are used to model cascades of neuron firing in the brain.
- In vision science, fixational eye movements are well described by a random walk.
- In psychology, random walks explain accurately the relation between the time needed to make a decision and the probability that a certain decision will be made. (Nosofsky, 1997)
- Random walk can be used to sample from a state space which is unknown or very large, for example to pick a random page off the internet or, for research of working conditions, a random illegal worker in a given country.
- When this last approach is used in computer science it is known as Markov Chain Monte Carlo or MCMC for short. Often, sampling from some complicated state space also allows one to get a probabilistic estimate of the space's size. The estimate of the permanent of a large matrix of zeros and ones was the first major problem tackled using this approach.
- In wireless networking, random walk is used to model node movement.
- Bacteria engage in a biased random walk.
- Random walk is used to model gambling.
- During World War II a random walk was used to model the distance that an escaped prisoner of war would travel in a given time.
# Probabilistic interpretation
A one-dimensional random walk can also be looked at as a Markov chain whose state space is given by the integers i=0,\pm 1,\pm 2,..., for some number \,0 , \,P_{i,i+1}=p=1-P_{i,i-1}. We can call it a random walk because we may think of it as being a model for an individual walking on a straight line who at each point of time either takes one step to the right with probability p or one step to the left with probability 1-p.
A random walk is a simple stochastic process. | Random walk
A random walk, sometimes denoted RW, is a mathematical formalization of a trajectory that consists of taking successive random steps. The results of random walk analysis have been applied to computer science, physics, ecology, economics and a number of other fields as a fundamental model for random processes in time. For example, the path traced by a molecule as it travels in a liquid or a gas, the search path of a foraging animal, the price of a fluctuating stock and the financial status of a gambler can all be modeled as random walks.
Specific cases or limits of random walks include the drunkard's walk and Lévy flight. Random walks are related to the diffusion models and are a fundamental topic in discussions of Markov processes. Several properties of random walks, including dispersal distributions, first-passage times and encounter rates, have been extensively studied.
Various different types of random walks are of interest. Often, random walks are assumed to be Markov, but other, more complicated walks are also of interest. Some random walks are on graphs, others on the line, in the plane, or in higher dimensions, while some random walks are on groups. Random walks also vary with regards to the time parameter. Often, the walk is indexed by the natural numbers, as in <math>X_0,X_1,X_2,\dots</math>. However, some walks take their steps at random times, and in that case the position <math>X_t</math> is defined for <math>t\ge 0</math>.
# One-dimensional random walk
A particularly elementary and concrete random walk is the random walk on the integers <math>\mathbb Z</math>, which starts at <math>S_0=0</math> and at each step moves by <math>\pm1</math> with equal probability. To define this walk formally, take independent random variables <math>Z_1,Z_2,\dots</math>, each of which is <math>1</math> with probability <math>1/2</math> and <math>-1</math> with probability <math>1/2</math>, and set <math>S_n:=\sum_{j=1}^nZ_j</math>. This sequence <math>\{S_n\}</math> is called the simple random walk on <math>\mathbb Z</math>.
This walk can be illustrated as follows. Say you flip a fair coin. If it lands on heads, you move one to the right on the number line. If it lands on tails, you move one to the left. So after five flips, you have the possibility of landing on 1, -1, 3, -3, 5, or -5. You can land on 1 by flipping three heads and two tails in any order. There are 10 possible ways of landing on 1. Similarly, there are 10 ways of landing on -1 (by flipping three tails and two heads), 5 ways of landing on 3 (by flipping four heads and one tail), 5 ways of landing on -3 (by flipping four tails and one head), 1 way of landing on 5 (by flipping five heads), and 1 way of landing on -5 (by flipping five tails). See the figure below for an illustration of this example.
What can we say about the position <math>S_n</math> of the walk after <math>n</math> steps? Of course, it is random, so we cannot calculate it. But we may say quite a bit about its distribution. It is not hard to see that the expectation <math>E(S_n)</math> of <math>S_n</math> is zero. For example, this follows by the additivity property of expectation: <math>E(S_n)=\sum_{j=1}^n E(Z_n)=0</math>.
A similar calculation, using the independence of the random variables <math>Z_n</math>, shows that <math>E(S_n^2)=n</math>. This hints that <math>E|S_n|</math>, the expected translation distance after <math>n</math> steps, should be of the order of <math>\sqrt{n}</math>. In fact,
Suppose we draw a line some distance from the origin of the walk. How many times will the random walk cross the line if permitted to continue walking forever? The following, perhaps surprising theorem is the answer: simple random walk on <math>\mathbb Z</math> will almost surely cross every point an infinite number of times. This result has many names: the level-crossing phenomenon, recurrence or the gambler's ruin. The reason for the last name is as follows: if you are a gambler with a finite amount of money playing a fair game against a bank with an infinite amount of money, you will surely lose. The amount of money you have will perform a random walk, and it will almost surely, at some time, reach 0 and the game will be over.
If <math>a</math> and <math>b</math> are positive integers, then the expected number of steps until a one dimensional simple random walk starting at <math>0</math> first hits b or -a is <math>a\,b</math>. The probability that this walk will hit b before -a steps is <math>a \over a+b</math>.
Some of the results mentioned above can be derived from properties of Pascal's triangle. The number of different walks of <math>n</math> steps where each step is <math>+1</math> or <math>-1</math> is clearly <math>2^n</math>. For the simple random walk, each of these walks are equally likely. In order for <math>S_n</math> to be equal to a number <math>k</math> it is necessary and sufficient that the number of <math>+1</math> in the walk exceeds those of <math>-1</math> by <math>k</math>. Thus, the number of walks which satisfy <math>S_n=k</math> is precisely the number of ways of choosing <math>(n+k)/2</math> elements from an <math>n</math> element set (for this to be non-zero, it is necessary that <math>n+k</math> be an even number), which is an entry in Pascal's triangle denoted by <math>n \choose (n+k)/2</math>. Therefore, the probability that <math>S_n=k</math> is equal to <math>2^{-n}{n\choose (n+k)/2}</math>. By representing entries of Pascal's triangle in terms of factorials and using Stirling's formula, one can obtain good estimates for these probabilities for large values of <math>n</math>.
This relation with Pascal's triangle is easily demonstrated for small values of <math>n</math>. At zero turns, the only possibility will be to remain at zero. However, at one turn, you can move either to the left or the right of zero, meaning there is one chance of landing on -1 or one chance of landing on 1. At two turns, you examine the turns from before. If you had been at 1, you could move to 2 or back to zero. If you had been at -1, you could move to -2 or back to zero. So there is one chance of landing on -2, two chances of landing on zero, and one chance of landing on 2.
The central limit theorem and the law of the iterated logarithm describe important aspects of the behavior of simple random walk on <math>\mathbb Z</math>.
# Higher dimensions
Imagine now a drunkard walking randomly in a city. The city is realistically infinite and arranged in a square grid, and at every intersection, the drunkard chooses one of the four possible routes (including the one he came from) with equal probability. Formally, this is a random walk on the set of all points in the plane with integer coordinates. Will the drunkard ever get back to his home from the bar? It turns out that he will. This is the high dimensional equivalent of the level crossing problem discussed above. However, in dimensions 3 and above, this no longer holds. In other words, a drunk bird might forever wander the sky, never finding its nest. The formal terms to describe this phenomenon is that a random walk in dimensions 1 and 2 is recurrent, while in dimension 3 and above it is transient. This was proven by Pólya in 1921, and is discussed in a section of Markov Chains available online.
The trajectory of a random walk is the collection of sites it visited, considered as a set with disregard to when the walk arrived at the point. In one dimension, the trajectory is simply all points between the minimum height the walk achieved and the maximum (both are, on average, on the order of √n). In higher dimensions the set has interesting geometric properties. In fact, one gets a discrete fractal, that is a set which exhibits stochastic self-similarity on large scales, but on small scales one can observe "jugginess" resulting from the grid on which the walk is performed. The two books of Lawler referenced below are a good source on this topic.
# Random walk on graphs
Assume now that our city is no longer a perfect square grid. When our drunkard reaches a certain junction he picks between the various available roads with equal probability. Thus, if the junction has seven exits the drunkard will go to each one with probability one seventh. This is a random walk on a graph. Will our drunkard reach his home? It turns out that under rather mild conditions, the answer is still yes. For example, if the lengths of all the blocks are between a and b (where a and b are any two finite positive numbers), then the drunkard will, almost surely, reach his home. Notice that we do not assume that the graph is planar, i.e. the city may contain tunnels and bridges. One way to prove this result is using the connection to electrical networks. Take a map of the city and place a one ohm resistor on every block. Now measure the "resistance between a point and infinity". In other words, choose some number R and take all the points in the electrical network with distance bigger than R from our point and wire them together. This is now a finite electrical network and we may measure the resistance from our point to the wired points. Take R to infinity. The limit is called the resistance between a point and infinity. It turns out that the following is true (an elementary proof can be found in the book by Doyle and Snell):
Theorem: a graph is transient if and only if the resistance between a point and infinity is finite. It is not important which point is chosen if the graph is connected.
In other words, in a transient system, one only needs to overcome a finite resistance to get to infinity from any point. In a recurrent system, the resistance from any point to infinity is infinite.
This characterization of recurrence and transience is very useful, and specifically it allows us to analyze the case of a city drawn in the plane with the distances bounded.
A random walk on a graph is a very special case of a Markov chain. Unlike a general Markov chain, random walk on a graph enjoys a property called time symmetry or reversibility. Roughly speaking, this property, also called the principle of detailed balance, means that the probabilities to traverse a given path in one direction or in the other have a very simple connection between them (if the graph is regular, they are just equal). This property has important consequences.
Starting in the 1980s, much research has gone into connecting properties of the graph to random walks. In addition to the electrical network connection described above, there are important connections to isoperimetric inequalities, see more here, functional inequalities such as Sobolev and Poincaré inequalities and properties of solutions of Laplace's equation. A significant portion of this research was focused on Cayley graphs of finitely generated groups. For example, the proof of Dave Bayer and Persi Diaconis that 7 riffle shuffles are enough to mix a pack of cards (see more details under shuffle) is in effect a result about random walk on the group Sn, and the proof uses the group structure in an essential way. In many cases these discrete results carry over to, or are derived from Manifolds and Lie groups.
A good reference for random walk on graphs is the online book by Aldous and Fill. For groups see the book of Woess.
If the graph itself is random, this topic is called "random walk in random environment" — see the book of Hughes.
# Relation to Brownian motion
Brownian motion is the scaling limit of random walk in dimension 1. This means that if you take a random walk with very small steps you get an approximation to Brownian motion. To be more precise, if the step size is ε, one needs to take a walk of length L/ε² to approximate a Brownian motion of length L. As the step size tends to 0 (and the number of steps increased comparatively) random walk converges to Brownian motion in an appropriate sense. Formally, if B is the space of all paths of length L with the maximum topology, and if M is the space of measure over B with the norm topology, then the convergence is in the space M. Similarly, Brownian motion in several dimensions is the scaling limit of random walk in the same number of dimensions. Note that Brownian motion in the present article refers to the mathematical definition of the term, rather than the actual physical phenomenon of a minute particle diffusing in a fluid.
A random walk is a discrete fractal, but Brownian motion is a true fractal, and there is a connection between the two. For example, take a random walk until it hits a circle of radius r times the step length. The average number of steps it performs is r². This fact is the discrete version of the fact that Brownian motion is a fractal of Hausdorff dimension 2
[1].
In two dimensions, the average number of points the same random walk has on the boundary of its trajectory is <math>r^{4/3}</math>. This corresponds to the fact that the boundary of the trajectory of Brownian motion is a fractal of dimension 4/3, a fact predicted by Mandelbrot using simulations but proved only in 2000 (Science, 2000).
Brownian motion enjoys many symmetries random walk does not. For example, Brownian motion is invariant to rotations, but random walk is not, since the underlying grid is not (random walk is invariant to rotations by 90 degrees, but Brownian motion is invariant to rotations by, for example, 17 degrees too). This means that in many cases, problems on random walk are easier to solve by translating them to Brownian motion, solving the problem there, and then translating back. On the other hand, some problems are easier to solve with random walks due to its discrete nature.
Random walk and Brownian motion can be coupled, namely manifested on the same probability space in a dependent way that forces them to be quite close. The simplest such coupling is the Skorokhod embedding, but other, more precise couplings exist as well.
The convergence of a random walk toward the Brownian motion is controlled by the central limit theorem. For a particle in a known fixed position at t=0, the theorem tells us that after a large number of independent steps in the random walk, the walker's position is distributed according to a normal distribution of total variance:
This corresponds to the Green function of the diffusion equation that controls the Brownian motion, which demonstrates that, after a large number of steps, the random walk converges toward a Brownian motion.
In 3D, the variance corresponding to the Green's function of the diffusion equation is:
By equalizing this quantity with the variance associated to the position of the random walker, one obtains the equivalent diffusion coefficient to be considered for the asymptotic Brownian motion toward which the random walk converges after a large number of steps:
Remark: the two expressions of the variance above correspond to the distribution associated to the vector <math>\vec R</math> that links the two ends of the random walk, in 3D. The variance associated to each component <math>R_x</math>, <math>R_y</math> or <math>R_z</math> is only one third of this value (still in 3D).
# Self-interacting random walks
There are a number of interesting models of random paths in which each step depends on the past in a complicated manner. All are more difficult to analyze than the usual random walk — some notoriously so. For example
- The self-avoiding walk. See the Madras and Slade book.
- The loop-erased random walk. See the two books of Lawler.
- The reinforced random walk. See the review by Robin Pemantle.
- The exploration process.
# Applications
The following are the applications of random walk:
- In economics, the "random walk hypothesis" is used to model shares prices and other factors. Empirical studies found some deviations from this theoretical model, especially in short term and long term correlations. See share prices.
- In population genetics, random walk describes the statistical properties of genetic drift
- In physics, random walks are used as simplified models of physical Brownian motion and the random movement of molecules in liquids and gases. See for example diffusion-limited aggregation.
- In mathematical ecology, random walks are used to describe individual animal movements, to empirically support processes of biodiffusion, and occasionally to model population dynamics.
- Also in physics, random walks and some of the self interacting walks play a role in quantum field theory.
- In polymer physics, random walk describes an ideal chain. It is the simplest model to study polymers.
- In other fields of mathematics, random walk is used to calculate solutions to Laplace's equation, to estimate the harmonic measure, and for various constructions in analysis and combinatorics.
- In computer science, random walks are used to estimate the size of the Web. In the World Wide Web conference-2006, bar-yossef et.al. published their findings and algorithms for the same. (This was awarded the best paper for the year 2006).
In all these cases, random walk is often substituted for Brownian motion.
- In brain research, random walks and reinforced random walks are used to model cascades of neuron firing in the brain.
- In vision science, fixational eye movements are well described by a random walk.
- In psychology, random walks explain accurately the relation between the time needed to make a decision and the probability that a certain decision will be made. (Nosofsky, 1997)
- Random walk can be used to sample from a state space which is unknown or very large, for example to pick a random page off the internet or, for research of working conditions, a random illegal worker in a given country.
- When this last approach is used in computer science it is known as Markov Chain Monte Carlo or MCMC for short. Often, sampling from some complicated state space also allows one to get a probabilistic estimate of the space's size. The estimate of the permanent of a large matrix of zeros and ones was the first major problem tackled using this approach.
- In wireless networking, random walk is used to model node movement.
- Bacteria engage in a biased random walk.
- Random walk is used to model gambling.
- During World War II a random walk was used to model the distance that an escaped prisoner of war would travel in a given time.
# Probabilistic interpretation
A one-dimensional random walk can also be looked at as a Markov chain whose state space is given by the integers <math>i=0,\pm 1,\pm 2,...</math>, for some number <math>\,0 < p < 1</math>, <math>\,P_{i,i+1}=p=1-P_{i,i-1}</math>. We can call it a random walk because we may think of it as being a model for an individual walking on a straight line who at each point of time either takes one step to the right with probability <math>p</math> or one step to the left with probability <math>1-p</math>.
A random walk is a simple stochastic process. | https://www.wikidoc.org/index.php/Random_walk | |
c9aaaaff3a93681a5a6f172d16180a199f47eddb | wikidoc | Rasburicase | Rasburicase
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# Black Box Warning
# Overview
Rasburicase is a Endocrine-Metabolic agent that is FDA approved for the treatment of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid. There is a Black Box Warning for this drug as shown here. Common adverse reactions include vomiting, nausea, pyrexia, peripheral edema, anxiety, headache, abdominal pain, constipation, and diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Elitek® is indicated for the initial management of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.
- The recommended dose of Elitek is 0.2 mg/kg as a 30 minute intravenous infusion daily for up to 5 days. Dosing beyond 5 days or administration of more than one course is not recommended.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rasburicase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rasburicase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Rasburicase in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rasburicase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rasburicase in pediatric patients.
# Contraindications
- Elitek is contraindicated in patients with a history of anaphylaxis or severe hypersensitivity to rasburicase or in patients with development of hemolytic reactions or methemoglobinemia with rasburicase.
- Elitek is contraindicated in individuals deficient in glucose-6-phosphate dehydrogenase (G6PD)
# Warnings
- The safety and efficacy of Elitek have been established only for a single course of treatment once daily for 5 days.
- Elitek can cause severe allergic reactions including anaphylaxis. In clinical studies, anaphylaxis was reported in <1% patients receiving Elitek. This can occur at any time during treatment including the first dose. Signs and symptoms of these reactions include bronchospasm, chest pain and tightness, dyspnea, hypoxia, hypotension, shock, and urticaria. Immediately and permanently discontinue Elitek administration in any patient developing clinical evidence of a serious hypersensitivity reaction.
- Elitek is contraindicated in patients with G6PD deficiency because hydrogen peroxide is one of the major by-products of the conversion of uric acid to allantoin. In clinical studies, hemolysis occurs in <1% patients receiving Elitek; severe hemolytic reactions occurred within 2–4 days of the start of Elitek. Immediately and permanently discontinue Elitek administration in any patient developing hemolysis. Institute appropriate patient monitoring and support measures (e.g., transfusion support). Screen patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting Elitek.
- In clinical studies, methemoglobinemia occurred in <1% patients receiving Elitek. These included cases of serious hypoxemia requiring intervention with medical support measures. It is not known whether patients with deficiency of cytochrome b5 reductase (formerly known as methemoglobin reductase) or of other enzymes with antioxidant activity are at increased risk for methemoglobinemia or hemolytic anemia. Immediately and permanently discontinue Elitek administration in any patient identified as having developed methemoglobinemia. Institute appropriate monitoring and support measures (e.g., transfusion support, methylene-blue administration).
- At room temperature, Elitek causes enzymatic degradation of the uric acid in blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings. The following special sample handling procedure must be followed to avoid ex vivo uric acid degradation.
- Uric acid must be analyzed in plasma. Blood must be collected into pre-chilled tubes containing heparin anticoagulant. Immediately immerse plasma samples for uric acid measurement in an ice water bath. Plasma samples must be prepared by centrifugation in a pre-cooled centrifuge (4°C). Finally, the plasma must be maintained in an ice water bath and analyzed for uric acid within four hours of collection
# Adverse Reactions
## Clinical Trials Experience
Clinical Trials
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data below reflect exposure to Elitek in 265 pediatric and 82 adult patients enrolled in one active-controlled trial (Study 1), two uncontrolled trials (Studies 2 and 3), and an uncontrolled safety trial (n=82). Additional data were obtained from an expanded access program of 356 patients, for whom data collection was limited to serious adverse reactions. Among these 703 patients 63% were male, the median age was 10 years (range 10 days to 88 years), 73% were Caucasian, 9% African, 4% Asian, and 14% other/unknown.
- Among the 347 patients for whom all adverse reactions regardless of severity were assessed, the most frequently observed adverse reactions (incidence ≥10%) were vomiting (50%), fever (46%), nausea (27%), headache (26%), abdominal pain (20%), constipation (20%), diarrhea (20%), mucositis (15%), and rash (13%). In Study 1, an active control study, the following adverse reactions occurred more frequently in Elitek-treated subjects than allopurinol-treated subjects: vomiting, fever, nausea, diarrhea, and headache. Although the incidence of rash was similar in the two arms, severe rash was reported only in one Elitek-treated patient.
- Further studies, including one-active controlled study (Study 4) and four supportive studies, have been conducted in adult patients. In these studies, Elitek was administered to a total of 434 adult patients .
- Of these 434 patients, 275 adult patients with leukemia, lymphoma, or solid tumor malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomized in an open label trial receiving either Elitek alone, Elitek in combination with allopurinol, or allopurinol alone (Study 4).
- A drug-related adverse reaction in Study 4 of any grade was experienced in 4.3% of Elitek-treated patients, 5.4% of Elitek/allopurinol-treated patients, and 1.1% of allopurinol-treated patients.
- Table 1 presents the per patient incidence of adverse reactions by study arm in Study 4.
- Hypersensitivity reactions occurred in 4.3% of Elitek-treated patients and 1.1% of Elitek/allopurinol-treated patients in Study 4. Clinical manifestations of hypersensitivity included arthralgia, injection site irritation, peripheral edema, and rash.
- The following serious adverse reactions occurred at a difference in incidence of ≥2% in patients receiving rasburicase compared to patients receiving allopurinol in randomized studies (Study 1 and Study 4): pulmonary hemorrhage, respiratory failure, supraventricular arrhythmias, ischemic coronary artery disorders, and abdominal and gastrointestinal infections.
- The incidence of anaphylaxis, hemolysis, and methemoglobinemia was less than 1% of the 887 rasburicase-treated patients entered on these clinical trials.
- As with all therapeutic proteins, there is potential for immunogenicity. Elitek can elicit anti-product antibodies that bind to rasburicase and in some instances inhibit the activity of rasburicase in vitro.
- In clinical trials of pediatric patients with hematologic malignancies, 24/218 patients tested (11%) developed antibodies by day 28 following Elitek administration as assessed by qualitative ELISA.
- Using quasi-quantitative immunoassays in rasburicase naïve adult patients with hematological malignancies, 47/260 (18%) patients were positive for anti-rasburicase immunoglobulin G (IgG), 21/260 (8%) patients were positive for anti-rasburicase neutralizing IgG, and 16/260 (6%) patients were positive for anti-rasburicase immunoglobulin E (IgE) from day 14 to 24 months after 5 daily doses of Elitek.
- The incidence of antibody responses detected is highly dependent on the sensitivity and specificity of the assay, which have not been fully evaluated. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including serum sampling, timing and methodology, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Elitek with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Rasburicase in the drug label.
# Drug Interactions
- No drug interaction studies have been conducted in humans.
- Rasburicase does not metabolize allopurinol, cytarabine, methylprednisolone, methotrexate, 6-mercaptopurine, thioguanine, etoposide, daunorubicin, cyclophosphamide or vincristine in vitro. No metabolic-based drug interactions are therefore anticipated with these agents in patients.
- In preclinical in vivo studies, rasburicase did not affect the activity of isoenzymes CYP1A, CYP2A, CYP2B, CYP2C, CYP2E, and CYP3A, suggesting no induction or inhibition potential. Clinically relevant P450-mediated drug-drug interactions are therefore not anticipated in patients treated with the recommended Elitek dose and dosing schedule.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no studies of rasburicase in pregnant women. Reproductive toxicity studies in rabbits treated during organogenesis with approximately 10 to 100 times the recommended human dose of rasburicase resulted in teratogenicity, including decreased fetal body weights and heart and great vessel malformations at all dose levels. Multiple heart and great vessel malformations were also observed in offspring of pregnant rats treated with approximately 250 times the recommended human dose of rasburicase. Other adverse effects were observed in rasburicase-treated pregnant rabbits at all dose levels tested and included pre- and post-implantation losses, abortions, and decreased uterine weights .
- It is unknown whether rasburicase can cross the placental barrier in humans and result in fetal harm. Because of the observed teratogenic effects of rasburicase in animal reproductive studies, use rasburicase during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rasburicase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rasburicase during labor and delivery.
### Nursing Mothers
- It is not known whether rasburicase is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rasburicase, a decision should be made whether to discontinue nursing or to discontinue rasburicase, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of Elitek was studied in 246 pediatric patients ranging in age from 1 month to 17 years. There were insufficient numbers of patients between 0 and 6 months (n=7) to determine whether they respond differently from older children. Mean uric acid AUC0–96 hr was higher in children <2 years of age (n=24; 150 ± s.e. 16 mg hr/dL) than those age 2 to 17 years (n=222; 108 ± s.e. 4 mg hr/dL). Children <2 years of age had a lower rate of achieving normal uric acid concentration by 48 hours than those 2 to 17 years .
### Geriatic Use
- Of the total number of adults treated with Elitek (n=434) in clinical studies, 30% were aged 65 and over while 8% were aged 75 and over. No overall differences in pharmacokinetics, safety, and effectiveness were observed between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Rasburicase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rasburicase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rasburicase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rasburicase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rasburicase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rasburicase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous infusion
- Elitek must be reconstituted with the diluent provided in the carton.
Reconstitute the 1.5 mg vial of Elitek with 1 mL of diluent. Reconstitute the 7.5 mg vial of Elitek with 5 mL of diluent. Mix by swirling gently. Do not shake or vortex.
- Inspect reconstituted Elitek visually for particulate matter and discoloration prior to administration. Discard solution if particulate matter is visible or product is discolored.
- Do not administer Elitek as a bolus injection.
- Inject the calculated dose of reconstituted Elitek solution into an infusion bag containing the appropriate volume of 0.9% sterile sodium chloride, to achieve a final total volume of 50 mL.
- Infuse over 30 minutes through a separate line or flush line with at least 15 mL of normal saline prior to and after Elitek infusion.
- Do not use filters during reconstitution or infusion of Elitek.
- Store reconstituted or diluted solution at 2–8°C.
- Discard unused product solution 24 hours following reconstitution.
### Monitoring
There is limited information regarding Monitoring of Rasburicase in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rasburicase in the drug label.
# Overdosage
- The maximum reported overdosage of Elitek is a single dose of 1.3 mg/kg. No adverse events occurred in reported cases of overdosage. Monitor patients who receive an overdose and initiate supportive measures if required.
# Pharmacology
## Mechanism of Action
- In humans, uric acid is the final step in the catabolic pathway of purines. Rasburicase catalyzes enzymatic oxidation of poorly soluble uric acid into an inactive and more soluble metabolite (allantoin).
## Structure
- Elitek (rasburicase) is a recombinant urate-oxidase produced by a genetically modified Saccharomyces cerevisiae strain. The cDNA coding for rasburicase was cloned from a strain of Aspergillus flavus.
- Rasburicase is a tetrameric protein with identical subunits. Each subunit is made up of a single 301 amino acid polypeptide chain with a molecular mass of about 34 kDa. The drug product is a sterile, white to off-white, lyophilized powder intended for intravenous administration following reconstitution with a diluent. Elitek is supplied in 3 mL and 10 mL colorless, glass vials containing rasburicase at a concentration of 1.5 mg/mL after reconstitution.
- Elitek 1.5 mg presentation contains 1.5 mg rasburicase, 10.6 mg mannitol, 15.9 mg L-alanine, between 12.6 and 14.3 mg of dibasic sodium phosphate (lyophilized powder), and a diluent (1 mL Water for Injection, USP, and 1 mg Poloxamer 188).
- Elitek 7.5 mg presentation contains 7.5 mg of rasburicase, 53 mg mannitol, 79.5 mg L-alanine, and between 63 and 71.5 mg dibasic sodium phosphate (lyophilized powder) and a diluent (5 mL Water for Injection, USP, and 5 mg Poloxamer 188).
## Pharmacodynamics
- The measurement of plasma uric acid was used to evaluate the effectiveness of rasburicase in clinical studies. Following administration of either 0.15 or 0.20 mg/kg rasburicase daily for up to 5 days, plasma uric acid levels decreased within 4 hours and were maintained below 7.5 mg/dL in 98% of adult and 90% of pediatric patients for at least 7 days. There was no evidence of a dose response effect on uric acid control for doses between 0.15 and 0.20 mg/kg rasburicase.
## Pharmacokinetics
- The pharmacokinetics of rasburicase were evaluated in both pediatric and adult patients with leukemia, lymphoma or other hematological malignancies. Rasburicase exposure, as measured by AUC0–24 hr and Cmax, tended to increase with a dose range from 0.15 to 0.2 mg/kg. The mean terminal half-life was similar between pediatric and adult patients and ranged from 15.7 to 22.5 hours. The mean volume of distribution of rasburicase ranged from 110 to 127 mL/kg in pediatric patients and from 75.8 to 138 mL/kg in adult patients, respectively. Minimal accumulation of rasburicase (<1.3 fold) was observed between days 1 and 5 of dosing. In adults, age, gender, baseline liver enzymes and creatinine clearance did not impact the pharmacokinetics of rasburicase. A cross-study comparison revealed that after administration of rasburicase at 0.15 or 0.20 mg/kg, the geometric mean values of body-weight normalized clearance were approximately 40% lower in Japanese (n=20) than that in Caucasians (n=22).
## Nonclinical Toxicology
- Carcinogenicity studies in animals to evaluate tumoriogenic potential of rasburicase have not been performed. Rasburicase was not mutagenic in the Ames, unscheduled DNA synthesis, chromosome analysis, mouse lymphoma, and micronucleus tests.
- Rasburicase did not affect reproductive performance or fertility in male or female rats at a dose 50-fold higher (10 mg/kg) than the recommended human dose.
- Pregnant rabbits dosed daily with 10 to 100 times the human dose of rasburicase during the period of organogenesis (gestation day 6 – 19) exhibited teratogenic effects, clinical signs of maternal toxicity including weight loss and mortality, decreases in uterine weights and viable fetuses, and increased fetal resorptions, post-implantation losses and abortions. Teratogenic effects included multiple heart and great vessel malformations at all dose levels. Multiple heart and great vessel malformations were also observed in offspring of pregnant rats treated with approximately 250 times the recommended human dose of rasburicase. There are no data available regarding the level of rasburicase exposure in the offspring.
# Clinical Studies
- Elitek was administered in three studies to 265 patients with acute leukemia or non-Hodgkin's lymphoma. These clinical studies were largely limited to pediatric patients (246 of 265). Elitek was administered as a 30-minute infusion once (n=251) or twice (n=14) daily at a dose of 0.15 or 0.2 mg/kg/dose (total daily dose 0.2–0.4 mg/kg/day). Elitek was administered prior to and concurrent with anti-tumor therapy, which consisted of either systemic chemotherapy (n=196) or steroids (n=69).
- Study 1 was a randomized, open-label, controlled study conducted at six institutions, in which 52 pediatric patients were randomized to receive either Elitek (n=27) or allopurinol (n=25). The dose of allopurinol varied according to local institutional practice. Elitek was administered as an intravenous infusion over 30 minutes once (n=26) or twice (n=1) daily at a dose of 0.2 mg/kg/dose (total daily dose 0.2–0.4 mg/kg/day). Initiation of dosing was permitted at any time between 4 to 48 hours before the start of anti-tumor therapy and could be continued for 5 to 7 days after initiation of anti-tumor therapy. Patients were stratified at randomization on the basis of underlying malignant disease (leukemia or lymphoma) and baseline serum or plasma uric acid levels (<8 mg/dL and ≥8 mg/dL). The primary study objective was to demonstrate a greater reduction in uric acid concentration over 96 hours (AUC0–96 hr) in the Elitek group as compared to the allopurinol group. Uric acid AUC0–96 hr was defined as the area under the curve for plasma uric acid levels (mg hr/dL), measured from the last value prior to the first dose of Elitek until 96 hours after that first dose. Plasma uric acid levels were used for all uric acid AUC0–96 hr calculations.
- The demographics of the two study arms (Elitek vs. allopurinol) were as follows: age <13 years (82% vs. 76%), males (59% vs. 72%), Caucasian (59% vs. 72%), ECOG performance status 0 (89% vs. 84%), and leukemia (74% vs. 76%). The median interval, in hours, between initiation of Elitek and of anti-tumor treatment was 20 hours, with a range of 70 hours before to 10 hours after the initiation of anti-tumor treatment (n=24, data not reported for 3 patients).
- The uric acid AUC0–96 hr was significantly lower in the Elitek group (128 ± s.e. 14 mg hr/dL) as compared to the allopurinol group (328 ± s.e. 26 mg hr/dL). All but one patient in the Elitek arm had reduction and maintenance of uric acid levels to within or below the normal range during the treatment. The incidence of renal dysfunction was similar in the two study arms; one patient in the allopurinol arm developed acute renal failure.
- Study 2 was a multi-institutional, single-arm study conducted in 89 pediatric and 18 adult patients with hematologic malignancies. Patients received Elitek at a dose of 0.15 mg/kg/day. The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours where maintenance of uric acid concentration was defined as: 1) achievement of uric acid concentration ≤6.5 mg/dL (patients <13 years) or ≤7.5 mg/dL (patients ≥13 years) within a designated time point (48 hours) from initiation of Elitek and maintained until 24 hours after the last administration of study drug; and 2) control of uric acid level without the need for allopurinol or other agents.
- The study population demographics were: age <13 years (76%), males (61%), Caucasian (91%), ECOG performance status=0 (92%), and leukemia (89%).
- The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 2 was 99% (106/107).
- Study 3 was a multi-institutional, single-arm study conducted in 130 pediatric patients and 1 adult patient with hematologic malignancies. Patients received Elitek at either a dose of 0.15 mg/kg/day (n=12) or 0.2 mg/kg/day (n=119). The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours as defined for Study 2 above.
- The study population demographics were: age <13 years (76%), Caucasian (83%), males (67%), ECOG=0 (67%), and leukemia (88%).
- The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 3 was 92% in the 0.15 mg/kg group (n=12) and 95% in the 0.2 mg/kg group (n=119).
- Data from the 3 studies (n=265) were pooled and analyzed according to the plasma uric acid levels over time. The pre-treatment plasma uric acid concentration was ≥8 mg/dL in 61 patients and was <8 mg/dL in 200 patients. The median uric acid concentration at baseline, at 4 hours following the first dose of Elitek, and the per patient fall in plasma uric acid concentration from baseline to 4 hours were calculated in those patients with both pre-treatment and 4-hour post-treatment values. Among patients with pre-treatment uric acid ≥8 mg/dL , the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 9.1 mg/dL (0.3 – 19.3 mg/dL). Among the patients with a pre-treatment plasma uric acid level <8 mg/dL , the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 4.1 mg/dL (0.1 – 7.6 mg/dL).
- Figure 1 is a box and whisker plot of plasma uric acid levels inclusive of 261 of the 265 Elitek treated patients from Studies 1, 2, and 3. Of the 261 evaluable patients, plasma uric acid concentration was maintained , by 4 hours for 92% of patients (240/261), by 24 hours for 93% of patients (245/261), by 48 hours for 97% of patients (254/261), by 72 hours for 99% of patients (260/261), and by 96 hours for 100% of patients (261/261). Of the subset of 61 patients whose plasma uric acid level was elevated at baseline (≥8 mg/dL), plasma uric acid concentration was maintained by 4 hours for 72% of patients (44/61), by 24 hours for 80% of patients (49/61), by 48 hours for 92% of patients (56/61), by 72 hours for 98% of patients (60/61), and by 96 hours for 100% (61/61).
- A total of 342 adults with either leukemia, lymphoma, or other hematologic malignancy received Elitek in five studies (one randomized study, Study 4, and four uncontrolled studies). Across the five studies, Elitek was administered at a dose of 0.15 mg/kg/day (n=38) or 0.2 mg/kg/day (n=304).
- Study 4 was a randomized (1:1:1), multi-center, open-label study conducted in patients with leukemia, lymphoma, and solid tumor malignancies at risk for hyperuricemia and TLS. A total of 275 adult patients received at least one dose of study drug. The median age was 56 years, 62% were males, 80% were Caucasian, 66% had leukemia, 29% had lymphoma, 18% were hyperuricemic (uric acid ≥7.5mg/dL) at study entry. Patients in Arm A received Elitek for 5 days (n=92). Patients in Arm B received Elitek from day 1 through day 3 followed by oral allopurinol from day 3 through day 5 (overlap on day 3: Elitek and allopurinol administered approximately 12 hours apart) (n=92). Patients in Arm C received oral allopurinol for 5 days (n=91). Elitek was administered at the dose of 0.2 mg/kg/day as a 30-minute infusion once daily. Allopurinol was administered orally at the dose of 300 mg once a day. Patients were eligible for the study if they were either at high risk, or potential risk for TLS. The major endpoint of this study was the uric acid response rate defined as the proportion of patients with plasma uric acid levels ≤7.5 mg/dL from day 3 to day 7, after initiation of antihyperuricemic treatment.
- Table 2 presents the response rates in the three treatment arms. The response rate in arm A was significantly greater than in arm C (p=0.0009). The response rate was higher for arm B compared to arm C; this difference was not statistically significant.
- There were no patients with documented failure to control uric acid in arms A or B. In arm C, 34% of patients did not have a uric acid response; 11% due to failure to control uric acid and 4.4% due to the need for extended antihyperuricemic treatment.
- Box and whisker plots of uric acid over time for the patient population (Figure 2) show that in the two arms containing Elitek, uric acid levels were ≤2 mg/dL in 96% of patients at 4 hours of the day 1 dose.
- Tumor lysis syndrome (TLS)
- Clinical TLS was defined by changes in at least two or more laboratory parameters for hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia and at least one of the following events occurring within 7 days of treatment: renal failure/injury, need for renal dialysis, and/or serum creatinine increase >1.5 ULN, arrhythmia or seizure. Clinical TLS occurred in 3% of Elitek-treated patients, 3% of Elitek/allopurinol-treated patients, and 4% of allopurinol-treated patients.
# How Supplied
- NDC 0024-5150-10: One carton contains 3 single-use vials each containing 1.5 mg of rasburicase and 3 ampules each containing 1 mL diluent.
NDC 0024-5151-75: One carton contains 1 single-use vial containing 7.5 mg of rasburicase and 1 ampule containing 5 mL diluent.
## Storage
The lyophilized drug product and the diluent for reconstitution should be stored at 2–8°C (36–46°F). Do not freeze. Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL - 1.5 mg Kit Carton
NDC 0024-5150-10
ELITEK®
rasburicase
1.5 mg
Three single-use vials
Three diluent ampules
FOR INTRAVENOUS INFUSION
Sterile – Contains No Preservatives – Single Use Vials
Rx only
sanofi aventis
PRINCIPAL DISPLAY PANEL - 7.5 mg Kit Carton
NDC 0024-5151-75
ELITEK®
rasburicase
7.5 mg
One single-use vial
One diluent ampule
FOR INTRAVENOUS INFUSION
Sterile – Contains No Preservatives – Single Use Vial
Rx only
sanofi aventis
### Ingredients and Appearance
# Patient Counseling Information
- Instruct patients to notify their physician immediately if any of the following occur: allergic reaction, bronchospasm, chest pain or tightness, dyspnea, hypoxia, hypotension, shock or urticaria.
# Precautions with Alcohol
- Alcohol-Rasburicase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ELITEK®
# Look-Alike Drug Names
There is limited information regarding Rasburicase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Rasburicase
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, M.B.B.S. [2]
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# Black Box Warning
# Overview
Rasburicase is a Endocrine-Metabolic agent that is FDA approved for the treatment of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid. There is a Black Box Warning for this drug as shown here. Common adverse reactions include vomiting, nausea, pyrexia, peripheral edema, anxiety, headache, abdominal pain, constipation, and diarrhea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indications
- Elitek® is indicated for the initial management of plasma uric acid levels in pediatric and adult patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of plasma uric acid.
- The recommended dose of Elitek is 0.2 mg/kg as a 30 minute intravenous infusion daily for up to 5 days. Dosing beyond 5 days or administration of more than one course is not recommended.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rasburicase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rasburicase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Rasburicase in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rasburicase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rasburicase in pediatric patients.
# Contraindications
- Elitek is contraindicated in patients with a history of anaphylaxis or severe hypersensitivity to rasburicase or in patients with development of hemolytic reactions or methemoglobinemia with rasburicase.
- Elitek is contraindicated in individuals deficient in glucose-6-phosphate dehydrogenase (G6PD)
# Warnings
- The safety and efficacy of Elitek have been established only for a single course of treatment once daily for 5 days.
- Elitek can cause severe allergic reactions including anaphylaxis. In clinical studies, anaphylaxis was reported in <1% patients receiving Elitek. This can occur at any time during treatment including the first dose. Signs and symptoms of these reactions include bronchospasm, chest pain and tightness, dyspnea, hypoxia, hypotension, shock, and urticaria. Immediately and permanently discontinue Elitek administration in any patient developing clinical evidence of a serious hypersensitivity reaction.
- Elitek is contraindicated in patients with G6PD deficiency because hydrogen peroxide is one of the major by-products of the conversion of uric acid to allantoin. In clinical studies, hemolysis occurs in <1% patients receiving Elitek; severe hemolytic reactions occurred within 2–4 days of the start of Elitek. Immediately and permanently discontinue Elitek administration in any patient developing hemolysis. Institute appropriate patient monitoring and support measures (e.g., transfusion support). Screen patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) prior to starting Elitek.
- In clinical studies, methemoglobinemia occurred in <1% patients receiving Elitek. These included cases of serious hypoxemia requiring intervention with medical support measures. It is not known whether patients with deficiency of cytochrome b5 reductase (formerly known as methemoglobin reductase) or of other enzymes with antioxidant activity are at increased risk for methemoglobinemia or hemolytic anemia. Immediately and permanently discontinue Elitek administration in any patient identified as having developed methemoglobinemia. Institute appropriate monitoring and support measures (e.g., transfusion support, methylene-blue administration).
- At room temperature, Elitek causes enzymatic degradation of the uric acid in blood/plasma/serum samples potentially resulting in spuriously low plasma uric acid assay readings. The following special sample handling procedure must be followed to avoid ex vivo uric acid degradation.
- Uric acid must be analyzed in plasma. Blood must be collected into pre-chilled tubes containing heparin anticoagulant. Immediately immerse plasma samples for uric acid measurement in an ice water bath. Plasma samples must be prepared by centrifugation in a pre-cooled centrifuge (4°C). Finally, the plasma must be maintained in an ice water bath and analyzed for uric acid within four hours of collection
# Adverse Reactions
## Clinical Trials Experience
Clinical Trials
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The data below reflect exposure to Elitek in 265 pediatric and 82 adult patients enrolled in one active-controlled trial (Study 1), two uncontrolled trials (Studies 2 and 3), and an uncontrolled safety trial (n=82). Additional data were obtained from an expanded access program of 356 patients, for whom data collection was limited to serious adverse reactions. Among these 703 patients 63% were male, the median age was 10 years (range 10 days to 88 years), 73% were Caucasian, 9% African, 4% Asian, and 14% other/unknown.
- Among the 347 patients for whom all adverse reactions regardless of severity were assessed, the most frequently observed adverse reactions (incidence ≥10%) were vomiting (50%), fever (46%), nausea (27%), headache (26%), abdominal pain (20%), constipation (20%), diarrhea (20%), mucositis (15%), and rash (13%). In Study 1, an active control study, the following adverse reactions occurred more frequently in Elitek-treated subjects than allopurinol-treated subjects: vomiting, fever, nausea, diarrhea, and headache. Although the incidence of rash was similar in the two arms, severe rash was reported only in one Elitek-treated patient.
- Further studies, including one-active controlled study (Study 4) and four supportive studies, have been conducted in adult patients. In these studies, Elitek was administered to a total of 434 adult patients [58% male, 42% female; median age 56 years (range 18 years to 89 years); 52% Caucasian, 7% African, 14% Asian, 28% other/unknown].
- Of these 434 patients, 275 adult patients with leukemia, lymphoma, or solid tumor malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomized in an open label trial receiving either Elitek alone, Elitek in combination with allopurinol, or allopurinol alone (Study 4).
- A drug-related adverse reaction in Study 4 of any grade was experienced in 4.3% of Elitek-treated patients, 5.4% of Elitek/allopurinol-treated patients, and 1.1% of allopurinol-treated patients.
- Table 1 presents the per patient incidence of adverse reactions by study arm in Study 4.
- Hypersensitivity reactions occurred in 4.3% of Elitek-treated patients and 1.1% of Elitek/allopurinol-treated patients in Study 4. Clinical manifestations of hypersensitivity included arthralgia, injection site irritation, peripheral edema, and rash.
- The following serious adverse reactions occurred at a difference in incidence of ≥2% in patients receiving rasburicase compared to patients receiving allopurinol in randomized studies (Study 1 and Study 4): pulmonary hemorrhage, respiratory failure, supraventricular arrhythmias, ischemic coronary artery disorders, and abdominal and gastrointestinal infections.
- The incidence of anaphylaxis, hemolysis, and methemoglobinemia was less than 1% of the 887 rasburicase-treated patients entered on these clinical trials.
- As with all therapeutic proteins, there is potential for immunogenicity. Elitek can elicit anti-product antibodies that bind to rasburicase and in some instances inhibit the activity of rasburicase in vitro.
- In clinical trials of pediatric patients with hematologic malignancies, 24/218 patients tested (11%) developed antibodies by day 28 following Elitek administration as assessed by qualitative ELISA.
- Using quasi-quantitative immunoassays in rasburicase naïve adult patients with hematological malignancies, 47/260 (18%) patients were positive for anti-rasburicase immunoglobulin G (IgG), 21/260 (8%) patients were positive for anti-rasburicase neutralizing IgG, and 16/260 (6%) patients were positive for anti-rasburicase immunoglobulin E (IgE) from day 14 to 24 months after 5 daily doses of Elitek.
- The incidence of antibody responses detected is highly dependent on the sensitivity and specificity of the assay, which have not been fully evaluated. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including serum sampling, timing and methodology, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Elitek with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Rasburicase in the drug label.
# Drug Interactions
- No drug interaction studies have been conducted in humans.
- Rasburicase does not metabolize allopurinol, cytarabine, methylprednisolone, methotrexate, 6-mercaptopurine, thioguanine, etoposide, daunorubicin, cyclophosphamide or vincristine in vitro. No metabolic-based drug interactions are therefore anticipated with these agents in patients.
- In preclinical in vivo studies, rasburicase did not affect the activity of isoenzymes CYP1A, CYP2A, CYP2B, CYP2C, CYP2E, and CYP3A, suggesting no induction or inhibition potential. Clinically relevant P450-mediated drug-drug interactions are therefore not anticipated in patients treated with the recommended Elitek dose and dosing schedule.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no studies of rasburicase in pregnant women. Reproductive toxicity studies in rabbits treated during organogenesis with approximately 10 to 100 times the recommended human dose of rasburicase resulted in teratogenicity, including decreased fetal body weights and heart and great vessel malformations at all dose levels. Multiple heart and great vessel malformations were also observed in offspring of pregnant rats treated with approximately 250 times the recommended human dose of rasburicase. Other adverse effects were observed in rasburicase-treated pregnant rabbits at all dose levels tested and included pre- and post-implantation losses, abortions, and decreased uterine weights .
- It is unknown whether rasburicase can cross the placental barrier in humans and result in fetal harm. Because of the observed teratogenic effects of rasburicase in animal reproductive studies, use rasburicase during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rasburicase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rasburicase during labor and delivery.
### Nursing Mothers
- It is not known whether rasburicase is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rasburicase, a decision should be made whether to discontinue nursing or to discontinue rasburicase, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of Elitek was studied in 246 pediatric patients ranging in age from 1 month to 17 years. There were insufficient numbers of patients between 0 and 6 months (n=7) to determine whether they respond differently from older children. Mean uric acid AUC0–96 hr was higher in children <2 years of age (n=24; 150 ± s.e. 16 mg hr/dL) than those age 2 to 17 years (n=222; 108 ± s.e. 4 mg hr/dL). Children <2 years of age had a lower rate of achieving normal uric acid concentration by 48 hours [83% (95% CI: 62, 95)] than those 2 to 17 years [93% (95% CI: 89, 95)].
### Geriatic Use
- Of the total number of adults treated with Elitek (n=434) in clinical studies, 30% were aged 65 and over while 8% were aged 75 and over. No overall differences in pharmacokinetics, safety, and effectiveness were observed between the elderly and younger patients.
### Gender
There is no FDA guidance on the use of Rasburicase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rasburicase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rasburicase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rasburicase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rasburicase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rasburicase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous infusion
- Elitek must be reconstituted with the diluent provided in the carton.
Reconstitute the 1.5 mg vial of Elitek with 1 mL of diluent. Reconstitute the 7.5 mg vial of Elitek with 5 mL of diluent. Mix by swirling gently. Do not shake or vortex.
- Inspect reconstituted Elitek visually for particulate matter and discoloration prior to administration. Discard solution if particulate matter is visible or product is discolored.
- Do not administer Elitek as a bolus injection.
- Inject the calculated dose of reconstituted Elitek solution into an infusion bag containing the appropriate volume of 0.9% sterile sodium chloride, to achieve a final total volume of 50 mL.
- Infuse over 30 minutes through a separate line or flush line with at least 15 mL of normal saline prior to and after Elitek infusion.
- Do not use filters during reconstitution or infusion of Elitek.
- Store reconstituted or diluted solution at 2–8°C.
- Discard unused product solution 24 hours following reconstitution.
### Monitoring
There is limited information regarding Monitoring of Rasburicase in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rasburicase in the drug label.
# Overdosage
- The maximum reported overdosage of Elitek is a single dose of 1.3 mg/kg. No adverse events occurred in reported cases of overdosage. Monitor patients who receive an overdose and initiate supportive measures if required.
# Pharmacology
## Mechanism of Action
- In humans, uric acid is the final step in the catabolic pathway of purines. Rasburicase catalyzes enzymatic oxidation of poorly soluble uric acid into an inactive and more soluble metabolite (allantoin).
## Structure
- Elitek (rasburicase) is a recombinant urate-oxidase produced by a genetically modified Saccharomyces cerevisiae strain. The cDNA coding for rasburicase was cloned from a strain of Aspergillus flavus.
- Rasburicase is a tetrameric protein with identical subunits. Each subunit is made up of a single 301 amino acid polypeptide chain with a molecular mass of about 34 kDa. The drug product is a sterile, white to off-white, lyophilized powder intended for intravenous administration following reconstitution with a diluent. Elitek is supplied in 3 mL and 10 mL colorless, glass vials containing rasburicase at a concentration of 1.5 mg/mL after reconstitution.
- Elitek 1.5 mg presentation contains 1.5 mg rasburicase, 10.6 mg mannitol, 15.9 mg L-alanine, between 12.6 and 14.3 mg of dibasic sodium phosphate (lyophilized powder), and a diluent (1 mL Water for Injection, USP, and 1 mg Poloxamer 188).
- Elitek 7.5 mg presentation contains 7.5 mg of rasburicase, 53 mg mannitol, 79.5 mg L-alanine, and between 63 and 71.5 mg dibasic sodium phosphate (lyophilized powder) and a diluent (5 mL Water for Injection, USP, and 5 mg Poloxamer 188).
## Pharmacodynamics
- The measurement of plasma uric acid was used to evaluate the effectiveness of rasburicase in clinical studies. Following administration of either 0.15 or 0.20 mg/kg rasburicase daily for up to 5 days, plasma uric acid levels decreased within 4 hours and were maintained below 7.5 mg/dL in 98% of adult and 90% of pediatric patients for at least 7 days. There was no evidence of a dose response effect on uric acid control for doses between 0.15 and 0.20 mg/kg rasburicase.
## Pharmacokinetics
- The pharmacokinetics of rasburicase were evaluated in both pediatric and adult patients with leukemia, lymphoma or other hematological malignancies. Rasburicase exposure, as measured by AUC0–24 hr and Cmax, tended to increase with a dose range from 0.15 to 0.2 mg/kg. The mean terminal half-life was similar between pediatric and adult patients and ranged from 15.7 to 22.5 hours. The mean volume of distribution of rasburicase ranged from 110 to 127 mL/kg in pediatric patients and from 75.8 to 138 mL/kg in adult patients, respectively. Minimal accumulation of rasburicase (<1.3 fold) was observed between days 1 and 5 of dosing. In adults, age, gender, baseline liver enzymes and creatinine clearance did not impact the pharmacokinetics of rasburicase. A cross-study comparison revealed that after administration of rasburicase at 0.15 or 0.20 mg/kg, the geometric mean values of body-weight normalized clearance were approximately 40% lower in Japanese (n=20) than that in Caucasians (n=22).
## Nonclinical Toxicology
- Carcinogenicity studies in animals to evaluate tumoriogenic potential of rasburicase have not been performed. Rasburicase was not mutagenic in the Ames, unscheduled DNA synthesis, chromosome analysis, mouse lymphoma, and micronucleus tests.
- Rasburicase did not affect reproductive performance or fertility in male or female rats at a dose 50-fold higher (10 mg/kg) than the recommended human dose.
- Pregnant rabbits dosed daily with 10 to 100 times the human dose of rasburicase during the period of organogenesis (gestation day 6 – 19) exhibited teratogenic effects, clinical signs of maternal toxicity including weight loss and mortality, decreases in uterine weights and viable fetuses, and increased fetal resorptions, post-implantation losses and abortions. Teratogenic effects included multiple heart and great vessel malformations at all dose levels. Multiple heart and great vessel malformations were also observed in offspring of pregnant rats treated with approximately 250 times the recommended human dose of rasburicase. There are no data available regarding the level of rasburicase exposure in the offspring.
# Clinical Studies
- Elitek was administered in three studies to 265 patients with acute leukemia or non-Hodgkin's lymphoma. These clinical studies were largely limited to pediatric patients (246 of 265). Elitek was administered as a 30-minute infusion once (n=251) or twice (n=14) daily at a dose of 0.15 or 0.2 mg/kg/dose (total daily dose 0.2–0.4 mg/kg/day). Elitek was administered prior to and concurrent with anti-tumor therapy, which consisted of either systemic chemotherapy (n=196) or steroids (n=69).
- Study 1 was a randomized, open-label, controlled study conducted at six institutions, in which 52 pediatric patients were randomized to receive either Elitek (n=27) or allopurinol (n=25). The dose of allopurinol varied according to local institutional practice. Elitek was administered as an intravenous infusion over 30 minutes once (n=26) or twice (n=1) daily at a dose of 0.2 mg/kg/dose (total daily dose 0.2–0.4 mg/kg/day). Initiation of dosing was permitted at any time between 4 to 48 hours before the start of anti-tumor therapy and could be continued for 5 to 7 days after initiation of anti-tumor therapy. Patients were stratified at randomization on the basis of underlying malignant disease (leukemia or lymphoma) and baseline serum or plasma uric acid levels (<8 mg/dL and ≥8 mg/dL). The primary study objective was to demonstrate a greater reduction in uric acid concentration over 96 hours (AUC0–96 hr) in the Elitek group as compared to the allopurinol group. Uric acid AUC0–96 hr was defined as the area under the curve for plasma uric acid levels (mg hr/dL), measured from the last value prior to the first dose of Elitek until 96 hours after that first dose. Plasma uric acid levels were used for all uric acid AUC0–96 hr calculations.
- The demographics of the two study arms (Elitek vs. allopurinol) were as follows: age <13 years (82% vs. 76%), males (59% vs. 72%), Caucasian (59% vs. 72%), ECOG performance status 0 (89% vs. 84%), and leukemia (74% vs. 76%). The median interval, in hours, between initiation of Elitek and of anti-tumor treatment was 20 hours, with a range of 70 hours before to 10 hours after the initiation of anti-tumor treatment (n=24, data not reported for 3 patients).
- The uric acid AUC0–96 hr was significantly lower in the Elitek group (128 ± s.e. 14 mg hr/dL) as compared to the allopurinol group (328 ± s.e. 26 mg hr/dL). All but one patient in the Elitek arm had reduction and maintenance of uric acid levels to within or below the normal range during the treatment. The incidence of renal dysfunction was similar in the two study arms; one patient in the allopurinol arm developed acute renal failure.
- Study 2 was a multi-institutional, single-arm study conducted in 89 pediatric and 18 adult patients with hematologic malignancies. Patients received Elitek at a dose of 0.15 mg/kg/day. The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours where maintenance of uric acid concentration was defined as: 1) achievement of uric acid concentration ≤6.5 mg/dL (patients <13 years) or ≤7.5 mg/dL (patients ≥13 years) within a designated time point (48 hours) from initiation of Elitek and maintained until 24 hours after the last administration of study drug; and 2) control of uric acid level without the need for allopurinol or other agents.
- The study population demographics were: age <13 years (76%), males (61%), Caucasian (91%), ECOG performance status=0 (92%), and leukemia (89%).
- The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 2 was 99% (106/107).
- Study 3 was a multi-institutional, single-arm study conducted in 130 pediatric patients and 1 adult patient with hematologic malignancies. Patients received Elitek at either a dose of 0.15 mg/kg/day (n=12) or 0.2 mg/kg/day (n=119). The primary efficacy objective was determination of the proportion of patients with maintained plasma uric acid concentration at 48 hours as defined for Study 2 above.
- The study population demographics were: age <13 years (76%), Caucasian (83%), males (67%), ECOG=0 (67%), and leukemia (88%).
- The proportion of patients with maintenance of uric acid concentration at 48 hours in Study 3 was 92% in the 0.15 mg/kg group (n=12) and 95% in the 0.2 mg/kg group (n=119).
- Data from the 3 studies (n=265) were pooled and analyzed according to the plasma uric acid levels over time. The pre-treatment plasma uric acid concentration was ≥8 mg/dL in 61 patients and was <8 mg/dL in 200 patients. The median uric acid concentration at baseline, at 4 hours following the first dose of Elitek, and the per patient fall in plasma uric acid concentration from baseline to 4 hours were calculated in those patients with both pre-treatment and 4-hour post-treatment values. Among patients with pre-treatment uric acid ≥8 mg/dL [baseline median 10.6 mg/dL (range 8.1 – 36.4)], the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 9.1 mg/dL (0.3 – 19.3 mg/dL). Among the patients with a pre-treatment plasma uric acid level <8 mg/dL [baseline median 4.6 mg/dL (range 0.2 – 7.9 mg/dL)], the median per-patient change in plasma uric acid concentration by 4 hours after the first dose was a decrease of 4.1 mg/dL (0.1 – 7.6 mg/dL).
- Figure 1 is a box and whisker plot of plasma uric acid levels inclusive of 261 of the 265 Elitek treated patients from Studies 1, 2, and 3. Of the 261 evaluable patients, plasma uric acid concentration was maintained [see STUDY 2 for the definition of uric acid concentration maintenance], by 4 hours for 92% of patients (240/261), by 24 hours for 93% of patients (245/261), by 48 hours for 97% of patients (254/261), by 72 hours for 99% of patients (260/261), and by 96 hours for 100% of patients (261/261). Of the subset of 61 patients whose plasma uric acid level was elevated at baseline (≥8 mg/dL), plasma uric acid concentration was maintained by 4 hours for 72% of patients (44/61), by 24 hours for 80% of patients (49/61), by 48 hours for 92% of patients (56/61), by 72 hours for 98% of patients (60/61), and by 96 hours for 100% (61/61).
- A total of 342 adults with either leukemia, lymphoma, or other hematologic malignancy received Elitek in five studies (one randomized study, Study 4, and four uncontrolled studies). Across the five studies, Elitek was administered at a dose of 0.15 mg/kg/day (n=38) or 0.2 mg/kg/day (n=304).
- Study 4 was a randomized (1:1:1), multi-center, open-label study conducted in patients with leukemia, lymphoma, and solid tumor malignancies at risk for hyperuricemia and TLS. A total of 275 adult patients received at least one dose of study drug. The median age was 56 years, 62% were males, 80% were Caucasian, 66% had leukemia, 29% had lymphoma, 18% were hyperuricemic (uric acid ≥7.5mg/dL) at study entry. Patients in Arm A received Elitek for 5 days (n=92). Patients in Arm B received Elitek from day 1 through day 3 followed by oral allopurinol from day 3 through day 5 (overlap on day 3: Elitek and allopurinol administered approximately 12 hours apart) (n=92). Patients in Arm C received oral allopurinol for 5 days (n=91). Elitek was administered at the dose of 0.2 mg/kg/day as a 30-minute infusion once daily. Allopurinol was administered orally at the dose of 300 mg once a day. Patients were eligible for the study if they were either at high risk, or potential risk for TLS. The major endpoint of this study was the uric acid response rate defined as the proportion of patients with plasma uric acid levels ≤7.5 mg/dL from day 3 to day 7, after initiation of antihyperuricemic treatment.
- Table 2 presents the response rates in the three treatment arms. The response rate in arm A was significantly greater than in arm C (p=0.0009). The response rate was higher for arm B compared to arm C; this difference was not statistically significant.
- There were no patients with documented failure to control uric acid in arms A or B. In arm C, 34% of patients did not have a uric acid response; 11% due to failure to control uric acid and 4.4% due to the need for extended antihyperuricemic treatment.
- Box and whisker plots of uric acid over time for the patient population (Figure 2) show that in the two arms containing Elitek, uric acid levels were ≤2 mg/dL in 96% of patients at 4 hours of the day 1 dose.
- Tumor lysis syndrome (TLS)
- Clinical TLS was defined by changes in at least two or more laboratory parameters for hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia and at least one of the following events occurring within 7 days of treatment: renal failure/injury, need for renal dialysis, and/or serum creatinine increase >1.5 ULN, arrhythmia or seizure. Clinical TLS occurred in 3% of Elitek-treated patients, 3% of Elitek/allopurinol-treated patients, and 4% of allopurinol-treated patients.
# How Supplied
- NDC 0024-5150-10: One carton contains 3 single-use vials each containing 1.5 mg of rasburicase and 3 ampules each containing 1 mL diluent.
NDC 0024-5151-75: One carton contains 1 single-use vial containing 7.5 mg of rasburicase and 1 ampule containing 5 mL diluent.
## Storage
The lyophilized drug product and the diluent for reconstitution should be stored at 2–8°C (36–46°F). Do not freeze. Protect from light.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
PRINCIPAL DISPLAY PANEL - 1.5 mg Kit Carton
NDC 0024-5150-10
ELITEK®
rasburicase
1.5 mg
Three single-use vials
Three diluent ampules
FOR INTRAVENOUS INFUSION
Sterile – Contains No Preservatives – Single Use Vials
Rx only
sanofi aventis
PRINCIPAL DISPLAY PANEL - 7.5 mg Kit Carton
NDC 0024-5151-75
ELITEK®
rasburicase
7.5 mg
One single-use vial
One diluent ampule
FOR INTRAVENOUS INFUSION
Sterile – Contains No Preservatives – Single Use Vial
Rx only
sanofi aventis
### Ingredients and Appearance
# Patient Counseling Information
- Instruct patients to notify their physician immediately if any of the following occur: allergic reaction, bronchospasm, chest pain or tightness, dyspnea, hypoxia, hypotension, shock or urticaria.
# Precautions with Alcohol
- Alcohol-Rasburicase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ELITEK®[1]
# Look-Alike Drug Names
There is limited information regarding Rasburicase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Rasburicase | |
ea0ec85351701660b0a0cf03c361a62a21de2b53 | wikidoc | Rattlesnake | Rattlesnake
Rattlesnakes are a group of venomous snakes, genera Crotalus and Sistrurus. They belong to the class of venomous snakes known commonly as pit vipers.
# Overview
There are approximately fifty species of rattlesnake, with numerous subspecies. They receive their name for the rattle located at the tip of their tails. The rattle is used as a warning device when threatened. The scientific name Crotalus derives from the Greek, κρόταλον, meaning "castanet". The name Sistrurus is the Latinized form of the Greek word for "tail rattler" (Σείστρουρος, Seistrouros) and shares its root with the ancient Egyptian musical instrument, the sistrum, a type of rattle.
Most rattlesnakes mate in the spring. All species give live birth, rather than laying eggs. The young are self-sufficient from birth. As they do not need their mother after birth, the mother does not remain with her young.
# Prey
Rattlesnakes consume rodents and other small animals, such as rabbits, rats, mice, etc., subduing their prey quickly with a venomous bite as opposed to constricting. The venom stuns or kills typical rattlesnake prey immediately. A rattlesnake will follow prey that does not quickly succumb to the venom and attempts to escape. They are specially known to strike at distances up to two-thirds their body length.
# Predators
Rattlesnakes are prey for kingsnakes, roadrunners, pigs, hawks, and eagles. They have been harvested as human food, such as at the Rattlesnake Round-Up in Sweetwater, Texas.
# The rattle
The rattle is composed of a series of nested, hollow beads which are actually modified scales from the tail tip. Each time the snake sheds its skin, a new rattle segment is added. They may shed their skins several times a year depending on food supply and growth rates. The rattle may break; there is little truth to the claim that one can tell a rattlesnake's age from the number of beads in its rattle. Newborn rattlesnakes do not have functional rattles; it isn't until after they have shed their skin for the first time that they gain an additional bead, which beats against the first bead, known as the button, to create the rattling sound. Adult snakes may lose their rattles on occasion, but more appear at each molting. If the rattle absorbs enough water in wet weather, it will not make noise.
# Paleontology
The earliest fossil found which can be definitively identified as a rattlesnake was discovered near Driftwood Creek in Hitchcock County, Nebraska, U.S.A. An exact age of the specimen is indeterminate. The fossilized remains usually consist of ribs, which makes accurate specie identification problematic, as even many species of modern rattlesnakes have nearly identical vertebral characteristics. One extinct species, of which fossils were discovered in Allen Cave in Citrus County, was given the name Croeus. Though it had many characters in common with the modern Crotalus adamanteus, it was a much larger animal, probably attaining lengths in excess of 12 feet. In general, the fossil record for rattlesnakes is quite limited, and their exact route of evolution from the more primitive true vipers to their current form is not well understood.
# Safety and identification
Different species of rattlesnake vary significantly in size, territory, markings, and temperament. If the rattlesnake is not cornered or imminently threatened, it will usually attempt to flee from encounters with humans, but will not always do so. Bites often occur when humans startle the snake or provoke it. Those bitten while provoking rattlesnakes have usually underestimated the range (roughly two-thirds of its total length) and speed with which a coiled snake can strike (literally faster than the human eye can follow). Be aware that they can actually strike without pulling their body back. Heavy boots and long pants reinforced with leather or canvas are recommended when hiking in areas known to harbor rattlesnakes.
For learning how to quickly and safely identify rattlesnakes by their markings, guides are available through booksellers, libraries, and local conservation and wildlife management agencies. The best way to avoid contact with rattlesnakes is to remain observant and avoid potential encounters. Hikers should always watch their steps when negotiating fallen logs or boulders and take extra caution when near rocky outcroppings and ledges where rattlesnakes may be hiding or sunning themselves. Snakes will occasionally sun themselves in the middle of a trail, so always watch your step. When encountering a rattlesnake on a trail, keep your distance and allow the snake room to retreat.
# Rattlesnake bites
Rattlesnakes are born with fully functioning fangs capable of injecting venom and can regulate the amount of venom they inject when biting. Generally they deliver a full dose of venom to their prey, but may deliver less venom or none at all when biting defensively. A frightened or injured snake may not exercise such control. Young snakes, although incapable of delivering an amount of venom equivalent to their adult counterparts, are still potentially deadly. Any bite must be considered dangerous and professional medical care should immediately be sought.
## Toxicity
Most species of rattlesnakes have hemotoxic venom, destroying tissue, degenerating organs and causing coagulopathy (disrupted blood clotting). Some degree of permanent scarring is very likely in the event of a venomous bite, even with prompt, effective treatment, and a severe envenomation, combined with delayed or ineffective treatment, can lead to the loss of a limb and rarely, death. Thus, a rattlesnake bite is always a potentially serious, or even fatal, injury. Untreated rattlesnake bites, especially from larger species, are very often fatal. However, antivenin, when applied in time, reduces the death rate to less than 4%.
Around 8,000 people are bitten by venomous snakes in the United States each year. On average, fewer than 15 snakebite deaths are reported.
Some rattlesnakes, especially the tropical species, have neurotoxic venom. A bite from these snakes can interfere with the function of the heart, paralyze the lungs, and shut down parts of the nervous system.
The Common Kingsnake (Lampropeltis getula), a constrictor, is famous for being largely immune to the venom of rattlesnakes and other vipers, and therefore rattlesnakes form part of this snake's natural diet in the wild.
## First aid
When a bite occurs, the amount of venom injected cannot be gauged easily. Symptoms and swelling may occur quickly, and may cause death easily but in some cases hours may pass before serious effects appear.
Experienced health workers typically gauge envenomation in stages ranging from 0, when there is no evident venom, to 5, when there is a life-threatening amount of venom present. The stages reflect the amount of bruising and swelling around the fang marks and the speed with which that bruising and swelling progresses. In more severe envenomation cases (stage 4 or 5) there may also be proximal symptoms, such as lip-tingling, dizziness, bleeding, vomiting, or shock. Difficulty breathing, paralysis, drooling, and massive hemorrhaging are also common symptoms.
Quick medical attention is critical, and treatment typically requires antivenin/antivenom to block the tissue destruction, nerve effects, and blood-clotting disorders common with rattlesnake venom, Most medical experts recommend keeping the area of the bite below the level of the heart. It is important to keep a snake bite victim calm in order to avoid elevating their heart rate and accelerating the circulation of venom within the body. Untrained individuals should not attempt to make incisions at or around bite sites, or to use tourniquets, as either treatment may be more destructive than the envenomation itself.
Any bite from a rattlesnake should be regarded as a life-threatening medical emergency that requires immediate hospital treatment from trained professionals.
# Rattlesnakes as food
Rattlesnakes are also a popular food in some southwestern cuisines and are sometimes sold in speciality meat shops. It has a flavor that has been described as similar to chicken or frog legs and a chewy texture similar to alligator.
# Rattlesnakes in captivity
There are fairly obvious risks with private ownership of rattlesnakes. A bite can result in a large bill for emergency medical care. Some jurisdictions outlaw the possession of venomous snakes. Where it is legal, some form of license or insurance policy may be required.
# Media | Rattlesnake
Rattlesnakes are a group of venomous snakes, genera Crotalus and Sistrurus. They belong to the class of venomous snakes known commonly as pit vipers.
# Overview
There are approximately fifty species of rattlesnake, with numerous subspecies. They receive their name for the rattle located at the tip of their tails. The rattle is used as a warning device when threatened. The scientific name Crotalus derives from the Greek, κρόταλον, meaning "castanet". The name Sistrurus is the Latinized form of the Greek word for "tail rattler" (Σείστρουρος, Seistrouros) and shares its root with the ancient Egyptian musical instrument, the sistrum, a type of rattle.
Most rattlesnakes mate in the spring. All species give live birth, rather than laying eggs. The young are self-sufficient from birth. As they do not need their mother after birth, the mother does not remain with her young.
# Prey
Rattlesnakes consume rodents and other small animals, such as rabbits, rats, mice, etc., subduing their prey quickly with a venomous bite as opposed to constricting. The venom stuns or kills typical rattlesnake prey immediately. A rattlesnake will follow prey that does not quickly succumb to the venom and attempts to escape. They are specially known to strike at distances up to two-thirds their body length.
# Predators
Rattlesnakes are prey for kingsnakes, roadrunners, pigs, hawks, and eagles. They have been harvested as human food, such as at the Rattlesnake Round-Up in Sweetwater, Texas.
# The rattle
The rattle is composed of a series of nested, hollow beads which are actually modified scales from the tail tip. Each time the snake sheds its skin, a new rattle segment is added. They may shed their skins several times a year depending on food supply and growth rates. The rattle may break; there is little truth to the claim that one can tell a rattlesnake's age from the number of beads in its rattle. Newborn rattlesnakes do not have functional rattles; it isn't until after they have shed their skin for the first time that they gain an additional bead, which beats against the first bead, known as the button, to create the rattling sound. Adult snakes may lose their rattles on occasion, but more appear at each molting. If the rattle absorbs enough water in wet weather, it will not make noise.
# Paleontology
The earliest fossil found which can be definitively identified as a rattlesnake was discovered near Driftwood Creek in Hitchcock County, Nebraska, U.S.A. An exact age of the specimen is indeterminate. The fossilized remains usually consist of ribs, which makes accurate specie identification problematic, as even many species of modern rattlesnakes have nearly identical vertebral characteristics. One extinct species, of which fossils were discovered in Allen Cave in Citrus County, was given the name Croeus. Though it had many characters in common with the modern Crotalus adamanteus, it was a much larger animal, probably attaining lengths in excess of 12 feet. In general, the fossil record for rattlesnakes is quite limited, and their exact route of evolution from the more primitive true vipers to their current form is not well understood.[1]
# Safety and identification
Different species of rattlesnake vary significantly in size, territory, markings, and temperament. If the rattlesnake is not cornered or imminently threatened, it will usually attempt to flee from encounters with humans, but will not always do so. Bites often occur when humans startle the snake or provoke it. Those bitten while provoking rattlesnakes have usually underestimated the range (roughly two-thirds of its total length) and speed with which a coiled snake can strike (literally faster than the human eye can follow). Be aware that they can actually strike without pulling their body back. Heavy boots and long pants reinforced with leather or canvas are recommended when hiking in areas known to harbor rattlesnakes.
For learning how to quickly and safely identify rattlesnakes by their markings, guides are available through booksellers, libraries, and local conservation and wildlife management agencies. The best way to avoid contact with rattlesnakes is to remain observant and avoid potential encounters. Hikers should always watch their steps when negotiating fallen logs or boulders and take extra caution when near rocky outcroppings and ledges where rattlesnakes may be hiding or sunning themselves. Snakes will occasionally sun themselves in the middle of a trail, so always watch your step. When encountering a rattlesnake on a trail, keep your distance and allow the snake room to retreat.
# Rattlesnake bites
Rattlesnakes are born with fully functioning fangs capable of injecting venom and can regulate the amount of venom they inject when biting. Generally they deliver a full dose of venom to their prey, but may deliver less venom or none at all when biting defensively. A frightened or injured snake may not exercise such control. Young snakes, although incapable of delivering an amount of venom equivalent to their adult counterparts, are still potentially deadly. Any bite must be considered dangerous and professional medical care should immediately be sought.
## Toxicity
Most species of rattlesnakes have hemotoxic venom, destroying tissue, degenerating organs and causing coagulopathy (disrupted blood clotting). Some degree of permanent scarring is very likely in the event of a venomous bite, even with prompt, effective treatment, and a severe envenomation, combined with delayed or ineffective treatment, can lead to the loss of a limb and rarely, death. Thus, a rattlesnake bite is always a potentially serious, or even fatal, injury. Untreated rattlesnake bites, especially from larger species, are very often fatal. However, antivenin, when applied in time, reduces the death rate to less than 4%.
Around 8,000 people are bitten by venomous snakes in the United States each year[1]. On average, fewer than 15 snakebite deaths are reported.
Some rattlesnakes, especially the tropical species, have neurotoxic venom. A bite from these snakes can interfere with the function of the heart, paralyze the lungs, and shut down parts of the nervous system.
The Common Kingsnake (Lampropeltis getula), a constrictor, is famous for being largely immune to the venom of rattlesnakes and other vipers,[2] and therefore rattlesnakes form part of this snake's natural diet in the wild.
## First aid
When a bite occurs, the amount of venom injected cannot be gauged easily. Symptoms and swelling may occur quickly, and may cause death easily but in some cases hours may pass before serious effects appear.
Experienced health workers typically gauge envenomation in stages ranging from 0, when there is no evident venom, to 5, when there is a life-threatening amount of venom present. The stages reflect the amount of bruising and swelling around the fang marks and the speed with which that bruising and swelling progresses. In more severe envenomation cases (stage 4 or 5) there may also be proximal symptoms, such as lip-tingling, dizziness, bleeding, vomiting, or shock. Difficulty breathing, paralysis, drooling, and massive hemorrhaging are also common symptoms.
Quick medical attention is critical, and treatment typically requires antivenin/antivenom to block the tissue destruction, nerve effects, and blood-clotting disorders common with rattlesnake venom, Most medical experts recommend keeping the area of the bite below the level of the heart. It is important to keep a snake bite victim calm in order to avoid elevating their heart rate and accelerating the circulation of venom within the body. Untrained individuals should not attempt to make incisions at or around bite sites, or to use tourniquets, as either treatment may be more destructive than the envenomation itself.
Any bite from a rattlesnake should be regarded as a life-threatening medical emergency that requires immediate hospital treatment from trained professionals.
# Rattlesnakes as food
Rattlesnakes are also a popular food in some southwestern cuisines and are sometimes sold in speciality meat shops. It has a flavor that has been described as similar to chicken or frog legs and a chewy texture similar to alligator.[2]
# Rattlesnakes in captivity
There are fairly obvious risks with private ownership of rattlesnakes. A bite can result in a large bill [3] for emergency medical care. Some jurisdictions outlaw the possession of venomous snakes. Where it is legal, some form of license or insurance policy may be required.
# Media
Template:Listen | https://www.wikidoc.org/index.php/Rattlesnake | |
31c73205bd668bf0f05d2695ce92bf553d1f6496 | wikidoc | Ravulizumab | Ravulizumab
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Ravulizumab is a monoclonal antibody that is FDA approved for the treatment of adults with a disease called Paroxysmal Nocturnal Hemoglobinuria (PNH), and for adults and children 1 month of age and older with a disease called atypical hemolytic uremic syndrome (aHUS). ULTOMIRIS is only available through a program called the ULTOMIRIS REMS. There is a Black Box Warning for this drug as shown here. Common adverse reactions include respiratory tract infection, headache, diarrhea and fever
ULTOMIRIS is a prescription medicine called a monoclonal antibody..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### ULTOMIRIS is indicated for:
- The treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).
- The treatment of adults and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).
### Limitations of Use
- ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).
### Recommended Vaccination and Prophylaxis
- Provide 2 weeks of antibacterial drug prophylaxis to patients if ULTOMIRIS must be initiated immediately and vaccines are administered less than 2 weeks before starting ULTOMIRIS therapy.
### Recommended Weight-Based Dosage Regimen - PNH
- The recommended dosing regimen in adult patients with PNH weighing 40 kg or greater, consists of a loading dose followed by maintenance dosing, administered by intravenous infusion. Administer the doses based on the patient’s body weight.
- Starting 2 weeks after the loading dose administration, begin maintenance doses at a once every 8-week interval.
- The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but the subsequent doses should be administered according to the original schedule.
### Recommended Weight-Based Dosage Regimen - aHUS
- The recommended dosing regimen in adult and pediatric patients one month of age and older with aHUS weighing 5 kg or greater, consists of a loading dose followed by maintenance dosing, administered by intravenous infusion.
- Administer the doses basedon the patient’s body weight
- Starting 2 weeks after the loading dose administration, begin maintenance doses once every 8 weeks or every 4 weeks (depending on body weight).
- The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but the subsequent doses should be administered according to the original schedule.
### Dosing Considerations
- For patients switching from eculizumab to ULTOMIRIS, administer the loading dose of ULTOMIRIS 2 weeks after the last eculizumab infusion, and then administer maintenance doses once every 8 weeks or every 4 weeks (depending on body weight), starting 2 weeks after loading dose administration.
- Administration of PE/PI (plasmapheresis or plasma exchange, or fresh frozen plasma infusion) may reduce ULTOMIRIS serum levels. There is no experience with administration of supplemental doses of ULTOMIRIS.
### Preparation of ULTOMIRIS
- Each vial of ULTOMIRIS is intended for single-dose only.
- ULTOMIRIS requires dilution to a final concentration of 5 mg/mL.
- Use aseptic technique to prepare ULTOMIRIS as follows:
1. The number of vials to be diluted is determined based on the individual patient’s weight and the prescribed dose
2. Prior to dilution, visually inspect the solution in the vials; the solution should be free of any particulate matter or precipitation. Do not use if there is evidence of particulate matter or precipitation.
3. Withdraw the calculated volume of ULTOMIRIS from the appropriate number of vials and dilute in an infusion bag using 0.9% Sodium Chloride Injection, USP to a final concentration of 5 mg/mL. The product should be mixed gently. Do not shake. Protect from light. Do not freeze.
4. Administer the prepared solution immediately following preparation. Infusion must be administered through a 0.2 or 0.22 micron filter.
5. If the diluted ULTOMIRIS infusion solution is not used immediately, storage under refrigeration at 2°C - 8°C (36°F - 46°F) must not exceed 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer the diluted ULTOMIRIS infusion solution within 6 hours.
- 1. The number of vials to be diluted is determined based on the individual patient’s weight and the prescribed dose
- 2. Prior to dilution, visually inspect the solution in the vials; the solution should be free of any particulate matter or precipitation. Do not use if there is evidence of particulate matter or precipitation.
- 3. Withdraw the calculated volume of ULTOMIRIS from the appropriate number of vials and dilute in an infusion bag using 0.9% Sodium Chloride Injection, USP to a final concentration of 5 mg/mL. The product should be mixed gently. Do not shake. Protect from light. Do not freeze.
- 4. Administer the prepared solution immediately following preparation. Infusion must be administered through a 0.2 or 0.22 micron filter.
- 5. If the diluted ULTOMIRIS infusion solution is not used immediately, storage under refrigeration at 2°C - 8°C (36°F - 46°F) must not exceed 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer the diluted ULTOMIRIS infusion solution within 6 hours.
### Administration of ULTOMIRIS
- Only administer as an intravenous infusion.
- Dilute ULTOMIRIS to a final concentration of 5 mg/mL.
- Administer ULTOMIRIS only through a 0.2 or 0.22 micron filter.
- Prior to administration, allow the admixture to adjust to room temperature (18°C-25°C, 64°F-77°F). Do not heat the admixture in a microwave or with any heat source other than ambient air temperature.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding ULTOMIRIS Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ULTOMIRIS Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding ULTOMIRIS FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding ULTOMIRIS Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ULTOMIRIS Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Patients with unresolved Neisseria meningitidis infection.
- Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing a meningococcal infection
# Warnings
### Serious Meningococcal Infections
- The use of ULTOMIRIS increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis). Meningococcal disease due to any serogroup may occur.
- Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of ULTOMIRIS. If urgent ULTOMIRIS therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide patients with 2 weeks of antibacterial drug prophylaxis.
- Vaccination reduces, but does not eliminate, the risk of meningococcal infections.
- Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected.
- If ULTOMIRIS therapy is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection.
- In clinical studies, 59 patients with PNH were treated with ULTOMIRIS less than 2 weeks after meningococcal vaccination. All of these patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after meningococcal vaccination. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established.
- In PNH clinical studies, 3 out of 261 PNH patients developed serious meningococcal infections/sepsis while receiving treatment with ULTOMIRIS; all 3 had been vaccinated. These 3 patients recovered while continuing treatment with ULTOMIRIS.
- ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to encapsulated bacteria infections, especially infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae.
- Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).
Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections accordingto ACIP guidelines.
- Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections accordingto ACIP guidelines.
Treatment Discontinuation for PNH
- After discontinuing treatment with ULTOMIRIS, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH along with sudden decrease in PNH clone size or hemoglobin, or re-appearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction.
Monitor any patient who discontinues ULTOMIRIS for at least 16 weeks to detect hemolysis and other reactions.
If signs and symptoms of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ULTOMIRIS.
- Monitor any patient who discontinues ULTOMIRIS for at least 16 weeks to detect hemolysis and other reactions.
- If signs and symptoms of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ULTOMIRIS.
Treatment Discontinuation for aHUS
- ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months.
- Patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.
- TMA complications post-discontinuation can be identified if any of the following is observed:
Changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure
At least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption:
A decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment;
An increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
An increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
- Changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure
- At least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption:
A decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment;
An increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
An increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
- A decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment;
- An increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
- An increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
- If TMA complications occur after ULTOMIRIS discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.
### Infusion Reactions
- In clinical trials, 5 out of 296 patients treated with ULTOMIRIS experienced infusion reactions (lower back pain, drop in blood pressure, infusion-related pain, elevation in blood pressure and limb discomfort) during ULTOMIRIS administration.
- Interrupt ULTOMIRIS infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.
# Adverse Reactions
## Clinical Trials Experience
### Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Most common adverse reactions in patients with PNH (incidence ≥10%) were upper respiratory tract infection and headache
### Atypical Hemolytic Uremic Syndrome (aHUS)
- Most common adverse reactions in patients with aHUS (incidence ≥20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia
### Immunogenicity
- The immunogenicity of ravulizumab-cwvz has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding anti-ravulizumab-cwvz antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
- In clinical studies, treatment-emergent antibodies to ravulizumab-cwvz were detected in 1 of 206 (0.5%) patients with PNH and 1 of 71 (1.4%) patients with aHUS.
- No apparent correlation of antibody development to altered pharmacokinetic profile, clinical response, or adverse events was observed.
## Postmarketing Experience
There is limited information regarding Ravulizumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ravulizumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There are no available data on ULTOMIRIS use in pregnant women to inform a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ravulizumab in women who are pregnant.
### Labor and Delivery
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
### Nursing Mothers
There is no FDA guidance on the use of Ravulizumab in women who are nursing.
### Pediatric Use
The safety and efficacy of Ultomiris for the treatment of PNH in pediatric patients have not been established.
### Geriatic Use
Clinical studies of Ultomiris did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Ultomiris with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ultomiris with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ultomiris in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ultomiris in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ultomiris in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ultomiris in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Injection: 300 mg/30 mL (10 mg/mL) as a clear to translucent, slight whitish color solution in a single-dose vial.
### Monitoring
- Monitor patients for early signs and symptoms of meningococcal infection.
- Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion reaction.
- After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.
Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure.
- Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure.
# IV Compatibility
There is limited information regarding the compatibility of Ravulizumab and IV administrations.
# Overdosage
There is limited information regarding Andexanet alfa overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Ravulizumab-cwvz is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex ) and preventing the generation of the terminal complement complex C5b9.
- ULTOMIRIS inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.
## Structure
There is limited information regarding Ultomiris Structure in the drug label.
## Pharmacodynamics
- The extent and duration of the pharmacodynamic response in patients with PNH and aHUS were exposure-dependent for ULTOMIRIS. Free C5 levels of <0.5 mcg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in patients with PNH.
- Complete terminal complement inhibition following initiation of ULTOMIRIS treatment led to normalization of serum LDH by week 4 in complement-inhibitor naïve patients with PNH, and maintained LDH normalization in patients previously treated with eculizumab with PNH.
## Pharmacokinetics
Ravulizumab-cwvz pharmacokinetics increase proportionally over a dose range of 200 to 5400 mg.
The mean (%CV) volume of distribution at steady state was 5.34 (17.2) L and 5.22 (35.4) L in patients with PNH and aHUS, respectively.
The mean (%CV) terminal elimination half-life of ravulizumab-cwvz in patients with
PNH and aHUS are 49.7 (18.0) days and 51.8 (31.3) days, respectively. The mean (%CV)
clearance of ravulizumab-cwvz in patients with PNH and aHUS are 0.08 (29.5) L/day
and 0.08 (53.3) L/day, respectively.
No clinically significant differences in the pharmacokinetics of ravulizumab-cwvz were observed based on sex, age (10 months to 83 years), race, hepatic impairment, or any degree of renal impairment, including patients with proteinuria or receiving dialysis. Body weight was a clinically significant covariate on the pharmacokinetics of ravulizumab-cwvz.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No animal studies were performed to evaluate the effects of ravulizumab-cwvz on carcinogenesis, or mutagenesis.
- Effects of ravulizumab-cwvz upon fertility have not been studied in animals.
Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility.
- Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility.
# Clinical Studies
- The safety and efficacy of ULTOMIRIS in patients with PNH was assessed in two openlabel, randomized, active-controlled, non-inferiority Phase 3 studies: PNH Study 301 and PNH Study 302.
- ULTOMIRIS was dosed intravenously in accordance with the weightbased dosing (4 infusions of ULTOMIRIS over 26 weeks). Eculizumab was administered on Days 1, 8, 15, and 22, followed by maintenance treatment with 900 mg of eculizumab on Day 29 and every 2 weeks (q2w) thereafter for a total of 26 weeks of treatment, according to the approved dosing regimen of eculizumab which was the standard-of-care for PNH at the time of studies.
- Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment with ULTOMIRIS or eculizumab, or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.
- There was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared to baseline as measured by the FACIT-fatigue instrument. Patient-reported fatigue may be an under-or over-estimation, because patients were not blinded to treatment assignment.
### PNH Study 301
- enrolled patients with PNH who were complement inhibitor naïve and had active hemolysis
- 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase 3 study conducted in 246 patients naïve to complement inhibitor treatment prior to study entry
- Patients with PNH with flow cytometric confirmation of at least 5% PNH cells were randomized 1:1 to either ULTOMIRIS or eculizumab.
### PNH Study 302
- Enrolled patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months.
- Patients who demonstrated clinically stable disease after being treated with eculizumab for at least the prior 6 months were randomized 1:1 to either continue eculizumab or to switch to ULTOMIRIS.
- The efficacy of ULTOMIRIS in patients with aHUS was assessed in 2 open-label,single-arm studies. Study ALXN1210-aHUS-311 and ALXN1210-aHUS-312.
- In order to qualify for enrollment, patients were required to have a platelet count ≤150 x109/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine level ≥97.5% percentile at screening or required dialysis.
- Enrollment criteria excluded patients presenting with TMA due to a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, Shiga toxin Escherichia coli related hemolytic uremic syndrome (STEC-HUS) and genetic defect in cobalamin C metabolism.
### Study in Adult Patients with aHUS
- Conducted in patients who were naïve to complement inhibitor treatment prior to study entry.
- The study consisted of a 26-week Initial Evaluation Period and patients were allowed to enter an extension period for up to 4.5 years.
- A total of 56 patients with aHUS were evaluated for efficacy.
- Ninety-three percent of patients had extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline.
- At baseline,71.4% (n = 40) of patients had Stage 5 chronic kidney disease (CKD). Fourteen percent had a medical history of kidney transplant and 51.8% were on dialysis at study entry. Eight patients entered the study with evidence of TMA for > 3 days after childbirth (ie, postpartum).
- Renal function, as measured by eGFR, was improved or maintained during ULTOMIRIS therapy.
### Study in Pediatric Patients with aHUS
- A total of 14 eculizumab-naïve patients with documented diagnosis of aHUS were enrolled and included in this interim analysis.
- Complete TMA Response was observed in 10 of the 14 patients (71%) during the 26-week Initial Evaluation Period.
- Four of the 5 patients who required dialysis at study entry were able to discontinue dialysis after the first month in study and for the duration of ULTOMIRIS treatment.
# How Supplied
- ULTOMIRIS (ravulizumab-cwvz) injection is a clear to translucent, slight whitish color preservative-free, solution supplied as one 300 mg/30 mL (10 mg/mL) single-dose vial per carton. NDC 25682-022-01.
## Storage
- Store ULTOMIRIS vials refrigerated at 2°C - 8°C (36°F - 46°F) in the original carton to protect from light. Do not freeze. Do not shake.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients that they are required to receive meningococcal vaccination at least 2 weeks prior to receiving the first dose of ULTOMIRIS, if they have not previously been vaccinated.
- They are required to be revaccinated according to current medical guidelines for meningococcal vaccines use while on ULTOMIRIS therapy.
- Inform patients about the signs and symptoms of meningococcal infection/sepsis, and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms are as follows:
headache with nausea or vomiting
headache and a fever
headache with a stiff neck or stiff back
fever
fever and a rash
confusion
muscle aches with flu-like symptoms
eyes sensitive to light
- headache with nausea or vomiting
- headache and a fever
- headache with a stiff neck or stiff back
- fever
- fever and a rash
- confusion
- muscle aches with flu-like symptoms
- eyes sensitive to light
- Inform patients that they will be given an ULTOMIRIS Patient Safety Card that they should carry with them at all times.
### Other Infections
- Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species.
- Counsel patients about gonorrhea prevention and advise regular testing for patients at risk.
### Discontinuation
- Inform patients with PNH or aHUS that they may develop hemolysis or TMA, respectively, when ULTOMIRIS is discontinued and that they will be monitored by their healthcare professional for at least 16 weeks for PNH or at least 12 months for aHUS following ULTOMIRIS discontinuation.
- Inform patients who discontinue ULTOMIRIS to keep the ULTOMIRIS Patient Safety Card with them for eight months after the last ULTOMIRIS dose.
### Infusion reactions
- Advise patients that administration of ULTOMIRIS may result in infusion reactions.
# Precautions with Alcohol
Alcohol-Ravulizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Ultomiris
# Look-Alike Drug Names
There is limited information regarding Ultomiris Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Ravulizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Bhavya Bellannagari[2]
# Disclaimer
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# Black Box Warning
# Overview
Ravulizumab is a monoclonal antibody that is FDA approved for the treatment of adults with a disease called Paroxysmal Nocturnal Hemoglobinuria (PNH), and for adults and children 1 month of age and older with a disease called atypical hemolytic uremic syndrome (aHUS). ULTOMIRIS is only available through a program called the ULTOMIRIS REMS. There is a Black Box Warning for this drug as shown here. Common adverse reactions include respiratory tract infection, headache, diarrhea and fever
ULTOMIRIS is a prescription medicine called a monoclonal antibody..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### ULTOMIRIS is indicated for:
- The treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).
- The treatment of adults and pediatric patients one month of age and older with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).
### Limitations of Use
- ULTOMIRIS is not indicated for the treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).
### Recommended Vaccination and Prophylaxis
- Provide 2 weeks of antibacterial drug prophylaxis to patients if ULTOMIRIS must be initiated immediately and vaccines are administered less than 2 weeks before starting ULTOMIRIS therapy.
### Recommended Weight-Based Dosage Regimen - PNH
- The recommended dosing regimen in adult patients with PNH weighing 40 kg or greater, consists of a loading dose followed by maintenance dosing, administered by intravenous infusion. Administer the doses based on the patient’s body weight.
- Starting 2 weeks after the loading dose administration, begin maintenance doses at a once every 8-week interval.
- The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but the subsequent doses should be administered according to the original schedule.
### Recommended Weight-Based Dosage Regimen - aHUS
- The recommended dosing regimen in adult and pediatric patients one month of age and older with aHUS weighing 5 kg or greater, consists of a loading dose followed by maintenance dosing, administered by intravenous infusion.
- Administer the doses basedon the patient’s body weight
- Starting 2 weeks after the loading dose administration, begin maintenance doses once every 8 weeks or every 4 weeks (depending on body weight).
- The dosing schedule is allowed to occasionally vary within 7 days of the scheduled infusion day (except for the first maintenance dose of ULTOMIRIS); but the subsequent doses should be administered according to the original schedule.
### Dosing Considerations
- For patients switching from eculizumab to ULTOMIRIS, administer the loading dose of ULTOMIRIS 2 weeks after the last eculizumab infusion, and then administer maintenance doses once every 8 weeks or every 4 weeks (depending on body weight), starting 2 weeks after loading dose administration.
- Administration of PE/PI (plasmapheresis or plasma exchange, or fresh frozen plasma infusion) may reduce ULTOMIRIS serum levels. There is no experience with administration of supplemental doses of ULTOMIRIS.
### Preparation of ULTOMIRIS
- Each vial of ULTOMIRIS is intended for single-dose only.
- ULTOMIRIS requires dilution to a final concentration of 5 mg/mL.
- Use aseptic technique to prepare ULTOMIRIS as follows:
1. The number of vials to be diluted is determined based on the individual patient’s weight and the prescribed dose
2. Prior to dilution, visually inspect the solution in the vials; the solution should be free of any particulate matter or precipitation. Do not use if there is evidence of particulate matter or precipitation.
3. Withdraw the calculated volume of ULTOMIRIS from the appropriate number of vials and dilute in an infusion bag using 0.9% Sodium Chloride Injection, USP to a final concentration of 5 mg/mL. The product should be mixed gently. Do not shake. Protect from light. Do not freeze.
4. Administer the prepared solution immediately following preparation. Infusion must be administered through a 0.2 or 0.22 micron filter.
5. If the diluted ULTOMIRIS infusion solution is not used immediately, storage under refrigeration at 2°C - 8°C (36°F - 46°F) must not exceed 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer the diluted ULTOMIRIS infusion solution within 6 hours.
- 1. The number of vials to be diluted is determined based on the individual patient’s weight and the prescribed dose
- 2. Prior to dilution, visually inspect the solution in the vials; the solution should be free of any particulate matter or precipitation. Do not use if there is evidence of particulate matter or precipitation.
- 3. Withdraw the calculated volume of ULTOMIRIS from the appropriate number of vials and dilute in an infusion bag using 0.9% Sodium Chloride Injection, USP to a final concentration of 5 mg/mL. The product should be mixed gently. Do not shake. Protect from light. Do not freeze.
- 4. Administer the prepared solution immediately following preparation. Infusion must be administered through a 0.2 or 0.22 micron filter.
- 5. If the diluted ULTOMIRIS infusion solution is not used immediately, storage under refrigeration at 2°C - 8°C (36°F - 46°F) must not exceed 24 hours taking into account the expected infusion time. Once removed from refrigeration, administer the diluted ULTOMIRIS infusion solution within 6 hours.
### Administration of ULTOMIRIS
- Only administer as an intravenous infusion.
- Dilute ULTOMIRIS to a final concentration of 5 mg/mL.
- Administer ULTOMIRIS only through a 0.2 or 0.22 micron filter.
- Prior to administration, allow the admixture to adjust to room temperature (18°C-25°C, 64°F-77°F). Do not heat the admixture in a microwave or with any heat source other than ambient air temperature.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding ULTOMIRIS Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ULTOMIRIS Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding ULTOMIRIS FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding ULTOMIRIS Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding ULTOMIRIS Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Patients with unresolved Neisseria meningitidis infection.
- Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying ULTOMIRIS treatment outweigh the risks of developing a meningococcal infection
# Warnings
### Serious Meningococcal Infections
- The use of ULTOMIRIS increases a patient’s susceptibility to serious meningococcal infections (septicemia and/or meningitis). Meningococcal disease due to any serogroup may occur.
- Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of ULTOMIRIS. If urgent ULTOMIRIS therapy is indicated in an unvaccinated patient, administer meningococcal vaccine(s) as soon as possible and provide patients with 2 weeks of antibacterial drug prophylaxis.
- Vaccination reduces, but does not eliminate, the risk of meningococcal infections.
- Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected.
- If ULTOMIRIS therapy is administered to patients with active systemic infections, monitor closely for signs and symptoms of worsening infection.
- In clinical studies, 59 patients with PNH were treated with ULTOMIRIS less than 2 weeks after meningococcal vaccination. All of these patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after meningococcal vaccination. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving ULTOMIRIS have not been established.
- In PNH clinical studies, 3 out of 261 PNH patients developed serious meningococcal infections/sepsis while receiving treatment with ULTOMIRIS; all 3 had been vaccinated. These 3 patients recovered while continuing treatment with ULTOMIRIS.
- ULTOMIRIS blocks terminal complement activation; therefore, patients may have increased susceptibility to encapsulated bacteria infections, especially infections caused by Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae.
- Children treated with ULTOMIRIS may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib).
Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections accordingto ACIP guidelines.
- Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections accordingto ACIP guidelines.
Treatment Discontinuation for PNH
- After discontinuing treatment with ULTOMIRIS, closely monitor for signs and symptoms of hemolysis, identified by elevated LDH along with sudden decrease in PNH clone size or hemoglobin, or re-appearance of symptoms such as fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction.
Monitor any patient who discontinues ULTOMIRIS for at least 16 weeks to detect hemolysis and other reactions.
If signs and symptoms of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ULTOMIRIS.
- Monitor any patient who discontinues ULTOMIRIS for at least 16 weeks to detect hemolysis and other reactions.
- If signs and symptoms of hemolysis occur after discontinuation, including elevated LDH, consider restarting treatment with ULTOMIRIS.
Treatment Discontinuation for aHUS
- ULTOMIRIS treatment of aHUS should be a minimum duration of 6 months.
- Patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.
- TMA complications post-discontinuation can be identified if any of the following is observed:
Changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure
At least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption:
A decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment;
An increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
An increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
- Changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure
- At least two of the following laboratory signs observed concurrently and results should be confirmed by a second measurement 28 days apart with no interruption:
A decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment;
An increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
An increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
- A decrease in platelet count of 25% or more as compared to either baseline or to peak platelet count during ULTOMIRIS treatment;
- An increase in serum creatinine of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
- An increase in serum LDH of 25% or more as compared to baseline or to nadir during ULTOMIRIS treatment
- If TMA complications occur after ULTOMIRIS discontinuation, consider reinitiation of ULTOMIRIS treatment or appropriate organ-specific supportive measures.
### Infusion Reactions
- In clinical trials, 5 out of 296 patients treated with ULTOMIRIS experienced infusion reactions (lower back pain, drop in blood pressure, infusion-related pain, elevation in blood pressure and limb discomfort) during ULTOMIRIS administration.
- Interrupt ULTOMIRIS infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.
# Adverse Reactions
## Clinical Trials Experience
### Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Most common adverse reactions in patients with PNH (incidence ≥10%) were upper respiratory tract infection and headache
### Atypical Hemolytic Uremic Syndrome (aHUS)
- Most common adverse reactions in patients with aHUS (incidence ≥20%) were upper respiratory tract infection, diarrhea, nausea, vomiting, headache, hypertension and pyrexia
### Immunogenicity
- The immunogenicity of ravulizumab-cwvz has been evaluated using an enzyme-linked immunosorbent assay (ELISA) for the detection of binding anti-ravulizumab-cwvz antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.
- In clinical studies, treatment-emergent antibodies to ravulizumab-cwvz were detected in 1 of 206 (0.5%) patients with PNH and 1 of 71 (1.4%) patients with aHUS.
- No apparent correlation of antibody development to altered pharmacokinetic profile, clinical response, or adverse events was observed.
## Postmarketing Experience
There is limited information regarding Ravulizumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ravulizumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There are no available data on ULTOMIRIS use in pregnant women to inform a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ravulizumab in women who are pregnant.
### Labor and Delivery
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
### Nursing Mothers
There is no FDA guidance on the use of Ravulizumab in women who are nursing.
### Pediatric Use
The safety and efficacy of Ultomiris for the treatment of PNH in pediatric patients have not been established.
### Geriatic Use
Clinical studies of Ultomiris did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
### Gender
There is no FDA guidance on the use of Ultomiris with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ultomiris with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ultomiris in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ultomiris in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ultomiris in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ultomiris in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Injection: 300 mg/30 mL (10 mg/mL) as a clear to translucent, slight whitish color solution in a single-dose vial.
### Monitoring
- Monitor patients for early signs and symptoms of meningococcal infection.
- Monitor the patient for at least one hour following completion of the infusion for signs or symptoms of an infusion reaction.
- After discontinuing treatment with ULTOMIRIS, patients should be monitored for clinical symptoms and laboratory signs of TMA complications for at least 12 months.
Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure.
- Clinical symptoms of TMA include changes in mental status, seizures, angina, dyspnea, thrombosis or increasing blood pressure.
# IV Compatibility
There is limited information regarding the compatibility of Ravulizumab and IV administrations.
# Overdosage
There is limited information regarding Andexanet alfa overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Ravulizumab-cwvz is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b (the initiating subunit of the terminal complement complex [C5b-9]) and preventing the generation of the terminal complement complex C5b9.
- ULTOMIRIS inhibits terminal complement-mediated intravascular hemolysis in patients with PNH and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS.
## Structure
There is limited information regarding Ultomiris Structure in the drug label.
## Pharmacodynamics
- The extent and duration of the pharmacodynamic response in patients with PNH and aHUS were exposure-dependent for ULTOMIRIS. Free C5 levels of <0.5 mcg/mL were correlated with maximal intravascular hemolysis control and complete terminal complement inhibition in patients with PNH.
- Complete terminal complement inhibition following initiation of ULTOMIRIS treatment led to normalization of serum LDH by week 4 in complement-inhibitor naïve patients with PNH, and maintained LDH normalization in patients previously treated with eculizumab with PNH.
## Pharmacokinetics
Ravulizumab-cwvz pharmacokinetics increase proportionally over a dose range of 200 to 5400 mg.
The mean (%CV) volume of distribution at steady state was 5.34 (17.2) L and 5.22 (35.4) L in patients with PNH and aHUS, respectively.
The mean (%CV) terminal elimination half-life of ravulizumab-cwvz in patients with
PNH and aHUS are 49.7 (18.0) days and 51.8 (31.3) days, respectively. The mean (%CV)
clearance of ravulizumab-cwvz in patients with PNH and aHUS are 0.08 (29.5) L/day
and 0.08 (53.3) L/day, respectively.
No clinically significant differences in the pharmacokinetics of ravulizumab-cwvz were observed based on sex, age (10 months to 83 years), race, hepatic impairment, or any degree of renal impairment, including patients with proteinuria or receiving dialysis. Body weight was a clinically significant covariate on the pharmacokinetics of ravulizumab-cwvz.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- No animal studies were performed to evaluate the effects of ravulizumab-cwvz on carcinogenesis, or mutagenesis.
- Effects of ravulizumab-cwvz upon fertility have not been studied in animals.
Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility.
- Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 0.8-2.2 times the equivalent of the clinical dose of ULTOMIRIS had no adverse effects on mating or fertility.
# Clinical Studies
- The safety and efficacy of ULTOMIRIS in patients with PNH was assessed in two openlabel, randomized, active-controlled, non-inferiority Phase 3 studies: PNH Study 301 and PNH Study 302.
- ULTOMIRIS was dosed intravenously in accordance with the weightbased dosing (4 infusions of ULTOMIRIS over 26 weeks). Eculizumab was administered on Days 1, 8, 15, and 22, followed by maintenance treatment with 900 mg of eculizumab on Day 29 and every 2 weeks (q2w) thereafter for a total of 26 weeks of treatment, according to the approved dosing regimen of eculizumab which was the standard-of-care for PNH at the time of studies.
- Patients were vaccinated against meningococcal infection prior to or at the time of initiating treatment with ULTOMIRIS or eculizumab, or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination.
- There was no observable difference in fatigue between ULTOMIRIS and eculizumab after 26 weeks of treatment compared to baseline as measured by the FACIT-fatigue instrument. Patient-reported fatigue may be an under-or over-estimation, because patients were not blinded to treatment assignment.
### PNH Study 301 [ALXN1210-PNH-301; NCT02946463]
- enrolled patients with PNH who were complement inhibitor naïve and had active hemolysis
- 26-week, multicenter, open-label, randomized, active-controlled, non-inferiority Phase 3 study conducted in 246 patients naïve to complement inhibitor treatment prior to study entry
- Patients with PNH with flow cytometric confirmation of at least 5% PNH cells were randomized 1:1 to either ULTOMIRIS or eculizumab.
### PNH Study 302 [ALXN1210-PNH-302; NCT03056040]
- Enrolled patients with PNH who were clinically stable after having been treated with eculizumab for at least the past 6 months.
- Patients who demonstrated clinically stable disease after being treated with eculizumab for at least the prior 6 months were randomized 1:1 to either continue eculizumab or to switch to ULTOMIRIS.
- The efficacy of ULTOMIRIS in patients with aHUS was assessed in 2 open-label,single-arm studies. Study ALXN1210-aHUS-311 and ALXN1210-aHUS-312.
- In order to qualify for enrollment, patients were required to have a platelet count ≤150 x109/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine level ≥97.5% percentile at screening or required dialysis.
- Enrollment criteria excluded patients presenting with TMA due to a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency, Shiga toxin Escherichia coli related hemolytic uremic syndrome (STEC-HUS) and genetic defect in cobalamin C metabolism.
### Study in Adult Patients with aHUS [ALXN1210-aHUS-311; NCT02949128]
- Conducted in patients who were naïve to complement inhibitor treatment prior to study entry.
- The study consisted of a 26-week Initial Evaluation Period and patients were allowed to enter an extension period for up to 4.5 years.
- A total of 56 patients with aHUS were evaluated for efficacy.
- Ninety-three percent of patients had extra-renal signs (cardiovascular, pulmonary, central nervous system, gastrointestinal, skin, skeletal muscle) or symptoms of aHUS at baseline.
- At baseline,71.4% (n = 40) of patients had Stage 5 chronic kidney disease (CKD). Fourteen percent had a medical history of kidney transplant and 51.8% were on dialysis at study entry. Eight patients entered the study with evidence of TMA for > 3 days after childbirth (ie, postpartum).
- Renal function, as measured by eGFR, was improved or maintained during ULTOMIRIS therapy.
### Study in Pediatric Patients with aHUS [ALXN1210-aHUS-312; NCT03131219]
- A total of 14 eculizumab-naïve patients with documented diagnosis of aHUS were enrolled and included in this interim analysis.
- Complete TMA Response was observed in 10 of the 14 patients (71%) during the 26-week Initial Evaluation Period.
- Four of the 5 patients who required dialysis at study entry were able to discontinue dialysis after the first month in study and for the duration of ULTOMIRIS treatment.
# How Supplied
- ULTOMIRIS (ravulizumab-cwvz) injection is a clear to translucent, slight whitish color preservative-free, solution supplied as one 300 mg/30 mL (10 mg/mL) single-dose vial per carton. NDC 25682-022-01.
## Storage
- Store ULTOMIRIS vials refrigerated at 2°C - 8°C (36°F - 46°F) in the original carton to protect from light. Do not freeze. Do not shake.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients that they are required to receive meningococcal vaccination at least 2 weeks prior to receiving the first dose of ULTOMIRIS, if they have not previously been vaccinated.
- They are required to be revaccinated according to current medical guidelines for meningococcal vaccines use while on ULTOMIRIS therapy.
- Inform patients about the signs and symptoms of meningococcal infection/sepsis, and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms are as follows:
headache with nausea or vomiting
headache and a fever
headache with a stiff neck or stiff back
fever
fever and a rash
confusion
muscle aches with flu-like symptoms
eyes sensitive to light
- headache with nausea or vomiting
- headache and a fever
- headache with a stiff neck or stiff back
- fever
- fever and a rash
- confusion
- muscle aches with flu-like symptoms
- eyes sensitive to light
- Inform patients that they will be given an ULTOMIRIS Patient Safety Card that they should carry with them at all times.
### Other Infections
- Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species.
- Counsel patients about gonorrhea prevention and advise regular testing for patients at risk.
### Discontinuation
- Inform patients with PNH or aHUS that they may develop hemolysis or TMA, respectively, when ULTOMIRIS is discontinued and that they will be monitored by their healthcare professional for at least 16 weeks for PNH or at least 12 months for aHUS following ULTOMIRIS discontinuation.
- Inform patients who discontinue ULTOMIRIS to keep the ULTOMIRIS Patient Safety Card with them for eight months after the last ULTOMIRIS dose.
### Infusion reactions
- Advise patients that administration of ULTOMIRIS may result in infusion reactions.
# Precautions with Alcohol
Alcohol-Ravulizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Ultomiris
# Look-Alike Drug Names
There is limited information regarding Ultomiris Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Ravulizumab | |
538891e8d8c3a2941c778e0f1aca46dfb1d568a0 | wikidoc | Raxibacumab | Raxibacumab
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# Overview
Raxibacumab is a monoclonal antibody that is FDA approved for the treatment of inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs, and for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate. Common adverse reactions include rash, pain in extremity, pruritus, and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Raxibacumab is indicated for the treatment of adult with inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs. Raxibacumab is also indicated for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate.
- Administer raxibacumab as a single dose of 40 mg/kg intravenously over 2 hours and 15 minutes after dilution in 0.9% Sodium Chloride Injection, USP (normal saline) to a final volume of 250 mL. Administer 25 to 50 mg diphenhydramine within 1 hour prior to raxibacumab infusion to reduce the risk of infusion reactions. Diphenhydramine route of administration (oral or IV) should be based on the temporal proximity to the start of raxibacumab infusion.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Raxibacumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Raxibacumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Raxibacumab is indicated for the treatment of pediatric patients with inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs. Raxibacumab is also indicated for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate.
- The recommended dose for pediatric patients is based on weight as shown in Table 1.
- Premedicate with diphenhydramine within 1 hour prior to raxibacumab infusion. Diphenhydramine route of administration (oral or IV) should be based on the temporal proximity to the start of raxibacumab infusion. Infuse raxibacumab over 2 hours and 15 minutes. No pediatric patients were studied during the development of raxibacumab. The dosing recommendations in Table 1 are derived from simulations designed to match the observed adult exposure to raxibacumab at a 40 mg/kg dose.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Raxibacumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Raxibacumab in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Infusion Reactions
- Infusion-related reactions were reported during administration of raxibacumab in clinical trials including reports of rash, urticaria, and pruritus. If these reactions occur, slow or interrupt raxibacumab infusion and administer appropriate treatment based on severity of the reaction.
- Premedicate with diphenhydramine within 1 hour prior to administering raxibacumab to reduce the risk of infusion reactions.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of raxibacumab has been studied only in healthy volunteers. It has not been studied in patients with inhalational anthrax.
- The safety of raxibacumab has been evaluated in 326 healthy subjects treated with a dose of 40 mg/kg in 3 clinical trials: a drug interaction trial with ciprofloxacin (Study 1), a repeat-dose trial of 20 subjects with the second raxibacumab dose administered ≥4 months after the first dose (Study 2), and a placebo-controlled trial evaluating single doses with a subset of subjects receiving 2 raxibacumab doses 14 days apart (Study 3). Raxibacumab was administered to 86 healthy subjects in Study 1. In Study 3, 240 healthy subjects received raxibacumab (217 received 1 dose and 23 received 2 doses) and 80 subjects received placebo.
- The overall safety of raxibacumab was evaluated as an integrated summary of these 3 clinical trials. Of 326 raxibacumab subjects, 283 received single doses, 23 received 2 doses 14 days apart, and 20 received 2 doses more than 4 months apart. The subjects were 18 to 88 years of age, 53% female, 74% white, 17% black/African American, 6% Asian, and 15% Hispanic.
- Adverse Reactions Leading to Discontinuation of Raxibacumab Infusion
- Four subjects (1.2%) had their infusion of raxibacumab discontinued for adverse reactions: 2 subjects (neither of whom received diphenhydramine premedication) due to urticaria (mild), and 1 subject each discontinued for clonus (mild) and dyspnea (moderate).
- Most Frequently Reported Adverse Reactions
- The most frequently reported adverse reactions were rash, pain in extremity, pruritus, and somnolence.
- Rashes
- For all subjects exposed to raxibacumab in clinical trials, the rate of rash was 2.8% (9/326) compared with 1.3% (1/80) of placebo subjects. Mild to moderate infusion-related rashes were reported in 22.2% (6/27) of subjects who did not receive diphenhydramine premedication compared to 3.3% (2/61) of subjects who were premedicated with diphenhydramine in the ciprofloxacin/raxibacumab combination trial (Study 1). In the placebo-controlled raxibacumab study where all subjects received diphenhydramine (Study 3), the rate of rash was 2.5% in both placebo- and raxibacumab-treated subjects.
- Less Common Adverse Reactions
- Clinically significant adverse reactions that were reported in <1.5% of subjects exposed to raxibacumab and at rates higher than in placebo subjects are listed below:
Anemia, leukopenia, lymphadenopathy
Palpitations
Vertigo
Fatigue, infusion site pain, peripheral edema
Blood amylase increased, blood creatine phosphokinase increased, prothrombin time prolonged
Back pain, muscle spasms
Syncope vasovagal
Insomnia
Flushing, hypertension
- Immunogenicity
- The development of anti-raxibacumab antibodies was evaluated in all subjects receiving single and double doses of raxibacumab in Studies 1, 2, and 3. Immunogenic responses against raxibacumab were not detected in any raxibacumab-treated human subjects following single or repeat doses of raxibacumab.
- The incidence of antibody formation is highly dependent on the sensitivity and specificity of the immunogenicity assay. Additionally, the observed incidence of any antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to raxibacumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Raxibacumab in the drug label.
# Drug Interactions
- Ciprofloxacin
- Co-administration of 40 mg/kg raxibacumab IV with IV or oral ciprofloxacin in human subjects did not alter the PK of either ciprofloxacin or raxibacumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- A single embryonic-fetal development study was conducted in pregnant, healthy New Zealand White rabbits administered 2 intravenous doses of raxibacumab up to 120 mg/kg (3 times the human dose on a mg/kg basis) on gestation days 7 and 14. No evidence of harm to the pregnant dam or the fetuses due to raxibacumab was observed. Cmax values in rabbits after dosing with 120 mg/kg were 3,629 mcg/mL and 4,337 mcg/mL after the first and second dose of raxibacumab, respectively; these are more than 3 and 4 times the mean Cmax values in humans. Estimates of exposure (AUC) were not generated in the embryo-fetal rabbit study. No adequate and well-controlled studies in pregnant women were conducted. Because animal reproduction studies are not always predictive of human response, raxibacumab should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Raxibacumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Raxibacumab during labor and delivery.
### Nursing Mothers
- Raxibacumab has not been evaluated in nursing women. Although human immunoglobulins are excreted in human milk, published data suggest that neonatal consumption of human milk does not result in substantial absorption of these maternal immunoglobulins into circulation. Inform a nursing woman that the effects of local gastrointestinal and systemic exposure to raxibacumab on a nursing infant are unknown.
### Pediatric Use
- As in adults, the effectiveness of raxibacumab in pediatric patients is based solely on efficacy studies in animal models of inhalational anthrax. As exposure of healthy children to raxibacumab is not ethical, a population PK approach was used to derive dosing regimens that are predicted to provide pediatric patients with exposure comparable to the observed exposure in adults receiving 40 mg/kg. The dose for pediatric patients is based on weight.
- Safety or PK of raxibacumab have not been studied in the pediatric population.
### Geriatic Use
- Clinical trials of raxibacumab did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the total number of subjects in clinical trials of raxibacumab, 6.4% (21/326) were 65 years and older, while 1.5% (5/326) were 75 years and older. However, no alteration of dosing is needed for patients ≥65 years of age.
### Gender
There is no FDA guidance on the use of Raxibacumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Raxibacumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Raxibacumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Raxibacumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Raxibacumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Raxibacumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- The recommended dose of raxibacumab is weight-based, given as an intravenous infusion after dilution in a compatible solution to a final volume of 250 mL (adults and children 50 kg or heavier) or to a volume indicated based on the child’s weight (Table 2). Dilute raxibacumab using one of the following compatible solutions:
- 0.9% Sodium Chloride Injection, USP
- 0.45% Sodium Chloride Injection, USP
- Keep vials in their cartons prior to preparation of an infusion solution to protect raxibacumab from light. Raxibacumab vials contain no preservative.
- Preparation: Follow the steps below to prepare the raxibacumab intravenous infusion solution.
- Calculate the milligrams of raxibacumab injection by multiplying the recommended mg/kg dose in Table 2 by patient weight in kilograms.
- Calculate the required volume in milliliters of raxibacumab injection needed for the dose by dividing the calculated dose in milligrams (step 1) by the concentration, 50 mg/mL. Each single-use vial allows delivery of 34 mL raxibacumab.
- Based on the total infusion volume selected in Table 2, prepare either a syringe or infusion bag as appropriate following the steps below.
- Syringe Preparation
- Select an appropriate size syringe for the total volume of infusion to be administered, as described in Table 2.
- Using the selected syringe, withdraw the volume of raxibacumab as calculated in step 2.
- Withdraw an appropriate amount of compatible solution to prepare a total volume infusion syringe as specified in Table 2.
- Gently mix the solution. Do not shake.
- Discard any unused portion remaining in the raxibacumab vial(s).
- The prepared solution is stable for 8 hours stored at room temperature.
- Infusion Bag Preparation
- Select appropriate size bag of compatible solution (see compatible solutions listed in Table 2), withdraw a volume of solution from the bag equal to the calculated volume in milliliters of raxibacumab in Table 2. Discard the solution that was withdrawn from the bag.
- Withdraw the required volume of raxibacumab injection from the raxibacumab vial(s).
- Transfer the required volume of raxibacumab injection to the selected infusion bag (step 3). Gently invert the bag to mix the solution. Do not shake.
- Discard any unused portion remaining in the raxibacumab vial(s).
- The prepared solution is stable for 8 hours stored at room temperature.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if particulate matter is present or color is abnormal.
- Administration: Administer the infusion solution as described in Table 2. The rate of infusion may be slowed or interrupted if the patient develops any signs of adverse reactions, including infusion-associated symptoms.
### Monitoring
There is limited information regarding Monitoring of Raxibacumab in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Raxibacumab in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Raxibacumab in the drug label.
# Pharmacology
## Mechanism of Action
- Raxibacumab is a monoclonal antibody that binds free PA with an affinity equilibrium dissociation constant (Kd) of 2.78 ± 0.9 nM. Raxibacumab inhibits the binding of PA to its cellular receptors, preventing the intracellular entry of the anthrax lethal factor and edema factor, the enzymatic toxin components responsible for the pathogenic effects of anthrax toxin.
## Structure
- Raxibacumab is a human IgG1λ monoclonal antibody that binds the PA component of B. anthracis toxin. Raxibacumab has a molecular weight of approximately 146 kilodaltons. Raxibacumab is produced by recombinant DNA technology in a murine cell expression system.
- Raxibacumab is supplied as a sterile, liquid formulation in single-dose vials for intravenous infusion. Each vial contains 50 mg/mL raxibacumab in citric acid (0.13 mg/mL), glycine (18 mg/mL), polysorbate 80 , sodium citrate (2.8 mg/mL), and sucrose (10 mg/mL), with a pH of 6.5. Each vial contains a minimum of 35.1 mL filled into a 50 mL vial (to allow delivery of 1,700 mg/34 mL). Raxibacumab is a clear to opalescent, colorless to pale yellow, liquid.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Raxibacumab in the drug label.
## Pharmacokinetics
- The PK of raxibacumab are linear over the dose range of 1 to 40 mg/kg following single IV dosing in humans; raxibacumab was not tested at doses higher than 40 mg/kg in humans. Following single IV administration of raxibacumab 40 mg/kg in healthy, male and female human subjects, the mean Cmax and AUCinf were 1,020.3 ± 140.6 mcg/mL and 15,845.8 ± 4,333.5 mcgday/mL, respectively. Mean raxibacumab steady-state volume of distribution was greater than plasma volume, suggesting some tissue distribution. Clearance values were much smaller than the glomerular filtration rate indicating that there is virtually no renal clearance of raxibacumab.
- Because the effectiveness of raxibacumab cannot be tested in humans, a comparison of raxibacumab exposures achieved in healthy human subjects to those observed in animal models of inhalational anthrax in therapeutic efficacy studies is necessary to support the dosage regimen of 40 mg/kg IV as a single dose for the treatment of inhalational anthrax in humans. Humans achieve similar or greater systemic exposure (Cmax and AUCinf) to raxibacumab following a single 40 mg/kg IV dose compared with New Zealand White rabbits and cynomolgus macaques receiving the same dosage regimen.
- Effects of Gender, Age, and Race
- Raxibacumab PK were evaluated via a population PK analysis using serum samples from 322 healthy subjects who received a single 40 mg/kg IV dose across 3 clinical trials. Based on this analysis, gender (female versus male), race (non-white versus white), or age (elderly versus young) had no meaningful effects on the PK parameters for raxibacumab.
- Raxibacumab PK have not been evaluated in children.
- Repeat Dosing
- Although raxibacumab is intended for single dose administration, the PK of raxibacumab following a second administration of 40 mg/kg IV given 14 days after the first 40 mg/kg IV dose was assessed in 23 healthy subjects (Study 3). The mean raxibacumab concentration at 28 days after the second dose was approximately twice the mean raxibacumab concentration at 14 days following the first dose. In the human trial assessing the immunogenicity of raxibacumab (Study 2), 20 healthy subjects who had initially received a single dose of raxibacumab 40 mg/kg IV received a second 40 mg/kg IV dose at ≥4 months following their first dose. No statistically significant differences in mean estimates of AUCinf, CL, or half-life of raxibacumab between the 2 doses administered ≥4 months apart were observed. The mean Cmax following the second dose was 15% lower than the Cmax following the first dose.
- Ciprofloxacin Interaction Trial
- In an open-label trial evaluating the effect of raxibacumab on ciprofloxacin PK in healthy adult male and female subjects (Study 1), the administration of 40 mg/kg raxibacumab IV following ciprofloxacin IV infusion or ciprofloxacin oral tablet ingestion did not alter the PK of ciprofloxacin administered orally and/or intravenously. Likewise, ciprofloxacin did not alter the PK of raxibacumab.
## Nonclinical Toxicology
- Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.
- Healthy cynomolgus macaques administered 3 intravenous doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days, or a single intramuscular dose (40 mg/kg) of raxibacumab, showed no adverse effects, including no effects up to 120 days post-dosing.
- Studies with raxibacumab in rabbit, cynomolgus macaque, and human donor tissues showed no cross reactivity with brain.
- Anthrax-infected rabbits and monkeys administered an intravenous injection of raxibacumab (40 mg/kg) at time of PA toxemia reproducibly showed greater severity of central nervous system (CNS) lesions (bacteria, inflammation, hemorrhage, and necrosis) in non-surviving animals compared to dead placebo control animals, with no difference in mean time to death from spore challenge. The raxibacumab monoclonal antibody appears unable to penetrate the CNS until compromise of the blood-brain barrier (BBB) during the later stages of anthrax infection. The most severe brain lesions in rabbits were associated with bacteria and raxibacumab tissue binding in a similar pattern as endogenous IgG antibody that leaked across the compromised BBB. No dose/exposure-response relationship for brain histopathology was identified. Surviving rabbits and monkeys at the end of the 28-day studies showed no microscopic evidence of CNS lesions. CNS toxicity was not observed in healthy monkeys administered raxibacumab (40 mg/kg) or in GLP combination treatment studies with antibacterials in rabbits (levofloxacin) or in monkeys (ciprofloxacin) at any time.
# Clinical Studies
- Because it is not feasible or ethical to conduct controlled clinical trials in humans with inhalational anthrax, the effectiveness of raxibacumab for therapeutic treatment of inhalational anthrax is based on efficacy studies in rabbits and monkeys. Raxibacumab effectiveness has not been studied in humans. Because the animal efficacy studies are conducted under widely varying conditions, the survival rates observed in the animal studies cannot be directly compared between studies and may not reflect the rates observed in clinical practice.
- The efficacy of raxibacumab for treatment of inhalational anthrax was studied in a monkey model (study 2) and a rabbit model (studies 3 and 4) of inhalational anthrax disease. These 3 studies tested raxibacumab efficacy compared to placebo. Another study in a rabbit model (study 1) evaluated the efficacy of raxibacumab in combination with an antibacterial drug relative to the antibacterial drug alone. Studies were randomized and blinded.
- The animals were challenged with aerosolized B. anthracis spores (Ames strain) at 200xLD50 to achieve 100% mortality if untreated. In rabbit study 1, treatment was delayed until 84 hours after spore challenge. In monkey study 2, study treatment commenced at the time of a positive serum electrochemiluminescence (ECL) assay for B. anthracis PA. The mean time between spore challenge and initiation of study treatment was 42 hours. In rabbit studies 3 and 4, sustained elevation of body temperature above baseline for 2 hours or a positive result on serum ECL assay for PA served as the trigger for initiation of study treatment. The mean time between spore challenge and initiation of study treatment was 28 hours post-exposure. Efficacy in all therapeutic studies in animals was determined based on survival at the end of the study. Most study animals (88% to 100%) were bacteremic and had a positive ECL assay for PA prior to treatment in all 4 studies.
- The efficacy of raxibacumab administered with levofloxacin as treatment of animals with systemic anthrax disease (84 hours after spore challenge) was evaluated in New Zealand White rabbits (study 1). The dose of levofloxacin was chosen to yield a comparable exposure to that achieved by the recommended doses in humans. Levofloxacin and raxibacumab PK in this study were unaffected by product co-administration. Forty-two percent of challenged animals survived to treatment. Treatment with antibacterial drug plus raxibacumab resulted in 82% survival compared to 65% survival in rabbits treated with antibacterial drug alone, P = 0.0874 (Table 4).
- Monkey study 2 and rabbit studies 3 and 4 evaluated treatment with raxibacumab alone at an earlier time point after exposure than rabbit study 1. Treatment with raxibacumab alone resulted in a statistically significant dose-dependent improvement in survival relative to placebo when administered at the time of initial manifestations of anthrax disease in the rabbit and monkey infection models (Table 5). Raxibacumab at 40 mg/kg IV single dose was superior to placebo in the rabbit and monkey studies in the all treated and the bacteremic animal analysis populations. All surviving animals developed toxin-neutralizing antibodies.
- In other animal studies evaluating antibacterial drug alone and raxibacumab-antibacterial drug combination, the efficacy of an antibacterial drug alone (levofloxacin in rabbits and ciprofloxacin in monkeys) was very high (95-100%) when given at the initial manifestations of inhalational anthrax disease. The timing of treatment was similar to that reported for studies 2, 3, and 4 above.
- In another study, rabbits were exposed to 100xLD50 B. anthracis spores and administered raxibacumab at a single dose of 40 mg/kg at the time of exposure, 12 hours, 24 hours, or 36 hours after exposure. Survival was 12/12 (100%) in animals treated at time of exposure or 12 hours, but decreased to 6/12 (50%) and 5/12 (42%) at 24 hours and 36 hours, respectively.
# How Supplied
- Raxibacumab is supplied in single-use vials containing 1,700 mg/34 mL (50 mg/mL) raxibacumab injection and is available in the following packaging configuration:
- Single Unit Carton: Contains one (1) single-use vial of raxibacumab 1,700 mg/34 mL (deliverable) (NDC 49401-103-01).
- Raxibacumab must be refrigerated at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Protect the vial from exposure to light, prior to use. Brief exposure to light, as with normal use, is acceptable. Store vial in original carton until time of use.
## Storage
There is limited information regarding Raxibacumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Efficacy Based on Animal Models: Inform patients that the efficacy of raxibacumab is based solely on efficacy studies demonstrating a survival benefit in animals and that the effectiveness of raxibacumab has not been tested in humans with anthrax. The safety of raxibacumab has been tested in healthy adults, but no safety data are available in children or pregnant women. Limited data are available in geriatric patients.
- Pregnancy and Nursing Mothers: Inform patients that raxibacumab has not been studied in pregnant women or nursing mothers so the effects of raxibacumab on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare professional if they are pregnant, become pregnant, or are thinking about becoming pregnant. Instruct patients to tell their healthcare professional if they plan to breastfeed their infant.
- Infusion Reactions: Infusion-related reactions were reported during administration of raxibacumab in clinical trials, including reports of rash, urticaria, and pruritus.
- Prophylactic administration of diphenhydramine is recommended within 1 hour prior to administering raxibacumab. Diphenhydramine route of administration (oral or IV) should be based on the temporal proximity to the start of raxibacumab infusion.
# Precautions with Alcohol
- Alcohol-Raxibacumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- RAXIBACUMAB®
# Look-Alike Drug Names
There is limited information regarding Raxibacumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Raxibacumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Raxibacumab is a monoclonal antibody that is FDA approved for the treatment of inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs, and for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate. Common adverse reactions include rash, pain in extremity, pruritus, and somnolence.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Raxibacumab is indicated for the treatment of adult with inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs. Raxibacumab is also indicated for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate.
- Administer raxibacumab as a single dose of 40 mg/kg intravenously over 2 hours and 15 minutes after dilution in 0.9% Sodium Chloride Injection, USP (normal saline) to a final volume of 250 mL. Administer 25 to 50 mg diphenhydramine within 1 hour prior to raxibacumab infusion to reduce the risk of infusion reactions. Diphenhydramine route of administration (oral or IV) should be based on the temporal proximity to the start of raxibacumab infusion.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Raxibacumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Raxibacumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Raxibacumab is indicated for the treatment of pediatric patients with inhalational anthrax due to Bacillus anthracis in combination with appropriate antibacterial drugs. Raxibacumab is also indicated for prophylaxis of inhalational anthrax when alternative therapies are not available or are not appropriate.
- The recommended dose for pediatric patients is based on weight as shown in Table 1.
- Premedicate with diphenhydramine within 1 hour prior to raxibacumab infusion. Diphenhydramine route of administration (oral or IV) should be based on the temporal proximity to the start of raxibacumab infusion. Infuse raxibacumab over 2 hours and 15 minutes. No pediatric patients were studied during the development of raxibacumab. The dosing recommendations in Table 1 are derived from simulations designed to match the observed adult exposure to raxibacumab at a 40 mg/kg dose.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Raxibacumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Raxibacumab in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Infusion Reactions
- Infusion-related reactions were reported during administration of raxibacumab in clinical trials including reports of rash, urticaria, and pruritus. If these reactions occur, slow or interrupt raxibacumab infusion and administer appropriate treatment based on severity of the reaction.
- Premedicate with diphenhydramine within 1 hour prior to administering raxibacumab to reduce the risk of infusion reactions.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of raxibacumab has been studied only in healthy volunteers. It has not been studied in patients with inhalational anthrax.
- The safety of raxibacumab has been evaluated in 326 healthy subjects treated with a dose of 40 mg/kg in 3 clinical trials: a drug interaction trial with ciprofloxacin (Study 1), a repeat-dose trial of 20 subjects with the second raxibacumab dose administered ≥4 months after the first dose (Study 2), and a placebo-controlled trial evaluating single doses with a subset of subjects receiving 2 raxibacumab doses 14 days apart (Study 3). Raxibacumab was administered to 86 healthy subjects in Study 1. In Study 3, 240 healthy subjects received raxibacumab (217 received 1 dose and 23 received 2 doses) and 80 subjects received placebo.
- The overall safety of raxibacumab was evaluated as an integrated summary of these 3 clinical trials. Of 326 raxibacumab subjects, 283 received single doses, 23 received 2 doses 14 days apart, and 20 received 2 doses more than 4 months apart. The subjects were 18 to 88 years of age, 53% female, 74% white, 17% black/African American, 6% Asian, and 15% Hispanic.
- Adverse Reactions Leading to Discontinuation of Raxibacumab Infusion
- Four subjects (1.2%) had their infusion of raxibacumab discontinued for adverse reactions: 2 subjects (neither of whom received diphenhydramine premedication) due to urticaria (mild), and 1 subject each discontinued for clonus (mild) and dyspnea (moderate).
- Most Frequently Reported Adverse Reactions
- The most frequently reported adverse reactions were rash, pain in extremity, pruritus, and somnolence.
- Rashes
- For all subjects exposed to raxibacumab in clinical trials, the rate of rash was 2.8% (9/326) compared with 1.3% (1/80) of placebo subjects. Mild to moderate infusion-related rashes were reported in 22.2% (6/27) of subjects who did not receive diphenhydramine premedication compared to 3.3% (2/61) of subjects who were premedicated with diphenhydramine in the ciprofloxacin/raxibacumab combination trial (Study 1). In the placebo-controlled raxibacumab study where all subjects received diphenhydramine (Study 3), the rate of rash was 2.5% in both placebo- and raxibacumab-treated subjects.
- Less Common Adverse Reactions
- Clinically significant adverse reactions that were reported in <1.5% of subjects exposed to raxibacumab and at rates higher than in placebo subjects are listed below:
Anemia, leukopenia, lymphadenopathy
Palpitations
Vertigo
Fatigue, infusion site pain, peripheral edema
Blood amylase increased, blood creatine phosphokinase increased, prothrombin time prolonged
Back pain, muscle spasms
Syncope vasovagal
Insomnia
Flushing, hypertension
- Immunogenicity
- The development of anti-raxibacumab antibodies was evaluated in all subjects receiving single and double doses of raxibacumab in Studies 1, 2, and 3. Immunogenic responses against raxibacumab were not detected in any raxibacumab-treated human subjects following single or repeat doses of raxibacumab.
- The incidence of antibody formation is highly dependent on the sensitivity and specificity of the immunogenicity assay. Additionally, the observed incidence of any antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to raxibacumab with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Raxibacumab in the drug label.
# Drug Interactions
- Ciprofloxacin
- Co-administration of 40 mg/kg raxibacumab IV with IV or oral ciprofloxacin in human subjects did not alter the PK of either ciprofloxacin or raxibacumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- A single embryonic-fetal development study was conducted in pregnant, healthy New Zealand White rabbits administered 2 intravenous doses of raxibacumab up to 120 mg/kg (3 times the human dose on a mg/kg basis) on gestation days 7 and 14. No evidence of harm to the pregnant dam or the fetuses due to raxibacumab was observed. Cmax values in rabbits after dosing with 120 mg/kg were 3,629 mcg/mL and 4,337 mcg/mL after the first and second dose of raxibacumab, respectively; these are more than 3 and 4 times the mean Cmax values in humans. Estimates of exposure (AUC) were not generated in the embryo-fetal rabbit study. No adequate and well-controlled studies in pregnant women were conducted. Because animal reproduction studies are not always predictive of human response, raxibacumab should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Raxibacumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Raxibacumab during labor and delivery.
### Nursing Mothers
- Raxibacumab has not been evaluated in nursing women. Although human immunoglobulins are excreted in human milk, published data suggest that neonatal consumption of human milk does not result in substantial absorption of these maternal immunoglobulins into circulation. Inform a nursing woman that the effects of local gastrointestinal and systemic exposure to raxibacumab on a nursing infant are unknown.
### Pediatric Use
- As in adults, the effectiveness of raxibacumab in pediatric patients is based solely on efficacy studies in animal models of inhalational anthrax. As exposure of healthy children to raxibacumab is not ethical, a population PK approach was used to derive dosing regimens that are predicted to provide pediatric patients with exposure comparable to the observed exposure in adults receiving 40 mg/kg. The dose for pediatric patients is based on weight.
- Safety or PK of raxibacumab have not been studied in the pediatric population.
### Geriatic Use
- Clinical trials of raxibacumab did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Of the total number of subjects in clinical trials of raxibacumab, 6.4% (21/326) were 65 years and older, while 1.5% (5/326) were 75 years and older. However, no alteration of dosing is needed for patients ≥65 years of age.
### Gender
There is no FDA guidance on the use of Raxibacumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Raxibacumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Raxibacumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Raxibacumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Raxibacumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Raxibacumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- The recommended dose of raxibacumab is weight-based, given as an intravenous infusion after dilution in a compatible solution to a final volume of 250 mL (adults and children 50 kg or heavier) or to a volume indicated based on the child’s weight (Table 2). Dilute raxibacumab using one of the following compatible solutions:
- 0.9% Sodium Chloride Injection, USP
- 0.45% Sodium Chloride Injection, USP
- Keep vials in their cartons prior to preparation of an infusion solution to protect raxibacumab from light. Raxibacumab vials contain no preservative.
- Preparation: Follow the steps below to prepare the raxibacumab intravenous infusion solution.
- Calculate the milligrams of raxibacumab injection by multiplying the recommended mg/kg dose in Table 2 by patient weight in kilograms.
- Calculate the required volume in milliliters of raxibacumab injection needed for the dose by dividing the calculated dose in milligrams (step 1) by the concentration, 50 mg/mL. Each single-use vial allows delivery of 34 mL raxibacumab.
- Based on the total infusion volume selected in Table 2, prepare either a syringe or infusion bag as appropriate following the steps below.
- Syringe Preparation
- Select an appropriate size syringe for the total volume of infusion to be administered, as described in Table 2.
- Using the selected syringe, withdraw the volume of raxibacumab as calculated in step 2.
- Withdraw an appropriate amount of compatible solution to prepare a total volume infusion syringe as specified in Table 2.
- Gently mix the solution. Do not shake.
- Discard any unused portion remaining in the raxibacumab vial(s).
- The prepared solution is stable for 8 hours stored at room temperature.
- Infusion Bag Preparation
- Select appropriate size bag of compatible solution (see compatible solutions listed in Table 2), withdraw a volume of solution from the bag equal to the calculated volume in milliliters of raxibacumab in Table 2. Discard the solution that was withdrawn from the bag.
- Withdraw the required volume of raxibacumab injection from the raxibacumab vial(s).
- Transfer the required volume of raxibacumab injection to the selected infusion bag (step 3). Gently invert the bag to mix the solution. Do not shake.
- Discard any unused portion remaining in the raxibacumab vial(s).
- The prepared solution is stable for 8 hours stored at room temperature.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if particulate matter is present or color is abnormal. [See Description (11).]
- Administration: Administer the infusion solution as described in Table 2. The rate of infusion may be slowed or interrupted if the patient develops any signs of adverse reactions, including infusion-associated symptoms.
### Monitoring
There is limited information regarding Monitoring of Raxibacumab in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Raxibacumab in the drug label.
# Overdosage
## Chronic Overdose
There is limited information regarding Chronic Overdose of Raxibacumab in the drug label.
# Pharmacology
## Mechanism of Action
- Raxibacumab is a monoclonal antibody that binds free PA with an affinity equilibrium dissociation constant (Kd) of 2.78 ± 0.9 nM. Raxibacumab inhibits the binding of PA to its cellular receptors, preventing the intracellular entry of the anthrax lethal factor and edema factor, the enzymatic toxin components responsible for the pathogenic effects of anthrax toxin.
## Structure
- Raxibacumab is a human IgG1λ monoclonal antibody that binds the PA component of B. anthracis toxin. Raxibacumab has a molecular weight of approximately 146 kilodaltons. Raxibacumab is produced by recombinant DNA technology in a murine cell expression system.
- Raxibacumab is supplied as a sterile, liquid formulation in single-dose vials for intravenous infusion. Each vial contains 50 mg/mL raxibacumab in citric acid (0.13 mg/mL), glycine (18 mg/mL), polysorbate 80 [0.2 mg/mL (w/v)], sodium citrate (2.8 mg/mL), and sucrose (10 mg/mL), with a pH of 6.5. Each vial contains a minimum of 35.1 mL filled into a 50 mL vial (to allow delivery of 1,700 mg/34 mL). Raxibacumab is a clear to opalescent, colorless to pale yellow, liquid.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Raxibacumab in the drug label.
## Pharmacokinetics
- The PK of raxibacumab are linear over the dose range of 1 to 40 mg/kg following single IV dosing in humans; raxibacumab was not tested at doses higher than 40 mg/kg in humans. Following single IV administration of raxibacumab 40 mg/kg in healthy, male and female human subjects, the mean Cmax and AUCinf were 1,020.3 ± 140.6 mcg/mL and 15,845.8 ± 4,333.5 mcg•day/mL, respectively. Mean raxibacumab steady-state volume of distribution was greater than plasma volume, suggesting some tissue distribution. Clearance values were much smaller than the glomerular filtration rate indicating that there is virtually no renal clearance of raxibacumab.
- Because the effectiveness of raxibacumab cannot be tested in humans, a comparison of raxibacumab exposures achieved in healthy human subjects to those observed in animal models of inhalational anthrax in therapeutic efficacy studies is necessary to support the dosage regimen of 40 mg/kg IV as a single dose for the treatment of inhalational anthrax in humans. Humans achieve similar or greater systemic exposure (Cmax and AUCinf) to raxibacumab following a single 40 mg/kg IV dose compared with New Zealand White rabbits and cynomolgus macaques receiving the same dosage regimen.
- Effects of Gender, Age, and Race
- Raxibacumab PK were evaluated via a population PK analysis using serum samples from 322 healthy subjects who received a single 40 mg/kg IV dose across 3 clinical trials. Based on this analysis, gender (female versus male), race (non-white versus white), or age (elderly versus young) had no meaningful effects on the PK parameters for raxibacumab.
- Raxibacumab PK have not been evaluated in children.
- Repeat Dosing
- Although raxibacumab is intended for single dose administration, the PK of raxibacumab following a second administration of 40 mg/kg IV given 14 days after the first 40 mg/kg IV dose was assessed in 23 healthy subjects (Study 3). The mean raxibacumab concentration at 28 days after the second dose was approximately twice the mean raxibacumab concentration at 14 days following the first dose. In the human trial assessing the immunogenicity of raxibacumab (Study 2), 20 healthy subjects who had initially received a single dose of raxibacumab 40 mg/kg IV received a second 40 mg/kg IV dose at ≥4 months following their first dose. No statistically significant differences in mean estimates of AUCinf, CL, or half-life of raxibacumab between the 2 doses administered ≥4 months apart were observed. The mean Cmax following the second dose was 15% lower than the Cmax following the first dose.
- Ciprofloxacin Interaction Trial
- In an open-label trial evaluating the effect of raxibacumab on ciprofloxacin PK in healthy adult male and female subjects (Study 1), the administration of 40 mg/kg raxibacumab IV following ciprofloxacin IV infusion or ciprofloxacin oral tablet ingestion did not alter the PK of ciprofloxacin administered orally and/or intravenously. Likewise, ciprofloxacin did not alter the PK of raxibacumab.
## Nonclinical Toxicology
- Carcinogenicity, genotoxicity, and fertility studies have not been conducted with raxibacumab.
- Healthy cynomolgus macaques administered 3 intravenous doses or 3 subcutaneous doses of 40 mg/kg raxibacumab once every 12 days, or a single intramuscular dose (40 mg/kg) of raxibacumab, showed no adverse effects, including no effects up to 120 days post-dosing.
- Studies with raxibacumab in rabbit, cynomolgus macaque, and human donor tissues showed no cross reactivity with brain.
- Anthrax-infected rabbits and monkeys administered an intravenous injection of raxibacumab (40 mg/kg) at time of PA toxemia reproducibly showed greater severity of central nervous system (CNS) lesions (bacteria, inflammation, hemorrhage, and necrosis) in non-surviving animals compared to dead placebo control animals, with no difference in mean time to death from spore challenge. The raxibacumab monoclonal antibody appears unable to penetrate the CNS until compromise of the blood-brain barrier (BBB) during the later stages of anthrax infection. The most severe brain lesions in rabbits were associated with bacteria and raxibacumab tissue binding in a similar pattern as endogenous IgG antibody that leaked across the compromised BBB. No dose/exposure-response relationship for brain histopathology was identified. Surviving rabbits and monkeys at the end of the 28-day studies showed no microscopic evidence of CNS lesions. CNS toxicity was not observed in healthy monkeys administered raxibacumab (40 mg/kg) or in GLP combination treatment studies with antibacterials in rabbits (levofloxacin) or in monkeys (ciprofloxacin) at any time.
# Clinical Studies
- Because it is not feasible or ethical to conduct controlled clinical trials in humans with inhalational anthrax, the effectiveness of raxibacumab for therapeutic treatment of inhalational anthrax is based on efficacy studies in rabbits and monkeys. Raxibacumab effectiveness has not been studied in humans. Because the animal efficacy studies are conducted under widely varying conditions, the survival rates observed in the animal studies cannot be directly compared between studies and may not reflect the rates observed in clinical practice.
- The efficacy of raxibacumab for treatment of inhalational anthrax was studied in a monkey model (study 2) and a rabbit model (studies 3 and 4) of inhalational anthrax disease. These 3 studies tested raxibacumab efficacy compared to placebo. Another study in a rabbit model (study 1) evaluated the efficacy of raxibacumab in combination with an antibacterial drug relative to the antibacterial drug alone. Studies were randomized and blinded.
- The animals were challenged with aerosolized B. anthracis spores (Ames strain) at 200xLD50 to achieve 100% mortality if untreated. In rabbit study 1, treatment was delayed until 84 hours after spore challenge. In monkey study 2, study treatment commenced at the time of a positive serum electrochemiluminescence (ECL) assay for B. anthracis PA. The mean time between spore challenge and initiation of study treatment was 42 hours. In rabbit studies 3 and 4, sustained elevation of body temperature above baseline for 2 hours or a positive result on serum ECL assay for PA served as the trigger for initiation of study treatment. The mean time between spore challenge and initiation of study treatment was 28 hours post-exposure. Efficacy in all therapeutic studies in animals was determined based on survival at the end of the study. Most study animals (88% to 100%) were bacteremic and had a positive ECL assay for PA prior to treatment in all 4 studies.
- The efficacy of raxibacumab administered with levofloxacin as treatment of animals with systemic anthrax disease (84 hours after spore challenge) was evaluated in New Zealand White rabbits (study 1). The dose of levofloxacin was chosen to yield a comparable exposure to that achieved by the recommended doses in humans. Levofloxacin and raxibacumab PK in this study were unaffected by product co-administration. Forty-two percent of challenged animals survived to treatment. Treatment with antibacterial drug plus raxibacumab resulted in 82% survival compared to 65% survival in rabbits treated with antibacterial drug alone, P = 0.0874 (Table 4).
- Monkey study 2 and rabbit studies 3 and 4 evaluated treatment with raxibacumab alone at an earlier time point after exposure than rabbit study 1. Treatment with raxibacumab alone resulted in a statistically significant dose-dependent improvement in survival relative to placebo when administered at the time of initial manifestations of anthrax disease in the rabbit and monkey infection models (Table 5). Raxibacumab at 40 mg/kg IV single dose was superior to placebo in the rabbit and monkey studies in the all treated and the bacteremic animal analysis populations. All surviving animals developed toxin-neutralizing antibodies.
- In other animal studies evaluating antibacterial drug alone and raxibacumab-antibacterial drug combination, the efficacy of an antibacterial drug alone (levofloxacin in rabbits and ciprofloxacin in monkeys) was very high (95-100%) when given at the initial manifestations of inhalational anthrax disease. The timing of treatment was similar to that reported for studies 2, 3, and 4 above.
- In another study, rabbits were exposed to 100xLD50 B. anthracis spores and administered raxibacumab at a single dose of 40 mg/kg at the time of exposure, 12 hours, 24 hours, or 36 hours after exposure. Survival was 12/12 (100%) in animals treated at time of exposure or 12 hours, but decreased to 6/12 (50%) and 5/12 (42%) at 24 hours and 36 hours, respectively.
# How Supplied
- Raxibacumab is supplied in single-use vials containing 1,700 mg/34 mL (50 mg/mL) raxibacumab injection and is available in the following packaging configuration:
- Single Unit Carton: Contains one (1) single-use vial of raxibacumab 1,700 mg/34 mL (deliverable) (NDC 49401-103-01).
- Raxibacumab must be refrigerated at 2° to 8°C (36° to 46°F). DO NOT FREEZE. Protect the vial from exposure to light, prior to use. Brief exposure to light, as with normal use, is acceptable. Store vial in original carton until time of use.
## Storage
There is limited information regarding Raxibacumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Efficacy Based on Animal Models: Inform patients that the efficacy of raxibacumab is based solely on efficacy studies demonstrating a survival benefit in animals and that the effectiveness of raxibacumab has not been tested in humans with anthrax. The safety of raxibacumab has been tested in healthy adults, but no safety data are available in children or pregnant women. Limited data are available in geriatric patients.
- Pregnancy and Nursing Mothers: Inform patients that raxibacumab has not been studied in pregnant women or nursing mothers so the effects of raxibacumab on pregnant women or nursing infants are not known. Instruct patients to tell their healthcare professional if they are pregnant, become pregnant, or are thinking about becoming pregnant. Instruct patients to tell their healthcare professional if they plan to breastfeed their infant.
- Infusion Reactions: Infusion-related reactions were reported during administration of raxibacumab in clinical trials, including reports of rash, urticaria, and pruritus.
- Prophylactic administration of diphenhydramine is recommended within 1 hour prior to administering raxibacumab. Diphenhydramine route of administration (oral or IV) should be based on the temporal proximity to the start of raxibacumab infusion.
# Precautions with Alcohol
- Alcohol-Raxibacumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- RAXIBACUMAB®[1]
# Look-Alike Drug Names
There is limited information regarding Raxibacumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Raxibacumab | |
f1b8bc421b8a61b70f3010cd1a651b5dc72fe0e7 | wikidoc | Recall bias | Recall bias
In psychology, recall bias (or reporting bias) is a type of systematic bias which occurs when the way a survey respondent answers a question is affected not just by the correct answer, but also by the respondent's memory.
This can affect the results of the survey. As a hypothetical example, suppose that a survey in 2005 asked respondents whether they believed that O.J. Simpson had killed his wife, 10 years after the criminal trial. Respondents who believed him innocent might be more likely to have forgotten about the case, and therefore to state no opinion, than respondents who thought him guilty. If this is the case, then the survey would find a higher-than-accurate proportion of people who believed that Simpson did kill his wife.
Relatedly but distinctly, the term might also be used to describe an instance where a survey respondent intentionally responds incorrectly to a question about their personal history which results in response bias. As a hypothetical example, suppose that a researcher conducts a survey among women of group A, asking whether they have had an abortion, and the same survey among women of group B.
If the results are different between the two groups, it might be that women of one group are less likely to have had an abortion, or it might simply be that women of one group who have had abortions are less likely to admit to it. If the latter is the case, then this would skew the survey results; this is a kind of response bias. (It is also possible that both are the case: women of one group are less likely to have had abortions, and women of one group who have had abortions are less likely to admit to it. This would still affect the survey statistics.)
In experimental sciences, "reporting bias" refers to a tendency to under-report unexpected or undesirable experimental results, attributing the results to experimental error, while being more trusting of expected or desirable results, though these may be subject to the same experimental errors. Over time, reporting bias can lead to a status quo where multiple investigators discover and discard experimental results, and later experimenters justify their own reporting bias by observing that previous experimenters reported different results (even though those earlier experimenters may have fallen victim to a weaker case of reporting bias). Thus, each incident of reporting bias can make future incidents more likely. | Recall bias
In psychology, recall bias (or reporting bias) is a type of systematic bias which occurs when the way a survey respondent answers a question is affected not just by the correct answer, but also by the respondent's memory.[1][2]
This can affect the results of the survey. As a hypothetical example, suppose that a survey in 2005 asked respondents whether they believed that O.J. Simpson had killed his wife, 10 years after the criminal trial. Respondents who believed him innocent might be more likely to have forgotten about the case, and therefore to state no opinion, than respondents who thought him guilty. If this is the case, then the survey would find a higher-than-accurate proportion of people who believed that Simpson did kill his wife.
Relatedly but distinctly, the term might also be used to describe an instance where a survey respondent intentionally responds incorrectly to a question about their personal history which results in response bias. As a hypothetical example, suppose that a researcher conducts a survey among women of group A, asking whether they have had an abortion, and the same survey among women of group B.
If the results are different between the two groups, it might be that women of one group are less likely to have had an abortion, or it might simply be that women of one group who have had abortions are less likely to admit to it. If the latter is the case, then this would skew the survey results; this is a kind of response bias. (It is also possible that both are the case: women of one group are less likely to have had abortions, and women of one group who have had abortions are less likely to admit to it. This would still affect the survey statistics.)
In experimental sciences, "reporting bias" refers to a tendency to under-report unexpected or undesirable experimental results, attributing the results to experimental error, while being more trusting of expected or desirable results, though these may be subject to the same experimental errors. Over time, reporting bias can lead to a status quo where multiple investigators discover and discard experimental results, and later experimenters justify their own reporting bias by observing that previous experimenters reported different results (even though those earlier experimenters may have fallen victim to a weaker case of reporting bias). Thus, each incident of reporting bias can make future incidents more likely. | https://www.wikidoc.org/index.php/Recall_bias | |
e5a7933210f5d2a81bea2e306709fe44328b0323 | wikidoc | Zoledronate | Zoledronate
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# Overview
Zoledronate is a bisphosphonate that is FDA approved for the treatment of hypercalcemia of malignancy, multiple myeloma, bone metastases of solid tumors, osteoporosis,paget's disease, postmenopausal osteoporosis. Common adverse reactions include nausea, fatigue, anemia, bone pain, constipation, fever, vomiting, dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Hypercalcemia of Malignancy
Zoledronic acid Injection is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL using the formula: cCa in mg/dL =Ca in mg/dL + 0.8 ( 4.0 g/dL – patient albumin ).
Multiple Myeloma and Bone Metastases of Solid Tumors
Zoledronic acid Injection is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.
Important Limitation of Use
The safety and efficacy of Zoledronic acid Injection in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions have not been established.
# Dosage
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Hypercalcemia of Malignancy
The maximum recommended dose of Zoledronic acid Injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL ) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive Zoledronic acid Injection should have serum creatinine assessed prior to each treatment.
Dose adjustments of Zoledronic acid Injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 mcmol/L or less than 4.5 mg/dL).
Patients should be adequately rehydrated prior to administration of Zoledronic acid Injection .
Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zoledronic acid Injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.
Retreatment with Zoledronic acid Injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zoledronic acid Injection and serum creatinine must be assessed prior to retreatment with Zoledronic acid Injection.
Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors
The recommended dose of Zoledronic acid Injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.
Upon treatment initiation, the recommended Zoledronic acid Injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula .
During treatment, serum creatinine should be measured before each Zoledronic acid Injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:
For patients with normal baseline creatinine, increase of 0.5 mg/dL
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL
In the clinical studies, Zoledronic acid Injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid Injection should be reinitiated at the same dose as that prior to treatment interruption.
Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily.
Preparation of Solution
Zoledronic acid Injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs.
4 mg / 5 mL Single-Use Vial
Vials of Zoledronic acid Injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.
To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the Zoledronic acid Injection concentrate from the vial for the dose required (see Table 2)
The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.
If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.
# Dosage Forms and Strengths
4 mg/5 mL single-use vial of concentrate
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zoledronate in adult patients.
### Non–Guideline-Supported Use
# Indications
- Monoclonal gammopathy of uncertain significance, with osteopenia or osteoporosis.
- Osteopenia, secondary to androgen-deprivation therapy in prostate cancer patients;
- Osteopenia, secondary to hormone therapy in breast cancer patients;
- Osteopenia, secondary to ovarian dysfunction induced by adjuvant chemotherapy in premenopausal women with early-stage breast cancer;
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Zoledronate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zoledronate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zoledronate in pediatric patients.
# Contraindications
Hypersensitivity to Zoledronic Acid or Any Components of Zoledronic acid Injection
Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported.
# Warnings
Drugs with Same Active Ingredient or in the Same Drug Class
- Zoledronic acid Injection contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zoledronic acid Injection should not be treated with Reclast or other bisphosphonates.
Hydration and Electrolyte Monitoring
- Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zoledronic acid Injection. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zoledronic acid Injection in order to avoid hypocalcemia. Zoledronic acid Injection should be used with caution with other nephrotoxic drugs.
- Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zoledronic acid Injection. If hypocalcemia hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary.
Renal Impairment
- Zoledronic acid Injection is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased . Preexisting renal insufficiency and multiple cycles of Zoledronic acid Injection and other bisphosphonates are risk factors for subsequent renal deterioration with Zoledronic acid Injection. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible.
- Zoledronic acid Injection treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine greater than 400 mcmol/L or greater than 4.5 mg/dL were excluded.
- Zoledronic acid Injection treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine greater than 265 mcmol/L or greater than 3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zoledronic acid Injection 4 mg by 15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance less than 30 mL/min.
Osteonecrosis of the Jaw
- Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zoledronic acid Injection. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis.
- Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.
- While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Musculoskeletal Pain
- In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates, including Zoledronic acid Injection. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
Atypical Subtrochanteric and Diaphyseal Femoral Fractures
- Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including Zoledronic acid Injection. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established.
- Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of Zoledronic acid Injection therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.
Patients with Asthma
- While not observed in clinical trials with Zoledronic acid Injection, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates.
Hepatic Impairment
- Only limited clinical data are available for use of Zoledronic acid Injection to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zoledronic acid Injection in these patients.
Use in Pregnancy
- Bisphosphonates, such as Zoledronic acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy.
- Zoledronic acid Injection may cause fetal harm when administered to a pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre- and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus .
Hypocalcemia
- Hypocalcemia has been reported in patients treated with Zoledronic acid Injection. Cardiac arrhythmias and neurologic adverse events (seizures, tetany, and numbness) have been reported secondary to cases of severe hypocalcemia. In some instances, hypocalcemia may be life-threatening. Hypocalcemia must be corrected before initiating Zoledronic acid Injection. Adequately supplement patients with calcium and vitamin D.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Hypercalcemia of Malignancy
The safety of Zoledronic acid Injection was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials.
Renal Toxicity
Administration of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zoledronic acid Injection 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid Injection should be administered by intravenous infusion over no less than 15 minutes.
The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3).
Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zoledronic acid Injection 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Zoledronate in the drug label.
# Drug Interactions
In vitro studiesindicate that the plasma protein binding of zoledronic acid is low, with the unbound fraction ranging from 60% to77%. In vitrostudies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug.
Aminoglycosides
Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zoledronic acid Injection clinical trials.
Loop Diuretics
Caution should also be exercised when Zoledronic acid Injection is used in combination with loop diuretics due to an increased risk of hypocalcemia.
Nephrotoxic Drugs
Caution is indicated when Zoledronic acid Injection is used with other potentially nephrotoxic drugs.
Thalidomide
No dose adjustment for Zoledronic acid Injection 4 mg is needed when co-administered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, Zoledronic acid Injection 4 mg given as a 15 minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28). Co-administration of thalidomide with Zoledronic acid Injection did not significantly change the pharmacokinetics of Zoledronic acid or creatinine clearance.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category D
- There are no adequate and well-controlled studies of Zoledronic acid Injection in pregnant women. Zoledronic acid Injection may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as Zoledronic acid Injection, are incorporated into the bone matrix and are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. If this drug is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be apprised of the potential hazard to the fetus.
- In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect.
- In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study.
- In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zoledronate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Zoledronate during labor and delivery.
### Nursing Mothers
It is not known whether Zoledronic acid is excreted in human milk and because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Zoledronic acid Injection, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Zoledronic acid binds to bone long term and may be released over weeks to years.
### Pediatric Use
- Zoledronic acid Injection is not indicated for use in children.
- The safety and effectiveness of zoledronic acid was studied in a one-year, active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine bone mineral density (BMD) of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zoledronic acid Injection use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zoledronic acid Injection should only be used in children if the potential benefit outweighs the potential risk.
- Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ngh/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose.
### Geriatic Use
Clinical studies of Zoledronic acid Injection in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zoledronic acid Injection as compared to younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.
### Gender
There is no FDA guidance on the use of Zoledronate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Zoledronate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Zoledronate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Zoledronate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Zoledronate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Zoledronate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
Method of Administration
Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zoledronic acid Injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial Zoledronic acid Injection dose.
### Monitoring
There is limited information regarding Monitoring of Zoledronate in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Zoledronate in the drug label.
# Overdosage
- Clinical experience with acute overdosage of Zoledronic acid Injection is limited. Two patients received Zoledronic acid Injection 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.
- In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose.
- A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known.
- In controlled clinical trials, administration of Zoledronic acid Injection 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zoledronic acid Injection 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zoledronic acid Injection 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy.
# Pharmacology
## Mechanism of Action
The principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.
## Structure
- Zoledronic acid Injection contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula is:
## Pharmacodynamics
- Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of Zoledronic acid Injection are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion.
- Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying - pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia). Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy.
- Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia due to tumor invasion of bone. In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous cell malignancies of the lung or head and neck or in genitourinary tumors such as renal cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients.
- Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma.
- Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for differences in albumin levels (corrected serum calcium, CSC) is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation
## Pharmacokinetics
Pharmacokinetic data in patients with hypercalcemia are not available.
Distribution
- Single or multiple (q 28 days) 5-minute or 15-minute infusions of 2, 4, 8 or 16 mg Zoledronic acid Injection were given to 64 patients with cancer and bone metastases. The postinfusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process showing a rapid decrease from peak concentrations at end of infusion to less than 1% of Cmax 24 hours postinfusion with population half-lives of t1/2α0.24 hours and t1/2β1.87 hours for the early disposition phases of the drug. The terminal elimination phase of zoledronic acid was prolonged, with very low concentrations in plasma between Days 2 and 28 postinfusion, and a terminal elimination half-life t 1/2⛛ of 146 hours. The area under the plasma concentration versus time curve (AUC0-24h) of zoledronic acid was dose proportional from 2-16 mg. The accumulation of zoledronic acid measured over three cycles was low, with mean AUC0-24h ratios for cycles 2 and 3 versus 1 of 1.13 ± 0.30 and 1.16 ± 0.36, respectively.
- In vitroand ex vivo studies showed low affinity of zoledronic acid for the cellular components of human blood, with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/mL to 5000 ng/mL. In vitro, the plasma protein binding is low, with the unbound fraction ranging from 60% at 2 ng/mL to 77% at 2000 ng/mL of zoledronic acid.
Metabolism
- Zoledronic acid does not inhibit human P450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, less than 3% of the administered intravenous dose was found in the feces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney. Following an intravenous dose of 20 nCi 14C-zoledronic acid in a patient with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug was recovered in urine, which suggests that zoledronic acid is not metabolized.
Excretion
- In 64 patients with cancer and bone metastases, on average (± SD) 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-Day 2. The cumulative percent of drug excreted in the urine over 0-24 hours was independent of dose. The balance of drug not recovered in urine over 0-24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0-24 hour renal clearance of zoledronic acid was 3.7 ± 2.0 L/h.
- Zoledronic acid clearance was independent of dose but dependent upon the patient’s creatinine clearance. In a study in patients with cancer and bone metastases, increasing the infusion time of a 4-mg dose of zoledronic acid from 5 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion ( 403 ± 118 ng/mL versus 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng x h/mL versus 420 ± 218 ng x h/mL). The difference between the AUC means was not statistically significant.
## Special Populations
Pediatrics
Zoledronic acid Injection is not indicated for use in children.
Geriatrics
- The pharmacokinetics of zoledronic acid were not affected by age in patients with cancer and bone metastases who ranged in age from 38 years to 84 years.
Race
- Population pharmacokinetic analyses did not indicate any differences in pharmacokinetics among Japanese and North American (Caucasian and African American) patients with cancer and bone metastases.
Hepatic Insufficiency
- No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid.
Renal Insufficiency
- The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately impaired renal function. Compared to patients with normal renal function (N=37), patients with mild renal impairment (N=15) showed an average increase in plasma AUC of 15%, whereas patients with moderate renal impairment (N=11) showed an average increase in plasma AUC of 43%. Limited pharmacokinetic data are available for Zoledronic acid Injection in patients with severe renal impairment (creatinine clearance less than 30 mL/min). Based on population PK/PD modeling, the risk of renal deterioration appears to increase with AUC, which is doubled at a creatinine clearance of 10 mL/min. Creatinine clearance is calculated by the Cockcroft-Gault formula:
CrCl= x weight (kg) {x 0.85 for female patients}
- Zoledronic acid Injection systemic clearance in individual patients can be calculated from the population clearance of Zoledronic acid Injection, CL (L/h)=6.5(CrCl/90)0.4. These formulae can be used to predict the Zoledronic acid Injection AUC in patients, where CL = Dose/AUC0-∞. The average AUC0-24in patients with normal renal function was 0.42 mgh/L and the calculated AUC0-∞ for a patient with creatinine clearance of 75 mL/min was 0.66 mgh/L following a 4-mg dose of Zoledronic acid Injection. However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed
## Nonclinical Toxicology
Carcinogenesis & Mutagenesis & Impairment Of Fertility
- Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. There was an increased incidence of Harderian gland adenomas in males and females in all treatment groups (at doses ≥0.002 times a human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Rats were given oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. No increased incidence of tumors was observed (at doses ≤0.2 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas).
- Zoledronic acid was not genotoxic in the Ames bacterial mutagenicity assay, in the Chinese hamster ovary cell assay, or in the Chinese hamster gene mutation assay, with or without metabolic activation. Zoledronic acid was not genotoxic in the in-vivo rat micronucleus assay.
- Female rats were given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation. Effects observed in the high-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on AUC comparison) included inhibition of ovulation and a decrease in the number of pregnant rats. Effects observed in both the mid-dose group (with systemic exposure of 0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and high-dose group included an increase in preimplantation losses and a decrease in the number of implantations and live fetuses.
# Clinical Studies
Hypercalcemia of Malignancy
- Two identical multicenter, randomized, double-blind, double-dummy studies of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion or pamidronate 90 mg given as a 2-hour intravenous infusion were conducted in 185 patients with hypercalcemia of malignancy (HCM). NOTE: Administration of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zoledronic acid Injection 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid Injection should be administered by intravenous infusion over no less than 15 minutes .The treatment groups in the clinical studies were generally well balanced with regards to age, sex, race, and tumor types. The mean age of the study population was 59 years; 81% were Caucasian, 15% were Black, and 4% were of other races. 60% of the patients were male. The most common tumor types were lung, breast, head and neck, and renal.
- In these studies, HCM was defined as a corrected serum calcium (CSC) concentration of greater than or equal to 12.0 mg/dL (3.00 mmol/L). The primary efficacy variable was the proportion of patients having a complete response, defined as the lowering of the CSC to less than or equal to 10.8 mg/dL (2.70 mmol/L) within 10 days after drug infusion.
- To assess the effects of Zoledronic acid Injection versus those of pamidronate, the two multicenter HCM studies were combined in a preplanned analysis. The results of the primary analysis revealed that the proportion of patients that had normalization of corrected serum calcium by Day 10 were 88% and 70% for Zoledronic acid Injection 4 mg and pamidronate 90 mg, respectively (P=0.002) (see Figure 1). In these studies, no additional benefit was seen for Zoledronic acid Injection 8 mg over Zoledronic acid Injection 4 mg; however, the risk of renal toxicity of Zoledronic acid Injection 8 mg was significantly greater than that seen with Zoledronic acid Injection 4 mg.
Secondary efficacy variables from the pooled HCM studies included the proportion of patients who had normalization of corrected serum calcium (CSC) by Day 4; the proportion of patients who had normalization of CSC by Day 7; time to relapse of HCM; and duration of complete response. Time to relapse of HCM was defined as the duration (in days) of normalization of serum calcium from study drug infusion until the last CSC value less than 11.6 mg/dL (less than 2.90 mmol/L). Patients who did not have a complete response were assigned a time to relapse of 0 days. Duration of complete response was defined as the duration (in days) from the occurrence of a complete response until the last CSC ≤10.8 mg/dL (2.70 mmol/L). The results of these secondary analyses for Zoledronic acid Injection 4 mg and pamidronate 90 mg are shown in Table 10.
Clinical Trials in Multiple Myeloma and Bone Metastases of Solid Tumors
Table 11 describes an overview of the efficacy population in three randomized Zoledronic acid Injection trials in patients with multiple myeloma and bone metastases of solid tumors. These trials included a pamidronate-controlled study in breast cancer and multiple myeloma, a placebo-controlled study in prostate cancer, and a placebo-controlled study in other solid tumors. The prostate cancer study required documentation of previous bone metastases and 3 consecutive rising PSAs while on hormonal therapy. The other placebo-controlled solid tumor study included patients with bone metastases from malignancies other than breast cancer and prostate cancer, including NSCLC, renal cell cancer, small cell lung cancer, colorectal cancer, bladder cancer, GI/genitourinary cancer, head and neck cancer, and others. These trials were comprised of a core phase and an extension phase. In the solid tumor, breast cancer and multiple myeloma trials, only the core phase was evaluated for efficacy as a high percentage of patients did not choose to participate in the extension phase. In the prostate cancer trials, both the core and extension phases were evaluated for efficacy showing the Zoledronic acid Injection effect during the first 15 months was maintained without decrement or improvement for another 9 months. The design of these clinical trials does not permit assessment of whether more than one-year administration of Zoledronic acid Injection is beneficial. The optimal duration of Zoledronic acid Injection administration is not known.
The studies were amended twice because of renal toxicity. The Zoledronic acid Injection infusion duration was increased from 5 minutes to 15 minutes. After all patients had been accrued, but while dosing and follow-up continued, patients in the 8 mg Zoledronic acid Injection treatment arm were switched to 4 mg due to toxicity. Patients who were randomized to the Zoledronic acid Injection 8 mg group are not included in these analyses.
Each study evaluated skeletal-related events (SREs), defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Change in antineoplastic therapy due to increased pain was a SRE in the prostate cancer study only. Planned analyses included the proportion of patients with a SRE during the study and time to the first SRE. Results for the two Zoledronic acid Injection placebo-controlled studies are given in Table 12.
In the breast cancer and myeloma trial, efficacy was determined by a noninferiority analysis comparing Zoledronic acid Injection to pamidronate 90 mg for the proportion of patients with a SRE. This analysis required an estimation of pamidronate efficacy. Historical data from 1,128 patients in three pamidronate placebo-controlled trials demonstrated that pamidronate decreased the proportion of patients with a SRE by 13.1% (95% CI = 7.3%, 18.9%). Results of the comparison of treatment with Zoledronic acid Injection compared to pamidronate are given in Table 13.
# How Supplied
Zoledronic Acid Injection 4 mg/5 mL single-use vial of concentrate
Carton of 1 vial………………………………………………NDC 68083-116-01
## Storage
Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to tell their doctor if they have kidney problems before being given Zoledronic acid Injection.
- Patients should be informed of the importance of getting their blood tests (serum creatinine) during the course of their Zoledronic acid Injection therapy.
- Zoledronic acid Injection should not be given if the patient is pregnant or plans to become pregnant, or if she is breast-feeding.
- Patients should be advised to have a dental examination prior to treatment with Zoledronic acid Injection and should avoid invasive dental procedures during treatment.
- Patients should be informed of the importance of good dental hygiene and routine dental care.
- Patients with multiple myeloma and bone metastasis of solid tumors should be advised to take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily.
- Patients should be advised to report any thigh, hip or groin pain. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.
- Patients should be aware of the most common side effects including: anemia, nausea, vomiting, constipation, diarrhea, fatigue, fever, weakness, lower limb edema, anorexia, decreased weight, bone pain, myalgia, arthralgia, back pain, malignant neoplasm aggravated, headache, dizziness, insomnia, paresthesia, dyspnea, cough, and abdominal pain.
- There have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates, including Zoledronic acid. Before being given Zoledronic acid, patients should tell their doctor if they are aspirin-sensitive.
# Precautions with Alcohol
- Alcohol-Zoledronate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ZOLEDRONIC- ®
# Look-Alike Drug Names
There is limited information regarding Zoledronate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Zoledronate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Overview
Zoledronate is a bisphosphonate that is FDA approved for the treatment of hypercalcemia of malignancy, multiple myeloma, bone metastases of solid tumors, osteoporosis,paget's disease, postmenopausal osteoporosis. Common adverse reactions include nausea, fatigue, anemia, bone pain, constipation, fever, vomiting, dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
Hypercalcemia of Malignancy
Zoledronic acid Injection is indicated for the treatment of hypercalcemia of malignancy defined as an albumin-corrected calcium (cCa) of greater than or equal to 12 mg/dL [3.0 mmol/L] using the formula: cCa in mg/dL =Ca in mg/dL + 0.8 ( 4.0 g/dL – patient albumin [g/dL]).
Multiple Myeloma and Bone Metastases of Solid Tumors
Zoledronic acid Injection is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.
Important Limitation of Use
The safety and efficacy of Zoledronic acid Injection in the treatment of hypercalcemia associated with hyperparathyroidism or with other nontumor-related conditions have not been established.
# Dosage
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Hypercalcemia of Malignancy
The maximum recommended dose of Zoledronic acid Injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive Zoledronic acid Injection should have serum creatinine assessed prior to each treatment.
Dose adjustments of Zoledronic acid Injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 mcmol/L or less than 4.5 mg/dL).
Patients should be adequately rehydrated prior to administration of Zoledronic acid Injection .
Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of Zoledronic acid Injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.
Retreatment with Zoledronic acid Injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving Zoledronic acid Injection and serum creatinine must be assessed prior to retreatment with Zoledronic acid Injection.
Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors
The recommended dose of Zoledronic acid Injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.
Upon treatment initiation, the recommended Zoledronic acid Injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under the curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula .
During treatment, serum creatinine should be measured before each Zoledronic acid Injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:
For patients with normal baseline creatinine, increase of 0.5 mg/dL
For patients with abnormal baseline creatinine, increase of 1.0 mg/dL
In the clinical studies, Zoledronic acid Injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid Injection should be reinitiated at the same dose as that prior to treatment interruption.
Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily.
Preparation of Solution
Zoledronic acid Injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs.
4 mg / 5 mL Single-Use Vial
Vials of Zoledronic acid Injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.
To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the Zoledronic acid Injection concentrate from the vial for the dose required (see Table 2)
The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.
If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.
# Dosage Forms and Strengths
4 mg/5 mL single-use vial of concentrate
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zoledronate in adult patients.
### Non–Guideline-Supported Use
# Indications
- Monoclonal gammopathy of uncertain significance, with osteopenia or osteoporosis[1].
- Osteopenia, secondary to androgen-deprivation therapy in prostate cancer patients;
- Osteopenia, secondary to hormone therapy in breast cancer patients[2];
- Osteopenia, secondary to ovarian dysfunction induced by adjuvant chemotherapy in premenopausal women with early-stage breast cancer[3];
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Zoledronate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Zoledronate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Zoledronate in pediatric patients.
# Contraindications
Hypersensitivity to Zoledronic Acid or Any Components of Zoledronic acid Injection
Hypersensitivity reactions including rare cases of urticaria and angioedema, and very rare cases of anaphylactic reaction/shock have been reported.
# Warnings
Drugs with Same Active Ingredient or in the Same Drug Class
- Zoledronic acid Injection contains the same active ingredient as found in Reclast® (zoledronic acid). Patients being treated with Zoledronic acid Injection should not be treated with Reclast or other bisphosphonates.
Hydration and Electrolyte Monitoring
- Patients with hypercalcemia of malignancy must be adequately rehydrated prior to administration of Zoledronic acid Injection. Loop diuretics should not be used until the patient is adequately rehydrated and should be used with caution in combination with Zoledronic acid Injection in order to avoid hypocalcemia. Zoledronic acid Injection should be used with caution with other nephrotoxic drugs.
- Standard hypercalcemia-related metabolic parameters, such as serum levels of calcium, phosphate, and magnesium, as well as serum creatinine, should be carefully monitored following initiation of therapy with Zoledronic acid Injection. If hypocalcemia hypophosphatemia, or hypomagnesemia occur, short-term supplemental therapy may be necessary.
Renal Impairment
- Zoledronic acid Injection is excreted intact primarily via the kidney, and the risk of adverse reactions, in particular renal adverse reactions, may be greater in patients with impaired renal function. Safety and pharmacokinetic data are limited in patients with severe renal impairment and the risk of renal deterioration is increased . Preexisting renal insufficiency and multiple cycles of Zoledronic acid Injection and other bisphosphonates are risk factors for subsequent renal deterioration with Zoledronic acid Injection. Factors predisposing to renal deterioration, such as dehydration or the use of other nephrotoxic drugs, should be identified and managed, if possible.
- Zoledronic acid Injection treatment in patients with hypercalcemia of malignancy with severe renal impairment should be considered only after evaluating the risks and benefits of treatment. In the clinical studies, patients with serum creatinine greater than 400 mcmol/L or greater than 4.5 mg/dL were excluded.
- Zoledronic acid Injection treatment is not recommended in patients with bone metastases with severe renal impairment. In the clinical studies, patients with serum creatinine greater than 265 mcmol/L or greater than 3.0 mg/dL were excluded and there were only 8 of 564 patients treated with Zoledronic acid Injection 4 mg by 15-minute infusion with a baseline creatinine greater than 2 mg/dL. Limited pharmacokinetic data exists in patients with creatinine clearance less than 30 mL/min.
Osteonecrosis of the Jaw
- Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zoledronic acid Injection. Many of these patients were also receiving chemotherapy and corticosteroids which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma), and dental status (dental extraction, periodontal disease, local trauma including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection including osteomyelitis.
- Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates.
- While on treatment, these patients should avoid invasive dental procedures if possible. For patients who develop ONJ while on bisphosphonate therapy, dental surgery may exacerbate the condition. For patients requiring dental procedures, there are no data available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of ONJ. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Musculoskeletal Pain
- In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates, including Zoledronic acid Injection. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate.
Atypical Subtrochanteric and Diaphyseal Femoral Fractures
- Atypical subtrochanteric and diaphyseal femoral fractures have been reported in patients receiving bisphosphonate therapy, including Zoledronic acid Injection. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to just above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. These fractures occur after minimal or no trauma. Patients may experience thigh or groin pain weeks to months before presenting with a completed femoral fracture. Fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures has also been reported. A number of case reports noted that patients were also receiving treatment with glucocorticoids (such as prednisone or dexamethasone) at the time of fracture. Causality with bisphosphonate therapy has not been established.
- Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain in the absence of trauma should be suspected of having an atypical fracture and should be evaluated. Discontinuation of Zoledronic acid Injection therapy in patients suspected to have an atypical femur fracture should be considered pending evaluation of the patient, based on an individual benefit risk assessment. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.
Patients with Asthma
- While not observed in clinical trials with Zoledronic acid Injection, there have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates.
Hepatic Impairment
- Only limited clinical data are available for use of Zoledronic acid Injection to treat hypercalcemia of malignancy in patients with hepatic insufficiency, and these data are not adequate to provide guidance on dosage selection or how to safely use Zoledronic acid Injection in these patients.
Use in Pregnancy
- Bisphosphonates, such as Zoledronic acid Injection, are incorporated into the bone matrix, from where they are gradually released over periods of weeks to years. There may be a risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy.
- Zoledronic acid Injection may cause fetal harm when administered to a pregnant woman. In reproductive studies in pregnant rats, subcutaneous doses equivalent to 2.4 or 4.8 times the human systemic exposure resulted in pre- and post-implantation losses, decreases in viable fetuses and fetal skeletal, visceral, and external malformations. There are no adequate and well controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus .
Hypocalcemia
- Hypocalcemia has been reported in patients treated with Zoledronic acid Injection. Cardiac arrhythmias and neurologic adverse events (seizures, tetany, and numbness) have been reported secondary to cases of severe hypocalcemia. In some instances, hypocalcemia may be life-threatening. Hypocalcemia must be corrected before initiating Zoledronic acid Injection. Adequately supplement patients with calcium and vitamin D.
# Adverse Reactions
## Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Hypercalcemia of Malignancy
The safety of Zoledronic acid Injection was studied in 185 patients with hypercalcemia of malignancy (HCM) who received either Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion (n=86) or pamidronate 90 mg given as a 2-hour intravenous infusion (n=103). The population was aged 33-84 years, 60% male and 81% Caucasian, with breast, lung, head and neck, and renal cancer as the most common forms of malignancy. NOTE: pamidronate 90 mg was given as a 2-hour intravenous infusion. The relative safety of pamidronate 90 mg given as a 2-hour intravenous infusion compared to the same dose given as a 24-hour intravenous infusion has not been adequately studied in controlled clinical trials.
Renal Toxicity
Administration of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zoledronic acid Injection 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid Injection should be administered by intravenous infusion over no less than 15 minutes.
The most frequently observed adverse events were fever, nausea, constipation, anemia, and dyspnea (see Table 3).
Table 3 provides adverse events that were reported by 10% or more of the 189 patients treated with Zoledronic acid Injection 4 mg or Pamidronate 90 mg from the two HCM trials. Adverse events are listed regardless of presumed causality to study drug.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Zoledronate in the drug label.
# Drug Interactions
In vitro studiesindicate that the plasma protein binding of zoledronic acid is low, with the unbound fraction ranging from 60% to77%. In vitrostudies also indicate that zoledronic acid does not inhibit microsomal CYP450 enzymes. In vivo studies showed that zoledronic acid is not metabolized, and is excreted into the urine as the intact drug.
Aminoglycosides
Caution is advised when bisphosphonates are administered with aminoglycosides, since these agents may have an additive effect to lower serum calcium level for prolonged periods. This effect has not been reported in Zoledronic acid Injection clinical trials.
Loop Diuretics
Caution should also be exercised when Zoledronic acid Injection is used in combination with loop diuretics due to an increased risk of hypocalcemia.
Nephrotoxic Drugs
Caution is indicated when Zoledronic acid Injection is used with other potentially nephrotoxic drugs.
Thalidomide
No dose adjustment for Zoledronic acid Injection 4 mg is needed when co-administered with thalidomide. In a pharmacokinetic study of 24 patients with multiple myeloma, Zoledronic acid Injection 4 mg given as a 15 minute infusion was administered either alone or with thalidomide (100 mg once daily on days 1-14 and 200 mg once daily on days 15-28). Co-administration of thalidomide with Zoledronic acid Injection did not significantly change the pharmacokinetics of Zoledronic acid or creatinine clearance.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category D
- There are no adequate and well-controlled studies of Zoledronic acid Injection in pregnant women. Zoledronic acid Injection may cause fetal harm when administered to a pregnant woman. Bisphosphonates, such as Zoledronic acid Injection, are incorporated into the bone matrix and are gradually released over periods of weeks to years. The extent of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the total dose and duration of bisphosphonate use. Although there are no data on fetal risk in humans, bisphosphonates do cause fetal harm in animals, and animal data suggest that uptake of bisphosphonates into fetal bone is greater than into maternal bone. Therefore, there is a theoretical risk of fetal harm (e.g., skeletal and other abnormalities) if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on this risk has not been established. If this drug is used during pregnancy or if the patient becomes pregnant while taking or after taking this drug, the patient should be apprised of the potential hazard to the fetus.
- In female rats given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation, the number of stillbirths was increased and survival of neonates was decreased in the mid- and high-dose groups (≥0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Adverse maternal effects were observed in all dose groups (with a systemic exposure of ≥0.07 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and included dystocia and periparturient mortality in pregnant rats allowed to deliver. Maternal mortality may have been related to drug-induced inhibition of skeletal calcium mobilization, resulting in periparturient hypocalcemia. This appears to be a bisphosphonate-class effect.
- In pregnant rats given a subcutaneous dose of zoledronic acid of 0.1, 0.2, or 0.4 mg/kg/day during gestation, adverse fetal effects were observed in the mid- and high-dose groups (with systemic exposures of 2.4 and 4.8 times, respectively, the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). These adverse effects included increases in pre- and postimplantation losses, decreases in viable fetuses, and fetal skeletal, visceral, and external malformations. Fetal skeletal effects observed in the high-dose group included unossified or incompletely ossified bones, thickened, curved or shortened bones, wavy ribs, and shortened jaw. Other adverse fetal effects observed in the high-dose group included reduced lens, rudimentary cerebellum, reduction or absence of liver lobes, reduction of lung lobes, vessel dilation, cleft palate, and edema. Skeletal variations were also observed in the low-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison). Signs of maternal toxicity were observed in the high-dose group and included reduced body weights and food consumption, indicating that maximal exposure levels were achieved in this study.
- In pregnant rabbits given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day during gestation (≤0.5 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas), no adverse fetal effects were observed. Maternal mortality and abortion occurred in all treatment groups (at doses ≥0.05 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Adverse maternal effects were associated with, and may have been caused by, drug-induced hypocalcemia.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Zoledronate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Zoledronate during labor and delivery.
### Nursing Mothers
It is not known whether Zoledronic acid is excreted in human milk and because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Zoledronic acid Injection, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Zoledronic acid binds to bone long term and may be released over weeks to years.
### Pediatric Use
- Zoledronic acid Injection is not indicated for use in children.
- The safety and effectiveness of zoledronic acid was studied in a one-year, active-controlled trial of 152 pediatric subjects (74 receiving zoledronic acid). The enrolled population was subjects with severe osteogenesis imperfecta, aged 1-17 years, 55% male, 84% Caucasian, with a mean lumbar spine bone mineral density (BMD) of 0.431 gm/cm2, which is 2.7 standard deviations below the mean for age-matched controls (BMD Z-score of -2.7). At one year, increases in BMD were observed in the zoledronic acid treatment group. However, changes in BMD in individual patients with severe osteogenesis imperfecta did not necessarily correlate with the risk for fracture or the incidence or severity of chronic bone pain. The adverse events observed with Zoledronic acid Injection use in children did not raise any new safety findings beyond those previously seen in adults treated for hypercalcemia of malignancy. However, adverse reactions seen more commonly in pediatric patients included pyrexia (61%), arthralgia (26%), hypocalcemia (22%) and headache (22%). These reactions, excluding arthralgia, occurred most frequently within 3 days after the first infusion and became less common with repeat dosing. Because of long-term retention in bone, Zoledronic acid Injection should only be used in children if the potential benefit outweighs the potential risk.
- Plasma zoledronic acid concentration data was obtained from 10 patients with severe osteogenesis imperfecta (4 in the age group of 3-8 years and 6 in the age group of 9-17 years) infused with 0.05 mg/kg dose over 30 min. Mean Cmax and AUC(0-last) was 167 ng/mL and 220 ng•h/mL, respectively. The plasma concentration time profile of zoledronic acid in pediatric patients represent a multi-exponential decline, as observed in adult cancer patients at an approximately equivalent mg/kg dose.
### Geriatic Use
Clinical studies of Zoledronic acid Injection in hypercalcemia of malignancy included 34 patients who were 65 years of age or older. No significant differences in response rate or adverse reactions were seen in geriatric patients receiving Zoledronic acid Injection as compared to younger patients. Because decreased renal function occurs more commonly in the elderly, special care should be taken to monitor renal function.
### Gender
There is no FDA guidance on the use of Zoledronate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Zoledronate with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Zoledronate in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Zoledronate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Zoledronate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Zoledronate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
Method of Administration
Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zoledronic acid Injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial Zoledronic acid Injection dose.
### Monitoring
There is limited information regarding Monitoring of Zoledronate in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Zoledronate in the drug label.
# Overdosage
- Clinical experience with acute overdosage of Zoledronic acid Injection is limited. Two patients received Zoledronic acid Injection 32 mg over 5 minutes in clinical trials. Neither patient experienced any clinical or laboratory toxicity. Overdosage may cause clinically significant hypocalcemia, hypophosphatemia, and hypomagnesemia. Clinically relevant reductions in serum levels of calcium, phosphorus, and magnesium should be corrected by intravenous administration of calcium gluconate, potassium or sodium phosphate, and magnesium sulfate, respectively.
- In an open-label study of zoledronic acid 4 mg in breast cancer patients, a female patient received a single 48-mg dose of zoledronic acid in error. Two days after the overdose, the patient experienced a single episode of hyperthermia (38°C), which resolved after treatment. All other evaluations were normal, and the patient was discharged seven days after the overdose.
- A patient with non-Hodgkin’s lymphoma received zoledronic acid 4 mg daily on four successive days for a total dose of 16 mg. The patient developed paresthesia and abnormal liver function tests with increased GGT (nearly 100U/L, each value unknown). The outcome of this case is not known.
- In controlled clinical trials, administration of Zoledronic acid Injection 4 mg as an intravenous infusion over 5 minutes has been shown to increase the risk of renal toxicity compared to the same dose administered as a 15-minute intravenous infusion. In controlled clinical trials, Zoledronic acid Injection 8 mg has been shown to be associated with an increased risk of renal toxicity compared to Zoledronic acid Injection 4 mg, even when given as a 15-minute intravenous infusion, and was not associated with added benefit in patients with hypercalcemia of malignancy.
# Pharmacology
## Mechanism of Action
The principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Although the antiresorptive mechanism is not completely understood, several factors are thought to contribute to this action. In vitro, zoledronic acid inhibits osteoclastic activity and induces osteoclast apoptosis. Zoledronic acid also blocks the osteoclastic resorption of mineralized bone and cartilage through its binding to bone. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors.
## Structure
- Zoledronic acid Injection contains zoledronic acid, a bisphosphonic acid which is an inhibitor of osteoclastic bone resorption. Zoledronic acid is designated chemically as (1-Hydroxy-2-imidazol-1-yl-phosphonoethyl) phosphonic acid monohydrate and its structural formula is:
## Pharmacodynamics
- Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of Zoledronic acid Injection are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion.
- Osteoclastic hyperactivity resulting in excessive bone resorption is the underlying * pathophysiologic derangement in hypercalcemia of malignancy (HCM, tumor-induced hypercalcemia). Excessive release of calcium into the blood as bone is resorbed results in polyuria and gastrointestinal disturbances, with progressive dehydration and decreasing glomerular filtration rate. This, in turn, results in increased renal resorption of calcium, setting up a cycle of worsening systemic hypercalcemia. Reducing excessive bone resorption and maintaining adequate fluid administration are, therefore, essential to the management of hypercalcemia of malignancy.
- Patients who have hypercalcemia of malignancy can generally be divided into two groups according to the pathophysiologic mechanism involved: humoral hypercalcemia and hypercalcemia due to tumor invasion of bone. In humoral hypercalcemia, osteoclasts are activated and bone resorption is stimulated by factors such as parathyroid hormone-related protein, which are elaborated by the tumor and circulate systemically. Humoral hypercalcemia usually occurs in squamous cell malignancies of the lung or head and neck or in genitourinary tumors such as renal cell carcinoma or ovarian cancer. Skeletal metastases may be absent or minimal in these patients.
- Extensive invasion of bone by tumor cells can also result in hypercalcemia due to local tumor products that stimulate bone resorption by osteoclasts. Tumors commonly associated with locally mediated hypercalcemia include breast cancer and multiple myeloma.
- Total serum calcium levels in patients who have hypercalcemia of malignancy may not reflect the severity of hypercalcemia, since concomitant hypoalbuminemia is commonly present. Ideally, ionized calcium levels should be used to diagnose and follow hypercalcemic conditions; however, these are not commonly or rapidly available in many clinical situations. Therefore, adjustment of the total serum calcium value for differences in albumin levels (corrected serum calcium, CSC) is often used in place of measurement of ionized calcium; several nomograms are in use for this type of calculation
## Pharmacokinetics
Pharmacokinetic data in patients with hypercalcemia are not available.
Distribution
- Single or multiple (q 28 days) 5-minute or 15-minute infusions of 2, 4, 8 or 16 mg Zoledronic acid Injection were given to 64 patients with cancer and bone metastases. The postinfusion decline of zoledronic acid concentrations in plasma was consistent with a triphasic process showing a rapid decrease from peak concentrations at end of infusion to less than 1% of Cmax 24 hours postinfusion with population half-lives of t1/2α0.24 hours and t1/2β1.87 hours for the early disposition phases of the drug. The terminal elimination phase of zoledronic acid was prolonged, with very low concentrations in plasma between Days 2 and 28 postinfusion, and a terminal elimination half-life t 1/2⛛ of 146 hours. The area under the plasma concentration versus time curve (AUC0-24h) of zoledronic acid was dose proportional from 2-16 mg. The accumulation of zoledronic acid measured over three cycles was low, with mean AUC0-24h ratios for cycles 2 and 3 versus 1 of 1.13 ± 0.30 and 1.16 ± 0.36, respectively.
- In vitroand ex vivo studies showed low affinity of zoledronic acid for the cellular components of human blood, with a mean blood to plasma concentration ratio of 0.59 in a concentration range of 30 ng/mL to 5000 ng/mL. In vitro, the plasma protein binding is low, with the unbound fraction ranging from 60% at 2 ng/mL to 77% at 2000 ng/mL of zoledronic acid.
Metabolism
- Zoledronic acid does not inhibit human P450 enzymes in vitro. Zoledronic acid does not undergo biotransformation in vivo. In animal studies, less than 3% of the administered intravenous dose was found in the feces, with the balance either recovered in the urine or taken up by bone, indicating that the drug is eliminated intact via the kidney. Following an intravenous dose of 20 nCi 14C-zoledronic acid in a patient with cancer and bone metastases, only a single radioactive species with chromatographic properties identical to those of parent drug was recovered in urine, which suggests that zoledronic acid is not metabolized.
Excretion
- In 64 patients with cancer and bone metastases, on average (± SD) 39 ± 16% of the administered zoledronic acid dose was recovered in the urine within 24 hours, with only trace amounts of drug found in urine post-Day 2. The cumulative percent of drug excreted in the urine over 0-24 hours was independent of dose. The balance of drug not recovered in urine over 0-24 hours, representing drug presumably bound to bone, is slowly released back into the systemic circulation, giving rise to the observed prolonged low plasma concentrations. The 0-24 hour renal clearance of zoledronic acid was 3.7 ± 2.0 L/h.
- Zoledronic acid clearance was independent of dose but dependent upon the patient’s creatinine clearance. In a study in patients with cancer and bone metastases, increasing the infusion time of a 4-mg dose of zoledronic acid from 5 minutes (n=5) to 15 minutes (n=7) resulted in a 34% decrease in the zoledronic acid concentration at the end of the infusion ([mean ± SD] 403 ± 118 ng/mL versus 264 ± 86 ng/mL) and a 10% increase in the total AUC (378 ± 116 ng x h/mL versus 420 ± 218 ng x h/mL). The difference between the AUC means was not statistically significant.
## Special Populations
Pediatrics
Zoledronic acid Injection is not indicated for use in children.
Geriatrics
- The pharmacokinetics of zoledronic acid were not affected by age in patients with cancer and bone metastases who ranged in age from 38 years to 84 years.
Race
- Population pharmacokinetic analyses did not indicate any differences in pharmacokinetics among Japanese and North American (Caucasian and African American) patients with cancer and bone metastases.
Hepatic Insufficiency
- No clinical studies were conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of zoledronic acid.
Renal Insufficiency
- The pharmacokinetic studies conducted in 64 cancer patients represented typical clinical populations with normal to moderately impaired renal function. Compared to patients with normal renal function (N=37), patients with mild renal impairment (N=15) showed an average increase in plasma AUC of 15%, whereas patients with moderate renal impairment (N=11) showed an average increase in plasma AUC of 43%. Limited pharmacokinetic data are available for Zoledronic acid Injection in patients with severe renal impairment (creatinine clearance less than 30 mL/min). Based on population PK/PD modeling, the risk of renal deterioration appears to increase with AUC, which is doubled at a creatinine clearance of 10 mL/min. Creatinine clearance is calculated by the Cockcroft-Gault formula:
CrCl= [140-age (years)] x weight (kg) {x 0.85 for female patients}
[72 x serum creatinine (mg/dL)]
- Zoledronic acid Injection systemic clearance in individual patients can be calculated from the population clearance of Zoledronic acid Injection, CL (L/h)=6.5(CrCl/90)0.4. These formulae can be used to predict the Zoledronic acid Injection AUC in patients, where CL = Dose/AUC0-∞. The average AUC0-24in patients with normal renal function was 0.42 mg•h/L and the calculated AUC0-∞ for a patient with creatinine clearance of 75 mL/min was 0.66 mg•h/L following a 4-mg dose of Zoledronic acid Injection. However, efficacy and safety of adjusted dosing based on these formulae have not been prospectively assessed
## Nonclinical Toxicology
Carcinogenesis & Mutagenesis & Impairment Of Fertility
- Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Mice were given oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. There was an increased incidence of Harderian gland adenomas in males and females in all treatment groups (at doses ≥0.002 times a human intravenous dose of 4 mg, based on a comparison of relative body surface areas). Rats were given oral doses of zoledronic acid of 0.1, 0.5, or 2.0 mg/kg/day. No increased incidence of tumors was observed (at doses ≤0.2 times the human intravenous dose of 4 mg, based on a comparison of relative body surface areas).
- Zoledronic acid was not genotoxic in the Ames bacterial mutagenicity assay, in the Chinese hamster ovary cell assay, or in the Chinese hamster gene mutation assay, with or without metabolic activation. Zoledronic acid was not genotoxic in the in-vivo rat micronucleus assay.
- Female rats were given subcutaneous doses of zoledronic acid of 0.01, 0.03, or 0.1 mg/kg/day beginning 15 days before mating and continuing through gestation. Effects observed in the high-dose group (with systemic exposure of 1.2 times the human systemic exposure following an intravenous dose of 4 mg, based on AUC comparison) included inhibition of ovulation and a decrease in the number of pregnant rats. Effects observed in both the mid-dose group (with systemic exposure of 0.2 times the human systemic exposure following an intravenous dose of 4 mg, based on an AUC comparison) and high-dose group included an increase in preimplantation losses and a decrease in the number of implantations and live fetuses.
# Clinical Studies
Hypercalcemia of Malignancy
- Two identical multicenter, randomized, double-blind, double-dummy studies of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion or pamidronate 90 mg given as a 2-hour intravenous infusion were conducted in 185 patients with hypercalcemia of malignancy (HCM). NOTE: Administration of Zoledronic acid Injection 4 mg given as a 5-minute intravenous infusion has been shown to result in an increased risk of renal toxicity, as measured by increases in serum creatinine, which can progress to renal failure. The incidence of renal toxicity and renal failure has been shown to be reduced when Zoledronic acid Injection 4 mg is given as a 15-minute intravenous infusion. Zoledronic acid Injection should be administered by intravenous infusion over no less than 15 minutes [see Warnings and Precautions (5.1 and 5.2) and Dosage and Administration (2.4)].The treatment groups in the clinical studies were generally well balanced with regards to age, sex, race, and tumor types. The mean age of the study population was 59 years; 81% were Caucasian, 15% were Black, and 4% were of other races. 60% of the patients were male. The most common tumor types were lung, breast, head and neck, and renal.
- In these studies, HCM was defined as a corrected serum calcium (CSC) concentration of greater than or equal to 12.0 mg/dL (3.00 mmol/L). The primary efficacy variable was the proportion of patients having a complete response, defined as the lowering of the CSC to less than or equal to 10.8 mg/dL (2.70 mmol/L) within 10 days after drug infusion.
- To assess the effects of Zoledronic acid Injection versus those of pamidronate, the two multicenter HCM studies were combined in a preplanned analysis. The results of the primary analysis revealed that the proportion of patients that had normalization of corrected serum calcium by Day 10 were 88% and 70% for Zoledronic acid Injection 4 mg and pamidronate 90 mg, respectively (P=0.002) (see Figure 1). In these studies, no additional benefit was seen for Zoledronic acid Injection 8 mg over Zoledronic acid Injection 4 mg; however, the risk of renal toxicity of Zoledronic acid Injection 8 mg was significantly greater than that seen with Zoledronic acid Injection 4 mg.
Secondary efficacy variables from the pooled HCM studies included the proportion of patients who had normalization of corrected serum calcium (CSC) by Day 4; the proportion of patients who had normalization of CSC by Day 7; time to relapse of HCM; and duration of complete response. Time to relapse of HCM was defined as the duration (in days) of normalization of serum calcium from study drug infusion until the last CSC value less than 11.6 mg/dL (less than 2.90 mmol/L). Patients who did not have a complete response were assigned a time to relapse of 0 days. Duration of complete response was defined as the duration (in days) from the occurrence of a complete response until the last CSC ≤10.8 mg/dL (2.70 mmol/L). The results of these secondary analyses for Zoledronic acid Injection 4 mg and pamidronate 90 mg are shown in Table 10.
Clinical Trials in Multiple Myeloma and Bone Metastases of Solid Tumors
Table 11 describes an overview of the efficacy population in three randomized Zoledronic acid Injection trials in patients with multiple myeloma and bone metastases of solid tumors. These trials included a pamidronate-controlled study in breast cancer and multiple myeloma, a placebo-controlled study in prostate cancer, and a placebo-controlled study in other solid tumors. The prostate cancer study required documentation of previous bone metastases and 3 consecutive rising PSAs while on hormonal therapy. The other placebo-controlled solid tumor study included patients with bone metastases from malignancies other than breast cancer and prostate cancer, including NSCLC, renal cell cancer, small cell lung cancer, colorectal cancer, bladder cancer, GI/genitourinary cancer, head and neck cancer, and others. These trials were comprised of a core phase and an extension phase. In the solid tumor, breast cancer and multiple myeloma trials, only the core phase was evaluated for efficacy as a high percentage of patients did not choose to participate in the extension phase. In the prostate cancer trials, both the core and extension phases were evaluated for efficacy showing the Zoledronic acid Injection effect during the first 15 months was maintained without decrement or improvement for another 9 months. The design of these clinical trials does not permit assessment of whether more than one-year administration of Zoledronic acid Injection is beneficial. The optimal duration of Zoledronic acid Injection administration is not known.
The studies were amended twice because of renal toxicity. The Zoledronic acid Injection infusion duration was increased from 5 minutes to 15 minutes. After all patients had been accrued, but while dosing and follow-up continued, patients in the 8 mg Zoledronic acid Injection treatment arm were switched to 4 mg due to toxicity. Patients who were randomized to the Zoledronic acid Injection 8 mg group are not included in these analyses.
Each study evaluated skeletal-related events (SREs), defined as any of the following: pathologic fracture, radiation therapy to bone, surgery to bone, or spinal cord compression. Change in antineoplastic therapy due to increased pain was a SRE in the prostate cancer study only. Planned analyses included the proportion of patients with a SRE during the study and time to the first SRE. Results for the two Zoledronic acid Injection placebo-controlled studies are given in Table 12.
In the breast cancer and myeloma trial, efficacy was determined by a noninferiority analysis comparing Zoledronic acid Injection to pamidronate 90 mg for the proportion of patients with a SRE. This analysis required an estimation of pamidronate efficacy. Historical data from 1,128 patients in three pamidronate placebo-controlled trials demonstrated that pamidronate decreased the proportion of patients with a SRE by 13.1% (95% CI = 7.3%, 18.9%). Results of the comparison of treatment with Zoledronic acid Injection compared to pamidronate are given in Table 13.
# How Supplied
Zoledronic Acid Injection 4 mg/5 mL single-use vial of concentrate
Carton of 1 vial………………………………………………NDC 68083-116-01
## Storage
Store at 25ºC (77ºF); excursions permitted to 15-30ºC (59-86ºF).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to tell their doctor if they have kidney problems before being given Zoledronic acid Injection.
- Patients should be informed of the importance of getting their blood tests (serum creatinine) during the course of their Zoledronic acid Injection therapy.
- Zoledronic acid Injection should not be given if the patient is pregnant or plans to become pregnant, or if she is breast-feeding.
- Patients should be advised to have a dental examination prior to treatment with Zoledronic acid Injection and should avoid invasive dental procedures during treatment.
- Patients should be informed of the importance of good dental hygiene and routine dental care.
- Patients with multiple myeloma and bone metastasis of solid tumors should be advised to take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily.
- Patients should be advised to report any thigh, hip or groin pain. It is unknown whether the risk of atypical femur fracture continues after stopping therapy.
- Patients should be aware of the most common side effects including: anemia, nausea, vomiting, constipation, diarrhea, fatigue, fever, weakness, lower limb edema, anorexia, decreased weight, bone pain, myalgia, arthralgia, back pain, malignant neoplasm aggravated, headache, dizziness, insomnia, paresthesia, dyspnea, cough, and abdominal pain.
- There have been reports of bronchoconstriction in aspirin-sensitive patients receiving bisphosphonates, including Zoledronic acid. Before being given Zoledronic acid, patients should tell their doctor if they are aspirin-sensitive.
# Precautions with Alcohol
- Alcohol-Zoledronate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ZOLEDRONIC* ®[4]
# Look-Alike Drug Names
There is limited information regarding Zoledronate Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Reclast | |
2f0b0282f5a9825d09e17462fee8a541b70c6e57 | wikidoc | Red nucleus | Red nucleus
The red nucleus is a structure in the rostral midbrain involved in motor coordination.
# Function
In animals without a significant corticospinal tract, gait is mainly controlled by the red nucleus.
In humans, the red nucleus mainly controls the muscles of the shoulder and upper arm, but it has some control over the lower arm and hand as well. It is less important in its motor functions for humans than in many other mammals, because, in humans, the corticospinal tract is dominant. However the crawling of babies is controlled by the red nucleus, as is arm-swinging in normal walking. Since the red nucleus has sparse control over hands (as the Rubrospinal tract is more involved in large muscle movement such as that for Arms and Legs), fine control of the fingers is not modified by the functioning of the red nucleus (rather it relies on the corticobulbar tract ).
# Input and output
The red nucleus receives many inputs from the contralateral cerebellum and an input from the ipsilateral motor cortex.
It sends efferent axons (the rubrospinal projection) to the contralateral half of the rhombencephalic reticular formation and spinal cord. These efferent axons cross just ventral to the nucleus and descend through the midbrain to the spinal cord, where the rubrospinal tract which they make up runs ventral to the lateral corticospinal tract in the lateral funiculus.
# Meaning of name
Its name derives from an iron-containing pigment in many of the cells, which in fresh samples gives it a pink appearance. | Red nucleus
Template:Infobox Brain
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The red nucleus is a structure in the rostral midbrain involved in motor coordination.
# Function
In animals without a significant corticospinal tract, gait is mainly controlled by the red nucleus.
In humans, the red nucleus mainly controls the muscles of the shoulder and upper arm, but it has some control over the lower arm and hand as well. It is less important in its motor functions for humans than in many other mammals, because, in humans, the corticospinal tract is dominant. However the crawling of babies is controlled by the red nucleus, as is arm-swinging in normal walking. Since the red nucleus has sparse control over hands (as the Rubrospinal tract is more involved in large muscle movement such as that for Arms and Legs), fine control of the fingers is not modified by the functioning of the red nucleus (rather it relies on the corticobulbar tract [CoBuTr]).
# Input and output
The red nucleus receives many inputs from the contralateral cerebellum and an input from the ipsilateral motor cortex.
It sends efferent axons (the rubrospinal projection) to the contralateral half of the rhombencephalic reticular formation and spinal cord. These efferent axons cross just ventral to the nucleus and descend through the midbrain to the spinal cord, where the rubrospinal tract which they make up runs ventral to the lateral corticospinal tract in the lateral funiculus.
# Meaning of name
Its name derives from an iron-containing pigment in many of the cells, which in fresh samples gives it a pink appearance. | https://www.wikidoc.org/index.php/Red_Nucleus | |
a133a9ea7a2f9afe9999ae076c21903cf359a249 | wikidoc | Redirection | Redirection
To go back to the WikiDoc scholar program homepage, click here.
# Why redirect a page?
Sometimes a topic will have multiple names or abbreviations, and you will want to direct them all to one page
For example take the page ST Elevation Myocardial Infarction. The names STEMI, MI, Acute MI, Myocardial Infarction, AMI all are redirected to the page ST Elevation Myocardial Infarction.
# How to make a redirect (redirect command)
To redirect a page A to a different page B (also called target page), enter the following redirecting command (using "edit source") at the top of the redirecting page.
For example, to redirect the MI page ( redirecting page ) to the ST Elevation Myocardial Infarction page (target page), edit the MI page (using "edit source") and enter:
# How Do I Redirect To A Subheading of the Page Instead of the Page in General?
Say you want to redirect the page "Alcohol septal ablation" to a section of the parent page entitled Hypertrophic cardiomyopathy interventional cardiology. You can redirect to a specific subheading within a page by putting the name of the page followed by the hatch mark of the subheading you want to direct to. The example for alcohol septal ablation is shown below:
## What if I misspell the name of a page that I create?
If a spelling mistake occurs in a title such as STElevation Myocardial Infarction, it is not possible for a regular user to move the page with all its history. It is however possible to create a redirect. A new page ST Elevation Myocardial Infarction must be created first, and the contents from the old page must be copied manually. Then the old page STElevation Myocardial Infarction must be edited and its source code replaced by:
## Undesirable redirects
Don't make a redirect that points to another redirect. This is called a double redirect. These redirects don't work, and they can create a slow, unpleasant experience for the reader. | Redirection
To go back to the WikiDoc scholar program homepage, click here.
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Why redirect a page?
Sometimes a topic will have multiple names or abbreviations, and you will want to direct them all to one page
For example take the page ST Elevation Myocardial Infarction. The names STEMI, MI, Acute MI, Myocardial Infarction, AMI all are redirected to the page ST Elevation Myocardial Infarction.
# How to make a redirect (redirect command)
To redirect a page A to a different page B (also called target page), enter the following redirecting command (using "edit source") at the top of the redirecting page.
For example, to redirect the MI page ( redirecting page ) to the ST Elevation Myocardial Infarction page (target page), edit the MI page (using "edit source") and enter:
# How Do I Redirect To A Subheading of the Page Instead of the Page in General?
Say you want to redirect the page "Alcohol septal ablation" to a section of the parent page entitled Hypertrophic cardiomyopathy interventional cardiology. You can redirect to a specific subheading within a page by putting the name of the page followed by the hatch mark of the subheading you want to direct to. The example for alcohol septal ablation is shown below:
## What if I misspell the name of a page that I create?
If a spelling mistake occurs in a title such as STElevation Myocardial Infarction, it is not possible for a regular user to move the page with all its history. It is however possible to create a redirect. A new page ST Elevation Myocardial Infarction must be created first, and the contents from the old page must be copied manually. Then the old page STElevation Myocardial Infarction must be edited and its source code replaced by:
## Undesirable redirects
Don't make a redirect that points to another redirect. This is called a double redirect. These redirects don't work, and they can create a slow, unpleasant experience for the reader.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Redirect | |
581756dfa9a675b401d94d47cd4545d6f3693a52 | wikidoc | Reflexology | Reflexology
Reflexology, or zone therapy, is the practice of massaging, squeezing, or pushing on parts of the feet, or sometimes the hands and ears, with the goal of encouraging a beneficial effect on other parts of the body, or to improve general health.
There is no consensus on how reflexology does or could work in practice; a unifying theme is the idea that areas on the foot correspond to areas of the body, and that by manipulating these one can improve health through one's qi.
Concerns have been raised by medical professionals that treating potentially serious illnesses with reflexology, which has no proven efficacy, could delay the seeking of help from proven conventional medicine. However, registered reflexologists operate according to a code of conduct and would not diagnose a serious medical condition or treat one without medical consent.
# Claimed mechanisms of operation
Reflexologists posit that the body contains an energy field, invisible life force, or Qi, the blockage of which can prevent healing.
Other reflexologists claim to be able to relieve stress and pain in other parts of the body through the manipulation of the feet.
Other proposed effects of reflexology include the release of endorphins (natural pain killers found in the body), the promotion of lymphatic flow in the body or the dissolving of uric acid crystals.Template:Who
These hypotheses are rejected by the general medical community, citing a lack of scientific evidence and the well-tested germ theory of disease.
# History
The precursor of modern reflexology was introduced to the United States in 1913 by William H. Fitzgerald, M.D. (1872-1942), an ear, nose, and throat specialist, and Dr. Edwin Bowers. Fitzgerald claimed that applying pressure had an anesthetic effect on other areas of the body.
Reflexology was further developed by Eunice D. Ingham (1899-1974), a nurse and physiotherapist, in the 1930s and 1940s. Ingham claimed that the feet and hands were especially sensitive, and mapped the entire body into "reflexes" on the feet. It was at this time that "zone therapy" was renamed reflexology.
Modern reflexologists in the United States and the United Kingdom often learn Ingham's method first, although there are other more recently developed methods.
# Criticism
Common criticisms of reflexology are the lack of central regulation, accreditation and licensing, the lack of medical training provided to reflexologists, and the short duration of training programmes. Diplomas in reflexology can be attained with as little as six months of home study; and the lack of licensing and regulation allows anyone to practice as a reflexologist with no qualifications. However in certain European countries, for example; Switzerland, you have to be a medical practitioner to practice Reflexology, due to the required understanding of anatomy and physiology.
Reflexology's claim to manipulate energy (Qi) has been called pseudoscientific as there is no scientific evidence for the existence of life energy, Qi, 'crystalline structures' or 'pathways' in the body.
# Reflexology charts
A reflexology chart shows the "reflex zones" worked by reflexologists on the soles of the feet. Similar maps exist for the position of the reflexes on the hands and ears.
In this chart, the color codes represent the following organs or parts of the body:
-ther charts
# Reflexology in the Media
An episode of Penn & Teller: Bullshit! (1-02 Alternative Medicine) focused on reflexology. The original airing was February 7, 2003.
The Real Hustle mentioned reflexology as part of a weight loss scam (Season 4 Episode 2). | Reflexology
Template:Totally-disputed
Reflexology, or zone therapy, is the practice of massaging, squeezing, or pushing on parts of the feet, or sometimes the hands and ears, with the goal of encouraging a beneficial effect on other parts of the body, or to improve general health.
There is no consensus on how reflexology does or could work in practice; a unifying theme is the idea that areas on the foot correspond to areas of the body, and that by manipulating these one can improve health through one's qi.[1]
Concerns have been raised by medical professionals that treating potentially serious illnesses with reflexology, which has no proven efficacy, could delay the seeking of help from proven conventional medicine.[2] However, registered reflexologists operate according to a code of conduct and would not diagnose a serious medical condition or treat one without medical consent.
# Claimed mechanisms of operation
Reflexologists posit that the body contains an energy field, invisible life force, or Qi, the blockage of which can prevent healing.[1]
Other reflexologists claim to be able to relieve stress and pain in other parts of the body through the manipulation of the feet.[3]
Other proposed effects of reflexology include the release of endorphins (natural pain killers found in the body), the promotion of lymphatic flow in the body or the dissolving of uric acid crystals.Template:Who
These hypotheses are rejected by the general medical community, citing a lack of scientific evidence and the well-tested germ theory of disease.[4]
# History
The precursor of modern reflexology was introduced to the United States in 1913 by William H. Fitzgerald, M.D. (1872-1942), an ear, nose, and throat specialist, and Dr. Edwin Bowers. Fitzgerald claimed that applying pressure had an anesthetic effect on other areas of the body.[5]
Reflexology was further developed by Eunice D. Ingham (1899-1974), a nurse and physiotherapist, in the 1930s and 1940s.[6][7] Ingham claimed that the feet and hands were especially sensitive, and mapped the entire body into "reflexes" on the feet. It was at this time that "zone therapy" was renamed reflexology.
Modern reflexologists in the United States and the United Kingdom often learn Ingham's method first, although there are other more recently developed methods.[4]
# Criticism
Common criticisms of reflexology are the lack of central regulation, accreditation and licensing, the lack of medical training provided to reflexologists, and the short duration of training programmes. Diplomas in reflexology can be attained with as little as six months of home study;[8] and the lack of licensing and regulation allows anyone to practice as a reflexologist with no qualifications. However in certain European countries, for example; Switzerland, you have to be a medical practitioner to practice Reflexology, due to the required understanding of anatomy and physiology.
Reflexology's claim to manipulate energy (Qi) has been called pseudoscientific as there is no scientific evidence for the existence of life energy, Qi, 'crystalline structures' or 'pathways' in the body.[9]
# Reflexology charts
A reflexology chart shows the "reflex zones" worked by reflexologists on the soles of the feet. Similar maps exist for the position of the reflexes on the hands and ears.
In this chart, the color codes represent the following organs or parts of the body:
other charts
http://www.passthetest.com/images/reflexology.gif
http://www.quest4arts.org/productions/tours/hongkong/media/reflexlology.gif
http://www.healthgoods.com/images/Medirub_Hand_Reflexlology.gif
# Reflexology in the Media
An episode of Penn & Teller: Bullshit! (1-02 Alternative Medicine) focused on reflexology. The original airing was February 7, 2003.
The Real Hustle mentioned reflexology as part of a weight loss scam (Season 4 Episode 2). | https://www.wikidoc.org/index.php/Reflexology | |
3f1ab0f2e8f503a1003a7df1ff7f28061062a6ee | wikidoc | Regadenoson | Regadenoson
Gerald Chi
Regadenoson
a
vasodilator
radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress
angina, dysrhythmia, chest discomfort, chest pain, tachycardia, ventricular premature complex, nausea, dizziness, headache, dyspnea, and flushing
Title
ConditionName:
- Content
- Lexiscan® (regadenoson) injection is a pharmacologic stress agent indicated for radionuclide myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress.
- Dosing Information
- The recommended intravenous dose of Lexiscan is 5 mL (0.4 mg regadenoson).
- Administer Lexiscan as a rapid (approximately 10 seconds) injection into a peripheral vein using a 22 gauge or larger catheter or needle.
- Administer a 5 mL saline flush immediately after the injection of Lexiscan.
- Administer the radionuclide myocardial perfusion imaging agent 10–20 seconds after the saline flush. The radionuclide may be injected directly into the same catheter as Lexiscan.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Lexiscan if it contains particulate matter or is discolored.
There is limited information regarding Off-Label Guideline-Supported Use of Regadenoson in adult patients.
There is limited information regarding Off-Label Non–Guideline-Supported Use of Regadenoson in adult patients.
- Safety and effectiveness in pediatric patients (< 18 years of age) have not been established.
There is limited information regarding Off-Label Guideline-Supported Use of Regadenoson in pediatric patients.
There is limited information regarding Off-Label Non–Guideline-Supported Use of Regadenoson in pediatric patients.
- Do not administer Lexiscan to patients with the following conditions (unless these patients have a functioning artificial pacemaker):
- Second- or third- degree AV block
- Sinus node dysfunction
- Myocardial Ischemia
- Fatal and nonfatal myocardial infarction, ventricular arrhythmias, and cardiac arrest have occurred following Lexiscan injection. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example unstable angina or cardiovascular instability; these patients may be at greater risk of serious cardiovascular reactions to Lexiscan. Cardiac resuscitation equipment and trained staff should be available before administering Lexiscan. If serious reactions to Lexiscan occur, consider the use of aminophylline, an adenosine antagonist, to shorten the duration of increased coronary blood flow induced by Lexiscan.
- Sinoatrial and Atrioventricular Nodal Block
- Adenosine receptor agonists, including Lexiscan, can depress the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia requiring intervention. In clinical trials first-degree AV block (PR prolongation > 220 msec) developed in 3% of patients within 2 hours of Lexiscan administration; transient second-degree AV block with one dropped beat was observed in one patient receiving Lexiscan. In postmarketing experience, third degree heart block and asystole within minutes of Lexiscan administration have occurred.
- Hypersensitivity, Including Anaphylaxis
- Anaphylaxis, angioedema, cardiac or respiratory arrest, respiratory distress, decreased oxygen saturation, hypotension, throat tightness, urticaria and rashes have occurred. In clinical trials, hypersensitivity reactions were reported in fewer than 1 percent of patients. Have personnel and resuscitative equipment immediately available.
- Hypotension
- Adenosine receptor agonists, including Lexiscan, induce arterial vasodilation and hypotension. In clinical trials, decreased systolic blood pressure (> 35 mm Hg) was observed in 7% of patients and decreased diastolic blood pressure (> 25 mm Hg) was observed in 4% of patients within 45 min of Lexiscan administration. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, left main coronary artery stenosis, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. In postmarketing experience, syncope, transient ischemic attacks and seizures have been observed.
- Hypertension
- Administration of adenosine receptor agonists, including Lexiscan, may result in clinically significant increases in blood pressure in some patients. Among patients who experienced an increase in blood pressure in clinical trials, the increase was observed within minutes of Lexiscan administration. Most increases resolved within 10 to 15 minutes, but in some cases, increases were observed at 45 minutes following administration. In post-marketing experience, cases of potentially clinically significant hypertension have been reported, particularly with underlying hypertension and when low-level exercise was included in the MPI.
- Bronchoconstriction
- Adenosine receptor agonists, including Lexiscan, may cause dyspnea, bronchoconstriction, and respiratory compromise. Appropriate bronchodilator therapy and resuscitative measures should be available prior to Lexiscan administration.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- During clinical development, 1,651 subjects were exposed to Lexiscan, with most receiving 0.4 mg as a rapid (≤ 10 seconds) intravenous injection. Most of these subjects received Lexiscan in two clinical studies that enrolled patients who had no history of bronchospastic lung disease as well as no history of a cardiac conduction block of greater than first-degree AV block, except for patients with functioning artificial pacemakers. In these studies (Studies 1 and 2), 2,015 patients underwent myocardial perfusion imaging after administration of Lexiscan (N = 1,337) or Adenoscan® (N = 678). The population was 26–93 years of age (median 66 years), 70% male and primarily Caucasian (76% Caucasian, 7% African American, 9% Hispanic, 5% Asian). Table 1 shows the most frequently reported adverse reactions.
- Overall, any adverse reaction occurred at similar rates between the study groups (80% for the Lexiscan group and 83% for the Adenoscan group). Aminophylline was used to treat the reactions in 3% of patients in the Lexiscan group and 2% of patients in the Adenoscan group. Most adverse reactions began soon after dosing, and generally resolved within approximately 15 minutes, except for headache which resolved in most patients within 30 minutes.
- ECG Abnormalities
- The frequency of rhythm or conduction abnormalities following Lexiscan or Adenoscan is shown in Table 2.
- Respiratory Abnormalities
- In a randomized, placebo-controlled trial (Study 3) of 999 subjects with asthma (n=532) or stable chronic obstructive pulmonary disease (n=467), the overall incidence of pre-specified respiratory adverse reactions was greater in the Lexiscan group compared to the placebo group (p 15% from baseline at two-hours in FEV1 (Table 3).
- Renal Impairment
- In a randomized, placebo-controlled trial of 504 subjects (Lexiscan n=334 and placebo n=170) with a diagnosis or risk factors for coronary artery disease and NKFK/DOQI Stage III or IV renal impairment (defined as GFR 15-59 mL/min/1.73 m2), no serious adverse events were reported through the 24-hour follow-up period.
- Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Lexiscan exposure.
Myocardial infarction, cardiac arrest, ventricular arrhythmias, supraventricular tachyarrhythmias including atrial fibrillation or flutter, heart block (including third degree block), asystole, marked hypertension, symptomatic hypotension in association with transient ischemic attack, seizures and syncope have been reported. Some events required intervention with fluids and/or aminophylline. QTc prolongation shortly after Lexiscan administration has been reported.
Abdominal pain, occasionally severe, has been reported a few minutes after Lexiscan administration, in association with nausea, vomiting, or myalgias; administration of aminophylline, an adenosine antagonist, appeared to lessen the pain. Diarrhea and fecal incontinence have also been reported following Lexiscan administration.
Musculoskeletal pain has occurred, typically 10-20 minutes after Lexiscan administration; the pain was occasionally severe, localized in the arms and lower back and extended to the buttocks and lower legs bilaterally. Administration of aminophylline appeared to lessen the pain.
Tremor, seizure (particularly with a history of seizure)
Respiratory arrest, dyspnea and wheezing have been reported following Lexiscan administration.
Anaphylaxis, angioedema, cardiac or respiratory arrest, respiratory distress, decreased oxygen saturation, hypotension, throat tightness, urticaria, rashes have occurred and have required treatment including resuscitation.
- No formal pharmacokinetic drug interaction studies have been conducted with Lexiscan.
- Methylxanthines (e.g., caffeine and theophylline) are non-specific adenosine receptor antagonists that interfere with the vasodilation activity of Lexiscan. Patients should avoid consumption of any products containing methylxanthines as well as any drugs containing theophylline for at least 12 hours before Lexiscan administration. Aminophylline may be used to attenuate severe or persistent adverse reactions to Lexiscan.
- In clinical studies, Lexiscan was administered to patients taking other cardioactive drugs (i.e., β-blockers, calcium channel blockers, ACE inhibitors, nitrates, cardiac glycosides, and angiotensin receptor blockers) without reported adverse reactions or apparent effects on efficacy.
- Dipyridamole may change the effects of Lexiscan. When possible, withhold dipyridamole for at least two days prior to Lexiscan administration.
- Regadenoson does not inhibit the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in human liver microsomes, indicating that it is unlikely to alter the pharmacokinetics of drugs metabolized by these cytochrome P450 enzymes.
- Pregnancy Category C
- There are no adequate well-controlled studies with Lexiscan in pregnant women. Lexiscan should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.
- Reproductive studies in rats showed that regadenoson doses 10 and 20 times the maximum recommended human dose (MRHD) based on body surface area, caused reduced fetal body weights and significant ossification delays in fore- and hind limb phalanges and metatarsals; however, maternal toxicity also occurred at these doses. Skeletal variations were increased in all treated groups. In rabbits, there were no Teratogenic effects in offspring at regadenoson doses 4 times the MRHD, although signs of maternal toxicity occurred at this dose. At regadenoson doses equivalent to 12 and 20 times the MRHD, maternal toxicity occurred along with increased embryo-fetal loss and fetal malformations. It is not clear whether malformations that occurred at maternally toxic doses of regadenoson in both animal species were due to fetal drug effects or only to the maternal toxic effects.
- Because animals received repeated doses of regadenoson, their exposure was significantly higher than that achieved with the standard single dose administered to humans.
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Regadenoson in women who are pregnant.
There is no FDA guidance on use of Regadenoson during labor and delivery.
- It is not known whether Lexiscan is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Lexiscan in nursing infants, the decision to interrupt nursing after administration of Lexiscan or not to administer Lexiscan, should take into account the importance of the drug to the mother. Based on the pharmacokinetics of Lexiscan, it should be cleared 10 hours after administration. Therefore, nursing women may consider interrupting nursing for 10 hours after administration.
- Safety and effectiveness in pediatric patients (< 18 years of age) have not been established.
- Of the 1,337 patients receiving Lexiscan in Studies 1 and 2, 56% were 65 years of age and over and 24% were 75 years of age and over. Older patients (> 75 years of age) had a similar adverse event profile compared to younger patients (< 65 years of age), but had a higher incidence of hypotension (2% vs. < 1%).
There is no FDA guidance on the use of Regadenoson with respect to specific gender populations.
There is no FDA guidance on the use of Regadenoson with respect to specific racial populations.
- Lexiscan was assessed in a randomized, placebo-controlled trial of patients with NKFK/DOQI Stage III or IV renal impairment (defined as a GFR 15-59 mL/min/1.73 m2). No serious adverse events were reported through the 24-hour follow-up period.
There is no FDA guidance on the use of Regadenoson in patients with hepatic impairment.
There is no FDA guidance on the use of Regadenoson in women of reproductive potentials and males.
There is no FDA guidance one the use of Regadenoson in patients who are immunocompromised.
- Intravenous
There is limited information regarding Monitoring of Regadenoson in the drug label.
There is limited information regarding IV Compatibility of Regadenoson in the drug label.
# Acute Overdose
## Signs and Symptoms
- Lexiscan overdosage may result in serious reactions. In a study of healthy volunteers, symptoms of flushing, dizziness and increased heart rate were assessed as intolerable at Lexiscan doses greater than 0.02 mg/kg.
## Management
- Aminophylline may be administered in doses ranging from 50 mg to 250 mg by slow intravenous injection (50 mg to 100 mg over 30–60 seconds) to attenuate severe and/or persistent adverse reactions to Lexiscan.
# Chronic Overdose
There is limited information regarding Chronic Overdose of Regadenoson in the drug label.
- Regadenoson is a low affinity agonist (Ki ≈ 1.3 µM) for the A2A adenosine receptor, with at least 10-fold lower affinity for the A1 adenosine receptor (Ki > 16.5 µM), and weak, if any, affinity for the A2B and A3 adenosine receptors. Activation of the A2A adenosine receptor by regadenoson produces coronary vasodilation and increases coronary blood flow (CBF).
- Regadenoson is an A2A adenosine receptor agonist that is a coronary vasodilator. Regadenoson is chemically described as adenosine, 2--1H-pyrazol-1-yl]-, monohydrate. Its structural formula is:
- The molecular formula for regadenoson is C15H18N8O5 - H2O and its molecular weight is 408.37.
- Lexiscan is a sterile, nonpyrogenic solution for intravenous injection. The solution is clear and colorless. Each 1 mL in the 5 mL pre-filled syringe contains 0.084 mg of regadenoson monohydrate, corresponding to 0.08 mg regadenoson on an anhydrous basis, 10.9 mg dibasic sodium phosphate dihydrate or 8.7 mg dibasic sodium phosphate anhydrous, 5.4 mg monobasic sodium phosphate monohydrate, 150 mg propylene glycol, 1 mg edetate disodium dihydrate, and Water for Injection, with pH between 6.3 and 7.7.
- Coronary Blood Flow
- Lexiscan causes a rapid increase in CBF which is sustained for a short duration. In patients undergoing coronary catheterization, pulsed-wave Doppler ultrasonography was used to measure the average peak velocity (APV) of coronary blood flow before and up to 30 minutes after administration of regadenoson (0.4 mg, intravenously). Mean APV increased to greater than twice baseline by 30 seconds and decreased to less than twice the baseline level within 10 minutes.
- Myocardial uptake of the radiopharmaceutical is proportional to CBF. Because Lexiscan increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, Lexiscan causes relatively less uptake of the radiopharmaceutical in vascular territories supplied by stenotic arteries. MPI intensity after Lexiscan administration is therefore greater in areas perfused by normal relative to stenosed arteries.
- Effect of Aminophylline
- Aminophylline (100 mg, administered by slow iv injection over 60 seconds) injected 1 minute after 0.4 mg Lexiscan in subjects undergoing cardiac catheterization, was shown to shorten the duration of the coronary blood flow response to Lexiscan as measured by pulsed-wave Doppler ultrasonography.
- Effect of Caffeine
- Ingestion of caffeine decreases the ability to detect reversible ischemic defects. In a placebo-controlled, parallel group clinical study, patients with known or suspected myocardial ischemia received a baseline rest/stress MPI followed by a second stress MPI. Patients received caffeine or placebo 90 minutes before the second Lexiscan stress MPI. Following caffeine administration (200 or 400 mg), the mean number of reversible defects identified was reduced by approximately 60%. This decrease was statistically significant.
- Hemodynamic Effects
- In clinical studies, the majority of patients had an increase in heart rate and a decrease in blood pressure within 45 minutes after administration of Lexiscan. Maximum hemodynamic changes after Lexiscan and Adenoscan in Studies 1 and 2 are summarized in Table 4.
- Respiratory Effects
- The A2B and A3 adenosine receptors have been implicated in the pathophysiology of bronchoconstriction in susceptible individuals (i.e., asthmatics). In in vitro studies, regadenoson has not been shown to have appreciable binding affinity for the A2B and A3 adenosine receptors.
- In a randomized, placebo-controlled clinical trial (Study 3) of 999 subjects with a diagnosis, or risk factors for, coronary artery disease and concurrent asthma or COPD, the incidence of respiratory adverse reactions (dyspnea, wheezing) was greater with Lexiscan compared to placebo. Moderate (2.5%) or severe (<1%) respiratory reactions were observed more frequently in the Lexiscan group compared to placebo
- In healthy volunteers, the regadenoson plasma concentration-time profile is multi-exponential in nature and best characterized by 3-compartment model. The maximal plasma concentration of regadenoson is achieved within 1 to 4 minutes after injection of Lexiscan and parallels the onset of the pharmacodynamic response. The half-life of this initial phase is approximately 2 to 4 minutes. An intermediate phase follows, with a half-life on average of 30 minutes coinciding with loss of the pharmacodynamic effect. The terminal phase consists of a decline in plasma concentration with a half-life of approximately 2 hours. Within the dose range of 0.3–20 µg/kg in healthy subjects, clearance, terminal half-life or volume of distribution do not appear dependent upon the dose.
- A population pharmacokinetic analysis including data from subjects and patients demonstrated that regadenoson clearance decreases in parallel with a reduction in creatinine clearance and clearance increases with increased body weight. Age, gender, and race have minimal effects on the pharmacokinetics of regadenoson.
- Renally Impaired Patients
- The disposition of regadenoson was studied in 18 subjects with various degrees of renal function and in 6 healthy subjects. With increasing renal impairment, from mild (CLcr 50 to < 80 mL/min) to moderate (CLcr 30 to < 50 mL/min) to severe renal impairment (CLcr < 30 mL/min), the fraction of regadenoson excreted unchanged in urine and the renal clearance decreased, resulting in increased elimination half-lives and AUC values compared to healthy subjects (CLcr ≥ 80 mL/min). However, the maximum observed plasma concentrations as well as volumes of distribution estimates were similar across the groups. The plasma concentration-time profiles were not significantly altered in the early stages after dosing when most pharmacologic effects are observed. No dose adjustment is needed in patients with renal impairment.
- Patients with End Stage Renal Disease
- The pharmacokinetics of regadenoson in patients on dialysis has not been assessed.
- Hepatically Impaired Patients
- The influence of hepatic impairment on the pharmacokinetics of regadenoson has not been evaluated. Because greater than 55% of the dose is excreted in the urine as unchanged drug and factors that decrease clearance do not affect the plasma concentration in the early stages after dosing when clinically meaningful pharmacologic effects are observed, no dose adjustment is needed in patients with hepatic impairment.
- Geriatric Patients
- Based on a population pharmacokinetic analysis, age has a minor influence on the pharmacokinetics of regadenoson. No dose adjustment is needed in elderly patients.
- The metabolism of regadenoson is unknown in humans. Incubation with rat, dog, and human liver microsomes as well as human hepatocytes produced no detectable metabolites of regadenoson.
- In healthy volunteers, 57% of the regadenoson dose is excreted unchanged in the urine (range 19–77%), with an average plasma renal clearance around 450 mL/min, i.e., in excess of the glomerular filtration rate. This indicates that renal tubular secretion plays a role in regadenoson elimination.
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Regadenoson was negative in the Ames bacterial mutation assay, chromosomal aberration assay in Chinese hamster ovary (CHO) cells, and mouse bone marrow micronucleus assay.
- Long-term animal studies have not been conducted to evaluate Lexiscan's carcinogenic potential or potential effects on fertility.
- Animal Toxicology and/or Pharmacology
- Reproductive Toxicology Studies
- Reproduction studies were conducted in rabbits and rats using doses of Lexiscan that were 2 to 20 times (rats) and 4 to 20 times (rabbits) the maximum recommended human dose (MRHD), based on body surface area comparison.
- When administered to rabbits during organogenesis, regadenoson caused maternal toxicity including tachypnea, soft, liquid or scant feces, and localized alopecia in all treated groups, and caused reduction in body weight and feed consumption at 0.3 and 0.5 mg/kg/day (12 and 20 X MRHD, respectively). At regadenoson doses equivalent to 12 and 20 times the MRHD, maternal toxicity occurred along with decreased number of live fetuses, reduced fetal body weight, and occurrence of fetal variations and malformations. At regadenoson doses equivalent to 20 times the MRHD, resorptions were increased and fetal body weights reduced. Fetal malformations included microphthalmia (1/116 at 20 X MRHD), interrelated vertebrae/rib alterations (2/145 and 2/116 each at 12 and 20 X MRHD), and misaligned caudal vertebrae (3/145 at 12 X MRHD). Fetal toxicity was only observed at maternally toxic doses. The no effect dose level for fetal toxicity is 0.1 mg/kg (4 X MRHD). A no effect dose level was not identified for maternal toxicity.
- When regadenoson was administered to pregnant rats during the period of major organogenesis, 4/25 rats from the 1.0 mg/kg/day group (20 X MRHD) and 1/25 rats from the 0.8 mg/kg (16 X MRHD) group died immediately following the first dose of regadenoson. All dams had decreased motor activity and one was gasping post-dosing. At doses ≥ 0.5 mg/kg (10 X MRHD), maternal toxicity included decreased motor activity, increased limb extension, excess salivation, and reduction in body weight and feed consumption. At doses ≥ 0.5 mg/kg, fetal body weights were significantly reduced and significant ossification delays were observed in fore- and hind limb phalanges and metatarsals. Skeletal malformations included delayed ossification of the skull (1/167), and hemivertebra present at a thoracic vertebra (1/167), observed at 16-20 X MRHD, and small arches of a lumbar and sacral vertebrae (1/174) observed at 2 X MRHD. The no effect dose level for maternal toxicity is 0.1 mg/kg/day (2 X MRHD).
- Cardiomyopathy
- Minimal cardiomyopathy (myocyte necrosis and inflammation) was observed in rats following single dose administration of regadenoson. Increased incidence of minimal cardiomyopathy was observed on day 2 in males at doses of 0.08, 0.2 and 0.8 mg/kg (1/5, 2/5, and 5/5) and in females (2/5) at 0.8 mg/kg. In a separate study in male rats, the mean arterial pressure was decreased by 30 to 50% of baseline values for up to 90 minutes at regadenoson doses of 0.2 and 0.8 mg/kg, respectively. No cardiomyopathy was noted in rats sacrificed 15 days following single administration of regadenoson. The mechanism of the cardiomyopathy induced by regadenoson was not elucidated in this study but was associated with the hypotensive effects of regadenoson. Profound hypotension induced by vasoactive drugs is known to cause cardiomyopathy in rats.
- Local Irritation
- Intravenous administration of Lexiscan to rabbits resulted in perivascular hemorrhage, vein vasculitis, inflammation, thrombosis and necrosis, with inflammation and thrombosis persisting through day 8 (last observation day). Perivascular administration of Lexiscan to rabbits resulted in hemorrhage, inflammation, pustule formation and epidermal hyperplasia, which persisted through day 8 except for the hemorrhage which resolved. Subcutaneous administration of Lexiscan to rabbits resulted in hemorrhage, acute inflammation, and necrosis; on day 8 muscle fiber regeneration was observed.
- The efficacy and safety of Lexiscan were determined relative to Adenoscan in two randomized, double-blind studies (Studies 1 and 2) in 2,015 patients with known or suspected coronary artery disease who were indicated for pharmacologic stress MPI. A total of 1,871 of these patients had images considered valid for the primary efficacy evaluation, including 1,294 (69%) men and 577 (31%) women with a median age of 66 years (range 26–93 years of age). Each patient received an initial stress scan using Adenoscan (6-minute infusion using a dose of 0.14 mg/kg/min, without exercise) with a radionuclide gated SPECT imaging protocol. After the initial scan, patients were randomized to either Lexiscan or Adenoscan, and received a second stress scan with the same radionuclide imaging protocol as that used for the initial scan. The median time between scans was 7 days (range of 1–104 days).
- The most common cardiovascular histories included hypertension (81%), CABG, PTCA or stenting (51%), angina (63%), and history of myocardial infarction (41%) or arrhythmia (33%); other medical history included diabetes (32%) and COPD (5%). Patients with a recent history of serious uncontrolled ventricular arrhythmia, myocardial infarction, or unstable angina, a history of greater than first-degree AV block, or with symptomatic bradycardia, sick sinus syndrome, or a heart transplant were excluded. A number of patients took cardioactive medications on the day of the scan, including β-blockers (18%), calcium channel blockers (9%), and nitrates (6%). In the pooled study population, 68% of patients had 0–1 segments showing reversible defects on the initial scan, 24% had 2–4 segments, and 9% had ≥ 5 segments.
- Comparison of the images obtained with Lexiscan to those obtained with Adenoscan was performed as follows. Using the 17-segment model, the number of segments showing a reversible perfusion defect was calculated for the initial Adenoscan study and for the randomized study obtained using Lexiscan or Adenoscan. The agreement rate for the image obtained with Lexiscan or Adenoscan relative to the initial Adenoscan image was calculated by determining how frequently the patients assigned to each initial Adenoscan category (0–1, 2–4, 5–17 reversible segments) were placed in the same category with the randomized scan. The agreement rates for Lexiscan and Adenoscan were calculated as the average of the agreement rates across the three categories determined by the initial scan. Studies 1 and 2 each demonstrated that Lexiscan is similar to Adenoscan in assessing the extent of reversible perfusion abnormalities (Table 5).
- Lexiscan is supplied as a sterile, preservative-free solution containing 0.08 mg/mL regadenoson in the following package:
- Single-use 5 mL pre-filled plastic Ansyr® syringes with luer-lock fitting (NDC 0469-6501-89).
- Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30°C (59°–86°F).
- Methylxanthine Consumption
- Patients should be instructed to avoid consumption of any products containing methylxanthines, including caffeinated coffee, tea or other caffeinated beverages, caffeine-containing drug products, and theophylline for at least 12 hours before a scheduled radionuclide MPI.
- Common Reactions
- Prior to Lexiscan administration, patients should be informed of the most common reactions (such as shortness of breath, headache and flushing) that have been reported in association with Lexiscan during MPI.
- Patients with COPD or Asthma
- Patients with COPD or asthma should be informed to discuss their respiratory history and administration of pre-and post-study bronchodilator therapy with their clinician before scheduling an MPI study with Lexiscan.
- Alcohol-Regadenoson interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
- Lexiscan®
- N/A
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- ↑ "". External link in |title= (help) | Regadenoson
Gerald Chi
Regadenoson
a
vasodilator
radionuclide myocardial perfusion imaging in patients unable to undergo adequate exercise stress
angina, dysrhythmia, chest discomfort, chest pain, tachycardia, ventricular premature complex, nausea, dizziness, headache, dyspnea, and flushing
Title
ConditionName:
- Content
- Lexiscan® (regadenoson) injection is a pharmacologic stress agent indicated for radionuclide myocardial perfusion imaging (MPI) in patients unable to undergo adequate exercise stress.
- Dosing Information
- The recommended intravenous dose of Lexiscan is 5 mL (0.4 mg regadenoson).
- Administer Lexiscan as a rapid (approximately 10 seconds) injection into a peripheral vein using a 22 gauge or larger catheter or needle.
- Administer a 5 mL saline flush immediately after the injection of Lexiscan.
- Administer the radionuclide myocardial perfusion imaging agent 10–20 seconds after the saline flush. The radionuclide may be injected directly into the same catheter as Lexiscan.
- Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Lexiscan if it contains particulate matter or is discolored.
There is limited information regarding Off-Label Guideline-Supported Use of Regadenoson in adult patients.
There is limited information regarding Off-Label Non–Guideline-Supported Use of Regadenoson in adult patients.
- Safety and effectiveness in pediatric patients (< 18 years of age) have not been established.
There is limited information regarding Off-Label Guideline-Supported Use of Regadenoson in pediatric patients.
There is limited information regarding Off-Label Non–Guideline-Supported Use of Regadenoson in pediatric patients.
- Do not administer Lexiscan to patients with the following conditions (unless these patients have a functioning artificial pacemaker):
- Second- or third- degree AV block
- Sinus node dysfunction
- Myocardial Ischemia
- Fatal and nonfatal myocardial infarction, ventricular arrhythmias, and cardiac arrest have occurred following Lexiscan injection. Avoid use in patients with symptoms or signs of acute myocardial ischemia, for example unstable angina or cardiovascular instability; these patients may be at greater risk of serious cardiovascular reactions to Lexiscan. Cardiac resuscitation equipment and trained staff should be available before administering Lexiscan. If serious reactions to Lexiscan occur, consider the use of aminophylline, an adenosine antagonist, to shorten the duration of increased coronary blood flow induced by Lexiscan.
- Sinoatrial and Atrioventricular Nodal Block
- Adenosine receptor agonists, including Lexiscan, can depress the SA and AV nodes and may cause first-, second- or third-degree AV block, or sinus bradycardia requiring intervention. In clinical trials first-degree AV block (PR prolongation > 220 msec) developed in 3% of patients within 2 hours of Lexiscan administration; transient second-degree AV block with one dropped beat was observed in one patient receiving Lexiscan. In postmarketing experience, third degree heart block and asystole within minutes of Lexiscan administration have occurred.
- Hypersensitivity, Including Anaphylaxis
- Anaphylaxis, angioedema, cardiac or respiratory arrest, respiratory distress, decreased oxygen saturation, hypotension, throat tightness, urticaria and rashes have occurred. In clinical trials, hypersensitivity reactions were reported in fewer than 1 percent of patients. Have personnel and resuscitative equipment immediately available.
- Hypotension
- Adenosine receptor agonists, including Lexiscan, induce arterial vasodilation and hypotension. In clinical trials, decreased systolic blood pressure (> 35 mm Hg) was observed in 7% of patients and decreased diastolic blood pressure (> 25 mm Hg) was observed in 4% of patients within 45 min of Lexiscan administration. The risk of serious hypotension may be higher in patients with autonomic dysfunction, hypovolemia, left main coronary artery stenosis, stenotic valvular heart disease, pericarditis or pericardial effusions, or stenotic carotid artery disease with cerebrovascular insufficiency. In postmarketing experience, syncope, transient ischemic attacks and seizures have been observed.
- Hypertension
- Administration of adenosine receptor agonists, including Lexiscan, may result in clinically significant increases in blood pressure in some patients. Among patients who experienced an increase in blood pressure in clinical trials, the increase was observed within minutes of Lexiscan administration. Most increases resolved within 10 to 15 minutes, but in some cases, increases were observed at 45 minutes following administration. In post-marketing experience, cases of potentially clinically significant hypertension have been reported, particularly with underlying hypertension and when low-level exercise was included in the MPI.
- Bronchoconstriction
- Adenosine receptor agonists, including Lexiscan, may cause dyspnea, bronchoconstriction, and respiratory compromise. Appropriate bronchodilator therapy and resuscitative measures should be available prior to Lexiscan administration.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- During clinical development, 1,651 subjects were exposed to Lexiscan, with most receiving 0.4 mg as a rapid (≤ 10 seconds) intravenous injection. Most of these subjects received Lexiscan in two clinical studies that enrolled patients who had no history of bronchospastic lung disease as well as no history of a cardiac conduction block of greater than first-degree AV block, except for patients with functioning artificial pacemakers. In these studies (Studies 1 and 2), 2,015 patients underwent myocardial perfusion imaging after administration of Lexiscan (N = 1,337) or Adenoscan® (N = 678). The population was 26–93 years of age (median 66 years), 70% male and primarily Caucasian (76% Caucasian, 7% African American, 9% Hispanic, 5% Asian). Table 1 shows the most frequently reported adverse reactions.
- Overall, any adverse reaction occurred at similar rates between the study groups (80% for the Lexiscan group and 83% for the Adenoscan group). Aminophylline was used to treat the reactions in 3% of patients in the Lexiscan group and 2% of patients in the Adenoscan group. Most adverse reactions began soon after dosing, and generally resolved within approximately 15 minutes, except for headache which resolved in most patients within 30 minutes.
- ECG Abnormalities
- The frequency of rhythm or conduction abnormalities following Lexiscan or Adenoscan is shown in Table 2.
- Respiratory Abnormalities
- In a randomized, placebo-controlled trial (Study 3) of 999 subjects with asthma (n=532) or stable chronic obstructive pulmonary disease (n=467), the overall incidence of pre-specified respiratory adverse reactions was greater in the Lexiscan group compared to the placebo group (p < 0.001). Most respiratory adverse reactions resolved without therapy; a few subjects received aminophylline or a short acting bronchodilator. No differences were observed between treatment arms in the reduction of >15% from baseline at two-hours in FEV1 (Table 3).
- Renal Impairment
- In a randomized, placebo-controlled trial of 504 subjects (Lexiscan n=334 and placebo n=170) with a diagnosis or risk factors for coronary artery disease and NKFK/DOQI Stage III or IV renal impairment (defined as GFR 15-59 mL/min/1.73 m2), no serious adverse events were reported through the 24-hour follow-up period.
- Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Lexiscan exposure.
Myocardial infarction, cardiac arrest, ventricular arrhythmias, supraventricular tachyarrhythmias including atrial fibrillation or flutter, heart block (including third degree block), asystole, marked hypertension, symptomatic hypotension in association with transient ischemic attack, seizures and syncope have been reported. Some events required intervention with fluids and/or aminophylline. QTc prolongation shortly after Lexiscan administration has been reported.
Abdominal pain, occasionally severe, has been reported a few minutes after Lexiscan administration, in association with nausea, vomiting, or myalgias; administration of aminophylline, an adenosine antagonist, appeared to lessen the pain. Diarrhea and fecal incontinence have also been reported following Lexiscan administration.
Musculoskeletal pain has occurred, typically 10-20 minutes after Lexiscan administration; the pain was occasionally severe, localized in the arms and lower back and extended to the buttocks and lower legs bilaterally. Administration of aminophylline appeared to lessen the pain.
Tremor, seizure (particularly with a history of seizure)
Respiratory arrest, dyspnea and wheezing have been reported following Lexiscan administration.
Anaphylaxis, angioedema, cardiac or respiratory arrest, respiratory distress, decreased oxygen saturation, hypotension, throat tightness, urticaria, rashes have occurred and have required treatment including resuscitation.
- No formal pharmacokinetic drug interaction studies have been conducted with Lexiscan.
- Methylxanthines (e.g., caffeine and theophylline) are non-specific adenosine receptor antagonists that interfere with the vasodilation activity of Lexiscan. Patients should avoid consumption of any products containing methylxanthines as well as any drugs containing theophylline for at least 12 hours before Lexiscan administration. Aminophylline may be used to attenuate severe or persistent adverse reactions to Lexiscan.
- In clinical studies, Lexiscan was administered to patients taking other cardioactive drugs (i.e., β-blockers, calcium channel blockers, ACE inhibitors, nitrates, cardiac glycosides, and angiotensin receptor blockers) without reported adverse reactions or apparent effects on efficacy.
- Dipyridamole may change the effects of Lexiscan. When possible, withhold dipyridamole for at least two days prior to Lexiscan administration.
- Regadenoson does not inhibit the metabolism of substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 in human liver microsomes, indicating that it is unlikely to alter the pharmacokinetics of drugs metabolized by these cytochrome P450 enzymes.
- Pregnancy Category C
- There are no adequate well-controlled studies with Lexiscan in pregnant women. Lexiscan should be used during pregnancy only if the potential benefit to the patient justifies the potential risk to the fetus.
- Reproductive studies in rats showed that regadenoson doses 10 and 20 times the maximum recommended human dose (MRHD) based on body surface area, caused reduced fetal body weights and significant ossification delays in fore- and hind limb phalanges and metatarsals; however, maternal toxicity also occurred at these doses. Skeletal variations were increased in all treated groups. In rabbits, there were no Teratogenic effects in offspring at regadenoson doses 4 times the MRHD, although signs of maternal toxicity occurred at this dose. At regadenoson doses equivalent to 12 and 20 times the MRHD, maternal toxicity occurred along with increased embryo-fetal loss and fetal malformations. It is not clear whether malformations that occurred at maternally toxic doses of regadenoson in both animal species were due to fetal drug effects or only to the maternal toxic effects.
- Because animals received repeated doses of regadenoson, their exposure was significantly higher than that achieved with the standard single dose administered to humans.
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Regadenoson in women who are pregnant.
There is no FDA guidance on use of Regadenoson during labor and delivery.
- It is not known whether Lexiscan is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Lexiscan in nursing infants, the decision to interrupt nursing after administration of Lexiscan or not to administer Lexiscan, should take into account the importance of the drug to the mother. Based on the pharmacokinetics of Lexiscan, it should be cleared 10 hours after administration. Therefore, nursing women may consider interrupting nursing for 10 hours after administration.
- Safety and effectiveness in pediatric patients (< 18 years of age) have not been established.
- Of the 1,337 patients receiving Lexiscan in Studies 1 and 2, 56% were 65 years of age and over and 24% were 75 years of age and over. Older patients (> 75 years of age) had a similar adverse event profile compared to younger patients (< 65 years of age), but had a higher incidence of hypotension (2% vs. < 1%).
There is no FDA guidance on the use of Regadenoson with respect to specific gender populations.
There is no FDA guidance on the use of Regadenoson with respect to specific racial populations.
- Lexiscan was assessed in a randomized, placebo-controlled trial of patients with NKFK/DOQI Stage III or IV renal impairment (defined as a GFR 15-59 mL/min/1.73 m2). No serious adverse events were reported through the 24-hour follow-up period.
There is no FDA guidance on the use of Regadenoson in patients with hepatic impairment.
There is no FDA guidance on the use of Regadenoson in women of reproductive potentials and males.
There is no FDA guidance one the use of Regadenoson in patients who are immunocompromised.
- Intravenous
There is limited information regarding Monitoring of Regadenoson in the drug label.
There is limited information regarding IV Compatibility of Regadenoson in the drug label.
## Acute Overdose
### Signs and Symptoms
- Lexiscan overdosage may result in serious reactions. In a study of healthy volunteers, symptoms of flushing, dizziness and increased heart rate were assessed as intolerable at Lexiscan doses greater than 0.02 mg/kg.
### Management
- Aminophylline may be administered in doses ranging from 50 mg to 250 mg by slow intravenous injection (50 mg to 100 mg over 30–60 seconds) to attenuate severe and/or persistent adverse reactions to Lexiscan.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Regadenoson in the drug label.
- Regadenoson is a low affinity agonist (Ki ≈ 1.3 µM) for the A2A adenosine receptor, with at least 10-fold lower affinity for the A1 adenosine receptor (Ki > 16.5 µM), and weak, if any, affinity for the A2B and A3 adenosine receptors. Activation of the A2A adenosine receptor by regadenoson produces coronary vasodilation and increases coronary blood flow (CBF).
- Regadenoson is an A2A adenosine receptor agonist that is a coronary vasodilator. Regadenoson is chemically described as adenosine, 2-[4-[(methylamino)carbonyl]-1H-pyrazol-1-yl]-, monohydrate. Its structural formula is:
- The molecular formula for regadenoson is C15H18N8O5 • H2O and its molecular weight is 408.37.
- Lexiscan is a sterile, nonpyrogenic solution for intravenous injection. The solution is clear and colorless. Each 1 mL in the 5 mL pre-filled syringe contains 0.084 mg of regadenoson monohydrate, corresponding to 0.08 mg regadenoson on an anhydrous basis, 10.9 mg dibasic sodium phosphate dihydrate or 8.7 mg dibasic sodium phosphate anhydrous, 5.4 mg monobasic sodium phosphate monohydrate, 150 mg propylene glycol, 1 mg edetate disodium dihydrate, and Water for Injection, with pH between 6.3 and 7.7.
- Coronary Blood Flow
- Lexiscan causes a rapid increase in CBF which is sustained for a short duration. In patients undergoing coronary catheterization, pulsed-wave Doppler ultrasonography was used to measure the average peak velocity (APV) of coronary blood flow before and up to 30 minutes after administration of regadenoson (0.4 mg, intravenously). Mean APV increased to greater than twice baseline by 30 seconds and decreased to less than twice the baseline level within 10 minutes.
- Myocardial uptake of the radiopharmaceutical is proportional to CBF. Because Lexiscan increases blood flow in normal coronary arteries with little or no increase in stenotic arteries, Lexiscan causes relatively less uptake of the radiopharmaceutical in vascular territories supplied by stenotic arteries. MPI intensity after Lexiscan administration is therefore greater in areas perfused by normal relative to stenosed arteries.
- Effect of Aminophylline
- Aminophylline (100 mg, administered by slow iv injection over 60 seconds) injected 1 minute after 0.4 mg Lexiscan in subjects undergoing cardiac catheterization, was shown to shorten the duration of the coronary blood flow response to Lexiscan as measured by pulsed-wave Doppler ultrasonography.
- Effect of Caffeine
- Ingestion of caffeine decreases the ability to detect reversible ischemic defects. In a placebo-controlled, parallel group clinical study, patients with known or suspected myocardial ischemia received a baseline rest/stress MPI followed by a second stress MPI. Patients received caffeine or placebo 90 minutes before the second Lexiscan stress MPI. Following caffeine administration (200 or 400 mg), the mean number of reversible defects identified was reduced by approximately 60%. This decrease was statistically significant.
- Hemodynamic Effects
- In clinical studies, the majority of patients had an increase in heart rate and a decrease in blood pressure within 45 minutes after administration of Lexiscan. Maximum hemodynamic changes after Lexiscan and Adenoscan in Studies 1 and 2 are summarized in Table 4.
- Respiratory Effects
- The A2B and A3 adenosine receptors have been implicated in the pathophysiology of bronchoconstriction in susceptible individuals (i.e., asthmatics). In in vitro studies, regadenoson has not been shown to have appreciable binding affinity for the A2B and A3 adenosine receptors.
- In a randomized, placebo-controlled clinical trial (Study 3) of 999 subjects with a diagnosis, or risk factors for, coronary artery disease and concurrent asthma or COPD, the incidence of respiratory adverse reactions (dyspnea, wheezing) was greater with Lexiscan compared to placebo. Moderate (2.5%) or severe (<1%) respiratory reactions were observed more frequently in the Lexiscan group compared to placebo
- In healthy volunteers, the regadenoson plasma concentration-time profile is multi-exponential in nature and best characterized by 3-compartment model. The maximal plasma concentration of regadenoson is achieved within 1 to 4 minutes after injection of Lexiscan and parallels the onset of the pharmacodynamic response. The half-life of this initial phase is approximately 2 to 4 minutes. An intermediate phase follows, with a half-life on average of 30 minutes coinciding with loss of the pharmacodynamic effect. The terminal phase consists of a decline in plasma concentration with a half-life of approximately 2 hours. Within the dose range of 0.3–20 µg/kg in healthy subjects, clearance, terminal half-life or volume of distribution do not appear dependent upon the dose.
- A population pharmacokinetic analysis including data from subjects and patients demonstrated that regadenoson clearance decreases in parallel with a reduction in creatinine clearance and clearance increases with increased body weight. Age, gender, and race have minimal effects on the pharmacokinetics of regadenoson.
- Renally Impaired Patients
- The disposition of regadenoson was studied in 18 subjects with various degrees of renal function and in 6 healthy subjects. With increasing renal impairment, from mild (CLcr 50 to < 80 mL/min) to moderate (CLcr 30 to < 50 mL/min) to severe renal impairment (CLcr < 30 mL/min), the fraction of regadenoson excreted unchanged in urine and the renal clearance decreased, resulting in increased elimination half-lives and AUC values compared to healthy subjects (CLcr ≥ 80 mL/min). However, the maximum observed plasma concentrations as well as volumes of distribution estimates were similar across the groups. The plasma concentration-time profiles were not significantly altered in the early stages after dosing when most pharmacologic effects are observed. No dose adjustment is needed in patients with renal impairment.
- Patients with End Stage Renal Disease
- The pharmacokinetics of regadenoson in patients on dialysis has not been assessed.
- Hepatically Impaired Patients
- The influence of hepatic impairment on the pharmacokinetics of regadenoson has not been evaluated. Because greater than 55% of the dose is excreted in the urine as unchanged drug and factors that decrease clearance do not affect the plasma concentration in the early stages after dosing when clinically meaningful pharmacologic effects are observed, no dose adjustment is needed in patients with hepatic impairment.
- Geriatric Patients
- Based on a population pharmacokinetic analysis, age has a minor influence on the pharmacokinetics of regadenoson. No dose adjustment is needed in elderly patients.
- The metabolism of regadenoson is unknown in humans. Incubation with rat, dog, and human liver microsomes as well as human hepatocytes produced no detectable metabolites of regadenoson.
- In healthy volunteers, 57% of the regadenoson dose is excreted unchanged in the urine (range 19–77%), with an average plasma renal clearance around 450 mL/min, i.e., in excess of the glomerular filtration rate. This indicates that renal tubular secretion plays a role in regadenoson elimination.
- Carcinogenesis, Mutagenesis, Impairment of Fertility
- Regadenoson was negative in the Ames bacterial mutation assay, chromosomal aberration assay in Chinese hamster ovary (CHO) cells, and mouse bone marrow micronucleus assay.
- Long-term animal studies have not been conducted to evaluate Lexiscan's carcinogenic potential or potential effects on fertility.
- Animal Toxicology and/or Pharmacology
- Reproductive Toxicology Studies
- Reproduction studies were conducted in rabbits and rats using doses of Lexiscan that were 2 to 20 times (rats) and 4 to 20 times (rabbits) the maximum recommended human dose (MRHD), based on body surface area comparison.
- When administered to rabbits during organogenesis, regadenoson caused maternal toxicity including tachypnea, soft, liquid or scant feces, and localized alopecia in all treated groups, and caused reduction in body weight and feed consumption at 0.3 and 0.5 mg/kg/day (12 and 20 X MRHD, respectively). At regadenoson doses equivalent to 12 and 20 times the MRHD, maternal toxicity occurred along with decreased number of live fetuses, reduced fetal body weight, and occurrence of fetal variations and malformations. At regadenoson doses equivalent to 20 times the MRHD, resorptions were increased and fetal body weights reduced. Fetal malformations included microphthalmia (1/116 at 20 X MRHD), interrelated vertebrae/rib alterations (2/145 and 2/116 each at 12 and 20 X MRHD), and misaligned caudal vertebrae (3/145 at 12 X MRHD). Fetal toxicity was only observed at maternally toxic doses. The no effect dose level for fetal toxicity is 0.1 mg/kg (4 X MRHD). A no effect dose level was not identified for maternal toxicity.
- When regadenoson was administered to pregnant rats during the period of major organogenesis, 4/25 rats from the 1.0 mg/kg/day group (20 X MRHD) and 1/25 rats from the 0.8 mg/kg (16 X MRHD) group died immediately following the first dose of regadenoson. All dams had decreased motor activity and one was gasping post-dosing. At doses ≥ 0.5 mg/kg (10 X MRHD), maternal toxicity included decreased motor activity, increased limb extension, excess salivation, and reduction in body weight and feed consumption. At doses ≥ 0.5 mg/kg, fetal body weights were significantly reduced and significant ossification delays were observed in fore- and hind limb phalanges and metatarsals. Skeletal malformations included delayed ossification of the skull (1/167), and hemivertebra present at a thoracic vertebra (1/167), observed at 16-20 X MRHD, and small arches of a lumbar and sacral vertebrae (1/174) observed at 2 X MRHD. The no effect dose level for maternal toxicity is 0.1 mg/kg/day (2 X MRHD).
- Cardiomyopathy
- Minimal cardiomyopathy (myocyte necrosis and inflammation) was observed in rats following single dose administration of regadenoson. Increased incidence of minimal cardiomyopathy was observed on day 2 in males at doses of 0.08, 0.2 and 0.8 mg/kg (1/5, 2/5, and 5/5) and in females (2/5) at 0.8 mg/kg. In a separate study in male rats, the mean arterial pressure was decreased by 30 to 50% of baseline values for up to 90 minutes at regadenoson doses of 0.2 and 0.8 mg/kg, respectively. No cardiomyopathy was noted in rats sacrificed 15 days following single administration of regadenoson. The mechanism of the cardiomyopathy induced by regadenoson was not elucidated in this study but was associated with the hypotensive effects of regadenoson. Profound hypotension induced by vasoactive drugs is known to cause cardiomyopathy in rats.
- Local Irritation
- Intravenous administration of Lexiscan to rabbits resulted in perivascular hemorrhage, vein vasculitis, inflammation, thrombosis and necrosis, with inflammation and thrombosis persisting through day 8 (last observation day). Perivascular administration of Lexiscan to rabbits resulted in hemorrhage, inflammation, pustule formation and epidermal hyperplasia, which persisted through day 8 except for the hemorrhage which resolved. Subcutaneous administration of Lexiscan to rabbits resulted in hemorrhage, acute inflammation, and necrosis; on day 8 muscle fiber regeneration was observed.
- The efficacy and safety of Lexiscan were determined relative to Adenoscan in two randomized, double-blind studies (Studies 1 and 2) in 2,015 patients with known or suspected coronary artery disease who were indicated for pharmacologic stress MPI. A total of 1,871 of these patients had images considered valid for the primary efficacy evaluation, including 1,294 (69%) men and 577 (31%) women with a median age of 66 years (range 26–93 years of age). Each patient received an initial stress scan using Adenoscan (6-minute infusion using a dose of 0.14 mg/kg/min, without exercise) with a radionuclide gated SPECT imaging protocol. After the initial scan, patients were randomized to either Lexiscan or Adenoscan, and received a second stress scan with the same radionuclide imaging protocol as that used for the initial scan. The median time between scans was 7 days (range of 1–104 days).
- The most common cardiovascular histories included hypertension (81%), CABG, PTCA or stenting (51%), angina (63%), and history of myocardial infarction (41%) or arrhythmia (33%); other medical history included diabetes (32%) and COPD (5%). Patients with a recent history of serious uncontrolled ventricular arrhythmia, myocardial infarction, or unstable angina, a history of greater than first-degree AV block, or with symptomatic bradycardia, sick sinus syndrome, or a heart transplant were excluded. A number of patients took cardioactive medications on the day of the scan, including β-blockers (18%), calcium channel blockers (9%), and nitrates (6%). In the pooled study population, 68% of patients had 0–1 segments showing reversible defects on the initial scan, 24% had 2–4 segments, and 9% had ≥ 5 segments.
- Comparison of the images obtained with Lexiscan to those obtained with Adenoscan was performed as follows. Using the 17-segment model, the number of segments showing a reversible perfusion defect was calculated for the initial Adenoscan study and for the randomized study obtained using Lexiscan or Adenoscan. The agreement rate for the image obtained with Lexiscan or Adenoscan relative to the initial Adenoscan image was calculated by determining how frequently the patients assigned to each initial Adenoscan category (0–1, 2–4, 5–17 reversible segments) were placed in the same category with the randomized scan. The agreement rates for Lexiscan and Adenoscan were calculated as the average of the agreement rates across the three categories determined by the initial scan. Studies 1 and 2 each demonstrated that Lexiscan is similar to Adenoscan in assessing the extent of reversible perfusion abnormalities (Table 5).
- Lexiscan is supplied as a sterile, preservative-free solution containing 0.08 mg/mL regadenoson in the following package:
- Single-use 5 mL pre-filled plastic Ansyr® syringes with luer-lock fitting (NDC 0469-6501-89).
- Store at controlled room temperature, 25°C (77°F); excursions permitted to 15° to 30°C (59°–86°F).
- Methylxanthine Consumption
- Patients should be instructed to avoid consumption of any products containing methylxanthines, including caffeinated coffee, tea or other caffeinated beverages, caffeine-containing drug products, and theophylline for at least 12 hours before a scheduled radionuclide MPI.
- Common Reactions
- Prior to Lexiscan administration, patients should be informed of the most common reactions (such as shortness of breath, headache and flushing) that have been reported in association with Lexiscan during MPI.
- Patients with COPD or Asthma
- Patients with COPD or asthma should be informed to discuss their respiratory history and administration of pre-and post-study bronchodilator therapy with their clinician before scheduling an MPI study with Lexiscan.
- Alcohol-Regadenoson interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
- Lexiscan®[1]
- N/A[2]
- ↑ "LEXISCAN (regadenoson) injection, solution"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ "http://www.ismp.org". External link in |title= (help) | https://www.wikidoc.org/index.php/Regadenoson | |
d27467359c7ca87738f3c707f9494da396553d05 | wikidoc | Regorafenib | Regorafenib
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# Black Box Warning
# Overview
Regorafenib is an antineoplastic that is FDA approved for the treatment of colorectal cancer, gastrointestinal stromal tumors. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, mucositis, dysphonia, infection, pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Regorafenib® is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.
- Regorafenib is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.
- The recommended dose is 160 mg regorafenib (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity.
- Take Regorafenib at the same time each day. Swallow tablet whole with a low-fat breakfast that contains less than 30% fat. Examples of a low-fat breakfast include 2 slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly, and 8 ounces of skim milk (319 calories and 8.2 g fat); or 1 cup of cereal, 8 ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 calories and 2 g fat). Do not take two doses of Regorafenib on the same day to make up for a missed dose from the previous day.
- Interrupt Regorafenib for the following
- NCI CTCAE Grade 2 hand-foot skin reaction (HFSR) that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR
- Any NCI CTCAE Grade 3 or 4 adverse reaction
- Reduce the dose of Regorafenib to 120 mg:
- For the first occurrence of Grade 2 HFSR of any duration
- After recovery of any Grade 3 or 4 adverse reaction
- For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity
- Reduce the dose of Regorafenib to 80 mg
- For re-occurrence of Grade 2 HFSR at the 120 mg dose
- After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity)
- Discontinue Regorafenib permanently for the following
- Failure to tolerate 80 mg dose
- Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)
- Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN
- Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg
- For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Regorafenib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Regorafenib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Regorafenib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Regorafenib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Regorafenib in pediatric patients.
# Contraindications
There is limited information regarding Regorafenib Contraindications in the drug label.
# Warnings
- Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1200 Regorafenib-treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. In Study 2, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm.
- Obtain liver function tests (ALT, AST and bilirubin) before initiation of Regorafenib and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline.
- Temporarily hold and then reduce or permanently discontinue Regorafenib depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.
- Regorafenib caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% in Regorafenib-treated patients compared to 8% and 3% in placebo-treated patients in Studies 1 and 2. Fatal hemorrhage occurred in 4 of 632 (0.6%) of Regorafenib-treated patients in Studies 1 and 2 and involved the respiratory, gastrointestinal, or genitourinary tracts.
- Permanently discontinue Regorafenib in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin.
- Regorafenib caused increased incidences of adverse reactions involving the skin and subcutaneous tissues (72% versus 24% in Study 1 and 78% versus 24% in Study 2), including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE), and severe rash requiring dose modification.
- The overall incidence of HFSR was higher in Regorafenib-treated patients, (45% versus 7% in Study 1 and 67% versus 12% in Study 2), than in the placebo-treated patients. Most cases of HFSR in Regorafenib-treated patients appeared during the first cycle of treatment (69% and 71% of patients who developed HFSR in Study 1 and Study 2, respectively). The incidence of Grade 3 HFSR (17% versus 0% in Study 1 and 22% versus 0% in Study 2), Grade 3 rash (6% versus <1% in Study 1 and 7% versus 0% in Study 2), serious adverse reactions of erythema multiforme (0.2% vs. 0% in Study 1) and Stevens Johnson Syndrome (0.2% vs. 0% in Study 1) was higher in Regorafenib-treated patients.
- Toxic epidermal necrolysis occurred in 0.17% of 1200 Regorafenib-treated patients across all clinical trials.
- Withhold Regorafenib, reduce the dose, or permanently discontinue Regorafenib depending on the severity and persistence of dermatologic toxicity. Institute supportive measures for symptomatic relief.
- Regorafenib caused an increased incidence of hypertension (30% versus 8% in Study 1 and 59% versus 27% in Study 2). Hypertensive crisis occurred in 0.25% of 1200 Regorafenib-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (72% in Study 1 and Study 2).
- Do not initiate Regorafenib unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold Regorafenib for severe or uncontrolled hypertension.
- Regorafenib increased the incidence of myocardial ischemia and infarction in Study 1 (1.2% versus 0.4%). Withhold Regorafenib in patients who develop new or acute onset cardiac ischemia or infarction. Resume Regorafenib only after resolution of acute cardiac ischemic events, if the potential benefits outweigh the risks of further cardiac ischemia.
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 1200 Regorafenib-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Regorafenib in patients who develop RPLS.
- Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with Regorafenib across all clinical trials; this included four fatal events. In Study 2, 2.1% (4/188) of Regorafenib-treated patients who were treated during the blinded or open-label portion of the study developed gastrointestinal fistula or perforation; of these, two cases of gastrointestinal perforation were fatal. Permanently discontinue Regorafenib in patients who develop gastrointestinal perforation or fistula.
- No formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as regorafenib can impair wound healing, treatment with regorafenib should be stopped at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on clinical judgment of adequate wound healing. Regorafenib should be discontinued in patients with wound dehiscence.
- Regorafenib can cause fetal harm when administered to a pregnant woman. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are discussed elsewhere in the labeling:
- Hepatotoxicity
- Hemorrhage
- Dermatological Toxicity
- Hypertension
- Cardiac Ischemia and Infarction
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
- Gastrointestinal Perforation or Fistula
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.
- The most frequently observed adverse drug reactions (≥20%) in patients receiving Regorafenib are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea.
- The most serious adverse drug reactions in patients receiving Regorafenib are hepatotoxicity, hemorrhage, and gastrointestinal perforation.
- The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer received Regorafenib as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 7.3 (range 0.3, 47.0) weeks for patients receiving Regorafenib. Due to adverse reactions, 61% of the patients receiving Regorafenib required a dose interruption and 38% of the patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 8.2% of Regorafenib-treated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of Regorafenib.
- TABLE 1 compares the incidence of adverse reactions (≥10%) in patients receiving Regorafenib and reported more commonly than in patients receiving placebo (Study 1).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Regorafenib in the drug label.
# Drug Interactions
- Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Regorafenib decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of Regorafenib with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort).
- Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Regorafenib increased the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of Regorafenib with strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on its mechanism of action, Regorafenib can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Regorafenib in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC).
- In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. In a repeat dose study with daily administration of regorafenib to pregnant rats during organogenesis, findings included delayed ossification in fetuses at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) with dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis.
- In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Regorafenib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Regorafenib during labor and delivery.
### Nursing Mothers
- It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Regorafenib, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of Regorafenib in pediatric patients less than 18 years of age have not been established.
- In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings were observed at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose).
- Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate.
### Geriatic Use
- Of the 632 Regorafenib-treated patients enrolled in Studies 1 and 2, 37% were 65 years of age or and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.
### Gender
There is no FDA guidance on the use of Regorafenib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Regorafenib with respect to specific racial populations.
### Renal Impairment
- No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days. No dose adjustment is recommended for patients with mild renal impairment.
- Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). Regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease.
### Hepatic Impairment
- No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic functions.
- No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions.
- Regorafenib is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C), as it has not been studied in this population.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Regorafenib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Regorafenib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Regorafenib in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Regorafenib in the drug label.
# Overdosage
- The highest dose of Regorafenib studied clinically is 220 mg per day. In the event of suspected overdose, interrupt Regorafenib, institute supportive care, and observe until clinical stabilization.
# Pharmacology
## Mechanism of Action
- Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically.
- In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.
## Structure
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Regorafenib in the drug label.
## Pharmacokinetics
- Following a single 160 mg dose of Regorafenib in patients with advanced solid tumors, regorafenib reaches a geometric mean peak plasma level (Cmax) of 2.5 µg/mL at a median time of 4 hours and a geometric mean area under the plasma concentration vs. time curve (AUC) of 70.4 µg*h/mL. The AUC of regorafenib at steady-state increases less than dose proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean Cmax of 3.9 µg/mL and a geometric mean AUC of 58.3 µg*h/mL. The coefficient of variation of AUC and Cmax is between 35% and 44%.
- The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.
- In a food-effect study, 24 healthy men received a single 160 mg dose of Regorafenib on three separate occasions: under a fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%, respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions. Regorafenib was administered with a low-fat meal in Studies 1 and 2.
- Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins.
- Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively).
- Following a single 160 mg oral dose of Regorafenib, the geometric mean (range) elimination half-lives for regorafenib and the M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer mean (range) elimination half-life of 51 hours (32 to 70 hours).
- Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.
- Based on the population pharmacokinetic analysis, there is no clinically relevant effect of age, gender or weight on the pharmacokinetics of regorafenib.
- The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 14 patients with hepatocellular carcinoma (HCC) and mild hepatic impairment (Child-Pugh A); 4 patients with HCC and moderate hepatic impairment (Child-Pugh B); and 10 patients with solid tumors and normal hepatic function after the administration of a single 100 mg dose of Regorafenib. No clinically important differences in the mean exposure of regorafenib, M-2, or M-5 were observed in patients with mild or moderate hepatic impairment compared to the patients with normal hepatic function. The pharmacokinetics of regorafenib has not been studied in patients with severe hepatic impairment (Child-Pugh C).
- The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 10 patients with mild renal impairment (CLcr 60-89 mL/min) and 18 patients with normal renal function following the administration of Regorafenib at a dose of 160 mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in patients with mild renal impairment compared to patients with normal renal function. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). The pharmacokinetics of regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease.
- Effect of Regorafenib on Cytochrome P450 Substrates
- In vitro studies suggested that regorafenib is an inhibitor of CYP2C8, CYP2C9, CYP2B6, CYP3A4 and CYP2C19; M-2 metabolite is an inhibitor of CYP2C9, CYP2C8, CYP3A4 and CYP2D6, and M-5 metabolite is an inhibitor of CYP2C8. In vitro studies suggested that regorafenib is not an inducer of CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.
- Patients with advanced solid tumors received single oral doses of CYP substrates, 2 mg of midazolam (CYP3A4), 40 mg of omeprazole (CYP2C19) and 10 mg of warfarin (CYP2C9) or 4 mg of rosiglitazone (CYP2C8) one week before and two weeks after Regorafenib at a dose of 160 mg once daily. No clinically relevant change was observed in the mean AUC of rosiglitazone (N=12) or the mean omeprazole (N=11) plasma concentrations measured 6 hours after dosing or the mean AUC of midazolam (N=15). The mean AUC of warfarin (N=8) increased by 25%.
- Effect of CYP3A4 Strong Inducers on Regorafenib: Twenty-two healthy men received a single 160 mg dose of Regorafenib alone and then 7 days after starting rifampin. Rifampin, a strong CYP3A4 inducer, was administered at a dose of 600 mg daily for 9 days. The mean AUC of regorafenib decreased by 50% and mean AUC of M-5 increased by 264%. No change in the mean AUC of M-2 was observed.
- Effect of CYP3A4 Strong Inhibitors on Regorafenib: Eighteen healthy men received a single 160 mg dose of Regorafenib alone and then 5 days after starting ketoconazole. Ketoconazole, a strong CYP3A4 inhibitor, was administered at a dose of 400 mg daily for 18 days. The mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93%.
- Effect of Regorafenib on UGT1A1 Substrates: In vitro studies showed that regorafenib, M-2, and M-5 competitively inhibit UGT1A9 and UGT1A1 at therapeutically relevant concentrations. Eleven patients received irinotecan-containing combination chemotherapy with Regorafenib at a dose of 160 mg. The mean AUC of irinotecan increased 28% and the mean AUC of SN-38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of Regorafenib.
- In vitro screening of transporters: In vitro data suggested that regorafenib is an inhibitor of ABCG2 (Breast Cancer Resistance Protein) and ABCB1 (P-glycoprotein).
- The effect of multiple doses of Regorafenib (160 mg once daily for 21 days) on the QTc interval was evaluated in an open label, single arm study in 25 patients with advanced solid tumors. No large changes in the mean QTc interval (i.e., > 20 msec) were detected in the study.
## Nonclinical Toxicology
- Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity in in vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells.
- Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans.
- In a chronic 26-week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure.
# Clinical Studies
- The clinical efficacy and safety of Regorafenib were evaluated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 1) in 760 patients with previously-treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS); supportive efficacy outcome measures included progression-free survival (PFS) and objective tumor response rate.
- Patients were randomized to receive 160 mg regorafenib orally once daily (N=505) plus Best Supportive Care (BSC) or placebo (N=255) plus BSC for the first 21 days of each 28-day cycle. Regorafenib was administered with a low-fat breakfast that contains less than 30% fat. Treatment continued until disease progression or unacceptable toxicity.
- In the all-randomized population, median age was 61 years, 61% were men, 78% were White, and all patients had baseline ECOG performance status of 0 or 1. The primary site of disease was colon (65%), rectum (29%), or both (6%). History of KRAS evaluation was reported for 729 (96%) patients; 430 (59%) of these patients were reported to have KRAS mutation. The median number of prior lines of therapy for metastatic disease was 3. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and with bevacizumab. All but one patient with KRAS mutation-negative tumors received panitumumab or cetuximab.
- The efficacy and safety of Regorafenib were evaluated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 2) in 199 patients with unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST), who had been previously treated with imatinib mesylate and sunitinib malate. Randomization was stratified by line of therapy (third vs. four or more) and geographic region (Asia vs. rest of the world).
- The major efficacy outcome measure of Study 2 was progression-free survival (PFS) based on disease assessment by independent radiological review using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodule within a pre-existing tumor mass was progression. The key secondary outcome measure was overall survival.
- Patients were randomized to receive 160 mg regorafenib orally once daily (N=133) plus best supportive care (BSC) or placebo (N=66) plus BSC for the first 21 days of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. In Study 2, the median age of patients was 60 years, 64% were men, 68% were White, and all patients had baseline ECOG performance status of 0 (55%) or 1 (45%). At the time of disease progression as assessed by central review, the study blind was broken and all patients were offered the opportunity to take Regorafenib at the investigator’s discretion. Fifty-six (85%) patients randomized to placebo and 41 (31%) patients randomized to Regorafenib received open-label Regorafenib.
- A statistically significant improvement in PFS was demonstrated among patients treated with Regorafenib compared to placebo (see Table 6 and Figure 2). There was no statistically significant difference in overall survival at the time of the planned interim analysis based on 29% of the total events for the final analysis.
# How Supplied
- Regorafenib tablets are supplied in packages containing three bottles, with each bottle containing 28 tablets, for a total of 84 tablets per package (NDC 50419-171-03).
## Storage
- Store Regorafenib at 25°C (77°F); excursions are permitted from 15 to 30°C (59 to 86°F).
- Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening.
- Discard any unused tablets 7 weeks after opening the bottle.Dispose of unused tablets in accordance with local requirements.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- See FDA-Approved Patient Labeling (Patient Information).
- Inform your patients of the following:
- Regorafenib may cause severe or life-threatening liver damage. Inform patients that they will need to undergo monitoring for liver damage and to immediately report any signs or symptoms of severe liver damage to their health care provider.
- Regorafenib can cause severe bleeding. Advise patients to contact their health care provider for any episode of bleeding.
- Regorafenib can cause hand-foot skin reactions or rash elsewhere. Advise patients to contact their health care provider if they experience skin changes associated with redness, pain, blisters, bleeding, or swelling.
- Regorafenib can cause or exacerbate existing hypertension. Advise patients they will need to undergo blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.
- Regorafenib increased the risk for myocardial ischemia and infarction. Advise patients to seek immediate emergency help if they experience chest pain, shortness of breath, or feel dizzy or like passing out.
Contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting, severe diarrhea (frequent or loose bowel movements), or dehydration.
- Regorafenib may complicate wound healing. Advise patients to inform their health care provider if they plan to undergo a surgical procedure or had recent surgery.
- Inform patients that regorafenib can cause fetal harm. Advise women of reproductive potential and men of the need for effective contraception during Regorafenib treatment and for up to 2 months after completion of treatment. Instruct women of reproductive potential to immediately contact her health care provider if pregnancy is suspected or confirmed during or within 2 months of completing treatment with Regorafenib.
- Advise nursing mothers that it is not known whether regorafenib is present in breast milk and discuss whether to discontinue nursing or to discontinue regorafenib.
- Inform patients to take any missed dose on the same day, as soon as they remember, and that they must not take two doses on the same day to make up for a dose missed on the previous day.
- Inform patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes . Any remaining tablets should be discarded 7 weeks after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle.
# Precautions with Alcohol
- Alcohol-Regorafenib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Regorafenib ®
# Look-Alike Drug Names
There is limited information regarding Regorafenib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Regorafenib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
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# Black Box Warning
# Overview
Regorafenib is an antineoplastic that is FDA approved for the treatment of colorectal cancer, gastrointestinal stromal tumors. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, mucositis, dysphonia, infection, pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Regorafenib® is indicated for the treatment of patients with metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy.
- Regorafenib is indicated for the treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.
- The recommended dose is 160 mg regorafenib (four 40 mg tablets) taken orally once daily for the first 21 days of each 28-day cycle. Continue treatment until disease progression or unacceptable toxicity.
- Take Regorafenib at the same time each day. Swallow tablet whole with a low-fat breakfast that contains less than 30% fat. Examples of a low-fat breakfast include 2 slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of jelly, and 8 ounces of skim milk (319 calories and 8.2 g fat); or 1 cup of cereal, 8 ounces of skim milk, 1 slice of toast with jam, apple juice, and 1 cup of coffee or tea (520 calories and 2 g fat). Do not take two doses of Regorafenib on the same day to make up for a missed dose from the previous day.
- Interrupt Regorafenib for the following
- NCI CTCAE Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia (PPE)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR
- Any NCI CTCAE Grade 3 or 4 adverse reaction
- Reduce the dose of Regorafenib to 120 mg:
- For the first occurrence of Grade 2 HFSR of any duration
- After recovery of any Grade 3 or 4 adverse reaction
- For Grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation; only resume if the potential benefit outweighs the risk of hepatotoxicity
- Reduce the dose of Regorafenib to 80 mg
- For re-occurrence of Grade 2 HFSR at the 120 mg dose
- After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except hepatotoxicity)
- Discontinue Regorafenib permanently for the following
- Failure to tolerate 80 mg dose
- Any occurrence of AST or ALT more than 20 times the upper limit of normal (ULN)
- Any occurrence of AST or ALT more than 3 times ULN with concurrent bilirubin more than 2 times ULN
- Re-occurrence of AST or ALT more than 5 times ULN despite dose reduction to 120 mg
- For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Regorafenib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Regorafenib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Regorafenib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Regorafenib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Regorafenib in pediatric patients.
# Contraindications
There is limited information regarding Regorafenib Contraindications in the drug label.
# Warnings
- Severe drug induced liver injury with fatal outcome occurred in 0.3% of 1200 Regorafenib-treated patients across all clinical trials. Liver biopsy results, when available, showed hepatocyte necrosis with lymphocyte infiltration. In Study 1, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 0.4% of patients in the placebo arm; all the patients with hepatic failure had metastatic disease in the liver. In Study 2, fatal hepatic failure occurred in 0.8% of patients in the regorafenib arm.
- Obtain liver function tests (ALT, AST and bilirubin) before initiation of Regorafenib and monitor at least every two weeks during the first 2 months of treatment. Thereafter, monitor monthly or more frequently as clinically indicated. Monitor liver function tests weekly in patients experiencing elevated liver function tests until improvement to less than 3 times the ULN or baseline.
- Temporarily hold and then reduce or permanently discontinue Regorafenib depending on the severity and persistence of hepatotoxicity as manifested by elevated liver function tests or hepatocellular necrosis.
- Regorafenib caused an increased incidence of hemorrhage. The overall incidence (Grades 1-5) was 21% and 11% in Regorafenib-treated patients compared to 8% and 3% in placebo-treated patients in Studies 1 and 2. Fatal hemorrhage occurred in 4 of 632 (0.6%) of Regorafenib-treated patients in Studies 1 and 2 and involved the respiratory, gastrointestinal, or genitourinary tracts.
- Permanently discontinue Regorafenib in patients with severe or life-threatening hemorrhage. Monitor INR levels more frequently in patients receiving warfarin.
- Regorafenib caused increased incidences of adverse reactions involving the skin and subcutaneous tissues (72% versus 24% in Study 1 and 78% versus 24% in Study 2), including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia (PPE), and severe rash requiring dose modification.
- The overall incidence of HFSR was higher in Regorafenib-treated patients, (45% versus 7% in Study 1 and 67% versus 12% in Study 2), than in the placebo-treated patients. Most cases of HFSR in Regorafenib-treated patients appeared during the first cycle of treatment (69% and 71% of patients who developed HFSR in Study 1 and Study 2, respectively). The incidence of Grade 3 HFSR (17% versus 0% in Study 1 and 22% versus 0% in Study 2), Grade 3 rash (6% versus <1% in Study 1 and 7% versus 0% in Study 2), serious adverse reactions of erythema multiforme (0.2% vs. 0% in Study 1) and Stevens Johnson Syndrome (0.2% vs. 0% in Study 1) was higher in Regorafenib-treated patients.
- Toxic epidermal necrolysis occurred in 0.17% of 1200 Regorafenib-treated patients across all clinical trials.
- Withhold Regorafenib, reduce the dose, or permanently discontinue Regorafenib depending on the severity and persistence of dermatologic toxicity. Institute supportive measures for symptomatic relief.
- Regorafenib caused an increased incidence of hypertension (30% versus 8% in Study 1 and 59% versus 27% in Study 2). Hypertensive crisis occurred in 0.25% of 1200 Regorafenib-treated patients across all clinical trials. The onset of hypertension occurred during the first cycle of treatment in most patients who developed hypertension (72% in Study 1 and Study 2).
- Do not initiate Regorafenib unless blood pressure is adequately controlled. Monitor blood pressure weekly for the first 6 weeks of treatment and then every cycle, or more frequently, as clinically indicated. Temporarily or permanently withhold Regorafenib for severe or uncontrolled hypertension.
- Regorafenib increased the incidence of myocardial ischemia and infarction in Study 1 (1.2% versus 0.4%). Withhold Regorafenib in patients who develop new or acute onset cardiac ischemia or infarction. Resume Regorafenib only after resolution of acute cardiac ischemic events, if the potential benefits outweigh the risks of further cardiac ischemia.
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one of 1200 Regorafenib-treated patients across all clinical trials. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue Regorafenib in patients who develop RPLS.
- Gastrointestinal perforation or fistula occurred in 0.6% of 1200 patients treated with Regorafenib across all clinical trials; this included four fatal events. In Study 2, 2.1% (4/188) of Regorafenib-treated patients who were treated during the blinded or open-label portion of the study developed gastrointestinal fistula or perforation; of these, two cases of gastrointestinal perforation were fatal. Permanently discontinue Regorafenib in patients who develop gastrointestinal perforation or fistula.
- No formal studies of the effect of regorafenib on wound healing have been conducted. Since vascular endothelial growth factor receptor (VEGFR) inhibitors such as regorafenib can impair wound healing, treatment with regorafenib should be stopped at least 2 weeks prior to scheduled surgery. The decision to resume regorafenib after surgery should be based on clinical judgment of adequate wound healing. Regorafenib should be discontinued in patients with wound dehiscence.
- Regorafenib can cause fetal harm when administered to a pregnant woman. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions are discussed elsewhere in the labeling:
- Hepatotoxicity
- Hemorrhage
- Dermatological Toxicity
- Hypertension
- Cardiac Ischemia and Infarction
- Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
- Gastrointestinal Perforation or Fistula
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in practice.
- The most frequently observed adverse drug reactions (≥20%) in patients receiving Regorafenib are asthenia/fatigue, HFSR, diarrhea, decreased appetite/food intake, hypertension, mucositis, dysphonia, infection, pain (not otherwise specified), decreased weight, gastrointestinal and abdominal pain, rash, fever, and nausea.
- The most serious adverse drug reactions in patients receiving Regorafenib are hepatotoxicity, hemorrhage, and gastrointestinal perforation.
- The safety data described below, except where noted, are derived from a randomized (2:1), double-blind, placebo-controlled trial (Study 1) in which 500 patients (median age 61 years; 61% men) with previously-treated metastatic colorectal cancer received Regorafenib as a single agent at the dose of 160 mg daily for the first 3 weeks of each 4 week treatment cycle and 253 patients (median age 61 years; 60% men) received placebo. The median duration of therapy was 7.3 (range 0.3, 47.0) weeks for patients receiving Regorafenib. Due to adverse reactions, 61% of the patients receiving Regorafenib required a dose interruption and 38% of the patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 8.2% of Regorafenib-treated patients compared to 1.2% of patients who received placebo. Hand-foot skin reaction (HFSR) and rash were the most common reasons for permanent discontinuation of Regorafenib.
- TABLE 1 compares the incidence of adverse reactions (≥10%) in patients receiving Regorafenib and reported more commonly than in patients receiving placebo (Study 1).
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Regorafenib in the drug label.
# Drug Interactions
- Co-administration of a strong CYP3A4 inducer (rifampin) with a single 160 mg dose of Regorafenib decreased the mean exposure of regorafenib, increased the mean exposure of the active metabolite M-5, and resulted in no change in the mean exposure of the active metabolite M-2. Avoid concomitant use of Regorafenib with strong CYP3A4 inducers (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort).
- Co-administration of a strong CYP3A4 inhibitor (ketoconazole) with a single 160 mg dose of Regorafenib increased the mean exposure of regorafenib and decreased the mean exposure of the active metabolites M-2 and M-5. Avoid concomitant use of Regorafenib with strong inhibitors of CYP3A4 activity (e.g. clarithromycin, grapefruit juice, itraconazole, ketoconazole, nefazodone, posaconazole, telithromycin, and voriconazole).
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on its mechanism of action, Regorafenib can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies with Regorafenib in pregnant women. Regorafenib was embryolethal and teratogenic in rats and rabbits at exposures lower than human exposures at the recommended dose, with increased incidences of cardiovascular, genitourinary, and skeletal malformations. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- In embryo-fetal development studies, a total loss of pregnancy (100% resorption of litter) was observed in rats at doses as low as 1 mg/kg (approximately 6% of the recommended human dose, based on body surface area) and in rabbits at doses as low as 1.6 mg/kg (approximately 25% of the human exposure at the clinically recommended dose measured by AUC).
- In a single dose distribution study in pregnant rats, there was increased penetration of regorafenib across the blood-brain barrier in fetuses compared to dams. In a repeat dose study with daily administration of regorafenib to pregnant rats during organogenesis, findings included delayed ossification in fetuses at doses > 0.8 mg/kg (approximately 5% of the recommended human dose based on body surface area) with dose-dependent increases in skeletal malformations including cleft palate and enlarged fontanelle at doses ≥ 1 mg/kg (approximately 10% of the clinical exposure based on AUC). At doses ≥ 1.6 mg/kg (approximately 11% of the recommended human dose based on body surface area), there were dose-dependent increases in the incidence of cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis.
- In pregnant rabbits administered regorafenib daily during organogenesis, there were findings of ventricular septal defects evident at the lowest tested dose of 0.4 mg/kg (approximately 7% of the AUC in patients at the recommended dose). At doses of ≥ 0.8 mg/kg (approximately 15% of the human exposure at the recommended human dose based on AUC), administration of regorafenib resulted in dose-dependent increases in the incidence of additional cardiovascular malformations and skeletal anomalies as well as significant adverse effects on the urinary system including missing kidney/ureter; small, deformed and malpositioned kidney; and hydronephrosis. The proportion of viable fetuses that were male decreased with increasing dose in two rabbit embryo-fetal toxicity studies.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Regorafenib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Regorafenib during labor and delivery.
### Nursing Mothers
- It is unknown whether regorafenib or its metabolites are excreted in human milk. In rats, regorafenib and its metabolites are excreted in milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Regorafenib, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and efficacy of Regorafenib in pediatric patients less than 18 years of age have not been established.
- In 28-day repeat dose studies in rats there were dose-dependent findings of dentin alteration and angiectasis. These findings were observed at regorafenib doses as low as 4 mg/kg (approximately 25% of the AUC in humans at the recommended dose). In 13-week repeat dose studies in dogs there were similar findings of dentin alteration at doses as low as 20 mg/kg (approximately 43% of the AUC in humans at the recommended dose).
- Administration of regorafenib in these animals also led to persistent growth and thickening of the femoral epiphyseal growth plate.
### Geriatic Use
- Of the 632 Regorafenib-treated patients enrolled in Studies 1 and 2, 37% were 65 years of age or and over, while 8% were 75 and over. No overall differences in safety or efficacy were observed between these patients and younger patients.
### Gender
There is no FDA guidance on the use of Regorafenib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Regorafenib with respect to specific racial populations.
### Renal Impairment
- No clinically relevant differences in the mean exposure of regorafenib and the active metabolites M-2 and M-5 were observed in patients with mild renal impairment (CLcr 60-89 mL/min) compared to patients with normal renal function following regorafenib 160 mg daily for 21 days. No dose adjustment is recommended for patients with mild renal impairment.
- Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). Regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease.
### Hepatic Impairment
- No clinically important differences in the mean exposure of regorafenib or the active metabolites M-2 and M-5 were observed in patients with hepatocellular carcinoma and mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment compared to patients with normal hepatic functions.
- No dose adjustment is recommended in patients with mild or moderate hepatic impairment. Closely monitor patients with hepatic impairment for adverse reactions.
- Regorafenib is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C), as it has not been studied in this population.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Regorafenib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Regorafenib in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Regorafenib in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Regorafenib in the drug label.
# Overdosage
- The highest dose of Regorafenib studied clinically is 220 mg per day. In the event of suspected overdose, interrupt Regorafenib, institute supportive care, and observe until clinical stabilization.
# Pharmacology
## Mechanism of Action
- Regorafenib is a small molecule inhibitor of multiple membrane-bound and intracellular kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, tumor angiogenesis, and maintenance of the tumor microenvironment. In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites M-2 and M-5 inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, TrkA, Eph2A, RAF-1, BRAF, BRAFV600E , SAPK2, PTK5, and Abl at concentrations of regorafenib that have been achieved clinically.
- In in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and inhibition of tumor growth as well as anti-metastatic activity in several mouse xenograft models including some for human colorectal carcinoma.
## Structure
-
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Regorafenib in the drug label.
## Pharmacokinetics
- Following a single 160 mg dose of Regorafenib in patients with advanced solid tumors, regorafenib reaches a geometric mean peak plasma level (Cmax) of 2.5 µg/mL at a median time of 4 hours and a geometric mean area under the plasma concentration vs. time curve (AUC) of 70.4 µg*h/mL. The AUC of regorafenib at steady-state increases less than dose proportionally at doses greater than 60 mg. At steady-state, regorafenib reaches a geometric mean Cmax of 3.9 µg/mL and a geometric mean AUC of 58.3 µg*h/mL. The coefficient of variation of AUC and Cmax is between 35% and 44%.
- The mean relative bioavailability of tablets compared to an oral solution is 69% to 83%.
- In a food-effect study, 24 healthy men received a single 160 mg dose of Regorafenib on three separate occasions: under a fasted state, with a high-fat meal and with a low-fat meal. A high-fat meal (945 calories and 54.6 g fat) increased the mean AUC of regorafenib by 48% and decreased the mean AUC of the M-2 and M-5 metabolites by 20% and 51%, respectively, as compared to the fasted state. A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions. Regorafenib was administered with a low-fat meal in Studies 1 and 2.
- Regorafenib undergoes enterohepatic circulation with multiple plasma concentration peaks observed across the 24-hour dosing interval. Regorafenib is highly bound (99.5%) to human plasma proteins.
- Regorafenib is metabolized by CYP3A4 and UGT1A9. The main circulating metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 (N-oxide and N-desmethyl), both of them having similar in vitro pharmacological activity and steady-state concentrations as regorafenib. M-2 and M-5 are highly protein bound (99.8% and 99.95%, respectively).
- Following a single 160 mg oral dose of Regorafenib, the geometric mean (range) elimination half-lives for regorafenib and the M-2 metabolite in plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively. M-5 has a longer mean (range) elimination half-life of 51 hours (32 to 70 hours).
- Approximately 71% of a radiolabeled dose was excreted in feces (47% as parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% as glucuronides) within 12 days after administration of a radiolabeled oral solution at a dose of 120 mg.
- Based on the population pharmacokinetic analysis, there is no clinically relevant effect of age, gender or weight on the pharmacokinetics of regorafenib.
- The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 14 patients with hepatocellular carcinoma (HCC) and mild hepatic impairment (Child-Pugh A); 4 patients with HCC and moderate hepatic impairment (Child-Pugh B); and 10 patients with solid tumors and normal hepatic function after the administration of a single 100 mg dose of Regorafenib. No clinically important differences in the mean exposure of regorafenib, M-2, or M-5 were observed in patients with mild or moderate hepatic impairment compared to the patients with normal hepatic function. The pharmacokinetics of regorafenib has not been studied in patients with severe hepatic impairment (Child-Pugh C).
- The pharmacokinetics of regorafenib, M-2, and M-5 was evaluated in 10 patients with mild renal impairment (CLcr 60-89 mL/min) and 18 patients with normal renal function following the administration of Regorafenib at a dose of 160 mg daily for 21 days. No differences in the mean steady-state exposure of regorafenib, M-2, or M-5 were observed in patients with mild renal impairment compared to patients with normal renal function. Limited pharmacokinetic data are available from patients with moderate renal impairment (CLcr 30-59 mL/min). The pharmacokinetics of regorafenib has not been studied in patients with severe renal impairment or end-stage renal disease.
- Effect of Regorafenib on Cytochrome P450 Substrates
- In vitro studies suggested that regorafenib is an inhibitor of CYP2C8, CYP2C9, CYP2B6, CYP3A4 and CYP2C19; M-2 metabolite is an inhibitor of CYP2C9, CYP2C8, CYP3A4 and CYP2D6, and M-5 metabolite is an inhibitor of CYP2C8. In vitro studies suggested that regorafenib is not an inducer of CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.
- Patients with advanced solid tumors received single oral doses of CYP substrates, 2 mg of midazolam (CYP3A4), 40 mg of omeprazole (CYP2C19) and 10 mg of warfarin (CYP2C9) or 4 mg of rosiglitazone (CYP2C8) one week before and two weeks after Regorafenib at a dose of 160 mg once daily. No clinically relevant change was observed in the mean AUC of rosiglitazone (N=12) or the mean omeprazole (N=11) plasma concentrations measured 6 hours after dosing or the mean AUC of midazolam (N=15). The mean AUC of warfarin (N=8) increased by 25%.
- Effect of CYP3A4 Strong Inducers on Regorafenib: Twenty-two healthy men received a single 160 mg dose of Regorafenib alone and then 7 days after starting rifampin. Rifampin, a strong CYP3A4 inducer, was administered at a dose of 600 mg daily for 9 days. The mean AUC of regorafenib decreased by 50% and mean AUC of M-5 increased by 264%. No change in the mean AUC of M-2 was observed.
- Effect of CYP3A4 Strong Inhibitors on Regorafenib: Eighteen healthy men received a single 160 mg dose of Regorafenib alone and then 5 days after starting ketoconazole. Ketoconazole, a strong CYP3A4 inhibitor, was administered at a dose of 400 mg daily for 18 days. The mean AUC of regorafenib increased by 33% and the mean AUC of M-2 and M-5 both decreased by 93%.
- Effect of Regorafenib on UGT1A1 Substrates: In vitro studies showed that regorafenib, M-2, and M-5 competitively inhibit UGT1A9 and UGT1A1 at therapeutically relevant concentrations. Eleven patients received irinotecan-containing combination chemotherapy with Regorafenib at a dose of 160 mg. The mean AUC of irinotecan increased 28% and the mean AUC of SN-38 increased by 44% when irinotecan was administered 5 days after the last of 7 daily doses of Regorafenib.
- In vitro screening of transporters: In vitro data suggested that regorafenib is an inhibitor of ABCG2 (Breast Cancer Resistance Protein) and ABCB1 (P-glycoprotein).
- The effect of multiple doses of Regorafenib (160 mg once daily for 21 days) on the QTc interval was evaluated in an open label, single arm study in 25 patients with advanced solid tumors. No large changes in the mean QTc interval (i.e., > 20 msec) were detected in the study.
## Nonclinical Toxicology
- Studies examining the carcinogenic potential of regorafenib have not been conducted. Regorafenib itself did not demonstrate genotoxicity in in vitro or in vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for clastogenicity, causing chromosome aberration in Chinese hamster V79 cells.
- Dedicated studies to examine the effects of regorafenib on fertility have not been conducted; however, there were histological findings of tubular atrophy and degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in the epididymides in male rats at doses similar to those in human at the clinical recommended dose based on AUC. In female rats, there were increased findings of necrotic corpora lutea in the ovaries at the same exposures. There were similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of the human exposure at the recommended human dose based on AUC. These findings suggest that regorafenib may adversely affect fertility in humans.
- In a chronic 26-week repeat dose study in rats there was a dose-dependent increase in the finding of thickening of the atrioventricular valve. At a dose that resulted in an exposure of approximately 12% of the human exposure.
# Clinical Studies
- The clinical efficacy and safety of Regorafenib were evaluated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 1) in 760 patients with previously-treated metastatic colorectal cancer. The major efficacy outcome measure was overall survival (OS); supportive efficacy outcome measures included progression-free survival (PFS) and objective tumor response rate.
- Patients were randomized to receive 160 mg regorafenib orally once daily (N=505) plus Best Supportive Care (BSC) or placebo (N=255) plus BSC for the first 21 days of each 28-day cycle. Regorafenib was administered with a low-fat breakfast that contains less than 30% fat. Treatment continued until disease progression or unacceptable toxicity.
- In the all-randomized population, median age was 61 years, 61% were men, 78% were White, and all patients had baseline ECOG performance status of 0 or 1. The primary site of disease was colon (65%), rectum (29%), or both (6%). History of KRAS evaluation was reported for 729 (96%) patients; 430 (59%) of these patients were reported to have KRAS mutation. The median number of prior lines of therapy for metastatic disease was 3. All patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and with bevacizumab. All but one patient with KRAS mutation-negative tumors received panitumumab or cetuximab.
- The efficacy and safety of Regorafenib were evaluated in an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial (Study 2) in 199 patients with unresectable, locally advanced or metastatic gastrointestinal stromal tumor (GIST), who had been previously treated with imatinib mesylate and sunitinib malate. Randomization was stratified by line of therapy (third vs. four or more) and geographic region (Asia vs. rest of the world).
- The major efficacy outcome measure of Study 2 was progression-free survival (PFS) based on disease assessment by independent radiological review using modified RECIST 1.1 criteria, in which lymph nodes and bone lesions were not target lesions and progressively growing new tumor nodule within a pre-existing tumor mass was progression. The key secondary outcome measure was overall survival.
- Patients were randomized to receive 160 mg regorafenib orally once daily (N=133) plus best supportive care (BSC) or placebo (N=66) plus BSC for the first 21 days of each 28-day cycle. Treatment continued until disease progression or unacceptable toxicity. In Study 2, the median age of patients was 60 years, 64% were men, 68% were White, and all patients had baseline ECOG performance status of 0 (55%) or 1 (45%). At the time of disease progression as assessed by central review, the study blind was broken and all patients were offered the opportunity to take Regorafenib at the investigator’s discretion. Fifty-six (85%) patients randomized to placebo and 41 (31%) patients randomized to Regorafenib received open-label Regorafenib.
- A statistically significant improvement in PFS was demonstrated among patients treated with Regorafenib compared to placebo (see Table 6 and Figure 2). There was no statistically significant difference in overall survival at the time of the planned interim analysis based on 29% of the total events for the final analysis.
# How Supplied
- Regorafenib tablets are supplied in packages containing three bottles, with each bottle containing 28 tablets, for a total of 84 tablets per package (NDC 50419-171-03).
## Storage
- Store Regorafenib at 25°C (77°F); excursions are permitted from 15 to 30°C (59 to 86°F).
- Store tablets in the original bottle and do not remove the desiccant. Keep the bottle tightly closed after first opening.
- Discard any unused tablets 7 weeks after opening the bottle.Dispose of unused tablets in accordance with local requirements.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- See FDA-Approved Patient Labeling (Patient Information).
- Inform your patients of the following:
- Regorafenib may cause severe or life-threatening liver damage. Inform patients that they will need to undergo monitoring for liver damage and to immediately report any signs or symptoms of severe liver damage to their health care provider.
- Regorafenib can cause severe bleeding. Advise patients to contact their health care provider for any episode of bleeding.
- Regorafenib can cause hand-foot skin reactions or rash elsewhere. Advise patients to contact their health care provider if they experience skin changes associated with redness, pain, blisters, bleeding, or swelling.
- Regorafenib can cause or exacerbate existing hypertension. Advise patients they will need to undergo blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms.
- Regorafenib increased the risk for myocardial ischemia and infarction. Advise patients to seek immediate emergency help if they experience chest pain, shortness of breath, or feel dizzy or like passing out.
Contact a healthcare provider immediately if they experience severe pains in their abdomen, persistent swelling of the abdomen, high fever, chills, nausea, vomiting, severe diarrhea (frequent or loose bowel movements), or dehydration.
- Regorafenib may complicate wound healing. Advise patients to inform their health care provider if they plan to undergo a surgical procedure or had recent surgery.
- Inform patients that regorafenib can cause fetal harm. Advise women of reproductive potential and men of the need for effective contraception during Regorafenib treatment and for up to 2 months after completion of treatment. Instruct women of reproductive potential to immediately contact her health care provider if pregnancy is suspected or confirmed during or within 2 months of completing treatment with Regorafenib.
- Advise nursing mothers that it is not known whether regorafenib is present in breast milk and discuss whether to discontinue nursing or to discontinue regorafenib.
- Inform patients to take any missed dose on the same day, as soon as they remember, and that they must not take two doses on the same day to make up for a dose missed on the previous day.
- Inform patients to store medicine in the original container. Do not place medication in daily or weekly pill boxes . Any remaining tablets should be discarded 7 weeks after opening the bottle. Tightly close bottle after each opening and keep the desiccant in the bottle.
# Precautions with Alcohol
- Alcohol-Regorafenib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Regorafenib ®[1]
# Look-Alike Drug Names
There is limited information regarding Regorafenib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Regorafenib | |
76932fa592ebaaf7721df5af5679c9fc7320bf2d | wikidoc | Reinsurance | Reinsurance
Reinsurance is a means by which an insurance company can protect itself against the risk of losses with other insurance companies. Individuals and corporations obtain insurance policies to provide protection for various risks (hurricanes, earthquakes, lawsuits, collisions, sickness and death, etc.). Reinsurers, in turn, provide insurance to insurance companies.
# Functions of reinsurance
There are many reasons why an insurance company would choose to reinsure as part of its responsibility to manage a portfolio of risks for the benefit of its policyholders and investors :
## Risk transfer
The main use of any insurer that might practice reinsurance is to allow the company to assume greater individual risks than its size would otherwise allow, and to protect a company against losses. Reinsurance allows an insurance company to offer higher limits of protection to a policyholder than its own assets would allow. For example, if the principal insurance company can write only $10 million in limits on any given policy, it can reinsure (or cede) the amount of the limits in excess of $10 million.
Reinsurance’s highly refined uses in recent years include applications where reinsurance was used as part of a carefully planned hedge strategy.
## Income smoothing
Reinsurance can help to make an insurance company’s results more predictable by absorbing larger losses and reducing the amount of capital needed to provide coverage.
## Surplus relief
An insurance company's writings are limited by its balance sheet (this test is known as the solvency margin). When that limit is reached, an insurer can either stop writing new business, increase its capital or buy "surplus relief" reinsurance. The latter is usually done on a quota share basis and is an efficient way of not having to turn clients away or raise additional capital.
## Arbitrage
The insurance company may be motivated by arbitrage in purchasing reinsurance coverage at a lower rate than what they charge the insured for the underlying risk.
# Types of reinsurance
## Proportional
Proportional reinsurance (the types of which are quota share & surplus reinsurance) involves one or more reinsurers taking a stated percent share of each policy that an insurer produces ("writes"). This means that the reinsurer will receive that stated percentage of each dollar of premiums and will pay that percentage of each dollar of losses. In addition, the reinsurer will allow a "ceding commission" to the insurer to compensate the insurer for the costs of writing and administering the business (agents' commissions, modelling, paperwork, etc.).
The insurer may seek such coverage for several reasons. First, the insurer may not have sufficient capital to prudently retain all of the exposure that it is capable of producing. For example, it may only be able to offer $1 million in coverage, but by purchasing proportional reinsurance it might double or triple that limit. Premiums and losses are then shared on a pro rata basis. For example, an insurance company might purchase a 50% quota share treaty; in this case they would share half of all premium and losses with the reinsurer. In a 75% quota share, they would share (cede) 3/4 of all premiums and losses.
The other form of proportional reinsurance is surplus share or surplus of line treaty. In this case, a retained “line” is defined as the ceding company's retention - say $100,000. In a 9 line surplus treaty the reinsurer would then accept up to $900,000 (9 lines). So if the insurance company issues a policy for $100,000, they would keep all of the premiums and losses from that policy. If they issue a $200,000 policy, they would give (cede) half of the premiums and losses to the reinsurer (1 line each). The maximum underwriting capacity of the cedant would be $ 1,000,000 in this example. Surplus treaties are also known as variable quota shares.
## Non-proportional
Non-proportional reinsurance only responds if the loss suffered by the insurer exceeds a certain amount, called the retention or priority. An example of this form of reinsurance is where the insurer is prepared to accept a loss of $1 million for any loss which may occur and purchases a layer of reinsurance of $4m in excess of $1 million - if a loss of $3 million occurs the insurer pays the $3 million to the insured(s), and then recovers $2 million from its reinsurer(s). In this example, the reinsured will retain any loss exceeding $5 million unless they have purchased a further excess layer (second layer) of say $10 million excess of $5 million.
The main forms of non-proportional reinsurance are excess of loss and stop loss.
Excess of loss reinsurance can have three forms - "Per Risk XL" (Working XL), "Per Occurrence or Per Event XL" (Catastrophe or Cat XL), and "Aggregate XL". In per risk, the cedant’s insurance policy limits are greater than the reinsurance retention. For example, an insurance company might insure commercial property risks with policy limits up to $10 million and then buy per risk reinsurance of $5 million in excess of $5 million. In this case a loss of $6 million on that policy will result in the recovery of $1 million from the reinsurer.
In catastrophe excess of loss, the cedant’s per risk retention is usually be less than the cat reinsurance retention (this is not important as these contracts usually contain a 2 risk warranty i.e. they are designed to protect the reinsured against catastrophic events that involve more than 1 policy). For example, an insurance company issues homeowner's policies with limits of up to $500,000 and then buys catastrophe reinsurance of $22,000,000 in excess of $3,000,000. In that case, the insurance company would only recover from reinsurers in the event of multiple policy losses in one event (i.e., hurricane, earthquake, flood, etc.).
Aggregate XL afford a frequency protection to the reinsured. For instance if the company retains $1m net any one vessel, the cover $10m in the aggregate excess $5m in the aggregate would equate to 10 total losses in excess of 5 total losses (or more partial losses). Aggregate covers can also be linked to the cedant's gross premium income during a 12 month period, with limit and deductible expressed as percentages and amounts. Such covers are then known as "Stop Loss" or annual aggregate XL.
# Contracts
Most of the above examples concern reinsurance contracts that cover more than one policy (treaty). Reinsurance can also be purchased on a per policy basis, in which case it is known as facultative reinsurance. Facultative reinsurance can be written on either a quota share or excess of loss basis. Facultative reinsurance is commonly used for large or unusual risks that do not fit within standard reinsurance treaties due to their exclusions. The term of a facultative agreement coincides with the term of the policy. Facultative reinsurance is usually purchased by the insurance underwriter who underwrote the original insurance policy, whereas treaty reinsurance is typically purchased by a senior executive at the insurance company.
Reinsurance treaties can either be written on a “continuous” or “term” basis. A continuous contract continues indefinitely, but generally has a “notice” period whereby either party can give its intent to cancel or amend the treaty within 90 days. A term agreement has a built-in expiration date. It is common for insurers and reinsurers to have long term relationships that span many years.
# Markets
Most reinsurance placements are not placed with a single reinsurer but are shared between a number of reinsurers. For example a $30,000,000 xs of $20,000,000 layer may be shared by 30 or more reinsurers. The reinsurer who sets the terms (premium and contract conditions) for the reinsurance contract is called the lead reinsurer; the other companies subscribing to the contract are called following reinsurers.
About half of all reinsurance is handled by reinsurance brokers who then place business with reinsurance companies. The other half is with “direct writing” reinsurers who have their own production staff and thus reinsure insurance companies directly. In Europe reinsurers write both direct and brokered accounts.
Using game-theoretic modeling, Professors Michael R. Powers (Temple University) and Martin Shubik (Yale University) have argued that the number of active reinsurers in a given national market should be approximately equal to the square-root of the number of primary insurers active in the same market. Econometric analysis has provided empirical support for the Powers-Shubik rule.
Reinsureds tend to choose their reinsurers with great care as they are exchanging insurance risk for credit risk. Risk managers monitor reinsurers' financial ratings (S&P, A.M. Best, etc.)and aggregated exposures regularly.
# Retrocession
Reinsurance companies themselves also purchase reinsurance and this is known as a retrocession. They purchase this reinsurance from other reinsurance companies. The reinsurance company who sells the reinsurance in this scenario are known as “retrocessionaires.” The reinsurance company that purchases the reinsurance is known as the “retrocedent.”
It is not unusual for a reinsurer to buy reinsurance protection from other reinsurers. For example, a reinsurer that provides proportional, or pro rata, reinsurance capacity to insurance companies may wish to protect its own exposure to catastrophes by buying excess of loss protection. Another situation would be that a reinsurer which provides excess of loss reinsurance protection may wish to protect itself against an accumulation of losses in different branches of business which may all become affected by the same catastrophe. This may happen when a windstorm causes damage to property, automobiles, boats, aircraft and loss of life, for example.
This process can sometimes continue until the original reinsurance company unknowingly gets some of its own business (and therefore its own liabilities) back. This is known as a “spiral” and was common in some specialty lines of business such as marine and aviation. Sophisticated reinsurance companies are aware of this danger and through careful underwriting attempt to avoid it.
In the 1980s, the London market was badly affected by the creation of reinsurance spirals. This resulted in the same loss going around the market thereby artificially inflating market loss figures of big claims (such as the Piper Alpha oil rig). The LMX spiral (as it was called) has been stopped by excluding retrocessional business from reinsurance covers protecting direct insurance accounts.
It is important to note that the insurance company is obliged to indemnify its policyholder for the loss under the insurance policy whether or not the reinsurer reimburses the insurer. Many insurance companies have experienced difficulties by purchasing reinsurance from companies that did not or could not pay their share of the loss (these unpaid claims are known as uncollectibles). This is particularly important on long-tail lines of business where the claims may arise many years after the premium is paid. | Reinsurance
Reinsurance is a means by which an insurance company can protect itself against the risk of losses with other insurance companies. Individuals and corporations obtain insurance policies to provide protection for various risks (hurricanes, earthquakes, lawsuits, collisions, sickness and death, etc.). Reinsurers, in turn, provide insurance to insurance companies.
# Functions of reinsurance
There are many reasons why an insurance company would choose to reinsure as part of its responsibility to manage a portfolio of risks for the benefit of its policyholders and investors :
## Risk transfer
The main use of any insurer that might practice reinsurance is to allow the company to assume greater individual risks than its size would otherwise allow, and to protect a company against losses. Reinsurance allows an insurance company to offer higher limits of protection to a policyholder than its own assets would allow. For example, if the principal insurance company can write only $10 million in limits on any given policy, it can reinsure (or cede) the amount of the limits in excess of $10 million.
Reinsurance’s highly refined uses in recent years include applications where reinsurance was used as part of a carefully planned hedge strategy.
## Income smoothing
Reinsurance can help to make an insurance company’s results more predictable by absorbing larger losses and reducing the amount of capital needed to provide coverage.
## Surplus relief
An insurance company's writings are limited by its balance sheet (this test is known as the solvency margin). When that limit is reached, an insurer can either stop writing new business, increase its capital or buy "surplus relief" reinsurance. The latter is usually done on a quota share basis and is an efficient way of not having to turn clients away or raise additional capital.
## Arbitrage
The insurance company may be motivated by arbitrage in purchasing reinsurance coverage at a lower rate than what they charge the insured for the underlying risk.
# Types of reinsurance
## Proportional
Proportional reinsurance (the types of which are quota share & surplus reinsurance) involves one or more reinsurers taking a stated percent share of each policy that an insurer produces ("writes"). This means that the reinsurer will receive that stated percentage of each dollar of premiums and will pay that percentage of each dollar of losses. In addition, the reinsurer will allow a "ceding commission" to the insurer to compensate the insurer for the costs of writing and administering the business (agents' commissions, modelling, paperwork, etc.).
The insurer may seek such coverage for several reasons. First, the insurer may not have sufficient capital to prudently retain all of the exposure that it is capable of producing. For example, it may only be able to offer $1 million in coverage, but by purchasing proportional reinsurance it might double or triple that limit. Premiums and losses are then shared on a pro rata basis. For example, an insurance company might purchase a 50% quota share treaty; in this case they would share half of all premium and losses with the reinsurer. In a 75% quota share, they would share (cede) 3/4 of all premiums and losses.
The other form of proportional reinsurance is surplus share or surplus of line treaty. In this case, a retained “line” is defined as the ceding company's retention - say $100,000. In a 9 line surplus treaty the reinsurer would then accept up to $900,000 (9 lines). So if the insurance company issues a policy for $100,000, they would keep all of the premiums and losses from that policy. If they issue a $200,000 policy, they would give (cede) half of the premiums and losses to the reinsurer (1 line each). The maximum underwriting capacity of the cedant would be $ 1,000,000 in this example. Surplus treaties are also known as variable quota shares.
## Non-proportional
Non-proportional reinsurance only responds if the loss suffered by the insurer exceeds a certain amount, called the retention or priority. An example of this form of reinsurance is where the insurer is prepared to accept a loss of $1 million for any loss which may occur and purchases a layer of reinsurance of $4m in excess of $1 million - if a loss of $3 million occurs the insurer pays the $3 million to the insured(s), and then recovers $2 million from its reinsurer(s). In this example, the reinsured will retain any loss exceeding $5 million unless they have purchased a further excess layer (second layer) of say $10 million excess of $5 million.
The main forms of non-proportional reinsurance are excess of loss and stop loss.
Excess of loss reinsurance can have three forms - "Per Risk XL" (Working XL), "Per Occurrence or Per Event XL" (Catastrophe or Cat XL), and "Aggregate XL". In per risk, the cedant’s insurance policy limits are greater than the reinsurance retention. For example, an insurance company might insure commercial property risks with policy limits up to $10 million and then buy per risk reinsurance of $5 million in excess of $5 million. In this case a loss of $6 million on that policy will result in the recovery of $1 million from the reinsurer.
In catastrophe excess of loss, the cedant’s per risk retention is usually be less than the cat reinsurance retention (this is not important as these contracts usually contain a 2 risk warranty i.e. they are designed to protect the reinsured against catastrophic events that involve more than 1 policy). For example, an insurance company issues homeowner's policies with limits of up to $500,000 and then buys catastrophe reinsurance of $22,000,000 in excess of $3,000,000. In that case, the insurance company would only recover from reinsurers in the event of multiple policy losses in one event (i.e., hurricane, earthquake, flood, etc.).
Aggregate XL afford a frequency protection to the reinsured. For instance if the company retains $1m net any one vessel, the cover $10m in the aggregate excess $5m in the aggregate would equate to 10 total losses in excess of 5 total losses (or more partial losses). Aggregate covers can also be linked to the cedant's gross premium income during a 12 month period, with limit and deductible expressed as percentages and amounts. Such covers are then known as "Stop Loss" or annual aggregate XL.
# Contracts
Most of the above examples concern reinsurance contracts that cover more than one policy (treaty). Reinsurance can also be purchased on a per policy basis, in which case it is known as facultative reinsurance. Facultative reinsurance can be written on either a quota share or excess of loss basis. Facultative reinsurance is commonly used for large or unusual risks that do not fit within standard reinsurance treaties due to their exclusions. The term of a facultative agreement coincides with the term of the policy. Facultative reinsurance is usually purchased by the insurance underwriter who underwrote the original insurance policy, whereas treaty reinsurance is typically purchased by a senior executive at the insurance company.
Reinsurance treaties can either be written on a “continuous” or “term” basis. A continuous contract continues indefinitely, but generally has a “notice” period whereby either party can give its intent to cancel or amend the treaty within 90 days. A term agreement has a built-in expiration date. It is common for insurers and reinsurers to have long term relationships that span many years.
# Markets
Most reinsurance placements are not placed with a single reinsurer but are shared between a number of reinsurers. For example a $30,000,000 xs of $20,000,000 layer may be shared by 30 or more reinsurers. The reinsurer who sets the terms (premium and contract conditions) for the reinsurance contract is called the lead reinsurer; the other companies subscribing to the contract are called following reinsurers.
About half of all reinsurance is handled by reinsurance brokers who then place business with reinsurance companies. The other half is with “direct writing” reinsurers who have their own production staff and thus reinsure insurance companies directly. In Europe reinsurers write both direct and brokered accounts.
Using game-theoretic modeling, Professors Michael R. Powers (Temple University) and Martin Shubik (Yale University) have argued that the number of active reinsurers in a given national market should be approximately equal to the square-root of the number of primary insurers active in the same market.[1] Econometric analysis has provided empirical support for the Powers-Shubik rule.[2]
Reinsureds tend to choose their reinsurers with great care as they are exchanging insurance risk for credit risk. Risk managers monitor reinsurers' financial ratings (S&P, A.M. Best, etc.)and aggregated exposures regularly.
# Retrocession
Reinsurance companies themselves also purchase reinsurance and this is known as a retrocession. They purchase this reinsurance from other reinsurance companies. The reinsurance company who sells the reinsurance in this scenario are known as “retrocessionaires.” The reinsurance company that purchases the reinsurance is known as the “retrocedent.”
It is not unusual for a reinsurer to buy reinsurance protection from other reinsurers. For example, a reinsurer that provides proportional, or pro rata, reinsurance capacity to insurance companies may wish to protect its own exposure to catastrophes by buying excess of loss protection. Another situation would be that a reinsurer which provides excess of loss reinsurance protection may wish to protect itself against an accumulation of losses in different branches of business which may all become affected by the same catastrophe. This may happen when a windstorm causes damage to property, automobiles, boats, aircraft and loss of life, for example.
This process can sometimes continue until the original reinsurance company unknowingly gets some of its own business (and therefore its own liabilities) back. This is known as a “spiral” and was common in some specialty lines of business such as marine and aviation. Sophisticated reinsurance companies are aware of this danger and through careful underwriting attempt to avoid it.
In the 1980s, the London market was badly affected by the creation of reinsurance spirals. This resulted in the same loss going around the market thereby artificially inflating market loss figures of big claims (such as the Piper Alpha oil rig). The LMX spiral (as it was called) has been stopped by excluding retrocessional business from reinsurance covers protecting direct insurance accounts.
It is important to note that the insurance company is obliged to indemnify its policyholder for the loss under the insurance policy whether or not the reinsurer reimburses the insurer. Many insurance companies have experienced difficulties by purchasing reinsurance from companies that did not or could not pay their share of the loss (these unpaid claims are known as uncollectibles). This is particularly important on long-tail lines of business where the claims may arise many years after the premium is paid. | https://www.wikidoc.org/index.php/Reinsurance | |
f73c313c1f35c68b154e7342c5d0e0d4c30f9738 | wikidoc | Religiosity | Religiosity
Religiosity, in its broadest sense, is a comprehensive sociological term used to refer to the numerous aspects of religious activity, dedication, and belief (religious doctrine). Another term that would work equally well, though is less often used, is religiousness. In its narrowest sense, religiosity deals more with how religious a person is, and less with how a person is religious (in terms of practicing certain rituals, retelling certain myths, revering certain symbols, or accepting certain doctrines about deities and afterlife).
# Components
Numerous studies have explored the different components of human religiosity (Brink, 1993; Hill & Hood 1999). What most have found is that there are multiple dimensions (they often employ factor analysis). For instance, Cornwall, Albrecht, Cunningham and Pitcher (1986) identify six dimensions of religiosity based on the understanding that there are at least three components to religious behavior: knowing (cognition), feeling (affect), and doing (behavior). For each of these components of religiosity there were two cross classifications resulting in the six dimensions:
- Cognition
traditional orthodoxy
particularistic orthodoxy
- traditional orthodoxy
- particularistic orthodoxy
- Affect
spiritual
church commitment
physical
- spiritual
- church commitment
- physical
- Behavior
religious behavior
religious participation
- religious behavior
- religious participation
Other researchers have found different dimensions, ranging generally from four to twelve components. What most measures of religiosity find is that there is at least some distinction between religious doctrine, religious practice, and spirituality.
For example, one can accept the truthfulness of the Bible (belief dimension), but never attend a church or even belong to an organized religion (practice dimension). Another example is an individual who does not hold orthodox Christian doctrines (belief dimension), but does attend a charismatic worship service (practice dimension) in order to develop his/her sense of oneness with the divine (spirituality dimension).
An individual could disavow all doctrines associated with organized religions (belief dimension), not affiliate with an organized religion or attend religious services (practice dimension), and at the same time be strongly committed to a higher power and feel that the connection with that higher power is ultimately relevant (spirituality dimension). These are explanatory examples of the broadest dimensions of religiosity and that they may not be reflected in specific religiosity measures.
Most dimensions of religiosity are correlated, meaning people who often attend church services (practice dimension) are also likely to score highly on the belief and spirituality dimensions. But individuals do not have to score high on all dimensions or low on all dimensions; their scores can vary by dimension.
# Genes and environment
The contributions of genes and environment to religiosity have been quantified in twin studies (Bouchard et al', 1999; Kirk et al', 1999). Koenig et al (2005) report that the contribution of genes to variation in religiosity (called heritability) increases from 12% to 44% and the contribution of shared (family) effects decreases from 56% to 18% between adolescence and adulthood. | Religiosity
Religiosity, in its broadest sense, is a comprehensive sociological term used to refer to the numerous aspects of religious activity, dedication, and belief (religious doctrine). Another term that would work equally well, though is less often used, is religiousness. In its narrowest sense, religiosity deals more with how religious a person is, and less with how a person is religious (in terms of practicing certain rituals, retelling certain myths, revering certain symbols, or accepting certain doctrines about deities and afterlife).
# Components
Numerous studies have explored the different components of human religiosity (Brink, 1993; Hill & Hood 1999). What most have found is that there are multiple dimensions (they often employ factor analysis). For instance, Cornwall, Albrecht, Cunningham and Pitcher (1986) identify six dimensions of religiosity based on the understanding that there are at least three components to religious behavior: knowing (cognition), feeling (affect), and doing (behavior). For each of these components of religiosity there were two cross classifications resulting in the six dimensions:
- Cognition
traditional orthodoxy
particularistic orthodoxy
- traditional orthodoxy
- particularistic orthodoxy
- Affect
spiritual
church commitment
physical
- spiritual
- church commitment
- physical
- Behavior
religious behavior
religious participation
- religious behavior
- religious participation
Other researchers have found different dimensions, ranging generally from four to twelve components. What most measures of religiosity find is that there is at least some distinction between religious doctrine, religious practice, and spirituality.
For example, one can accept the truthfulness of the Bible (belief dimension), but never attend a church or even belong to an organized religion (practice dimension). Another example is an individual who does not hold orthodox Christian doctrines (belief dimension), but does attend a charismatic worship service (practice dimension) in order to develop his/her sense of oneness with the divine (spirituality dimension).
An individual could disavow all doctrines associated with organized religions (belief dimension), not affiliate with an organized religion or attend religious services (practice dimension), and at the same time be strongly committed to a higher power and feel that the connection with that higher power is ultimately relevant (spirituality dimension). These are explanatory examples of the broadest dimensions of religiosity and that they may not be reflected in specific religiosity measures.
Most dimensions of religiosity are correlated, meaning people who often attend church services (practice dimension) are also likely to score highly on the belief and spirituality dimensions. But individuals do not have to score high on all dimensions or low on all dimensions; their scores can vary by dimension.
# Genes and environment
The contributions of genes and environment to religiosity have been quantified in twin studies (Bouchard et al', 1999; Kirk et al', 1999). Koenig et al (2005) report that the contribution of genes to variation in religiosity (called heritability) increases from 12% to 44% and the contribution of shared (family) effects decreases from 56% to 18% between adolescence and adulthood. | https://www.wikidoc.org/index.php/Religiosity | |
eb6a2dec2026217ad21092a2ebcd1e07de0f4e03 | wikidoc | Renal colic | Renal colic
# Overview
Renal colic is a type of pain commonly caused by kidney stones or accumulation of crystals.
These kidney stones cause interference with the flow of urine and the kidney may swell up causing pain (colic).
The pain typically begins in the kidney area or below it and radiates through the flank until it reaches the bladder. The pain is colicky in nature, meaning that it comes on in spasmodic waves as opposed to being a steady continuous pain. It may come in two varieties: dull and acute; the acute variation is particularly unpleasant and has been described as one of the strongest pain sensations felt by humans.
Depending on the type and sizes of the kidney stones moving through the urinal tract the pain may be stronger in the renal or bladder area or equally strong in both.
# Differential diagnosis | Renal colic
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Steven C. Campbell, M.D., Ph.D.Soumya Sachdeva Luke Rusowicz-Orazem, B.S.
# Overview
Renal colic is a type of pain commonly caused by kidney stones or accumulation of crystals.
These kidney stones cause interference with the flow of urine and the kidney may swell up causing pain (colic).
The pain typically begins in the kidney area or below it and radiates through the flank until it reaches the bladder. The pain is colicky in nature, meaning that it comes on in spasmodic waves as opposed to being a steady continuous pain. It may come in two varieties: dull and acute; the acute variation is particularly unpleasant and has been described as one of the strongest pain sensations felt by humans.[2]
Depending on the type and sizes of the kidney stones moving through the urinal tract the pain may be stronger in the renal or bladder area or equally strong in both.
# Differential diagnosis | https://www.wikidoc.org/index.php/Renal_colic | |
1e410e2e14fd458b90c8ceaa52afb069e8f45a99 | wikidoc | Resveratrol | Resveratrol
# Overview
Resveratrol is a phytoalexin produced naturally by several plants when under attack by bacteria or fungi. Phytoalexins are antibacterial and anti-fungal chemicals produced by plants as a defense against infection by pathogens. Resveratrol has also been produced by chemical synthesis, and is sold as a nutritional supplement. A number of beneficial health effects, such as anti-cancer, antiviral, neuroprotective, anti-aging, anti-inflammatory and life-prolonging effects have been reported, although some of these studies used animal subjects (e.g. rats). Resveratrol is found in the skin of red grapes and is a constituent of red wine but, based on extrapolation from animal trials, apparently not in sufficient amounts to explain the “French paradox” that the incidence of coronary heart disease is relatively low in southern France despite high dietary intake of saturated fats.
Konrad T. Howitz and Robert Zipkin of BIOMOL International discovered that resveratrol increases the activity of an enzyme called SIRT1. They then contacted David Sinclair of the Harvard Medical School, and cofounder of Sirtris Pharmaceuticals, in order to initiate a collaboration. Sinclair found that resveratrol significantly increases the lifespan of yeast and mice. There is hope that it could do the same for humans.
The four stilbenes cis and trans resveratrol, and cis and trans piceid are similar and related, and sometimes analyzed together as a group.
# Chemical and physical properties
Resveratrol (3,5,4'-trihydroxystilbene) is a polyphenolic phytoalexin. It is a stilbenoid, a derivate of stilbene, and is produced in plants with the help of the enzyme stilbene synthase.
It exists as two structural isomers: cis- (Z) and trans- (E), with the trans-isomer shown in the top image. Trans-resveratrol can undergo isomerisation to the cis- form when heated or exposed to ultraviolet irradiation. In a 2004 issue of Science, Dr. Sinclair of Harvard University said resveratrol is not an easy molecule to protect from oxidation. It has been claimed that it is readily degraded by exposure to light, heat, and oxygen. However, studies find that Trans-resveratrol undergoes negligible oxidation in normal atmosphere at room temperature.
# Plants and foods
Resveratrol is produced by several plants, apparently due to its antifungal properties. It is found in widely varying amounts in grapes (primarily the skins), raspberries, mulberries, in plums, peanuts, berries of Vaccinium species, including blueberries, bilberries, and cranberries, some pines, such as Scots pine and eastern white pine, and the roots and stalks of giant knotweed and Japanese knotweed, called hu zhang in China. Resveratrol was first isolated from an extract of the Peruvian legume Cassia quinquangulata in 1974; however, the strength of its anti inflammatory activity was not recognized until 1997
The amount of resveratrol in food varies greatly. Ordinary non-muscadine Red wine contains between 0.2 and 5.8 mg/L, depending on the grape variety, while white wine has much less — the reason being that red wine is fermented with the skins, allowing the wine to absorb the resveratrol, whereas white wine is fermented after the skin has been removed. Wines produced from muscadine grapes, however, both red and white, may contain more than 40 mg/L.
Fresh grape skin contains about 50 to 100 micrograms of resveratrol per gram.
In grapes, resveratrol is found primarily in the skin and seeds. This is particularly true for muscadine grapes, whose skin and seeds have about 100 times the concentration as the pulp. The amount found in grape skins also varies with the grape cultivar, its geographic origin, and exposure to fungal infection. The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content.
## Content in wines and grape juice
The trans-resveratrol concentration in 40 Tuscan wines ranged from 0.3 to 2.1 mg/L in the 32 red wines and had a maximum of 0.1 mg/L in the 8 white wines tested. Both the cis- and trans- isomers of resveratrol were detected in all tested samples. Cis-resveratrol levels were comparable to those of the trans-isomer. They ranged from 0.5 mg/L to 1.9 mg/L in red wines and had a maximum of 0.2 mg/L in white wines.
Reports suggest that some aspect of the wine making process converts piceid to resveratrol in wine, as wine seems to have twice the average resveratrol concentration of the equivalent commercial juices.
"All of the muscadine table wines sampled had
greater trans and cis resveratrol concentrations than any other wines sampled. The muscadine
table wines varied between 9.2 and 31.9 mg/L cis resveratrol and between 4.9 and 13.4 mg/L
trans resveratrol."
## Content in selected foods
Ounce for ounce, peanuts have more than half the amount of resveratrol in red wine. The average amount of resveratrol in one ounce of peanuts in the marketplace (about 15 whole) is 79.4 µg/ounce. In comparison, some red wines contains approximately 160 µg/fluid ounce. The concentrations of resveratrol were similar in cranberry and grape juice.
Blueberries have about twice as much resveratrol as bilberries, but there is great regional variation. These fruits have less than ten percent of the resveratrol of grapes. Cooking or heat processing of these berries will contribute to the degradation of resveratrol, reducing it by up to half.
When humans ingest resveratrol orally, most of it seems to be rapidly metabolized and excreted.
# Supplement
Resveratrol is available as a nutritional supplement but not as a therapeutic agent (although it has been registered as an investigational drug in some jurisdictions). Supplements, first sourced from ground dried muscadine and red grape skins and seeds (sometimes from residual byproducts of winemaking), are now primarily derived from the cheaper, more concentrated Japanese knotweed. Capsules are sold containing from 1 mg to 500 mg of resveratrol. A less common form is plain powder, which might be more convenient for frequent ingestion as suggested by the rapid metabolism in the body.
Although no studies have yet appeared regarding proper dosage of Resveratrol for humans, Sirtris Pharmaceuticals along with David Sinclair, have taken to use a dosage of 2500 mg and 5000 mg of their resveratrol supplement formulation for their phase 1b human trials, and have recently completed phase 1a trials using the formulation.
Some supplement makers claim that only the trans- form matters, and that the cis- form is not useful or perhaps even a bad thing. Other makers simply report total resveratrol content—or in some cases, just the quantity of an "extract" source, which only contains some percentage of resveratrol.
The following is an excerpt from a FDA New Dietary Ingredient Notification:
First, trans-Resveratrol is excluded from the definition of a “dietary supplement” under 21 U.S.C. 321 (ff) (3) (B), because it is an article authorized for investigation as a new drug for which substantial clinical investigations have been instituted and made public in the U. S.
FDA authorized trans-Resveratrol, which is also known as “resveratrol” or 3,5,4’-trihydroxystilbene, to be an Investigational New Drug on January 30, 2001. The Dietary Supplement Health and Education Act (DSHEA) of 1994 defined a “new dietary ingredient” as one that was marketed in the U.S. on or after October 15, 1994. This office does not have any information that indicates that trans-Resveratrol was legally marketed as a dietary ingredient in the U.S. before October 15, 1994.
Resveratrol is often called a nutraceutical, like other bioactive plant compounds studied for potential clinical applications: curcumin, EGCG, silibinin, etc.
As a result of extensive news coverage, sales of supplements greatly increased in 2006, despite cautions that benefits to humans are unproven.
The US government is concerned about the potential dangers of increased, unregulated usage but a "preliminary study of existing research found little evidence that resveratrol is toxic, even at very high dosages."
Media reports have claimed that a number of prominent scientists take resveratrol supplements, including Sinclair and Nobelist Frank Wilczek.
A study by Professor Roger Corder has identified a particular group of polyphenols, known as oligomeric procyanidins, which they believe offer the greatest degree of protection to human blood-vessel cells. These are found in greatest concentration in European red wines from certain areas, which correlates with longevity in those regions. This new data may impact the supplement market. Because they are present in red wine in more significant quantities, they are a more reasonable explanation of the French paradox than resveratrol (which would seem to require drinking hundreds of glasses of wine a day to get enough to matter). Procyanidins are also found in similar quantities in purple grape juice, green tea, dark-colored fruits and high-cocoa chocolate.
# Physiological effects
## Mechanism of action
Resveratrol interferes with all three stages of carcinogenesis - initiation, promotion and progression. Experiments in cell cultures of varied types and isolated subcellular systems in vitro imply many mechanisms in the pharmacological activity of resveratrol. These mechanisms include modulation of the transcription factor NF-kB, inhibition of the cytochrome P450 isoenzyme CYP1A1 (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene), alterations in androgenic actions and expression and activity of cyclooxygenase (COX) enzymes.
Resveratrol was reported effective against neuronal cell dysfunction and cell death, and in theory could help against diseases such as Huntington's disease and Alzheimer's disease. Again, this has not yet been tested in humans for any disease.
Research at the Northeastern Ohio Universities College of Medicine and Ohio State University indicates that resveratrol has direct inhibitory action on cardiac fibroblasts and may inhibit the progression of cardiac fibrosis.
Note that resveratrol bioavailability depends on its conjugate forms: glucuronate and sulfonate, despite that most in vitro studies use the aglycone form of resveratrol ('aglycone' means without a sugar molecule attached, as in the figure in this article).
## Metabolism
In humans resveratrol rapidly undergoes phase II conjugation, both glucuronidation and sulphation at multiple sites on the molecule. The effect of conjugation on efficacy is debated. The pharmacokinetics of resveratrol metabolism have not been investigated in humans. Rat studies, however, suggest a half life up to 1.6 hours. In a 2002 issue of J Pharm Exper Therapeutics, Dr. Marier reported that rats given a single oral dose of 50 mg/kg body weight initially experienced a rapid drop in serum resveratrol levels: the half life, or T1/2, of the drug was found to be 8 minutes, meaning that blood levels had dropped to half of peak by that time. However, detectable levels of the drug remained for 12 hours, probably due to enterohepatic recirculation—that it, a release of stored resveratrol from liver tissue, yielding an overall half life of between 1.3 and 1.6 hours. It is expected that chemically modified resveratrol-like molecules (drugs) will have a longer half-life and thus more potency.
## Cancer Prevention
In some lineages of cancer cell culture, resveratrol has been shown to induce apoptosis, which means it kills cells and may kill cancer cells. Resveratrol has been shown to induce Fas/Fas ligand mediated apoptosis, p53 and cyclins A, B1 and cyclin-dependent kinases cdk 1 and 2. Resveratrol also possesses antioxidant and anti-angiogenic properties.
Resveratrol is under extensive investigation as a cancer chemopreventive agent. Indeed, there are studies showing that small doses of dietary resveratrol can reduce colon carcinogenesis in rats and mice. One German study has already been shown to that under special conditions, resveratrol induces apoptosis in human fat cells. In addition, it inhibits production of cytokines which are involved in the development of obesity-related disorders.
## Life extension and anti-aging
Experiments from the Harvard laboratory of David Sinclair published in 2003 the journal Nature demonstrated that resveratrol significantly extends the lifespan of the yeast Saccharomyces cerevisiae. Dr. Sinclair then founded Sirtris Pharmaceuticals to commercialize resveratrol or related compounds as an anti-aging drug.
Later studies showed that resveratrol prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. In 2006, it also extended the maximum lifespan of a short-lived fish, Nothobranchius furzeri, by 59%, and extended its median lifespan by 56%. Also noted were an increase in swimming performance, an increase in cognitive performance (learning tasks), and a lack of neurofibrillary degeneration (found in a control group). The authors observed that " supplementation with food extends vertebrate lifespan and delays motor and cognitive age-related decline could be of high relevance for the prevention of aging-related diseases in the human population." Later in 2006, a report in the journal Nature from Sinclair's laboratory and the Laboratory of Experimental Gerontology at the National Institute on Aging showed that the compound improves health and survival of mice on a high-calorie diet.
The mechanisms of resveratrol's apparent effects on life extension are not fully understood, but they appear to mimic several of the biochemical effects of calorie restriction. This seems to function by means of lipase inhibition, reducing the absorption of fat through intestinal walls. A new report indicates that resveratrol activates SIRT1 and PGC-1α and improve functioning of the mitochondria.
Only the "Trans" form of the molecule is capable of activating the mammalian SIRT1 gene in vitro; this is also the form predominantly found in red grape skins and red wine. Red grapes grown in some regions (such as New York state) often have much higher concentrations of resveratrol based on the cooler climate and the resulting increase in fungal attacks that promote resveratrol production. However, the amount in any wine, including Muscadine grape wines, is negligible compared to the amount that in theory is needed for health benefits: 1–10 milligrams per liter of wine versus hundreds to thousands of milligrams/day.
Recent research calls into question this theory connecting resveratrol, SIRT1 and calorie restriction.
Follow up studies by the National Institute on Aging and David Sinclair, published in November 2006 by the journal Nature, replicated the life extending benefits of resveratrol in mice, the first such demonstration in a mammal. Preliminary results showed that obese mice provided with resveratrol lived an average of 15% longer than obese mice not provided the supplement.
The amounts used in the mouse study were approximately 22.4 mg/kg body weight per day. Scaling this amount to human body weights would imply an "equivalent human dose" of 1.5 to 2.0 grams/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to the range of 150 to 200 mg/day if the resveratrol plasma levels in humans were not known and we wanted to predict a human dosage using FDA guidelines.
The truth is that many differences exist between mouse and human metabolism, and the effects of any given oral dose in humans remain unknown. In 2004, there was a study to determine absorption, bioavailability, and metabolism of Resveratrol in humans. It indicated that Resveratrol was quickly metabolized using 25mg doses in humans. Only trace amounts were found in human plasma, and that most of the oral dose was recovered in urine. Mice, on the other hand were found to have much larger amounts of resveratrol measured in their plasma using equivalent doses of resveratrol per kilogram of weight. It was also stated in the study that the systemic bioavailability of resveratrol is very low in humans compared to that of mice, but that accumulation of resveratrol in the human epithelial cells along the aerodigestive tract along with potentially active resveratrol metabolites may still produce cancer-preventive and other effects. Large dosages could theoretically increase the resveratrol in human plasma.
There is no human evidence yet that quantities found in red wine or in standard supplements are sufficient for any health effect.
## Athletic performance
Johan Auwerx (at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France) and coauthors published an online article in the journal CELL in November 2006. Mice fed resveratrol for 15 weeks had better treadmill endurance than controls. The study supported Sinclair's hypothesis that the effects of resveratrol are indeed due to the activation of SIRT1.
Nicholas Wade's interview-article with Dr. Auwerx states that the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). For an 80 kg (176 lb) person, the 400 mg/kg of body weight amount used in Dr. Auwerx's mouse study would come to 32,000 mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4571 mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There is limited human safety data (see above). It is premature to take resveratrol and expect any particular results. Long-term safety has not been evaluated in humans.
In a study of 123 Finnish adults, those born with certain increased variations of the SIRT1 gene had faster metabolisms, helping them to burn energy more efficiently—indicating that the same pathway shown in the lab mice works in humans too.
## Antiviral effects
Resveratrol seems to increase the potency of some antiretroviral drugs against HIV in vitro.
Infection by herpes simplex virus ordinarily activates the cell protein Nuclear Factor κB (NF-κB). A Northeastern Ohio Universities College of Medicine study undertaken in Vero cells found that resveratrol suppresses the activation of this transcription- and apoptosis-related protein. The study further found that multiple viral protein products were reduced or completely blocked, as well as a reduction in viral DNA production.
A cell culture study found that resveratrol blocks the influenza virus from transporting viral proteins to the viral assembly site, hence restricting its ability to replicate. The effect was 90% when resveratrol was added six hours after infection and continued for 24 hours thereafter.
## Adverse effects and unknowns
While the health benefits of resveratrol seem promising, one study has theorized that it may stimulate the growth of human breast cancer cells, possibly because of resveratrol's chemical structure, which is similar to a phytoestrogen. However, other studies have found that resveratrol actually fights breast cancer.
Citing the evidence that resveratrol is estrogenic, some retailers of resveratrol advise that the compound may interfere with oral contraceptives and that women who are pregnant or intending to become pregnant should not use the product, while others advise that resveratrol should not be taken by children or young adults under 18, as no studies have shown how it affects their natural development.
An independent study of resveratrol found "no significant effects on lifespan in seven independent trials" in Drosophila and found "slight increases in lifespan in some trials but not others" in C. elegans. This finding refutes Sinclair's study published in 2004: Sirtuin activators mimic caloric restriction and delay ageing in metazoans. | Resveratrol
Template:Chembox new
# Overview
Resveratrol is a phytoalexin produced naturally by several plants when under attack by bacteria or fungi. Phytoalexins are antibacterial and anti-fungal chemicals produced by plants as a defense against infection by pathogens. Resveratrol has also been produced by chemical synthesis,[1] and is sold as a nutritional supplement. A number of beneficial health effects, such as anti-cancer, antiviral, neuroprotective, anti-aging, anti-inflammatory and life-prolonging effects have been reported, although some of these studies used animal subjects (e.g. rats). Resveratrol is found in the skin of red grapes and is a constituent of red wine but, based on extrapolation from animal trials, apparently not in sufficient amounts to explain the “French paradox” that the incidence of coronary heart disease is relatively low in southern France despite high dietary intake of saturated fats.[2]
Konrad T. Howitz and Robert Zipkin of BIOMOL International discovered that resveratrol increases the activity of an enzyme called SIRT1. They then contacted David Sinclair of the Harvard Medical School, and cofounder of Sirtris Pharmaceuticals,[3] in order to initiate a collaboration. Sinclair found that resveratrol significantly increases the lifespan of yeast and mice. There is hope that it could do the same for humans.[4]
The four stilbenes cis and trans resveratrol, and cis and trans piceid are similar and related, and sometimes analyzed together as a group.[5]
# Chemical and physical properties
Resveratrol (3,5,4'-trihydroxystilbene) is a polyphenolic phytoalexin. It is a stilbenoid, a derivate of stilbene, and is produced in plants with the help of the enzyme stilbene synthase.
It exists as two structural isomers: cis- (Z) and trans- (E), with the trans-isomer shown in the top image. Trans-resveratrol can undergo isomerisation to the cis- form when heated or exposed to ultraviolet irradiation.[6] In a 2004 issue of Science, Dr. Sinclair of Harvard University said resveratrol is not an easy molecule to protect from oxidation. It has been claimed that it is readily degraded by exposure to light, heat, and oxygen.[7] However, studies find that Trans-resveratrol undergoes negligible oxidation in normal atmosphere at room temperature.[8]
# Plants and foods
Resveratrol is produced by several plants, apparently due to its antifungal properties. It is found in widely varying amounts in grapes (primarily the skins), raspberries, mulberries, in plums, peanuts, berries of Vaccinium species, including blueberries, bilberries, and cranberries, some pines, such as Scots pine and eastern white pine, and the roots and stalks of giant knotweed and Japanese knotweed, called hu zhang in China. Resveratrol was first isolated from an extract of the Peruvian legume Cassia quinquangulata in 1974; however, the strength of its anti inflammatory activity was not recognized until 1997[9]
The amount of resveratrol in food varies greatly. Ordinary non-muscadine Red wine contains between 0.2 and 5.8 mg/L,[10] depending on the grape variety, while white wine has much less — the reason being that red wine is fermented with the skins, allowing the wine to absorb the resveratrol, whereas white wine is fermented after the skin has been removed. Wines produced from muscadine grapes, however, both red and white, may contain more than 40 mg/L.[11][5]
Fresh grape skin contains about 50 to 100 micrograms of resveratrol per gram.[4]
In grapes, resveratrol is found primarily in the skin and seeds. This is particularly true for muscadine grapes, whose skin and seeds have about 100 times the concentration as the pulp.[12] The amount found in grape skins also varies with the grape cultivar, its geographic origin, and exposure to fungal infection. The amount of fermentation time a wine spends in contact with grape skins is an important determinant of its resveratrol content.[13]
## Content in wines and grape juice
The trans-resveratrol concentration in 40 Tuscan wines ranged from 0.3 to 2.1 mg/L in the 32 red wines and had a maximum of 0.1 mg/L in the 8 white wines tested. Both the cis- and trans- isomers of resveratrol were detected in all tested samples. Cis-resveratrol levels were comparable to those of the trans-isomer. They ranged from 0.5 mg/L to 1.9 mg/L in red wines and had a maximum of 0.2 mg/L in white wines.[14]
Reports suggest that some aspect of the wine making process converts piceid to resveratrol in wine, as wine seems to have twice the average resveratrol concentration of the equivalent commercial juices.[5]
"All of the muscadine table wines sampled had
greater trans and cis resveratrol concentrations than any other wines sampled. The muscadine
table wines varied between 9.2 and 31.9 mg/L cis resveratrol and between 4.9 and 13.4 mg/L
trans resveratrol."[5]
## Content in selected foods
Ounce for ounce, peanuts have more than half the amount of resveratrol in red wine. The average amount of resveratrol in one ounce of peanuts in the marketplace (about 15 whole) is 79.4 µg/ounce. In comparison, some red wines contains approximately 160 µg/fluid ounce.[16] The concentrations of resveratrol were similar in cranberry and grape juice.[17]
Blueberries have about twice as much resveratrol as bilberries, but there is great regional variation. These fruits have less than ten percent of the resveratrol of grapes. Cooking or heat processing of these berries will contribute to the degradation of resveratrol, reducing it by up to half.
[18]
When humans ingest resveratrol orally, most of it seems to be rapidly metabolized and excreted.[15][19]
# Supplement
Resveratrol is available as a nutritional supplement but not as a therapeutic agent (although it has been registered as an investigational drug in some jurisdictions). Supplements, first sourced from ground dried muscadine and red grape skins and seeds (sometimes from residual byproducts of winemaking),[20] are now primarily derived from the cheaper, more concentrated Japanese knotweed. Capsules are sold containing from 1 mg to 500 mg of resveratrol. A less common form is plain powder, which might be more convenient for frequent ingestion as suggested by the rapid metabolism in the body.
Although no studies have yet appeared regarding proper dosage of Resveratrol for humans, Sirtris Pharmaceuticals along with David Sinclair, have taken to use a dosage of 2500 mg and 5000 mg of their resveratrol supplement formulation for their phase 1b human trials, and have recently completed phase 1a trials using the formulation.[21]
Some supplement makers claim that only the trans- form matters, and that the cis- form is not useful or perhaps even a bad thing. Other makers simply report total resveratrol content—or in some cases, just the quantity of an "extract" source, which only contains some percentage of resveratrol.
The following is an excerpt from a FDA New Dietary Ingredient Notification:
First, trans-Resveratrol is excluded from the definition of a “dietary supplement” under 21 U.S.C. 321 (ff) (3) (B), because it is an article authorized for investigation as a new drug for which substantial clinical investigations have been instituted and made public in the U. S.
FDA authorized trans-Resveratrol, which is also known as “resveratrol” or 3,5,4’-trihydroxystilbene, to be an Investigational New Drug on January 30, 2001. The Dietary Supplement Health and Education Act (DSHEA) of 1994 defined a “new dietary ingredient” as one that was marketed in the U.S. on or after October 15, 1994. This office does not have any information that indicates that trans-Resveratrol was legally marketed as a dietary ingredient in the U.S. before October 15, 1994.
Resveratrol is often called a nutraceutical, like other bioactive plant compounds studied for potential clinical applications: curcumin, EGCG, silibinin, etc.
As a result of extensive news coverage,[22] sales of supplements greatly increased in 2006,[23] despite cautions that benefits to humans are unproven.[24][25]
The US government is concerned about the potential dangers of increased, unregulated usage but a "preliminary study of existing [non-human] research found little evidence that resveratrol is toxic, even at very high dosages."
[26] Media reports have claimed that a number of prominent scientists take resveratrol supplements, including Sinclair and Nobelist Frank Wilczek.[27]
A study by Professor Roger Corder has identified a particular group of polyphenols, known as oligomeric procyanidins, which they believe offer the greatest degree of protection to human blood-vessel cells. These are found in greatest concentration in European red wines from certain areas, which correlates with longevity in those regions. This new data may impact the supplement market.[28] Because they are present in red wine in more significant quantities, they are a more reasonable explanation of the French paradox than resveratrol (which would seem to require drinking hundreds of glasses of wine a day to get enough to matter). Procyanidins are also found in similar quantities in purple grape juice, green tea, dark-colored fruits and high-cocoa chocolate.
# Physiological effects
## Mechanism of action
Resveratrol interferes with all three stages of carcinogenesis - initiation, promotion and progression. Experiments in cell cultures of varied types and isolated subcellular systems in vitro imply many mechanisms in the pharmacological activity of resveratrol. These mechanisms include modulation of the transcription factor NF-kB,[29] inhibition of the cytochrome P450 isoenzyme CYP1A1[30] (although this may not be relevant to the CYP1A1-mediated bioactivation of the procarcinogen benzo(a)pyrene[31]), alterations in androgenic[32] actions and expression and activity of cyclooxygenase (COX) enzymes.
Resveratrol was reported effective against neuronal cell dysfunction and cell death, and in theory could help against diseases such as Huntington's disease and Alzheimer's disease.[33][34] Again, this has not yet been tested in humans for any disease.
Research at the Northeastern Ohio Universities College of Medicine and Ohio State University indicates that resveratrol has direct inhibitory action on cardiac fibroblasts and may inhibit the progression of cardiac fibrosis.[35]
Note that resveratrol bioavailability depends on its conjugate forms: glucuronate and sulfonate, despite that most in vitro studies use the aglycone form of resveratrol ('aglycone' means without a sugar molecule attached, as in the figure in this article).
## Metabolism
In humans resveratrol rapidly undergoes phase II conjugation, both glucuronidation and sulphation at multiple sites on the molecule. The effect of conjugation on efficacy is debated.[36][37] The pharmacokinetics of resveratrol metabolism have not been investigated in humans. Rat studies, however, suggest a half life up to 1.6 hours. In a 2002 issue of J Pharm Exper Therapeutics,[38] Dr. Marier reported that rats given a single oral dose of 50 mg/kg body weight initially experienced a rapid drop in serum resveratrol levels: the half life, or T1/2, of the drug was found to be 8 minutes, meaning that blood levels had dropped to half of peak by that time. However, detectable levels of the drug remained for 12 hours, probably due to enterohepatic recirculation—that it, a release of stored resveratrol from liver tissue, yielding an overall half life of between 1.3 and 1.6 hours.[39] It is expected that chemically modified resveratrol-like molecules (drugs) will have a longer half-life and thus more potency.
## Cancer Prevention
In some lineages of cancer cell culture, resveratrol has been shown to induce apoptosis, which means it kills cells and may kill cancer cells.[32][40][41][42][43][44] Resveratrol has been shown to induce Fas/Fas ligand mediated apoptosis, p53 and cyclins A, B1 and cyclin-dependent kinases cdk 1 and 2. Resveratrol also possesses antioxidant and anti-angiogenic properties.[45][46]
Resveratrol is under extensive investigation as a cancer chemopreventive agent.[47][48] Indeed, there are studies showing that small doses of dietary resveratrol can reduce colon carcinogenesis in rats and mice.[49] One German study has already been shown to that under special conditions, resveratrol induces apoptosis in human fat cells. In addition, it inhibits production of cytokines which are involved in the development of obesity-related disorders.[50]
## Life extension and anti-aging
Experiments from the Harvard laboratory of David Sinclair published in 2003 the journal Nature demonstrated that resveratrol significantly extends the lifespan of the yeast Saccharomyces cerevisiae.[51] Dr. Sinclair then founded Sirtris Pharmaceuticals to commercialize resveratrol or related compounds as an anti-aging drug.
Later studies showed that resveratrol prolongs the lifespan of the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster.[52] In 2006, it also extended the maximum lifespan of a short-lived fish, Nothobranchius furzeri, by 59%, and extended its median lifespan by 56%. Also noted were an increase in swimming performance, an increase in cognitive performance (learning tasks), and a lack of neurofibrillary degeneration (found in a control group). The authors observed that "[resveratrol's] supplementation with food extends vertebrate lifespan and delays motor and cognitive age-related decline could be of high relevance for the prevention of aging-related diseases in the human population."[53] Later in 2006, a report in the journal Nature from Sinclair's laboratory and the Laboratory of Experimental Gerontology at the National Institute on Aging showed that the compound improves health and survival of mice on a high-calorie diet.[54]
The mechanisms of resveratrol's apparent effects on life extension are not fully understood, but they appear to mimic several of the biochemical effects of calorie restriction. This seems to function by means of lipase inhibition, reducing the absorption of fat through intestinal walls. A new report indicates that resveratrol activates SIRT1 and PGC-1α and improve functioning of the mitochondria.[55]
Only the "Trans" form of the molecule is capable of activating the mammalian SIRT1 gene in vitro; this is also the form predominantly found in red grape skins and red wine. Red grapes grown in some regions (such as New York state) often have much higher concentrations of resveratrol based on the cooler climate and the resulting increase in fungal attacks that promote resveratrol production. However, the amount in any wine, including Muscadine grape wines, is negligible compared to the amount that in theory is needed for health benefits: 1–10 milligrams per liter of wine versus hundreds to thousands of milligrams/day.
Recent research calls into question this theory connecting resveratrol, SIRT1 and calorie restriction.[56][57]
Follow up studies by the National Institute on Aging and David Sinclair, published in November 2006 by the journal Nature, replicated the life extending benefits of resveratrol in mice, the first such demonstration in a mammal. Preliminary results showed that obese mice provided with resveratrol lived an average of 15% longer than obese mice not provided the supplement.
The amounts used in the mouse study were approximately 22.4 mg/kg body weight per day. Scaling this amount to human body weights would imply an "equivalent human dose" of 1.5 to 2.0 grams/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to the range of 150 to 200 mg/day if the resveratrol plasma levels in humans were not known and we wanted to predict a human dosage using FDA guidelines.[58]
The truth is that many differences exist between mouse and human metabolism, and the effects of any given oral dose in humans remain unknown. In 2004, there was a study to determine absorption, bioavailability, and metabolism of Resveratrol in humans. It indicated that Resveratrol was quickly metabolized using 25mg doses in humans.[19] Only trace amounts were found in human plasma, and that most of the oral dose was recovered in urine. Mice, on the other hand were found to have much larger amounts of resveratrol measured in their plasma using equivalent doses of resveratrol per kilogram of weight. It was also stated in the study that the systemic bioavailability of resveratrol is very low in humans compared to that of mice, but that accumulation of resveratrol in the human epithelial cells along the aerodigestive tract along with potentially active resveratrol metabolites may still produce cancer-preventive and other effects. Large dosages could theoretically increase the resveratrol in human plasma.
There is no human evidence yet that quantities found in red wine or in standard supplements are sufficient for any health effect.
## Athletic performance
Johan Auwerx (at the Institute of Genetics and Molecular and Cell Biology in Illkirch, France) and coauthors published an online article in the journal CELL in November 2006. Mice fed resveratrol for 15 weeks had better treadmill endurance than controls. The study supported Sinclair's hypothesis that the effects of resveratrol are indeed due to the activation of SIRT1.
Nicholas Wade's interview-article with Dr. Auwerx[59] states that the dose was 400 mg/kg of body weight (much higher than the 22 mg/kg of the Sinclair study). For an 80 kg (176 lb) person, the 400 mg/kg of body weight amount used in Dr. Auwerx's mouse study would come to 32,000 mg/day. Compensating for the fact that humans have slower metabolic rates than mice would change the equivalent human dose to roughly 4571 mg/day. Again, there is no published evidence anywhere in the scientific literature of any clinical trial for efficacy in humans. There is limited human safety data (see above). It is premature to take resveratrol and expect any particular results. Long-term safety has not been evaluated in humans.
In a study of 123 Finnish adults, those born with certain increased variations of the SIRT1 gene had faster metabolisms, helping them to burn energy more efficiently—indicating that the same pathway shown in the lab mice works in humans too.[60]
## Antiviral effects
Resveratrol seems to increase the potency of some antiretroviral drugs against HIV in vitro.[61]
Infection by herpes simplex virus ordinarily activates the cell protein Nuclear Factor κB (NF-κB). A Northeastern Ohio Universities College of Medicine study undertaken in Vero cells found that resveratrol suppresses the activation of this transcription- and apoptosis-related protein. The study further found that multiple viral protein products were reduced or completely blocked, as well as a reduction in viral DNA production.[62]
A cell culture study found that resveratrol blocks the influenza virus from transporting viral proteins to the viral assembly site, hence restricting its ability to replicate. The effect was 90% when resveratrol was added six hours after infection and continued for 24 hours thereafter.[63]
## Adverse effects and unknowns
While the health benefits of resveratrol seem promising, one study has theorized that it may stimulate the growth of human breast cancer cells, possibly because of resveratrol's chemical structure, which is similar to a phytoestrogen.[64][65] However, other studies have found that resveratrol actually fights breast cancer.[66][67]
Citing the evidence that resveratrol is estrogenic, some retailers of resveratrol advise that the compound may interfere with oral contraceptives and that women who are pregnant or intending to become pregnant should not use the product, while others advise that resveratrol should not be taken by children or young adults under 18, as no studies have shown how it affects their natural development.[68]
An independent study of resveratrol found "no significant effects on lifespan in seven independent trials" in Drosophila and found "slight increases in lifespan in some trials but not others" in C. elegans.[69] This finding refutes Sinclair's study published in 2004: Sirtuin activators mimic caloric restriction and delay ageing in metazoans. | https://www.wikidoc.org/index.php/Resveratrol | |
c212e8166bb9ec51e974e1a914e02ec9206ccf43 | wikidoc | Retapamulin | Retapamulin
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# Overview
Retapamulin is a pleuromutilin antibacterial that is FDA approved for the treatment of impetigo due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes in patients aged 9 months or older. Common adverse reactions include application site irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ALTABAX® is indicated for use in adults for the topical treatment of impetigo (up to 100 cm2 in total area in adults) due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes. Safety in patients younger than 9 months has not been established.
- A thin layer of ALTABAX should be applied to the affected area (up to 100 cm2 in total area in adults) twice daily for 5 days. The treated area may be covered with a sterile bandage or gauze dressing if desired.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Retapamulin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Retapamulin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- ALTABAX® is indicated for use in pediatric patients aged 9 months and older for the topical treatment of impetigo (2% total body surface area in pediatric patients aged 9 months or older) due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes. Safety in patients younger than 9 months has not been established.
- A thin layer of ALTABAX should be applied to the affected area (2% total body surface area in pediatric patients aged 9 months or older) twice daily for 5 days. The treated area may be covered with a sterile bandage or gauze dressing if desired.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Retapamulin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Retapamulin in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Local Irritation
- In the event of sensitization or severe local irritation from ALTABAX, usage should be discontinued, the ointment wiped off, and appropriate alternative therapy for the infection instituted.
- Not for Systemic or Mucosal Use
- ALTABAX is not intended for ingestion or for oral, intranasal, ophthalmic, or intravaginal use. The efficacy and safety of ALTABAX on mucosal surfaces have not been established. Epistaxis has been reported with the use of ALTABAX on nasal mucosa.
- Potential for Microbial Overgrowth
- The use of antibiotics may promote the selection of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.
- Prescribing ALTABAX in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from the clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
- The safety profile of ALTABAX was assessed in 2,115 adult and pediatric subjects ≥9 months who used at least one dose from a 5-day, twice a day regimen of retapamulin ointment. Control groups included 819 adult and pediatric subjects who used at least one dose of the active control (oral cephalexin), 172 subjects who used an active topical comparator (not available in the US), and 71 subjects who used placebo.
- Adverse events rated by investigators as drug-related occurred in 5.5% (116/2,115) of subjects treated with retapamulin ointment, 6.6% (54/819) of subjects receiving cephalexin, and 2.8% (2/71) of subjects receiving placebo. The most common drug-related adverse events (≥1% of subjects) were application site irritation (1.4%) in the retapamulin group, diarrhea (1.7%) in the cephalexin group, and application site pruritus (1.4%) and application site paresthesia (1.4%) in the placebo group.
- Adults:
- The adverse events, regardless of attribution, reported in at least 1% of adults (aged 18 years and older) who received ALTABAX or comparator are presented in Table 1.
- Pediatrics:
- The adverse events, regardless of attribution, reported in at least 1% of pediatric subjects aged 9 months to 17 years who received ALTABAX are presented in Table 2.
- Other Adverse Events:
- Application site pain, erythema, and contact dermatitis were reported in less than 1% of subjects in clinical trials.
## Postmarketing Experience
- In addition to reports in clinical trials, the following events have been identified during postmarketing use of ALTABAX. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Application site burning.
Hypersensitivity including angioedema.
# Drug Interactions
- Coadministration of oral ketoconazole 200 mg twice daily increased retapamulin geometric mean AUC(0-24) and Cmaxby 81% after topical application of retapamulin ointment, 1% on the abraded skin of healthy adult males. Due to low systemic exposure to retapamulin following topical application in adults and pediatric patients aged 2 years and older, dosage adjustments for retapamulin are unnecessary when coadministered with CYP3A4 inhibitors, such as ketoconazole. Based on in vitro P450 inhibition studies and the low systemic exposure observed following topical application of ALTABAX, retapamulin is unlikely to affect the metabolism of other P450 substrates.
- Concomitant administration of retapamulin and CYP3A4 inhibitors, such as ketoconazole, has not been studied in pediatric patients. In pediatric subjects aged 2 to 24 months, systemic exposure of retapamulin was higher compared with subjects aged 2 years and older after topical application. Based on the higher exposure of retapamulin, it is not recommended to coadminister ALTABAX with strong CYP3A4 inhibitors in patients younger than 24 months.
- The effect of concurrent application of ALTABAX and other topical products to the same area of skin has not been studied.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Effects on embryo-fetal development were assessed in pregnant rats given 50, 150, or 450 mg/kg/day by oral gavage on days 6 to 17 postcoitus. Maternal toxicity (decreased body weight gain and food consumption) and developmental toxicity (decreased fetal body weight and delayed skeletal ossification) were evident at doses ≥150 mg/kg/day. There were no treatment-related malformations observed in fetal rats.
- Retapamulin was given as a continuous intravenous infusion to pregnant rabbits at dosages of 2.4, 7.2, or 24 mg/kg/day from day 7 to 19 of gestation. Maternal toxicity (decreased body weight gain, food consumption, and abortions) was demonstrated at dosages ≥7.2 mg/kg/day (8-fold the estimated maximum achievable human exposure, based on AUC, at 7.2 mg/kg/day). There was no treatment-related effect on embryo-fetal development.
- There are no adequate and well-controlled trials in pregnant women. Because animal reproduction studies are not always predictive of human response, ALTABAX should be used in pregnancy only when the potential benefits outweigh the potential risk.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Retapamulin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Retapamulin during labor and delivery.
### Nursing Mothers
- It is not known whether retapamulin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ALTABAX is administered to a nursing woman. The safe use of retapamulin during breastfeeding has not been established.
### Pediatric Use
- The safety and effectiveness of ALTABAX in the treatment of impetigo have been established in pediatric patients aged 9 months to 17 years. Use of ALTABAX in pediatric patients (9 months to 17 years) is supported by evidence from adequate and well-controlled trials of ALTABAX in which 588 pediatric subjects received at least one dose of retapamulin ointment, 1%. The magnitude of efficacy and the safety profile of ALTABAX in pediatric subjects 9 months and older were similar to those in adults.
- The safety and effectiveness of ALTABAX in pediatric patients younger than 9 months of age have not been established. An open-label clinical trial of topical treatment with ALTABAX (twice daily for 5 days) was conducted in patients aged 2 to 24 months. Plasma samples were obtained from 79 subjects. In these pediatric subjects, systemic exposure of retapamulin was higher compared with subjects aged 2 to 17 years. Furthermore, a higher proportion of pediatric subjects aged 2 to 9 months had measurable concentrations (>0.5 ng/mL) of retapamulin compared with subjects aged 9 to 24 months. The highest levels were seen in subjects aged 2 to 6 months. The use of retapamulin is not indicated in pediatric patients younger than 9 months.
### Geriatic Use
- Of the total number of subjects in the adequate and well-controlled trials of ALTABAX, 234 subjects were 65 years of age and older, of whom 114 subjects were 75 years of age and older. No overall differences in effectiveness or safety were observed between these subjects and younger adult subjects.
### Gender
There is no FDA guidance on the use of Retapamulin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Retapamulin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Retapamulin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Retapamulin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Retapamulin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Retapamulin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Retapamulin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Retapamulin in the drug label.
# Overdosage
## Acute Overdose
- Overdosage with ALTABAX has not been reported. Any signs or symptoms of overdose, either topically or by accidental ingestion, should be treated symptomatically consistent with good clinical practice.
- There is no known antidote for overdoses of ALTABAX.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Retapamulin in the drug label.
# Pharmacology
## Mechanism of Action
- Retapamulin selectively inhibits bacterial protein synthesis by interacting at a site on the 50S subunit of the bacterial ribosome through an interaction that is different from that of other antibiotics. This binding site involves ribosomal protein L3 and is in the region of the ribosomal P site and peptidyl transferase center. By virtue of binding to this site, pleuromutilins inhibit peptidyl transfer, block P-site interactions, and prevent the normal formation of active 50S ribosomal subunits. Retapamulin is bacteriostatic against Staphylococcus aureus and Streptococcus pyogenes at the retapamulin in vitro minimum inhibitory concentration (MIC) for these organisms. At concentrations 1,000x the in vitro MIC, retapamulin is bactericidal against these same organisms. Although cross-resistance between retapamulin and other antibacterial classes (such as clindamycin and oxazolidones) exist, isolates resistant to these classes may be susceptible to retapamulin.
## Structure
- ALTABAX contains retapamulin, a semisynthetic pleuromutilin antibiotic. The chemical name of retapamulin is acetic acid, oct-3-yl]thio]-, (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyldecahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9-propano-3aH-cyclopentacycloocten-8-yl ester. Retapamulin, a white to pale-yellow crystalline solid, has a molecular formula of C30H47NO4S, and a molecular weight of 517.78. The chemical structure is:
- Each gram of ointment for dermatological use contains 10 mg of retapamulin in white petrolatum.
## Pharmacodynamics
- In post-hoc analyses of manually over-read 12-lead ECGs from healthy subjects (N = 103), no significant effects on QT/QTc intervals were observed after topical application of retapamulin ointment on intact and abraded skin. Due to the low systemic exposure to retapamulin with topical application, QT prolongation in patients is unlikely.
## Pharmacokinetics
- Absorption:
- In a trial of healthy adult subjects, retapamulin ointment, 1% was applied once daily to intact skin (800 cm2 surface area) and to abraded skin (200 cm2 surface area) under occlusion for up to 7 days. Systemic exposure following topical application of retapamulin through intact and abraded skin was low. Three percent of blood samples obtained on Day 1 after topical application to intact skin had measurable retapamulin concentrations (lower limit of quantitation 0.5 ng/mL); thus Cmax values on Day 1 could not be determined. Eighty-two percent of blood samples obtained on Day 7 after topical application to intact skin and 97% and 100% of blood samples obtained after topical application to abraded skin on Days 1 and 7, respectively, had measurable retapamulin concentrations. The median Cmax value in plasma after application to 800 cm2 of intact skin was 3.5 ng/mL on Day 7 (range: 1.2 to 7.8 ng/mL). The median Cmax value in plasma after application to 200 cm2 of abraded skin was 11.7 ng/mL on Day 1 (range: 5.6 to 22.1 ng/mL) and 9.0 ng/mL on Day 7 (range: 6.7 to 12.8 ng/mL).
- Plasma samples were obtained from 380 adult subjects and 136 pediatric subjects (aged 2 to 17 years) who were receiving topical treatment with ALTABAX topically twice daily. Eleven percent had measurable retapamulin concentrations (lower limit of quantitation 0.5 ng/mL), of which the median concentration was 0.8 ng/mL. The maximum measured retapamulin concentration in adults was 10.7 ng/mL and in pediatric subjects (aged 2 to 17 years) was 18.5 ng/mL.
- A single plasma sample was obtained from 79 pediatric subjects (aged 2 to 24 months) who were receiving topical treatment with ALTABAX twice daily. Forty-six percent had measurable retapamulin concentrations (>0.5 ng/mL) compared with 7% in pediatric subjects aged 2 to 17 years. A higher proportion (69%) of pediatric subjects aged 2 to 9 months had measurable concentrations of retapamulin compared with subjects aged 9 to 24 months (32%). Among pediatric subjects aged 2 to 9 months (n = 29), 4 subjects had retapamulin concentrations that were higher (≥26.9 ng/mL) than the maximum concentration observed in pediatric subjects aged 2 to 17 years (18.5 ng/mL). Among pediatric subjects aged 9 to 24 months (n = 50), 1 subject had a retapamulin concentration that was higher (95.1 ng/mL) than the maximum level observed in pediatric subjects aged 2 to 17 years.
- Distribution:
- Retapamulin is approximately 94% bound to human plasma proteins, and the protein binding is independent of concentration. The apparent volume of distribution of retapamulin has not been determined in humans.
- Metabolism:
- In vitro studies with human hepatocytes showed that the main routes of metabolism were mono-oxygenation and di-oxygenation. In vitro studies with human liver microsomes demonstrated that retapamulin is extensively metabolized to numerous metabolites, of which the predominant routes of metabolism were mono-oxygenation and N-demethylation. The major enzyme responsible for metabolism of retapamulin in human liver microsomes was cytochrome P450 3A4 (CYP3A4).
- Elimination:
- Retapamulin elimination in humans has not been investigated due to low systemic exposure after topical application.
## Nonclinical Toxicology
- Long-term studies in animals to evaluate carcinogenic potential have not been conducted with retapamulin.
- Retapamulin showed no genotoxicity when evaluated in vitro for gene mutation and/or chromosomal effects in the mouse lymphoma cell assay, in cultured human peripheral blood lymphocytes, or when evaluated in vivo in a rat micronucleus test.
- No evidence of impaired fertility was found in male or female rats given retapamulin 50, 150, or 450 mg/kg/day orally.
# Clinical Studies
- ALTABAX was evaluated in a placebo-controlled trial that enrolled adult and pediatric subjects aged 9 months and older for treatment of impetigo up to 100 cm2 in total area (up to 10 lesions) or a total body surface area not exceeding 2%. The majority of subjects enrolled (164/210, 78%) were under the age of 13. The trial was a double-blind, randomized, multi-center, parallel-group comparison of the safety of ALTABAX and placebo ointment, both applied twice daily for 5 days. Patients were randomized to ALTABAX or placebo (2:1). Subjects with underlying skin disease (e.g., pre-existing eczematous dermatitis) or skin trauma, with clinical evidence of secondary infection were excluded from these trials. In addition, subjects with any systemic signs and symptoms of infection (such as fever) were excluded from the trial. Clinical success was defined as the absence of treated lesions, or treated lesions had become dry without crusts with or without erythema compared with baseline, or had improved (defined as a decline in the size of the affected area, number of lesions or both) such that no further antimicrobial therapy was required. The intent-to-treat clinical (ITTC) population consisted of all randomized subjects who took at least 1 dose of trial medication. The clinical per protocol (PPC) population included all ITTC subjects who satisfied the inclusion/exclusion criteria and subsequently adhered to the protocol. The intent-to-treat bacteriological (ITTB) population consisted of all randomized subjects who took at least 1 dose of trial medication and had a pathogen identified at trial entry. The bacteriological per protocol (PPB) population included all ITTB subjects who satisfied the inclusion/exclusion criteria and subsequently adhered to the protocol.
- Table 4 presents the results for clinical response at end of therapy (2 days after treatment) and follow-up (9 days after treatment), by analysis population:
- Examination of age and gender subgroups did not identify differences in response to ALTABAX among these groups. The majority of subjects entered into this trial were classified as White/Caucasian or of Asian heritage; when response rates by racial subgroups were viewed across trials, differences in response to ALTABAX were not identified.
# How Supplied
- ALTABAX is supplied in 15-, and 30-gram tubes.
- NDC 0007-5180-22 (15 gram tube)
- NDC 0007-5180-25 (30 gram tube)
- Store at 25°C (77°F) with excursions permitted to 15°-30°C (59°-86°F).
## Storage
There is limited information regarding Retapamulin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients using ALTABAX and/or their guardians should receive the following information and instructions:
- Use ALTABAX as directed by the healthcare practitioner. As with any topical medication, patients and caregivers should wash their hands after application if the hands are not the area for treatment.
- ALTABAX is for external use only. Do not swallow ALTABAX or use it in the eyes, on the mouth or lips, inside the nose, or inside the female genital area.
- The treated area may be covered by a sterile bandage or gauze dressing, if desired. This may also be helpful for infants and young children who accidentally touch or lick the lesion site. A bandage will protect the treated area and avoid accidental transfer of ointment to the eyes or other areas.
- Use the medication for the full time recommended by the healthcare practitioner, even though symptoms may have improved.
- Notify the healthcare practitioner if there is no improvement in symptoms within 3 to 4 days after starting use of ALTABAX.
- ALTABAX may cause reactions at the site of application of the ointment. Inform the healthcare practitioner if the area of application worsens in irritation, redness, itching, burning, swelling, blistering, or oozing.
# Precautions with Alcohol
- Alcohol-Retapamulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ALTABAX®
# Look-Alike Drug Names
There is limited information regarding Retapamulin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Retapamulin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Retapamulin is a pleuromutilin antibacterial that is FDA approved for the treatment of impetigo due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes in patients aged 9 months or older. Common adverse reactions include application site irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- ALTABAX® is indicated for use in adults for the topical treatment of impetigo (up to 100 cm2 in total area in adults) due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes. Safety in patients younger than 9 months has not been established.
- A thin layer of ALTABAX should be applied to the affected area (up to 100 cm2 in total area in adults) twice daily for 5 days. The treated area may be covered with a sterile bandage or gauze dressing if desired.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Retapamulin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Retapamulin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- ALTABAX® is indicated for use in pediatric patients aged 9 months and older for the topical treatment of impetigo (2% total body surface area in pediatric patients aged 9 months or older) due to Staphylococcus aureus (methicillin-susceptible isolates only) or Streptococcus pyogenes. Safety in patients younger than 9 months has not been established.
- A thin layer of ALTABAX should be applied to the affected area (2% total body surface area in pediatric patients aged 9 months or older) twice daily for 5 days. The treated area may be covered with a sterile bandage or gauze dressing if desired.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Retapamulin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Retapamulin in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Local Irritation
- In the event of sensitization or severe local irritation from ALTABAX, usage should be discontinued, the ointment wiped off, and appropriate alternative therapy for the infection instituted.
- Not for Systemic or Mucosal Use
- ALTABAX is not intended for ingestion or for oral, intranasal, ophthalmic, or intravaginal use. The efficacy and safety of ALTABAX on mucosal surfaces have not been established. Epistaxis has been reported with the use of ALTABAX on nasal mucosa.
- Potential for Microbial Overgrowth
- The use of antibiotics may promote the selection of nonsusceptible organisms. Should superinfection occur during therapy, appropriate measures should be taken.
- Prescribing ALTABAX in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from the clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.
- The safety profile of ALTABAX was assessed in 2,115 adult and pediatric subjects ≥9 months who used at least one dose from a 5-day, twice a day regimen of retapamulin ointment. Control groups included 819 adult and pediatric subjects who used at least one dose of the active control (oral cephalexin), 172 subjects who used an active topical comparator (not available in the US), and 71 subjects who used placebo.
- Adverse events rated by investigators as drug-related occurred in 5.5% (116/2,115) of subjects treated with retapamulin ointment, 6.6% (54/819) of subjects receiving cephalexin, and 2.8% (2/71) of subjects receiving placebo. The most common drug-related adverse events (≥1% of subjects) were application site irritation (1.4%) in the retapamulin group, diarrhea (1.7%) in the cephalexin group, and application site pruritus (1.4%) and application site paresthesia (1.4%) in the placebo group.
- Adults:
- The adverse events, regardless of attribution, reported in at least 1% of adults (aged 18 years and older) who received ALTABAX or comparator are presented in Table 1.
- Pediatrics:
- The adverse events, regardless of attribution, reported in at least 1% of pediatric subjects aged 9 months to 17 years who received ALTABAX are presented in Table 2.
- Other Adverse Events:
- Application site pain, erythema, and contact dermatitis were reported in less than 1% of subjects in clinical trials.
## Postmarketing Experience
- In addition to reports in clinical trials, the following events have been identified during postmarketing use of ALTABAX. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Application site burning.
Hypersensitivity including angioedema.
# Drug Interactions
- Coadministration of oral ketoconazole 200 mg twice daily increased retapamulin geometric mean AUC(0-24) and Cmaxby 81% after topical application of retapamulin ointment, 1% on the abraded skin of healthy adult males. Due to low systemic exposure to retapamulin following topical application in adults and pediatric patients aged 2 years and older, dosage adjustments for retapamulin are unnecessary when coadministered with CYP3A4 inhibitors, such as ketoconazole. Based on in vitro P450 inhibition studies and the low systemic exposure observed following topical application of ALTABAX, retapamulin is unlikely to affect the metabolism of other P450 substrates.
- Concomitant administration of retapamulin and CYP3A4 inhibitors, such as ketoconazole, has not been studied in pediatric patients. In pediatric subjects aged 2 to 24 months, systemic exposure of retapamulin was higher compared with subjects aged 2 years and older after topical application. Based on the higher exposure of retapamulin, it is not recommended to coadminister ALTABAX with strong CYP3A4 inhibitors in patients younger than 24 months.
- The effect of concurrent application of ALTABAX and other topical products to the same area of skin has not been studied.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Effects on embryo-fetal development were assessed in pregnant rats given 50, 150, or 450 mg/kg/day by oral gavage on days 6 to 17 postcoitus. Maternal toxicity (decreased body weight gain and food consumption) and developmental toxicity (decreased fetal body weight and delayed skeletal ossification) were evident at doses ≥150 mg/kg/day. There were no treatment-related malformations observed in fetal rats.
- Retapamulin was given as a continuous intravenous infusion to pregnant rabbits at dosages of 2.4, 7.2, or 24 mg/kg/day from day 7 to 19 of gestation. Maternal toxicity (decreased body weight gain, food consumption, and abortions) was demonstrated at dosages ≥7.2 mg/kg/day (8-fold the estimated maximum achievable human exposure, based on AUC, at 7.2 mg/kg/day). There was no treatment-related effect on embryo-fetal development.
- There are no adequate and well-controlled trials in pregnant women. Because animal reproduction studies are not always predictive of human response, ALTABAX should be used in pregnancy only when the potential benefits outweigh the potential risk.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Retapamulin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Retapamulin during labor and delivery.
### Nursing Mothers
- It is not known whether retapamulin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ALTABAX is administered to a nursing woman. The safe use of retapamulin during breastfeeding has not been established.
### Pediatric Use
- The safety and effectiveness of ALTABAX in the treatment of impetigo have been established in pediatric patients aged 9 months to 17 years. Use of ALTABAX in pediatric patients (9 months to 17 years) is supported by evidence from adequate and well-controlled trials of ALTABAX in which 588 pediatric subjects received at least one dose of retapamulin ointment, 1%. The magnitude of efficacy and the safety profile of ALTABAX in pediatric subjects 9 months and older were similar to those in adults.
- The safety and effectiveness of ALTABAX in pediatric patients younger than 9 months of age have not been established. An open-label clinical trial of topical treatment with ALTABAX (twice daily for 5 days) was conducted in patients aged 2 to 24 months. Plasma samples were obtained from 79 subjects. In these pediatric subjects, systemic exposure of retapamulin was higher compared with subjects aged 2 to 17 years. Furthermore, a higher proportion of pediatric subjects aged 2 to 9 months had measurable concentrations (>0.5 ng/mL) of retapamulin compared with subjects aged 9 to 24 months. The highest levels were seen in subjects aged 2 to 6 months. The use of retapamulin is not indicated in pediatric patients younger than 9 months.
### Geriatic Use
- Of the total number of subjects in the adequate and well-controlled trials of ALTABAX, 234 subjects were 65 years of age and older, of whom 114 subjects were 75 years of age and older. No overall differences in effectiveness or safety were observed between these subjects and younger adult subjects.
### Gender
There is no FDA guidance on the use of Retapamulin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Retapamulin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Retapamulin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Retapamulin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Retapamulin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Retapamulin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Retapamulin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Retapamulin in the drug label.
# Overdosage
## Acute Overdose
- Overdosage with ALTABAX has not been reported. Any signs or symptoms of overdose, either topically or by accidental ingestion, should be treated symptomatically consistent with good clinical practice.
- There is no known antidote for overdoses of ALTABAX.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Retapamulin in the drug label.
# Pharmacology
## Mechanism of Action
- Retapamulin selectively inhibits bacterial protein synthesis by interacting at a site on the 50S subunit of the bacterial ribosome through an interaction that is different from that of other antibiotics. This binding site involves ribosomal protein L3 and is in the region of the ribosomal P site and peptidyl transferase center. By virtue of binding to this site, pleuromutilins inhibit peptidyl transfer, block P-site interactions, and prevent the normal formation of active 50S ribosomal subunits. Retapamulin is bacteriostatic against Staphylococcus aureus and Streptococcus pyogenes at the retapamulin in vitro minimum inhibitory concentration (MIC) for these organisms. At concentrations 1,000x the in vitro MIC, retapamulin is bactericidal against these same organisms. Although cross-resistance between retapamulin and other antibacterial classes (such as clindamycin and oxazolidones) exist, isolates resistant to these classes may be susceptible to retapamulin.
## Structure
- ALTABAX contains retapamulin, a semisynthetic pleuromutilin antibiotic. The chemical name of retapamulin is acetic acid, [(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]thio]-, (3aS,4R,5S,6S,8R,9R,9aR,10R)-6-ethenyldecahydro-5-hydroxy-4,6,9,10-tetramethyl-1-oxo-3a,9-propano-3aH-cyclopentacycloocten-8-yl ester. Retapamulin, a white to pale-yellow crystalline solid, has a molecular formula of C30H47NO4S, and a molecular weight of 517.78. The chemical structure is:
- Each gram of ointment for dermatological use contains 10 mg of retapamulin in white petrolatum.
## Pharmacodynamics
- In post-hoc analyses of manually over-read 12-lead ECGs from healthy subjects (N = 103), no significant effects on QT/QTc intervals were observed after topical application of retapamulin ointment on intact and abraded skin. Due to the low systemic exposure to retapamulin with topical application, QT prolongation in patients is unlikely.
## Pharmacokinetics
- Absorption:
- In a trial of healthy adult subjects, retapamulin ointment, 1% was applied once daily to intact skin (800 cm2 surface area) and to abraded skin (200 cm2 surface area) under occlusion for up to 7 days. Systemic exposure following topical application of retapamulin through intact and abraded skin was low. Three percent of blood samples obtained on Day 1 after topical application to intact skin had measurable retapamulin concentrations (lower limit of quantitation 0.5 ng/mL); thus Cmax values on Day 1 could not be determined. Eighty-two percent of blood samples obtained on Day 7 after topical application to intact skin and 97% and 100% of blood samples obtained after topical application to abraded skin on Days 1 and 7, respectively, had measurable retapamulin concentrations. The median Cmax value in plasma after application to 800 cm2 of intact skin was 3.5 ng/mL on Day 7 (range: 1.2 to 7.8 ng/mL). The median Cmax value in plasma after application to 200 cm2 of abraded skin was 11.7 ng/mL on Day 1 (range: 5.6 to 22.1 ng/mL) and 9.0 ng/mL on Day 7 (range: 6.7 to 12.8 ng/mL).
- Plasma samples were obtained from 380 adult subjects and 136 pediatric subjects (aged 2 to 17 years) who were receiving topical treatment with ALTABAX topically twice daily. Eleven percent had measurable retapamulin concentrations (lower limit of quantitation 0.5 ng/mL), of which the median concentration was 0.8 ng/mL. The maximum measured retapamulin concentration in adults was 10.7 ng/mL and in pediatric subjects (aged 2 to 17 years) was 18.5 ng/mL.
- A single plasma sample was obtained from 79 pediatric subjects (aged 2 to 24 months) who were receiving topical treatment with ALTABAX twice daily. Forty-six percent had measurable retapamulin concentrations (>0.5 ng/mL) compared with 7% in pediatric subjects aged 2 to 17 years. A higher proportion (69%) of pediatric subjects aged 2 to 9 months had measurable concentrations of retapamulin compared with subjects aged 9 to 24 months (32%). Among pediatric subjects aged 2 to 9 months (n = 29), 4 subjects had retapamulin concentrations that were higher (≥26.9 ng/mL) than the maximum concentration observed in pediatric subjects aged 2 to 17 years (18.5 ng/mL). Among pediatric subjects aged 9 to 24 months (n = 50), 1 subject had a retapamulin concentration that was higher (95.1 ng/mL) than the maximum level observed in pediatric subjects aged 2 to 17 years.
- Distribution:
- Retapamulin is approximately 94% bound to human plasma proteins, and the protein binding is independent of concentration. The apparent volume of distribution of retapamulin has not been determined in humans.
- Metabolism:
- In vitro studies with human hepatocytes showed that the main routes of metabolism were mono-oxygenation and di-oxygenation. In vitro studies with human liver microsomes demonstrated that retapamulin is extensively metabolized to numerous metabolites, of which the predominant routes of metabolism were mono-oxygenation and N-demethylation. The major enzyme responsible for metabolism of retapamulin in human liver microsomes was cytochrome P450 3A4 (CYP3A4).
- Elimination:
- Retapamulin elimination in humans has not been investigated due to low systemic exposure after topical application.
## Nonclinical Toxicology
- Long-term studies in animals to evaluate carcinogenic potential have not been conducted with retapamulin.
- Retapamulin showed no genotoxicity when evaluated in vitro for gene mutation and/or chromosomal effects in the mouse lymphoma cell assay, in cultured human peripheral blood lymphocytes, or when evaluated in vivo in a rat micronucleus test.
- No evidence of impaired fertility was found in male or female rats given retapamulin 50, 150, or 450 mg/kg/day orally.
# Clinical Studies
- ALTABAX was evaluated in a placebo-controlled trial that enrolled adult and pediatric subjects aged 9 months and older for treatment of impetigo up to 100 cm2 in total area (up to 10 lesions) or a total body surface area not exceeding 2%. The majority of subjects enrolled (164/210, 78%) were under the age of 13. The trial was a double-blind, randomized, multi-center, parallel-group comparison of the safety of ALTABAX and placebo ointment, both applied twice daily for 5 days. Patients were randomized to ALTABAX or placebo (2:1). Subjects with underlying skin disease (e.g., pre-existing eczematous dermatitis) or skin trauma, with clinical evidence of secondary infection were excluded from these trials. In addition, subjects with any systemic signs and symptoms of infection (such as fever) were excluded from the trial. Clinical success was defined as the absence of treated lesions, or treated lesions had become dry without crusts with or without erythema compared with baseline, or had improved (defined as a decline in the size of the affected area, number of lesions or both) such that no further antimicrobial therapy was required. The intent-to-treat clinical (ITTC) population consisted of all randomized subjects who took at least 1 dose of trial medication. The clinical per protocol (PPC) population included all ITTC subjects who satisfied the inclusion/exclusion criteria and subsequently adhered to the protocol. The intent-to-treat bacteriological (ITTB) population consisted of all randomized subjects who took at least 1 dose of trial medication and had a pathogen identified at trial entry. The bacteriological per protocol (PPB) population included all ITTB subjects who satisfied the inclusion/exclusion criteria and subsequently adhered to the protocol.
- Table 4 presents the results for clinical response at end of therapy (2 days after treatment) and follow-up (9 days after treatment), by analysis population:
- Examination of age and gender subgroups did not identify differences in response to ALTABAX among these groups. The majority of subjects entered into this trial were classified as White/Caucasian or of Asian heritage; when response rates by racial subgroups were viewed across trials, differences in response to ALTABAX were not identified.
# How Supplied
- ALTABAX is supplied in 15-, and 30-gram tubes.
- NDC 0007-5180-22 (15 gram tube)
- NDC 0007-5180-25 (30 gram tube)
- Store at 25°C (77°F) with excursions permitted to 15°-30°C (59°-86°F).
## Storage
There is limited information regarding Retapamulin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients using ALTABAX and/or their guardians should receive the following information and instructions:
- Use ALTABAX as directed by the healthcare practitioner. As with any topical medication, patients and caregivers should wash their hands after application if the hands are not the area for treatment.
- ALTABAX is for external use only. Do not swallow ALTABAX or use it in the eyes, on the mouth or lips, inside the nose, or inside the female genital area.
- The treated area may be covered by a sterile bandage or gauze dressing, if desired. This may also be helpful for infants and young children who accidentally touch or lick the lesion site. A bandage will protect the treated area and avoid accidental transfer of ointment to the eyes or other areas.
- Use the medication for the full time recommended by the healthcare practitioner, even though symptoms may have improved.
- Notify the healthcare practitioner if there is no improvement in symptoms within 3 to 4 days after starting use of ALTABAX.
- ALTABAX may cause reactions at the site of application of the ointment. Inform the healthcare practitioner if the area of application worsens in irritation, redness, itching, burning, swelling, blistering, or oozing.
# Precautions with Alcohol
- Alcohol-Retapamulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ALTABAX®[1]
# Look-Alike Drug Names
There is limited information regarding Retapamulin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Retapamulin | |
c6be2dbfad045e9242f3a6af3160882780aa27d9 | wikidoc | Reticulon 4 | Reticulon 4
Reticulon 4, also known as Neurite outgrowth inhibitor or Nogo, is a protein that in humans is encoded by the RTN4 gene that has been identified as an inhibitor of neurite outgrowth specific to the central nervous system. During neural development Nogo is expressed mainly by neurons and provides an inhibitory signal for the migration and sprouting of CNS endothelial (tip) cells, thereby restricting blood vessel density.
This gene belongs to the family of reticulon-encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. The product of this gene is a potent neurite outgrowth inhibitor that may also help block the regeneration of the central nervous system in higher vertebrates. Alternatively spliced transcript variants derived both from differential splicing and differential promoter usage and encoding different isoforms have been identified. There are three isoforms: Nogo A, B and C. Nogo-A has two known inhibitory domains including amino-Nogo, at the N-terminus and Nogo-66, which makes up the molecules extracellular loop. Both amino-Nogo and Nogo-66 are involved in inhibitory responses, where amino-Nogo is a strong inhibitor of neurite outgrowth, and Nogo-66 is involved in growth cone destruction.
Research suggests that blocking Nogo-A during neuronal damage (from diseases such as Multiple Sclerosis) will help to protect or restore the damaged neurons. The investigation into the mechanisms of this protein presents a great potential for the treatment of auto-immune mediated demyelinating diseases and spinal cord injury regeneration. It has also been found to be a key player in the process whereby physical exercise enhances learning and memory processes in the brain.
# Interactions
Reticulon 4 has been shown to interact with WWP1, BCL2-like 1 and Bcl-2. | Reticulon 4
Reticulon 4, also known as Neurite outgrowth inhibitor or Nogo, is a protein that in humans is encoded by the RTN4 gene[1][2][3] that has been identified as an inhibitor of neurite outgrowth specific to the central nervous system. During neural development Nogo is expressed mainly by neurons and provides an inhibitory signal for the migration and sprouting of CNS endothelial (tip) cells, thereby restricting blood vessel density.
This gene belongs to the family of reticulon-encoding genes. Reticulons are associated with the endoplasmic reticulum, and are involved in neuroendocrine secretion or in membrane trafficking in neuroendocrine cells. The product of this gene is a potent neurite outgrowth inhibitor that may also help block the regeneration of the central nervous system in higher vertebrates. Alternatively spliced transcript variants derived both from differential splicing and differential promoter usage and encoding different isoforms have been identified.[3] There are three isoforms: Nogo A, B and C. Nogo-A has two known inhibitory domains including amino-Nogo, at the N-terminus and Nogo-66, which makes up the molecules extracellular loop. Both amino-Nogo and Nogo-66 are involved in inhibitory responses, where amino-Nogo is a strong inhibitor of neurite outgrowth, and Nogo-66 is involved in growth cone destruction.[4]
Research suggests that blocking Nogo-A during neuronal damage (from diseases such as Multiple Sclerosis) will help to protect or restore the damaged neurons.[4][5] The investigation into the mechanisms of this protein presents a great potential for the treatment of auto-immune mediated demyelinating diseases and spinal cord injury regeneration. It has also been found to be a key player in the process whereby physical exercise enhances learning and memory processes in the brain.[6]
# Interactions
Reticulon 4 has been shown to interact with WWP1,[7] BCL2-like 1[8] and Bcl-2.[8] | https://www.wikidoc.org/index.php/Reticulon_4 | |
c4306f414479c0bd858cc2ab1c682d50c5d91c07 | wikidoc | Retinoscopy | Retinoscopy
# Overview
Retinoscopy is a technique to obtain an objective measurement of the refractive condition of a patient's eyes. The examiner uses a retinoscope to shine light into the patient's eye and observes the reflection (reflex) off the patient's retina. While moving the streak or spot of light across the pupil the examiner observes the relative movement of the reflex then uses a phoropter or manually places lenses over the eye to "neutralize" the reflex.
Retinoscopy is especially useful in prescribing corrective lenses for patients who are unable to undergo a subjective refraction that requires a judgement and response from the patient (such as mentally handicapped or non-verbal people). It is also used to evaluate accommodative ability of the eye and detect latent hyperopia.
Retinoscope works on a principle called Foucault's principle. Basically it indicates that the examiner should simulate the infinity to obtain the correct refractive power. Hence a power corresponding to the working distance is subtracted from the gross retinoscope value.
Static retinoscopy is performed when the patient has relaxed accommodative status viewing a distance target; dynamic retinoscopy is performed when the patient has active accommodation from viewing a near target. | Retinoscopy
# Overview
Retinoscopy is a technique to obtain an objective measurement of the refractive condition of a patient's eyes. The examiner uses a retinoscope to shine light into the patient's eye and observes the reflection (reflex) off the patient's retina. While moving the streak or spot of light across the pupil the examiner observes the relative movement of the reflex then uses a phoropter or manually places lenses over the eye to "neutralize" the reflex.
Retinoscopy is especially useful in prescribing corrective lenses for patients who are unable to undergo a subjective refraction that requires a judgement and response from the patient (such as mentally handicapped or non-verbal people). It is also used to evaluate accommodative ability of the eye and detect latent hyperopia.
Retinoscope works on a principle called Foucault's principle. Basically it indicates that the examiner should simulate the infinity to obtain the correct refractive power. Hence a power corresponding to the working distance is subtracted from the gross retinoscope value.
Static retinoscopy is performed when the patient has relaxed accommodative status viewing a distance target; dynamic retinoscopy is performed when the patient has active accommodation from viewing a near target. | https://www.wikidoc.org/index.php/Retinoscope | |
fddfcba77190f499a1f9db11fc626782006c2e3d | wikidoc | Revefenacin | Revefenacin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Revefenacin is a anticholinergics that is FDA approved for the treatment of The treatment of patients with chronic obstructive pulmonary disorder
- Should not be given to patients experiencing life threatening episodes
- In other words, Revefenacin should not be used as a rescue drug
- Discontinue the drug if patients appears to suffer from paradoxical bronchospasm or hypersensitivity reactions. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Headache, Cough, Problems regarding the upper respiratory system, Back Pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Revefenacin is indicated for:
- The treatment of patients with chronic obstructive pulmonary disorder
Should not be given to patients experiencing life threatening episodes
In other words, Revefenacin should not be used as a rescue drug
- Should not be given to patients experiencing life threatening episodes
- In other words, Revefenacin should not be used as a rescue drug
- Discontinue the drug if patients appears to suffer from paradoxical bronchospasm or hypersensitivity reactions
### Limitations of Use
- Revefenacin delivered via jet nebulizer can result in "longer administration time, variability in residual volume and particle size, daily cleaning requirements, limited portability, and need for device assembly"
The benefits may outweigh this because some patients are required to use nebulizers
- The benefits may outweigh this because some patients are required to use nebulizers
### Dosing Considerations
- Patients are not allowed to use nephrotoxic or hepatotoxic medications for 4 weeks before drug administration
They may use the following medications: acetaminophen, ibuprofen, milk of magnesia (magnesium hydroxide), and routine vitamins and minerals
- They may use the following medications: acetaminophen, ibuprofen, milk of magnesia (magnesium hydroxide), and routine vitamins and minerals
### Administration of Revefenacin
- Only administer as an intravenous infusion.
- Intravenous solution in healthy volunteers
Volume of distribution was 218 L
Intravenous solution radioactivity:
54% came out as solid waste
27% came out as liquid waste
- Volume of distribution was 218 L
- Intravenous solution radioactivity:
- 54% came out as solid waste
- 27% came out as liquid waste
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Revefenacin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Revefenacin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Children are not administered Revefenacin because of the strength and long-lasting effects it has with on daily dose.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Revefenacin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Revefenacin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Revefenacin is contraindicated in patients with hypersensitivity to revefenacin or any component of this product.
# Warnings
- Revefenacin should not be given to patients during an acutely deteriorating or potentially life-threatening episode of COPD
- Revefenacin is a one dose daily medication to treat patients with Chronic Obstructive Pulmonary Disease, and it should not be used as a bronchodilator to relieve acute symptoms. An extra dose should not be administered at any given time unless a doctor prescribes it. Instead, acute symptoms should be relieved with "an inhaled, short-acting beta2-agonist."
- If the beta2-agonist and the daily-dose of Revefenacin are becoming increasingly less effective, patients should be re-evaluated as it may be a sign of COPD deteriorating. Patients should talk to their medical examiner to determine the next steps.
### Worsening of Narrow-Angle Glaucoma
- If patients have narrow-angle glaucoma, they should be closely monitored while on treatment with Revefenacin.
- Some signs and symptoms of worsening of narrow-angle glaucoma include eye pain/ discomfort of the eye, blurry vision, visual halos, or "colored images in association with red eyes from conjunctival congestion and corneal edema"
- If these symptoms arise, patients should immediately contact their healthcare provider.
### Worsening of Urinary Retention
- Patients with urinary retention should be monitored carefully while being treated with Revefenacin.
- Signs and symptoms patients, prescribers, and doctors should watch out for include having difficulty passing urine and/or painful urination. This should be monitored extremely carefully and thoroughly in patients with prostatic hyperplasia or bladder-neck obstruction.
- If these signs and symptoms show up, patients are heavily advised to call their doctor.
### Immediate Hypersensitivity Reactions
- Patients may be allergic or sensitive to some of the ingredients, and if hypersensitivity arises, their treatment with Revefenacin should be discontinued immediately.
- Patients should consult their doctors to consider alternative treatments.
# Adverse Reactions
## Clinical Trials Experience
- Some Adverse Reactions include cough,nasopharyngitis, upper respiratory tract infection, headache, and back pain
- These reactions were present in at least 2% of patients in the clinical trials, and they were much more common that placebo reactions.
If there is a suspicion surrounding the adverse reactions, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800 FDA-1088 or visit www.fda.gov/medwatch.
## Postmarketing Experience
There is limited information regarding Yupelri Postmarketing Experience in the drug label.
# Drug Interactions
- Anticholinergic medicines coadministered with Yupelri (Revefenacin) can cause heightened Anticholinergic Adverse effects.
- Additionally, OATP1B1 and OATP1B3 inhibitors could potentially harm and increase the exposure of a metabolite, so it is not recommended that these be coadministered with Yupelri
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There are no available data on Revefencain use in pregnant women to inform a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Revefenacin in women who are pregnant.
### Labor and Delivery
Patients are advised to contact their physician if they become pregnant during treatment with Revefenacin. It is important to converse and address all the effect it could have on a fetus. Since there are no adequate information from studies indicating the effect on pregnant women and people who can become pregnant, patients should contact their doctor immediately.
### Nursing Mothers
Patients should be aware that the active metabolite of Revefenacin was present for rats producing breast-feeding milk. Patients should consider the developmental effects that the active metabolite in the milk can have on the baby.
### Pediatric Use
Revefenacin is not administered to children. Therefore, the safety and well-being of children administered this medication is unknown.
### Geriatic Use
Clinical studies have shown no need to alter doses in older patients.
### Gender
There is no FDA guidance on the use of Revefenacin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Revefenacin with respect to specific racial populations.
### Renal Impairment
Patients with renal impairment should be monitored on the side, but there is no need of dose adjustment for patients with renal impairment.
### Hepatic Impairment
It is recommended that patients with any level of hepatic impairment should not take this medication. Studies have shown there is an increased exposure in metabolite of Revefenacin for patients with mild hepatic impairment. Therefore, it is advised that patients with any level of impairment stay away from this medication.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Revefenacin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Revefenacin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- After intravenous administration of revefenacin, the reported volume of distribution is 218 L which suggests an extensive distribution to the tissues
### Monitoring
There is limited information regarding Revefenacin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Revefenacin and IV administrations.
# Overdosage
Common signs and symptoms of overdosage of Revefenacin:
- nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure, obstipation and difficulties in voiding
- If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Revefenacin is a bronchodilator taken through inhalation that is a muscarinic antagonist with a long-lasting bronchodilation activity. Through studies and monitoring, it has been found to have a high affinity and it behaves as a competitive antagonist to the five muscarinic cholinergic receptors. Revefenacin is shown to dissociate slower from the receptor M3 compared to the receptor M2. That shows a kinetic selectivity for this subtype of receptors. It produces a suppressive action of the acetocholine evoked calcium mobilization and contractile responses in the airway tissue. Revefenacin is a long-lasting muscarinic antagonist, so it can only be administered one dose daily. The activity of Revefenacin produces a long-lasting protection against the bronchoconstrictor response acetylcholine and methacholine.
## Structure
## Pharmacodynamics
The reported volume of distribution is 218 L which suggests an extensive distribution to the tissues
There are two phases of elimination: Kinetics Elimination: rapid declining plasma concentration followed by slow bi-exponential elimination. Renal Elimination: the amount excreted in urine is the unchanged drug, <0.2% of the administered dose.
Following the IV administration, 54% of dose is recovered in feces and 27- in urine
In clinical trials that tested Yupelri effect on pregnant rats and rabbits at exposures that would be 209 times the maximum exposure compared to the maximum human dose, it produced no birth defects or harm.
## Pharmacokinetics
There is limited information regarding Revefenacin Pharmacokinetics in the drug label.
## Nonclinical Toxicology
### Impairment of Fertility
- There are no studies performed on humans and the harm rate is unknown for pregnant women. However, studies performed on pregnant rats and rabbits resulted in slim to 0 fetal harm.
# Clinical Studies
### Study in Adult Patients with Chronic Obstructive Pulmonary Disease
- The clinical trials are secured and conducted in many different conditions, so it cannot be compared to other drugs undergoing clinical trials
- There were two 12-week trials and one 52-week trial
- The patients received a total of 175 mcg of Yupelri one-time daily
- 12-week trials: There were two 12-week trials. They are replicated trials that use placebo.
These trials were conducted on patients with moderate to severe COPD. There were a total of 395 patients, ages ranging from 41-88. The demographics are 50% male, and 90% Caucasian out of the total patients. 13% of the Yupelri treated patients discontinued the trial due to adverse reactions, and 19% of the placebo patients.
- These trials were conducted on patients with moderate to severe COPD. There were a total of 395 patients, ages ranging from 41-88. The demographics are 50% male, and 90% Caucasian out of the total patients. 13% of the Yupelri treated patients discontinued the trial due to adverse reactions, and 19% of the placebo patients.
- 52-week trial: This was one 52-week length trial that provided the subjects with a 18 mcg dose of tiotropium daily once. There were 335 subjects treated with 175 mcg of Yupelri daily, and 356 patients with the dose of tiotropium mentioned above.
### Study in Pediatric Patients with Chronic Obstructive Pulmonary Disease
- There is limited information regarding Revefenacin Studies in Pediatric Patients
# How Supplied
- YUPELRI inhalation solution: as a sterile, clear, colorless, aqueous solution for nebulization in low-density polyethylene unit-dose vials
- Each vial: 175 mcg of revefenacin in 3 mL of aqueous solution.
## Storage
- Revefenacin is stored as a preservative-free aqueous solution product
- The storage condition is dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Get medical help right away if these symptoms show up
Wheezing
Choking
Blurred Vision
Tunnel Vision
Eye Pain, Redness
Difficulty Urinating or Emptying your bladder
- Wheezing
- Choking
- Blurred Vision
- Tunnel Vision
- Eye Pain, Redness
- Difficulty Urinating or Emptying your bladder
- Inform Patients to report side effects to the FDA at: 1-800-FDA-1088
### Other Infections
- Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species.
### Discontinuation
- Patients who express Paradoxical Bronchospasm, which means breathing or wheezing will worsen, should discontinue Revefenacin and initiate therapy with another agent
### Infusion reactions
- Advise patients that administration of Revefenacin may result in infusion reactions.
- Headache, Cough, Problems regarding the upper respiratory system, Back Pain are all examples of infusion reactions
# Precautions with Alcohol
Alcohol-Revefenacin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Ultomiris
# Look-Alike Drug Names
There is limited information regarding Revefenacin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Revefenacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Uma Maveli[2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Black Box Warning
# Overview
Revefenacin is a anticholinergics that is FDA approved for the treatment of The treatment of patients with chronic obstructive pulmonary disorder
- Should not be given to patients experiencing life threatening episodes
- In other words, Revefenacin should not be used as a rescue drug
- Discontinue the drug if patients appears to suffer from paradoxical bronchospasm or hypersensitivity reactions. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Headache, Cough, Problems regarding the upper respiratory system, Back Pain.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Revefenacin is indicated for:
- The treatment of patients with chronic obstructive pulmonary disorder
Should not be given to patients experiencing life threatening episodes
In other words, Revefenacin should not be used as a rescue drug
- Should not be given to patients experiencing life threatening episodes
- In other words, Revefenacin should not be used as a rescue drug
- Discontinue the drug if patients appears to suffer from paradoxical bronchospasm or hypersensitivity reactions
### Limitations of Use
- Revefenacin delivered via jet nebulizer can result in "longer administration time, variability in residual volume and particle size, daily cleaning requirements, limited portability, and need for device assembly"
The benefits may outweigh this because some patients are required to use nebulizers
- The benefits may outweigh this because some patients are required to use nebulizers
### Dosing Considerations
- Patients are not allowed to use nephrotoxic or hepatotoxic medications for 4 weeks before drug administration
They may use the following medications: acetaminophen, ibuprofen, milk of magnesia (magnesium hydroxide), and routine vitamins and minerals
- They may use the following medications: acetaminophen, ibuprofen, milk of magnesia (magnesium hydroxide), and routine vitamins and minerals
### Administration of Revefenacin
- Only administer as an intravenous infusion.
- Intravenous solution in healthy volunteers
Volume of distribution was 218 L
Intravenous solution radioactivity:
54% came out as solid waste
27% came out as liquid waste
- Volume of distribution was 218 L
- Intravenous solution radioactivity:
- 54% came out as solid waste
- 27% came out as liquid waste
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Revefenacin Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Revefenacin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Children are not administered Revefenacin because of the strength and long-lasting effects it has with on daily dose.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Revefenacin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Revefenacin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Revefenacin is contraindicated in patients with hypersensitivity to revefenacin or any component of this product.
# Warnings
- Revefenacin should not be given to patients during an acutely deteriorating or potentially life-threatening episode of COPD
- Revefenacin is a one dose daily medication to treat patients with Chronic Obstructive Pulmonary Disease, and it should not be used as a bronchodilator to relieve acute symptoms. An extra dose should not be administered at any given time unless a doctor prescribes it. Instead, acute symptoms should be relieved with "an inhaled, short-acting beta2-agonist."
- If the beta2-agonist and the daily-dose of Revefenacin are becoming increasingly less effective, patients should be re-evaluated as it may be a sign of COPD deteriorating. Patients should talk to their medical examiner to determine the next steps.
### Worsening of Narrow-Angle Glaucoma
- If patients have narrow-angle glaucoma, they should be closely monitored while on treatment with Revefenacin.
- Some signs and symptoms of worsening of narrow-angle glaucoma include eye pain/ discomfort of the eye, blurry vision, visual halos, or "colored images in association with red eyes from conjunctival congestion and corneal edema"
- If these symptoms arise, patients should immediately contact their healthcare provider.
### Worsening of Urinary Retention
- Patients with urinary retention should be monitored carefully while being treated with Revefenacin.
- Signs and symptoms patients, prescribers, and doctors should watch out for include having difficulty passing urine and/or painful urination. This should be monitored extremely carefully and thoroughly in patients with prostatic hyperplasia or bladder-neck obstruction.
- If these signs and symptoms show up, patients are heavily advised to call their doctor.
### Immediate Hypersensitivity Reactions
- Patients may be allergic or sensitive to some of the ingredients, and if hypersensitivity arises, their treatment with Revefenacin should be discontinued immediately.
- Patients should consult their doctors to consider alternative treatments.
# Adverse Reactions
## Clinical Trials Experience
- Some Adverse Reactions include cough,nasopharyngitis, upper respiratory tract infection, headache, and back pain
- These reactions were present in at least 2% of patients in the clinical trials, and they were much more common that placebo reactions.
If there is a suspicion surrounding the adverse reactions, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800 FDA-1088 or visit www.fda.gov/medwatch.
## Postmarketing Experience
There is limited information regarding Yupelri Postmarketing Experience in the drug label.
# Drug Interactions
- Anticholinergic medicines coadministered with Yupelri (Revefenacin) can cause heightened Anticholinergic Adverse effects.
- Additionally, OATP1B1 and OATP1B3 inhibitors could potentially harm and increase the exposure of a metabolite, so it is not recommended that these be coadministered with Yupelri
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There are no available data on Revefencain use in pregnant women to inform a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Revefenacin in women who are pregnant.
### Labor and Delivery
Patients are advised to contact their physician if they become pregnant during treatment with Revefenacin. It is important to converse and address all the effect it could have on a fetus. Since there are no adequate information from studies indicating the effect on pregnant women and people who can become pregnant, patients should contact their doctor immediately.
### Nursing Mothers
Patients should be aware that the active metabolite of Revefenacin was present for rats producing breast-feeding milk. Patients should consider the developmental effects that the active metabolite in the milk can have on the baby.
### Pediatric Use
Revefenacin is not administered to children. Therefore, the safety and well-being of children administered this medication is unknown.
### Geriatic Use
Clinical studies have shown no need to alter doses in older patients.
### Gender
There is no FDA guidance on the use of Revefenacin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Revefenacin with respect to specific racial populations.
### Renal Impairment
Patients with renal impairment should be monitored on the side, but there is no need of dose adjustment for patients with renal impairment.
### Hepatic Impairment
It is recommended that patients with any level of hepatic impairment should not take this medication. Studies have shown there is an increased exposure in metabolite of Revefenacin for patients with mild hepatic impairment. Therefore, it is advised that patients with any level of impairment stay away from this medication.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Revefenacin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Revefenacin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- After intravenous administration of revefenacin, the reported volume of distribution is 218 L which suggests an extensive distribution to the tissues
### Monitoring
There is limited information regarding Revefenacin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Revefenacin and IV administrations.
# Overdosage
Common signs and symptoms of overdosage of Revefenacin:
- nausea, vomiting, dizziness, lightheadedness, blurred vision, increased intraocular pressure, obstipation and difficulties in voiding
- If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
Revefenacin is a bronchodilator taken through inhalation that is a muscarinic antagonist with a long-lasting bronchodilation activity. Through studies and monitoring, it has been found to have a high affinity and it behaves as a competitive antagonist to the five muscarinic cholinergic receptors. Revefenacin is shown to dissociate slower from the receptor M3 compared to the receptor M2. That shows a kinetic selectivity for this subtype of receptors. It produces a suppressive action of the acetocholine evoked calcium mobilization and contractile responses in the airway tissue. Revefenacin is a long-lasting muscarinic antagonist, so it can only be administered one dose daily. The activity of Revefenacin produces a long-lasting protection against the bronchoconstrictor response acetylcholine and methacholine.
## Structure
-
## Pharmacodynamics
The reported volume of distribution is 218 L which suggests an extensive distribution to the tissues
There are two phases of elimination: Kinetics Elimination: rapid declining plasma concentration followed by slow bi-exponential elimination. Renal Elimination: the amount excreted in urine is the unchanged drug, <0.2% of the administered dose.
Following the IV administration, 54% of dose is recovered in feces and 27* in urine
In clinical trials that tested Yupelri effect on pregnant rats and rabbits at exposures that would be 209 times the maximum exposure compared to the maximum human dose, it produced no birth defects or harm.
## Pharmacokinetics
There is limited information regarding Revefenacin Pharmacokinetics in the drug label.
## Nonclinical Toxicology
### Impairment of Fertility
- There are no studies performed on humans and the harm rate is unknown for pregnant women. However, studies performed on pregnant rats and rabbits resulted in slim to 0 fetal harm.
# Clinical Studies
### Study in Adult Patients with Chronic Obstructive Pulmonary Disease [ALXN1210-aHUS-311; NCT02949128]
- The clinical trials are secured and conducted in many different conditions, so it cannot be compared to other drugs undergoing clinical trials
- There were two 12-week trials and one 52-week trial
- The patients received a total of 175 mcg of Yupelri one-time daily
- 12-week trials: There were two 12-week trials. They are replicated trials that use placebo.
These trials were conducted on patients with moderate to severe COPD. There were a total of 395 patients, ages ranging from 41-88. The demographics are 50% male, and 90% Caucasian out of the total patients. 13% of the Yupelri treated patients discontinued the trial due to adverse reactions, and 19% of the placebo patients.
- These trials were conducted on patients with moderate to severe COPD. There were a total of 395 patients, ages ranging from 41-88. The demographics are 50% male, and 90% Caucasian out of the total patients. 13% of the Yupelri treated patients discontinued the trial due to adverse reactions, and 19% of the placebo patients.
- 52-week trial: This was one 52-week length trial that provided the subjects with a 18 mcg dose of tiotropium daily once. There were 335 subjects treated with 175 mcg of Yupelri daily, and 356 patients with the dose of tiotropium mentioned above.
### Study in Pediatric Patients with Chronic Obstructive Pulmonary Disease [ALXN1210-aHUS-312; NCT03131219]
- There is limited information regarding Revefenacin Studies in Pediatric Patients
# How Supplied
- YUPELRI inhalation solution: as a sterile, clear, colorless, aqueous solution for nebulization in low-density polyethylene unit-dose vials
- Each vial: 175 mcg of revefenacin in 3 mL of aqueous solution.
## Storage
- Revefenacin is stored as a preservative-free aqueous solution product
- The storage condition is dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years)
# Images
## Drug Images
## Package and Label Display Panel
-
# Patient Counseling Information
- Get medical help right away if these symptoms show up
Wheezing
Choking
Blurred Vision
Tunnel Vision
Eye Pain, Redness
Difficulty Urinating or Emptying your bladder
- Wheezing
- Choking
- Blurred Vision
- Tunnel Vision
- Eye Pain, Redness
- Difficulty Urinating or Emptying your bladder
- Inform Patients to report side effects to the FDA at: 1-800-FDA-1088
### Other Infections
- Counsel patients of the increased risk of infections, particularly those due to encapsulated bacteria, especially Neisseria species.
### Discontinuation
- Patients who express Paradoxical Bronchospasm, which means breathing or wheezing will worsen, should discontinue Revefenacin and initiate therapy with another agent
### Infusion reactions
- Advise patients that administration of Revefenacin may result in infusion reactions.
- Headache, Cough, Problems regarding the upper respiratory system, Back Pain are all examples of infusion reactions
# Precautions with Alcohol
Alcohol-Revefenacin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
Ultomiris
# Look-Alike Drug Names
There is limited information regarding Revefenacin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Revefenacin | |
eececa2aa1f9f7356c723b526f453acbf8e068b8 | wikidoc | Rhodamine B | Rhodamine B
Molecular Formula: C28H31N2O3Cl
Molecular Weight: 479.02 grams per mole
CAS Number: 81-88-9
SMILES structure: Template:SMILES
Rhodamine B is used in biology as a staining fluorescent dye, sometimes in combination with auramine O, as the auramine-rhodamine stain to demonstrate acid-fast organisms, notably Mycobacterium.
Rhodamine B is tunable around 610 nm when used as a laser dye.
Rhodamine B is also called Rhodamine 610, C.I. Pigment Violet 1, Basic Violet 10, or C.I. 45170.
In California, Rhodamine B is suspected to be carcinogenic and thus products containing it must contain a warning on its label.
- ↑ , Naval Jelly msds with Rhodamine B | Rhodamine B
Template:Chembox new
Molecular Formula: C28H31N2O3Cl
Molecular Weight: 479.02 grams per mole
CAS Number: 81-88-9
SMILES structure: Template:SMILES
Rhodamine B is used in biology as a staining fluorescent dye, sometimes in combination with auramine O, as the auramine-rhodamine stain to demonstrate acid-fast organisms, notably Mycobacterium.
Rhodamine B is tunable around 610 nm when used as a laser dye.
Rhodamine B is also called Rhodamine 610, C.I. Pigment Violet 1, Basic Violet 10, or C.I. 45170.
In California, Rhodamine B is suspected to be carcinogenic and thus products containing it must contain a warning on its label.[1]
Template:Stains
Template:WH
Template:WS
- ↑ http://www.brown.edu/Departments/Visual_Art/documents/NavalJelly.pdf, Naval Jelly msds with Rhodamine B | https://www.wikidoc.org/index.php/Rhodamine_B | |
4c40940d7cc0f54e7038a20ec7fa6a6c5c20dbd1 | wikidoc | Rhodococcus | Rhodococcus
# Overview
Rhodococcus is a genus of aerobic, non-sporulating, non-motile gram-positive bacteria closely related to Mycobacteria and Corynebacteria . While a few species are pathogenic, most are benign and have been found to thrive in a broad range of environments, including soil, water, and eukaryotic cells. Fully sequenced in October 2006, the genome is know to be 9.7 megabasepairs long and 67% G/C .
Strains of Rhodococcus are applicably important due to their ability to catabolize a wide range of compounds and produce bioactive steroids, acrylamide and acrylic acid and their involvement in fossil fuel biodesulfurization . This genetic and catabolic diversity is not only due to the large bacterial chromosome, but the presence of three large linear plasmids. Rhodococcus is also an experimentally advantageous system due to a relatively fast growth rate and simple developmental cycle. However, as it stands now, Rhodococcus is not well characterized .
Another important application of Rhodococcus comes from bioconversion, utilizing biological systems to convert cheap starting material into more valuable compounds. This use of Rhodococcus is born out of its ability to metabolize harmful environmental pollutants such as toluene, naphthalene, herbicides, PCBs. Rhodococci typically metabolize aromatic substrates by first oxygenating the aromatic ring to form a diol (two alcohol groups). Then, the ring is cleaved with intra/extradiol mechanisms, opening the ring and exposing the substrate to further metabolism. Since the chemistry here is very stereospecific, the diols are created with predictable chirality. While controlling the chirality of chemical reaction presents a significant challenge for synthetic chemists, biological processes can be used instead to faithfully produce chiral molecules in cases where direct chemical synthesis is infeasible or inefficient. An example of this is the use of Rhodococcus to produce indene, a precursor to the AIDS drug Crixivan(TM), a protease inhibitor, and containing two of the five chiral centers needed in the complex .
# Biodegradation of Organic Pollutants
The burgeoning amount of bacterial genomic data provides unparalleled opportunities for understanding the genetic and molecular bases of the microbial biodegradation of organic pollutants. Aromatic compounds are among the most recalcitrant of these pollutants and lessons can be learned from the recent genomic studies of Rhodococcus sp. strain RHA1, one of the largest bacterial genomes completely sequenced to date. These studies have helped expand our understanding of bacterial catabolism, non-catabolic physiological adaptation to organic compounds, and the evolution of large bacterial genomes. A large number of "peripheral aromatic" pathways funnel a range of natural and xenobiotic compounds into a restricted number of "central aromatic" pathways. Some pathways are more widespread than initially thought. The Box and Paa pathways illustrate the prevalence of non-oxygenolytic ring-cleavage strategies in aerobic aromatic degradation processes. Functional genomic studies have been useful in establishing that even organisms harboring high numbers of homologous enzymes apparently contain few examples of true redundancy. For example, the multiplicity of ring-cleaving dioxygenases in certain rhodococcal isolates may be attributed to the cryptic aromatic catabolism of different terpenoids and steroids. The large gene repertoires of pollutant degraders such as Rhodococcus RHA1 have evolved principally through more ancient processes.
# Species
- Rhodococcus aurantiacus (ex Tsukamura & Mizuno 1971) Tsukamura & Yano 1985, nom. rev.
- Rhodococcus baikonurensis Li et al. 2004
- Rhodococcus boritolerans
- Rhodococcus equi (Magnusson 1923) Goodfellow & Alderson 1977; most important species for infections of animals (horse, goat) and immunsupprimised humans (AIDS-Infected)
- Rhodococcus coprophilus Rowbotham & Cross 1979
- Rhodococcus corynebacterioides (Serrano et al. 1972) Yassin & Schaal 2005 (synonym: Nocardia corynebacterioides Serrano et al. 1972)
- Rhodococcus erythropolis (Gray & Thornton 1928) Goodfellow & Alderson 1979
- Rhodococcus globerulus Goodfellow et al. 1985
- Rhodococcus gordoniae Jones et al. 2004
- Rhodococcus jostii Takeuchi et al. 2002
- Rhodococcus koreensis Yoon et al. 2000
- Rhodococcus kroppenstedtii Mayilraj et al. 2006
- Rhodococcus luteus (ex Söhngen 1913) Nesterenko et al. 1982, nom. rev. (Synonym: R. fascians (Tilford 1936) Goodfellow 1984)
- Rhodococcus maanshanensis Zhang et al. 2002
- Rhodococcus marinonascens Helmke & Weyland 1984
- Rhodococcus opacus Klatte et al. 1995
- Rhodococcus percolatus Briglia et al. 1996
- Rhodococcus phenolicus Rehfuss & Urban 2006
- Rhodococcus polyvorum
- Rhodococcus pyridinivorans Yoon et al. 2000
- Rhodococcus rhodochrous (Zopf 1891) Tsukamura 1974
- Rhodococcus rhodnii Goodfellow & Alderson 1979 (synonym: Nocardia rhodnii)
- Rhodococcus ruber (Kruse 1896) Goodfellow & Alderson 1977 (synonym: Streptothrix rubra Kruse 1896)
- Rhodococcus triatomae Yassin 2005
- Rhodococcus tukisamuensis Matsuyama et al. 2003
- Rhodococcus wratislaviensis (Goodfellow et al. 1995) Goodfellow et al. 2002 (synonym: Tsukamurella wratislaviensis Goodfellow et al. 1995)
- Rhodococcus yunnanensis Zhang et al. 2005
- Rhodococcus zopfii Stoecker et al. 1994 | Rhodococcus
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Rhodococcus is a genus of aerobic, non-sporulating, non-motile gram-positive bacteria closely related to Mycobacteria and Corynebacteria [1]. While a few species are pathogenic, most are benign and have been found to thrive in a broad range of environments, including soil, water, and eukaryotic cells. Fully sequenced in October 2006, the genome is know to be 9.7 megabasepairs long and 67% G/C [2].
Strains of Rhodococcus are applicably important due to their ability to catabolize a wide range of compounds and produce bioactive steroids, acrylamide and acrylic acid and their involvement in fossil fuel biodesulfurization [2]. This genetic and catabolic diversity is not only due to the large bacterial chromosome, but the presence of three large linear plasmids[1]. Rhodococcus is also an experimentally advantageous system due to a relatively fast growth rate and simple developmental cycle. However, as it stands now, Rhodococcus is not well characterized [2].
Another important application of Rhodococcus comes from bioconversion, utilizing biological systems to convert cheap starting material into more valuable compounds. This use of Rhodococcus is born out of its ability to metabolize harmful environmental pollutants such as toluene, naphthalene, herbicides, PCBs. Rhodococci typically metabolize aromatic substrates by first oxygenating the aromatic ring to form a diol (two alcohol groups). Then, the ring is cleaved with intra/extradiol mechanisms, opening the ring and exposing the substrate to further metabolism. Since the chemistry here is very stereospecific, the diols are created with predictable chirality. While controlling the chirality of chemical reaction presents a significant challenge for synthetic chemists, biological processes can be used instead to faithfully produce chiral molecules in cases where direct chemical synthesis is infeasible or inefficient. An example of this is the use of Rhodococcus to produce indene, a precursor to the AIDS drug Crixivan(TM), a protease inhibitor, and containing two of the five chiral centers needed in the complex [3].
# Biodegradation of Organic Pollutants
The burgeoning amount of bacterial genomic data provides unparalleled opportunities for understanding the genetic and molecular bases of the microbial biodegradation of organic pollutants. Aromatic compounds are among the most recalcitrant of these pollutants and lessons can be learned from the recent genomic studies of Rhodococcus sp. strain RHA1, one of the largest bacterial genomes completely sequenced to date. These studies have helped expand our understanding of bacterial catabolism, non-catabolic physiological adaptation to organic compounds, and the evolution of large bacterial genomes. A large number of "peripheral aromatic" pathways funnel a range of natural and xenobiotic compounds into a restricted number of "central aromatic" pathways. Some pathways are more widespread than initially thought. The Box and Paa pathways illustrate the prevalence of non-oxygenolytic ring-cleavage strategies in aerobic aromatic degradation processes. Functional genomic studies have been useful in establishing that even organisms harboring high numbers of homologous enzymes apparently contain few examples of true redundancy. For example, the multiplicity of ring-cleaving dioxygenases in certain rhodococcal isolates may be attributed to the cryptic aromatic catabolism of different terpenoids and steroids. The large gene repertoires of pollutant degraders such as Rhodococcus RHA1 have evolved principally through more ancient processes. [4]
# Species
- Rhodococcus aurantiacus (ex Tsukamura & Mizuno 1971) Tsukamura & Yano 1985, nom. rev.
- Rhodococcus baikonurensis Li et al. 2004
- Rhodococcus boritolerans
- Rhodococcus equi (Magnusson 1923) Goodfellow & Alderson 1977; most important species for infections of animals (horse, goat) and immunsupprimised humans (AIDS-Infected)
- Rhodococcus coprophilus Rowbotham & Cross 1979
- Rhodococcus corynebacterioides (Serrano et al. 1972) Yassin & Schaal 2005 (synonym: Nocardia corynebacterioides Serrano et al. 1972)
- Rhodococcus erythropolis (Gray & Thornton 1928) Goodfellow & Alderson 1979
- Rhodococcus globerulus Goodfellow et al. 1985
- Rhodococcus gordoniae Jones et al. 2004
- Rhodococcus jostii Takeuchi et al. 2002
- Rhodococcus koreensis Yoon et al. 2000
- Rhodococcus kroppenstedtii Mayilraj et al. 2006
- Rhodococcus luteus (ex Söhngen 1913) Nesterenko et al. 1982, nom. rev. (Synonym: R. fascians (Tilford 1936) Goodfellow 1984)
- Rhodococcus maanshanensis Zhang et al. 2002
- Rhodococcus marinonascens Helmke & Weyland 1984
- Rhodococcus opacus Klatte et al. 1995
- Rhodococcus percolatus Briglia et al. 1996
- Rhodococcus phenolicus Rehfuss & Urban 2006
- Rhodococcus polyvorum
- Rhodococcus pyridinivorans Yoon et al. 2000
- Rhodococcus rhodochrous (Zopf 1891) Tsukamura 1974
- Rhodococcus rhodnii Goodfellow & Alderson 1979 (synonym: Nocardia rhodnii)
- Rhodococcus ruber (Kruse 1896) Goodfellow & Alderson 1977 (synonym: Streptothrix rubra Kruse 1896)
- Rhodococcus triatomae Yassin 2005
- Rhodococcus tukisamuensis Matsuyama et al. 2003
- Rhodococcus wratislaviensis (Goodfellow et al. 1995) Goodfellow et al. 2002 (synonym: Tsukamurella wratislaviensis Goodfellow et al. 1995)
- Rhodococcus yunnanensis Zhang et al. 2005
- Rhodococcus zopfii Stoecker et al. 1994 | https://www.wikidoc.org/index.php/Rhodococcus | |
53e4f9042cd2c4d14d8f6dda0f2fcb05c66cb448 | wikidoc | Rilmenidine | Rilmenidine
# Overview
Rilmenidine is a prescription medication administered to treat hypertension. It is marketed under the brand name HYPERIUM®.
# Form and Composition
Each tablet contains 1.544 mg rilmenidine dihydrogen phosphate, an amount equivalent to 1 mg rilmenidine base.
# Properties
Hyperium, an oxazoline compound with antihypertensive properties, acts on both medullary and peripheral vasomotor structures. Hyperium shows greater selectivity for imidazoline receptors than for cerebral alpha2-adrenergic receptors, distinguishing it from reference alpha2-agonists.
# Indications
Hypertension.
# Contraindications
Severe depression, severe renal failure (creatinine clearance <15 ml/min), as a precaution in the absence of currently available studies.
# Warning
Therapy should never be interrupted suddenly; the dosage should be reduced gradually.
# Precautions
- As with all antihypertensive agents, regular medical monitoring is required when Hyperium is administered to patients with a recent history of cardiovascular disease (stroke, myocardial infarction).
- Alcohol consumption should be avoided during treatment.
- In patients with renal failure, no dosage adjustment is necessary if creatinine clearance is greater than 15 mL/min.
- In the absence of documented experiments in this area, Hyperium is not recommended for prescription to children.
- Pregnancy: as with all new molecules, administration of Hyperium should be avoided in pregnant women, although no teratogenic or embryotoxic effects have been observed in animal studies.
- Lactation: Hyperium is excreted in breast milk, and its use is therefore not recommended during lactation.
- Effects on the ability to drive motor vehicles or operate machinery: double-blind, placebo-controlled studies have not shown Hyperium to have any effect on alertness at therapeutic doses (1or 2 daily administrations of 1 mg). If these doses are exceeded, or if Hyperium is combined with other drugs capable of reducing alertness, vehicle drivers or machine operators should be warned of the possibility of drowsiness.
# Drug interactions
Combinations not recommended: combination with MAOIs is not recommended; combination with tricyclic antidepressants requires prudence, as the antihypertensive activity of Hyperium may be partly antagonized.
# Side Effects
- At a dose of 1 mg given as a single daily administration during controlled trials, the incidence of side effects was comparable to that observed with placebo.
- At a dose of 2 mg per day of Hyperium, controlled comparative studies versus clonidine (0.15 to 0.30 mg/day) or alpha2-methyldopa (500 to 1000 mg/day) demonstrated that the incidence of side effects was significantly lower with Hyperium than with either clonidine or a-methyldopa.
Side-effects are rare, non-severe, and transient at therapeutic doses: asthenia, palpitations, insomnia, drowsiness, fatigue on exercise, epigastric pain, dryness of the mouth, diarrhea, skin rash; and exceptionally, cold extremities, postural hypotension, sexual disorders, anxiety, depression, pruritus, edema, cramps, nausea, constipation, hot flushes.
# Dosage and Route of Administration
The recommended dosage is 1 tablet per day as a single morning administration. If results are not adequate after 1 month of treatment, the dosage may be increased to 2 tablets per day, given in divided doses (1 tablet morning and evening) before meals. As a result of its good clinical and biological acceptability, Hyperium may be administered to both elderly and diabetic hypertensive patients. In patients with renal failure, no dosage adjustment is necessary in principle when the creatinine clearance is greater than 15 mL/min.
Treatment may be continued indefinitely.
# Overdosage
No cases of massive absorption have been reported. Likely symptoms in such an eventuality would be marked hypotension and lowered alertness. In addition to gastric lavage, sympathomimetic agents may also required. Hyperium is only slightly dialysable. | Rilmenidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Rilmenidine is a prescription medication administered to treat hypertension. It is marketed under the brand name HYPERIUM®.
# Form and Composition
Each tablet contains 1.544 mg rilmenidine dihydrogen phosphate, an amount equivalent to 1 mg rilmenidine base.
# Properties
Hyperium, an oxazoline compound with antihypertensive properties, acts on both medullary and peripheral vasomotor structures. Hyperium shows greater selectivity for imidazoline receptors than for cerebral alpha2-adrenergic receptors, distinguishing it from reference alpha2-agonists.
# Indications
Hypertension.
# Contraindications
Severe depression, severe renal failure (creatinine clearance <15 ml/min), as a precaution in the absence of currently available studies.
# Warning
Therapy should never be interrupted suddenly; the dosage should be reduced gradually.
# Precautions
- As with all antihypertensive agents, regular medical monitoring is required when Hyperium is administered to patients with a recent history of cardiovascular disease (stroke, myocardial infarction).
- Alcohol consumption should be avoided during treatment.
- In patients with renal failure, no dosage adjustment is necessary if creatinine clearance is greater than 15 mL/min.
- In the absence of documented experiments in this area, Hyperium is not recommended for prescription to children.
- Pregnancy: as with all new molecules, administration of Hyperium should be avoided in pregnant women, although no teratogenic or embryotoxic effects have been observed in animal studies.
- Lactation: Hyperium is excreted in breast milk, and its use is therefore not recommended during lactation.
- Effects on the ability to drive motor vehicles or operate machinery: double-blind, placebo-controlled studies have not shown Hyperium to have any effect on alertness at therapeutic doses (1or 2 daily administrations of 1 mg). If these doses are exceeded, or if Hyperium is combined with other drugs capable of reducing alertness, vehicle drivers or machine operators should be warned of the possibility of drowsiness.
# Drug interactions
Combinations not recommended: combination with MAOIs is not recommended; combination with tricyclic antidepressants requires prudence, as the antihypertensive activity of Hyperium may be partly antagonized.
# Side Effects
- At a dose of 1 mg given as a single daily administration during controlled trials, the incidence of side effects was comparable to that observed with placebo.
- At a dose of 2 mg per day of Hyperium, controlled comparative studies versus clonidine (0.15 to 0.30 mg/day) or alpha2-methyldopa (500 to 1000 mg/day) demonstrated that the incidence of side effects was significantly lower with Hyperium than with either clonidine or a-methyldopa.
Side-effects are rare, non-severe, and transient at therapeutic doses: asthenia, palpitations, insomnia, drowsiness, fatigue on exercise, epigastric pain, dryness of the mouth, diarrhea, skin rash; and exceptionally, cold extremities, postural hypotension, sexual disorders, anxiety, depression, pruritus, edema, cramps, nausea, constipation, hot flushes.
# Dosage and Route of Administration
The recommended dosage is 1 tablet per day as a single morning administration. If results are not adequate after 1 month of treatment, the dosage may be increased to 2 tablets per day, given in divided doses (1 tablet morning and evening) before meals. As a result of its good clinical and biological acceptability, Hyperium may be administered to both elderly and diabetic hypertensive patients. In patients with renal failure, no dosage adjustment is necessary in principle when the creatinine clearance is greater than 15 mL/min.
Treatment may be continued indefinitely.
# Overdosage
No cases of massive absorption have been reported. Likely symptoms in such an eventuality would be marked hypotension and lowered alertness. In addition to gastric lavage, sympathomimetic agents may also required. Hyperium is only slightly dialysable. | https://www.wikidoc.org/index.php/Rilmenidine | |
ffbff9f92221d12975ed89d99a8ce243f6d1787d | wikidoc | Ring finger | Ring finger
The ring finger is the fourth digit of the human hand, and the second most ulnar finger, located between the middle finger and the little finger. It is also called digitus medicinalis, the fourth finger, digitus annularis, digitus quartus, or digitus IV in anatomy.
# Etymology
According to László A. Magyar, the names of the ring finger in many languages reflect an ancient belief that it is a magical finger. It is named after magic or rings, or called nameless.
- The medical finger. Some cultures named it after its supposed magic power, especially the healing power. An example of the idea of its healing power is Bhaisajyaguru, the Medicine Buddha, who uses his right ring finger for medicine.
English: leech finger
German: Arztfinger (doctor's finger)
Japanese: kusuri-yubi (medicine finger)
Japanese: kusushi-yubi (doctor's finger)
Latin: digitus medicinalis (medical finger)
- English: leech finger
- German: Arztfinger (doctor's finger)
- Japanese: kusuri-yubi (medicine finger)
- Japanese: kusushi-yubi (doctor's finger)
- Latin: digitus medicinalis (medical finger)
- The ring finger. Some cultures associated it to magic rings. This is particularly common in European languages.
Croatian: prstenjak (ring finger)
Czech: prsteníček (ring finger)
Danish: ringfinger (ring finger)
Dutch: ringvinger (ring finger)
English: ring finger
French: annulaire (ring finger)
German: Ringfinger (ring finger)
Hebrew:קמיצה
Hungarian: gyűrűsujj (ring finger)
Icelandic: baugfingur (ring finger)
Italian: dito anulare (ring finger)
Latin: digitus annularis (ring finger)
Malay: jari manis (sweet finger)
Norwegian: ring(e)finger (ring finger)
Persian:'انگشت انگشتری' (ring finger)
Polish: palec serdeczny (lit. cordial finger, etymology is from "heart" - in Polish "serce" which means "heart", because it's rather "finger of heart") (ring finger)
Slovak: prstenník (ring finger)
Swahili: cha pete (of the ring)
Portuguese: dedo anelar (ring finger)
Romanian: degetul inelar (ring finger)
Spanish: dedo anular (ring finger)
Swedish: ringfinger (ring finger)
Tamil: Mothira Viral (ring finger)
Turkish: Yüzük parmağı (ring finger)
- Croatian: prstenjak (ring finger)
- Czech: prsteníček (ring finger)
- Danish: ringfinger (ring finger)
- Dutch: ringvinger (ring finger)
- English: ring finger
- French: annulaire (ring finger)
- German: Ringfinger (ring finger)
- Hebrew:קמיצה
- Hungarian: gyűrűsujj (ring finger)
- Icelandic: baugfingur (ring finger)
- Italian: dito anulare (ring finger)
- Latin: digitus annularis (ring finger)
- Malay: jari manis (sweet finger)
- Norwegian: ring(e)finger (ring finger)
- Persian:'انگشت انگشتری' (ring finger)
- Polish: palec serdeczny (lit. cordial finger, etymology is from "heart" - in Polish "serce" which means "heart", because it's rather "finger of heart") (ring finger)
- Slovak: prstenník (ring finger)
- Swahili: cha pete (of the ring)
- Portuguese: dedo anelar (ring finger)
- Romanian: degetul inelar (ring finger)
- Spanish: dedo anular (ring finger)
- Swedish: ringfinger (ring finger)
- Tamil: Mothira Viral (ring finger)
- Turkish: Yüzük parmağı (ring finger)
- The nameless finger. Many cultures avoided the true name of a powerful entity, and called it indirectly or called it nameless.
Bulgarian: безименен пръст (nameless finger)
Cantonese: 無名指 mo ming ji (nameless finger)
Mandarin: 无名指 wúmíngzhǐ (nameless finger)
Finnish: nimetön sormi (nameless finger)
Japanese: nanashi-yubi (nameless finger)
Lithuanian: bevardis (nameless)
Persian: binàme (nameless)
Russian: bezymyannyi palets (nameless finger)
Sanskrit: anáman (nameless)
Tatar: atsyz parmak (nameless finger)
- Bulgarian: безименен пръст (nameless finger)
- Cantonese: 無名指 mo ming ji (nameless finger)
- Mandarin: 无名指 wúmíngzhǐ (nameless finger)
- Finnish: nimetön sormi (nameless finger)
- Japanese: nanashi-yubi (nameless finger)
- Lithuanian: bevardis (nameless)
- Persian: binàme (nameless)
- Russian: bezymyannyi palets (nameless finger)
- Sanskrit: anáman (nameless)
- Tatar: atsyz parmak (nameless finger)
- In other languages this finger takes its name from its place between the other fingers.
Latin: digitus medio proximus (the finger next to the middle)
Greek: paramesos παράμεσος (para = next to + mesos = in the middle: the finger next to the middle finger)
Serbian: domali prst (the finger next to the little)
- Latin: digitus medio proximus (the finger next to the middle)
- Greek: paramesos παράμεσος (para = next to + mesos = in the middle: the finger next to the middle finger)
- Serbian: domali prst (the finger next to the little)
# The wedding ring
Main Article: Wedding ring
In Western cultures a wedding ring is traditionally worn on the ring finger. According to tradition in some countries, the wedding ring is worn on the left ring finger because the vein in the left ring finger, referred to as the vena amoris was believed to be directly connected to the heart, a symbol of love.
In medieval Europe, the Christian wedding ceremony placed the ring in sequence on the index, middle, and ring fingers of the left hand, representing the trinity — God the Father, God the Son, and God the Holy Spirit. The ring was then left on the ring finger. In a few European countries, the ring is worn on the left hand prior to marriage, then transferred to the right during the ceremony. For example, a Greek Orthodox bride wears the ring on the left hand prior to the ceremony, then moves it to the right hand after the wedding.
In Norway, Russia, Poland, Germany, Austria, Denmark, countries of former Yugoslavia and in Spain (except in Catalonia) the wedding ring is worn on the ring finger on the right hand.
In the Jewish wedding ceremony, the groom places the ring on the bride's index finger, and not ring finger; the ring is usually moved to the ring finger after the ceremony.
In the Indian tradition, the right hand is considered as auspicious. Hence the wedding ring is worn on the right hand. However, despite tradition, some wear the ring on the left hand, matching cultural practice
in some western countries.
# Other
- There is evidence that the ratio between the lengths of the index finger and the ring finger is modulated by androgen exposure in the uterus.
- It is the weakest of the fingers on the hand, as it shares a flexor muscle with the middle and little fingers. It is the only finger that cannot be fully extended by itself. | Ring finger
Template:Infobox Anatomy
The ring finger is the fourth digit of the human hand, and the second most ulnar finger, located between the middle finger and the little finger. It is also called digitus medicinalis, the fourth finger, digitus annularis, digitus quartus, or digitus IV in anatomy.
# Etymology
According to László A. Magyar, the names of the ring finger in many languages reflect an ancient belief that it is a magical finger. It is named after magic or rings, or called nameless. [1]
- The medical finger. Some cultures named it after its supposed magic power, especially the healing power. An example of the idea of its healing power is Bhaisajyaguru, the Medicine Buddha, who uses his right ring finger for medicine.
English: leech finger
German: Arztfinger (doctor's finger)
Japanese: kusuri-yubi (medicine finger)
Japanese: kusushi-yubi (doctor's finger)
Latin: digitus medicinalis (medical finger)
- English: leech finger
- German: Arztfinger (doctor's finger)
- Japanese: kusuri-yubi (medicine finger)
- Japanese: kusushi-yubi (doctor's finger)
- Latin: digitus medicinalis (medical finger)
- The ring finger. Some cultures associated it to magic rings. This is particularly common in European languages.
Croatian: prstenjak (ring finger)
Czech: prsteníček (ring finger)
Danish: ringfinger (ring finger)
Dutch: ringvinger (ring finger)
English: ring finger
French: annulaire (ring finger)
German: Ringfinger (ring finger)
Hebrew:קמיצה
Hungarian: gyűrűsujj (ring finger)
Icelandic: baugfingur (ring finger)
Italian: dito anulare (ring finger)
Latin: digitus annularis (ring finger)
Malay: jari manis (sweet finger)
Norwegian: ring(e)finger (ring finger)
Persian:'انگشت انگشتری' (ring finger)
Polish: palec serdeczny (lit. cordial finger, etymology is from "heart" - in Polish "serce" which means "heart", because it's rather "finger of heart") (ring finger)
Slovak: prstenník (ring finger)
Swahili: cha pete (of the ring)
Portuguese: dedo anelar (ring finger)
Romanian: degetul inelar (ring finger)
Spanish: dedo anular (ring finger)
Swedish: ringfinger (ring finger)
Tamil: Mothira Viral (ring finger)
Turkish: Yüzük parmağı (ring finger)
- Croatian: prstenjak (ring finger)
- Czech: prsteníček (ring finger)
- Danish: ringfinger (ring finger)
- Dutch: ringvinger (ring finger)
- English: ring finger
- French: annulaire (ring finger)
- German: Ringfinger (ring finger)
- Hebrew:קמיצה
- Hungarian: gyűrűsujj (ring finger)
- Icelandic: baugfingur (ring finger)
- Italian: dito anulare (ring finger)
- Latin: digitus annularis (ring finger)
- Malay: jari manis (sweet finger)
- Norwegian: ring(e)finger (ring finger)
- Persian:'انگشت انگشتری' (ring finger)
- Polish: palec serdeczny (lit. cordial finger, etymology is from "heart" - in Polish "serce" which means "heart", because it's rather "finger of heart") (ring finger)
- Slovak: prstenník (ring finger)
- Swahili: cha pete (of the ring)
- Portuguese: dedo anelar (ring finger)
- Romanian: degetul inelar (ring finger)
- Spanish: dedo anular (ring finger)
- Swedish: ringfinger (ring finger)
- Tamil: Mothira Viral (ring finger)
- Turkish: Yüzük parmağı (ring finger)
- The nameless finger. Many cultures avoided the true name of a powerful entity, and called it indirectly or called it nameless.
Bulgarian: безименен пръст (nameless finger)
Cantonese: 無名指 mo ming ji (nameless finger)
Mandarin: 无名指 wúmíngzhǐ (nameless finger)
Finnish: nimetön sormi (nameless finger)
Japanese: nanashi-yubi (nameless finger)
Lithuanian: bevardis (nameless)
Persian: binàme (nameless)
Russian: bezymyannyi palets (nameless finger)
Sanskrit: anáman (nameless)
Tatar: atsyz parmak (nameless finger)
- Bulgarian: безименен пръст (nameless finger)
- Cantonese: 無名指 mo ming ji (nameless finger)
- Mandarin: 无名指 wúmíngzhǐ (nameless finger)
- Finnish: nimetön sormi (nameless finger)
- Japanese: nanashi-yubi (nameless finger)
- Lithuanian: bevardis (nameless)
- Persian: binàme (nameless)
- Russian: bezymyannyi palets (nameless finger)
- Sanskrit: anáman (nameless)
- Tatar: atsyz parmak (nameless finger)
- In other languages this finger takes its name from its place between the other fingers.
Latin: digitus medio proximus (the finger next to the middle)
Greek: paramesos παράμεσος (para = next to + mesos = in the middle: the finger next to the middle finger)
Serbian: domali prst (the finger next to the little)
- Latin: digitus medio proximus (the finger next to the middle)
- Greek: paramesos παράμεσος (para = next to + mesos = in the middle: the finger next to the middle finger)
- Serbian: domali prst (the finger next to the little)
# The wedding ring
Main Article: Wedding ring
In Western cultures a wedding ring is traditionally worn on the ring finger. According to tradition in some countries, the wedding ring is worn on the left ring finger because the vein in the left ring finger, referred to as the vena amoris was believed to be directly connected to the heart, a symbol of love.
In medieval Europe, the Christian wedding ceremony placed the ring in sequence on the index, middle, and ring fingers of the left hand, representing the trinity — God the Father, God the Son, and God the Holy Spirit. The ring was then left on the ring finger. In a few European countries, the ring is worn on the left hand prior to marriage, then transferred to the right during the ceremony. For example, a Greek Orthodox bride wears the ring on the left hand prior to the ceremony, then moves it to the right hand after the wedding.
In Norway, Russia, Poland, Germany, Austria, Denmark, countries of former Yugoslavia and in Spain (except in Catalonia) the wedding ring is worn on the ring finger on the right hand.
In the Jewish wedding ceremony, the groom places the ring on the bride's index finger, and not ring finger; the ring is usually moved to the ring finger after the ceremony.
In the Indian tradition, the right hand is considered as auspicious. Hence the wedding ring is worn on the right hand. However, despite tradition, some wear the ring on the left hand, matching cultural practice
in some western countries.
# Other
- There is evidence that the ratio between the lengths of the index finger and the ring finger is modulated by androgen exposure in the uterus.[1]
- It is the weakest of the fingers on the hand, as it shares a flexor muscle with the middle and little fingers. It is the only finger that cannot be fully extended by itself.[citation needed] | https://www.wikidoc.org/index.php/Ring_finger | |
e7efcac4c41fd3bc23296d5455372c58821c5631 | wikidoc | Risk factor | Risk factor
# Overview
A risk factor is a variable associated with an increased risk of disease or infection. Risk factors are correlational and not necessarily causal, because correlation does not imply causation. For example, being young cannot be said to cause measles, but young people are more at risk as they are less likely to have developed immunity during a previous epidemic.
Risk factors are evaluated by comparing the risk of those exposed to the potential risk factor to those not exposed. Let's say that at a wedding, 74 people ate the chicken and 22 of them were ill, while of the 35 people who had the fish or vegetarian meal only 2 were ill. Did the chicken make the people ill?
Risk = \frac {\mbox{number of persons experiencing event (food poisoning)}} {\mbox{number of persons exposed to risk factor (food)}}
So the chicken eaters' risk = 22/74 = 0.297
And non-chicken eaters' risk = 2/35 = 0.057.
Those who ate the chicken had a risk over five times as high as those who did not, suggesting that eating chicken was the cause of the illness. Note, however, that this is not proof. Statistical methods would be used in a less clear cut case to decide what level of risk the risk factor would have to present to be able to say the risk factor "causes" the disease (for example in a study of the link between smoking and lung cancer).
The term "risk factor" was first coined by heart researcher Dr. Thomas R. Dawber in a landmark scientific paper in 1961, where he attributed heart disease to specific conditions (blood pressure, cholesterol, smoking).
de:Risikofaktor
lt:Rizikos veiksnys
nl:Risicofactor | Risk factor
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A risk factor is a variable associated with an increased risk of disease or infection. Risk factors are correlational and not necessarily causal, because correlation does not imply causation. For example, being young cannot be said to cause measles, but young people are more at risk as they are less likely to have developed immunity during a previous epidemic.
Risk factors are evaluated by comparing the risk of those exposed to the potential risk factor to those not exposed. Let's say that at a wedding, 74 people ate the chicken and 22 of them were ill, while of the 35 people who had the fish or vegetarian meal only 2 were ill. Did the chicken make the people ill?
Risk = \frac {\mbox{number of persons experiencing event (food poisoning)}} {\mbox{number of persons exposed to risk factor (food)}}
</math>
So the chicken eaters' risk = 22/74 = 0.297
And non-chicken eaters' risk = 2/35 = 0.057.
Those who ate the chicken had a risk over five times as high as those who did not, suggesting that eating chicken was the cause of the illness. Note, however, that this is not proof. Statistical methods would be used in a less clear cut case to decide what level of risk the risk factor would have to present to be able to say the risk factor "causes" the disease (for example in a study of the link between smoking and lung cancer).
The term "risk factor" was first coined by heart researcher Dr. Thomas R. Dawber in a landmark scientific paper in 1961, where he attributed heart disease to specific conditions (blood pressure, cholesterol, smoking).
de:Risikofaktor
lt:Rizikos veiksnys
nl:Risicofactor
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Risk_factor | |
f452d35a790d5063e002ed9132d02f923bce86f0 | wikidoc | Rivaroxaban | Rivaroxaban
SPINAL/EPIDURAL HEMATOMA
SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas have occurred in patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
- Use of indwelling epidural catheters
- Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
- A history of traumatic or repeated epidural or spinal punctures
- A history of spinal deformity or spinal surgery.
- Optimal timing between the administration of rivaroxaban and neuraxial procedures is not known
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.
- For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of rivaroxaban is 20 mg taken orally once daily with the evening meal.
- For patients with CrCl 15 to 50 mL/min, the recommended dose is 15 mg once daily with the evening meal.
# Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE
- The recommended dose of rivaroxaban for the initial treatment of acute DVT and/or PE is 15 mg taken orally twice daily with food for the first 21 days.
- After this initial treatment period, the recommended dose of rivaroxaban is 20 mg taken orally once daily with food, at approximately the same time each day.
- The recommended dose of rivaroxaban for reduction in the risk of recurrence of DVT or PE is 20 mg taken orally once daily with food at approximately the same time each day.
# Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
- The recommended dose of rivaroxaban is 10 mg taken orally once daily with or without food.
- The initial dose should be taken 6 to 10 hours after surgery provided that hemostasis has been established.
- For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended.
- For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.
- Dosing Information
Rivaroxaban has been approved by the EMA to reduce the risk of recurrent MI, stroke and death following an ACS event in troponin positive patients based upon the ATLAS II trial. Rivaroxaban is not approved by the US FDA to reduce the risk of recurrent MI, stroke and death following an ACS event. In ATLAS II:
- Patients were randomized to 2.5 mg or 5 mg of rivaroxaban.
- Rivaroxaban 2.5 mg significantly reduced the risk of death from both cardiovascular causes (HR 0.66; p=0.002) and death from any cause (HR 0.68; p=0.002). (ATLAS ACS 2 - TIMI 51)
- Dosing Information
- 10 mg orally daily for 35 days (MAGELLAN)
- Severe hypersensitivity reaction to rivaroxaban.
- Premature discontinuation of any oral anticoagulant, including rivaroxaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events.
- An increased rate of stroke was observed during the transition from rivaroxaban to warfarin in clinical trials in atrial fibrillation patients.
- If rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
# Risk of Bleeding
- Rivaroxaban increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe rivaroxaban to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.
- Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement.
- Discontinue rivaroxaban in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
- Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs).
- Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.
- A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable.
- Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
- Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates (PCCs) in healthy volunteers.
- The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated.
# Spinal/Epidural Anesthesia or Puncture
- When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
- An epidural catheter should not be removed earlier than 18 hours after the last administration of rivaroxaban.
- The next rivaroxaban dose is not to be administered earlier than 6 hours after the removal of the catheter.
- If traumatic puncture occurs, the administration of rivaroxaban is to be delayed for 24 hours.
# Use in Patients with Renal Impairment
- Avoid the use of rivaroxaban in patients with CrCl <15 mL/min since drug exposure is increased.
- Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly.
- Discontinue rivaroxaban in patients who develop acute renal failure while on rivaroxaban.
- Avoid the use of rivaroxaban in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.
- Avoid the use of rivaroxaban in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.
- Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min.
- Patients who develop acute renal failure while on rivaroxaban should discontinue the treatment.
# Use in Patients with Hepatic Impairment
- No clinical data are available for patients with severe hepatic impairment.
- Avoid use of rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased.
# Use with P-gp and Strong CYP3A4 Inhibitors or Inducers
- Avoid concomitant use of rivaroxaban with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir, and conivaptan).
- Avoid concomitant use of rivaroxaban with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort).
# Risk of Pregnancy-Related Hemorrhage
- In pregnant women, rivaroxaban should be used only if the potential benefit justifies the potential risk to the mother and fetus. rivaroxaban dosing in pregnancy has not been studied.
- The anticoagulant effect of rivaroxaban cannot be monitored with standard laboratory testing nor readily reversed.
- Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
# Patients with Prosthetic Heart Valves
- The safety and efficacy of rivaroxaban have not been studied in patients with prosthetic heart valves. Therefore, use of rivaroxaban is not recommended in these patients.
# Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy
- Initiation of rivaroxaban is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy
# Hemorrhage
The most common adverse reactions with rivaroxaban were bleeding complications.
# Nonvalvular Atrial Fibrillation
In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for rivaroxaban vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.
Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.
# Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and to Reduce the Risk of Recurrence of DVT and of PE
In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with rivaroxaban vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for rivaroxaban-treated patients and 204 days for enoxaparin/VKA-treated patients.
Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.
In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for rivaroxaban vs. 0.2% for placebo treatment groups. The mean duration of treatment was 190 days for both rivaroxaban and placebo treatment groups.
Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN Extension study.
# Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with rivaroxaban.
The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4.
Following rivaroxaban treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.
# Other Adverse Reactions
Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban-treated patients in the EINSTEIN Extension study are shown in Table 5.
Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban-treated patients in RECORD 1–3 studies are shown in Table 6.
Other clinical trial experience: In an investigational study of acute medically ill patients being treated with rivaroxaban 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.
# Blood and lymphatic system disorders
- Agranulocytosis
# Gastrointestinal disorders
- Retroperitoneal hemorrhage
# Hepatobiliary disorders
- Jaundice
- Cholestasis
- Cytolytic hepatitis
# Immune system disorders
- Hypersensitivity
- Anaphylactic reaction
- Anaphylactic shock
- Angioedema
# Nervous system disorders
- Cerebral hemorrhage
- Subdural hematoma
- Epidural hematoma
- Hemiparesis
# Skin and subcutaneous tissue disorders
- Stevens-Johnson syndrome
# Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems
In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors the following increases in rivaroxaban exposure were observed.
- Similar increases in pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were also observed.
- Significant increases in rivaroxaban exposure may increase bleeding risk.
- Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively.
- Similar increases in pharmacodynamic effects were also observed.
- Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively.
- Similar increases in pharmacodynamic effects were also observed.
- Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively.
- The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.
- Both the single-dose rivaroxaban AUC and Cmax increased by 30%.
- Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.
# Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems
- In a drug interaction study, coadministration of rivaroxaban (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively.
- Similar decreases in pharmacodynamic effects were also observed.
- These decreases in exposure to rivaroxaban may decrease efficacy.
# Anticoagulants
In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and rivaroxaban (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity.
- Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
- In another study, single doses of warfarin (15 mg) and rivaroxaban (5 mg) resulted in an additive effect on factor Xa inhibition and PT.
- Warfarin did not affect the pharmacokinetics of rivaroxaban.
# NSAIDs/Aspirin
- In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding.
- NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with rivaroxaban.
- In a single-dose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with rivaroxaban.
# Clopidogrel
- In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and rivaroxaban (15 mg single dose) were coadministered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively.
- The change in bleeding time was approximately twice the maximum increase seen with either drug alone.
- There was no change in the pharmacokinetics of either drug.
# Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems
- In a pharmacokinetic trial, rivaroxaban was administered as a single dose in subjects with mild (CrCl = 50 to 79 mL/min) or moderate renal impairment (CrCl = 30 to 49 mL/min) receiving multiple doses of erythromycin (a combined P-gp and moderate CYP3A4 inhibitor).
- Compared to rivaroxaban administered alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving erythromycin reported a 76% and 99% increase in AUCinf and a 56% and 64% increase in Cmax, respectively.
- Similar trends in pharmacodynamic effects were also observed.
# Drugs that are Substrates of CYP3A4 and/or Drug Transport Systems
- In addition, there were no significant pharmacokinetic interactions observed in studies comparing concomitant rivaroxaban 20 mg and 7.5 mg single dose of midazolam (substrate of CYP3A4), 0.375 mg once-daily dose of digoxin (substrate of P-gp), or 20 mg once daily dose of atorvastatin (substrate of CYP3A4 and P-gp) in healthy volunteers.
- Use rivaroxaban with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible.
- The anticoagulant effect of rivaroxaban cannot be reliably monitored with standard laboratory testing.
- Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits.
- Rivaroxaban should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus.
- Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post‑implantation pregnancy loss in rabbits.
- Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis.
- This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day.
- Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug.
- Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue rovaroxaban, taking into account the importance of the drug to the mother.
- In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years.
- In clinical trials the efficacy of rivaroxaban in the elderly (65 years or older) was similar to that seen in patients younger than 65 years.
- Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups
- In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered rivaroxaban 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered rivaroxaban 20 mg once daily.
- Patients with CrCl 15 to 30 mL/min were not studied, but administration of rivaroxaban 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function.
# Treatment of DVT and/or PE, and Reduction in the Risk of Recurrence of DVT and of PE
- In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies.
- Avoid the use of rivaroxaban in patients with CrCl <30 mL/min.
# Prophylaxis of DVT Following Hip or Knee Replacement Surgery
- The combined analysis of the RECORD 1–3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population.
- Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of rivaroxaban in patients with CrCl <30 mL/min.
- The safety or PK of rivaroxaban in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated.
- Avoid the use of rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.
- The 15 mg and 20 mg rivaroxaban tablets should be taken with food, while the 10 mg tablet can be taken with or without food .
- In the nonvalvular atrial fibrillation efficacy study rivaroxaban was taken with the evening meal.
# Switching to and from rivaroxaban
- Switching from warfarin to rivaroxaban - When switching patients from warfarin to rivaroxaban, discontinue warfarin and start rivaroxaban as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.
- Switching from rivaroxaban to warfarin - No clinical trial data are available to guide converting patients from rivaroxaban to warfarin. rivaroxaban affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue rivaroxaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban would have been taken.
- Switching from rivaroxaban to anticoagulants other than warfarin - For patients currently taking rivaroxaban and transitioning to an anticoagulant with rapid onset, discontinue rivaroxaban and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next rivaroxaban dose would have been taken.
- Switching from anticoagulants other than warfarin to rivaroxaban - For patients currently receiving an anticoagulant other than warfarin, start rivaroxaban 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start rivaroxaban at the same time.
# Discontinuation for Surgery and other Interventions
- If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, rivaroxaban should be stopped at least 24 hours before the procedure to reduce the risk of bleeding.
- In deciding whether a procedure should be delayed until 24 hours after the last dose of rivaroxaban, the increased risk of bleeding should be weighed against the urgency of intervention.
- Rivaroxaban should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short.
- If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.
# Missed Dose
- If a dose of rivaroxaban is not taken at the scheduled time, administer the dose as soon as possible on the same day as follows:
- For patients receiving 15 mg twice daily: The patient should take rivaroxaban immediately to ensure intake of 30 mg rivaroxaban per day. In this particular instance, two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.
- For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed rivaroxaban dose immediately.
# Administration Options
- For patients who are unable to swallow whole tablets, 15 mg or 20 mg rivaroxaban tablets may be crushed and mixed with applesauce immediately prior to use and administered orally.
- After the administration of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should be immediately followed by food.
- After confirming gastric placement of the tube, 15 mg or 20 mg rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube.
- Since rivaroxaban absorption is dependent on the site of drug release, avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure.
- After the administration of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding.
- Crushed 15 mg or 20 mg rivaroxaban tablets are stable in water and in applesauce for up to 4 hours.
- An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed rivaroxaban tablet to PVC or silicone nasogastric (NG) tubing
- Discontinue rivaroxaban and initiate appropriate therapy if bleeding complications associated with overdosage occur.
- A specific antidote for rivaroxaban is not available.
- Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.
- The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.
- Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.
- Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products.
- Rivaroxaban inhibits free factor Xa and prothrombinase activity.
- Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin.
- By inhibiting factor Xa, rivaroxaban decreases thrombin generation.
Rivaroxaban, a FXa inhibitor, with the chemical name 5-Chloro-N-({(5S)-2-oxo-3--1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89.
Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.
The absolute bioavailability of rivaroxaban is dose-dependent. For the 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. rivaroxaban 10 mg tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of rivaroxaban with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). rivaroxaban 15 mg and 20 mg tablets should be taken with food .
The maximum concentrations (Cmax) of rivaroxaban appear 2 to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of rivaroxaban (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or rivaroxaban (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban.
Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.
In a study with 44 healthy subjects, both mean AUC and Cmax values for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and Cmax was 18% lower.
Plasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L.
Approximately 51% of an orally administered -rivaroxaban dose was recovered as inactive metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites.
Following oral administration, approximately one-third of the absorbed dose is excreted unchanged in the urine, with the remaining two-thirds excreted as inactive metabolites in both the urine and feces. In a Phase 1 study, following the administration of a -rivaroxaban dose, 66% of the radioactive dose was recovered in urine (36% as unchanged drug) and 28% was recovered in feces (7% as unchanged drug). Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxaban's affinity for influx transporter proteins is unknown.
Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
- The systemic exposures (AUCs) of unbound rivaroxaban in male and female mice at the highest dose tested (60 mg/kg/day) were 1- and 2-times, respectively, the human exposure of unbound drug at the human dose of 20 mg/day.
- Systemic exposures of unbound drug in male and female rats at the highest dose tested (60 mg/kg/day) were 2- and 4-times, respectively, the human exposure.
- Rivaroxaban was not mutagenic in bacteria (Ames-Test) or clastogenic in V79 Chinese hamster lung cells in vitro or in the mouse micronucleus test in vivo.
- No impairment of fertility was observed in male or female rats when given up to 200 mg/kg/day of rivaroxaban orally.
- This dose resulted in exposure levels, based on the unbound AUC, at least 13 times the exposure in humans given 20 mg rivaroxaban daily.
The evidence for the efficacy and safety of rivaroxaban was derived from ROCKET AF, a multi-national, double-blind study comparing rivaroxaban (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to <50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to have one or more of the following additional risk factors for stroke:
- A prior stroke (ischemic or unknown type),transient ischemic attack (TIA) or non‑CNS systemic embolism, or
- 2 or more of the following risk factors:
Age ≥75 years,
Hypertension,
Heart failure or left ventricular ejection fraction ≤35%, or
Diabetes mellitus
- Age ≥75 years,
- Hypertension,
- Heart failure or left ventricular ejection fraction ≤35%, or
- Diabetes mellitus
ROCKET AF was a non-inferiority study designed to demonstrate that rivaroxaban preserved more than 50% of warfarin's effect on stroke and non-CNS systemic embolism as established by previous placebo-controlled studies of warfarin in atrial fibrillation.
A total of 14264 patients were randomized and followed on study treatment for a median of 590 days. The mean age was 71 years and the mean CHADS2 score was 3.5. The population was 60% male, 83% Caucasian, 13% Asian and 1.3% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6 weeks at time of screening. Concomitant diseases of patients in this study included hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%. At baseline, 37% of patients were on aspirin (almost exclusively at a dose of 100 mg or less) and few patients were on clopidogrel. Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe (15%); and Latin America (13%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the first few months of the study.
In ROCKET AF, rivaroxaban was demonstrated non-inferior to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism , but superiority to warfarin was not demonstrated. There is insufficient experience to determine how rivaroxaban and warfarin compare when warfarin therapy is well-controlled.
Table 9 displays the overall results for the primary composite endpoint and its components.
Figure 1 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.
The efficacy of rivaroxaban was generally consistent across major subgroups.
The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but warfarin patients who completed the study were generally maintained on warfarin. rivaroxaban patients were generally switched to warfarin without a period of coadministration of warfarin and rivaroxaban, so that they were not adequately anticoagulated after stopping rivaroxaban until attaining a therapeutic INR. During the 28 days following the end of the study, there were 22 strokes in the 4637 patients taking rivaroxaban vs. 6 in the 4691 patients taking warfarin.
Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation. The utility of rivaroxaban for preventing post-cardioversion stroke and systemic embolism is unknown.
# Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE
Rivaroxaban for the treatment of DVT and/or PE and for the reduction in the risk of recurrence of DVT and of PE was studied in EINSTEIN DVT and EINSTEIN PE, multi-national, open-label, non-inferiority studies comparing rivaroxaban (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by rivaroxaban 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0–3.0) was reached. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the studies. The intended treatment duration was 3, 6, or 12 months based on investigator's assessment prior to randomization.
A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208 days in the rivaroxaban group and 204 days in the enoxaparin/VKA group. The mean age was approximately 57 years. The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black. About 73% and 92% of rivaroxaban-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for a median duration of 2 days. Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days. Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study.
In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at baseline. Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilicconditions (6%), or active cancer (5%).
In the EINSTEIN DVT and EINSTEIN PE studies, rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE . In each study the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0.
Table 10 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.
Figures 2 and 3 are plots of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE studies, respectively.
Rivaroxaban for reduction in the risk of recurrence of DVT and of PE was studied in the EINSTEIN Extension study, a multi-national, double-blind, superiority study comparing rivaroxaban (20 mg once daily with food) to placebo in patients who had completed 6 to 14 months of treatment for DVT and/or PE following the acute event. The intended treatment duration was 6 or 12 months based on investigator's assessment prior to randomization.
A total of 1196 patients were randomized and followed on study treatment for a mean of 190 days for both rivaroxaban and placebo treatment groups. The mean age was approximately 58 years. The population was 58% male, 78% Caucasian, 8% Asian and about 2% Black. Aspirin was taken as on-treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. In the EINSTEIN Extension study about 60% of patients had a history of proximal index DVT without PE event and 29% of patients had a PE without symptomatic DVT event. About 59% of patients had an idiopathic DVT/PE. Other risk factors included previous episode of DVT/PE (16%), immobilization (14%), known thrombophilic conditions (8%), or active cancer (5%).
In the EINSTEIN Extension study rivaroxaban was demonstrated to be superior to placebo for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE .
Table 11 displays the overall results for the primary composite endpoint and its components.
Figure 4 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.
# Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
Rivaroxaban was studied in 9011 patients (4487 rivaroxaban-treated, 4524 enoxaparin-treated patients) in the RECORD 1, 2, and 3 studies.
The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared rivaroxaban 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug. The mean age was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female. More than 82% of patients were White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis). In RECORD 1, the mean exposure duration (± SD) to active rivaroxaban and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively. In RECORD 2, the mean exposure duration to active rivaroxaban and enoxaparin was 33.5 ± 6.9 and 12.4 ± 2.9 days, respectively. After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration. The efficacy data for RECORD 1 and 2 are provided in Table 12.
One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared rivaroxaban 10 mg once daily started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin. In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively. The mean age (± SD) of patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years. Sixty-eight percent (68%) of patients were female. Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black. The study excluded patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or cirrhosis). The mean exposure duration (± SD) to active rivaroxaban and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, respectively. The efficacy data are provided in Table 13.
- 10 mg tablets are round, light red, biconvex film-coated tablets marked with a triangle pointing down above a "10" on one side, and "Xa" on the other side. The tablets are supplied in the packages listed:
- 15 mg tablets are round, red, biconvex film-coated tablets with a triangle pointing down above a "15" marked on one side and "Xa" on the other side. The tablets are supplied in the packages listed:
- 20 mg tablets are triangle-shaped, dark red film-coated tablets with a triangle pointing down above a "20" marked on one side and "Xa" on the other side. The tablets are supplied in the packages listed:
- Advise patients to take rivaroxaban only as directed.
- Remind patients to not discontinue rivaroxaban without first talking to their healthcare professional.
- Advise patients with atrial fibrillation to take rivaroxaban once daily with the evening meal.
- Advise patients with DVT and/or PE to take rivaroxaban 15 mg or 20 mg tablets with food at approximately the same time every day.
- Advise patients who cannot swallow the tablet whole to crush rivaroxaban and combine with a small amount of applesauce followed by food.
- For patients requiring an NG tube or gastric feeding tube, instruct the patient or caregiver to crush the rivaroxaban tablet and mix it with a small amount of water before administering via the tube.
- If a dose is missed, advise the patient to take rivaroxaban as soon as possible on the same day and continue on the following day with their recommended daily dose regimen.
# Bleeding Risks
- Advise patients to report any unusual bleeding or bruising to their physician.
- Inform patients that it might take them longer than usual to stop bleeding, and that they may bruise and/or bleed more easily when they are treated with rivaroxaban.
- If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur, advise the patient to contact his or her physician immediately.
# Invasive or Surgical Procedures
- Instruct patients to inform their healthcare professional that they are taking rivaroxaban before any invasive procedure (including dental procedures) is scheduled.
# Concomitant Medication and Herbals
- Advise patients to inform their physicians and dentists if they are taking, or plan to take, any prescription or over-the-counter drugs or herbals, so their healthcare professionals can evaluate potential interactions.
# Pregnancy and Pregnancy-Related Hemorrhage
- Advise patients to inform their physician immediately if they become pregnant or intend to become pregnant during treatment with rivaroxaban.
- Advise pregnant women receiving rivaroxaban to immediately report to their physician any bleeding or symptoms of blood loss.
# Nursing
- Advise patients to discuss with their physician if they are nursing or intend to nurse during anticoagulant treatment.
# Females of Reproductive Potential
- Advise patients who can become pregnant to discuss pregnancy planning with their physician.
- ↑ Jessica L. Mega, Eugene Braunwald, Stephen D. Wiviott, Jean-Pierre Bassand, Deepak L. Bhatt, Christoph Bode, Paul Burton, Marc Cohen, Nancy Cook-Bruns, Keith A. A. Fox, Shinya Goto, Sabina A. Murphy, Alexei N. Plotnikov, David Schneider, Xiang Sun, Freek W. A. Verheugt & C. Michael Gibson (2012). "Rivaroxaban in patients with a recent acute coronary syndrome". The New England journal of medicine. 366 (1): 9–19. doi:10.1056/NEJMoa1112277. PMID 22077192. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Alexander T. Cohen, Theodore E. Spiro, Harry R. Buller, Lloyd Haskell, Dayi Hu, Russell Hull, Alexandre Mebazaa, Geno Merli, Sebastian Schellong, Alex C. Spyropoulos & Victor Tapson (2013). "Rivaroxaban for thromboprophylaxis in acutely ill medical patients". The New England journal of medicine. 368 (6): 513–523. doi:10.1056/NEJMoa1111096. PMID 23388003. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link) | Rivaroxaban
SPINAL/EPIDURAL HEMATOMA
SPINAL/EPIDURAL HEMATOMA: Epidural or spinal hematomas have occurred in patients treated with rivaroxaban who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
- Use of indwelling epidural catheters
- Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
- A history of traumatic or repeated epidural or spinal punctures
- A history of spinal deformity or spinal surgery.
- Optimal timing between the administration of rivaroxaban and neuraxial procedures is not known
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.
- For patients with creatinine clearance (CrCl) >50 mL/min, the recommended dose of rivaroxaban is 20 mg taken orally once daily with the evening meal.
- For patients with CrCl 15 to 50 mL/min, the recommended dose is 15 mg once daily with the evening meal.
### Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE
- The recommended dose of rivaroxaban for the initial treatment of acute DVT and/or PE is 15 mg taken orally twice daily with food for the first 21 days.
- After this initial treatment period, the recommended dose of rivaroxaban is 20 mg taken orally once daily with food, at approximately the same time each day.
- The recommended dose of rivaroxaban for reduction in the risk of recurrence of DVT or PE is 20 mg taken orally once daily with food at approximately the same time each day.
### Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
- The recommended dose of rivaroxaban is 10 mg taken orally once daily with or without food.
- The initial dose should be taken 6 to 10 hours after surgery provided that hemostasis has been established.
- For patients undergoing hip replacement surgery, treatment duration of 35 days is recommended.
- For patients undergoing knee replacement surgery, treatment duration of 12 days is recommended.
- Dosing Information
Rivaroxaban has been approved by the EMA to reduce the risk of recurrent MI, stroke and death following an ACS event in troponin positive patients based upon the ATLAS II trial. Rivaroxaban is not approved by the US FDA to reduce the risk of recurrent MI, stroke and death following an ACS event. In ATLAS II:
- Patients were randomized to 2.5 mg or 5 mg of rivaroxaban.
- Rivaroxaban 2.5 mg significantly reduced the risk of death from both cardiovascular causes (HR 0.66; p=0.002) and death from any cause (HR 0.68; p=0.002). (ATLAS ACS 2 - TIMI 51) [1]
- Dosing Information
- 10 mg orally daily for 35 days (MAGELLAN)[2]
- Severe hypersensitivity reaction to rivaroxaban.
- Premature discontinuation of any oral anticoagulant, including rivaroxaban, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events.
- An increased rate of stroke was observed during the transition from rivaroxaban to warfarin in clinical trials in atrial fibrillation patients.
- If rivaroxaban is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
### Risk of Bleeding
- Rivaroxaban increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe rivaroxaban to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.
- Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement.
- Discontinue rivaroxaban in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
- Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and non-steroidal anti-inflammatory drugs (NSAIDs).
- Concomitant use of drugs that are combined P-gp and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir) increases rivaroxaban exposure and may increase bleeding risk.
- A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable.
- Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.
- Partial reversal of prothrombin time prolongation has been seen after administration of prothrombin complex concentrates (PCCs) in healthy volunteers.
- The use of other procoagulant reversal agents like activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (rFVIIa) has not been evaluated.
### Spinal/Epidural Anesthesia or Puncture
- When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
- An epidural catheter should not be removed earlier than 18 hours after the last administration of rivaroxaban.
- The next rivaroxaban dose is not to be administered earlier than 6 hours after the removal of the catheter.
- If traumatic puncture occurs, the administration of rivaroxaban is to be delayed for 24 hours.
### Use in Patients with Renal Impairment
- Avoid the use of rivaroxaban in patients with CrCl <15 mL/min since drug exposure is increased.
- Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly.
- Discontinue rivaroxaban in patients who develop acute renal failure while on rivaroxaban.
- Avoid the use of rivaroxaban in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.
- Avoid the use of rivaroxaban in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.
- Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min.
- Patients who develop acute renal failure while on rivaroxaban should discontinue the treatment.
### Use in Patients with Hepatic Impairment
- No clinical data are available for patients with severe hepatic impairment.
- Avoid use of rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased.
### Use with P-gp and Strong CYP3A4 Inhibitors or Inducers
- Avoid concomitant use of rivaroxaban with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir, and conivaptan).
- Avoid concomitant use of rivaroxaban with drugs that are combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort).
### Risk of Pregnancy-Related Hemorrhage
- In pregnant women, rivaroxaban should be used only if the potential benefit justifies the potential risk to the mother and fetus. rivaroxaban dosing in pregnancy has not been studied.
- The anticoagulant effect of rivaroxaban cannot be monitored with standard laboratory testing nor readily reversed.
- Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).
### Patients with Prosthetic Heart Valves
- The safety and efficacy of rivaroxaban have not been studied in patients with prosthetic heart valves. Therefore, use of rivaroxaban is not recommended in these patients.
### Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy
- Initiation of rivaroxaban is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy
### Hemorrhage
The most common adverse reactions with rivaroxaban were bleeding complications.
### Nonvalvular Atrial Fibrillation
In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for rivaroxaban vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.
Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.
### Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and to Reduce the Risk of Recurrence of DVT and of PE
In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with rivaroxaban vs. enoxaparin/Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for rivaroxaban-treated patients and 204 days for enoxaparin/VKA-treated patients.
Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.
In the EINSTEIN Extension clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1.8% for rivaroxaban vs. 0.2% for placebo treatment groups. The mean duration of treatment was 190 days for both rivaroxaban and placebo treatment groups.
Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN Extension study.
### Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with rivaroxaban.
The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4.
Following rivaroxaban treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.
### Other Adverse Reactions
Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban-treated patients in the EINSTEIN Extension study are shown in Table 5.
Non-hemorrhagic adverse reactions reported in ≥1% of rivaroxaban-treated patients in RECORD 1–3 studies are shown in Table 6.
Other clinical trial experience: In an investigational study of acute medically ill patients being treated with rivaroxaban 10 mg tablets, cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed.
### Blood and lymphatic system disorders
- Agranulocytosis
### Gastrointestinal disorders
- Retroperitoneal hemorrhage
### Hepatobiliary disorders
- Jaundice
- Cholestasis
- Cytolytic hepatitis
### Immune system disorders
- Hypersensitivity
- Anaphylactic reaction
- Anaphylactic shock
- Angioedema
### Nervous system disorders
- Cerebral hemorrhage
- Subdural hematoma
- Epidural hematoma
- Hemiparesis
### Skin and subcutaneous tissue disorders
- Stevens-Johnson syndrome
### Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems
In drug interaction studies evaluating the concomitant use with drugs that are combined P-gp and CYP3A4 inhibitors the following increases in rivaroxaban exposure were observed.
- Similar increases in pharmacodynamic effects (i.e., factor Xa inhibition and PT prolongation) were also observed.
- Significant increases in rivaroxaban exposure may increase bleeding risk.
- Steady-state rivaroxaban AUC and Cmax increased by 160% and 70%, respectively.
- Similar increases in pharmacodynamic effects were also observed.
- Single-dose rivaroxaban AUC and Cmax increased by 150% and 60%, respectively.
- Similar increases in pharmacodynamic effects were also observed.
- Single-dose rivaroxaban AUC and Cmax increased by 50% and 40%, respectively.
- The smaller increases in exposure observed for clarithromycin compared to ketoconazole or ritonavir may be due to the relative difference in P-gp inhibition.
- Both the single-dose rivaroxaban AUC and Cmax increased by 30%.
- Single-dose rivaroxaban AUC and Cmax increased by 40% and 30%, respectively.
### Drugs that Induce Cytochrome P450 3A4 Enzymes and Drug Transport Systems
- In a drug interaction study, coadministration of rivaroxaban (20 mg single dose with food) with a drug that is a combined P-gp and strong CYP3A4 inducer (rifampicin titrated up to 600 mg once daily) led to an approximate decrease of 50% and 22% in AUC and Cmax, respectively.
- Similar decreases in pharmacodynamic effects were also observed.
- These decreases in exposure to rivaroxaban may decrease efficacy.
### Anticoagulants
In a drug interaction study, single doses of enoxaparin (40 mg subcutaneous) and rivaroxaban (10 mg) given concomitantly resulted in an additive effect on anti-factor Xa activity.
- Enoxaparin did not affect the pharmacokinetics of rivaroxaban.
- In another study, single doses of warfarin (15 mg) and rivaroxaban (5 mg) resulted in an additive effect on factor Xa inhibition and PT.
- Warfarin did not affect the pharmacokinetics of rivaroxaban.
### NSAIDs/Aspirin
- In ROCKET AF, concomitant aspirin use (almost exclusively at a dose of 100 mg or less) during the double-blind phase was identified as an independent risk factor for major bleeding.
- NSAIDs are known to increase bleeding, and bleeding risk may be increased when NSAIDs are used concomitantly with rivaroxaban.
- In a single-dose drug interaction study there were no pharmacokinetic or pharmacodynamic interactions observed after concomitant administration of naproxen or aspirin (acetylsalicylic acid) with rivaroxaban.
### Clopidogrel
- In two drug interaction studies where clopidogrel (300 mg loading dose followed by 75 mg daily maintenance dose) and rivaroxaban (15 mg single dose) were coadministered in healthy subjects, an increase in bleeding time to 45 minutes was observed in approximately 45% and 30% of subjects in these studies, respectively.
- The change in bleeding time was approximately twice the maximum increase seen with either drug alone.
- There was no change in the pharmacokinetics of either drug.
### Drug-Disease Interactions with Drugs that Inhibit Cytochrome P450 3A4 Enzymes and Drug Transport Systems
- In a pharmacokinetic trial, rivaroxaban was administered as a single dose in subjects with mild (CrCl = 50 to 79 mL/min) or moderate renal impairment (CrCl = 30 to 49 mL/min) receiving multiple doses of erythromycin (a combined P-gp and moderate CYP3A4 inhibitor).
- Compared to rivaroxaban administered alone in subjects with normal renal function (CrCl >80 mL/min), subjects with mild and moderate renal impairment concomitantly receiving erythromycin reported a 76% and 99% increase in AUCinf and a 56% and 64% increase in Cmax, respectively.
- Similar trends in pharmacodynamic effects were also observed.
### Drugs that are Substrates of CYP3A4 and/or Drug Transport Systems
- In addition, there were no significant pharmacokinetic interactions observed in studies comparing concomitant rivaroxaban 20 mg and 7.5 mg single dose of midazolam (substrate of CYP3A4), 0.375 mg once-daily dose of digoxin (substrate of P-gp), or 20 mg once daily dose of atorvastatin (substrate of CYP3A4 and P-gp) in healthy volunteers.
- Use rivaroxaban with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible.
- The anticoagulant effect of rivaroxaban cannot be reliably monitored with standard laboratory testing.
- Animal reproduction studies showed no increased risk of structural malformations, but increased post-implantation pregnancy loss occurred in rabbits.
- Rivaroxaban should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus.
- Rivaroxaban crosses the placenta in animals. Animal reproduction studies have shown pronounced maternal hemorrhagic complications in rats and an increased incidence of post‑implantation pregnancy loss in rabbits.
- Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis.
- This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day.
- Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg. This dose corresponds to about 14 times the human exposure of unbound drug.
- Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from rivaroxaban, a decision should be made whether to discontinue nursing or discontinue rovaroxaban, taking into account the importance of the drug to the mother.
- In the EINSTEIN DVT, PE and Extension clinical studies approximately 37% were 65 years and over and about 16% were >75 years.
- In clinical trials the efficacy of rivaroxaban in the elderly (65 years or older) was similar to that seen in patients younger than 65 years.
- Both thrombotic and bleeding event rates were higher in these older patients, but the risk-benefit profile was favorable in all age groups
- In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered rivaroxaban 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered rivaroxaban 20 mg once daily.
- Patients with CrCl 15 to 30 mL/min were not studied, but administration of rivaroxaban 15 mg once daily is also expected to result in serum concentrations of rivaroxaban similar to those in patients with normal renal function.
### Treatment of DVT and/or PE, and Reduction in the Risk of Recurrence of DVT and of PE
- In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies.
- Avoid the use of rivaroxaban in patients with CrCl <30 mL/min.
### Prophylaxis of DVT Following Hip or Knee Replacement Surgery
- The combined analysis of the RECORD 1–3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population.
- Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Avoid the use of rivaroxaban in patients with CrCl <30 mL/min.
- The safety or PK of rivaroxaban in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated.
- Avoid the use of rivaroxaban in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.
- The 15 mg and 20 mg rivaroxaban tablets should be taken with food, while the 10 mg tablet can be taken with or without food [see Clinical Pharmacology (12.3)].
- In the nonvalvular atrial fibrillation efficacy study rivaroxaban was taken with the evening meal.
### Switching to and from rivaroxaban
- Switching from warfarin to rivaroxaban - When switching patients from warfarin to rivaroxaban, discontinue warfarin and start rivaroxaban as soon as the International Normalized Ratio (INR) is below 3.0 to avoid periods of inadequate anticoagulation.
- Switching from rivaroxaban to warfarin - No clinical trial data are available to guide converting patients from rivaroxaban to warfarin. rivaroxaban affects INR, so INR measurements made during coadministration with warfarin may not be useful for determining the appropriate dose of warfarin. One approach is to discontinue rivaroxaban and begin both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban would have been taken.
- Switching from rivaroxaban to anticoagulants other than warfarin - For patients currently taking rivaroxaban and transitioning to an anticoagulant with rapid onset, discontinue rivaroxaban and give the first dose of the other anticoagulant (oral or parenteral) at the time that the next rivaroxaban dose would have been taken.
- Switching from anticoagulants other than warfarin to rivaroxaban - For patients currently receiving an anticoagulant other than warfarin, start rivaroxaban 0 to 2 hours prior to the next scheduled evening administration of the drug (e.g., low molecular weight heparin or non-warfarin oral anticoagulant) and omit administration of the other anticoagulant. For unfractionated heparin being administered by continuous infusion, stop the infusion and start rivaroxaban at the same time.
### Discontinuation for Surgery and other Interventions
- If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, rivaroxaban should be stopped at least 24 hours before the procedure to reduce the risk of bleeding.
- In deciding whether a procedure should be delayed until 24 hours after the last dose of rivaroxaban, the increased risk of bleeding should be weighed against the urgency of intervention.
- Rivaroxaban should be restarted after the surgical or other procedures as soon as adequate hemostasis has been established, noting that the time to onset of therapeutic effect is short.
- If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant.
### Missed Dose
- If a dose of rivaroxaban is not taken at the scheduled time, administer the dose as soon as possible on the same day as follows:
- For patients receiving 15 mg twice daily: The patient should take rivaroxaban immediately to ensure intake of 30 mg rivaroxaban per day. In this particular instance, two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.
- For patients receiving 20 mg, 15 mg or 10 mg once daily: The patient should take the missed rivaroxaban dose immediately.
### Administration Options
- For patients who are unable to swallow whole tablets, 15 mg or 20 mg rivaroxaban tablets may be crushed and mixed with applesauce immediately prior to use and administered orally.
- After the administration of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should be immediately followed by food.
- After confirming gastric placement of the tube, 15 mg or 20 mg rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via an NG tube or gastric feeding tube.
- Since rivaroxaban absorption is dependent on the site of drug release, avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and thereby, reduced drug exposure.
- After the administration of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should then be immediately followed by enteral feeding.
- Crushed 15 mg or 20 mg rivaroxaban tablets are stable in water and in applesauce for up to 4 hours.
- An in vitro compatibility study indicated that there is no adsorption of rivaroxaban from a water suspension of a crushed rivaroxaban tablet to PVC or silicone nasogastric (NG) tubing
- Discontinue rivaroxaban and initiate appropriate therapy if bleeding complications associated with overdosage occur.
- A specific antidote for rivaroxaban is not available.
- Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption.
- The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.
- Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.
- Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products.
- Rivaroxaban inhibits free factor Xa and prothrombinase activity.
- Rivaroxaban has no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin.
- By inhibiting factor Xa, rivaroxaban decreases thrombin generation.
Rivaroxaban, a FXa inhibitor, with the chemical name 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide. The molecular formula of rivaroxaban is C19H18ClN3O5S and the molecular weight is 435.89.
Rivaroxaban is a pure (S)-enantiomer. It is an odorless, non-hygroscopic, white to yellowish powder. Rivaroxaban is only slightly soluble in organic solvents (e.g., acetone, polyethylene glycol 400) and is practically insoluble in water and aqueous media.
The absolute bioavailability of rivaroxaban is dose-dependent. For the 10 mg dose, it is estimated to be 80% to 100% and is not affected by food. rivaroxaban 10 mg tablets can be taken with or without food. For the 20 mg dose in the fasted state, the absolute bioavailability is approximately 66%. Coadministration of rivaroxaban with food increases the bioavailability of the 20 mg dose (mean AUC and Cmax increasing by 39% and 76% respectively with food). rivaroxaban 15 mg and 20 mg tablets should be taken with food [see Dosage and Administration (2.1)].
The maximum concentrations (Cmax) of rivaroxaban appear 2 to 4 hours after tablet intake. The pharmacokinetics of rivaroxaban were not affected by drugs altering gastric pH. Coadministration of rivaroxaban (30 mg single dose) with the H2-receptor antagonist ranitidine (150 mg twice daily), the antacid aluminum hydroxide/magnesium hydroxide (10 mL) or rivaroxaban (20 mg single dose) with the PPI omeprazole (40 mg once daily) did not show an effect on the bioavailability and exposure of rivaroxaban.
Absorption of rivaroxaban is dependent on the site of drug release in the GI tract. A 29% and 56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released in the proximal small intestine. Exposure is further reduced when drug is released in the distal small intestine, or ascending colon. Avoid administration of rivaroxaban distal to the stomach which can result in reduced absorption and related drug exposure.
In a study with 44 healthy subjects, both mean AUC and Cmax values for 20 mg rivaroxaban administered orally as a crushed tablet mixed in applesauce were comparable to that after the whole tablet. However, for the crushed tablet suspended in water and administered via an NG tube followed by a liquid meal, only mean AUC was comparable to that after the whole tablet, and Cmax was 18% lower.
Plasma protein binding of rivaroxaban in human plasma is approximately 92% to 95%, with albumin being the main binding component. The steady-state volume of distribution in healthy subjects is approximately 50 L.
Approximately 51% of an orally administered [14C]-rivaroxaban dose was recovered as inactive metabolites in urine (30%) and feces (21%). Oxidative degradation catalyzed by CYP3A4/5 and CYP2J2 and hydrolysis are the major sites of biotransformation. Unchanged rivaroxaban was the predominant moiety in plasma with no major or active circulating metabolites.
Following oral administration, approximately one-third of the absorbed dose is excreted unchanged in the urine, with the remaining two-thirds excreted as inactive metabolites in both the urine and feces. In a Phase 1 study, following the administration of a [14C]-rivaroxaban dose, 66% of the radioactive dose was recovered in urine (36% as unchanged drug) and 28% was recovered in feces (7% as unchanged drug). Unchanged drug is excreted into urine, mainly via active tubular secretion and to a lesser extent via glomerular filtration (approximate 5:1 ratio). Rivaroxaban is a substrate of the efflux transporter proteins P-gp and ABCG2 (also abbreviated Bcrp). Rivaroxaban's affinity for influx transporter proteins is unknown.
Rivaroxaban is a low-clearance drug, with a systemic clearance of approximately 10 L/hr in healthy volunteers following intravenous administration. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.
- The systemic exposures (AUCs) of unbound rivaroxaban in male and female mice at the highest dose tested (60 mg/kg/day) were 1- and 2-times, respectively, the human exposure of unbound drug at the human dose of 20 mg/day.
- Systemic exposures of unbound drug in male and female rats at the highest dose tested (60 mg/kg/day) were 2- and 4-times, respectively, the human exposure.
- Rivaroxaban was not mutagenic in bacteria (Ames-Test) or clastogenic in V79 Chinese hamster lung cells in vitro or in the mouse micronucleus test in vivo.
- No impairment of fertility was observed in male or female rats when given up to 200 mg/kg/day of rivaroxaban orally.
- This dose resulted in exposure levels, based on the unbound AUC, at least 13 times the exposure in humans given 20 mg rivaroxaban daily.
The evidence for the efficacy and safety of rivaroxaban was derived from ROCKET AF, a multi-national, double-blind study comparing rivaroxaban (at a dose of 20 mg once daily with the evening meal in patients with CrCl >50 mL/min and 15 mg once daily with the evening meal in patients with CrCl 30 to <50 mL/min) to warfarin (titrated to INR 2.0 to 3.0) to reduce the risk of stroke and non-central nervous system (CNS) systemic embolism in patients with nonvalvular atrial fibrillation (AF). Patients had to have one or more of the following additional risk factors for stroke:
- A prior stroke (ischemic or unknown type),transient ischemic attack (TIA) or non‑CNS systemic embolism, or
- 2 or more of the following risk factors:
Age ≥75 years,
Hypertension,
Heart failure or left ventricular ejection fraction ≤35%, or
Diabetes mellitus
- Age ≥75 years,
- Hypertension,
- Heart failure or left ventricular ejection fraction ≤35%, or
- Diabetes mellitus
ROCKET AF was a non-inferiority study designed to demonstrate that rivaroxaban preserved more than 50% of warfarin's effect on stroke and non-CNS systemic embolism as established by previous placebo-controlled studies of warfarin in atrial fibrillation.
A total of 14264 patients were randomized and followed on study treatment for a median of 590 days. The mean age was 71 years and the mean CHADS2 score was 3.5. The population was 60% male, 83% Caucasian, 13% Asian and 1.3% Black. There was a history of stroke, TIA, or non-CNS systemic embolism in 55% of patients, and 38% of patients had not taken a vitamin K antagonist (VKA) within 6 weeks at time of screening. Concomitant diseases of patients in this study included hypertension 91%, diabetes 40%, congestive heart failure 63%, and prior myocardial infarction 17%. At baseline, 37% of patients were on aspirin (almost exclusively at a dose of 100 mg or less) and few patients were on clopidogrel. Patients were enrolled in Eastern Europe (39%); North America (19%); Asia, Australia, and New Zealand (15%); Western Europe (15%); and Latin America (13%). Patients randomized to warfarin had a mean percentage of time in the INR target range of 2.0 to 3.0 of 55%, lower during the first few months of the study.
In ROCKET AF, rivaroxaban was demonstrated non-inferior to warfarin for the primary composite endpoint of time to first occurrence of stroke (any type) or non-CNS systemic embolism [HR (95% CI): 0.88 (0.74, 1.03)], but superiority to warfarin was not demonstrated. There is insufficient experience to determine how rivaroxaban and warfarin compare when warfarin therapy is well-controlled.
Table 9 displays the overall results for the primary composite endpoint and its components.
Figure 1 is a plot of the time from randomization to the occurrence of the first primary endpoint event in the two treatment arms.
The efficacy of rivaroxaban was generally consistent across major subgroups.
The protocol for ROCKET AF did not stipulate anticoagulation after study drug discontinuation, but warfarin patients who completed the study were generally maintained on warfarin. rivaroxaban patients were generally switched to warfarin without a period of coadministration of warfarin and rivaroxaban, so that they were not adequately anticoagulated after stopping rivaroxaban until attaining a therapeutic INR. During the 28 days following the end of the study, there were 22 strokes in the 4637 patients taking rivaroxaban vs. 6 in the 4691 patients taking warfarin.
Few patients in ROCKET AF underwent electrical cardioversion for atrial fibrillation. The utility of rivaroxaban for preventing post-cardioversion stroke and systemic embolism is unknown.
### Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE
Rivaroxaban for the treatment of DVT and/or PE and for the reduction in the risk of recurrence of DVT and of PE was studied in EINSTEIN DVT and EINSTEIN PE, multi-national, open-label, non-inferiority studies comparing rivaroxaban (at an initial dose of 15 mg twice daily with food for the first three weeks, followed by rivaroxaban 20 mg once daily with food) to enoxaparin 1 mg/kg twice daily for at least five days with VKA and then continued with VKA only after the target INR (2.0–3.0) was reached. Patients who required thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent and patients with creatinine clearance <30 mL/min, significant liver disease, or active bleeding were excluded from the studies. The intended treatment duration was 3, 6, or 12 months based on investigator's assessment prior to randomization.
A total of 8281 (3449 in EINSTEIN DVT and 4832 in EINSTEIN PE) patients were randomized and followed on study treatment for a mean of 208 days in the rivaroxaban group and 204 days in the enoxaparin/VKA group. The mean age was approximately 57 years. The population was 55% male, 70% Caucasian, 9% Asian and about 3% Black. About 73% and 92% of rivaroxaban-treated patients in the EINSTEIN DVT and EINSTEIN PE studies, respectively, received initial parenteral anticoagulant treatment for a median duration of 2 days. Enoxaparin/VKA-treated patients in the EINSTEIN DVT and EINSTEIN PE studies received initial parenteral anticoagulant treatment for a median duration of 8 days. Aspirin was taken as on treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. Patients randomized to VKA had an unadjusted mean percentage of time in the INR target range of 2.0 to 3.0 of 58% in EINSTEIN DVT study and 60% in EINSTEIN PE study, with the lower values occurring during the first month of the study.
In the EINSTEIN DVT and EINSTEIN PE studies, 49% of patients had an idiopathic DVT/PE at baseline. Other risk factors included previous episode of DVT/PE (19%), recent surgery or trauma (18%), immobilization (16%), use of estrogen-containing drug (8%), known thrombophilicconditions (6%), or active cancer (5%).
In the EINSTEIN DVT and EINSTEIN PE studies, rivaroxaban was demonstrated to be non-inferior to enoxaparin/VKA for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [EINSTEIN DVT HR (95% CI): 0.68 (0.44, 1.04); EINSTEIN PE HR (95% CI): 1.12 (0.75, 1.68)]. In each study the conclusion of non-inferiority was based on the upper limit of the 95% confidence interval for the hazard ratio being less than 2.0.
Table 10 displays the overall results for the primary composite endpoint and its components for EINSTEIN DVT and EINSTEIN PE studies.
Figures 2 and 3 are plots of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups in EINSTEIN DVT and EINSTEIN PE studies, respectively.
Rivaroxaban for reduction in the risk of recurrence of DVT and of PE was studied in the EINSTEIN Extension study, a multi-national, double-blind, superiority study comparing rivaroxaban (20 mg once daily with food) to placebo in patients who had completed 6 to 14 months of treatment for DVT and/or PE following the acute event. The intended treatment duration was 6 or 12 months based on investigator's assessment prior to randomization.
A total of 1196 patients were randomized and followed on study treatment for a mean of 190 days for both rivaroxaban and placebo treatment groups. The mean age was approximately 58 years. The population was 58% male, 78% Caucasian, 8% Asian and about 2% Black. Aspirin was taken as on-treatment concomitant antithrombotic medication by approximately 12% of patients in both treatment groups. In the EINSTEIN Extension study about 60% of patients had a history of proximal index DVT without PE event and 29% of patients had a PE without symptomatic DVT event. About 59% of patients had an idiopathic DVT/PE. Other risk factors included previous episode of DVT/PE (16%), immobilization (14%), known thrombophilic conditions (8%), or active cancer (5%).
In the EINSTEIN Extension study rivaroxaban was demonstrated to be superior to placebo for the primary composite endpoint of time to first occurrence of recurrent DVT or non-fatal or fatal PE [HR (95% CI): 0.18 (0.09, 0.39)].
Table 11 displays the overall results for the primary composite endpoint and its components.
Figure 4 is a plot of the time from randomization to the occurrence of the first primary efficacy endpoint event in the two treatment groups.
### Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
Rivaroxaban was studied in 9011 patients (4487 rivaroxaban-treated, 4524 enoxaparin-treated patients) in the RECORD 1, 2, and 3 studies.
The two randomized, double-blind, clinical studies (RECORD 1 and 2) in patients undergoing elective total hip replacement surgery compared rivaroxaban 10 mg once daily starting at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin 40 mg once daily started 12 hours preoperatively. In RECORD 1 and 2, a total of 6727 patients were randomized and 6579 received study drug. The mean age [± standard deviation (SD)] was 63 ± 12.2 (range 18 to 93) years with 49% of patients ≥65 years and 55% of patients were female. More than 82% of patients were White, 7% were Asian, and less than 2% were Black. The studies excluded patients undergoing staged bilateral total hip replacement, patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min, or patients with significant liver disease (hepatitis or cirrhosis). In RECORD 1, the mean exposure duration (± SD) to active rivaroxaban and enoxaparin was 33.3 ± 7.0 and 33.6 ± 8.3 days, respectively. In RECORD 2, the mean exposure duration to active rivaroxaban and enoxaparin was 33.5 ± 6.9 and 12.4 ± 2.9 days, respectively. After Day 13, oral placebo was continued in the enoxaparin group for the remainder of the double-blind study duration. The efficacy data for RECORD 1 and 2 are provided in Table 12.
One randomized, double-blind, clinical study (RECORD 3) in patients undergoing elective total knee replacement surgery compared rivaroxaban 10 mg once daily started at least 6 to 8 hours (about 90% of patients dosed 6 to 10 hours) after wound closure versus enoxaparin. In RECORD 3, the enoxaparin regimen was 40 mg once daily started 12 hours preoperatively. The mean age (± SD) of patients in the study was 68 ± 9.0 (range 28 to 91) years with 66% of patients ≥65 years. Sixty-eight percent (68%) of patients were female. Eighty-one percent (81%) of patients were White, less than 7% were Asian, and less than 2% were Black. The study excluded patients with severe renal impairment defined as an estimated creatinine clearance <30 mL/min or patients with significant liver disease (hepatitis or cirrhosis). The mean exposure duration (± SD) to active rivaroxaban and enoxaparin was 11.9 ± 2.3 and 12.5 ± 3.0 days, respectively. The efficacy data are provided in Table 13.
- 10 mg tablets are round, light red, biconvex film-coated tablets marked with a triangle pointing down above a "10" on one side, and "Xa" on the other side. The tablets are supplied in the packages listed:
- 15 mg tablets are round, red, biconvex film-coated tablets with a triangle pointing down above a "15" marked on one side and "Xa" on the other side. The tablets are supplied in the packages listed:
- 20 mg tablets are triangle-shaped, dark red film-coated tablets with a triangle pointing down above a "20" marked on one side and "Xa" on the other side. The tablets are supplied in the packages listed:
- Advise patients to take rivaroxaban only as directed.
- Remind patients to not discontinue rivaroxaban without first talking to their healthcare professional.
- Advise patients with atrial fibrillation to take rivaroxaban once daily with the evening meal.
- Advise patients with DVT and/or PE to take rivaroxaban 15 mg or 20 mg tablets with food at approximately the same time every day.
- Advise patients who cannot swallow the tablet whole to crush rivaroxaban and combine with a small amount of applesauce followed by food.
- For patients requiring an NG tube or gastric feeding tube, instruct the patient or caregiver to crush the rivaroxaban tablet and mix it with a small amount of water before administering via the tube.
- If a dose is missed, advise the patient to take rivaroxaban as soon as possible on the same day and continue on the following day with their recommended daily dose regimen.
### Bleeding Risks
- Advise patients to report any unusual bleeding or bruising to their physician.
- Inform patients that it might take them longer than usual to stop bleeding, and that they may bruise and/or bleed more easily when they are treated with rivaroxaban.
- If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs or platelet inhibitors, advise patients to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur, advise the patient to contact his or her physician immediately.
### Invasive or Surgical Procedures
- Instruct patients to inform their healthcare professional that they are taking rivaroxaban before any invasive procedure (including dental procedures) is scheduled.
### Concomitant Medication and Herbals
- Advise patients to inform their physicians and dentists if they are taking, or plan to take, any prescription or over-the-counter drugs or herbals, so their healthcare professionals can evaluate potential interactions.
### Pregnancy and Pregnancy-Related Hemorrhage
- Advise patients to inform their physician immediately if they become pregnant or intend to become pregnant during treatment with rivaroxaban.
- Advise pregnant women receiving rivaroxaban to immediately report to their physician any bleeding or symptoms of blood loss.
### Nursing
- Advise patients to discuss with their physician if they are nursing or intend to nurse during anticoagulant treatment.
### Females of Reproductive Potential
- Advise patients who can become pregnant to discuss pregnancy planning with their physician.
- ↑ Jessica L. Mega, Eugene Braunwald, Stephen D. Wiviott, Jean-Pierre Bassand, Deepak L. Bhatt, Christoph Bode, Paul Burton, Marc Cohen, Nancy Cook-Bruns, Keith A. A. Fox, Shinya Goto, Sabina A. Murphy, Alexei N. Plotnikov, David Schneider, Xiang Sun, Freek W. A. Verheugt & C. Michael Gibson (2012). "Rivaroxaban in patients with a recent acute coronary syndrome". The New England journal of medicine. 366 (1): 9–19. doi:10.1056/NEJMoa1112277. PMID 22077192. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Alexander T. Cohen, Theodore E. Spiro, Harry R. Buller, Lloyd Haskell, Dayi Hu, Russell Hull, Alexandre Mebazaa, Geno Merli, Sebastian Schellong, Alex C. Spyropoulos & Victor Tapson (2013). "Rivaroxaban for thromboprophylaxis in acutely ill medical patients". The New England journal of medicine. 368 (6): 513–523. doi:10.1056/NEJMoa1111096. PMID 23388003. Unknown parameter |month= ignored (help)CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Rivaroxaban | |
83f3f778c1100f2772134555f06b116bc24c8853 | wikidoc | Rizatriptan | Rizatriptan
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# Overview
Rizatriptan is a serotonin (5-HT) 1B/1D receptor agonist that is FDA approved for the {{{indicationType}}} of acute treatment of migraine with or without aura. Common adverse reactions include asthenia/fatigue, somnolence, pain/pressure sensation and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting dose of MAXALT is either 5 mg or 10 mg for the acute treatment of migraines in adults. The 10-mg dose may provide a greater effect than the 5-mg dose, but may have a greater risk of adverse reactions.
- Redosing in Adults
- Although the effectiveness of a second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache returns, a second dose may be administered 2 hours after the first dose. The maximum daily dose should not exceed 30 mg in any 24-hour period. The safety of treating, on average, more than four headaches in a 30-day period has not been established.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rizatriptan in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 10 mg rizatriptan.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Dosing in pediatric patients is based on the patient's body weight. The recommended dose of MAXALT is 5 mg in patients weighing less than 40 kg (88 lb), and 10 mg in patients weighing 40 kg (88 lb) or more.
- The efficacy and safety of treatment with more than one dose of MAXALT within 24 hours in pediatric patients 6 to 17 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rizatriptan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rizatriptan in pediatric patients.
# Contraindications
- Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease.
- Coronary artery vasospasm including Prinzmetal's angina.
- History of stroke or transient ischemic attack (TIA).
- Peripheral vascular disease (PVD).
- Ischemic bowel disease.
- Uncontrolled hypertension.
- Recent use (i.e., within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide).
- Hemiplegic or basilar migraine.
- Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor.
- Hypersensitivity to MAXALT or MAXALT-MLT (angioedema and anaphylaxis seen).
# Warnings
### Precautions
- Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina
- MAXALT should not be given to patients with ischemic or vasospastic coronary artery disease. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of MAXALT. Some of these reactions occurred in patients without known coronary artery disease (CAD). 5-HT1 agonists, including MAXALT may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD.
- Triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) should have a cardiovascular evaluation prior to receiving MAXALT. If there is evidence of CAD or coronary artery vasospasm, MAXALT should not be administered. For patients who have a negative cardiovascular evaluation, consideration should be given to administration of the first MAXALT dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following MAXALT administration. Periodic cardiovascular evaluation should be considered in intermittent long-term users of MAXALT who have cardiovascular risk factors.
- Arrhythmias
- Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue MAXALT if these disturbances occur.
- Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure
- As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with MAXALT and are usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT1 agonists.
- Cerebrovascular Events
- Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Discontinue MAXALT if a cerebrovascular event occurs.
- As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. MAXALT should not be administered to patients with a history of stroke or transient ischemic attack.
- Other Vasospasm Reactions
- 5-HT1 agonists, including MAXALT, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional MAXALT doses.
- Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.
- Medication Overuse Headache
- Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
- Serotonin Syndrome
- Serotonin syndrome may occur with triptans, including MAXALT particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication. MAXALT treatment should be discontinued if serotonin syndrome is suspected.
- Increase in Blood Pressure
- Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without a history of hypertension receiving 5-HT1 agonists, including MAXALT. In healthy young adult male and female patients who received maximal doses of MAXALT (10 mg every 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed. MAXALT is contraindicated in patients with uncontrolled hypertension.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- Adults
- Incidence in Controlled Clinical Trials
- Adverse reactions to MAXALT were assessed in controlled clinical trials that included over 3700 adult patients who received single or multiple doses of MAXALT Tablets. The most common adverse reactions during treatment with MAXALT (≥5% in either treatment group and greater than placebo) were asthenia/fatigue, somnolence, pain/pressure sensation and dizziness. These adverse reactions appeared to be dose related.
- Table 1 lists the adverse reactions (incidence ≥2% and greater than placebo) after a single dose of MAXALT in adults.
- The frequencies of adverse reactions in clinical trials did not increase when up to three doses were taken within 24 hours. Adverse reaction frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (including propranolol), oral contraceptives, or analgesics. The incidences of adverse reactions were not affected by age or gender. There were insufficient data to assess the impact of race on the incidence of adverse reactions.
- Other Events Observed in Association with the Administration of MAXALT in Adults
- In the following section, the frequencies of less commonly reported adverse events are presented that were not reported in other sections of the labeling. Because the reports include events observed in open studies, the role of MAXALT in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used MAXALT and reported an event divided by the total number of patients exposed to MAXALT (N=3716). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those defined as those occurring in at least (>)1/100 patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients.
Infrequent was facial edema. Rare were syncope and edema/swelling.
Frequent were warm sensations.
Frequent was palpitation. Infrequent were tachycardia, cold extremities, and bradycardia.
Frequent were diarrhea and vomiting. Infrequent were dyspepsia, tongue edema and abdominal distention.
Infrequent were muscle weakness, stiffness, myalgia and muscle cramp/spasm.
Frequent were hypoesthesia, euphoria and tremor. Infrequent were vertigo, insomnia, confusion/disorientation, gait abnormality, memory impairment, and agitation.
Frequent was dyspnea. Infrequent was pharyngeal edema.
Infrequent were blurred vision and tinnitus. Rare was eye swelling.
Frequent was flushing. Infrequent were sweating, pruritus, rash, and urticaria. Rare was erythema, hot flashes.
- The adverse reaction profile seen with MAXALT-MLT Orally Disintegrating Tablets was similar to that seen with MAXALT Tablets.
- Pediatric Patients 6 to 17 Years of Age
- Incidence in Controlled Clinical Trials in Pediatric Patients
- Adverse reactions to MAXALT-MLT were assessed in a controlled clinical trial in the acute treatment of migraines (Study 7) that included a total of 1382 pediatric patients 6-17 years of age, of which 977 (72%) administered at least one dose of study treatment (MAXALT-MLT and/or placebo). The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received MAXALT to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.
- Other Events Observed in Association with the Administration of MAXALT-MLT in Pediatric Patients
- In the following section, the frequencies of less commonly reported adverse events are presented. Because the reports include events observed in open studies, the role of MAXALT-MLT in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided.
- Event frequencies are calculated as the number of pediatric patients 6 to 17 years of age who used MAXALT-MLT and reported an event divided by the total number of patients exposed to MAXALT-MLT (N=1068). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within system organ class and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in (>)1/100 pediatric patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 pediatric patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients.
Frequent was fatigue.
Infrequent was hypoacusis.
Frequent was abdominal discomfort.
Infrequent were coordination abnormal, disturbance in attention, and presyncope.
Infrequent was hallucination.
## Postmarketing Experience
- The following section enumerates potentially important adverse events that have occurred in clinical practice and which have been reported spontaneously to various surveillance systems. The events enumerated include all except those already listed in other sections of the labeling or those too general to be informative. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of MAXALT in their causation cannot be reliably determined.
- Neurological/Psychiatric: Seizure.
- General: Allergic conditions including anaphylaxis/anaphylactoid reaction, angioedema, wheezing, and toxic epidermal necrolysis.
- Special Senses: Dysgeusia.
# Drug Interactions
- Propranolol
- The dose of MAXALT should be adjusted in propranolol-treated patients, as propranolol has been shown to increase the plasma AUC of rizatriptan by 70%.
- Ergot-Containing Drugs
- Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and MAXALT within 24 hours is contraindicated.
- Other 5-HT1 Agonists
- Because their vasospastic effects may be additive, co-administration of MAXALT and other 5-HT1 agonists within 24 hours of each other is contraindicated.
- SSRIs/SNRIs and Serotonin Syndrome
- Cases of serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
- Monoamine Oxidase Inhibitors
- MAXALT is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors. A specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. MAXALT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In a general reproductive study in rats, birth weights and pre- and post-weaning weight gain were reduced in the offspring of females treated prior to and during mating and throughout gestation and lactation with doses of 10 and 100 mg/kg/day. In a pre- and post-natal developmental toxicity study in rats, an increase in mortality of the offspring at birth and for the first three days after birth, a decrease in pre- and post-weaning weight gain, and decreased performance in a passive avoidance test (which indicates a decrease in learning capacity of the offspring) were observed at doses of 100 and 250 mg/kg/day. The no-effect dose for all of these effects was 5 mg/kg/day, associated with a maternal plasma exposure (AUC) approximately 7.5 times that in humans receiving the MRDD. With doses of 100 and 250 mg/kg/day, the decreases in average weight of both the male and female offspring persisted into adulthood. All effects on the offspring in both studies occurred in the absence of any apparent maternal toxicity.
- In embryofetal development studies, no teratogenic effects were observed when pregnant rats and rabbits were administered doses of 100 and 50 mg/kg/day, respectively, during organogenesis. Fetal weights were decreased in conjunction with decreased maternal weight gain at the highest doses tested. The developmental no-effect dose in these studies was 10 mg/kg/day in both rats and rabbits (maternal exposures approximately 15 times human exposure at the MRDD). Toxicokinetic studies demonstrated placental transfer of drug in both species.
- Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to MAXALT while pregnant. Healthcare providers are encouraged to report any prenatal exposure to MAXALT by calling the Pregnancy Registry at 1-800-986-8999.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rizatriptan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rizatriptan during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when MAXALT is administered to a nursing woman. Rizatriptan is extensively excreted in rat milk, with levels in milk at least 5-fold higher than levels in maternal plasma.
### Pediatric Use
- Safety and effectiveness in pediatric patients under 6 years of age have not been established.
- The efficacy and safety of MAXALT in the acute treatment of migraine in patients aged 6 to 17 years was established in an adequate and well-controlled study.
- The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received MAXALT to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.
### Geriatic Use
- Clinical studies of MAXALT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
- Although the pharmacokinetics of rizatriptan were similar in elderly (aged ≥65 years) and in younger adults (n=17), in general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range. This reflects the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving MAXALT.
### Gender
There is no FDA guidance on the use of Rizatriptan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rizatriptan with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rizatriptan in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rizatriptan in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rizatriptan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rizatriptan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Rizatriptan in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rizatriptan in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- No overdoses of MAXALT were reported during clinical trials in adults.
- Some adult patients who received 40 mg of MAXALT either a single dose or as two doses with a 2-hour interdose interval had dizziness and somnolence.
- In a clinical pharmacology study in which 12 adult subjects received MAXALT, at total cumulative doses of 80 mg (given within four hours), two of the subjects experienced syncope, dizziness, bradycardia including third degree AV block, vomiting, and/or incontinence.
- In the long-term, open label study, involving 606 treated pediatric migraineurs 12 to 17 years of age (of which 432 were treated for at least 12 months), 151 patients (25%) took two 10-mg doses of MAXALT-MLT within a 24-hour period. Adverse reactions for 3 of these patients included abdominal discomfort, fatigue, and dyspnea.
### Management
- In addition, based on the pharmacology of MAXALT, hypertension or myocardial ischemia could occur after overdosage. Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with MAXALT. Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if clinical symptoms are not observed.
- The effects of hemo- or peritoneal dialysis on serum concentrations of rizatriptan are unknown.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Rizatriptan in the drug label.
# Pharmacology
## Mechanism of Action
- Rizatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. MAXALT presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.
## Structure
- MAXALT contains rizatriptan benzoate, a selective 5-hydroxytryptamine1B/1D (5-HT1B/1D) receptor agonist.
- Rizatriptan benzoate is described chemically as: N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indole-3-ethanamine monobenzoate and its structural formula is:
- Its empirical formula is C15H19N5C7H6O2, representing a molecular weight of the free base of 269.4. Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C.
- MAXALT Tablets and MAXALT-MLT Orally Disintegrating Tablets are available for oral administration in strengths of 5 and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively). Each compressed tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, ferric oxide (red), and magnesium stearate.
- Each lyophilized orally disintegrating tablet contains the following inactive ingredients: gelatin, mannitol, glycine, aspartame, and peppermint flavor.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Rizatriptan in the drug label.
## Pharmacokinetics
- Absorption
- Rizatriptan is completely absorbed following oral administration. The mean oral absolute bioavailability of the MAXALT Tablet is about 45%, and mean peak plasma concentrations (Cmax) are reached in approximately 1-1.5 hours (Tmax). The presence of a migraine headache did not appear to affect the absorption or pharmacokinetics of rizatriptan. Food has no significant effect on the bioavailability of rizatriptan but delays the time to reach peak concentration by an hour. In clinical trials, MAXALT was administered without regard to food.
- he bioavailability and Cmax of rizatriptan were similar following administration of MAXALT Tablets and MAXALT-MLT Orally Disintegrating Tablets, but the rate of absorption is somewhat slower with MAXALT-MLT, with Tmax delayed by up to 0.7 hour. AUC of rizatriptan is approximately 30% higher in females than in males. No accumulation occurred on multiple dosing.
- Distribution
- The mean volume of distribution is approximately 140 liters in male subjects and 110 liters in female subjects. Rizatriptan is minimally bound (14%) to plasma proteins.
- Metabolism
- The primary route of rizatriptan metabolism is via oxidative deamination by monoamine oxidase-A (MAO-A) to the indole acetic acid metabolite, which is not active at the 5-HT1B/1D receptor. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT1B/1D receptor, is formed to a minor degree. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at a similar rate. Other minor metabolites, the N-oxide, the 6-hydroxy compound, and the sulfate conjugate of the 6-hydroxy metabolite are not active at the 5-HT1B/1D receptor.
- Elimination
- The total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively, following a single 10-mg oral administration of 14C-rizatriptan. Following oral administration of 14C-rizatriptan, rizatriptan accounted for about 17% of circulating plasma radioactivity. Approximately 14% of an oral dose is excreted in urine as unchanged rizatriptan while 51% is excreted as indole acetic acid metabolite, indicating substantial first pass metabolism.
- The plasma half-life of rizatriptan in males and females averages 2-3 hours.
- Cytochrome P450 Isoforms
- Rizatriptan is not an inhibitor of the activities of human liver cytochrome P450 isoforms 3A4/5, 1A2, 2C9, 2C19, or 2E1; rizatriptan is a competitive inhibitor (Ki=1400 nM) of cytochrome P450 2D6, but only at high, clinically irrelevant concentrations.
- Special Populations
- Geriatric: Rizatriptan pharmacokinetics in healthy elderly non-migraineur volunteers (age 65-77 years) were similar to those in younger non-migraineur volunteers (age 18-45 years).
- Pediatric: The pharmacokinetics of rizatriptan was determined in pediatric migraineurs 6 to 17 years of age. Exposures following single dose administration of 5 mg MAXALT-MLT to pediatric patients weighing 20-39 kg (44-87 lb) or 10 mg MAXALT-MLT to pediatric patients weighing ≥40 kg (88 lb) were similar to those observed following single dose administration of 10 mg MAXALT-MLT to adults.
- Gender: The mean AUC0-∞ and Cmax of rizatriptan (10 mg orally) were about 30% and 11% higher in females as compared to males, respectively, while Tmax occurred at approximately the same time.
- Hepatic impairment: Following oral administration in patients with hepatic impairment caused by mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were similar in patients with mild hepatic insufficiency compared to a control group of subjects with normal hepatic function; plasma concentrations of rizatriptan were approximately 30% greater in patients with moderate hepatic insufficiency.
- Renal impairment: In patients with renal impairment (creatinine clearance 10-60 mL/min/1.73 m2), the AUC0-∞ of rizatriptan was not significantly different from that in subjects with normal renal function. In hemodialysis patients, (creatinine clearance <2 mL/min/1.73 m2), however, the AUC for rizatriptan was approximately 44% greater than that in patients with normal renal function.
- Race: Pharmacokinetic data revealed no significant differences between African American and Caucasian subjects.
- Drug Interactions
- Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamine oxidase, 'A' subtype (MAO-A). Plasma concentrations of rizatriptan may be increased by drugs that are selective MAO-A inhibitors (e.g., moclobemide) or nonselective MAO inhibitors (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline). In a drug interaction study, when MAXALT 10 mg was administered to subjects (n=12) receiving concomitant therapy with the selective, reversible MAO-A inhibitor, moclobemide 150 mg t.i.d., there were mean increases in rizatriptan AUC and Cmax of 119% and 41% respectively; and the AUC of the active N-monodesmethyl metabolite of rizatriptan was increased more than 400%. The interaction would be expected to be greater with irreversible MAO inhibitors. No pharmacokinetic interaction is anticipated in patients receiving selective MAO-B inhibitors.
- Propranolol: In a study of concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg in healthy adult subjects (n=11), mean plasma AUC for rizatriptan was increased by 70% during propranolol administration, and a four-fold increase was observed in one subject. The AUC of the active N-monodesmethyl metabolite of rizatriptan was not affected by propranolol.
- Nadolol/Metoprolol: In a drug interactions study, effects of multiple doses of nadolol 80 mg or metoprolol 100 mg every 12 hours on the pharmacokinetics of a single dose of 10 mg rizatriptan were evaluated in healthy subjects (n=12). No pharmacokinetic interactions were observed.
- Paroxetine: In a study of the interaction between the selective serotonin reuptake inhibitor (SSRI) paroxetine 20 mg/day for two weeks and a single dose of MAXALT 10 mg in healthy subjects (n=12), neither the plasma concentrations of rizatriptan nor its safety profile were affected by paroxetine.
- Oral contraceptives: In a study of concurrent administration of an oral contraceptive during 6 days of administration of MAXALT (10-30 mg/day) in healthy female volunteers (n=18), rizatriptan did not affect plasma concentrations of ethinyl estradiol or norethindrone.
## Nonclinical Toxicology
- Carcinogenesis: Oral carcinogenicity studies were conducted in mice (100 weeks) and rats (106 weeks) at doses of up to 125 mg/kg/day. Plasma exposures (AUC) at the highest dose tested were approximately 150 (mice) and 240 times (rats) that in humans at the maximum recommended daily dose (MRDD) of 30 mg/day. There was no evidence of an increase in tumor incidence related to rizatriptan in either species.
- Mutagenesis: Rizatriptan was neither mutagenic nor clastogenic in a battery of in vitro and in vivo genetic toxicity studies, including: the microbial mutagenesis (Ames) assay, in vitro mammalian cell mutagenesis and chromosomal aberration assays, and the in vivo chromosomal aberration assay in mouse.
- Impairment of Fertility: In a fertility study in rats, altered estrus cyclicity and delays in time to mating were observed in females treated orally with 100 mg/kg/day rizatriptan. The no-effect dose was 10 mg/kg/day (approximately 15 times the human exposure at the MRDD). There were no other fertility-related effects in the female rats. There was no impairment of fertility or reproductive performance in male rats treated with up to 250 mg/kg/day (approximately 550 times the human exposure at the MRDD).
# Clinical Studies
- The efficacy of MAXALT Tablets was established in four multicenter, randomized, placebo-controlled trials. Patients enrolled in these studies were primarily female (84%) and Caucasian (88%), with a mean age of 40 years (range of 18 to 71). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction of moderate or severe headache pain to no or mild headache pain, was assessed for up to 2 hours (Study 1) or up to 4 hours after dosing (Studies 2, 3 and 4). Associated symptoms of nausea, photophobia, and phonophobia and maintenance of response up to 24 hours post-dose were evaluated. A second dose of MAXALT Tablets was allowed 2 to 24 hours after dosing for treatment of recurrent headache in Studies 1 and 2. Additional analgesics and/or antiemetics were allowed 2 hours after initial treatment for rescue in all four studies.
- In all studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received either MAXALT 5 or 10 mg compared to those who received placebo. In a separate study, doses of 2.5 mg were not different from placebo. Doses greater than 10 mg were associated with an increased incidence of adverse effects. The results from the four controlled studies are summarized in Table 2.
- Comparisons of drug performance based upon results obtained in different clinical trials may not be reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.
- The estimated probability of achieving an initial headache response within 2 hours following treatment in pooled Studies 1, 2, 3, and 4 is depicted in Figure 1.
- For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of MAXALT compared to placebo.
- Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.
- Efficacy was unaffected by the presence of aura; by the gender, or age of the patient; or by concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants) or oral contraceptives. In two additional similar studies, efficacy was unaffected by relationship to menses. There were insufficient data to assess the impact of race on efficacy.
- MAXALT-MLT Orally Disintegrating Tablets
- The efficacy of MAXALT-MLT was established in two multicenter, randomized, placebo-controlled trials that were similar in design to the trials of MAXALT Tablets (Studies 5 and 6). Patients were instructed to treat a moderate to severe headache. Patients treated in these studies were primarily female (88%) and Caucasian (95%), with a mean age of 42 years (range 18-72).
- In both studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received either MAXALT-MLT 5 or 10 mg compared to those who received placebo. The results from Studies 5 and 6 are summarized in Table 3.
- The estimated probability of achieving an initial headache response by 2 hours following treatment with MAXALT-MLT in pooled Studies 5 and 6 is depicted in Figure 3.
- For patients with migraine-associated photophobia and phonophobia at baseline, there was a decreased incidence of these symptoms following administration of MAXALT-MLT as compared to placebo.
- Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 4.
- The efficacy of MAXALT-MLT in pediatric patients 6 to 17 years was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial (Study 7). Patients had to have at least a 6-month history of migraine attacks (with or without aura) usually lasting 3 hours or more (when untreated). The patient population was historically non-responsive to NSAIDs and acetaminophen therapy.
- Patients were instructed to treat a single migraine attack with headache pain of moderate to severe intensity. The treatment phase of the study had two stages. Stage 1 was used to identify placebo non-responders, who then entered into Stage 2, in which patients were randomized to MAXALT-MLT or placebo. Using a weight-based dosing strategy, patients 20 kg to <40 kg (44 lb to <88 lb) received MAXALT-MLT 5 mg or placebo, and patients ≥40 kg (88 lb) received MAXALT-MLT 10 mg or placebo.
- The mean age for the studied patient population was 13 years. Sixty-one percent of the patients were Caucasian, and fifty-six percent of the patients were female. The percentage of patients achieving the primary efficacy endpoint of no headache pain at 2 hours after treatment was significantly greater in patients who received MAXALT-MLT, compared with those who received placebo (33% vs. 24%). Study 7 results are summarized in Table 4.
- The observed percentage of pediatric patients achieving no headache pain within 2 hours following initial treatment with MAXALT-MLT is shown in Figure 5.
- The prevalence of the exploratory endpoints of absence of migraine-associated symptoms (nausea, photophobia, and phonophobia) at 2 hours after taking the dose was not statistically significantly different between patients who received MAXALT-MLT and those who received placebo.
# How Supplied
- No. 3732 — MAXALT Tablets, 5 mg, are pale pink, capsule-shaped, compressed tablets coded MRK on one side and 266 on the other:
- NDC 0006-0266-18, carton of 18 tablets.
- No. 3733 — MAXALT Tablets, 10 mg, are pale pink, capsule-shaped, compressed tablets coded MAXALT on one side and MRK 267 on the other:
- NDC 0006-0267-18, carton of 18 tablets.
- No. 3800 — MAXALT-MLT Orally Disintegrating Tablets, 5 mg, are white to off-white, round lyophilized orally disintegrating tablets debossed with a modified triangle on one side, and measuring 10.0-11.5 mm (side-to-side) with a peppermint flavor. Each orally disintegrating tablet is individually packaged in a blister inside an aluminum pouch (sachet). They are supplied as follows:
- NDC 0006-3800-18, 6 × unit of use carrying case of 3 orally disintegrating tablets (18 tablets total).
- No. 3801 — MAXALT-MLT Orally Disintegrating Tablets, 10 mg, are white to off-white, round lyophilized orally disintegrating tablets debossed with a modified square on one side, and measuring 12.0-13.8 mm (side-to-side) with a peppermint flavor. Each orally disintegrating tablet is individually packaged in a blister inside an aluminum pouch (sachet). They are supplied as follows:
- NDC 0006-3801-18, 6 × unit of use carrying case of 3 orally disintegrating tablets (18 tablets total).
- Storage
- Store MAXALT Tablets at room temperature, 59-86°F (15-30°C).
- Store MAXALT-MLT Orally Disintegrating Tablets at room temperature, 59-86°F (15-30°C).
## Storage
There is limited information regarding Rizatriptan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Risk of Myocardial Ischemia and/or Infarction, Prinzmetal's Angina, Other Vasospasm-Related Events, and Cerebrovascular Events
- Inform patients that MAXALT may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up.
- Serotonin Syndrome
- Patients should be cautioned about the risk of serotonin syndrome with the use of MAXALT or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
- Pregnancy
- Inform patients that MAXALT should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.
- Nursing Mothers
- Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed.
- Ability to Perform Complex Tasks
- Since migraines or treatment with MAXALT may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of MAXALT.
- Medication Overuse Headache
- Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary).
- Handling of Orally Disintegrating Tablets Packages
- Instruct patients not to remove the blister from the outer aluminum pouch until ready to use the orally disintegrating tablet inside.
- Patients with Phenylketonuria
- Inform phenylketonuric patients that MAXALT-MLT Orally Disintegrating Tablets contain phenylalanine (a component of aspartame). Each 5-mg orally disintegrating tablet contains 1.1 mg phenylalanine, and each 10-mg orally disintegrating tablet contains 2.1 mg phenylalanine.
# Precautions with Alcohol
- Alcohol-Rizatriptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MAXALT®
# Look-Alike Drug Names
There is limited information regarding Rizatriptan Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Rizatriptan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Rizatriptan is a serotonin (5-HT) 1B/1D receptor agonist that is FDA approved for the {{{indicationType}}} of acute treatment of migraine with or without aura. Common adverse reactions include asthenia/fatigue, somnolence, pain/pressure sensation and dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended starting dose of MAXALT is either 5 mg or 10 mg for the acute treatment of migraines in adults. The 10-mg dose may provide a greater effect than the 5-mg dose, but may have a greater risk of adverse reactions.
- Redosing in Adults
- Although the effectiveness of a second dose or subsequent doses has not been established in placebo-controlled trials, if the migraine headache returns, a second dose may be administered 2 hours after the first dose. The maximum daily dose should not exceed 30 mg in any 24-hour period. The safety of treating, on average, more than four headaches in a 30-day period has not been established.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rizatriptan in adult patients.
### Non–Guideline-Supported Use
- Dosing Information
- 10 mg rizatriptan.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Dosing Information
- Dosing in pediatric patients is based on the patient's body weight. The recommended dose of MAXALT is 5 mg in patients weighing less than 40 kg (88 lb), and 10 mg in patients weighing 40 kg (88 lb) or more.
- The efficacy and safety of treatment with more than one dose of MAXALT within 24 hours in pediatric patients 6 to 17 years of age have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rizatriptan in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rizatriptan in pediatric patients.
# Contraindications
- Ischemic coronary artery disease (angina pectoris, history of myocardial infarction, or documented silent ischemia), or other significant underlying cardiovascular disease.
- Coronary artery vasospasm including Prinzmetal's angina.
- History of stroke or transient ischemic attack (TIA).
- Peripheral vascular disease (PVD).
- Ischemic bowel disease.
- Uncontrolled hypertension.
- Recent use (i.e., within 24 hours) of another 5-HT1 agonist, ergotamine-containing medication, or ergot-type medication (such as dihydroergotamine or methysergide).
- Hemiplegic or basilar migraine.
- Concurrent administration or recent discontinuation (i.e., within 2 weeks) of a MAO-A inhibitor.
- Hypersensitivity to MAXALT or MAXALT-MLT (angioedema and anaphylaxis seen).
# Warnings
### Precautions
- Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina
- MAXALT should not be given to patients with ischemic or vasospastic coronary artery disease. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of MAXALT. Some of these reactions occurred in patients without known coronary artery disease (CAD). 5-HT1 agonists, including MAXALT may cause coronary artery vasospasm (Prinzmetal's Angina), even in patients without a history of CAD.
- Triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) should have a cardiovascular evaluation prior to receiving MAXALT. If there is evidence of CAD or coronary artery vasospasm, MAXALT should not be administered. For patients who have a negative cardiovascular evaluation, consideration should be given to administration of the first MAXALT dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following MAXALT administration. Periodic cardiovascular evaluation should be considered in intermittent long-term users of MAXALT who have cardiovascular risk factors.
- Arrhythmias
- Life-threatening disturbances of cardiac rhythm, including ventricular tachycardia and ventricular fibrillation leading to death, have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue MAXALT if these disturbances occur.
- Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure
- As with other 5-HT1 agonists, sensations of tightness, pain, pressure, and heaviness in the precordium, throat, neck and jaw commonly occur after treatment with MAXALT and are usually non-cardiac in origin. However, if a cardiac origin is suspected, patients should be evaluated. Patients shown to have CAD and those with Prinzmetal's variant angina should not receive 5-HT1 agonists.
- Cerebrovascular Events
- Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. Also, patients with migraine may be at increased risk of certain cerebrovascular events (e.g., stroke, hemorrhage, transient ischemic attack). Discontinue MAXALT if a cerebrovascular event occurs.
- As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. MAXALT should not be administered to patients with a history of stroke or transient ischemic attack.
- Other Vasospasm Reactions
- 5-HT1 agonists, including MAXALT, may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), splenic infarction, and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of non-coronary vasospasm reaction following the use of any 5-HT1 agonist, the suspected vasospasm reaction should be ruled out before receiving additional MAXALT doses.
- Reports of transient and permanent blindness and significant partial vision loss have been reported with the use of 5-HT1 agonists. Since visual disorders may be part of a migraine attack, a causal relationship between these events and the use of 5-HT1 agonists have not been clearly established.
- Medication Overuse Headache
- Overuse of acute migraine drugs (e.g., ergotamine, triptans, opioids, or a combination of drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches, or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
- Serotonin Syndrome
- Serotonin syndrome may occur with triptans, including MAXALT particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and MAO inhibitors. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication. MAXALT treatment should be discontinued if serotonin syndrome is suspected.
- Increase in Blood Pressure
- Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients with and without a history of hypertension receiving 5-HT1 agonists, including MAXALT. In healthy young adult male and female patients who received maximal doses of MAXALT (10 mg every 2 hours for 3 doses), slight increases in blood pressure (approximately 2-3 mmHg) were observed. MAXALT is contraindicated in patients with uncontrolled hypertension.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
- Adults
- Incidence in Controlled Clinical Trials
- Adverse reactions to MAXALT were assessed in controlled clinical trials that included over 3700 adult patients who received single or multiple doses of MAXALT Tablets. The most common adverse reactions during treatment with MAXALT (≥5% in either treatment group and greater than placebo) were asthenia/fatigue, somnolence, pain/pressure sensation and dizziness. These adverse reactions appeared to be dose related.
- Table 1 lists the adverse reactions (incidence ≥2% and greater than placebo) after a single dose of MAXALT in adults.
- The frequencies of adverse reactions in clinical trials did not increase when up to three doses were taken within 24 hours. Adverse reaction frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (including propranolol), oral contraceptives, or analgesics. The incidences of adverse reactions were not affected by age or gender. There were insufficient data to assess the impact of race on the incidence of adverse reactions.
- Other Events Observed in Association with the Administration of MAXALT in Adults
- In the following section, the frequencies of less commonly reported adverse events are presented that were not reported in other sections of the labeling. Because the reports include events observed in open studies, the role of MAXALT in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided. Event frequencies are calculated as the number of patients who used MAXALT and reported an event divided by the total number of patients exposed to MAXALT (N=3716). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those defined as those occurring in at least (>)1/100 patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients.
Infrequent was facial edema. Rare were syncope and edema/swelling.
Frequent were warm sensations.
Frequent was palpitation. Infrequent were tachycardia, cold extremities, and bradycardia.
Frequent were diarrhea and vomiting. Infrequent were dyspepsia, tongue edema and abdominal distention.
Infrequent were muscle weakness, stiffness, myalgia and muscle cramp/spasm.
Frequent were hypoesthesia, euphoria and tremor. Infrequent were vertigo, insomnia, confusion/disorientation, gait abnormality, memory impairment, and agitation.
Frequent was dyspnea. Infrequent was pharyngeal edema.
Infrequent were blurred vision and tinnitus. Rare was eye swelling.
Frequent was flushing. Infrequent were sweating, pruritus, rash, and urticaria. Rare was erythema, hot flashes.
- The adverse reaction profile seen with MAXALT-MLT Orally Disintegrating Tablets was similar to that seen with MAXALT Tablets.
- Pediatric Patients 6 to 17 Years of Age
- Incidence in Controlled Clinical Trials in Pediatric Patients
- Adverse reactions to MAXALT-MLT were assessed in a controlled clinical trial in the acute treatment of migraines (Study 7) that included a total of 1382 pediatric patients 6-17 years of age, of which 977 (72%) administered at least one dose of study treatment (MAXALT-MLT and/or placebo). The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received MAXALT to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.
- Other Events Observed in Association with the Administration of MAXALT-MLT in Pediatric Patients
- In the following section, the frequencies of less commonly reported adverse events are presented. Because the reports include events observed in open studies, the role of MAXALT-MLT in their causation cannot be reliably determined. Furthermore, variability associated with adverse event reporting, the terminology used to describe adverse events, limit the value of the quantitative frequency estimates provided.
- Event frequencies are calculated as the number of pediatric patients 6 to 17 years of age who used MAXALT-MLT and reported an event divided by the total number of patients exposed to MAXALT-MLT (N=1068). All reported events occurred at an incidence ≥1%, or are believed to be reasonably associated with the use of the drug. Events are further classified within system organ class and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are those occurring in (>)1/100 pediatric patients; infrequent adverse experiences are those occurring in 1/100 to 1/1000 pediatric patients; and rare adverse experiences are those occurring in fewer than 1/1000 patients.
Frequent was fatigue.
Infrequent was hypoacusis.
Frequent was abdominal discomfort.
Infrequent were coordination abnormal, disturbance in attention, and presyncope.
Infrequent was hallucination.
## Postmarketing Experience
- The following section enumerates potentially important adverse events that have occurred in clinical practice and which have been reported spontaneously to various surveillance systems. The events enumerated include all except those already listed in other sections of the labeling or those too general to be informative. Because the reports cite events reported spontaneously from worldwide postmarketing experience, frequency of events and the role of MAXALT in their causation cannot be reliably determined.
- Neurological/Psychiatric: Seizure.
- General: Allergic conditions including anaphylaxis/anaphylactoid reaction, angioedema, wheezing, and toxic epidermal necrolysis.
- Special Senses: Dysgeusia.
# Drug Interactions
- Propranolol
- The dose of MAXALT should be adjusted in propranolol-treated patients, as propranolol has been shown to increase the plasma AUC of rizatriptan by 70%.
- Ergot-Containing Drugs
- Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and MAXALT within 24 hours is contraindicated.
- Other 5-HT1 Agonists
- Because their vasospastic effects may be additive, co-administration of MAXALT and other 5-HT1 agonists within 24 hours of each other is contraindicated.
- SSRIs/SNRIs and Serotonin Syndrome
- Cases of serotonin syndrome have been reported during co-administration of triptans and selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
- Monoamine Oxidase Inhibitors
- MAXALT is contraindicated in patients taking MAO-A inhibitors and non-selective MAO inhibitors. A specific MAO-A inhibitor increased the systemic exposure of rizatriptan and its metabolite
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- There are no adequate and well-controlled studies in pregnant women. MAXALT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- In a general reproductive study in rats, birth weights and pre- and post-weaning weight gain were reduced in the offspring of females treated prior to and during mating and throughout gestation and lactation with doses of 10 and 100 mg/kg/day. In a pre- and post-natal developmental toxicity study in rats, an increase in mortality of the offspring at birth and for the first three days after birth, a decrease in pre- and post-weaning weight gain, and decreased performance in a passive avoidance test (which indicates a decrease in learning capacity of the offspring) were observed at doses of 100 and 250 mg/kg/day. The no-effect dose for all of these effects was 5 mg/kg/day, associated with a maternal plasma exposure (AUC) approximately 7.5 times that in humans receiving the MRDD. With doses of 100 and 250 mg/kg/day, the decreases in average weight of both the male and female offspring persisted into adulthood. All effects on the offspring in both studies occurred in the absence of any apparent maternal toxicity.
- In embryofetal development studies, no teratogenic effects were observed when pregnant rats and rabbits were administered doses of 100 and 50 mg/kg/day, respectively, during organogenesis. Fetal weights were decreased in conjunction with decreased maternal weight gain at the highest doses tested. The developmental no-effect dose in these studies was 10 mg/kg/day in both rats and rabbits (maternal exposures approximately 15 times human exposure at the MRDD). Toxicokinetic studies demonstrated placental transfer of drug in both species.
- Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to MAXALT while pregnant. Healthcare providers are encouraged to report any prenatal exposure to MAXALT by calling the Pregnancy Registry at 1-800-986-8999.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rizatriptan in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rizatriptan during labor and delivery.
### Nursing Mothers
- It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when MAXALT is administered to a nursing woman. Rizatriptan is extensively excreted in rat milk, with levels in milk at least 5-fold higher than levels in maternal plasma.
### Pediatric Use
- Safety and effectiveness in pediatric patients under 6 years of age have not been established.
- The efficacy and safety of MAXALT in the acute treatment of migraine in patients aged 6 to 17 years was established in an adequate and well-controlled study.
- The incidence of adverse reactions reported for pediatric patients in the acute clinical trial was similar in patients who received MAXALT to those who received placebo. The adverse reaction pattern in pediatric patients is expected to be similar to that in adults.
### Geriatic Use
- Clinical studies of MAXALT did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
- Although the pharmacokinetics of rizatriptan were similar in elderly (aged ≥65 years) and in younger adults (n=17), in general, dose selection for an elderly patient should be cautious, starting at the low end of the dosing range. This reflects the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
- Geriatric patients who have other cardiovascular risk factors (e.g., diabetes, hypertension, smoking, obesity, strong family history of coronary artery disease) should have a cardiovascular evaluation prior to receiving MAXALT.
### Gender
There is no FDA guidance on the use of Rizatriptan with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rizatriptan with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rizatriptan in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rizatriptan in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rizatriptan in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rizatriptan in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Rizatriptan in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rizatriptan in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- No overdoses of MAXALT were reported during clinical trials in adults.
- Some adult patients who received 40 mg of MAXALT either a single dose or as two doses with a 2-hour interdose interval had dizziness and somnolence.
- In a clinical pharmacology study in which 12 adult subjects received MAXALT, at total cumulative doses of 80 mg (given within four hours), two of the subjects experienced syncope, dizziness, bradycardia including third degree AV block, vomiting, and/or incontinence.
- In the long-term, open label study, involving 606 treated pediatric migraineurs 12 to 17 years of age (of which 432 were treated for at least 12 months), 151 patients (25%) took two 10-mg doses of MAXALT-MLT within a 24-hour period. Adverse reactions for 3 of these patients included abdominal discomfort, fatigue, and dyspnea.
### Management
- In addition, based on the pharmacology of MAXALT, hypertension or myocardial ischemia could occur after overdosage. Gastrointestinal decontamination, (i.e., gastric lavage followed by activated charcoal) should be considered in patients suspected of an overdose with MAXALT. Clinical and electrocardiographic monitoring should be continued for at least 12 hours, even if clinical symptoms are not observed.
- The effects of hemo- or peritoneal dialysis on serum concentrations of rizatriptan are unknown.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Rizatriptan in the drug label.
# Pharmacology
## Mechanism of Action
- Rizatriptan binds with high affinity to human cloned 5-HT1B/1D receptors. MAXALT presumably exerts its therapeutic effects in the treatment of migraine headache by binding to 5-HT1B/1D receptors located on intracranial blood vessels and sensory nerves of the trigeminal system.
## Structure
- MAXALT contains rizatriptan benzoate, a selective 5-hydroxytryptamine1B/1D (5-HT1B/1D) receptor agonist.
- Rizatriptan benzoate is described chemically as: N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indole-3-ethanamine monobenzoate and its structural formula is:
- Its empirical formula is C15H19N5•C7H6O2, representing a molecular weight of the free base of 269.4. Rizatriptan benzoate is a white to off-white, crystalline solid that is soluble in water at about 42 mg per mL (expressed as free base) at 25°C.
- MAXALT Tablets and MAXALT-MLT Orally Disintegrating Tablets are available for oral administration in strengths of 5 and 10 mg (corresponding to 7.265 mg or 14.53 mg of the benzoate salt, respectively). Each compressed tablet contains the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, pregelatinized starch, ferric oxide (red), and magnesium stearate.
- Each lyophilized orally disintegrating tablet contains the following inactive ingredients: gelatin, mannitol, glycine, aspartame, and peppermint flavor.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Rizatriptan in the drug label.
## Pharmacokinetics
- Absorption
- Rizatriptan is completely absorbed following oral administration. The mean oral absolute bioavailability of the MAXALT Tablet is about 45%, and mean peak plasma concentrations (Cmax) are reached in approximately 1-1.5 hours (Tmax). The presence of a migraine headache did not appear to affect the absorption or pharmacokinetics of rizatriptan. Food has no significant effect on the bioavailability of rizatriptan but delays the time to reach peak concentration by an hour. In clinical trials, MAXALT was administered without regard to food.
- he bioavailability and Cmax of rizatriptan were similar following administration of MAXALT Tablets and MAXALT-MLT Orally Disintegrating Tablets, but the rate of absorption is somewhat slower with MAXALT-MLT, with Tmax delayed by up to 0.7 hour. AUC of rizatriptan is approximately 30% higher in females than in males. No accumulation occurred on multiple dosing.
- Distribution
- The mean volume of distribution is approximately 140 liters in male subjects and 110 liters in female subjects. Rizatriptan is minimally bound (14%) to plasma proteins.
- Metabolism
- The primary route of rizatriptan metabolism is via oxidative deamination by monoamine oxidase-A (MAO-A) to the indole acetic acid metabolite, which is not active at the 5-HT1B/1D receptor. N-monodesmethyl-rizatriptan, a metabolite with activity similar to that of parent compound at the 5-HT1B/1D receptor, is formed to a minor degree. Plasma concentrations of N-monodesmethyl-rizatriptan are approximately 14% of those of parent compound, and it is eliminated at a similar rate. Other minor metabolites, the N-oxide, the 6-hydroxy compound, and the sulfate conjugate of the 6-hydroxy metabolite are not active at the 5-HT1B/1D receptor.
- Elimination
- The total radioactivity of the administered dose recovered over 120 hours in urine and feces was 82% and 12%, respectively, following a single 10-mg oral administration of 14C-rizatriptan. Following oral administration of 14C-rizatriptan, rizatriptan accounted for about 17% of circulating plasma radioactivity. Approximately 14% of an oral dose is excreted in urine as unchanged rizatriptan while 51% is excreted as indole acetic acid metabolite, indicating substantial first pass metabolism.
- The plasma half-life of rizatriptan in males and females averages 2-3 hours.
- Cytochrome P450 Isoforms
- Rizatriptan is not an inhibitor of the activities of human liver cytochrome P450 isoforms 3A4/5, 1A2, 2C9, 2C19, or 2E1; rizatriptan is a competitive inhibitor (Ki=1400 nM) of cytochrome P450 2D6, but only at high, clinically irrelevant concentrations.
- Special Populations
- Geriatric: Rizatriptan pharmacokinetics in healthy elderly non-migraineur volunteers (age 65-77 years) were similar to those in younger non-migraineur volunteers (age 18-45 years).
- Pediatric: The pharmacokinetics of rizatriptan was determined in pediatric migraineurs 6 to 17 years of age. Exposures following single dose administration of 5 mg MAXALT-MLT to pediatric patients weighing 20-39 kg (44-87 lb) or 10 mg MAXALT-MLT to pediatric patients weighing ≥40 kg (88 lb) were similar to those observed following single dose administration of 10 mg MAXALT-MLT to adults.
- Gender: The mean AUC0-∞ and Cmax of rizatriptan (10 mg orally) were about 30% and 11% higher in females as compared to males, respectively, while Tmax occurred at approximately the same time.
- Hepatic impairment: Following oral administration in patients with hepatic impairment caused by mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of rizatriptan were similar in patients with mild hepatic insufficiency compared to a control group of subjects with normal hepatic function; plasma concentrations of rizatriptan were approximately 30% greater in patients with moderate hepatic insufficiency.
- Renal impairment: In patients with renal impairment (creatinine clearance 10-60 mL/min/1.73 m2), the AUC0-∞ of rizatriptan was not significantly different from that in subjects with normal renal function. In hemodialysis patients, (creatinine clearance <2 mL/min/1.73 m2), however, the AUC for rizatriptan was approximately 44% greater than that in patients with normal renal function.
- Race: Pharmacokinetic data revealed no significant differences between African American and Caucasian subjects.
- Drug Interactions
- Monoamine oxidase inhibitors: Rizatriptan is principally metabolized via monoamine oxidase, 'A' subtype (MAO-A). Plasma concentrations of rizatriptan may be increased by drugs that are selective MAO-A inhibitors (e.g., moclobemide) or nonselective MAO inhibitors [type A and B] (e.g., isocarboxazid, phenelzine, tranylcypromine, and pargyline). In a drug interaction study, when MAXALT 10 mg was administered to subjects (n=12) receiving concomitant therapy with the selective, reversible MAO-A inhibitor, moclobemide 150 mg t.i.d., there were mean increases in rizatriptan AUC and Cmax of 119% and 41% respectively; and the AUC of the active N-monodesmethyl metabolite of rizatriptan was increased more than 400%. The interaction would be expected to be greater with irreversible MAO inhibitors. No pharmacokinetic interaction is anticipated in patients receiving selective MAO-B inhibitors.
- Propranolol: In a study of concurrent administration of propranolol 240 mg/day and a single dose of rizatriptan 10 mg in healthy adult subjects (n=11), mean plasma AUC for rizatriptan was increased by 70% during propranolol administration, and a four-fold increase was observed in one subject. The AUC of the active N-monodesmethyl metabolite of rizatriptan was not affected by propranolol.
- Nadolol/Metoprolol: In a drug interactions study, effects of multiple doses of nadolol 80 mg or metoprolol 100 mg every 12 hours on the pharmacokinetics of a single dose of 10 mg rizatriptan were evaluated in healthy subjects (n=12). No pharmacokinetic interactions were observed.
- Paroxetine: In a study of the interaction between the selective serotonin reuptake inhibitor (SSRI) paroxetine 20 mg/day for two weeks and a single dose of MAXALT 10 mg in healthy subjects (n=12), neither the plasma concentrations of rizatriptan nor its safety profile were affected by paroxetine.
- Oral contraceptives: In a study of concurrent administration of an oral contraceptive during 6 days of administration of MAXALT (10-30 mg/day) in healthy female volunteers (n=18), rizatriptan did not affect plasma concentrations of ethinyl estradiol or norethindrone.
## Nonclinical Toxicology
- Carcinogenesis: Oral carcinogenicity studies were conducted in mice (100 weeks) and rats (106 weeks) at doses of up to 125 mg/kg/day. Plasma exposures (AUC) at the highest dose tested were approximately 150 (mice) and 240 times (rats) that in humans at the maximum recommended daily dose (MRDD) of 30 mg/day. There was no evidence of an increase in tumor incidence related to rizatriptan in either species.
- Mutagenesis: Rizatriptan was neither mutagenic nor clastogenic in a battery of in vitro and in vivo genetic toxicity studies, including: the microbial mutagenesis (Ames) assay, in vitro mammalian cell mutagenesis and chromosomal aberration assays, and the in vivo chromosomal aberration assay in mouse.
- Impairment of Fertility: In a fertility study in rats, altered estrus cyclicity and delays in time to mating were observed in females treated orally with 100 mg/kg/day rizatriptan. The no-effect dose was 10 mg/kg/day (approximately 15 times the human exposure at the MRDD). There were no other fertility-related effects in the female rats. There was no impairment of fertility or reproductive performance in male rats treated with up to 250 mg/kg/day (approximately 550 times the human exposure at the MRDD).
# Clinical Studies
- The efficacy of MAXALT Tablets was established in four multicenter, randomized, placebo-controlled trials. Patients enrolled in these studies were primarily female (84%) and Caucasian (88%), with a mean age of 40 years (range of 18 to 71). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction of moderate or severe headache pain to no or mild headache pain, was assessed for up to 2 hours (Study 1) or up to 4 hours after dosing (Studies 2, 3 and 4). Associated symptoms of nausea, photophobia, and phonophobia and maintenance of response up to 24 hours post-dose were evaluated. A second dose of MAXALT Tablets was allowed 2 to 24 hours after dosing for treatment of recurrent headache in Studies 1 and 2. Additional analgesics and/or antiemetics were allowed 2 hours after initial treatment for rescue in all four studies.
- In all studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received either MAXALT 5 or 10 mg compared to those who received placebo. In a separate study, doses of 2.5 mg were not different from placebo. Doses greater than 10 mg were associated with an increased incidence of adverse effects. The results from the four controlled studies are summarized in Table 2.
- Comparisons of drug performance based upon results obtained in different clinical trials may not be reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study.
- The estimated probability of achieving an initial headache response within 2 hours following treatment in pooled Studies 1, 2, 3, and 4 is depicted in Figure 1.
- For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of MAXALT compared to placebo.
- Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2.
- Efficacy was unaffected by the presence of aura; by the gender, or age of the patient; or by concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants) or oral contraceptives. In two additional similar studies, efficacy was unaffected by relationship to menses. There were insufficient data to assess the impact of race on efficacy.
- MAXALT-MLT Orally Disintegrating Tablets
- The efficacy of MAXALT-MLT was established in two multicenter, randomized, placebo-controlled trials that were similar in design to the trials of MAXALT Tablets (Studies 5 and 6). Patients were instructed to treat a moderate to severe headache. Patients treated in these studies were primarily female (88%) and Caucasian (95%), with a mean age of 42 years (range 18-72).
- In both studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater in patients who received either MAXALT-MLT 5 or 10 mg compared to those who received placebo. The results from Studies 5 and 6 are summarized in Table 3.
- The estimated probability of achieving an initial headache response by 2 hours following treatment with MAXALT-MLT in pooled Studies 5 and 6 is depicted in Figure 3.
- For patients with migraine-associated photophobia and phonophobia at baseline, there was a decreased incidence of these symptoms following administration of MAXALT-MLT as compared to placebo.
- Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain response in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 4.
- The efficacy of MAXALT-MLT in pediatric patients 6 to 17 years was evaluated in a multicenter, randomized, double-blind, placebo-controlled, parallel group clinical trial (Study 7). Patients had to have at least a 6-month history of migraine attacks (with or without aura) usually lasting 3 hours or more (when untreated). The patient population was historically non-responsive to NSAIDs and acetaminophen therapy.
- Patients were instructed to treat a single migraine attack with headache pain of moderate to severe intensity. The treatment phase of the study had two stages. Stage 1 was used to identify placebo non-responders, who then entered into Stage 2, in which patients were randomized to MAXALT-MLT or placebo. Using a weight-based dosing strategy, patients 20 kg to <40 kg (44 lb to <88 lb) received MAXALT-MLT 5 mg or placebo, and patients ≥40 kg (88 lb) received MAXALT-MLT 10 mg or placebo.
- The mean age for the studied patient population was 13 years. Sixty-one percent of the patients were Caucasian, and fifty-six percent of the patients were female. The percentage of patients achieving the primary efficacy endpoint of no headache pain at 2 hours after treatment was significantly greater in patients who received MAXALT-MLT, compared with those who received placebo (33% vs. 24%). Study 7 results are summarized in Table 4.
- The observed percentage of pediatric patients achieving no headache pain within 2 hours following initial treatment with MAXALT-MLT is shown in Figure 5.
- The prevalence of the exploratory endpoints of absence of migraine-associated symptoms (nausea, photophobia, and phonophobia) at 2 hours after taking the dose was not statistically significantly different between patients who received MAXALT-MLT and those who received placebo.
# How Supplied
- No. 3732 — MAXALT Tablets, 5 mg, are pale pink, capsule-shaped, compressed tablets coded MRK on one side and 266 on the other:
- NDC 0006-0266-18, carton of 18 tablets.
- No. 3733 — MAXALT Tablets, 10 mg, are pale pink, capsule-shaped, compressed tablets coded MAXALT on one side and MRK 267 on the other:
- NDC 0006-0267-18, carton of 18 tablets.
- No. 3800 — MAXALT-MLT Orally Disintegrating Tablets, 5 mg, are white to off-white, round lyophilized orally disintegrating tablets debossed with a modified triangle on one side, and measuring 10.0-11.5 mm (side-to-side) with a peppermint flavor. Each orally disintegrating tablet is individually packaged in a blister inside an aluminum pouch (sachet). They are supplied as follows:
- NDC 0006-3800-18, 6 × unit of use carrying case of 3 orally disintegrating tablets (18 tablets total).
- No. 3801 — MAXALT-MLT Orally Disintegrating Tablets, 10 mg, are white to off-white, round lyophilized orally disintegrating tablets debossed with a modified square on one side, and measuring 12.0-13.8 mm (side-to-side) with a peppermint flavor. Each orally disintegrating tablet is individually packaged in a blister inside an aluminum pouch (sachet). They are supplied as follows:
- NDC 0006-3801-18, 6 × unit of use carrying case of 3 orally disintegrating tablets (18 tablets total).
- Storage
- Store MAXALT Tablets at room temperature, 59-86°F (15-30°C).
- Store MAXALT-MLT Orally Disintegrating Tablets at room temperature, 59-86°F (15-30°C).
## Storage
There is limited information regarding Rizatriptan Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Risk of Myocardial Ischemia and/or Infarction, Prinzmetal's Angina, Other Vasospasm-Related Events, and Cerebrovascular Events
- Inform patients that MAXALT may cause serious cardiovascular side effects such as myocardial infarction or stroke. Although serious cardiovascular events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up.
- Serotonin Syndrome
- Patients should be cautioned about the risk of serotonin syndrome with the use of MAXALT or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs).
- Pregnancy
- Inform patients that MAXALT should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus.
- Nursing Mothers
- Advise patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed.
- Ability to Perform Complex Tasks
- Since migraines or treatment with MAXALT may cause somnolence and dizziness, instruct patients to evaluate their ability to perform complex tasks during migraine attacks and after administration of MAXALT.
- Medication Overuse Headache
- Inform patients that use of acute migraine drugs for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary).
- Handling of Orally Disintegrating Tablets Packages
- Instruct patients not to remove the blister from the outer aluminum pouch until ready to use the orally disintegrating tablet inside.
- Patients with Phenylketonuria
- Inform phenylketonuric patients that MAXALT-MLT Orally Disintegrating Tablets contain phenylalanine (a component of aspartame). Each 5-mg orally disintegrating tablet contains 1.1 mg phenylalanine, and each 10-mg orally disintegrating tablet contains 2.1 mg phenylalanine.
# Precautions with Alcohol
- Alcohol-Rizatriptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MAXALT®[1]
# Look-Alike Drug Names
There is limited information regarding Rizatriptan Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Rizatriptan | |
8fb84f0b1644b22c9b07f12ce7ea22ba71cf82fd | wikidoc | Rob Buckman | Rob Buckman
# Overview
Robert (Rob) Buckman (born August 22, 1948 in London) is a British-Canadian doctor of medicine, comedian and author, and since 1999 has been president of the Humanist Association of Canada. He first appeared in a Cambridge University Footlights Revue in 1969, and went on to present several television and radio programmes about medicine, as well as appearing on comedy programmes such as Just a Minute. He is also the author of many popular books on medicine.
# Broadcasting and comedy
Buckman graduated in medicine from Cambridge University in 1972, and continued his medical training at the Royal Marsden Hospital and University College Hospital, London, becoming a Fellow of the Royal College of Physicians.
Buckman was a familiar voice on BBC Radio 4 during the 1970s and 1980s, both on panel shows, and fronting one-off programmes on scientific topics. He contributed scripts to the Richard Gordon-adapted sitcom Doctor on the Go, and also acted in the spin-off Pink Medicine Show. He also was one of the performers and writers of the first The Secret Policeman's Ball fundraiser in 1979, alongside Billy Connolly, John Cleese and Eleanor Bron.
Rob Buckman was more distinguished as a popular science presenter and appeared on the programme Don't Ask Me in the 1970s. He continued this career in Canada where he has contributed to TV Ontario programmes such as Your Health and the CTV medical show Balance. His television series Magic or Medicine? investigated alternative medicine and won a Gemini award, while Human Wildlife covered microbes in the domestic environment.
# Writings in popular medicine
Besides tie-ins to his TV series, Buckman has authored several books of medical humour, such as Out of Practice (1978), Jogging from Memory: or letters to Sigmund Freud (1980), and The Buckman Treatment; or a doctor's tour in North America (1989). More recently, as Robert Buckman, he contributed as author or co-author to a series of What You Really Need to Know About... books on common medical conditions, including cancer, asthma, high blood pressure, HRT, (all 1999), diabetes, stroke, and irritable bowel syndrome (2000).
# Later career
Buckman emigrated to Toronto, Canada in 1985. In 1994 Buckman was named Canada’s Humanist of the Year. He was a signer of Humanist Manifesto 2000. Since 1999, he has been President of the Humanist Association of Canada, and is also currently Chair of the Advisory Board on Bioethics of the International Humanist and Ethical Union. His main popular work in humanism is Can We Be Good Without God? Biology, Behaviour and the Need to Believe.
As at 2005, Buckman is practising medical oncology at the Princess Margaret Hospital (Toronto). He is a Professor in the Department of Medicine at the University of Toronto, and also holds an adjunct professorship at the M.D. Anderson Cancer Center in Texas. He specialises in breast cancer and teaching communication skills in oncology.
In 2006 he began writing a weekly column in the Globe and Mail.
# Selected publications
- Out of Practice, illustrations by Bill Tidy. Deutsch. 1978.
- Medicine Balls Too
- Jogging from Memory. Pan. 1980.
- Not dead yet: the unauthorized autobiography of Dr. Robert Buckman, complete with a map, many photographs & irritating footnotes. Doublesday. 1990.
- How To Break Bad News: A Guide for Healthcare Professionals. Papermac. 1992.
- Magic or Medicine? An investigation of Healing and Healers (with Karl Sabbagh). Macmillan. 1993.
- Human Wildlife: The Life That Lives on Us
- What You Really Need to Know About Cancer:A Guide for Patients and their Families. Pan paperback. 1997.
- What You Really Need to Know About Living With Depression
- Who can ever understand? : talking about your cancer with John Elsegood. 1995.
- Cancer is a Word, Not a Sentence
- Can we be Good Without God? | Rob Buckman
# Overview
Robert (Rob) Buckman (born August 22, 1948 in London) is a British-Canadian doctor of medicine, comedian and author, and since 1999 has been president of the Humanist Association of Canada. He first appeared in a Cambridge University Footlights Revue in 1969, and went on to present several television and radio programmes about medicine, as well as appearing on comedy programmes such as Just a Minute. He is also the author of many popular books on medicine.
# Broadcasting and comedy
Buckman graduated in medicine from Cambridge University in 1972, and continued his medical training at the Royal Marsden Hospital and University College Hospital, London, becoming a Fellow of the Royal College of Physicians.
Buckman was a familiar voice on BBC Radio 4 during the 1970s and 1980s, both on panel shows, and fronting one-off programmes on scientific topics. He contributed scripts to the Richard Gordon-adapted sitcom Doctor on the Go, and also acted in the spin-off Pink Medicine Show. He also was one of the performers and writers of the first The Secret Policeman's Ball fundraiser in 1979, alongside Billy Connolly, John Cleese and Eleanor Bron.
Rob Buckman was more distinguished as a popular science presenter and appeared on the programme Don't Ask Me in the 1970s. He continued this career in Canada where he has contributed to TV Ontario programmes such as Your Health and the CTV medical show Balance. His television series Magic or Medicine? investigated alternative medicine and won a Gemini award, while Human Wildlife covered microbes in the domestic environment.
# Writings in popular medicine
Besides tie-ins to his TV series, Buckman has authored several books of medical humour, such as Out of Practice (1978), Jogging from Memory: or letters to Sigmund Freud (1980), and The Buckman Treatment; or a doctor's tour in North America (1989). More recently, as Robert Buckman, he contributed as author or co-author to a series of What You Really Need to Know About... books on common medical conditions, including cancer, asthma, high blood pressure, HRT, (all 1999), diabetes, stroke, and irritable bowel syndrome (2000).
# Later career
Buckman emigrated to Toronto, Canada in 1985. In 1994 Buckman was named Canada’s Humanist of the Year. He was a signer of Humanist Manifesto 2000. Since 1999, he has been President of the Humanist Association of Canada, and is also currently Chair of the Advisory Board on Bioethics of the International Humanist and Ethical Union. His main popular work in humanism is Can We Be Good Without God? Biology, Behaviour and the Need to Believe.
As at 2005, Buckman is practising medical oncology at the Princess Margaret Hospital (Toronto). He is a Professor in the Department of Medicine at the University of Toronto, and also holds an adjunct professorship at the M.D. Anderson Cancer Center in Texas. He specialises in breast cancer and teaching communication skills in oncology.
In 2006 he began writing a weekly column in the Globe and Mail.
# Selected publications
- Out of Practice, illustrations by Bill Tidy. Deutsch. 1978.
- Medicine Balls Too
- Jogging from Memory. Pan. 1980.
- Not dead yet: the unauthorized autobiography of Dr. Robert Buckman, complete with a map, many photographs & irritating footnotes. Doublesday. 1990.
- How To Break Bad News: A Guide for Healthcare Professionals. Papermac. 1992.
- Magic or Medicine? An investigation of Healing and Healers (with Karl Sabbagh). Macmillan. 1993.
- Human Wildlife: The Life That Lives on Us
- What You Really Need to Know About Cancer:A Guide for Patients and their Families. Pan paperback. 1997.
- What You Really Need to Know About Living With Depression
- Who can ever understand? : talking about your cancer with John Elsegood. 1995.
- Cancer is a Word, Not a Sentence
- Can we be Good Without God?
# External links
- The BBC Guide to Comedy
- University of Toronto biography
- Dr. Robert Buckman: Oncologist - Professor - Public Speaker
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Rob_Buckman | |
a38d6d6785c4670e8a6d83e5c945bc304182bc3e | wikidoc | Robert Koch | Robert Koch
Heinrich Hermann Robert Koch (December 11 1843 – May 27 1910) was a German physician. He became famous for isolating Bacillus anthracis (1877), the tuberculosis bacillus (1882) and the vibrio cholera (1883) and for his development of Koch's postulates.
He was awarded the Nobel Prize in Physiology or Medicine for his tuberculosis findings in 1905. He is considered one of the founders of microbiology - he inspired such major figures as Paul Ehrlich and Gerhard Domagk.
# Biography
Robert Koch was born in Clausthal, Germany as the son of a mining official. He studied medicine under Friedrich Gustav Jakob Henle at the University of Göttingen and graduated in 1866. He then served in the Franco-Prussian War and later became district medical officer in Wollstein (Wolsztyn), Prussian Poland. Working with very limited resources, he became one of the founders of bacteriology, the other major figure being Louis Pasteur.
After Casimir Davaine showed the direct transmission of the anthrax bacillus between cows, Koch studied anthrax more closely. He invented methods to purify the bacillus from blood samples and grow pure cultures. He found that, while it could not survive outside a host for long, anthrax built persisting endospores that could last a long time.
These endospores, embedded in soil, were the cause of unexplained "spontaneous" outbreaks of anthrax. Koch published his findings in 1876, and was rewarded with a job at the Imperial Health Office in Berlin in 1880. In 1881, he urged the sterilization of surgical instruments using heat.
In Berlin, he improved the methods he used in Wollstein, including staining and purification techniques, and bacterial growth media, including agar plates (thanks to the advice of Angelina and Walther Hesse) and the Petri dish, named after its inventor, his assistant Julius Richard Petri. These devices are still used today. With these techniques, he was able to discover the bacterium causing tuberculosis (Mycobacterium tuberculosis) in 1882 (he announced the discovery on March 24). Tuberculosis was the cause of one in seven deaths in the mid-19th century.
In 1883, Koch worked with a French research team in Alexandria, Egypt, studying cholera. Koch identified the vibrio bacterium that caused cholera, though he never managed to prove it in experiments. The bacterium had been previously isolated by Italian anatomist Filippo Pacini in 1854, but his work had been ignored due to the predominance of the miasma theory of disease. Koch was unaware of Pacini's work and made an independent discovery, and his greater preeminence allowed the discovery to be widely spread for the benefit of others. In 1965, however, the bacterium was formally renamed Vibrio cholera Pacini 1854.
In 1885, he became professor of hygiene at the University of Berlin, and later, in 1891, director of the newly formed Institute of Infectious Diseases, a position which he resigned from in 1904. He started traveling around the world, studying diseases in South Africa, India, and Java.
Probably as important as his work on tuberculosis, for which he was awarded a Nobel Prize (1905), are Koch's postulates, which say that to establish that an organism is the cause of a disease, it must be:
- found in all cases of the disease examined
- prepared and maintained in a pure culture
- capable of producing the original infection, even after several generations in culture
- retrievable from an inoculated animal and cultured again.
After Koch's success the quality of his own research declined (especially with the fiasco over his ineffective TB cure "tuberculin"), although his pupils found the organisms responsible for diphtheria, typhoid, pneumonia, gonorrhoea, cerebrospinal meningitis, leprosy, bubonic plague, tetanus, and syphilis, among others, by using his methods.
He died on 27 May 1910 of a heart-attack in Baden-Baden, aged 66.
# Honors
Koch crater on the Moon was named after him. The Robert Koch Prize and Medal were created to honour Microbiologists who make groundbreaking discoveries or who contribute to global health in a unique way. The now-defunct Robert Koch Hospital at Koch, Missouri (south of St. Louis, Missouri), was also named in his honor. | Robert Koch
Template:Infobox Scientist
Heinrich Hermann Robert Koch (December 11 1843 – May 27 1910) was a German physician. He became famous for isolating Bacillus anthracis (1877), the tuberculosis bacillus (1882) and the vibrio cholera (1883) and for his development of Koch's postulates.
He was awarded the Nobel Prize in Physiology or Medicine for his tuberculosis findings in 1905. He is considered one of the founders of microbiology - he inspired such major figures as Paul Ehrlich and Gerhard Domagk.
# Biography
Robert Koch was born in Clausthal, Germany as the son of a mining official. He studied medicine under Friedrich Gustav Jakob Henle at the University of Göttingen and graduated in 1866. He then served in the Franco-Prussian War and later became district medical officer in Wollstein (Wolsztyn), Prussian Poland. Working with very limited resources, he became one of the founders of bacteriology, the other major figure being Louis Pasteur.
After Casimir Davaine showed the direct transmission of the anthrax bacillus between cows, Koch studied anthrax more closely. He invented methods to purify the bacillus from blood samples and grow pure cultures. He found that, while it could not survive outside a host for long, anthrax built persisting endospores that could last a long time.
These endospores, embedded in soil, were the cause of unexplained "spontaneous" outbreaks of anthrax. Koch published his findings in 1876, and was rewarded with a job at the Imperial Health Office in Berlin in 1880. In 1881, he urged the sterilization of surgical instruments using heat.
In Berlin, he improved the methods he used in Wollstein, including staining and purification techniques, and bacterial growth media, including agar plates (thanks to the advice of Angelina and Walther Hesse) and the Petri dish, named after its inventor, his assistant Julius Richard Petri. These devices are still used today. With these techniques, he was able to discover the bacterium causing tuberculosis (Mycobacterium tuberculosis) in 1882 (he announced the discovery on March 24). Tuberculosis was the cause of one in seven deaths in the mid-19th century.
In 1883, Koch worked with a French research team in Alexandria, Egypt, studying cholera. Koch identified the vibrio bacterium that caused cholera, though he never managed to prove it in experiments. The bacterium had been previously isolated by Italian anatomist Filippo Pacini in 1854, but his work had been ignored due to the predominance of the miasma theory of disease. Koch was unaware of Pacini's work and made an independent discovery, and his greater preeminence allowed the discovery to be widely spread for the benefit of others. In 1965, however, the bacterium was formally renamed Vibrio cholera Pacini 1854.
In 1885, he became professor of hygiene at the University of Berlin, and later, in 1891, director of the newly formed Institute of Infectious Diseases, a position which he resigned from in 1904. He started traveling around the world, studying diseases in South Africa, India, and Java.
Probably as important as his work on tuberculosis, for which he was awarded a Nobel Prize (1905), are Koch's postulates, which say that to establish that an organism is the cause of a disease, it must be:
- found in all cases of the disease examined
- prepared and maintained in a pure culture
- capable of producing the original infection, even after several generations in culture
- retrievable from an inoculated animal and cultured again.
After Koch's success the quality of his own research declined (especially with the fiasco over his ineffective TB cure "tuberculin"), although his pupils found the organisms responsible for diphtheria, typhoid, pneumonia, gonorrhoea, cerebrospinal meningitis, leprosy, bubonic plague, tetanus, and syphilis, among others, by using his methods.
He died on 27 May 1910 of a heart-attack in Baden-Baden, aged 66.[1]
# Honors
Koch crater on the Moon was named after him. The Robert Koch Prize and Medal were created to honour Microbiologists who make groundbreaking discoveries or who contribute to global health in a unique way. The now-defunct Robert Koch Hospital at Koch, Missouri (south of St. Louis, Missouri), was also named in his honor. | https://www.wikidoc.org/index.php/Robert_Koch | |
7d25438a8a5289a4cc8aead4aa170aea33a165dc | wikidoc | Roflumilast | Roflumilast
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Roflumilast is a Phosphodiesterase inhibitor that is FDA approved for the treatment of COPD exacerbations. Common adverse reactions include diarrhea, weight loss, nausea, headache, back pain, influenza, insomnia, dizziness and decreased appetite.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Roflumilast is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.
Limitations of Use
- Roflumilast is not a bronchodilator and is not indicated for the relief of acute bronchospasm.
# Dosage
- The recommended dose of roflumilast is one 500 microgram (mcg) tablet per day, with or without food.
# Dosage Forms And Strengths
- Roflumilast is supplied as white to off-white, round tablets, embossed with “D” on one side and “500” on the other side. Each tablet contains 500 mcg of roflumilast.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Roflumilast in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Roflumilast in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Roflumilast FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Roflumilast in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Roflumilast in pediatric patients.
# Contraindications
The use of DALIRESP is contraindicated in the following condition:
Moderate to severe liver impairment (Child-Pugh B or C)
# Warnings
Treatment of Acute Bronchospasm
- Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.
Psychiatric Events including Suicidality
- Treatment with roflumilast is associated with an increase in psychiatric adverse reactions. In 8 controlled clinical trials 5.9% (263) of patients treated with roflumilast 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse reactions were insomnia, anxiety, and depression which were reported at higher rates in those treated with roflumilast 500 mcg daily (2.4%, 1.4%, and 1.2% for roflumilast versus 1.0%, 0.9%, and 0.9% for placebo, respectively). Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving roflumilast compared to one patient (suicidal ideation) who received placebo. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression.
- Before using roflumilast in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with roflumilast in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with roflumilast if such events occur.
Weight Decrease
- Weight loss was a common adverse reaction in roflumilast clinical trials and was reported in 7.5% (331) of patients treated with roflumilast 500 mcg once daily compared to 2.1% (89) treated with placebo. In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In these studies, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo. In addition, 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe (>10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving roflumilast. Patients treated with roflumilast should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of roflumilast should be considered.
Drug Interactions
- A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. The administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure, which may result in a decrease in the therapeutic effectiveness of roflumilast. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) with roflumilast is not recommended
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are described in greater detail in other sections:
- Psychiatric Events Including Suicidality.
- Weight Decrease.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety data described below reflect exposure of 4438 patients to roflumilast 500 mcg once daily in four 1-year placebo-controlled trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials. In these trials, 3136 and 1232 COPD patients were exposed to roflumilast 500 mcg once daily for 6 months and 1-year, respectively.
- The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with roflumilast reported an adverse reaction compared with 65.3% treated with placebo.
- The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for roflumilast-treated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of roflumilast were diarrhea (2.4%) and nausea (1.6%).
- Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in roflumilast-treated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure.
TABLE 1 summarizes the adverse reactions reported by ≥ 2% of patients in the roflumilast group in 8 controlled COPD clinical trials.
- Adverse reactions that occurred in the roflumilast group at a frequency of 1 to 2% where rates exceeded that in the placebo group include:
Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting
Infections and infestations - rhinitis , sinusitis, urinary tract infection,
Musculoskeletal and connective tissue disorders - muscle spasms
Nervous system disorders - tremor
Psychiatric disorders - anxiety, depression
## Postmarketing Experience
- The following adverse reactions have been identified from spontaneous reports of roflumilast received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to roflumilast. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to roflumilast exposure: hypersensitivity reactions including angioedema, urticaria, and rash.
# Drug Interactions
A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 .
Drugs That Induce Cytochrome P450 (CYP) Enzymes
Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of roflumilast. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with roflumilast is not recommended.
Drugs That Inhibit Cytochrome P450 (CYP) Enzymes
The co-administration of roflumilast (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit .
Oral Contraceptives Containing Gestodene and Ethinyl Estradiol
The co-administration of roflumilast (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully against benefit.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Teratogenic effects: Pregnancy Category C: There are no adequate and well controlled studies of roflumilast in pregnant women. roflumilast was not teratogenic in mice, rats, or rabbits. Roflumilast should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Roflumilast induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the maximum recommended human dose (MRHD) (on a mg/m2 basis at maternal doses > 2 mg/kg/day and 6 mg/kg/day, respectively). Roflumilast induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD (on a mg/m2 basis at maternal doses ≥ 0.6 mg/kg/day). No treatment-related effects on embryo-fetal development were observed in mice, rats, and rabbits at approximately 12, 3, and 26 times the MRHD, respectively (on a mg/m2 basis at maternal doses of 1.5, 0.2, and 0.8 mg/kg/day, respectively).
- Nonteratogenic effects: Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with the drug during pregnancy and lactation periods in mice. These studies found that roflumilast decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/mg2 basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. Roflumilast also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on a mg/m2 basis at a maternal dose of 12 mg/kg/day) during pregnancy and lactation.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Roflumilast in women who are pregnant.
### Labor and Delivery
- Roflumilast should not be used during labor and delivery. There are no human studies that have investigated effects of roflumilast on preterm labor or labor at term; however, animal studies showed that roflumilast disrupted the labor and delivery process in mice. roflumilast induced delivery retardation in pregnant mice at doses greater than or equal to approximately 16 times the MRHD (on a mg/m2 basis at a maternal dose of > 2 mg/kg/day).
### Nursing Mothers
- Roflumilast and/or its metabolites are excreted into the milk of lactating rats. Excretion of roflumilast and/or its metabolites into human milk is probable. There are no human studies that have investigated effects of roflumilast on breast-fed infants. Roflumilast should not be used by women who are nursing.
### Pediatric Use
- COPD does not normally occur in children. The safety and effectiveness of roflumilast in pediatric patients have not been established.
### Geriatic Use
- Of the 4438 COPD subjects exposed to roflumilast for up to 12 months in 8 controlled clinical trials, 2022 were > 65 years of age and 471 were > 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for roflumilast, no adjustment of dosage in geriatric patients is warranted.
### Gender
There is no FDA guidance on the use of Roflumilast with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Roflumilast with respect to specific racial populations.
### Renal Impairment
- In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, the AUCs of roflumilast and roflumilast N-oxide were decreased by 21% and 7%, respectively and Cmax were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment.
### Hepatic Impairment
- Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUCs of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in Child-Pugh A subjects and by 92% and 41%, respectively in Child-Pugh B subjects, as compared to age-, weight- and gender-matched healthy subjects. The Cmax of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. Roflumilast 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering roflumilast to patients who have mild liver impairment (Child-Pugh A). Roflumilast is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C) .
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Roflumilast in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Roflumilast in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Roflumilast in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Roflumilast in the drug label.
# Overdosage
Human Experience
No case of overdose has been reported in clinical studies with roflumilast. During the Phase I studies of roflumilast, the following symptoms were observed at an increased rate after a single oral dose of 2500 mcg and a single dose of 5000 mcg: headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess and arterial hypotension.
Management of Overdose
In case of overdose, patients should seek immediate medical help. Appropriate supportive medical care should be provided. Since roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of drug removal. It is not known whether roflumilast is dialyzable by peritoneal dialysis.
# Pharmacology
## Mechanism of Action
- Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which roflumilast exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells.
## Structure
- The active ingredient in roflumilast tablets is roflumilast. Roflumilast and its active metabolite (roflumilast N-oxide) are selective phosphodiesterase 4 (PDE4) inhibitors. The chemical name of roflumilast is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide. Its empirical formula is C17H14Cl2F2N2O3 and the molecular weight is 403.22.
- The chemical structure is:
- The drug substance is a white to off-white non-hygroscopic powder with a melting point of 160°C. It is practically insoluble in water and hexane, sparingly soluble in ethanol and freely soluble in acetone.
- Roflumilast is supplied as white to off-white, round tablets, embossed with “D” on one side and “500” on the other side. Each tablet contains 500 mcg of roflumilast.
- Each tablet of roflumilast for oral administration contains the following inactive ingredients: lactose monohydrate, corn starch, povidone and magnesium stearate.
## Pharmacodynamics
- In COPD patients, 4 week treatment with roflumilast 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, and 42%, respectively. In a pharmacodynamic study in healthy volunteers, roflumilast 500 mcg once daily reduced the number of total cells, neutrophils and eosinophils found in bronchoalveolar lavage fluid following segmental pulmonary lipopolysaccharide (LPS) challenge by 35%, 38% and 73%, respectively. The clinical significance of these findings is unknown.
## Pharmacokinetics
Absorption
- The absolute bioavailability of roflumilast following a 500 mcg oral dose is approximately 80%. Maximum plasma concentrations (Cmax) of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to 2 hours) in the fasted state while plateau-like maximum concentrations of the N-oxide metabolite are reached in approximately eight hours (ranging from 4 to 13 hours). Food has no effect on total drug absorption, but delays time to maximum concentration (Tmax) of roflumilast by one hour and reduces Cmax by approximately 40%, however, Cmax and Tmax of roflumilast N-oxide are unaffected. An in vitro study showed that roflumilast and roflumilast N-oxide did not inhibit P-gp transporter.
Distribution
- Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for single dose 500 mcg roflumilast is about 2.9 L/kg. Studies in rats with radiolabeled roflumilast indicate low penetration across the blood-brain barrier.
Metabolism
- Roflumilast is extensively metabolized via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is the only major metabolite observed in the plasma of humans. Together, roflumilast and roflumilast N-oxide account for the majority (87.5%) of total dose administered in plasma. In urine, roflumilast was not detectable while roflumilast N-oxide was only a trace metabolite (less than 1%). Other conjugated metabolites such as roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N-oxide were detected in urine.
- While roflumilast is three times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro, the plasma AUC of roflumilast N-oxide on average is about 10-fold greater than the plasma AUC of roflumilast.
- In vitro studies and clinical drug-drug interaction studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP 1A2 and 3A4. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is a low probability of relevant interactions with substances metabolized by these P450 enzymes. In addition, in vitro studies demonstrated no induction of the CYP 1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP 2B6 by roflumilast.
Elimination
- The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9.6 L/h. Following an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately 4 days for roflumilast and 6 days for roflumilast N-oxide following once daily dosing. Following intravenous or oral administration of radiolabeled roflumilast, about 70% of the radioactivity was recovered in the urine.
Special Populations
Hepatic Impairment
- Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in Child-Pugh A subjects and by 92% and 41%, respectively in Child-Pugh B subjects, as compared to age-, weight- and gender-matched healthy subjects. The Cmax of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. Roflumilast 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering roflumilast to patients who have mild liver impairment (Child-Pugh A). roflumilast is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C).
Renal Impairment
- In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, roflumilast and roflumilast N-oxide AUCs were decreased by 21% and 7%, respectively and Cmax were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment.
Age
- Roflumilast 500 mcg once daily for 15 days was studied in young, middle aged, and elderly healthy subjects. The exposure in elderly (> 65 years of age) were 27% higher in AUC and 16% higher in Cmax for roflumilast and 19% higher in AUC and 13% higher in Cmax for roflumilast-N-oxide than that in young volunteers (18-45 years old). No dosage adjustment is necessary for elderly patients.
Gender
- In a Phase I study evaluating the effect of age and gender on the pharmacokinetics of roflumilast and roflumilast N-oxide, a 39% and 33% increase in roflumilast and roflumilast N-oxide AUC were noted in healthy female subjects as compared to healthy male subjects. No dosage adjustment is necessary based on gender.
Smoking
- The pharmacokinetics of roflumilast and roflumilast N-oxide were comparable in smokers as compared to non-smokers. There was no difference in Cmax between smokers and non-smokers when roflumilast 500 mcg was administered as a single dose to 12 smokers and 12 non-smokers. The AUC of roflumilast in smokers was 13% less than that in non-smokers while the AUC of roflumilast N-oxide in smokers was 17% more than that in non-smokers.
Race
- As compared to Caucasians, African Americans, Hispanics, and Japanese showed 16%, 41%, and 15% higher AUC, respectively, for roflumilast and 43%, 27%, and 16% higher AUC, respectively, for roflumilast N-oxide. As compared to Caucasians, African Americans, Hispanics, and Japanese showed 8%, 21%, and 5% higher Cmax, respectively, for roflumilast and 43%, 27%, and 17% higher Cmax, respectively, for roflumilast N-oxide. No dosage adjustment is necessary for race.
Drug Interactions
- Drug interaction studies were performed with roflumilast and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction . No significant drug interactions were observed when 500 mcg oral roflumilast was administered with inhaled salbutamol, formoterol, budesonide and oral montelukast, digoxin, theophylline, warfarin, sildenafil, midazolam, or antacids.
- The effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide is shown below.
- Effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide. Note that the dashed lines indicate the lower and higher bounds (0.8-1.25) of the 90% confidence interval of the geometric mean ratio of Cmax or AUC for roflumilast or roflumilast N-oxide for Treatment (DALIRESP+Coadministered Drug) vs. Reference (DALIRESP). The dosing regimens of coadministered drugs was: Midazolam:2mg po SD; Erythromycin:500mg po TID; Ketoconazole:200mg po BID; Rifampicin:600mg po QD; Fluvoxamine:50mg po QD; Digoxin:250ug po SD; Maalox:30mL po SD; Salbutamol:0.2mg pi TID; Cimetidine:400mg po BID; Formoterol:40ug po BID; Budesonide:400ug po BID; Theophylline:375mg po BID; Warfarin:250mg po SD; Enoxacin:400mg po BID; Sildenafil:100mg SD; Minulet (combination oral contraceptive):0.075mg gestodene/0.03mg ethinylestradiol po QD; Montelukast:10mg po QD.
- Drug interactions considered to be significant are described in more detail below.
Inhibitors of CYP3A4 and CYP1A2:
- Erythromycin: In an open-label crossover study in 16 healthy volunteers, the coadministration of CYP 3A4 inhibitor erythromycin (500 mg three times daily for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 40% and 70% increase in Cmax and AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in Cmax and AUC for roflumilast N-oxide, respectively.
- Ketoconazole: In an open-label crossover study in 16 healthy volunteers, the coadministration of a strong CYP 3A4 inhibitor ketoconazole (200 mg twice daily for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 23% and 99% increase in Cmax and AUC for roflumilast, respectively, and a 38% reduction and 3% increase in Cmax and AUC for roflumilast N-oxide, respectively.
- Fluvoxamine: In an open-label crossover study in 16 healthy volunteers, the coadministration of dual CYP 3A4/1A2 inhibitor fluvoxamine (50 mg daily for 14 days) with a single oral dose of 500 mcg roflumilast showed a 12% and 156% increase in roflumilast Cmax and AUC along with a 210% decrease and 52% increase in roflumilast N-oxide Cmax and AUC, respectively.
- Enoxacin: In an open-label crossover study in 16 healthy volunteers, the coadministration of dual CYP 3A4/1A2 inhibitor enoxacin (400 mg twice daily for 12 days) with a single oral dose of 500 mcg roflumilast resulted in an increased Cmax and AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide Cmax was decreased by 14% while roflumilast N-oxide AUC was increased by 23%.
- Cimetidine: In an open-label crossover study in 16 healthy volunteers, the coadministration of a dual CYP 3A4/1A2 inhibitor cimetidine (400 mg twice daily for 7 days) with a single dose of 500 mcg oral roflumilast resulted in a 46% and 85% increase in roflumilast Cmax and AUC; and a 4% decrease in Cmax and 27% increase in AUC for roflumilast N-oxide, respectively.
Oral Contraceptives containing Gestodene and Ethinyl Estradiol'':
- In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single oral dose of 500 mcg roflumilast with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state caused a 38% increase and 12% decrease in Cmax of roflumilast and roflumilast N-oxide, respectively. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively.
Inducers of CYP enzymes:
- Rifampicin: In an open-label, three-period, fixed-sequence study in 15 healthy volunteers, coadministration of the strong CYP3A4 inducer rifampicin (600 mg once daily for 11 days) with a single oral dose of 500 mcg roflumilast resulted in reduction of roflumilast Cmax and AUC by 68% and 79%, respectively; and an increase of roflumilast N-oxide Cmax by 30% and reduced roflumilast N-oxide AUC by 56%.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term studies were conducted in hamsters and mice with roflumilast to evaluate its carcinogenic potential. In 2-year oral gavage carcinogenicity studies, roflumilast treatment resulted in dose-related, statistically significant increases in the incidence of undifferentiated carcinomas of nasal epithelium in hamsters at ≥ 8 mg/kg/day (approximately 11 times the MRHD based on summed AUCs of roflumilast and its metabolites). The tumorigenicity of roflumilast appears to be attributed to a reactive metabolite of 4-amino-3,5-dichloro-pyridine N-oxide (ADCP N-oxide). No evidence of tumorigenicity was observed in mice at roflumilast oral doses up to 12 and 18 mg/kg/day in females and males, respectively (approximately 10 and 15 times the MRHD, respectively, based on summed AUCs of roflumilast and its metabolites).
- Roflumilast tested positive in an in vivo mouse micronucleus test, but negative in the following assays: Ames test for bacterial gene mutation, in vitro chromosome aberration assay in human lymphocytes, in vitro HPRT test with V79 cells, an in vitro micronucleus test with V79 cells, DNA adduct formation assay in rat nasal mucosa, liver and testes, and in vivo mouse bone marrow chromosome aberration assay. Roflumilast N-oxide was negative in the Ames test and in vitro micronucleus test with V79 cells.
- In a human spermatogenesis study, roflumilast 500 mcg had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3-month off-treatment period. In a fertility study, roflumilast decreased fertility rates in male rats at 1.8-mg/kg/day (approximately 29 times the MRHD on a mg/m2 basis). These rats also showed increases in the incidence of tubular atrophy, degeneration in the testis and spermiogenic granuloma in the epididymides. No effect on male rat fertility rate or reproductive organ morphology was observed at 0.8 mg/kg/day (approximately 13 times the MRHD on a mg/m2 basis). No effect on female fertility was observed up to the highest roflumilast dose of 1.5 mg/kg/day in rats (approximately 24 times the MRHD on a mg/m2 basis).
# Clinical Studies
Chronic Obstructive Pulmonary Disease (COPD)
- The efficacy and safety of roflumilast (roflumilast) in COPD was evaluated in 8 randomized double-blind, controlled, parallel group clinical trials in 9394 adult patients (4425 receiving roflumilast 500 mcg) 40 years of age and older with COPD. Of the 8 trials, two were placebo-controlled dose selection trials (Trials 1 and 2) of 6 months duration that evaluated the efficacy of roflumilast 250 mcg and 500 mcg once daily, four were placebo-controlled 1-year trials (Trials 3, 4, 5, and 6) primarily designed to evaluate the efficacy of roflumilast on COPD exacerbations, and two were 6-month efficacy trials (Trials 7 and 8) which assessed the effect of roflumilast as add-on therapy to a long-acting beta agonist or long-acting anti-muscarinic. The 8 trials enrolled patients with nonreversible obstructive lung disease (FEV1/FVC ≤ 70% and ≤ 12% or 200 mL improvement in FEV1 in response to 4 puffs of albuterol/salbutamol) but the severity of airflow obstruction at baseline was different among the trials. Patients enrolled in the dose selection trials had the full range of COPD severity (FEV1 30-80% predicted); median age of 63 years, 73% male, and 99% Caucasian. Patients enrolled in the four exacerbation trials had severe COPD (FEV1 ≤ 50% predicted); median age of 64 years, 74% male, and 90% Caucasian. Patients enrolled in the two 6-month efficacy trials had moderate to severe COPD (FEV1 40-70% predicted); median age of 65 years, 68% male, and 97% Caucasian. COPD exacerbations and lung function (FEV1) were co-primary efficacy outcome measures in the four 1-year trials. In the two 6-month supportive efficacy trials, lung function (FEV1) alone was the primary efficacy outcome measure.
- The two 6-month dose-selection efficacy trials (Trials 1 and 2) explored doses of 250 mcg and 500 mcg once daily in a total of 1929 patients (751 and 724 on roflumilast 250 and 500 mcg, respectively). The selection of the 500 mcg dose was primarily based on nominal improvements in lung function (FEV1) over the 250 mcg dose. The once daily dosing regimen was primarily based on the determination of a plasma half-life of 17 hours for roflumilast and 30 hours for its active metabolite roflumilast N-oxide.
'Effect on Exacerbations'
- The effect of roflumilast 500 mcg once daily on COPD exacerbations was evaluated in four 1-year trials (Trials 3, 4, 5, and 6).
- Two of the trials (Trials 3 and 4) conducted initially enrolled a population of patients with severe COPD (FEV1 ≤ 50% of predicted) inclusive of those with chronic bronchitis and/or emphysema who had a history of smoking of at least 10 pack years. Inhaled corticosteroids were allowed as concomitant medications and used in 61% of both roflumilast and placebo-treated patients and short-acting beta agonists were allowed as rescue therapy. The use of long-acting beta agonists, long-acting anti-muscarinics, and theophylline were prohibited. The rate of moderate or severe COPD exacerbations was a co-primary endpoint in both trials. There was not a symptomatic definition of exacerbation in these 2 trials. Exacerbations were defined in terms of severity requiring treatment with a moderate exacerbation defined as treatment with systemic glucocorticosteroids in Trial 3 or systemic glucocorticosteroids and/or antibiotics in Trial 4 and a severe exacerbation defined as requiring hospitalizations and/or leading to death in Trial 3 or requiring hospitalization in Trial 4. The trials randomized 1176 patients (567 on roflumilast) in Trial 3 and 1514 patients (760 on roflumilast) in Trial 4. Both trials failed to demonstrate a significant reduction in the rate of COPD exacerbations.
- Exploratory analyses of the results of Trials 3 and 4 identified a subpopulation of patients with severe COPD associated with chronic bronchitis and COPD exacerbations within the previous year that appeared to demonstrate a better response in the reduction of the rate of COPD exacerbations compared to the overall population. As a result, two subsequent trials (Trial 5 and Trial 6) were conducted that enrolled patients with severe COPD but associated with chronic bronchitis, at least one COPD exacerbation in the previous year, and at least a 20 pack-year smoking history. In these trials, long-acting beta agonists and short-acting anti-muscarinics were allowed and were used by 44% and 35% of patients treated with roflumilast and 45% and 37% of patients treated with placebo, respectively. The use of inhaled corticosteroids was prohibited. As in trials 3 and 4, the rate of moderate exacerbations (defined as requiring intervention with systemic glucocorticosteroids) or severe exacerbations (defined as leading to hospitalization and/or to death) was a co-primary endpoint.
- Trial 5 randomized a total of 1525 patients (765 on roflumilast) and Trial 6 randomized a total of 1571 patients (772 on roflumilast). In both trials, roflumilast 500 mcg once daily demonstrated a significant reduction in the rate of moderate or severe exacerbations compared to placebo (TABLE 2). These two trials provide the evidence to support the use of roflumilast for the reduction of COPD exacerbations.
- For patients in Trials 5 and 6 who received concomitant long-acting beta agonists or short-acting anti-muscarinics, reduction of moderate or severe exacerbations with roflumilast was similar to that observed for the overall populations of the two trials.
'Effect on Lung Function'
- While roflumilast is not a bronchodilator, all 1-year trials (Trials 3, 4, 5, and 6) evaluated the effect of roflumilast on lung function as determined by the difference in FEV1 between roflumilast and placebo-treated patients (pre-bronchodilator FEV1 measured prior to study drug administration in three of the trials and post-bronchodilator FEV1 measured 30 minutes after administration of 4 puffs of albuterol/salbutamol in one trial) as a co-primary endpoint. In each of these trials roflumilast 500 mcg once daily demonstrated a statistically significant improvement in FEV1 which averaged approximately 50 mL across the four trials. TABLE 3 shows FEV1 results from Trials 5 and 6 which had demonstrated a significant reduction in COPD exacerbations.
- Lung function was also evaluated in two 6-month trials (Trials 7 and 8) to assess the effect of roflumilast when administered as add-on therapy to treatment with a long-acting beta agonist or a long-acting anti-muscarinic. These trials were conducted in a different population of COPD patients from that for which efficacy in reduction of exacerbations has been demonstrated and provide safety support to the roflumilast COPD program.
- No trials have been conducted to assess the effects of roflumilast on COPD exacerbations when added to a fixed-dose combination product containing a long-acting beta agonist and inhaled corticosteroid.
# How Supplied
- Roflumilast is supplied as white to off-white, round tablets, embossed with “D” on one side and “500” on the other side. Each tablet contains 500 mcg of roflumilast.
- DALIRESP tablets are available:
- Bottles of 30: NDC 0456-0095-30
- Bottles of 90: NDC 0456-0095-90
- 10X10 Unit Dose: NDC 0456-0095-63
## Storage
- Store DALIRESP 500 mcg tablets at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F). .
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Bronchospasm
- Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.
Psychiatric Events including Suicidality
- Treatment with roflumilast is associated with an increase in psychiatric adverse reactions. In clinical trials, 5.9% (263) of patients treated with roflumilast 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse events were insomnia, anxiety, and depression which were reported at higher rates in those treated with roflumilast 500 mcg (2.4%, 1.4%, and 1.2% for roflumilast versus 1.0%, 0.9%, and 0.9% for placebo, respectively). Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving roflumilast compared to one patient (suicidal ideation) who received placebo. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression.
- Before using roflumilast in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with roflumilast in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with roflumilast if such events occur.
Weight Decrease
Weight loss was a common adverse reaction in roflumilast clinical trials and was reported in - - - 7.5% (331) of patients treated with roflumilast 500 mcg once daily compared to 2.1% (89) treated with placebo. In two placebo-controlled clinical trials of one year duration in which weight was prospectively assessed, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo and 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe (>10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving roflumilast. Patients treated with roflumilast should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of roflumilast should be considered .
Drug Interactions
- The administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure which may result in a decrease in the therapeutic effectiveness of roflumilast. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) with roflumilast is not recommended.
## Medication Guide
# Precautions with Alcohol
- Alcohol-Roflumilast interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DALIRESP
# Look-Alike Drug Names
There is limited information regarding Roflumilast Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Roflumilast
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Overview
Roflumilast is a Phosphodiesterase inhibitor that is FDA approved for the treatment of COPD exacerbations. Common adverse reactions include diarrhea, weight loss, nausea, headache, back pain, influenza, insomnia, dizziness and decreased appetite.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Roflumilast is indicated as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations.
Limitations of Use
- Roflumilast is not a bronchodilator and is not indicated for the relief of acute bronchospasm.
# Dosage
- The recommended dose of roflumilast is one 500 microgram (mcg) tablet per day, with or without food.
# Dosage Forms And Strengths
- Roflumilast is supplied as white to off-white, round tablets, embossed with “D” on one side and “500” on the other side. Each tablet contains 500 mcg of roflumilast.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Roflumilast in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Roflumilast in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Roflumilast FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Roflumilast in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Roflumilast in pediatric patients.
# Contraindications
The use of DALIRESP is contraindicated in the following condition:
Moderate to severe liver impairment (Child-Pugh B or C)
# Warnings
Treatment of Acute Bronchospasm
- Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.
Psychiatric Events including Suicidality
- Treatment with roflumilast is associated with an increase in psychiatric adverse reactions. In 8 controlled clinical trials 5.9% (263) of patients treated with roflumilast 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse reactions were insomnia, anxiety, and depression which were reported at higher rates in those treated with roflumilast 500 mcg daily (2.4%, 1.4%, and 1.2% for roflumilast versus 1.0%, 0.9%, and 0.9% for placebo, respectively). Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving roflumilast compared to one patient (suicidal ideation) who received placebo. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression.
- Before using roflumilast in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with roflumilast in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with roflumilast if such events occur.
Weight Decrease
- Weight loss was a common adverse reaction in roflumilast clinical trials and was reported in 7.5% (331) of patients treated with roflumilast 500 mcg once daily compared to 2.1% (89) treated with placebo. In addition to being reported as adverse reactions, weight was prospectively assessed in two placebo-controlled clinical trials of one year duration. In these studies, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo. In addition, 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe (>10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving roflumilast. Patients treated with roflumilast should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of roflumilast should be considered.
Drug Interactions
- A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2. The administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure, which may result in a decrease in the therapeutic effectiveness of roflumilast. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) with roflumilast is not recommended
# Adverse Reactions
## Clinical Trials Experience
- The following adverse reactions are described in greater detail in other sections:
- Psychiatric Events Including Suicidality.
- Weight Decrease.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety data described below reflect exposure of 4438 patients to roflumilast 500 mcg once daily in four 1-year placebo-controlled trials, two 6-month placebo-controlled trials, and two 6-month drug add-on trials. In these trials, 3136 and 1232 COPD patients were exposed to roflumilast 500 mcg once daily for 6 months and 1-year, respectively.
- The population had a median age of 64 years (range 40-91), 73% were male, 92.9% were Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) of 8.9 to 89.1% predicted. In these trials, 68.5% of the patients treated with roflumilast reported an adverse reaction compared with 65.3% treated with placebo.
- The proportion of patients who discontinued treatment due to adverse reaction was 14.8% for roflumilast-treated patients and 9.9% for placebo-treated patients. The most common adverse reactions that led to discontinuation of roflumilast were diarrhea (2.4%) and nausea (1.6%).
- Serious adverse reactions, whether considered drug-related or not by the investigators, which occurred more frequently in roflumilast-treated patients include diarrhea, atrial fibrillation, lung cancer, prostate cancer, acute pancreatitis, and acute renal failure.
TABLE 1 summarizes the adverse reactions reported by ≥ 2% of patients in the roflumilast group in 8 controlled COPD clinical trials.
- Adverse reactions that occurred in the roflumilast group at a frequency of 1 to 2% where rates exceeded that in the placebo group include:
Gastrointestinal disorders - abdominal pain, dyspepsia, gastritis, vomiting
Infections and infestations - rhinitis , sinusitis, urinary tract infection,
Musculoskeletal and connective tissue disorders - muscle spasms
Nervous system disorders - tremor
Psychiatric disorders - anxiety, depression
## Postmarketing Experience
- The following adverse reactions have been identified from spontaneous reports of roflumilast received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to roflumilast. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to roflumilast exposure: hypersensitivity reactions including angioedema, urticaria, and rash.
# Drug Interactions
A major step in roflumilast metabolism is the N-oxidation of roflumilast to roflumilast N-oxide by CYP3A4 and CYP1A2 .
Drugs That Induce Cytochrome P450 (CYP) Enzymes
Strong cytochrome P450 enzyme inducers decrease systemic exposure to roflumilast and may reduce the therapeutic effectiveness of roflumilast. Therefore the use of strong cytochrome P450 inducers (e.g., rifampicin, phenobarbital, carbamazepine, and phenytoin) with roflumilast is not recommended.
Drugs That Inhibit Cytochrome P450 (CYP) Enzymes
The co-administration of roflumilast (500 mcg) with CYP3A4 inhibitors or dual inhibitors that inhibit both CYP3A4 and CYP1A2 simultaneously (e.g., erythromycin, ketoconazole, fluvoxamine, enoxacin, cimetidine) may increase roflumilast systemic exposure and may result in increased adverse reactions. The risk of such concurrent use should be weighed carefully against benefit .
Oral Contraceptives Containing Gestodene and Ethinyl Estradiol
The co-administration of roflumilast (500 mcg) with oral contraceptives containing gestodene and ethinyl estradiol may increase roflumilast systemic exposure and may result in increased side effects. The risk of such concurrent use should be weighed carefully against benefit.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Teratogenic effects: Pregnancy Category C: There are no adequate and well controlled studies of roflumilast in pregnant women. roflumilast was not teratogenic in mice, rats, or rabbits. Roflumilast should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Roflumilast induced stillbirth and decreased pup viability in mice at doses corresponding to approximately 16 and 49 times, respectively, the maximum recommended human dose (MRHD) (on a mg/m2 basis at maternal doses > 2 mg/kg/day and 6 mg/kg/day, respectively). Roflumilast induced post-implantation loss in rats at doses greater than or equal to approximately 10 times the MRHD (on a mg/m2 basis at maternal doses ≥ 0.6 mg/kg/day). No treatment-related effects on embryo-fetal development were observed in mice, rats, and rabbits at approximately 12, 3, and 26 times the MRHD, respectively (on a mg/m2 basis at maternal doses of 1.5, 0.2, and 0.8 mg/kg/day, respectively).
- Nonteratogenic effects: Roflumilast has been shown to adversely affect pup post-natal development when dams were treated with the drug during pregnancy and lactation periods in mice. These studies found that roflumilast decreased pup rearing frequencies at approximately 49 times the MRHD (on a mg/mg2 basis at a maternal dose of 6 mg/kg/day) during pregnancy and lactation. Roflumilast also decreased survival and forelimb grip reflex and delayed pinna detachment in mouse pups at approximately 97 times the MRHD (on a mg/m2 basis at a maternal dose of 12 mg/kg/day) during pregnancy and lactation.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Roflumilast in women who are pregnant.
### Labor and Delivery
- Roflumilast should not be used during labor and delivery. There are no human studies that have investigated effects of roflumilast on preterm labor or labor at term; however, animal studies showed that roflumilast disrupted the labor and delivery process in mice. roflumilast induced delivery retardation in pregnant mice at doses greater than or equal to approximately 16 times the MRHD (on a mg/m2 basis at a maternal dose of > 2 mg/kg/day).
### Nursing Mothers
- Roflumilast and/or its metabolites are excreted into the milk of lactating rats. Excretion of roflumilast and/or its metabolites into human milk is probable. There are no human studies that have investigated effects of roflumilast on breast-fed infants. Roflumilast should not be used by women who are nursing.
### Pediatric Use
- COPD does not normally occur in children. The safety and effectiveness of roflumilast in pediatric patients have not been established.
### Geriatic Use
- Of the 4438 COPD subjects exposed to roflumilast for up to 12 months in 8 controlled clinical trials, 2022 were > 65 years of age and 471 were > 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Based on available data for roflumilast, no adjustment of dosage in geriatric patients is warranted.
### Gender
There is no FDA guidance on the use of Roflumilast with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Roflumilast with respect to specific racial populations.
### Renal Impairment
- In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, the AUCs of roflumilast and roflumilast N-oxide were decreased by 21% and 7%, respectively and Cmax were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment.
### Hepatic Impairment
- Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUCs of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in Child-Pugh A subjects and by 92% and 41%, respectively in Child-Pugh B subjects, as compared to age-, weight- and gender-matched healthy subjects. The Cmax of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. Roflumilast 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering roflumilast to patients who have mild liver impairment (Child-Pugh A). Roflumilast is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C) .
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Roflumilast in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Roflumilast in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Roflumilast in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Roflumilast in the drug label.
# Overdosage
Human Experience
No case of overdose has been reported in clinical studies with roflumilast. During the Phase I studies of roflumilast, the following symptoms were observed at an increased rate after a single oral dose of 2500 mcg and a single dose of 5000 mcg: headache, gastrointestinal disorders, dizziness, palpitations, lightheadedness, clamminess and arterial hypotension.
Management of Overdose
In case of overdose, patients should seek immediate medical help. Appropriate supportive medical care should be provided. Since roflumilast is highly protein bound, hemodialysis is not likely to be an efficient method of drug removal. It is not known whether roflumilast is dialyzable by peritoneal dialysis.
# Pharmacology
## Mechanism of Action
- Roflumilast and its active metabolite (roflumilast N-oxide) are selective inhibitors of phosphodiesterase 4 (PDE4). Roflumilast and roflumilast N-oxide inhibition of PDE4 (a major cyclic-3′,5′-adenosine monophosphate (cyclic AMP)-metabolizing enzyme in lung tissue) activity leads to accumulation of intracellular cyclic AMP. While the specific mechanism(s) by which roflumilast exerts its therapeutic action in COPD patients is not well defined, it is thought to be related to the effects of increased intracellular cyclic AMP in lung cells.
## Structure
- The active ingredient in roflumilast tablets is roflumilast. Roflumilast and its active metabolite (roflumilast N-oxide) are selective phosphodiesterase 4 (PDE4) inhibitors. The chemical name of roflumilast is N-(3,5-dichloropyridin-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxy-benzamide. Its empirical formula is C17H14Cl2F2N2O3 and the molecular weight is 403.22.
- The chemical structure is:
- The drug substance is a white to off-white non-hygroscopic powder with a melting point of 160°C. It is practically insoluble in water and hexane, sparingly soluble in ethanol and freely soluble in acetone.
- Roflumilast is supplied as white to off-white, round tablets, embossed with “D” on one side and “500” on the other side. Each tablet contains 500 mcg of roflumilast.
- Each tablet of roflumilast for oral administration contains the following inactive ingredients: lactose monohydrate, corn starch, povidone and magnesium stearate.
## Pharmacodynamics
- In COPD patients, 4 week treatment with roflumilast 500 mcg oral once daily reduced sputum neutrophils and eosinophils by 31%, and 42%, respectively. In a pharmacodynamic study in healthy volunteers, roflumilast 500 mcg once daily reduced the number of total cells, neutrophils and eosinophils found in bronchoalveolar lavage fluid following segmental pulmonary lipopolysaccharide (LPS) challenge by 35%, 38% and 73%, respectively. The clinical significance of these findings is unknown.
## Pharmacokinetics
Absorption
- The absolute bioavailability of roflumilast following a 500 mcg oral dose is approximately 80%. Maximum plasma concentrations (Cmax) of roflumilast typically occur approximately one hour after dosing (ranging from 0.5 to 2 hours) in the fasted state while plateau-like maximum concentrations of the N-oxide metabolite are reached in approximately eight hours (ranging from 4 to 13 hours). Food has no effect on total drug absorption, but delays time to maximum concentration (Tmax) of roflumilast by one hour and reduces Cmax by approximately 40%, however, Cmax and Tmax of roflumilast N-oxide are unaffected. An in vitro study showed that roflumilast and roflumilast N-oxide did not inhibit P-gp transporter.
Distribution
- Plasma protein binding of roflumilast and its N-oxide metabolite is approximately 99% and 97%, respectively. Volume of distribution for single dose 500 mcg roflumilast is about 2.9 L/kg. Studies in rats with radiolabeled roflumilast indicate low penetration across the blood-brain barrier.
Metabolism
- Roflumilast is extensively metabolized via Phase I (cytochrome P450) and Phase II (conjugation) reactions. The N-oxide metabolite is the only major metabolite observed in the plasma of humans. Together, roflumilast and roflumilast N-oxide account for the majority (87.5%) of total dose administered in plasma. In urine, roflumilast was not detectable while roflumilast N-oxide was only a trace metabolite (less than 1%). Other conjugated metabolites such as roflumilast N-oxide glucuronide and 4-amino-3,5-dichloropyridine N-oxide were detected in urine.
- While roflumilast is three times more potent than roflumilast N-oxide at inhibition of the PDE4 enzyme in vitro, the plasma AUC of roflumilast N-oxide on average is about 10-fold greater than the plasma AUC of roflumilast.
- In vitro studies and clinical drug-drug interaction studies suggest that the biotransformation of roflumilast to its N-oxide metabolite is mediated by CYP 1A2 and 3A4. Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of roflumilast and roflumilast N-oxide do not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5, or 4A9/11. Therefore, there is a low probability of relevant interactions with substances metabolized by these P450 enzymes. In addition, in vitro studies demonstrated no induction of the CYP 1A2, 2A6, 2C9, 2C19, or 3A4/5 and only a weak induction of CYP 2B6 by roflumilast.
Elimination
- The plasma clearance after short-term intravenous infusion of roflumilast is on average about 9.6 L/h. Following an oral dose, the median plasma effective half-life of roflumilast and its N-oxide metabolite are approximately 17 and 30 hours, respectively. Steady state plasma concentrations of roflumilast and its N-oxide metabolite are reached after approximately 4 days for roflumilast and 6 days for roflumilast N-oxide following once daily dosing. Following intravenous or oral administration of radiolabeled roflumilast, about 70% of the radioactivity was recovered in the urine.
Special Populations
Hepatic Impairment
- Roflumilast 250 mcg once daily for 14 days was studied in subjects with mild-to-moderate hepatic impairment classified as Child-Pugh A and B (8 subjects in each group). The AUC of roflumilast and roflumilast N-oxide were increased by 51% and 24%, respectively in Child-Pugh A subjects and by 92% and 41%, respectively in Child-Pugh B subjects, as compared to age-, weight- and gender-matched healthy subjects. The Cmax of roflumilast and roflumilast N-oxide were increased by 3% and 26%, respectively in Child-Pugh A subjects and by 26% and 40%, respectively in Child-Pugh B subjects, as compared to healthy subjects. Roflumilast 500 mcg has not been studied in hepatically impaired patients. Clinicians should consider the risk-benefit of administering roflumilast to patients who have mild liver impairment (Child-Pugh A). roflumilast is not recommended for use in patients with moderate or severe liver impairment (Child-Pugh B or C).
Renal Impairment
- In twelve subjects with severe renal impairment administered a single dose of 500 mcg roflumilast, roflumilast and roflumilast N-oxide AUCs were decreased by 21% and 7%, respectively and Cmax were reduced by 16% and 12%, respectively. No dosage adjustment is necessary for patients with renal impairment.
Age
- Roflumilast 500 mcg once daily for 15 days was studied in young, middle aged, and elderly healthy subjects. The exposure in elderly (> 65 years of age) were 27% higher in AUC and 16% higher in Cmax for roflumilast and 19% higher in AUC and 13% higher in Cmax for roflumilast-N-oxide than that in young volunteers (18-45 years old). No dosage adjustment is necessary for elderly patients.
Gender
- In a Phase I study evaluating the effect of age and gender on the pharmacokinetics of roflumilast and roflumilast N-oxide, a 39% and 33% increase in roflumilast and roflumilast N-oxide AUC were noted in healthy female subjects as compared to healthy male subjects. No dosage adjustment is necessary based on gender.
Smoking
- The pharmacokinetics of roflumilast and roflumilast N-oxide were comparable in smokers as compared to non-smokers. There was no difference in Cmax between smokers and non-smokers when roflumilast 500 mcg was administered as a single dose to 12 smokers and 12 non-smokers. The AUC of roflumilast in smokers was 13% less than that in non-smokers while the AUC of roflumilast N-oxide in smokers was 17% more than that in non-smokers.
Race
- As compared to Caucasians, African Americans, Hispanics, and Japanese showed 16%, 41%, and 15% higher AUC, respectively, for roflumilast and 43%, 27%, and 16% higher AUC, respectively, for roflumilast N-oxide. As compared to Caucasians, African Americans, Hispanics, and Japanese showed 8%, 21%, and 5% higher Cmax, respectively, for roflumilast and 43%, 27%, and 17% higher Cmax, respectively, for roflumilast N-oxide. No dosage adjustment is necessary for race.
Drug Interactions
- Drug interaction studies were performed with roflumilast and other drugs likely to be coadministered or drugs commonly used as probes for pharmacokinetic interaction . No significant drug interactions were observed when 500 mcg oral roflumilast was administered with inhaled salbutamol, formoterol, budesonide and oral montelukast, digoxin, theophylline, warfarin, sildenafil, midazolam, or antacids.
- The effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide is shown below.
- Effect of concomitant drugs on the exposure of roflumilast and roflumilast N-oxide. Note that the dashed lines indicate the lower and higher bounds (0.8-1.25) of the 90% confidence interval of the geometric mean ratio of Cmax or AUC for roflumilast or roflumilast N-oxide for Treatment (DALIRESP+Coadministered Drug) vs. Reference (DALIRESP). The dosing regimens of coadministered drugs was: Midazolam:2mg po SD; Erythromycin:500mg po TID; Ketoconazole:200mg po BID; Rifampicin:600mg po QD; Fluvoxamine:50mg po QD; Digoxin:250ug po SD; Maalox:30mL po SD; Salbutamol:0.2mg pi TID; Cimetidine:400mg po BID; Formoterol:40ug po BID; Budesonide:400ug po BID; Theophylline:375mg po BID; Warfarin:250mg po SD; Enoxacin:400mg po BID; Sildenafil:100mg SD; Minulet (combination oral contraceptive):0.075mg gestodene/0.03mg ethinylestradiol po QD; Montelukast:10mg po QD.
- Drug interactions considered to be significant are described in more detail below.
Inhibitors of CYP3A4 and CYP1A2:
- Erythromycin: In an open-label crossover study in 16 healthy volunteers, the coadministration of CYP 3A4 inhibitor erythromycin (500 mg three times daily for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 40% and 70% increase in Cmax and AUC for roflumilast, respectively, and a 34% decrease and a 4% increase in Cmax and AUC for roflumilast N-oxide, respectively.
- Ketoconazole: In an open-label crossover study in 16 healthy volunteers, the coadministration of a strong CYP 3A4 inhibitor ketoconazole (200 mg twice daily for 13 days) with a single oral dose of 500 mcg roflumilast resulted in 23% and 99% increase in Cmax and AUC for roflumilast, respectively, and a 38% reduction and 3% increase in Cmax and AUC for roflumilast N-oxide, respectively.
- Fluvoxamine: In an open-label crossover study in 16 healthy volunteers, the coadministration of dual CYP 3A4/1A2 inhibitor fluvoxamine (50 mg daily for 14 days) with a single oral dose of 500 mcg roflumilast showed a 12% and 156% increase in roflumilast Cmax and AUC along with a 210% decrease and 52% increase in roflumilast N-oxide Cmax and AUC, respectively.
- Enoxacin: In an open-label crossover study in 16 healthy volunteers, the coadministration of dual CYP 3A4/1A2 inhibitor enoxacin (400 mg twice daily for 12 days) with a single oral dose of 500 mcg roflumilast resulted in an increased Cmax and AUC of roflumilast by 20% and 56%, respectively. Roflumilast N-oxide Cmax was decreased by 14% while roflumilast N-oxide AUC was increased by 23%.
- Cimetidine: In an open-label crossover study in 16 healthy volunteers, the coadministration of a dual CYP 3A4/1A2 inhibitor cimetidine (400 mg twice daily for 7 days) with a single dose of 500 mcg oral roflumilast resulted in a 46% and 85% increase in roflumilast Cmax and AUC; and a 4% decrease in Cmax and 27% increase in AUC for roflumilast N-oxide, respectively.
Oral Contraceptives containing Gestodene and Ethinyl Estradiol'':
- In an open-label crossover study in 20 healthy adult volunteers, coadministration of a single oral dose of 500 mcg roflumilast with repeated doses of a fixed combination oral contraceptive containing 0.075 mg gestodene and 0.03 mg ethinyl estradiol to steady state caused a 38% increase and 12% decrease in Cmax of roflumilast and roflumilast N-oxide, respectively. Roflumilast and roflumilast N-oxide AUCs were increased by 51% and 14%, respectively.
Inducers of CYP enzymes:
- Rifampicin: In an open-label, three-period, fixed-sequence study in 15 healthy volunteers, coadministration of the strong CYP3A4 inducer rifampicin (600 mg once daily for 11 days) with a single oral dose of 500 mcg roflumilast resulted in reduction of roflumilast Cmax and AUC by 68% and 79%, respectively; and an increase of roflumilast N-oxide Cmax by 30% and reduced roflumilast N-oxide AUC by 56%.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term studies were conducted in hamsters and mice with roflumilast to evaluate its carcinogenic potential. In 2-year oral gavage carcinogenicity studies, roflumilast treatment resulted in dose-related, statistically significant increases in the incidence of undifferentiated carcinomas of nasal epithelium in hamsters at ≥ 8 mg/kg/day (approximately 11 times the MRHD based on summed AUCs of roflumilast and its metabolites). The tumorigenicity of roflumilast appears to be attributed to a reactive metabolite of 4-amino-3,5-dichloro-pyridine N-oxide (ADCP N-oxide). No evidence of tumorigenicity was observed in mice at roflumilast oral doses up to 12 and 18 mg/kg/day in females and males, respectively (approximately 10 and 15 times the MRHD, respectively, based on summed AUCs of roflumilast and its metabolites).
- Roflumilast tested positive in an in vivo mouse micronucleus test, but negative in the following assays: Ames test for bacterial gene mutation, in vitro chromosome aberration assay in human lymphocytes, in vitro HPRT test with V79 cells, an in vitro micronucleus test with V79 cells, DNA adduct formation assay in rat nasal mucosa, liver and testes, and in vivo mouse bone marrow chromosome aberration assay. Roflumilast N-oxide was negative in the Ames test and in vitro micronucleus test with V79 cells.
- In a human spermatogenesis study, roflumilast 500 mcg had no effects on semen parameters or reproductive hormones during the 3-month treatment period and the following 3-month off-treatment period. In a fertility study, roflumilast decreased fertility rates in male rats at 1.8-mg/kg/day (approximately 29 times the MRHD on a mg/m2 basis). These rats also showed increases in the incidence of tubular atrophy, degeneration in the testis and spermiogenic granuloma in the epididymides. No effect on male rat fertility rate or reproductive organ morphology was observed at 0.8 mg/kg/day (approximately 13 times the MRHD on a mg/m2 basis). No effect on female fertility was observed up to the highest roflumilast dose of 1.5 mg/kg/day in rats (approximately 24 times the MRHD on a mg/m2 basis).
# Clinical Studies
Chronic Obstructive Pulmonary Disease (COPD)
- The efficacy and safety of roflumilast (roflumilast) in COPD was evaluated in 8 randomized double-blind, controlled, parallel group clinical trials in 9394 adult patients (4425 receiving roflumilast 500 mcg) 40 years of age and older with COPD. Of the 8 trials, two were placebo-controlled dose selection trials (Trials 1 and 2) of 6 months duration that evaluated the efficacy of roflumilast 250 mcg and 500 mcg once daily, four were placebo-controlled 1-year trials (Trials 3, 4, 5, and 6) primarily designed to evaluate the efficacy of roflumilast on COPD exacerbations, and two were 6-month efficacy trials (Trials 7 and 8) which assessed the effect of roflumilast as add-on therapy to a long-acting beta agonist or long-acting anti-muscarinic. The 8 trials enrolled patients with nonreversible obstructive lung disease (FEV1/FVC ≤ 70% and ≤ 12% or 200 mL improvement in FEV1 in response to 4 puffs of albuterol/salbutamol) but the severity of airflow obstruction at baseline was different among the trials. Patients enrolled in the dose selection trials had the full range of COPD severity (FEV1 30-80% predicted); median age of 63 years, 73% male, and 99% Caucasian. Patients enrolled in the four exacerbation trials had severe COPD (FEV1 ≤ 50% predicted); median age of 64 years, 74% male, and 90% Caucasian. Patients enrolled in the two 6-month efficacy trials had moderate to severe COPD (FEV1 40-70% predicted); median age of 65 years, 68% male, and 97% Caucasian. COPD exacerbations and lung function (FEV1) were co-primary efficacy outcome measures in the four 1-year trials. In the two 6-month supportive efficacy trials, lung function (FEV1) alone was the primary efficacy outcome measure.
- The two 6-month dose-selection efficacy trials (Trials 1 and 2) explored doses of 250 mcg and 500 mcg once daily in a total of 1929 patients (751 and 724 on roflumilast 250 and 500 mcg, respectively). The selection of the 500 mcg dose was primarily based on nominal improvements in lung function (FEV1) over the 250 mcg dose. The once daily dosing regimen was primarily based on the determination of a plasma half-life of 17 hours for roflumilast and 30 hours for its active metabolite roflumilast N-oxide.
'Effect on Exacerbations'
- The effect of roflumilast 500 mcg once daily on COPD exacerbations was evaluated in four 1-year trials (Trials 3, 4, 5, and 6).
- Two of the trials (Trials 3 and 4) conducted initially enrolled a population of patients with severe COPD (FEV1 ≤ 50% of predicted) inclusive of those with chronic bronchitis and/or emphysema who had a history of smoking of at least 10 pack years. Inhaled corticosteroids were allowed as concomitant medications and used in 61% of both roflumilast and placebo-treated patients and short-acting beta agonists were allowed as rescue therapy. The use of long-acting beta agonists, long-acting anti-muscarinics, and theophylline were prohibited. The rate of moderate or severe COPD exacerbations was a co-primary endpoint in both trials. There was not a symptomatic definition of exacerbation in these 2 trials. Exacerbations were defined in terms of severity requiring treatment with a moderate exacerbation defined as treatment with systemic glucocorticosteroids in Trial 3 or systemic glucocorticosteroids and/or antibiotics in Trial 4 and a severe exacerbation defined as requiring hospitalizations and/or leading to death in Trial 3 or requiring hospitalization in Trial 4. The trials randomized 1176 patients (567 on roflumilast) in Trial 3 and 1514 patients (760 on roflumilast) in Trial 4. Both trials failed to demonstrate a significant reduction in the rate of COPD exacerbations.
- Exploratory analyses of the results of Trials 3 and 4 identified a subpopulation of patients with severe COPD associated with chronic bronchitis and COPD exacerbations within the previous year that appeared to demonstrate a better response in the reduction of the rate of COPD exacerbations compared to the overall population. As a result, two subsequent trials (Trial 5 and Trial 6) were conducted that enrolled patients with severe COPD but associated with chronic bronchitis, at least one COPD exacerbation in the previous year, and at least a 20 pack-year smoking history. In these trials, long-acting beta agonists and short-acting anti-muscarinics were allowed and were used by 44% and 35% of patients treated with roflumilast and 45% and 37% of patients treated with placebo, respectively. The use of inhaled corticosteroids was prohibited. As in trials 3 and 4, the rate of moderate exacerbations (defined as requiring intervention with systemic glucocorticosteroids) or severe exacerbations (defined as leading to hospitalization and/or to death) was a co-primary endpoint.
- Trial 5 randomized a total of 1525 patients (765 on roflumilast) and Trial 6 randomized a total of 1571 patients (772 on roflumilast). In both trials, roflumilast 500 mcg once daily demonstrated a significant reduction in the rate of moderate or severe exacerbations compared to placebo (TABLE 2). These two trials provide the evidence to support the use of roflumilast for the reduction of COPD exacerbations.
- For patients in Trials 5 and 6 who received concomitant long-acting beta agonists or short-acting anti-muscarinics, reduction of moderate or severe exacerbations with roflumilast was similar to that observed for the overall populations of the two trials.
'Effect on Lung Function'
- While roflumilast is not a bronchodilator, all 1-year trials (Trials 3, 4, 5, and 6) evaluated the effect of roflumilast on lung function as determined by the difference in FEV1 between roflumilast and placebo-treated patients (pre-bronchodilator FEV1 measured prior to study drug administration in three of the trials and post-bronchodilator FEV1 measured 30 minutes after administration of 4 puffs of albuterol/salbutamol in one trial) as a co-primary endpoint. In each of these trials roflumilast 500 mcg once daily demonstrated a statistically significant improvement in FEV1 which averaged approximately 50 mL across the four trials. TABLE 3 shows FEV1 results from Trials 5 and 6 which had demonstrated a significant reduction in COPD exacerbations.
- Lung function was also evaluated in two 6-month trials (Trials 7 and 8) to assess the effect of roflumilast when administered as add-on therapy to treatment with a long-acting beta agonist or a long-acting anti-muscarinic. These trials were conducted in a different population of COPD patients [moderate to severe COPD (FEV1 40 to 70% of predicted) without a requirement for chronic bronchitis or frequent history of exacerbations] from that for which efficacy in reduction of exacerbations has been demonstrated and provide safety support to the roflumilast COPD program.
- No trials have been conducted to assess the effects of roflumilast on COPD exacerbations when added to a fixed-dose combination product containing a long-acting beta agonist and inhaled corticosteroid.
# How Supplied
- Roflumilast is supplied as white to off-white, round tablets, embossed with “D” on one side and “500” on the other side. Each tablet contains 500 mcg of roflumilast.
- DALIRESP tablets are available:
- Bottles of 30: NDC 0456-0095-30
- Bottles of 90: NDC 0456-0095-90
- 10X10 Unit Dose: NDC 0456-0095-63
## Storage
- Store DALIRESP 500 mcg tablets at 20° - 25°C (68° - 77°F); excursions permitted to 15° - 30°C (59° - 86°F). [See USP Controlled Room Temperature].
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Bronchospasm
- Roflumilast is not a bronchodilator and should not be used for the relief of acute bronchospasm.
Psychiatric Events including Suicidality
- Treatment with roflumilast is associated with an increase in psychiatric adverse reactions. In clinical trials, 5.9% (263) of patients treated with roflumilast 500 mcg daily reported psychiatric adverse reactions compared to 3.3% (137) treated with placebo. The most commonly reported psychiatric adverse events were insomnia, anxiety, and depression which were reported at higher rates in those treated with roflumilast 500 mcg (2.4%, 1.4%, and 1.2% for roflumilast versus 1.0%, 0.9%, and 0.9% for placebo, respectively). Instances of suicidal ideation and behavior, including completed suicide, have been observed in clinical trials. Three patients experienced suicide-related adverse reactions (one completed suicide and two suicide attempts) while receiving roflumilast compared to one patient (suicidal ideation) who received placebo. Cases of suicidal ideation and behavior, including completed suicide, have been observed in the post-marketing setting in patients with or without a history of depression.
- Before using roflumilast in patients with a history of depression and/or suicidal thoughts or behavior, prescribers should carefully weigh the risks and benefits of treatment with roflumilast in such patients. Patients, their caregivers, and families should be advised of the need to be alert for the emergence or worsening of insomnia, anxiety, depression, suicidal thoughts or other mood changes, and if such changes occur to contact their healthcare provider. Prescribers should carefully evaluate the risks and benefits of continuing treatment with roflumilast if such events occur.
Weight Decrease
Weight loss was a common adverse reaction in roflumilast clinical trials and was reported in * * * 7.5% (331) of patients treated with roflumilast 500 mcg once daily compared to 2.1% (89) treated with placebo. In two placebo-controlled clinical trials of one year duration in which weight was prospectively assessed, 20% of patients receiving roflumilast experienced moderate weight loss (defined as between 5-10% of body weight) compared to 7% of patients who received placebo and 7% of patients who received roflumilast compared to 2% of patients receiving placebo experienced severe (>10% body weight) weight loss. During follow-up after treatment discontinuation, the majority of patients with weight loss regained some of the weight they had lost while receiving roflumilast. Patients treated with roflumilast should have their weight monitored regularly. If unexplained or clinically significant weight loss occurs, weight loss should be evaluated, and discontinuation of roflumilast should be considered .
Drug Interactions
- The administration of the cytochrome P450 enzyme inducer rifampicin resulted in a reduction in exposure which may result in a decrease in the therapeutic effectiveness of roflumilast. Therefore, the use of strong cytochrome P450 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) with roflumilast is not recommended.
## Medication Guide
# Precautions with Alcohol
- Alcohol-Roflumilast interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- DALIRESP
# Look-Alike Drug Names
There is limited information regarding Roflumilast Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Roflumilast | |
f796e40f501153adfc9d86bf842b5bb03e492a8a | wikidoc | Romiplostim | Romiplostim
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# Overview
Romiplostim is a Thrombopoietin Receptor Agonist that is FDA approved for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. Common adverse reactions include abdominal pain, diarrhea, indigestion, nausea, arthralgia, backache, myalgia, pain in limb, dizziness, headache, insomnia, paresthesia, epistaxis, upper respiratory infection, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Romiplostim is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy.
- Romiplostim is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP.
- Romiplostim should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding .
- Romiplostim should not be used in an attempt to normalize platelet counts .
- Use the lowest dose of Romiplostim to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding. Administer Romiplostim as a weekly subcutaneous injection with dose adjustments based upon the platelet count response.
- The prescribed Romiplostim dose may consist of a very small volume (eg, 0.15 mL). Administer Romiplostim only with a syringe that contains 0.01 mL graduations.
- The initial dose for Romiplostim is 1 mcg/kg based on actual body weight.
- Use the actual body weight at initiation of therapy, then adjust the weekly dose of Romiplostim by increments of 1 mcg/kg until the patient achieves a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding; do not exceed a maximum weekly dose of 10 mcg/kg. In clinical studies, most patients who responded to Romiplostim achieved and maintained platelet counts ≥ 50 x 109/L with a median dose of 2 mcg/kg.
- During Romiplostim therapy, assess CBC, including platelet counts, weekly until a stable platelet count (≥ 50 x 109/L for at least 4 weeks without dose adjustment) has been achieved. Obtain CBC, including platelet counts, monthly thereafter.
- Adjust the dose as follows:
- If the platelet count is < 50 x 109/L, increase the dose by 1 mcg/kg.
- If platelet count is > 200 x 109/L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
- If platelet count is > 400 x 109/L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to < 200 x 109/L, resume Romiplostim at a dose reduced by 1 mcg/kg.
- Discontinue Romiplostim if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of Romiplostim therapy at the maximum weekly dose of 10 mcg/kg . Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Romiplostim .
- To mitigate against medication errors (both overdose and underdose), ensure that these preparation and administration instructions are followed.
- Calculate the dose and reconstitute with the correct volume of sterile water for injection. Withdraw the appropriate volume of the calculated dose from the vial. Only administer subcutaneously .
- Romiplostim is supplied in single-use vials as a sterile, preservative-free, white lyophilized powder that must be reconstituted as outlined in Table 1 and administered using a syringe with 0.01 mL graduations. Using aseptic technique, reconstitute Romiplostim with preservative-free Sterile Water for Injection, USP as described in Table 1. Do not use bacteriostatic water for injection.
- Gently swirl and invert the vial to reconstitute. Avoid excess or vigorous agitation: DO NOT SHAKE.Generally, dissolution of Romiplostim takes less than 2 minutes. The reconstituted Romiplostim solution should be clear and colorless. Visually inspect the reconstituted solution for particulate matter and/or discoloration. Do not administer Romiplostim if particulate matter and/or discoloration is observed.
- Reconstituted Romiplostim can be kept at room temperature (25°C/77°F) or refrigerated at 2° to 8°C (36° to 46°F) for up to 24 hours prior to administration. Protect the reconstituted product from light.
- To determine the injection volume to be administered, first identify the patient’s total dose in micrograms (mcg) using the dosing information . For example, a 75 kg patient initiating therapy at 1 mcg/kg will begin with a dose of 75 mcg. Next, calculate the volume of Romiplostim solution that is given to the patient by dividing the microgram dose by the concentration of the reconstituted Romiplostim solution (500 mcg/mL). For this patient example, the 75 mcg dose is divided by 500 mcg/mL, resulting in an injection volume of 0.15 mL.
- As the injection volume may be very small, use a syringe with graduations to 0.01 mL. Verify that the syringe contains the correct dosage.
- Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than one dose from a vial.
- Romiplostim may be used with other medical ITP therapies, such as corticosteroids, danazol, azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin. If the patient’s platelet count is ≥ 50 x 109/L, medical ITP therapies may be reduced or discontinued
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Romiplostim in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Romiplostim in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Romiplostim in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Romiplostim in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Romiplostim in pediatric patients.
# Contraindications
- None
# Warnings
- Progression from myelodysplastic syndromes (MDS) to acute myelogenous leukemia (AML) has been observed in clinical trials with Romiplostim. A randomized, double-blind, placebo-controlled trial enrolling patients with severe thrombocytopenia and International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS was terminated due to more cases of AML observed in the Romiplostim treatment arm. At the time of an interim analysis, among 219 MDS patients randomized 2:1 to treatment with Romiplostim or placebo (147 Romiplostim: 72 placebo), 11 patients showed progression to AML, including nine on the Romiplostim arm versus two on the placebo arm. In addition, in peripheral blood counts, the percentage of circulating myeloblasts increased to greater than 10% in 28 patients, 25 of whom were in the romiplostim treatment arm. Of the 28 patients who had an increase in circulating myeloblasts to greater than 10%, eight of these patients were diagnosed to have AML and 20 patients had not progressed to AML. In four patients, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Romiplostim. In a single-arm trial of Romiplostim given to 72 patients with thrombocytopenia related to MDS, eight (11%) patients were reported as having possible disease progression, and three patients had confirmation of AML during follow-up. In addition, in three patients, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Romiplostim.
- Romiplostim is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
- Thrombotic/thromboembolic complications may result from increases in platelet counts with Romiplostim use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Romiplostim. Romiplostim should be used with caution in patients with ITP and chronic liver disease.
- To minimize the risk for thrombotic/thromboembolic complications, do not use Romiplostim in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of ≥ 50 x 109/L .
- Romiplostim administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of Romiplostim. In a clinical trial, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Romiplostim therapy. Clinical trials are in progress to assess the risk of bone marrow fibrosis and clinical consequences with cytopenias.
- If new or worsening morphological abnormalities or cytopenia(s) occur, consider a bone marrow biopsy to include staining for fibrosis .
- In clinical studies of patients with chronic ITP who had Romiplostim discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Romiplostim therapy. This worsened thrombocytopenia resolved within 14 days. Following discontinuation of Romiplostim, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines .
- Hyporesponsiveness or failure to maintain a platelet response with Romiplostim should prompt a search for causative factors, including neutralizing antibodies to Romiplostim. To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Romiplostim and thrombopoietin (TPO). Discontinue Romiplostim if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg.
# Adverse Reactions
## Clinical Trials Experience
- Serious adverse reactions associated with Romiplostim in ITP clinical studies were bone marrow reticulin deposition and worsening thrombocytopenia after Romiplostim discontinuation
- The data described below reflect Romiplostim exposure to 271 patients with chronic ITP, aged 18 to 88, of whom 62% were female. Romiplostim was studied in two randomized, placebo-controlled, double-blind studies that were identical in design, with the exception that Study 1 evaluated nonsplenectomized patients with ITP and Study 2 evaluated splenectomized patients with ITP. Data are also reported from an open-label, single-arm study in which patients received Romiplostim over an extended period of time. Overall, Romiplostim was administered to 114 patients for at least 52 weeks and 53 patients for at least 96 weeks.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Romiplostim and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity. Table 2 presents adverse drug reactions from Studies 1 and 2 with a ≥ 5% higher patient incidence in Romiplostim versus placebo. The majority of these adverse drug reactions were mild to moderate in severity.
- Among 142 patients with chronic ITP who received Romiplostim in the single-arm extension study, the incidence rates of the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of Romiplostim. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Erythromelalgia
- Hypersensitivity
- Angioedema
- As with all therapeutic proteins, patients may develop antibodies to the therapeutic protein. Patients were screened for immunogenicity to romiplostim using a BIAcore-based biosensor immunoassay. This assay is capable of detecting both high- and low-affinity binding antibodies that bind to romiplostim and cross-react with TPO. The samples from patients that tested positive for binding antibodies were further evaluated for neutralizing capacity using a cell-based bioassay.
- In clinical studies, the incidence of preexisting antibodies to romiplostim was 8% (43/537) and the incidence of binding antibody development during Romiplostim treatment was 6% (31/537). The incidence of preexisting antibodies to endogenous TPO was 5% (29/537) and the incidence of binding antibody development to endogenous TPO during Romiplostim treatment was 4% (21/537). Of the patients with positive binding antibodies that developed to romiplostim or to TPO, two (0.4%) patients had neutralizing activity to romiplostim and none had neutralizing activity to TPO. No correlation was observed between antibody activity and clinical effectiveness or safety.
- Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to romiplostim with the incidence of antibodies to other products may be misleading.
# Drug Interactions
- No formal drug interaction studies of Romiplostim have been performed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of Romiplostim use in pregnant women. In animal reproduction and developmental toxicity studies, romiplostim crossed the placenta, and adverse fetal effects included thrombocytosis, postimplantation loss, and an increase in pup mortality. Romiplostim should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
- Pregnancy Registry: A pregnancy registry has been established to collect information about the effects of Romiplostim use during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the Romiplostim pregnancy registry by calling 1-800-77-AMGEN (1-800-772-6436).
- In rat and rabbit developmental toxicity studies, no evidence of fetal harm was observed at romiplostim doses up to 11 times (rats) and 82 times (rabbits) the maximum human dose (MHD) based on systemic exposure. In mice at doses 5 times the MHD, reductions in maternal body weight and increased postimplantation loss occurred.
- In a prenatal and postnatal development study in rats, at doses 11 times the MHD, there was an increase in perinatal pup mortality. Romiplostim crossed the placental barrier in rats and increased fetal platelet counts at clinically equivalent and higher doses.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Romiplostim in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Romiplostim during labor and delivery.
### Nursing Mothers
- It is not known whether Romiplostim is excreted in human milk; however, human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Romiplostim, a decision should be made whether to discontinue nursing or to discontinue Romiplostim, taking into account the importance of Romiplostim to the mother and the known benefits of nursing.
### Pediatric Use
- The safety and effectiveness in pediatric patients (<18 years) have not been established.
### Geriatic Use
- Of the 271 patients who received Romiplostim in ITP clinical studies, 55 (20%) were age 65 and over, and 27 (10%) were 75 and over. No overall differences in safety or efficacy have been observed between older and younger patients in the placebo-controlled studies, but greater sensitivity of some older individuals cannot be ruled out. In general, dose adjustment for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Romiplostim with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Romiplostim with respect to specific racial populations.
### Renal Impairment
- No clinical studies were conducted in patients with renal impairment. Use Romiplostim with caution in this population.
### Hepatic Impairment
- No clinical studies were conducted in patients with hepatic impairment. Use Romiplostim with caution in this population.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Romiplostim in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Romiplostim in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
- Obtain CBCs, including platelet counts, weekly during the dose-adjustment phase of Romiplostim therapy and then monthly following establishment of a stable Romiplostim dose.
- Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Romiplostim
# IV Compatibility
There is limited information regarding IV Compatibility of Romiplostim in the drug label.
# Overdosage
- Overdoses due to medication errors have been reported in patients receiving Romiplostim. In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In this case, discontinue Romiplostim and monitor platelet counts. Reinitiate treatment with Romiplostim in accordance with dosing and administration recommendations
# Pharmacology
## Mechanism of Action
- Romiplostim increases platelet production through binding and activation of the TPO receptor, a mechanism analogous to endogenous TPO.
## Structure
- Romiplostim, a member of the TPO mimetic class, is an Fc-peptide fusion protein (peptibody) that activates intracellular transcriptional pathways leading to increased platelet production via the TPO receptor (also known as cMpl). The peptibody molecule contains two identical single-chain subunits, each consisting of human immunoglobulin IgG1 Fc domain, covalently linked at the C-terminus to a peptide containing two thrombopoietin receptor-binding domains. Romiplostim has no amino acid sequence homology to endogenous TPO. Romiplostim is produced by recombinant DNA technology in Escherichia coli (E coli).
- Romiplostim is supplied as a sterile, preservative-free, lyophilized, solid white powder for subcutaneous injection. Two vial presentations are available, which contain a sufficient amount of active ingredient to provide either 250 mcg or 500 mcg of deliverable romiplostim, respectively. Each single-use 250 mcg vial of Romiplostim contains the following: 375 mcg romiplostim, 30 mg mannitol, 15 mg sucrose, 1.2 mg L-histidine, 0.03 mg polysorbate 20, and sufficient HCl to adjust the pH to a target of 5.0. Each single-use 500 mcg vial of Romiplostim contains the following: 625 mcg romiplostim, 50 mg mannitol, 25 mg sucrose, 1.9 mg L-histidine, 0.05 mg polysorbate 20, and sufficient HCl to adjust the pH to a target of 5.0
## Pharmacodynamics
- In clinical studies, treatment with Romiplostim resulted in dose-dependent increases in platelet counts. After a single subcutaneous dose of 1 to 10 mcg/kg Romiplostim in patients with chronic ITP, the peak platelet count was 1.3 to 14.9 times greater than the baseline platelet count over a 2- to 3-week period. The platelet counts were above 50 x 109/L for seven out of eight patients with chronic ITP who received six weekly doses of Romiplostim at 1 mcg/kg.
## Pharmacokinetics
- In the long-term extension study in patients with ITP receiving weekly treatment of Romiplostim subcutaneously, the pharmacokinetics of romiplostim over the dose range of 3 to 15 mcg/kg indicated that peak serum concentrations of romiplostim were observed about 7 to 50 hours post dose (median: 14 hours) with half-life values ranging from 1 to 34 days (median: 3.5 days). The serum concentrations varied among patients and did not correlate with the dose administered. The elimination of serum romiplostim is in part dependent on the TPO receptor on platelets. As a result, for a given dose, patients with high platelet counts are associated with low serum concentrations and vice versa. In another ITP clinical study, no accumulation in serum concentrations was observed (n = 4) after six weekly doses of Romiplostim (3 mcg/kg). The accumulation at higher doses of romiplostim is unknown.
## Nonclinical Toxicology
- The carcinogenic potential of romiplostim has not been evaluated. The mutagenic potential of romiplostim has not been evaluated. Romiplostim had no effect on the fertility of rats at doses up to 37 times the MHD based on systemic exposure.
- In a 4-week repeat-dose toxicity study in which rats were dosed subcutaneously three times per week, romiplostim caused extramedullary hematopoiesis, bone hyperostosis, and marrow fibrosis at clinically equivalent and higher doses. In this study, these findings were not observed in animals after a 4-week post treatment recovery period. Studies of long-term treatment with romiplostim in rats have not been conducted; therefore, it is not known if the fibrosis of the bone marrow is reversible in rats after long-term treatment.
# Clinical Studies
- The safety and efficacy of Romiplostim were assessed in two double-blind, placebo-controlled clinical studies and in an open-label extension study.
- In Studies 1 and 2, patients with chronic ITP who had completed at least one prior treatment and had a platelet count of ≤ 30 x 109/L prior to study entry were randomized (2:1) to 24 weeks of Romiplostim (1 mcg/kg subcutaneous ) or placebo. Prior ITP treatments in both study groups included corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine. Patients already receiving ITP medical therapies at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the studies. Rescue therapies (ie, corticosteroids, IVIG, platelet transfusions, and anti-D immunoglobulin) were permitted for bleeding, wet purpura, or if the patient was at immediate risk for hemorrhage. Patients received single weekly SC injections of Romiplostim, with individual dose adjustments to maintain platelet counts (50 x 109/L to 200 x 109/L).
- Study 1 evaluated patients who had not undergone a splenectomy. The patients had been diagnosed with ITP for approximately 2 years and had received a median of three prior ITP treatments. Overall, the median platelet count was 19 x 109/L at study entry. During the study, the median weekly Romiplostim dose was 2 mcg/kg (25th–75th percentile: 1–3 mcg/kg).
- Study 2 evaluated patients who had undergone a splenectomy. The patients had been diagnosed with ITP for approximately 8 years and had received a median of six prior ITP treatments. Overall, the median platelet count was 14 x 109/L at study entry. During the study, the median weekly Romiplostim dose was 3 mcg/kg (25th–75th percentile: 2–7 mcg/kg).
- Study 1 and 2 outcomes are shown in Table 3. A durable platelet response was the achievement of a weekly platelet count ≥ 50 x 109/L for any 6 of the last 8 weeks of the 24-week treatment period in the absence of rescue medication at any time. A transient platelet response was the achievement of any weekly platelet counts ≥ 50 x 109/L for any 4 weeks during the treatment period without a durable platelet response. An overall platelet response was the achievement of either a durable or a transient platelet response. Platelet responses were excluded for 8 weeks after receiving rescue medications.
- In Studies 1 and 2, nine patients reported a serious bleeding event . Bleeding events that were grade 2 severity or higher occurred in 15% of patients treated with Romiplostim and 34% of patients treated with placebo.
- Patients who had participated in either Study 1 or Study 2 were withdrawn from study medications. If platelet counts subsequently decreased to ≤ 50 x 109/L, the patients were allowed to receive Romiplostim in an open-label extension study with weekly dosing based on platelet counts. Following Romiplostim discontinuation in Studies 1 and 2, seven patients maintained platelet counts of ≥ 50 x 109/L. Among 100 patients who subsequently entered the extension study, platelet counts were increased and sustained regardless of whether they had received Romiplostim or placebo in the prior placebo-controlled studies. The majority of patients reached a median platelet count of 50 x 109/L after receiving one to three doses of Romiplostim, and these platelet counts were maintained throughout the remainder of the study with a median duration of Romiplostim treatment of 60 weeks and a maximum duration of 96 weeks.
# How Supplied
- Romiplostim is supplied in single-use vials containing 250 mcg (NDC 55513-221-01) and 500 mcg (NDC 55513-222-01) deliverable romiplostim.
## Storage
- Store Romiplostim vials in their carton to protect from light until time of use. Keep Romiplostim vials refrigerated at 2° to 8°C (36° to 46°F). Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Prior to treatment, patients should fully understand the risks and benefits of Romiplostim. Inform patients that the risks associated with long-term administration of Romiplostim are unknown.
- Inform patients of the following risks and considerations for Romiplostim:
- Romiplostim therapy is administered to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding; Romiplostim is not used to normalize platelet counts.
- Following discontinuation of Romiplostim, thrombocytopenia and risk of bleeding may develop that is worse than that experienced prior to the Romiplostim therapy.
- Romiplostim therapy may increase the risk of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation. Detection of peripheral blood cell abnormalities may necessitate a bone marrow examination.
- Too much Romiplostim may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.
- Romiplostim stimulates certain bone marrow cells to make platelets and increases the risk of progression to acute myelogenous leukemia in patients with myelodysplastic syndromes.
- Platelet counts and CBCs must be performed weekly until a stable Romiplostim dose has been achieved; thereafter, platelet counts and CBCs, must be performed monthly while taking Romiplostim.
- Patients must be closely monitored with weekly platelet counts and CBCs for at least 2 weeks following Romiplostim discontinuation.
- Even with Romiplostim therapy, patients should continue to avoid situations or medications that may increase the risk for bleeding.
# Precautions with Alcohol
- Alcohol-Romiplostim interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Nplate
# Look-Alike Drug Names
- romiPLOStim - romiDEPsin
# Drug Shortage Status
# Price | Romiplostim
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Overview
Romiplostim is a Thrombopoietin Receptor Agonist that is FDA approved for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy. Common adverse reactions include abdominal pain, diarrhea, indigestion, nausea, arthralgia, backache, myalgia, pain in limb, dizziness, headache, insomnia, paresthesia, epistaxis, upper respiratory infection, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Romiplostim is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins or splenectomy.
- Romiplostim is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP.
- Romiplostim should be used only in patients with ITP whose degree of thrombocytopenia and clinical condition increases the risk for bleeding .
- Romiplostim should not be used in an attempt to normalize platelet counts .
- Use the lowest dose of Romiplostim to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding. Administer Romiplostim as a weekly subcutaneous injection with dose adjustments based upon the platelet count response.
- The prescribed Romiplostim dose may consist of a very small volume (eg, 0.15 mL). Administer Romiplostim only with a syringe that contains 0.01 mL graduations.
- The initial dose for Romiplostim is 1 mcg/kg based on actual body weight.
- Use the actual body weight at initiation of therapy, then adjust the weekly dose of Romiplostim by increments of 1 mcg/kg until the patient achieves a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding; do not exceed a maximum weekly dose of 10 mcg/kg. In clinical studies, most patients who responded to Romiplostim achieved and maintained platelet counts ≥ 50 x 109/L with a median dose of 2 mcg/kg.
- During Romiplostim therapy, assess CBC, including platelet counts, weekly until a stable platelet count (≥ 50 x 109/L for at least 4 weeks without dose adjustment) has been achieved. Obtain CBC, including platelet counts, monthly thereafter.
- Adjust the dose as follows:
- If the platelet count is < 50 x 109/L, increase the dose by 1 mcg/kg.
- If platelet count is > 200 x 109/L for 2 consecutive weeks, reduce the dose by 1 mcg/kg.
- If platelet count is > 400 x 109/L, do not dose. Continue to assess the platelet count weekly. After the platelet count has fallen to < 200 x 109/L, resume Romiplostim at a dose reduced by 1 mcg/kg.
- Discontinue Romiplostim if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks of Romiplostim therapy at the maximum weekly dose of 10 mcg/kg . Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Romiplostim .
- To mitigate against medication errors (both overdose and underdose), ensure that these preparation and administration instructions are followed.
- Calculate the dose and reconstitute with the correct volume of sterile water for injection. Withdraw the appropriate volume of the calculated dose from the vial. Only administer subcutaneously .
- Romiplostim is supplied in single-use vials as a sterile, preservative-free, white lyophilized powder that must be reconstituted as outlined in Table 1 and administered using a syringe with 0.01 mL graduations. Using aseptic technique, reconstitute Romiplostim with preservative-free Sterile Water for Injection, USP as described in Table 1. Do not use bacteriostatic water for injection.
- Gently swirl and invert the vial to reconstitute. Avoid excess or vigorous agitation: DO NOT SHAKE.Generally, dissolution of Romiplostim takes less than 2 minutes. The reconstituted Romiplostim solution should be clear and colorless. Visually inspect the reconstituted solution for particulate matter and/or discoloration. Do not administer Romiplostim if particulate matter and/or discoloration is observed.
- Reconstituted Romiplostim can be kept at room temperature (25°C/77°F) or refrigerated at 2° to 8°C (36° to 46°F) for up to 24 hours prior to administration. Protect the reconstituted product from light.
- To determine the injection volume to be administered, first identify the patient’s total dose in micrograms (mcg) using the dosing information . For example, a 75 kg patient initiating therapy at 1 mcg/kg will begin with a dose of 75 mcg. Next, calculate the volume of Romiplostim solution that is given to the patient by dividing the microgram dose by the concentration of the reconstituted Romiplostim solution (500 mcg/mL). For this patient example, the 75 mcg dose is divided by 500 mcg/mL, resulting in an injection volume of 0.15 mL.
- As the injection volume may be very small, use a syringe with graduations to 0.01 mL. Verify that the syringe contains the correct dosage.
- Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than one dose from a vial.
- Romiplostim may be used with other medical ITP therapies, such as corticosteroids, danazol, azathioprine, intravenous immunoglobulin (IVIG), and anti-D immunoglobulin. If the patient’s platelet count is ≥ 50 x 109/L, medical ITP therapies may be reduced or discontinued
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Romiplostim in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Romiplostim in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Romiplostim in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Romiplostim in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Romiplostim in pediatric patients.
# Contraindications
- None
# Warnings
- Progression from myelodysplastic syndromes (MDS) to acute myelogenous leukemia (AML) has been observed in clinical trials with Romiplostim. A randomized, double-blind, placebo-controlled trial enrolling patients with severe thrombocytopenia and International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS was terminated due to more cases of AML observed in the Romiplostim treatment arm. At the time of an interim analysis, among 219 MDS patients randomized 2:1 to treatment with Romiplostim or placebo (147 Romiplostim: 72 placebo), 11 patients showed progression to AML, including nine on the Romiplostim arm versus two on the placebo arm. In addition, in peripheral blood counts, the percentage of circulating myeloblasts increased to greater than 10% in 28 patients, 25 of whom were in the romiplostim treatment arm. Of the 28 patients who had an increase in circulating myeloblasts to greater than 10%, eight of these patients were diagnosed to have AML and 20 patients had not progressed to AML. In four patients, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Romiplostim. In a single-arm trial of Romiplostim given to 72 patients with thrombocytopenia related to MDS, eight (11%) patients were reported as having possible disease progression, and three patients had confirmation of AML during follow-up. In addition, in three patients, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Romiplostim.
- Romiplostim is not indicated for the treatment of thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP.
- Thrombotic/thromboembolic complications may result from increases in platelet counts with Romiplostim use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Romiplostim. Romiplostim should be used with caution in patients with ITP and chronic liver disease.
- To minimize the risk for thrombotic/thromboembolic complications, do not use Romiplostim in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of ≥ 50 x 109/L .
- Romiplostim administration may increase the risk for development or progression of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation of Romiplostim. In a clinical trial, one patient with ITP and hemolytic anemia developed marrow fibrosis with collagen during Romiplostim therapy. Clinical trials are in progress to assess the risk of bone marrow fibrosis and clinical consequences with cytopenias.
- If new or worsening morphological abnormalities or cytopenia(s) occur, consider a bone marrow biopsy to include staining for fibrosis .
- In clinical studies of patients with chronic ITP who had Romiplostim discontinued, four of 57 patients developed thrombocytopenia of greater severity than was present prior to Romiplostim therapy. This worsened thrombocytopenia resolved within 14 days. Following discontinuation of Romiplostim, obtain weekly CBCs, including platelet counts, for at least 2 weeks and consider alternative treatments for worsening thrombocytopenia, according to current treatment guidelines .
- Hyporesponsiveness or failure to maintain a platelet response with Romiplostim should prompt a search for causative factors, including neutralizing antibodies to Romiplostim. To detect antibody formation, submit blood samples to Amgen (1-800-772-6436). Amgen will assay these samples for antibodies to Romiplostim and thrombopoietin (TPO). Discontinue Romiplostim if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 mcg/kg.
# Adverse Reactions
## Clinical Trials Experience
- Serious adverse reactions associated with Romiplostim in ITP clinical studies were bone marrow reticulin deposition and worsening thrombocytopenia after Romiplostim discontinuation
- The data described below reflect Romiplostim exposure to 271 patients with chronic ITP, aged 18 to 88, of whom 62% were female. Romiplostim was studied in two randomized, placebo-controlled, double-blind studies that were identical in design, with the exception that Study 1 evaluated nonsplenectomized patients with ITP and Study 2 evaluated splenectomized patients with ITP. Data are also reported from an open-label, single-arm study in which patients received Romiplostim over an extended period of time. Overall, Romiplostim was administered to 114 patients for at least 52 weeks and 53 patients for at least 96 weeks.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- In the placebo-controlled studies, headache was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Romiplostim and 32% of patients receiving placebo. Headaches were usually of mild or moderate severity. Table 2 presents adverse drug reactions from Studies 1 and 2 with a ≥ 5% higher patient incidence in Romiplostim versus placebo. The majority of these adverse drug reactions were mild to moderate in severity.
- Among 142 patients with chronic ITP who received Romiplostim in the single-arm extension study, the incidence rates of the adverse reactions occurred in a pattern similar to those reported in the placebo-controlled clinical studies.
## Postmarketing Experience
- The following adverse reactions have been identified during post approval use of Romiplostim. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Erythromelalgia
- Hypersensitivity
- Angioedema
- As with all therapeutic proteins, patients may develop antibodies to the therapeutic protein. Patients were screened for immunogenicity to romiplostim using a BIAcore-based biosensor immunoassay. This assay is capable of detecting both high- and low-affinity binding antibodies that bind to romiplostim and cross-react with TPO. The samples from patients that tested positive for binding antibodies were further evaluated for neutralizing capacity using a cell-based bioassay.
- In clinical studies, the incidence of preexisting antibodies to romiplostim was 8% (43/537) and the incidence of binding antibody development during Romiplostim treatment was 6% (31/537). The incidence of preexisting antibodies to endogenous TPO was 5% (29/537) and the incidence of binding antibody development to endogenous TPO during Romiplostim treatment was 4% (21/537). Of the patients with positive binding antibodies that developed to romiplostim or to TPO, two (0.4%) patients had neutralizing activity to romiplostim and none had neutralizing activity to TPO. No correlation was observed between antibody activity and clinical effectiveness or safety.
- Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to romiplostim with the incidence of antibodies to other products may be misleading.
# Drug Interactions
- No formal drug interaction studies of Romiplostim have been performed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies of Romiplostim use in pregnant women. In animal reproduction and developmental toxicity studies, romiplostim crossed the placenta, and adverse fetal effects included thrombocytosis, postimplantation loss, and an increase in pup mortality. Romiplostim should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus.
- Pregnancy Registry: A pregnancy registry has been established to collect information about the effects of Romiplostim use during pregnancy. Physicians are encouraged to register pregnant patients, or pregnant women may enroll themselves in the Romiplostim pregnancy registry by calling 1-800-77-AMGEN (1-800-772-6436).
- In rat and rabbit developmental toxicity studies, no evidence of fetal harm was observed at romiplostim doses up to 11 times (rats) and 82 times (rabbits) the maximum human dose (MHD) based on systemic exposure. In mice at doses 5 times the MHD, reductions in maternal body weight and increased postimplantation loss occurred.
- In a prenatal and postnatal development study in rats, at doses 11 times the MHD, there was an increase in perinatal pup mortality. Romiplostim crossed the placental barrier in rats and increased fetal platelet counts at clinically equivalent and higher doses.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Romiplostim in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Romiplostim during labor and delivery.
### Nursing Mothers
- It is not known whether Romiplostim is excreted in human milk; however, human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Romiplostim, a decision should be made whether to discontinue nursing or to discontinue Romiplostim, taking into account the importance of Romiplostim to the mother and the known benefits of nursing.
### Pediatric Use
- The safety and effectiveness in pediatric patients (<18 years) have not been established.
### Geriatic Use
- Of the 271 patients who received Romiplostim in ITP clinical studies, 55 (20%) were age 65 and over, and 27 (10%) were 75 and over. No overall differences in safety or efficacy have been observed between older and younger patients in the placebo-controlled studies, but greater sensitivity of some older individuals cannot be ruled out. In general, dose adjustment for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Romiplostim with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Romiplostim with respect to specific racial populations.
### Renal Impairment
- No clinical studies were conducted in patients with renal impairment. Use Romiplostim with caution in this population.
### Hepatic Impairment
- No clinical studies were conducted in patients with hepatic impairment. Use Romiplostim with caution in this population.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Romiplostim in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Romiplostim in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
- Obtain CBCs, including platelet counts, weekly during the dose-adjustment phase of Romiplostim therapy and then monthly following establishment of a stable Romiplostim dose.
- Obtain CBCs, including platelet counts, weekly for at least 2 weeks following discontinuation of Romiplostim
# IV Compatibility
There is limited information regarding IV Compatibility of Romiplostim in the drug label.
# Overdosage
- Overdoses due to medication errors have been reported in patients receiving Romiplostim. In the event of overdose, platelet counts may increase excessively and result in thrombotic/thromboembolic complications. In this case, discontinue Romiplostim and monitor platelet counts. Reinitiate treatment with Romiplostim in accordance with dosing and administration recommendations
# Pharmacology
## Mechanism of Action
- Romiplostim increases platelet production through binding and activation of the TPO receptor, a mechanism analogous to endogenous TPO.
## Structure
- Romiplostim, a member of the TPO mimetic class, is an Fc-peptide fusion protein (peptibody) that activates intracellular transcriptional pathways leading to increased platelet production via the TPO receptor (also known as cMpl). The peptibody molecule contains two identical single-chain subunits, each consisting of human immunoglobulin IgG1 Fc domain, covalently linked at the C-terminus to a peptide containing two thrombopoietin receptor-binding domains. Romiplostim has no amino acid sequence homology to endogenous TPO. Romiplostim is produced by recombinant DNA technology in Escherichia coli (E coli).
- Romiplostim is supplied as a sterile, preservative-free, lyophilized, solid white powder for subcutaneous injection. Two vial presentations are available, which contain a sufficient amount of active ingredient to provide either 250 mcg or 500 mcg of deliverable romiplostim, respectively. Each single-use 250 mcg vial of Romiplostim contains the following: 375 mcg romiplostim, 30 mg mannitol, 15 mg sucrose, 1.2 mg L-histidine, 0.03 mg polysorbate 20, and sufficient HCl to adjust the pH to a target of 5.0. Each single-use 500 mcg vial of Romiplostim contains the following: 625 mcg romiplostim, 50 mg mannitol, 25 mg sucrose, 1.9 mg L-histidine, 0.05 mg polysorbate 20, and sufficient HCl to adjust the pH to a target of 5.0
## Pharmacodynamics
- In clinical studies, treatment with Romiplostim resulted in dose-dependent increases in platelet counts. After a single subcutaneous dose of 1 to 10 mcg/kg Romiplostim in patients with chronic ITP, the peak platelet count was 1.3 to 14.9 times greater than the baseline platelet count over a 2- to 3-week period. The platelet counts were above 50 x 109/L for seven out of eight patients with chronic ITP who received six weekly doses of Romiplostim at 1 mcg/kg.
## Pharmacokinetics
- In the long-term extension study in patients with ITP receiving weekly treatment of Romiplostim subcutaneously, the pharmacokinetics of romiplostim over the dose range of 3 to 15 mcg/kg indicated that peak serum concentrations of romiplostim were observed about 7 to 50 hours post dose (median: 14 hours) with half-life values ranging from 1 to 34 days (median: 3.5 days). The serum concentrations varied among patients and did not correlate with the dose administered. The elimination of serum romiplostim is in part dependent on the TPO receptor on platelets. As a result, for a given dose, patients with high platelet counts are associated with low serum concentrations and vice versa. In another ITP clinical study, no accumulation in serum concentrations was observed (n = 4) after six weekly doses of Romiplostim (3 mcg/kg). The accumulation at higher doses of romiplostim is unknown.
## Nonclinical Toxicology
- The carcinogenic potential of romiplostim has not been evaluated. The mutagenic potential of romiplostim has not been evaluated. Romiplostim had no effect on the fertility of rats at doses up to 37 times the MHD based on systemic exposure.
- In a 4-week repeat-dose toxicity study in which rats were dosed subcutaneously three times per week, romiplostim caused extramedullary hematopoiesis, bone hyperostosis, and marrow fibrosis at clinically equivalent and higher doses. In this study, these findings were not observed in animals after a 4-week post treatment recovery period. Studies of long-term treatment with romiplostim in rats have not been conducted; therefore, it is not known if the fibrosis of the bone marrow is reversible in rats after long-term treatment.
# Clinical Studies
- The safety and efficacy of Romiplostim were assessed in two double-blind, placebo-controlled clinical studies and in an open-label extension study.
- In Studies 1 and 2, patients with chronic ITP who had completed at least one prior treatment and had a platelet count of ≤ 30 x 109/L prior to study entry were randomized (2:1) to 24 weeks of Romiplostim (1 mcg/kg subcutaneous [SC]) or placebo. Prior ITP treatments in both study groups included corticosteroids, immunoglobulins, rituximab, cytotoxic therapies, danazol, and azathioprine. Patients already receiving ITP medical therapies at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the studies. Rescue therapies (ie, corticosteroids, IVIG, platelet transfusions, and anti-D immunoglobulin) were permitted for bleeding, wet purpura, or if the patient was at immediate risk for hemorrhage. Patients received single weekly SC injections of Romiplostim, with individual dose adjustments to maintain platelet counts (50 x 109/L to 200 x 109/L).
- Study 1 evaluated patients who had not undergone a splenectomy. The patients had been diagnosed with ITP for approximately 2 years and had received a median of three prior ITP treatments. Overall, the median platelet count was 19 x 109/L at study entry. During the study, the median weekly Romiplostim dose was 2 mcg/kg (25th–75th percentile: 1–3 mcg/kg).
- Study 2 evaluated patients who had undergone a splenectomy. The patients had been diagnosed with ITP for approximately 8 years and had received a median of six prior ITP treatments. Overall, the median platelet count was 14 x 109/L at study entry. During the study, the median weekly Romiplostim dose was 3 mcg/kg (25th–75th percentile: 2–7 mcg/kg).
- Study 1 and 2 outcomes are shown in Table 3. A durable platelet response was the achievement of a weekly platelet count ≥ 50 x 109/L for any 6 of the last 8 weeks of the 24-week treatment period in the absence of rescue medication at any time. A transient platelet response was the achievement of any weekly platelet counts ≥ 50 x 109/L for any 4 weeks during the treatment period without a durable platelet response. An overall platelet response was the achievement of either a durable or a transient platelet response. Platelet responses were excluded for 8 weeks after receiving rescue medications.
- In Studies 1 and 2, nine patients reported a serious bleeding event [five (6%) Romiplostim, four (10%) placebo]. Bleeding events that were grade 2 severity or higher occurred in 15% of patients treated with Romiplostim and 34% of patients treated with placebo.
- Patients who had participated in either Study 1 or Study 2 were withdrawn from study medications. If platelet counts subsequently decreased to ≤ 50 x 109/L, the patients were allowed to receive Romiplostim in an open-label extension study with weekly dosing based on platelet counts. Following Romiplostim discontinuation in Studies 1 and 2, seven patients maintained platelet counts of ≥ 50 x 109/L. Among 100 patients who subsequently entered the extension study, platelet counts were increased and sustained regardless of whether they had received Romiplostim or placebo in the prior placebo-controlled studies. The majority of patients reached a median platelet count of 50 x 109/L after receiving one to three doses of Romiplostim, and these platelet counts were maintained throughout the remainder of the study with a median duration of Romiplostim treatment of 60 weeks and a maximum duration of 96 weeks.
# How Supplied
- Romiplostim is supplied in single-use vials containing 250 mcg (NDC 55513-221-01) and 500 mcg (NDC 55513-222-01) deliverable romiplostim.
## Storage
- Store Romiplostim vials in their carton to protect from light until time of use. Keep Romiplostim vials refrigerated at 2° to 8°C (36° to 46°F). Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Prior to treatment, patients should fully understand the risks and benefits of Romiplostim. Inform patients that the risks associated with long-term administration of Romiplostim are unknown.
- Inform patients of the following risks and considerations for Romiplostim:
- Romiplostim therapy is administered to achieve and maintain a platelet count ≥ 50 x 109/L as necessary to reduce the risk for bleeding; Romiplostim is not used to normalize platelet counts.
- Following discontinuation of Romiplostim, thrombocytopenia and risk of bleeding may develop that is worse than that experienced prior to the Romiplostim therapy.
- Romiplostim therapy may increase the risk of reticulin fiber formation within the bone marrow. This formation may improve upon discontinuation. Detection of peripheral blood cell abnormalities may necessitate a bone marrow examination.
- Too much Romiplostim may result in excessive platelet counts and a risk for thrombotic/thromboembolic complications.
- Romiplostim stimulates certain bone marrow cells to make platelets and increases the risk of progression to acute myelogenous leukemia in patients with myelodysplastic syndromes.
- Platelet counts and CBCs must be performed weekly until a stable Romiplostim dose has been achieved; thereafter, platelet counts and CBCs, must be performed monthly while taking Romiplostim.
- Patients must be closely monitored with weekly platelet counts and CBCs for at least 2 weeks following Romiplostim discontinuation.
- Even with Romiplostim therapy, patients should continue to avoid situations or medications that may increase the risk for bleeding.
# Precautions with Alcohol
- Alcohol-Romiplostim interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Nplate
# Look-Alike Drug Names
- romiPLOStim - romiDEPsin
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Romiplostim | |
c9dac11b984dd2f4eae3632462b675896943a201 | wikidoc | Rosa canina | Rosa canina
Rosa canina (lit. Dog Rose, often called incorrectly Rosehip) is a variable scrambling rose species native to Europe, northwest Africa and western Asia.
It is a deciduous shrub normally ranging in height from 1-5 m, though sometimes it can scramble higher into the crowns of taller trees. Its stems are covered with small, sharp, hooked spines, which aid it in climbing. The leaves are pinnate, with 5-7 leaflets. The flowers are usually pale pink, but can vary between a deep pink and white. They are 4-6 cm diameter with five petals, and mature into an oval 1.5-2 cm red-orange fruit, or hip.
# Cultivation and uses
The plant is high in certain antioxidants. The fruit is noted for its high vitamin C level and is used to make syrup, tea and marmalade. It has been grown or encouraged in the wild for the production of vitamin C, from its fruit (often as rose-hip syrup), especially during conditions of scarcity or wartime. The species has also been introduced to other temperate latitudes. During World War II in the United States Rosa canina was planted in victory gardens, and can still be found growing throughout the United States, including roadsides, and in wet, sandy areas up and down coastlines.
During the Vietnam War, for Steve Arnold fighting with the North, Rosa Canina was dried and then smoked with tobacco to produce mild hallucinogenic effects and abnormal dreams.
Forms of this plant are sometimes used as stocks for the grafting or budding of cultivated varieties.
The wild plant is planted as a nurse or cover crop, or stabilising plant in land reclamation and specialised landscaping schemes.
Numerous cultivars have been named, though few are common in cultivation. The cultivar Rosa canina 'Assisiensis' is the only dog rose without thorns.
The hips are used as a flavouring in the Slovenian soft drink Cockta.
The dog rose was the stylized rose of Medieval European heraldry, and is still used today.
The dog rose is the flower of Hampshire
# Etymology
The name 'dog' has a disparaging meaning in this context, indicating 'worthless' (by comparison with cultivated garden roses) (Vedel & Lange 1960).
Howard (1987) states that it was used in the eighteenth and nineteenth centuries to treat the bite of rabid dogs, hence the name "dog rose" arose.
Other old folk names include rose briar (also spelt brier), briar rose, dogberry,, herb patience, sweet briar, wild briar, witches' briar, and briar hip.
In Turkish, its name is 'kuşburnu', which translates as "bird nose". | Rosa canina
Rosa canina (lit. Dog Rose, often called incorrectly Rosehip) is a variable scrambling rose species native to Europe, northwest Africa and western Asia.
It is a deciduous shrub normally ranging in height from 1-5 m, though sometimes it can scramble higher into the crowns of taller trees. Its stems are covered with small, sharp, hooked spines, which aid it in climbing. The leaves are pinnate, with 5-7 leaflets. The flowers are usually pale pink, but can vary between a deep pink and white. They are 4-6 cm diameter with five petals, and mature into an oval 1.5-2 cm red-orange fruit, or hip.
# Cultivation and uses
The plant is high in certain antioxidants. The fruit is noted for its high vitamin C level and is used to make syrup, tea and marmalade. It has been grown or encouraged in the wild for the production of vitamin C, from its fruit (often as rose-hip syrup), especially during conditions of scarcity or wartime. The species has also been introduced to other temperate latitudes. During World War II in the United States Rosa canina was planted in victory gardens, and can still be found growing throughout the United States, including roadsides, and in wet, sandy areas up and down coastlines.
During the Vietnam War, for Steve Arnold fighting with the North, Rosa Canina was dried and then smoked with tobacco to produce mild hallucinogenic effects and abnormal dreams.
Forms of this plant are sometimes used as stocks for the grafting or budding of cultivated varieties.
The wild plant is planted as a nurse or cover crop, or stabilising plant in land reclamation and specialised landscaping schemes.
Numerous cultivars have been named, though few are common in cultivation. The cultivar Rosa canina 'Assisiensis' is the only dog rose without thorns.
The hips are used as a flavouring in the Slovenian soft drink Cockta.
The dog rose was the stylized rose of Medieval European heraldry, and is still used today[citation needed].
The dog rose is the flower of Hampshire
# Etymology
The name 'dog' has a disparaging meaning in this context, indicating 'worthless' (by comparison with cultivated garden roses) (Vedel & Lange 1960).
Howard (1987) states that it was used in the eighteenth and nineteenth centuries to treat the bite of rabid dogs, hence the name "dog rose" arose.[1]
Other old folk names include rose briar (also spelt brier), briar rose, dogberry,, herb patience, sweet briar, wild briar, witches' briar, and briar hip.
In Turkish, its name is 'kuşburnu', which translates as "bird nose". | https://www.wikidoc.org/index.php/Rosa_canina | |
a3e2adb09246eb9c9d123033bd5bdb3f08930782 | wikidoc | Ross Upshur | Ross Upshur
Ross Upshur, MA, MD, MSc, CCFP, FRCPC, is a Canadian physician and researcher. He is the Director of the University of Toronto Joint Centre for Bioethics, Director of the Primary Care Research Unit and a staff physician at the Department of Family and Community Medicine, Sunnybrook Health Sciences Centre.
# Biography
He received his BA (Hons.) in philosophy from the University of Manitoba in 1982, MA in philosophy from Queen's University in 1983, before receiving his MD from McMaster University in 1986. After 7 years of rural primary care practice in southern Ontario, he returned to university to complete a MSc in epidemiology and fellowship training in Community Medicine and Public Health at the University of Toronto in 1997.
From 1997 to 2003, he was appointed Adjunct Assistant Professor, School of Geography and Geology at McMaster University. He was appointed by the University of Toronto as Assistant Professor in 1998 and Associate Professor in 2004 in the Department of Family and Community Medicine, with Cross-Appointment to the Department of Public Health Sciences. Since 2000, he has been the Director of the Primary Care Research Unit at Sunnybrook Health Sciences Centre. In 2006, he was appointed Director of the University of Toronto Joint Centre for Bioethics.
He holds other academic positions, including the Canada Research Chair in Primary Care Research, Director of the PAHO/WHO Collaborating Centre for Bioethics, Adjunct Scientist at the Institute for Clinical Evaluative Sciences at the University of Toronto, Associate Member of the Institute of Environment and Health at McMaster University, affiliate of the Institute of the History and Philosophy of Science and Technology at the University of Toronto.
At the University of Toronto, he has designed and taught courses in the undergraduate, graduate and post-graduate curriculum in ethics and epidemiology, as well as supervising doctoral and master’s candidates, in addition to serving as a clinical supervisor for the post-graduate Family Medicine Residency program.
He has served on advisory boards for the International Joint Commission, Doctors Without Borders, and Scidev.net and consulted with the World Health Organization.
# Research
He has published over 90 articles in scientific journals such as Lancet, British Medical Journal, Canadian Medical Association Journal, among others.
His research interests include: the concept of evidence in health care, medical epistemology, clinical reasoning, public health ethics, ethics and health information, empirical approaches in bioethics, primary care research methods, time series applications in health services research, communicable disease and environmental epidemiology.
A list of Ross Upshur's publications is available on PubMed, click here. | Ross Upshur
Ross Upshur, MA, MD, MSc, CCFP, FRCPC, is a Canadian physician and researcher. He is the Director of the University of Toronto Joint Centre for Bioethics, Director of the Primary Care Research Unit and a staff physician at the Department of Family and Community Medicine, Sunnybrook Health Sciences Centre.
# Biography
He received his BA (Hons.) in philosophy from the University of Manitoba in 1982, MA in philosophy from Queen's University in 1983, before receiving his MD from McMaster University in 1986. After 7 years of rural primary care practice in southern Ontario, he returned to university to complete a MSc in epidemiology and fellowship training in Community Medicine and Public Health at the University of Toronto in 1997.
From 1997 to 2003, he was appointed Adjunct Assistant Professor, School of Geography and Geology at McMaster University. He was appointed by the University of Toronto as Assistant Professor in 1998 and Associate Professor in 2004 in the Department of Family and Community Medicine, with Cross-Appointment to the Department of Public Health Sciences. Since 2000, he has been the Director of the Primary Care Research Unit at Sunnybrook Health Sciences Centre. In 2006, he was appointed Director of the University of Toronto Joint Centre for Bioethics.
He holds other academic positions, including the Canada Research Chair in Primary Care Research, Director of the PAHO/WHO Collaborating Centre for Bioethics, Adjunct Scientist at the Institute for Clinical Evaluative Sciences at the University of Toronto, Associate Member of the Institute of Environment and Health at McMaster University, affiliate of the Institute of the History and Philosophy of Science and Technology at the University of Toronto.
At the University of Toronto, he has designed and taught courses in the undergraduate, graduate and post-graduate curriculum in ethics and epidemiology, as well as supervising doctoral and master’s candidates, in addition to serving as a clinical supervisor for the post-graduate Family Medicine Residency program.
He has served on advisory boards for the International Joint Commission, Doctors Without Borders, and Scidev.net and consulted with the World Health Organization.
# Research
He has published over 90 articles in scientific journals such as Lancet, British Medical Journal, Canadian Medical Association Journal, among others.
His research interests include: the concept of evidence in health care, medical epistemology, clinical reasoning, public health ethics, ethics and health information, empirical approaches in bioethics, primary care research methods, time series applications in health services research, communicable disease and environmental epidemiology.
A list of Ross Upshur's publications is available on PubMed, click here.
# External links
- Biography: Ross Upshur
- Researcher Profile: Ross Upshur
- Canada Research Chairholder Profile: Ross Upshur
- Primary Care Research Unit home page
- University of Toronto Joint Centre for Bioethics home page | https://www.wikidoc.org/index.php/Ross_Upshur | |
451fc2a678a78896df400b1aeb8beaf2cbf73949 | wikidoc | Rotigaptide | Rotigaptide
# Overview
Rotigaptide (ZP-123) is a stable gap junction conduction-enhancing antiarrhythmic peptide analog that has been shown to increase gap junction intercellular conductance in cardiac myocytes. Gap junctions are protein channels that are responsible for conducting electrical impulses between cells in the heart to maintain normal rhythm. It is currently under clinical investigation for the treatment of cardiac arrhythmias – specifically atrial fibrillation. Gap junction modulation is a promising and novel mechanism of action for the treatment of cardiovascular disorders.
# Indications
Rotigaptide is being studied for its antiarrhythmic effects, specifically for treating atrial fibrillation. Atrial fibrillation is an irregular and often rapid heart rhythm. The irregular rhythm, results from abnormal electrical impulses in the heart. The irregularity can be continuous or intermittent. In atrial fibrillation, multiple impulses travel through the atria at the same time. Instead of a coordinated contraction, the atrial contractions are irregular, disorganized and very rapid. These irregular impulses reach the AV node in rapid succession, but not all of them make it past the AV node. Therefore, the ventricles beat slower in an irregular rhythm. The resulting rapid, irregular heartbeat causes an irregular pulse and sometimes a sensation of fluttering in the chest.
# Mechanism of action
The exact mechanism of action of rotigaptide is not completely understood. However, rotigaptide is believed to exert its effects on cardiomyocyte gap junctions through phosphorylation events. Each gap junction is composed of a series of connexons in close proximity to each other. Each connexon is made up of 6 functional units (connexins) that associate together to form a channel between adjacent cells. Rotigaptide acts at connexins, preferentially to connexin 43 (Cx43). Treatment with rotigaptide has been shown to activate various protein kinase C (PKC) isoforms to cause the phosphorylation of Cx43, which aids in proper function of the connexon. This allows for a smoother conduction to pass through the myocytes to propagate a synchronous contraction. This has been shown to reduce the occurrence of atrial fibrillation.
# Limitations
A potential limitation for this drug is that animals being used for studies are most commonly anesthetized with isoflurane, which has been shown to be a partial gap junction uncoupler and thus would negate the effects of rotigaptide. However, this effect can be only minor, as one study showed that a low dose of isoflurane was kept continuous over the progression of the study, indicating that the dose was not high enough to uncouple rotigaptide. Therefore, it may be unlikely that isoflurane plays a role in the results presented. | Rotigaptide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Rotigaptide (ZP-123) is a stable gap junction conduction-enhancing antiarrhythmic peptide analog that has been shown to increase gap junction intercellular conductance in cardiac myocytes.[1] Gap junctions are protein channels that are responsible for conducting electrical impulses between cells in the heart to maintain normal rhythm. It is currently under clinical investigation for the treatment of cardiac arrhythmias – specifically atrial fibrillation. Gap junction modulation is a promising and novel mechanism of action for the treatment of cardiovascular disorders.[1]
# Indications
Rotigaptide is being studied for its antiarrhythmic effects, specifically for treating atrial fibrillation.[2] Atrial fibrillation is an irregular and often rapid heart rhythm. The irregular rhythm, results from abnormal electrical impulses in the heart. The irregularity can be continuous or intermittent. In atrial fibrillation, multiple impulses travel through the atria at the same time. Instead of a coordinated contraction, the atrial contractions are irregular, disorganized and very rapid.[2] These irregular impulses reach the AV node in rapid succession, but not all of them make it past the AV node. Therefore, the ventricles beat slower in an irregular rhythm. The resulting rapid, irregular heartbeat causes an irregular pulse and sometimes a sensation of fluttering in the chest.
# Mechanism of action
The exact mechanism of action of rotigaptide is not completely understood. However, rotigaptide is believed to exert its effects on cardiomyocyte gap junctions through phosphorylation events. Each gap junction is composed of a series of connexons in close proximity to each other. Each connexon is made up of 6 functional units (connexins) that associate together to form a channel between adjacent cells.[3] Rotigaptide acts at connexins, preferentially to connexin 43 (Cx43).[4] Treatment with rotigaptide has been shown to activate various protein kinase C (PKC) isoforms to cause the phosphorylation of Cx43, which aids in proper function of the connexon.[5] This allows for a smoother conduction to pass through the myocytes to propagate a synchronous contraction.[6] This has been shown to reduce the occurrence of atrial fibrillation.[2]
# Limitations
A potential limitation for this drug is that animals being used for studies are most commonly anesthetized with isoflurane, which has been shown to be a partial gap junction uncoupler and thus would negate the effects of rotigaptide.[7] However, this effect can be only minor, as one study showed that a low dose of isoflurane was kept continuous over the progression of the study, indicating that the dose was not high enough to uncouple rotigaptide. Therefore, it may be unlikely that isoflurane plays a role in the results presented.[2] | https://www.wikidoc.org/index.php/Rotigaptide | |
4bda99165f60adfef8e0a318da7f2201c5864c16 | wikidoc | Roy Walford | Roy Walford
# Overview
Roy Lee Walford, M. D. (June 29, 1924 San Diego, California – April 27, 2004) was a pioneer in the field of life extension. He died at age 79 of respiratory failure as a complication of amyotrophic lateral sclerosis (commonly known as Lou Gehrig’s Disease). He was a leading advocate of calorie restriction as a method of life extension and health improvement.
# Career highlights
Dr. Walford is credited with significantly furthering research on the discovery that laboratory mice, when fed a diet that restricted their caloric intake by 50% yet maintained nutritional requirements, could more than double their expected life span.
He received his medical degree from the University of Chicago in 1948. He completed his internship at Gorgas Memorial Hospital, Panama, and served his residency at the V.A. Medical Center in Los Angeles. He then served two years in the U.S. Air Force during the Korean War.
Dr. Walford joined the faculty at the University of California at Los Angeles (UCLA) in 1954. He became a Professor of Pathology at the UCLA School of Medicine in 1966. He became Professor of Pathology and Laboratory Medicine, Emeritus, for UCLA, when he left to join the crew of Biosphere 2 in 1991.
While at UCLA, Dr. Walford served in the following roles:
- Director of the Blood Bank and of the Hematology Division of the Clinical Laboratories (1959-1980)
- Director of the School of Medical Technology (1962-1972)
- Chairman of the Vivarium Committee (1965-1968)
In addition to his service at UCLA, he was an expert advisor in immunology for the World Health Organization from 1969 to 1984, was a senatorial delegate to the White House Conference on Aging in 1981, and a member of the National Institute on Aging.
His honors and awards include:
- Levine Award of the American Society of Clinical Pathology
- Research Award of the American Aging Association
- Kleemeier Award from the Gerontological Society of America
- Henderson Award from the American Geriatrics Society
- The Senator Alan Cranston Award
- Infinity Award of the American Academy of Anti-Aging Medicine
- Asteroid #4629 was named after him by its discoverer (E. Helene) in 1986
Dr. Walford and his work were featured in print in dozens of articles in popular publications such as Omni, Discover, and Scientific American. During his life he also made dozens of featured appearances on various television shows.
# Biosphere 2
Dr. Walford was one of the eight “crew members” who were sealed inside Biosphere 2 where they lived from September 26, 1991 - September 26, 1993. Dr. Walford served as the crew's physician. During his stay in Biosphere 2, the crew found that they could not grow as much food as anticipated, so Dr. Walford convinced the crew to follow his calorie restriction diet. It is claimed that this action “produced dramatic weight loss and improved health.”
# Published works
Walford authored several books, and set out his dietary beliefs in the bestseller Beyond the 120-Year Diet. In addition, he published at least 340 scientific papers, mainly focused on the biology of aging.
Dr. Walford authored or co-authored the following books:
- Walford, R. L. (1960). Leukocyte Antigens and Antibodies. New York: Grune and Stratton, Inc..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Template:Harvard reference
- Walford, R. L. (1969). The Immunological Theory of Aging. Copenhagen: Munksgaard.
- Walford, R. L. (1983). Maximum Life Span. New York: W.W. Norton & Co. ISBN 0-380-65524-1.
- Walford, R. L. (1986). The 120-Year Diet. New York: Simon and Schuster. ISBN 0-671-64904-3.
- Weindruch, R. H. and Walford, R. L. (1988). The Retardation of Aging and Disease by Dietary Restriction. New York: Charles C. Thomas.
- Walford, R. L. and Walford, Lisa J. (1994). The Anti-Aging Plan. New York: Four Walls Eight Windows. ISBN 1-569-24383-2.
- Walford, R. L. (2000). Beyond The 120-Year Diet. New York: Four Walls Eight Windows. ISBN 1-568-58157-2.
# Personal trivia
In 1949, while on vacation either from or after medical school (sources disagree), Walford and Albert Hibbs, a mathematics graduate student, used statistical analysis of biased roulette wheels to "break the bank" in Reno. They tracked the results of the spins, determined which wheels were biased, and then bet heavily on the ones which were unbalanced. The casinos eventually realized that Walford and his friend knew what they were doing and threw them out. A Life Magazine photographer captured the pair drinking milk and counting their chips in a photograph published in the December 7, 1949 issue. Their methods were also mentioned in the roulette book The Eudaemonic Pie by Thomas Bass. Different sources have the pair winning anywhere from $6,500 (Life Magazine) to $42,000 (an obituary by the Gerontology Research Group); the high end is more likely, as Walford was reputed to have paid for part of his medical school education and a house from his winnings. The pair also bought a yacht and sailed the Caribbean for over a year.
At UCLA, Walford was known for his quirks, notably his secretary, a statuesque blonde transvestite.
He was also mentioned in Let Them Eat Flax, a collection of essays on chemistry, written by Dr. Joe Schwarcz. | Roy Walford
# Overview
Roy Lee Walford, M. D. (June 29, 1924 San Diego, California – April 27, 2004) was a pioneer in the field of life extension. He died at age 79 of respiratory failure as a complication of amyotrophic lateral sclerosis (commonly known as Lou Gehrig’s Disease). He was a leading advocate of calorie restriction as a method of life extension and health improvement.
# Career highlights
Dr. Walford is credited with significantly furthering research on the discovery that laboratory mice, when fed a diet that restricted their caloric intake by 50% yet maintained nutritional requirements, could more than double their expected life span.
He received his medical degree from the University of Chicago in 1948. He completed his internship at Gorgas Memorial Hospital, Panama, and served his residency at the V.A. Medical Center in Los Angeles. He then served two years in the U.S. Air Force during the Korean War.
Dr. Walford joined the faculty at the University of California at Los Angeles (UCLA) in 1954. He became a Professor of Pathology at the UCLA School of Medicine in 1966. He became Professor of Pathology and Laboratory Medicine, Emeritus, for UCLA, when he left to join the crew of Biosphere 2 in 1991.
While at UCLA, Dr. Walford served in the following roles:
- Director of the Blood Bank and of the Hematology Division of the Clinical Laboratories (1959-1980)
- Director of the School of Medical Technology (1962-1972)
- Chairman of the Vivarium Committee (1965-1968)
In addition to his service at UCLA, he was an expert advisor in immunology for the World Health Organization from 1969 to 1984, was a senatorial delegate to the White House Conference on Aging in 1981, and a member of the National Institute on Aging.
His honors and awards include:
- Levine Award of the American Society of Clinical Pathology
- Research Award of the American Aging Association
- Kleemeier Award from the Gerontological Society of America
- Henderson Award from the American Geriatrics Society
- The Senator Alan Cranston Award
- Infinity Award of the American Academy of Anti-Aging Medicine
- Asteroid #4629 was named after him by its discoverer (E. Helene) in 1986
Dr. Walford and his work were featured in print in dozens of articles in popular publications such as Omni, Discover, and Scientific American. During his life he also made dozens of featured appearances on various television shows.
# Biosphere 2
Dr. Walford was one of the eight “crew members” who were sealed inside Biosphere 2 where they lived from September 26, 1991 - September 26, 1993. Dr. Walford served as the crew's physician. During his stay in Biosphere 2, the crew found that they could not grow as much food as anticipated, so Dr. Walford convinced the crew to follow his calorie restriction diet. It is claimed that this action “produced dramatic weight loss and improved health.”[1]
# Published works
Walford authored several books, and set out his dietary beliefs in the bestseller Beyond the 120-Year Diet. In addition, he published at least 340 scientific papers, mainly focused on the biology of aging.
Dr. Walford authored or co-authored the following books:[2]
- Walford, R. L. (1960). Leukocyte Antigens and Antibodies. New York: Grune and Stratton, Inc..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Template:Harvard reference
- Walford, R. L. (1969). The Immunological Theory of Aging. Copenhagen: Munksgaard.
- Walford, R. L. (1983). Maximum Life Span. New York: W.W. Norton & Co. ISBN 0-380-65524-1.
- Walford, R. L. (1986). The 120-Year Diet. New York: Simon and Schuster. ISBN 0-671-64904-3.
- Weindruch, R. H. and Walford, R. L. (1988). The Retardation of Aging and Disease by Dietary Restriction. New York: Charles C. Thomas.
- Walford, R. L. and Walford, Lisa J. (1994). The Anti-Aging Plan. New York: Four Walls Eight Windows. ISBN 1-569-24383-2.
- Walford, R. L. (2000). Beyond The 120-Year Diet. New York: Four Walls Eight Windows. ISBN 1-568-58157-2.
# Personal trivia
In 1949, while on vacation either from or after medical school (sources disagree), Walford and Albert Hibbs, a mathematics graduate student, used statistical analysis of biased roulette wheels to "break the bank" in Reno. They tracked the results of the spins, determined which wheels were biased, and then bet heavily on the ones which were unbalanced. The casinos eventually realized that Walford and his friend knew what they were doing and threw them out. A Life Magazine photographer captured the pair drinking milk and counting their chips in a photograph published in the December 7, 1949 issue. Their methods were also mentioned in the roulette book The Eudaemonic Pie by Thomas Bass. Different sources have the pair winning anywhere from $6,500 (Life Magazine) to $42,000 (an obituary by the Gerontology Research Group); the high end is more likely, as Walford was reputed to have paid for part of his medical school education and a house from his winnings. The pair also bought a yacht and sailed the Caribbean for over a year.
At UCLA, Walford was known for his quirks, notably his secretary, a statuesque blonde transvestite.
He was also mentioned in Let Them Eat Flax, a collection of essays on chemistry, written by Dr. Joe Schwarcz. | https://www.wikidoc.org/index.php/Roy_Walford | |
27491111e811ed4bc1b05442962217f0f74c67cc | wikidoc | Ruby Dhalla | Ruby Dhalla
Dr. Ruby Dhalla (born February 18, 1974) is a Canadian politician. She has represented the riding of Brampton—Springdale in the Canadian House of Commons since 2004 as a member of the Liberal Party of Canada. Dhalla and British Columbia Conservative Party of Canada Nina Grewal are the first Sikh women to serve in the Canadian House of Commons.
# Early life
Dhalla was born in Winnipeg, Manitoba to an immigrant family from Punjab (India), India. She first attracted international attention in 1984, when she was ten years old and living in Winnipeg's north end. When Indian soldiers took part in military actions at Punjab's Golden Temple, Dhalla wrote a letter to Indian Prime Minister of India Indira Gandhi, urging her to resolve the situation without further violence. Gandhi personally replied to Dhalla's letter, and referred to it at a press conference held months before her assassination.
Dhalla received a Bachelor of Science degree in Biochemistry with a minor in Political Science from the University of Winnipeg in 1995. She moved to Toronto in the same year, and graduated with a Doctor of Chiropractic from the Canadian Memorial Chiropractic College in 1999. She later co-owned a chain of chiropractic clinics in Toronto, Brampton, Ontario, Mississauga and Aurora, Ontario with her brother, Neil Dhalla. Dhalla has also pursued a career in acting, working in India for six months and playing a leading role in Kyon? Kis Liye? (translated as Why? and for Whom?), a Bollywood-inspired Hindi-language film shot in Hamilton, Ontario. She finished second in the Miss India Canada pageant in 1993.
Dhalla volunteered for Winnipeg Liberal candidate David Walker (Canadian politician)in the Canadian federal election, 1988, and later became a prominent member of the Winnipeg Young Liberals (Canada). In 1998, she was elected as youth representative of the party's standing committee on multiculturalism. Dhalla supported Paul Martin's bid to become Liberal Party leader in 2003.
Dhalla attempted to block the DVD release of Kyon? Kis Liye? in 2009, arguing that publicity photos and posters from the movie had been "doctored" by putting her face on someone else's body. She also said that the film was being released to exploit her status as an elected official. Producer Charanjit "Chico" Sihra has said that no images were doctored, while adding that there is no unsuitable content in the movie. Sinha also contends that Dhalla signed a distribution waiver and was paid $2000 (US), although he also says that the actual form was later destroyed in a fire. Dhalla has denied signing a waiver.
In a 2008 poll of parliamentary staffers from The Hill Times, Dhalla was tied for second-sexiest female MP with Helena Guergis, while that year Maxim magazine ranked her third in "The World's Hottest Politicians" behind Sarah Palin.
# Member of Parliament
## Government member (2004-06)
In May 2004, Paul Martin designated Dhalla as the Liberal candidate for Brampton—Springdale in the Canadian federal election, 2004. This decision was opposed by the local Liberal Party riding executive, who had favoured Andrew Kania for the nomination. Kania informed the media that Martin had previously allowed him to run for the nomination, and said that he would not rule out standing for election as an independent. The deputy campaign director for the Liberal Party defended Dhalla's selection, describing her as a star candidate who would be beneficial to the party. This controversy took place against a backdrop of 2004 Liberal Party of Canada infighting among other Liberal candidates for riding nominations, in which some rejected candidates accused Martin of undermining party democracy. When the election was called, the Liberal riding association endorsed New Democratic Party candidate Kathy Pounder in protest.
One of Dhalla's supporters in the 2004 election was comedian Mike Bullard (television), for whom Dhalla has worked as a chiropractor. Bullard joked during the campaign that he was helping Dhalla because "all my back trouble is on the Right-wing politics". She was elected by a comfortable margin as the Liberals were reduced to a minority government nationally. After the election, she was appointed to the Standing Committee on Health.
Dhalla was a prominent organizer of the "Canada for Asia" benefit concert in January 2005, along with Canadian Senator Jerry Grafstein and singer Tom Cochrane. The event raised money for victims of the previous month's tsunami disaster in southeast Asia. In October 2005, Dhalla organized a relief effort for victims of an earthquake in Pakistan. She also promoted an accelerated foreign credential recognition process to assist recent Canadian immigrants in gaining professional employment.
Dhalla voted in favour of Canada's Same-sex marriage in Canada legislation in 2005, on the grounds that the Canadian Charter of Rights and Freedoms must confer equality on different groups in society.
The Liberal government was defeated by a motion of no confidence in late 2005, and Canadian federal election, 2006 was called for early 2006. Dhalla officially launched her re-election campaign in early December, with Bollywood actor Arjun Rampal as a star attendee. Conservative candidate Sam Hundal attempted to use same-sex marriage as a wedge issue among recent immigrant voters, but was unsuccessful. Dhalla was easily re-elected, while the Conservatives won a minority government at the national level.
## Opposition member (2006-present)
After the election, Dhalla was appointed as the Liberal Health Critic in the Official Opposition. In June 2006, she criticized Minister of Health (Canada) Tony Clement over a possible conflict-of-interest relating to his ownership of shares in Prudential Chem Inc. The following month, she described Prime Minister of Canada Stephen Harper's refusal to attend an international AIDS conference in Toronto as "extremely upsetting".
In June 2006, Dhalla alleged that the Conservatives had tried to convince her to cross the floor and join the party, as part of a campaign to win the support of youth, women and ethnic voters. She turned down the offer, saying that the Conservatives do not represent her values. She later criticized Wajid Khan for crossing from the Liberals to the Conservatives. (Khan was defeated in the Canadian federal election, 2008.)
Paul Martin resigned as Liberal leader after his party's defeat in the 2006 election. Dhalla initially considered entering the contest to succeed him, but instead gave her support to Michael Ignatieff. She was the Ignatieff Leadership Campaign's national co-chair, alongside Canadian Senatr David Smith (Canadian Senator) and Member of Parliament Denis Coderre. Ignatieff was defeated by Stéphane Dion on the final ballot of the 2006 Liberal leadership convention.
Dion announced his new shadow cabinet in January 2007, and reassigned Dhalla from Health to Social Development. She criticized the Conservatives for canceling the Martin government's national day-care plan, and spoke against the prospect of large, for-profit foreign firms taking over the industry. She also wrote an opinion piece for the Toronto Star newspaper in early 2008, calling for developed countries to invest the necessary resources to target tuberculosis in the global south.
Dhalla opposed the Conservative government's changes to Canada's immigration laws in early 2008, wherein the government set an annual limit on the number of cases to be heard and gave the Minister of Citizenship and Immigration (Canada) the discretion to fast-track some applicants. Dhalla suggested that the Conservatives would show favouritism to immigrants from certain communities. She was quoted as saying, "I think they're really picking and choosing for political purposes which communities they want to work with, and that is why there is a fear among these communities that the immigration laws being proposed right now are going to have an impact on them."
Dhalla issued a Private Member's Bill in April 2008, calling on the federal government to apologize for the 1914 Komagata Maru incident, in which a ship with 376 mostly Sikh immigrants was denied access to Canada. The bill was unanimously passed the following month.
She faced a difficult re-election in Canadian federal election, 2008, and ultimately defeated Conservative candidate Parm Gill by a small margin amid a provincial swing from the Liberals to Conservatives. This contest was marked by open animosity between the candidates. The Conservatives were re-elected to a second minority government on the national level. Shortly after the election, a Toronto man was charged with making a death threat against Dhalla.
Dhalla traveled to the Indian state of Punjab in January 2008. While attending a Non-Resident Indian (NRI) seminar, she called on the state government to introduce more stringent laws to prevent the abuse of married women. She later visited her parent's village of Mullanpur.
During this trip, a member of Dhalla's staff had a Handbag stolen by two children. It was later claimed that these children were beaten by the police after being apprehended. A local television news anchorman quoted Dhalla as saying that she "cannot control what the police do … and that those young kids learn from this incident". The anchorman called this "shockingly callous". Dhalla later said that her comments were taken out of context and that she had spoken before she found out how the children had been treated. She clarified that she condemned any type of violence against children and called for an investigation into the incident. The local media later issued a full retraction, acknowledging that Dhalla's initial comments had been presented out of context.
Stéphane Dion stepped down as Liberal leader after a poor showing in the 2008 federal election, and Dhalla was mentioned as a possible candidate to succeed him. The Toronto Star listed her as an outside contender, noting that her national profile was not very strong. Before she was able to make her decision, other prominent candidates withdrew from the contest and gave their support to Michael Ignatieff. In December, Dhalla announced she would not be a candidate. Ignatieff was duly acclaimed as interim leader in January 2009, and was officially confirmed as party leader later in the year.
In January 2009, Ignatieff appointed Dhalla as the Liberal critic for Youth and Multiculturalism. She stepped down from the position in May.
## Caregivers controversy
On May 5, 2009, the Toronto Star newspaper ran a front-page story with allegations that two Filipina caregivers hired to look after Dhalla's mother had been illegally employed and mistreated. The caregivers alleged that Ruby Dhalla had improperly seized their passports, and that the family forced them to do chores such as "washing cars, shining shoes and cleaning family-owned chiropractic clinics". Dhalla responded that she was "shocked and appalled" by the allegations, saying that the caregivers were never abused and that she had never taken anyone's passport. She later released a statement indicating that she had no involvement with the hiring or supervision of the women. Ruby's brother Neil Dhalla has also denied the charges, saying that his family was " victim of an unscrupulous agency, as well as the caregivers". A third caregiver later came forward with similar charges.
The Star reported that these allegations had originally surfaced at a public meeting held by provincial Minister of Education (Ontario) Kathleen Wynne and Minister of Labour (Ontario) Peter Fonseca to address violations of Canada's Live-In Caregiver Program. Opposition legislators later called for Fonseca to resign for not having investigated the matter further; he responded that he attended the meeting as an "impartial" observer, and had distributed pamphlets to all complainants outlining their rights under Ontario's labour laws. Premier of Ontario Dalton McGuinty added that around thirty other caregivers had raised similar concerns, and that it would have been inappropriate for Fonseca to "pick and choose" individual cases to address himself. He added that investigators from the Labour Ministry would attend future meetings.
Dhalla stepped down as the Liberal Youth and Multiculturalism Critic on May 6, and called for a federal ethics investigation to clear her name. A subsequent Globe and Mail article suggested that she had few supporters within the federal Liberal caucus, and that other MPs considered her a "high maintenance" self-promoter, demanding on her staff and unwilling to engage in the mundane details of parliamentary life. Some Liberal MPs have publicly defended her, however, including Judy Sgro. Bob Rae has said of the controversy over Dhalla, "In my, dare I say it, 30-year career, I've seen a lot of feeding frenzies. I've seen a lot of lynch mob activity. And this is just another example of it".
Dhalla held a press conference on May 8, in which she described the allegations against her as a coordinated attack on her reputation. Her lawyer described Dhalla as the victim in the affair, and brought forward several signed documents which he said would verify his client's position. He added that Neil Dhalla was responsible for hiring the caregivers, and suggested that the controversy was part of a partisan smear campaign orchestrated by Dhalla's political opponents.
Both Dhalla and the caregivers testified before the House of Commons Immigration Committee on May 12, 2009. Many journalists wrote that the hearings failed to shed any light on the matter, which they argued should not have been investigated by a political committee in the first place. Committee chair David Tilson said, "They both had opposite stories. Who's telling the truth, I have no idea." Following Dhalla's testimony, Michael Ignatieff said, "A member of my caucus has been accused of a serious, serious issue. She's mounted a vigorous and convincing defence ... and I take her at her word".
On the day after Dhalla's appearance, Agathe Mason, the executive director of a Toronto support group for immigrant women called Intercede, testified before the Commons committee that she had called Dhalla (rather than her brother) when one of the caregivers complained about her passport being withheld. Mason said that she informed Dhalla she was breaking the law and had 24 hours to return the passport, and that to her recollection the passport was returned the following day. Dhalla had previously rejected Mason's accusations, saying that she had never spoken with anyone at Intercede. On the same day as Mason's testimony, Dhalla's lawyer informed the media that one of the caregivers had made unfounded charges against another employer in the past.
Minister of Citizenship and Immigration (Canada) Jason Kenney has denied the suggestion of political interference, saying that he had no personal knowledge of the matter until it was reported by the media. His ministerial assistant Alykhan Velshi was later seen handing out documents to reporters at a meeting of the Immigration Committee, in a bid to discredit Dhalla. Some believe that this could have a chilling effect among civil servants in Kenney's department, and prevent them from reviewing the case in a fair and open manner.
No charges have been filed. Dhalla has asked the public and media to "hold judgment and give family privacy".
# Electoral record
All electoral information is taken from Elections Canada. Italicized expenditures refer to submitted totals, and are presented when the final reviewed totals are not available.
# Footnotes
- ↑ Randall King, "Screen Gem", Winnipeg Free Press, 30 May 2003, D1.
- ↑ Renu Mehta, "House Bound", Femina, 1 September 2004.
- ↑ Randall King, "Screen Gem", Winnipeg Free Press, 30 May 2003, D1; "Liberal Ruby Dhalla trying to block release of movie in which she co-starred", Canadian Press, 12 March 2009, 6:11am.
- ↑ Rebecca Myers, "Unconventional Resumes", Time Magazine (Canadian edition), 14 June 2004, p. 17.
- ↑ Canada Votes 2004, Canadian Broadcasting Corporation, Brampton—Springdale riding profile.
- ↑ "Young Liberals elevate Manitoban", Winnipeg Free Press, 1 April 1998, A4.
- ↑ Jim Brown, "BC-Martin-Democracy, Bgt", Canadian Press, 9 May 2004, 16:43 report.
- ↑ Mark McNeil, "Bollywood poster body not me: MP", Hamilton Spectator, 13 March 2009, A5.
- ↑ "Indo-Canadian Lawmaker up in arms on her role in a movie", The Press Trust of India Limited, 14 March 2009.
- ↑ "Peter MacKay est le parlementaire le plus sexy selon The Hill Times", La Presse Canadienne - Le fil radio, 15 April 2009, 12:06am.
- ↑ "The wild, the whimsical and the wacky from the campaign trail", Canadian Press, 11 September 2008, 4:14pm.
- ↑ "Would-be Liberal candidates cry foul", Kitchener-Waterloo Record, 10 May 2004, A4.
- ↑ Graham Fraser, "Anger as 'stars' oust Liberal hopefuls", Toronto Star, 10 May 2004, A6.
- ↑ Katherine Harding, "Party infighting plagues riding", Globe and Mail, 8 June 2004, A6; "Correction", Globe and Mail, 8 May 2009, A2 indicates that Kania himself did not endorse the NDP candidate.
- ↑ Jane Taber, "Nell Martin: the woman behind the portrait", Globe and Mail, 26 June 2004, A6.
- ↑ Randall King, "MP plans relief concert", Winnipeg Free Press, 12 January 2005, D10.
- ↑ "Indo-Canadian MP seeks quake relief", Hindustan Times, 21 October 2005, page number not listed.
- ↑ Ishani Duttagupta, "New Canada govt may serve Indian immigrants better", Economic Times (English edition), 25 January 2006.
- ↑ Jump up to: 19.0 19.1 Heba Aly, "Tories say stand on gay marriage tightens race in Brampton", Globe and Mail, 23 December 2005, A15.
- ↑ "Arjun Rampal kick-starts Canadian MP's campaign", Hindustan Times (English edition), 8 December 2005.
- ↑ Bill Curry, "Clement resists conflict claims", Globe and Mail, 14 June 2006, A4.
- ↑ Beth Duff-Brown, "Canada's PM will not be among record number of delegates at Toronto AIDS summit", Associated Press, 31 July 2006, 16:45 report.
- ↑ John Ivison and Peter O'Neil, "Indo-Canadian Liberal MP invited to join Tory ranks", Vancouver Sun, 16 June 2006, A6.
- ↑ Richard Brennan, "Taxpayers have right to see Khan's report, critics argue", Toronto Star, 15 January 2007, A10.
- ↑ John Ivison, "It takes a quitter to start a race", National Post, 9 February 2006, A8; Michael Ignatieff with his national campaign co-chairs, accessed October 2006.
- ↑ Juliet O'Neill, "47 Liberals to shadow 30 Tories", National Post, 19 January 2007, A4.
- ↑ Tonda MacCharles, "Opposition parties unite to fight big-box daycare", Toronto Star, 1 November 2007, A1; Laurie Monsebraaten, "Canada letting kids down, report says", Toronto Star, 20 November 2007, A4.
- ↑ Ruby Dhalla, "It's time for action; Tuberculosis is easy to cure but the lack of resources permits epidemic to spread", Toronto Star, 26 March 2008, A6.
- ↑ Susan Delacourt, "Opposition raises discrimination fears; But immigration plan clears one challenge", Toronto Star, 10 April 2008, A21; David Akin, "Tory budget legislation passes with help from Grits", Ottawa Citizen, 10 June 2008, A1. The Liberals as a whole decided not to bring down Harper's minority government on this bill; Dhalla was one of a number of Liberal MPs who voted in opposition.
- ↑ Kim Bolan, "Apology on the way for Indo-Canadians", Vancouver Sun, 12 May 2008, B1; Joanna Smith, "Apologies for past wrongs abound", Toronto Star, 20 May 2008, A13.
- ↑ Theresa Boyle, "Bitter battle between Dhalla and Gill", Globe and Mail, 15 October 2008, U10.
- ↑ "Toronto man charged with threatening MP", Globe and Mail, 21 October 2008, A10.
- ↑ "Canadian lawmaker calls on Punjab to check domestic violence", Asian News International, 7 January 2008.
- ↑ "NRIs cherish visiting their ancestral villages", Asian News International, 21 January 2008.
- ↑ CTV.ca News Staff, "It MP touring India calls for change after kids beaten ", CTV.ca, 10 January 2008, , accessed January 2008.
- ↑ Sonya Fateh, "Indian police quietly drop case of MP, stolen purse", Toronto Star, 10 March 2008, A1.
- ↑ For instance, see Norma Greenaway, "Possible successors a varied lot", Montreal Gazette, 21 October 2008, A2; Juliet O'Neill, "Dion vows 'respectful' leadership contest", Edmonton Journal, 24 October 2008, A6; "Two Manitobans among Liberal leadership contenders", Winnipeg Free Press, 24 October 2008, W1; Brian Laghi, Jane Taber, Campbell Clark, "The race to renew the Liberal identity", Globe and Mail, 30 October 2008, A17.
- ↑ "Taking bets on next Liberal leader" editorial, Toronto Star, 23 October 2008, A6.
- ↑ Roger Belgrave, "Leadership run not in the cards for local MP", Brampton Guardian, 18 December 2008.
- ↑ "No place for Dion on Ignatieff's front bench", National Post, 23 January 2009.
- ↑ Jump up to: 41.0 41.1 Dale Brazao, "Ruby's nanny trouble", Toronto Star, 5 May 2009, A1.
- ↑ Dale Brazao, "Housekeeper 'paid under table'", Toronto Star, 8 May 2009, A1.
- ↑ Dale Brazao, Robert Benzie and Rob Ferguson, "Provincial ministers defend actions", Toronto Star, 7 May 2009, A1.
- ↑ Keith Leslie, "Ont. Tories demand labour minister resign over Ruby Dhalla nanny allegations", Canadian Press, 6 May 2009, 4:26pm.
- ↑ "Dhalla quits critic's role amid family controversy", Canadian Press, 6 May 2009, 10:36am; Mike de Souza, "Dhalla resigns critic post, vows to clear name", National Post, 7 May 2009, A6; Susan Delacourt, "Dhalla seeks federal ethics investigation", Toronto Star, 7 May 2009, A1.
- ↑ CAMPBELL CLARK, GLORIA GALLOWAY AND KAREN HOWLETT, "Scandal sidelines ‘high-maintenance' Liberal MP", Globe and Mail, 7 May 2009, A3.
- ↑ Susan Delacourt, "Fellow MP says Dhalla 'devastated'", Toronto Star, 8 May 2009, A6.
- ↑ Gloria Galloway and Karen Howlett, "Committee to hear from MP's ex-workers", Globe and Mail, 8 May 2009, A5.
- ↑ Caroline Alphonso, Kate Hammer and Daniel LeBlanc, "Political conspiracy fuelling nanny scandal, Dhalla says; Caregivers' claims ‘complete nonsense'", Globe and Mail, 9 May 2009, A1; David Akin, "Dhalla caregivers' allegations a partisan smear, lawyer says", Ottawa Citizen, 9 May 2009, A3.
- ↑ Juliet O'Neill, "Dhalla denies caregivers' allegations made at Commons committee", CanWest News Service, 12 May 2009.
- ↑ "No light on live-in caregivers" , Globe and Mail, 13 May 2009, A14; "The Ruby Dhalla sideshow was a waste of MPs' time", Montreal Gazette , 13 May 2009, A16; "Politicians shouldn't investigate each other", Waterloo Region Record editorial, 13 May 2009, A6.
- ↑ Juliet O'Neill, "Contradictions abound in Dhalla, caregivers testimony", CanWest News Service, 12 May 2009.
- ↑ Susan Delacourt, "Ignatieff standing by Dhalla; But Liberal leader refuses to take sides in affair where caregivers allege abuse in MP's household", Toronto Star, 13 May 2009, A14.
- ↑ Gloria Galloway, "Foreign-caregiver advocate contradicts Dhalla", Globe and Mail, 14 May 2009; Susan Delacourt and Dale Brazao, "Advocate for caregivers says MP's recollections are the opposite of hers", Toronto Star, 15 May 2009, A1.
- ↑ Susan Delacourt and Dale Brazao, "Nanny trouble", Toronto Star, 6 May 2009, A1.
- ↑ Emily Senger, "Dhalla counsel turns tables on accuser; Man says he was falsely accused of mistreating nanny at centre of issue", National Post, 15 May 2009, A2.
- ↑ "Tory minister Kenney denies conspiring against Ruby Dhalla", Canadian Press, 10 May 2009, 2:19pm; Gloria Galloway, "Tory minister rejects Dhalla ‘conspiracy'; Kenney says he has never met caregivers", Globe and Mail, 11 May 2009, A3.
- ↑ Sue Bailey, "Kenney's stance on Dhalla could taint probe: critics", Canadian Press, 14 May 2009, 5:01pm.
- ↑ "Statement from Dr. Ruby Dhalla, Member of Parliament Brampton-Springdale", Ruby Dhalla, 8 May 2009. This document is available at Dhalla's website. | Ruby Dhalla
Template:Infobox CanadianMP
Dr. Ruby Dhalla (born February 18, 1974) is a Canadian politician. She has represented the riding of Brampton—Springdale in the Canadian House of Commons since 2004 as a member of the Liberal Party of Canada. Dhalla and British Columbia Conservative Party of Canada Nina Grewal are the first Sikh women to serve in the Canadian House of Commons.
# Early life
Dhalla was born in Winnipeg, Manitoba to an immigrant family from Punjab (India), India. She first attracted international attention in 1984, when she was ten years old and living in Winnipeg's north end. When Indian soldiers took part in military actions at Punjab's Golden Temple, Dhalla wrote a letter to Indian Prime Minister of India Indira Gandhi, urging her to resolve the situation without further violence. Gandhi personally replied to Dhalla's letter, and referred to it at a press conference held months before her assassination.[1]
Dhalla received a Bachelor of Science degree in Biochemistry with a minor in Political Science from the University of Winnipeg in 1995. She moved to Toronto in the same year, and graduated with a Doctor of Chiropractic from the Canadian Memorial Chiropractic College in 1999. She later co-owned a chain of chiropractic clinics in Toronto, Brampton, Ontario, Mississauga and Aurora, Ontario with her brother, Neil Dhalla.[2] Dhalla has also pursued a career in acting, working in India for six months and playing a leading role in Kyon? Kis Liye? (translated as Why? and for Whom?), a Bollywood-inspired Hindi-language film shot in Hamilton, Ontario.[3] She finished second in the Miss India Canada pageant in 1993.[4]
Dhalla volunteered for Winnipeg Liberal candidate David Walker (Canadian politician)in the Canadian federal election, 1988, and later became a prominent member of the Winnipeg Young Liberals (Canada).[5] In 1998, she was elected as youth representative of the party's standing committee on multiculturalism.[6] Dhalla supported Paul Martin's bid to become Liberal Party leader in 2003.[7]
Dhalla attempted to block the DVD release of Kyon? Kis Liye? in 2009, arguing that publicity photos and posters from the movie had been "doctored" by putting her face on someone else's body. She also said that the film was being released to exploit her status as an elected official. Producer Charanjit "Chico" Sihra has said that no images were doctored, while adding that there is no unsuitable content in the movie.[8] Sinha also contends that Dhalla signed a distribution waiver and was paid $2000 (US), although he also says that the actual form was later destroyed in a fire. Dhalla has denied signing a waiver.[9]
In a 2008 poll of parliamentary staffers from The Hill Times, Dhalla was tied for second-sexiest female MP with Helena Guergis,[10] while that year Maxim magazine ranked her third in "The World's Hottest Politicians" behind Sarah Palin.[11]
# Member of Parliament
## Government member (2004-06)
In May 2004, Paul Martin designated Dhalla as the Liberal candidate for Brampton—Springdale in the Canadian federal election, 2004. This decision was opposed by the local Liberal Party riding executive, who had favoured Andrew Kania for the nomination.[12] Kania informed the media that Martin had previously allowed him to run for the nomination, and said that he would not rule out standing for election as an independent. The deputy campaign director for the Liberal Party defended Dhalla's selection, describing her as a star candidate who would be beneficial to the party. This controversy took place against a backdrop of 2004 Liberal Party of Canada infighting among other Liberal candidates for riding nominations, in which some rejected candidates accused Martin of undermining party democracy.[13] When the election was called, the Liberal riding association endorsed New Democratic Party candidate Kathy Pounder in protest.[14]
One of Dhalla's supporters in the 2004 election was comedian Mike Bullard (television), for whom Dhalla has worked as a chiropractor. Bullard joked during the campaign that he was helping Dhalla because "all my back trouble is on the Right-wing politics".[15] She was elected by a comfortable margin as the Liberals were reduced to a minority government nationally. After the election, she was appointed to the Standing Committee on Health.
Dhalla was a prominent organizer of the "Canada for Asia" benefit concert in January 2005, along with Canadian Senator Jerry Grafstein and singer Tom Cochrane. The event raised money for victims of the previous month's tsunami disaster in southeast Asia.[16] In October 2005, Dhalla organized a relief effort for victims of an earthquake in Pakistan.[17] She also promoted an accelerated foreign credential recognition process to assist recent Canadian immigrants in gaining professional employment.[18]
Dhalla voted in favour of Canada's Same-sex marriage in Canada legislation in 2005, on the grounds that the Canadian Charter of Rights and Freedoms must confer equality on different groups in society.[19]
The Liberal government was defeated by a motion of no confidence in late 2005, and Canadian federal election, 2006 was called for early 2006. Dhalla officially launched her re-election campaign in early December, with Bollywood actor Arjun Rampal as a star attendee.[20] Conservative candidate Sam Hundal attempted to use same-sex marriage as a wedge issue among recent immigrant voters, but was unsuccessful.[19] Dhalla was easily re-elected, while the Conservatives won a minority government at the national level.
## Opposition member (2006-present)
After the election, Dhalla was appointed as the Liberal Health Critic in the Official Opposition. In June 2006, she criticized Minister of Health (Canada) Tony Clement over a possible conflict-of-interest relating to his ownership of shares in Prudential Chem Inc.[21] The following month, she described Prime Minister of Canada Stephen Harper's refusal to attend an international AIDS conference in Toronto as "extremely upsetting".[22]
In June 2006, Dhalla alleged that the Conservatives had tried to convince her to cross the floor and join the party, as part of a campaign to win the support of youth, women and ethnic voters. She turned down the offer, saying that the Conservatives do not represent her values.[23] She later criticized Wajid Khan for crossing from the Liberals to the Conservatives.[24] (Khan was defeated in the Canadian federal election, 2008.)
Paul Martin resigned as Liberal leader after his party's defeat in the 2006 election. Dhalla initially considered entering the contest to succeed him, but instead gave her support to Michael Ignatieff. She was the Ignatieff Leadership Campaign's national co-chair, alongside Canadian Senatr David Smith (Canadian Senator) and Member of Parliament Denis Coderre.[25] Ignatieff was defeated by Stéphane Dion on the final ballot of the 2006 Liberal leadership convention.
Dion announced his new shadow cabinet in January 2007, and reassigned Dhalla from Health to Social Development.[26] She criticized the Conservatives for canceling the Martin government's national day-care plan, and spoke against the prospect of large, for-profit foreign firms taking over the industry.[27] She also wrote an opinion piece for the Toronto Star newspaper in early 2008, calling for developed countries to invest the necessary resources to target tuberculosis in the global south.[28]
Dhalla opposed the Conservative government's changes to Canada's immigration laws in early 2008, wherein the government set an annual limit on the number of cases to be heard and gave the Minister of Citizenship and Immigration (Canada) the discretion to fast-track some applicants. Dhalla suggested that the Conservatives would show favouritism to immigrants from certain communities. She was quoted as saying, "I think they're really picking and choosing for political purposes which communities they want to work with, and that is why there is a fear among these communities that the immigration laws being proposed right now are going to have an impact on them."[29]
Dhalla issued a Private Member's Bill in April 2008, calling on the federal government to apologize for the 1914 Komagata Maru incident, in which a ship with 376 mostly Sikh immigrants was denied access to Canada. The bill was unanimously passed the following month.[30]
She faced a difficult re-election in Canadian federal election, 2008, and ultimately defeated Conservative candidate Parm Gill by a small margin amid a provincial swing from the Liberals to Conservatives. This contest was marked by open animosity between the candidates.[31] The Conservatives were re-elected to a second minority government on the national level. Shortly after the election, a Toronto man was charged with making a death threat against Dhalla.[32]
Dhalla traveled to the Indian state of Punjab in January 2008. While attending a Non-Resident Indian (NRI) seminar, she called on the state government to introduce more stringent laws to prevent the abuse of married women.[33] She later visited her parent's village of Mullanpur.[34]
During this trip, a member of Dhalla's staff had a Handbag stolen by two children. It was later claimed that these children were beaten by the police after being apprehended. A local television news anchorman quoted Dhalla as saying that she "cannot control what the police do … and [hoped] that those young kids learn from this incident". The anchorman called this "shockingly callous". Dhalla later said that her comments were taken out of context and that she had spoken before she found out how the children had been treated. She clarified that she condemned any type of violence against children and called for an investigation into the incident.[35] The local media later issued a full retraction, acknowledging that Dhalla's initial comments had been presented out of context.[36]
Stéphane Dion stepped down as Liberal leader after a poor showing in the 2008 federal election, and Dhalla was mentioned as a possible candidate to succeed him.[37] The Toronto Star listed her as an outside contender, noting that her national profile was not very strong.[38] Before she was able to make her decision, other prominent candidates withdrew from the contest and gave their support to Michael Ignatieff. In December, Dhalla announced she would not be a candidate.[39] Ignatieff was duly acclaimed as interim leader in January 2009, and was officially confirmed as party leader later in the year.
In January 2009, Ignatieff appointed Dhalla as the Liberal critic for Youth and Multiculturalism.[40] She stepped down from the position in May.
## Caregivers controversy
On May 5, 2009, the Toronto Star newspaper ran a front-page story with allegations that two Filipina caregivers hired to look after Dhalla's mother had been illegally employed and mistreated. The caregivers alleged that Ruby Dhalla had improperly seized their passports, and that the family forced them to do chores such as "washing cars, shining shoes and cleaning family-owned chiropractic clinics". Dhalla responded that she was "shocked and appalled" by the allegations, saying that the caregivers were never abused and that she had never taken anyone's passport. She later released a statement indicating that she had no involvement with the hiring or supervision of the women. Ruby's brother Neil Dhalla has also denied the charges, saying that his family was "[the] victim of an unscrupulous agency, as well as the caregivers".[41] A third caregiver later came forward with similar charges.[42]
The Star reported that these allegations had originally surfaced at a public meeting held by provincial Minister of Education (Ontario) Kathleen Wynne and Minister of Labour (Ontario) Peter Fonseca to address violations of Canada's Live-In Caregiver Program.[41] Opposition legislators later called for Fonseca to resign for not having investigated the matter further; he responded that he attended the meeting as an "impartial" observer, and had distributed pamphlets to all complainants outlining their rights under Ontario's labour laws.[43] Premier of Ontario Dalton McGuinty added that around thirty other caregivers had raised similar concerns, and that it would have been inappropriate for Fonseca to "pick and choose" individual cases to address himself. He added that investigators from the Labour Ministry would attend future meetings.[44]
Dhalla stepped down as the Liberal Youth and Multiculturalism Critic on May 6, and called for a federal ethics investigation to clear her name.[45] A subsequent Globe and Mail article suggested that she had few supporters within the federal Liberal caucus, and that other MPs considered her a "high maintenance" self-promoter, demanding on her staff and unwilling to engage in the mundane details of parliamentary life.[46] Some Liberal MPs have publicly defended her, however, including Judy Sgro.[47] Bob Rae has said of the controversy over Dhalla, "In my, dare I say it, 30-year career, I've seen a lot of feeding frenzies. I've seen a lot of lynch mob activity. And this is just another example of it".[48]
Dhalla held a press conference on May 8, in which she described the allegations against her as a coordinated attack on her reputation. Her lawyer described Dhalla as the victim in the affair, and brought forward several signed documents which he said would verify his client's position. He added that Neil Dhalla was responsible for hiring the caregivers, and suggested that the controversy was part of a partisan smear campaign orchestrated by Dhalla's political opponents.[49]
Both Dhalla and the caregivers testified before the House of Commons Immigration Committee on May 12, 2009.[50] Many journalists wrote that the hearings failed to shed any light on the matter, which they argued should not have been investigated by a political committee in the first place.[51] Committee chair David Tilson said, "They both had opposite stories. Who's telling the truth, I have no idea."[52] Following Dhalla's testimony, Michael Ignatieff said, "A member of my caucus has been accused of a serious, serious issue. She's mounted a vigorous and convincing defence ... and I take her at her word".[53]
On the day after Dhalla's appearance, Agathe Mason, the executive director of a Toronto support group for immigrant women called Intercede, testified before the Commons committee that she had called Dhalla (rather than her brother) when one of the caregivers complained about her passport being withheld. Mason said that she informed Dhalla she was breaking the law and had 24 hours to return the passport, and that to her recollection the passport was returned the following day.[54] Dhalla had previously rejected Mason's accusations, saying that she had never spoken with anyone at Intercede.[55] On the same day as Mason's testimony, Dhalla's lawyer informed the media that one of the caregivers had made unfounded charges against another employer in the past.[56]
Minister of Citizenship and Immigration (Canada) Jason Kenney has denied the suggestion of political interference, saying that he had no personal knowledge of the matter until it was reported by the media.[57] His ministerial assistant Alykhan Velshi was later seen handing out documents to reporters at a meeting of the Immigration Committee, in a bid to discredit Dhalla. Some believe that this could have a chilling effect among civil servants in Kenney's department, and prevent them from reviewing the case in a fair and open manner.[58]
No charges have been filed. Dhalla has asked the public and media to "hold judgment and give [her] family privacy".[59]
# Electoral record
Template:Canadian federal election, 2008/Electoral District/Brampton—Springdale
Template:Canadian federal election, 2006/Electoral District/Brampton—Springdale
Template:Canadian federal election, 2004/Electoral District/Brampton—Springdale
All electoral information is taken from Elections Canada. Italicized expenditures refer to submitted totals, and are presented when the final reviewed totals are not available.
# Footnotes
- ↑ Randall King, "Screen Gem", Winnipeg Free Press, 30 May 2003, D1.
- ↑ Renu Mehta, "House Bound", Femina, 1 September 2004.
- ↑ Randall King, "Screen Gem", Winnipeg Free Press, 30 May 2003, D1; "Liberal Ruby Dhalla trying to block release of movie in which she co-starred", Canadian Press, 12 March 2009, 6:11am.
- ↑ Rebecca Myers, "Unconventional Resumes", Time Magazine (Canadian edition), 14 June 2004, p. 17.
- ↑ Canada Votes 2004, Canadian Broadcasting Corporation, Brampton—Springdale riding profile.
- ↑ "Young Liberals elevate Manitoban", Winnipeg Free Press, 1 April 1998, A4.
- ↑ Jim Brown, "BC-Martin-Democracy, Bgt", Canadian Press, 9 May 2004, 16:43 report.
- ↑ Mark McNeil, "Bollywood poster body not me: MP", Hamilton Spectator, 13 March 2009, A5.
- ↑ "Indo-Canadian Lawmaker up in arms on her role in a movie", The Press Trust of India Limited, 14 March 2009.
- ↑ "Peter MacKay est le parlementaire le plus sexy selon The Hill Times", La Presse Canadienne - Le fil radio, 15 April 2009, 12:06am.
- ↑ "The wild, the whimsical and the wacky from the campaign trail", Canadian Press, 11 September 2008, 4:14pm.
- ↑ "Would-be Liberal candidates cry foul", Kitchener-Waterloo Record, 10 May 2004, A4.
- ↑ Graham Fraser, "Anger as 'stars' oust Liberal hopefuls", Toronto Star, 10 May 2004, A6.
- ↑ Katherine Harding, "Party infighting plagues riding", Globe and Mail, 8 June 2004, A6; "Correction", Globe and Mail, 8 May 2009, A2 indicates that Kania himself did not endorse the NDP candidate.
- ↑ Jane Taber, "Nell Martin: the woman behind the portrait", Globe and Mail, 26 June 2004, A6.
- ↑ Randall King, "MP plans relief concert", Winnipeg Free Press, 12 January 2005, D10.
- ↑ "Indo-Canadian MP seeks quake relief", Hindustan Times, 21 October 2005, page number not listed.
- ↑ Ishani Duttagupta, "New Canada govt may serve Indian immigrants better", Economic Times (English edition), 25 January 2006.
- ↑ Jump up to: 19.0 19.1 Heba Aly, "Tories say stand on gay marriage tightens race in Brampton", Globe and Mail, 23 December 2005, A15.
- ↑ "Arjun Rampal kick-starts Canadian MP's campaign", Hindustan Times (English edition), 8 December 2005.
- ↑ Bill Curry, "Clement resists conflict claims", Globe and Mail, 14 June 2006, A4.
- ↑ Beth Duff-Brown, "Canada's PM will not be among record number of delegates at Toronto AIDS summit", Associated Press, 31 July 2006, 16:45 report.
- ↑ John Ivison and Peter O'Neil, "Indo-Canadian Liberal MP invited to join Tory ranks", Vancouver Sun, 16 June 2006, A6.
- ↑ Richard Brennan, "Taxpayers have right to see Khan's report, critics argue", Toronto Star, 15 January 2007, A10.
- ↑ John Ivison, "It takes a quitter to start a race", National Post, 9 February 2006, A8; Michael Ignatieff with his national campaign co-chairs, accessed October 2006.
- ↑ Juliet O'Neill, "47 Liberals to shadow 30 Tories", National Post, 19 January 2007, A4.
- ↑ Tonda MacCharles, "Opposition parties unite to fight big-box daycare", Toronto Star, 1 November 2007, A1; Laurie Monsebraaten, "Canada letting kids down, report says", Toronto Star, 20 November 2007, A4.
- ↑ Ruby Dhalla, "It's time for action; Tuberculosis is easy to cure but the lack of resources permits epidemic to spread", Toronto Star, 26 March 2008, A6.
- ↑ Susan Delacourt, "Opposition raises discrimination fears; But immigration plan clears one challenge", Toronto Star, 10 April 2008, A21; David Akin, "Tory budget legislation passes with help from Grits", Ottawa Citizen, 10 June 2008, A1. The Liberals as a whole decided not to bring down Harper's minority government on this bill; Dhalla was one of a number of Liberal MPs who voted in opposition.
- ↑ Kim Bolan, "Apology on the way for Indo-Canadians", Vancouver Sun, 12 May 2008, B1; Joanna Smith, "Apologies for past wrongs abound", Toronto Star, 20 May 2008, A13.
- ↑ Theresa Boyle, "Bitter battle between Dhalla and Gill", Globe and Mail, 15 October 2008, U10.
- ↑ "Toronto man charged with threatening MP", Globe and Mail, 21 October 2008, A10.
- ↑ "Canadian lawmaker calls on Punjab to check domestic violence", Asian News International, 7 January 2008.
- ↑ "NRIs cherish visiting their ancestral villages", Asian News International, 21 January 2008.
- ↑ CTV.ca News Staff, "It MP touring India calls for change after kids beaten ", CTV.ca, 10 January 2008, [1], accessed January 2008.
- ↑ Sonya Fateh, "Indian police quietly drop case of MP, stolen purse", Toronto Star, 10 March 2008, A1.
- ↑ For instance, see Norma Greenaway, "Possible successors a varied lot", Montreal Gazette, 21 October 2008, A2; Juliet O'Neill, "Dion vows 'respectful' leadership contest", Edmonton Journal, 24 October 2008, A6; "Two Manitobans among Liberal leadership contenders", Winnipeg Free Press, 24 October 2008, W1; Brian Laghi, Jane Taber, Campbell Clark, "The race to renew the Liberal identity", Globe and Mail, 30 October 2008, A17.
- ↑ "Taking bets on next Liberal leader" editorial, Toronto Star, 23 October 2008, A6.
- ↑ Roger Belgrave, "Leadership run not in the cards for local MP", Brampton Guardian, 18 December 2008.
- ↑ "No place for Dion on Ignatieff's front bench", National Post, 23 January 2009.
- ↑ Jump up to: 41.0 41.1 Dale Brazao, "Ruby's nanny trouble", Toronto Star, 5 May 2009, A1.
- ↑ Dale Brazao, "Housekeeper 'paid under table'", Toronto Star, 8 May 2009, A1.
- ↑ Dale Brazao, Robert Benzie and Rob Ferguson, "Provincial ministers defend actions", Toronto Star, 7 May 2009, A1.
- ↑ Keith Leslie, "Ont. Tories demand labour minister resign over Ruby Dhalla nanny allegations", Canadian Press, 6 May 2009, 4:26pm.
- ↑ "Dhalla quits critic's role amid family controversy", Canadian Press, 6 May 2009, 10:36am; Mike de Souza, "Dhalla resigns critic post, vows to clear name", National Post, 7 May 2009, A6; Susan Delacourt, "Dhalla seeks federal ethics investigation", Toronto Star, 7 May 2009, A1.
- ↑ CAMPBELL CLARK, GLORIA GALLOWAY AND KAREN HOWLETT, "Scandal sidelines ‘high-maintenance' Liberal MP", Globe and Mail, 7 May 2009, A3.
- ↑ Susan Delacourt, "Fellow MP says Dhalla 'devastated'", Toronto Star, 8 May 2009, A6.
- ↑ Gloria Galloway and Karen Howlett, "Committee to hear from MP's ex-workers", Globe and Mail, 8 May 2009, A5.
- ↑ Caroline Alphonso, Kate Hammer and Daniel LeBlanc, "Political conspiracy fuelling nanny scandal, Dhalla says; Caregivers' claims ‘complete nonsense'", Globe and Mail, 9 May 2009, A1; David Akin, "Dhalla caregivers' allegations a partisan smear, lawyer says", Ottawa Citizen, 9 May 2009, A3.
- ↑ Juliet O'Neill, "Dhalla denies caregivers' allegations made at Commons committee", CanWest News Service, 12 May 2009.
- ↑ "No light on live-in caregivers" [editorial], Globe and Mail, 13 May 2009, A14; "The Ruby Dhalla sideshow was a waste of MPs' time", Montreal Gazette [editorial], 13 May 2009, A16; "Politicians shouldn't investigate each other", Waterloo Region Record editorial, 13 May 2009, A6.
- ↑ Juliet O'Neill, "Contradictions abound in Dhalla, caregivers testimony", CanWest News Service, 12 May 2009.
- ↑ Susan Delacourt, "Ignatieff standing by Dhalla; But Liberal leader refuses to take sides in affair where caregivers allege abuse in MP's household", Toronto Star, 13 May 2009, A14.
- ↑ Gloria Galloway, "Foreign-caregiver advocate contradicts Dhalla", Globe and Mail, 14 May 2009; Susan Delacourt and Dale Brazao, "Advocate for caregivers says MP's recollections are the opposite of hers", Toronto Star, 15 May 2009, A1.
- ↑ Susan Delacourt and Dale Brazao, "Nanny trouble", Toronto Star, 6 May 2009, A1.
- ↑ Emily Senger, "Dhalla counsel turns tables on accuser; Man says he was falsely accused of mistreating nanny at centre of issue", National Post, 15 May 2009, A2.
- ↑ "Tory minister Kenney denies conspiring against Ruby Dhalla", Canadian Press, 10 May 2009, 2:19pm; Gloria Galloway, "Tory minister rejects Dhalla ‘conspiracy'; Kenney says he has never met caregivers", Globe and Mail, 11 May 2009, A3.
- ↑ Sue Bailey, "Kenney's stance on Dhalla could taint probe: critics", Canadian Press, 14 May 2009, 5:01pm.
- ↑ "Statement from Dr. Ruby Dhalla, Member of Parliament Brampton-Springdale", Ruby Dhalla, 8 May 2009. This document is available at Dhalla's website.
# External links
- Twitter
- Ruby Dhalla
- How'd They Vote?: Ruby Dhalla's voting history and quotes
- Template:CanParlbio
Template:Persondata
Template:ATTRIB | https://www.wikidoc.org/index.php/Ruby_Dhalla | |
2a31913108ff7b0dd83e09079709758f9f8ec3c0 | wikidoc | Russian Flu | Russian Flu
H1N1 is a subtype of the species Influenza A virus. H1N1 has mutated into various strains including the Spanish Flu strain (now extinct in the wild), mild human flu strains, endemic pig strains, and various strains found in birds.
A variant of H1N1 was responsible for the Spanish flu pandemic that killed some 50 million to 100 million people worldwide over about a year in 1918 and 1919 . A different variant exists in pig populations. Controversy arose in October 2005, after the H1N1 genome was published in the journal Science. Many fear that this information could be used for bioterrorism.
"When he compared the 1918 virus with today's human flu viruses, Dr. Taubenberger noticed that it had alterations in just 25 to 30 of the virus's 4,400 amino acids. Those few changes turned a bird virus into a killer that could spread from person to person."
Low pathogenic H1N1 strains still exist in the wild today, causing roughly half of all flu infections in 2006.
# Spanish Flu
The Spanish Flu, also known as La Grippe, or La Pesadilla, was an unusually severe and deadly strain of avian influenza, a viral infectious disease, that killed some 50 million to 100 million people worldwide over about a year in 1918 and 1919. It is thought to have been one of the most deadly pandemics so far in human history. It was caused by the H1N1 type of influenza virus, which is similar to bird flu of today, mainly H5N1 and H5N2.
The Spanish flu caused an unusual number of deaths because it, like H5N1, caused a cytokine storm in the body. The virus infected lung cells, leading to overstimulation of the immune system via release of cytokine bursts into the lung tissue. This leads to extensive leukocyte migration towards the lungs, causing destruction of lung tissue and secretion of liquid into the lung, and making it difficult for the patient to breathe. Due to the nature of the infection, people with a normal healthy immune system were more susceptible to the disease, such as young adults compared to young children and the elderly.
# Russian flu
The Russian flu was a 1977-1978 flu epidemic caused by strain Influenza A/USSR/90/77 (H1N1). It infected mostly children and young adults under 23 because a similar strain was prevalent in 1947-57, causing most adults to have substantial immunity. Some have called it a flu pandemic but because it only affected the young it is not considered a true pandemic. The virus was included in the 1978-1979 influenza vaccine. | Russian Flu
Template:Flu
H1N1 is a subtype of the species Influenza A virus. H1N1 has mutated into various strains including the Spanish Flu strain (now extinct in the wild), mild human flu strains, endemic pig strains, and various strains found in birds.
A variant of H1N1 was responsible for the Spanish flu pandemic that killed some 50 million to 100 million people worldwide over about a year in 1918 and 1919 [1]. A different variant exists in pig populations. Controversy arose in October 2005, after the H1N1 genome was published in the journal Science. Many fear that this information could be used for bioterrorism.
"When he compared the 1918 virus with today's human flu viruses, Dr. Taubenberger noticed that it had alterations in just 25 to 30 of the virus's 4,400 amino acids. Those few changes turned a bird virus into a killer that could spread from person to person." [2]
Low pathogenic H1N1 strains still exist in the wild today, causing roughly half of all flu infections in 2006. [3]
# Spanish Flu
The Spanish Flu, also known as La Grippe, or La Pesadilla, was an unusually severe and deadly strain of avian influenza, a viral infectious disease, that killed some 50 million to 100 million people worldwide over about a year in 1918 and 1919. It is thought to have been one of the most deadly pandemics so far in human history. It was caused by the H1N1 type of influenza virus, which is similar to bird flu of today, mainly H5N1 and H5N2.
The Spanish flu caused an unusual number of deaths because it, like H5N1, caused a cytokine storm in the body. The virus infected lung cells, leading to overstimulation of the immune system via release of cytokine bursts into the lung tissue. This leads to extensive leukocyte migration towards the lungs, causing destruction of lung tissue and secretion of liquid into the lung, and making it difficult for the patient to breathe. Due to the nature of the infection, people with a normal healthy immune system were more susceptible to the disease, such as young adults compared to young children and the elderly.
# Russian flu
The Russian flu was a 1977-1978 flu epidemic caused by strain Influenza A/USSR/90/77 (H1N1). It infected mostly children and young adults under 23 because a similar strain was prevalent in 1947-57, causing most adults to have substantial immunity. Some have called it a flu pandemic but because it only affected the young it is not considered a true pandemic. The virus was included in the 1978-1979 influenza vaccine.[4][5][6][7] | https://www.wikidoc.org/index.php/Russian_Flu | |
7f6d054b13ada07adc764e36bcda2f54acf56ac0 | wikidoc | Rømer scale | Rømer scale
Rømer is a disused temperature scale named after the Danish astronomer Ole Christensen Rømer, who proposed it in 1701.
In this scale, the zero was initially set using freezing brine. The boiling point of water was defined as 60 degrees. Rømer then saw that the freezing point of water fell at roughly one eighth of that value (7.5 degrees), so he used that value as the other fixed point. Thus the unit of this scale, a Rømer degree, is 40/21 of a kelvin (or of a Celsius degree). The symbol is sometimes given as °R, but since that is also sometimes used for the Rankine scale, the other symbol °Rø is to be preferred. The name should not be confused with Réaumur.
A plausible story of how the Fahrenheit scale was invented is that Daniel Gabriel Fahrenheit learned of Rømer's work and visited him in 1708; he improved on the scale, increasing the number of divisions by a factor of four and eventually establishing what is now known as the Fahrenheit scale, in 1724. | Rømer scale
Template:Temperature
Rømer is a disused temperature scale named after the Danish astronomer Ole Christensen Rømer, who proposed it in 1701.
In this scale, the zero was initially set using freezing brine. The boiling point of water was defined as 60 degrees. Rømer then saw that the freezing point of water fell at roughly one eighth of that value (7.5 degrees), so he used that value as the other fixed point. Thus the unit of this scale, a Rømer degree, is 40/21 of a kelvin (or of a Celsius degree). The symbol is sometimes given as °R, but since that is also sometimes used for the Rankine scale, the other symbol °Rø is to be preferred. The name should not be confused with Réaumur.
A plausible story of how the Fahrenheit scale was invented is that Daniel Gabriel Fahrenheit learned of Rømer's work and visited him in 1708; he improved on the scale, increasing the number of divisions by a factor of four and eventually establishing what is now known as the Fahrenheit scale, in 1724. | https://www.wikidoc.org/index.php/R%C3%B8mer_scale | |
a1fa39511997d89756f8e52a87f5880b3de01dd0 | wikidoc | SARS (gene) | SARS (gene)
SARS and cytoplasmic seryl-tRNA synthetase are a human gene and its encoded enzyme product, respectively. SARS belongs to the class II amino-acyl tRNA family and is found in all humans; its encoded enzyme, seryl-tRNA synthetase, is involved in protein translation and is related to several bacterial and yeast counterparts.
Mutations in SARS have been associated with several conditions, including HUPRA syndrome.
# Discovery
Since the 1960s, seryl-tRNA synthetases have been described in various eukaryotic species, in both biochemical and structural analyses. It was not until 1997 that human SARS and its enzyme product were isolated and expressed in Escherichia coli by a team from The European Molecular Biology Laboratory in France.
# Gene location
The human SARS gene is located on the plus strand of chromosome 1, from base pair 109,213,893 to base pair 109,238,182.
# Protein
Seryl-tRNA synthetase is made up of 514 amino acid residues as weighs 58,777 Da. It exists as a homodimer of two identical subunits, with the tRNA molecule binding across the dimer by similarity. It has two distinct domains:
- A catalytic core
- A 3 base pair serine binding N-terminal extension
# Function and mechanism
"SARS" and it’s enzyme product seryl-tRNA synthetase are involved in protein translation; specifically, seryl-tRNA synthetase catalyses the transfer of L-serine to tRNA (Ser). The cytosolic enzyme recognises its cognate tRNA species and binds with a high level of specificity, allowing the accurate interaction between corresponding codons and anticodons on mRNA and tRNA during protein translation.
# Mutations
As with many mutations that affect protein translation, mutations in the SARS gene set have been shown to cause a collection of diseases, such as hyperuricemia, metabolic alkalosis, pulmonary hypertension, and progressive renal failure in infancy; together, these conditions are known as HUPRA syndrome.
In these cases, the SARS gene (in particular, "SARS2") undergoes a missense mutation, which results in a complete lack of acetylated seryl-tRNA synthetase and a severely reduced amount of non-acetylated enzyme. This results in the ineffective or complete inability of L-serine to be transferred to its cognate tRNA, resulting in incomplete protein translation and folding. The impacts appear to only reach a phenotypic pathology in certain high energy expenditure cells, such as renal cells and lung tissue. It has been suggested that the residual activity of the SARS2 gene allows most other tissues to avoid cytopathic symptoms, however, is unable to protect high-energy requirement cells from damage.
The prevalence of SARS mutations resulting in HUPRA syndrome are incredibly rare, with less than 1 in 1,000,000 babies born with the condition. A Palestinian community in the Greater Jerusalem region appears to have a much higher incidence of the mutation, potentially due to a common ancestor. | SARS (gene)
SARS and cytoplasmic seryl-tRNA synthetase are a human gene and its encoded enzyme product, respectively.[1][2] SARS belongs to the class II amino-acyl tRNA family and is found in all humans; its encoded enzyme, seryl-tRNA synthetase, is involved in protein translation and is related to several bacterial and yeast counterparts.[2]
Mutations in SARS have been associated with several conditions, including HUPRA syndrome.[3]
# Discovery
Since the 1960s, seryl-tRNA synthetases have been described in various eukaryotic species, in both biochemical and structural analyses.[4][5] It was not until 1997 that human SARS and its enzyme product were isolated and expressed in Escherichia coli by a team from The European Molecular Biology Laboratory in France.[1]
# Gene location
The human SARS gene is located on the plus strand of chromosome 1, from base pair 109,213,893 to base pair 109,238,182.[6]
# Protein
Seryl-tRNA synthetase is made up of 514 amino acid residues as weighs 58,777 Da.[7] It exists as a homodimer of two identical subunits, with the tRNA molecule binding across the dimer by similarity.[8] It has two distinct domains:
- A catalytic core[6]
- A 3 base pair serine binding N-terminal extension[6]
# Function and mechanism
"SARS" and it’s enzyme product seryl-tRNA synthetase are involved in protein translation; specifically, seryl-tRNA synthetase catalyses the transfer of L-serine to tRNA (Ser).[9] The cytosolic enzyme recognises its cognate tRNA species and binds with a high level of specificity, allowing the accurate interaction between corresponding codons and anticodons on mRNA and tRNA during protein translation.[1]
# Mutations
As with many mutations that affect protein translation,[10] mutations in the SARS gene set have been shown to cause a collection of diseases, such as hyperuricemia, metabolic alkalosis, pulmonary hypertension, and progressive renal failure in infancy; together, these conditions are known as HUPRA syndrome.[3]
In these cases, the SARS gene (in particular, "SARS2") undergoes a missense mutation, which results in a complete lack of acetylated seryl-tRNA synthetase and a severely reduced amount of non-acetylated enzyme.[3] This results in the ineffective or complete inability of L-serine to be transferred to its cognate tRNA, resulting in incomplete protein translation and folding. The impacts appear to only reach a phenotypic pathology in certain high energy expenditure cells, such as renal cells and lung tissue. It has been suggested that the residual activity of the SARS2 gene allows most other tissues to avoid cytopathic symptoms, however, is unable to protect high-energy requirement cells from damage.[3]
The prevalence of SARS mutations resulting in HUPRA syndrome are incredibly rare, with less than 1 in 1,000,000 babies born with the condition.[11] A Palestinian community in the Greater Jerusalem region appears to have a much higher incidence of the mutation, potentially due to a common ancestor.[3] | https://www.wikidoc.org/index.php/SARS_(gene) | |
7e8b1ce17edbe1293de4b95bfd6619da449cb6d9 | wikidoc | SAT1 (gene) | SAT1 (gene)
Diamine acetyltransferase 1 is an enzyme that in humans is encoded by the SAT1 gene found on the X chromosome.
# Function
Spermidine/spermine N(1)-acetyltransferase (SPD/SPM acetyltransferase) is a rate-limiting enzyme in the catabolic pathway of polyamine metabolism. It catalyzes the N(1)-acetylation of spermidine and spermine and, by the successive activity of polyamine oxidase, spermine can be converted to spermidine and spermidine to putrescine. The SAT1 gene is used to help regulate polymamies levels inside the cell by regulating their transport in and out of the cell. SAT1 is also involved in the first step to synthesize N-actylputrescine from putrescine. PMF1 and NRF2 work together to transcript the SAT1 gene.
# Structure
The SAT1 gene is 3,069 base pairs long. There are 171 amino acids and its molecular mass is 20024 Da Daltons). In 1992 at The Johns Hopkins University School of Medicine, Lei Xiao and several others cloned over 4000 base pairs of the region containing the coding sequence of the SAT1 gene also referred to as SSAT-1, SSAT,SAT,KFSD,DC21, KFSDX gene. This gene is located on the X chromosome in the region Xp22.1. The primer extension analysis indicated that the transcription started 179 bases upstream from the translational start site. Furthermore, they determined that it appeared to be controlled by a "TATA-less" promoter. Normally, there would be a TATA box where RNA polymerase II would be involved in assisting with initiation by properly positioning the enzyme, however in a TATA-less promoter situation the TATA box is absent.
# Clinical significance
An association with Keratosis follicularis spinulosa decalvans has been suggested. Data shows that Keratosis Follicularis Spinulosa Decalvans (KSFD) could be caused by mutations in the SAT 1 gene. KSFD is also believed to be X-linked which helps prove that the disease is caused by a mutation found in the SAT 1 gene which is located on the X chromosome. The mutation most likely occurs at the location Xp22.1. KDSF mostly affects men which makes since for it to be a x-linked disease,caused by a mutation of the SAT1 gene.
Elevated levels of RNA transcripts of SAT1 in the bloodstream have been associated with a higher risk of suicide.
The SAT1 gene has implications with NLS-2 Neu-Laxova syndrome, type 2 (NLS). It is inherited as an autosomal recessive trait and is considered a rare lethal congenital disorder. Severe growth delays before birth including low birth weight and shorter than normal length occur. After birth, outward observable characteristics include significant small skull size (microcephaly), wider than normal spaced eyes, sloped forehead and other disfiguring facial features. There may also be random places of fluid retention (edema)throughout the body and permanent joint limitations due to limb malformations. NLS can be detected in pregnant woman with ultrasound examination. In some people of Neu-Laxova syndrome, other areas were severely affected such as skin, genitals, and other internal organs including the heart. Males and females are equally affected and could be most closely associated with persons of Pakistani origin. However, there have been cases reported in several other diverse backgrounds. The prognosis is extremely poor and in most cases the infant dies shortly after birth or are stillborn. The first documented and reported case in Japan involved a baby girl exhibiting microcephaly, severe edema, and other symptoms. In her case she had a condition known as congenital vertical talus or rocker-feet. The foot is abnormally shaped in a convex position. She survived 134 days.
The SAT1 gene plays a vital role in the catabolic pathway of polyamine metabolism. It acts as a rate-limiting enzyme in the pathway of polyamine metabolism, meaning it is significant in the involvement of cell survival. Research has shown that the tumor protein known as p53 can specifically target the SAT1 gene that results in ferroptotic cell-death. Ferroptosis is when a death of a cell is caused by an iron-dependent accumulation of a lipid.
# SAT1 flipping method
SAT1 flipping refers to the excision of a target gene and integration of a new different gene to create a mutant genome different than the wild type genome. This method uses the effects of a cassette - movable piece of genetic material that includes a recombination site and a specific gene about 500 - 1000 base pairs long. In the SAT1 flipping method, the specific gene within the cassette is a dominant nourseothricin resistance marker, also known as a caSAT1 gene, which is used to select and excise the target gene within the string of DNA being examined. Cassettes are the optimal choice of methodology for SAT1 gene flipping because they are known to carry antibiotic resistant genes within their genetic material. The SAT1 flipping method is preferred over other knock-out methods for gene excision when other said methods provide less than optimal results. | SAT1 (gene)
Diamine acetyltransferase 1 is an enzyme that in humans is encoded by the SAT1 gene found on the X chromosome.[1][2][3]
# Function
Spermidine/spermine N(1)-acetyltransferase (SPD/SPM acetyltransferase) is a rate-limiting enzyme in the catabolic pathway of polyamine metabolism. It catalyzes the N(1)-acetylation of spermidine and spermine and, by the successive activity of polyamine oxidase, spermine can be converted to spermidine and spermidine to putrescine.[3] The SAT1 gene is used to help regulate polymamies levels inside the cell by regulating their transport in and out of the cell.[4][5] SAT1 is also involved in the first step to synthesize N-actylputrescine from putrescine.[6] PMF1 and NRF2 work together to transcript the SAT1 gene.[7]
# Structure
The SAT1 gene is 3,069 base pairs long. There are 171 amino acids and its molecular mass is 20024 Da Daltons). In 1992 at The Johns Hopkins University School of Medicine, Lei Xiao and several others cloned over 4000 base pairs of the region containing the coding sequence of the SAT1 gene also referred to as SSAT-1, SSAT,SAT,KFSD,DC21, KFSDX gene.[8] This gene is located on the X chromosome in the region Xp22.1. The primer extension analysis indicated that the transcription started 179 bases upstream from the translational start site. Furthermore, they determined that it appeared to be controlled by a "TATA-less" promoter. Normally, there would be a TATA box where RNA polymerase II would be involved in assisting with initiation by properly positioning the enzyme, however in a TATA-less promoter situation the TATA box is absent.[9]
# Clinical significance
An association with Keratosis follicularis spinulosa decalvans has been suggested.[10] Data shows that Keratosis Follicularis Spinulosa Decalvans (KSFD) could be caused by mutations in the SAT 1 gene. KSFD is also believed to be X-linked which helps prove that the disease is caused by a mutation found in the SAT 1 gene which is located on the X chromosome.[11] The mutation most likely occurs at the location Xp22.1.[12] KDSF mostly affects men which makes since for it to be a x-linked disease,caused by a mutation of the SAT1 gene.[13]
Elevated levels of RNA transcripts of SAT1 in the bloodstream have been associated with a higher risk of suicide.[14][15][16]
The SAT1 gene has implications with NLS-2 Neu-Laxova syndrome, type 2 (NLS). It is inherited as an autosomal recessive trait and is considered a rare lethal congenital disorder. Severe growth delays before birth including low birth weight and shorter than normal length occur. After birth, outward observable characteristics include significant small skull size (microcephaly), wider than normal spaced eyes, sloped forehead and other disfiguring facial features. There may also be random places of fluid retention (edema)throughout the body and permanent joint limitations due to limb malformations. NLS can be detected in pregnant woman with ultrasound examination. In some people of Neu-Laxova syndrome, other areas were severely affected such as skin, genitals, and other internal organs including the heart. Males and females are equally affected and could be most closely associated with persons of Pakistani origin. However, there have been cases reported in several other diverse backgrounds. The prognosis is extremely poor and in most cases the infant dies shortly after birth or are stillborn. The first documented and reported case in Japan involved a baby girl exhibiting microcephaly, severe edema, and other symptoms. In her case she had a condition known as congenital vertical talus or rocker-feet. The foot is abnormally shaped in a convex position. She survived 134 days.[17][18][19]
The SAT1 gene plays a vital role in the catabolic pathway of polyamine metabolism. It acts as a rate-limiting enzyme in the pathway of polyamine metabolism, meaning it is significant in the involvement of cell survival. Research has shown that the tumor protein known as p53 can specifically target the SAT1 gene that results in ferroptotic cell-death. Ferroptosis is when a death of a cell is caused by an iron-dependent accumulation of a lipid.[20]
# SAT1 flipping method
SAT1 flipping refers to the excision of a target gene and integration of a new different gene to create a mutant genome different than the wild type genome. This method uses the effects of a cassette - movable piece of genetic material that includes a recombination site and a specific gene about 500 - 1000 base pairs long. In the SAT1 flipping method, the specific gene within the cassette is a dominant nourseothricin resistance marker, also known as a caSAT1 gene, which is used to select and excise the target gene within the string of DNA being examined. Cassettes are the optimal choice of methodology for SAT1 gene flipping because they are known to carry antibiotic resistant genes within their genetic material. The SAT1 flipping method is preferred over other knock-out methods for gene excision when other said methods provide less than optimal results.[21] | https://www.wikidoc.org/index.php/SAT1_(gene) | |
4a7f431d8230a187ffd1eb67e3130b9c23af321d | wikidoc | SCAN domain | SCAN domain
"The SCAN domain is a highly conserved, leucine-rich motif of approximately 60 aa originally found within a subfamily of zinc finger proteins."
"The SCAN domain (named after SRE-ZBP, CTfin51, AW-1 and Number 18 cDNA) is found in several pfam00096 proteins. The domain has been shown to be able to mediate homo- and hetero-oligomerization."
# SRE-ZBP
The "SRE-ZBP a human zinc finger protein that binds to the c-Fos serum response element (17)".
"The promoters of many genes whose transcription is rapidly and transiently induced following growth factor or mitogen stimulation of susceptible cells contain a common regulatory element, the serum response element (SRE)."
"The serum response element (SRE), a region of the c-fos gene which controls growth factor-induced transcription, is shown to mediate c-fos transcription in response to activation of L-type voltage-sensitive calcium channels. Calcium-dependent transcriptional activation through the SRE is mediated by the serum response factor (SRF). Membrane depolarization induces phosphorylation of SRF at Ser-103, an event shown to enhance the ability of SRF to bind the SRE."
The SRE wild type (SREwt) contains the nucleotide sequence ACAGGATGTCCATATTAGGACATCTGC, of which CCATATTAGG is the CArG box, TTAGGACAT is the C/EBP box, and CATCTG is the E box.
"Less flexibility has been attributed to the backbone structure of Z-DNA than to B-DNA (Wang et al., 1979). Initially, Z-DNA was seen in crystal structures of molecules which have strict alternations of purines and pyrimidines involving GC and AT base pairs (Wang et al., 1979, 1984). However, it has recently been shown that Z-DNA will also form in the structure d(CGATCG) in which the cytosines are methylated or brominated on the C5 position (Wang et al., 1985) as well as the brominated d(CGCGATCGCG) (Feigon et al., 1985). In this non-alternating purine/pyrimidine sequence, the thymidines assume the syn conformation and the deoxyadenosines are in the anti conformation thereby preserving the dinucleotide repeat. The resulting deformations in the d(CGATCG) backbone are comparable in magnitude with those described above for a Z-DNA sequence having a wobble GT base pair. Thus, even though it is less flexible, the Z-DNA structure represents an energy minimum which can accommodate a number of modifications in base sequence and base pairing without major changes in the backbone conformation."
Gene ID: 81030 is ZBP1 Z-DNA binding protein 1. "This gene encodes a Z-DNA binding protein. The encoded protein plays a role in the innate immune response by binding to foreign DNA and inducing type-I interferon production. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene."
# CTfin51
"This expression pattern in testis has been described for other C2H2-type zinc-finger proteins in mouse and human, like CTfin51, Zpf29, Sp1, and Zpf37."
Gene ID: 7589 is ZSCAN21 zinc finger and SCAN domain containing 21. Mouse ortholog is Gene ID: 22697 Zscan21 zinc finger and SCAN domain containing 21 also known as RU49; Zfp38; Zfp-38; Zipro1; CTfin51; AI326272.
# AW-1
AW-1 is ZNF174.
Gene ID: 7727 is ZNF174 zinc finger protein 174. "This gene encodes a protein with three Cys2-His2-type zinc fingers in the carboxy-terminus, a putative nuclear localization signal, and an amino-terminus SCAN box which forms homodimers. This protein is believed to function as a transcriptional repressor. Alternative splicing results in multiple transcript variants encoding distinct isoforms." Aka AW-1 and zinc finger and SCAN domain-containing protein 8.
# Number 18 cDNA
"The SCAN box, a leucine-rich region, was named after SRE-ZBP, CTfin51, AW-1 (ZNF174), number 18 cDNA (ZnF20) ."
Gene ID: 7568 is ZNF20 zinc finger protein 20.
# pfam00096 proteins
"The Pfam database is a large collection of protein families, each represented by multiple sequence alignments and hidden Markov models (HMMs)."
"Proteins are generally composed of one or more functional regions, commonly termed domains. Different combinations of domains give rise to the diverse range of proteins found in nature. The identification of domains that occur within proteins can therefore provide insights into their function."
"Pfam also generates higher-level groupings of related entries, known as clans. A clan is a collection of Pfam entries which are related by similarity of sequence, structure or profile-HMM."
"The data presented for each entry is based on the UniProt Reference Proteomes but information on individual UniProtKB sequences can still be found by entering the protein accession. Pfam full alignments are available from searching a variety of databases, either to provide different accessions (e.g. all UniProt and NCBI GI) or different levels of redundancy."
Family: zf-C2H2 (PF00096), "The C2H2 zinc finger is the classical zinc finger domain. The two conserved cysteines and histidines co-ordinate a zinc ion. The following pattern describes the zinc finger. #-X-C-X(1-5)-C-X3-#-X5-#-X2-H-X(3-6)- Where X can be any amino acid, and numbers in brackets indicate the number of residues. The positions marked # are those that are important for the stable fold of the zinc finger. The final position can be either his or cys. The C2H2 zinc finger is composed of two short beta strands followed by an alpha helix. The amino terminal part of the helix binds the major groove in DNA binding zinc fingers. The accepted consensus binding sequence for Sp1 is usually defined by the asymmetric hexanucleotide core GGGCGG but this sequence does not include, among others, the GAG (=CTC) repeat that constitutes a high-affinity site for Sp1 binding to the wt1 promoter ." | SCAN domain
"The SCAN domain is a highly conserved, leucine-rich motif of approximately 60 aa originally found within a subfamily of zinc finger proteins."[1]
"The SCAN domain (named after SRE-ZBP, CTfin51, AW-1 and Number 18 cDNA) is found in several pfam00096 proteins. The domain has been shown to be able to mediate homo- and hetero-oligomerization."[2]
# SRE-ZBP
The "SRE-ZBP [is] a human zinc finger protein that binds to the c-Fos serum response element (17)".[3]
"The promoters of many genes whose transcription is rapidly and transiently induced following growth factor or mitogen stimulation of susceptible cells contain a common regulatory element, the serum response element (SRE)."[4]
"The serum response element (SRE), a region of the c-fos gene which controls growth factor-induced transcription, is [...] shown to mediate c-fos transcription in response to activation of L-type voltage-sensitive calcium channels. Calcium-dependent transcriptional activation through the SRE is mediated by the serum response factor (SRF). Membrane depolarization induces phosphorylation of SRF at Ser-103, an event shown to enhance the ability of SRF to bind the SRE."[5]
The SRE wild type (SREwt) contains the nucleotide sequence ACAGGATGTCCATATTAGGACATCTGC, of which CCATATTAGG is the CArG box, TTAGGACAT is the C/EBP box, and CATCTG is the E box.[5]
"Less flexibility has been attributed to the backbone structure of Z-DNA than to B-DNA (Wang et al., 1979). Initially, Z-DNA was seen in crystal structures of molecules which have strict alternations of purines and pyrimidines involving GC and AT base pairs (Wang et al., 1979, 1984). However, it has recently been shown that Z-DNA will also form in the structure d(CGATCG) in which the cytosines are methylated or brominated on the C5 position (Wang et al., 1985) as well as the brominated d(CGCGATCGCG) (Feigon et al., 1985). In this non-alternating purine/pyrimidine sequence, the thymidines assume the syn conformation and the deoxyadenosines are in the anti conformation thereby preserving the dinucleotide repeat. The resulting deformations in the d(CGATCG) backbone are comparable in magnitude with those described above for a Z-DNA sequence having a wobble GT base pair. Thus, even though it is less flexible, the Z-DNA structure represents an energy minimum which can accommodate a number of modifications in base sequence and base pairing without major changes in the backbone conformation."[6]
Gene ID: 81030 is ZBP1 Z-DNA binding protein 1. "This gene encodes a Z-DNA binding protein. The encoded protein plays a role in the innate immune response by binding to foreign DNA and inducing type-I interferon production. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene."[7]
# CTfin51
"This expression pattern in testis has been described for other C2H2-type zinc-finger proteins in mouse and human, like CTfin51, Zpf29, Sp1, and Zpf37."[8]
Gene ID: 7589 is ZSCAN21 zinc finger and SCAN domain containing 21.[9] Mouse ortholog is Gene ID: 22697 Zscan21 zinc finger and SCAN domain containing 21 also known as RU49; Zfp38; Zfp-38; Zipro1; CTfin51; AI326272.[10]
# AW-1
AW-1 is ZNF174.[11]
Gene ID: 7727 is ZNF174 zinc finger protein 174. "This gene encodes a protein with three Cys2-His2-type zinc fingers in the carboxy-terminus, a putative nuclear localization signal, and an amino-terminus SCAN box which forms homodimers. This protein is believed to function as a transcriptional repressor. Alternative splicing results in multiple transcript variants encoding distinct isoforms."[12] Aka AW-1 and zinc finger and SCAN domain-containing protein 8.[12]
# Number 18 cDNA
"The SCAN box, a leucine-rich region, was named after SRE-ZBP, CTfin51, AW-1 (ZNF174), number 18 cDNA (ZnF20) [53]."[13]
Gene ID: 7568 is ZNF20 zinc finger protein 20.[14]
# pfam00096 proteins
"The Pfam database is a large collection of protein families, each represented by multiple sequence alignments and hidden Markov models (HMMs)."[15]
"Proteins are generally composed of one or more functional regions, commonly termed domains. Different combinations of domains give rise to the diverse range of proteins found in nature. The identification of domains that occur within proteins can therefore provide insights into their function."[15]
"Pfam also generates higher-level groupings of related entries, known as clans. A clan is a collection of Pfam entries which are related by similarity of sequence, structure or profile-HMM."[15]
"The data presented for each entry is based on the UniProt Reference Proteomes but information on individual UniProtKB sequences can still be found by entering the protein accession. Pfam full alignments are available from searching a variety of databases, either to provide different accessions (e.g. all UniProt and NCBI GI) or different levels of redundancy."[15]
Family: zf-C2H2 (PF00096), "The C2H2 zinc finger is the classical zinc finger domain. The two conserved cysteines and histidines co-ordinate a zinc ion. The following pattern describes the zinc finger. #-X-C-X(1-5)-C-X3-#-X5-#-X2-H-X(3-6)-[H/C] Where X can be any amino acid, and numbers in brackets indicate the number of residues. The positions marked # are those that are important for the stable fold of the zinc finger. The final position can be either his or cys. The C2H2 zinc finger is composed of two short beta strands followed by an alpha helix. The amino terminal part of the helix binds the major groove in DNA binding zinc fingers. The accepted consensus binding sequence for Sp1 is usually defined by the asymmetric hexanucleotide core GGGCGG but this sequence does not include, among others, the GAG (=CTC) repeat that constitutes a high-affinity site for Sp1 binding to the wt1 promoter [2]."[16] | https://www.wikidoc.org/index.php/SCAN_domain | |
873a4000a4c078c1ef165fd153de6ef6ea40f8e2 | wikidoc | SKI protein | SKI protein
The SKI protein is a nuclear proto-oncogene that is associated with tumors at high cellular concentrations. SKI has been shown to interfere with normal cellular functioning by both directly impeding expression of certain genes inside the nucleus of the cell as well as disrupting signaling proteins that activate genes.
SKI negatively regulates transforming growth factor-beta (TGF-beta) by directly interacting with Smads and repressing the transcription of TGF-beta responsive genes. This has been associated with cancer due to the large number of roles that peptide growth factors, of which TGF-beta are a subfamily, play in regulating cellular functions such as cell proliferation, apoptosis, specification, and developmental fate.
The name SKI comes from the Sloan-Kettering Institute where the protein was initially discovered.
# Structure
## Gene
The SKI proto-oncogene is located at a region close to the p73 tumor suppressor gene at the locus 1p36.3 locus of a gene, suggesting a similar function to the p73 gene.
## Protein
The SKI protein has a 728 amino acid sequence, with multiple domains and is expressed both inside and outside of the nucleus. It is in the same family as the SnoN protein. The different domains have different functions, with the primary domains interacting with Smad proteins. The protein has a helix-turn-helix motif, a cysteine and histidine rich area which gives rise to the zinc finger motif, a basic amino acid region, and leucine zipper. All these domains, including a proline rich region, are consistent with the fact that the protein must have domains that allow it to interact with other proteins. The protein also has hydrophobic regions which come into contact with Smad proteins rich in leucine and phenylalanine amino acid regions. Recent studies have suggested a domain similar to the Dachshund protein. The SKI-Dachshund homology domain (SKI-DHD) contains the helix turn helix domains of the protein and the beta-alpha-beta turn motifs.
# Function
The SKI oncogene is present in all cells, and is commonly active during development. Specifically, avian fibroblasts depend on the SKI protein as a transcription co-regulator inducing transformation. The aforementioned DHD region is specifically employed for protein-protein interactions, while the 191 amino acid C terminus mediates oligomerization. Recent research shows that the SKI protein in cancerous cells acts as a suppressor, inhibiting transforming growth factor β (TGF- β) signaling. TGF- β is a protein which regulates cell growth. Signaling is regulated by a family of proteins called the Smad proteins. SKI is present in all adult and embryonic cells at low levels, however an over expression of the protein is characteristic of tumor cells. It is thought that high levels of SKI protein inactivate tumor suppression by displacement of other proteins and interference with the signaling pathway of TGF- β. The SKI protein and the CPB protein compete for binding with the Smad proteins, specifically competing with the Smad-3 and CReB-binding protein interactions. SKI also directly interacts with the R-Smad ∙ Smad-4 complex, which directly represses normal transcription of the TGF-β responsive genes, inactivating the cell’s ability to stop growth and division, creating cancerous cells.
SKI has been linked to various cancers including human melanomas, esophageal squamous cell carcinoma, cervical cancer and the process of tumor progression. The link of SKI with human melanoma has been the most studied area of the protein’s link to cancer. Currently it is thought that the SKI protein prevents response to TFG- β levels, causing tumor formation.
# Related research
Other research has identified proteins similar to Ski. The SnoN protein was identified as a similar protein and is often discussed in conjugation with the Ski protein in publications. Recent research suggests that the role of SnoN could be somewhat different, and could potentially even play an antagonistic role.
Other recent studies have determined Fussel-15 and Fussel-18 to be homologous to the Ski/Sno family of proteins. Fussel-15 has been found to play much the same role as the Ski/Sno proteins, however its expression is not as ubiquitous as the Ski/Sno proteins. Fussel-18 has been found to have an inhibitory role in the TGF-beta signaling.
# Interactions
SKI protein has been shown to interact with:
- HIPK2,
- MECP2,
- Mothers against decapentaplegic homolog 1 and
- Mothers against decapentaplegic homolog 2,
- Mothers against decapentaplegic homolog 3,
- NFIX,
- Promyelocytic leukemia protein,
- SKIL, and
- SNW1. | SKI protein
The SKI protein is a nuclear proto-oncogene that is associated with tumors at high cellular concentrations.[1] SKI has been shown to interfere with normal cellular functioning by both directly impeding expression of certain genes inside the nucleus of the cell as well as disrupting signaling proteins that activate genes.[2]
SKI negatively regulates transforming growth factor-beta (TGF-beta) by directly interacting with Smads and repressing the transcription of TGF-beta responsive genes.[3] This has been associated with cancer due to the large number of roles that peptide growth factors, of which TGF-beta are a subfamily, play in regulating cellular functions such as cell proliferation, apoptosis, specification, and developmental fate.[4]
The name SKI comes from the Sloan-Kettering Institute where the protein was initially discovered.
# Structure
## Gene
The SKI proto-oncogene is located at a region close to the p73 tumor suppressor gene at the locus 1p36.3 locus of a gene, suggesting a similar function to the p73 gene.[5]
## Protein
The SKI protein has a 728 amino acid sequence, with multiple domains and is expressed both inside and outside of the nucleus.[5] It is in the same family as the SnoN protein. The different domains have different functions, with the primary domains interacting with Smad proteins. The protein has a helix-turn-helix motif, a cysteine and histidine rich area which gives rise to the zinc finger motif, a basic amino acid region, and leucine zipper. All these domains, including a proline rich region, are consistent with the fact that the protein must have domains that allow it to interact with other proteins.[5] The protein also has hydrophobic regions which come into contact with Smad proteins rich in leucine and phenylalanine amino acid regions.[7] Recent studies have suggested a domain similar to the Dachshund protein. The SKI-Dachshund homology domain (SKI-DHD) contains the helix turn helix domains of the protein and the beta-alpha-beta turn motifs.[3]
# Function
The SKI oncogene is present in all cells, and is commonly active during development. Specifically, avian fibroblasts depend on the SKI protein as a transcription co-regulator inducing transformation.[5] The aforementioned DHD region is specifically employed for protein-protein interactions, while the 191 amino acid C terminus mediates oligomerization.[3] Recent research shows that the SKI protein in cancerous cells acts as a suppressor, inhibiting transforming growth factor β (TGF- β) signaling. TGF- β is a protein which regulates cell growth. Signaling is regulated by a family of proteins called the Smad proteins. SKI is present in all adult and embryonic cells at low levels, however an over expression of the protein is characteristic of tumor cells.[7] It is thought that high levels of SKI protein inactivate tumor suppression by displacement of other proteins and interference with the signaling pathway of TGF- β.[5] The SKI protein and the CPB protein compete for binding with the Smad proteins, specifically competing with the Smad-3 and CReB-binding protein interactions. SKI also directly interacts with the R-Smad ∙ Smad-4 complex, which directly represses normal transcription of the TGF-β responsive genes, inactivating the cell’s ability to stop growth and division, creating cancerous cells.[7]
SKI has been linked to various cancers including human melanomas, esophageal squamous cell carcinoma, cervical cancer and the process of tumor progression. The link of SKI with human melanoma has been the most studied area of the protein’s link to cancer. Currently it is thought that the SKI protein prevents response to TFG- β levels, causing tumor formation.[5]
# Related research
Other research has identified proteins similar to Ski. The SnoN protein was identified as a similar protein and is often discussed in conjugation with the Ski protein in publications. Recent research suggests that the role of SnoN could be somewhat different, and could potentially even play an antagonistic role.[8]
Other recent studies have determined Fussel-15 and Fussel-18 to be homologous to the Ski/Sno family of proteins. Fussel-15 has been found to play much the same role as the Ski/Sno proteins, however its expression is not as ubiquitous as the Ski/Sno proteins. Fussel-18 has been found to have an inhibitory role in the TGF-beta signaling.[9]
# Interactions
SKI protein has been shown to interact with:
- HIPK2,[10]
- MECP2,[11]
- Mothers against decapentaplegic homolog 1[10] and
- Mothers against decapentaplegic homolog 2,[10][12]
- Mothers against decapentaplegic homolog 3,[10][13]
- NFIX,[14]
- Promyelocytic leukemia protein,[15]
- SKIL,[16] and
- SNW1.[17][18][19] | https://www.wikidoc.org/index.php/SKI_protein | |
0b1435a058f50271c8eb05be91dbe23f99541fb4 | wikidoc | ST interval | ST interval
Synonyms and keywords: ST segment depression, ST segment elevation; J point elevation; vaulting of the ST segments; current of injury
# Overview
The ST interval represents the initial, slow phase of ventricular repolarization. The ST segment commonly refers to the morphology of the segment between the end of the S wave (the terminal deflection of the QRS) and the beginning of the T wave.
# The Normal ST segment
The ST segment represents the ventricular repolarisation. Repolarisation follows upon contraction and depolarisation. During repolarisation the cardiomyocytes elongate and prepare for the next heartbeat. This process takes much more time than the depolarisation. Repolarisation is not passive elongation by stretch, it is an active process during which energy is consumed. On the ECG, the repolarisation phase starts at the junction, or j point, and continues until the T wave. The normal ST segment should not be flat. It should have an upward concavity sometimes referred to as a “take-off”.
The T wave is usually concordant with the QRS complex. Thus if the QRS complex is positive in a certain lead (the area under the curve above the baseline is greater than the area under the curve below the baseline) than the T wave usually is positive too in that lead. Accordingly the T wave is normally upright or positive in leads I, II, AVL, AVF and V3-V6. The T wave is negative in V1 and AVR. The T wave flips around V2, but there is some genetical influence in this as in Blacks the T wave usually flips around V3.
The T wave angle is the result of small differences in the duration of the repolarisation between the endocardial and epicardial layers of the left ventricle. The endocardial myocytes need a little more time to repolarise (about 22 msec). This difference causes an electrical current from the endocardium to the epicardium, which reads as a positive signal on the ECG.
# ST Segment Changes in Acute Myocardial Injury or Ischemia
EKG manifestations of acute myocardial injury or ischemia in absence of left ventricular hypertrophy and LBBB are as follow:
- ST segment elevation
In general, ST segment elevation reflects myocardial injury, which may be irreversible (unlike ischemia which may be reversible) and which is associated with a risk of necrosis. ST elevation is defined as new ST segment elevation at the J point in two contiguous leads with the cut off points ≥0.2 mV in men or ≥0.15 mV in women in V2-V3 and ≥0.1 mV in other leads.
- ST segment depression and T wave changes
In general, ST depresstion represents reversible ischemia (less likely to result in irreversible necorsis). One exception is the presence of ST depression in the anterior precordial leads that can reflect posterior injury rather than anterior ischemia. Ischemia is defined as new horizontal or downsloping ST segment changes as ≥0.05 mV in two contiguous leads and/or T wave inversion ≥0.1 mV in two contiguous leads with prominent R wave or in situations which R wave amplitude / S wave amplitude ratio is >1.
Althought it is not observed in women, the J point elevation in men decreases with increasing age.
The term of contiguous lead represents lead groups such as anterior leads (V1-V6), inferior leads (II, III, and aVF), or lateral/apical leads (I and aVL).
Shown below is a table depicting the interpretation of ST elevation and ST depression by the involved contiguous leads.
# ST Depression
## Causes of ST Segment Depression
- Ischemia particularly if the ST segment is downsloping
- "Reciprocal changes" which are associated with a pattern of injury (ST segment elevation) in other leads. It is unclear if the ST depression is truly simply a reciprocal change which is a mirror image electrically of the injury in the other leads or if the ST depression is due to active ischemia in the other territory. Reciprocal changes are associated with a poorer prognosis. Reciprocal changes in the anterior precordial leads in association with an inferior MI are associated with slower flow in the LAD
- Digoxin effect (concave up;"reverse-checkmark")
- LV "strain"-associated with LVH (asymmetric ST depression, concave up, with slow downstroke and rapid upstroke, most often in I, aVL, V4-6)
- RV "strain"-associated with RVH (asymmetric ST depression, concave up, with slow downstroke and rapid upstroke, most often in V1-2)
- Hypokalemia (usually slight ST depression)
- Hypercalcemia
- Hypomagnesemia
- Heart rate-induced changes (post tachycardia)
- Neurologic events
Shown below is an ECG depicting ST depression in the precordial leads.
# ST Elevation
## Pathophysiology
ST segment corresponds to a period of ventrical systolic depolarization, when the cardiac muscle is contracted. Subsequent relaxation occurs during the diastolic repolarization phase. The normal course of ST segment reflects a certain sequence of muscular layers undergoing repolarization and certain timing of this activity. When the cardiac muscle is damaged or undergoes a pathological process (e.g. inflammation), its contractile and electrical properties change. Usually, this leads to early repolarization, or premature ending of the systole.
The exact topology and distribution of the affected areas depend on the underlying condition. Thus, ST elevation may be present on all or some leads of ECG.
## Measurement
The optimal time after the J point to measure ST elevation is debated. This example shows the technique of measuring the magnitude of ST elevation 60 milliseconds or 1.5 small boxes after the J point.
## Causes
### Common Causes
- Acute MI or heart attack
- Early repolarization
- Left ventricular aneurysm
- Pericarditis
### Causes in Alphabetical Order
- Acute MI or heart attack
- Brugada syndrome
- Coronary vasospasm
- Early repolarization
- Hyperkalemia and this is known as a dialyzable current of injury
- Intracranial hemorrhage
- Left bundle branch block
- Left ventricular aneurysm
- Pericardiocentesis with contact of the needle with the myocardium creating a current of injury
- Pericarditis
- Prinzmetal's angina
- Pulmonary embolism
- Short QT syndrome (some variants)
- Vasospastic angina
## Differentiating the Causes of ST Segment Elevation
### Myocardial Injury
- The ST elevation is usually localized to an anatomic distribution that follows the coronary arteries (e.g. leads II,III, aVF).
- In the setting of myocardial injury, "reciprocal changes" representing ischemia in other leads or a mirror like effect of the ST elevation presenting as ST depression in other leads, may be present. For example, ST elevation in the anterior leads in acute MI may be accompanied by ST depression in the inferior leads.
- Prinzmetal's angina can cause transient ST elevation during chest pain.
- Contact of the needle can cause a "current of injury" and ST segment elevation during pericardiocentesis.
### Pericarditis
- There is diffuse ST segment elevation (usually flat or concave up) together with PR segment depression. ST elevation reflects inflammation of the ventricular subepicardial layer and PR segment depression reflects inflammation of the atrial subepicardial layer.
- T wave inversion can be seen in pericarditis but usually not until the ST elevation has resolved, so *T wave inversion accompanying ST elevation is probably not due to pericarditis
### Hyperkalemia
Hyperkalemia may not affect all leads.
### Ventricular Aneurysm
- Ventricular aneurysm should be suspected if the ST segment elevation persists > 6 weeks after acute MI and if there is a wall motion abnormality on echocardiography.
### Early Repolarization
- "J point" elevation aka "early repolarization" is a concave-upward ST segment deflection.
- Vaulting ST segment or J point elevation is a normal variant in leads V1-V3.
### Differentiating the Causes of ST Segment Elevation EKG Examples
Shown below is an example of EKG illustrating ST elevation in various pathological states.
Shown below is an example of an EKG showing early repolarization ST elevation and normal ST elevation variants.
Shown below is a example of an ECG demonstrating early repolarization ST changes. | ST interval
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Synonyms and keywords: ST segment depression, ST segment elevation; J point elevation; vaulting of the ST segments; current of injury
# Overview
The ST interval represents the initial, slow phase of ventricular repolarization.[1] The ST segment commonly refers to the morphology of the segment between the end of the S wave (the terminal deflection of the QRS) and the beginning of the T wave.
# The Normal ST segment
The ST segment represents the ventricular repolarisation. Repolarisation follows upon contraction and depolarisation. During repolarisation the cardiomyocytes elongate and prepare for the next heartbeat. This process takes much more time than the depolarisation. Repolarisation is not passive elongation by stretch, it is an active process during which energy is consumed. On the ECG, the repolarisation phase starts at the junction, or j point, and continues until the T wave. The normal ST segment should not be flat. It should have an upward concavity sometimes referred to as a “take-off”.
The T wave is usually concordant with the QRS complex. Thus if the QRS complex is positive in a certain lead (the area under the curve above the baseline is greater than the area under the curve below the baseline) than the T wave usually is positive too in that lead. Accordingly the T wave is normally upright or positive in leads I, II, AVL, AVF and V3-V6. The T wave is negative in V1 and AVR. The T wave flips around V2, but there is some genetical influence in this as in Blacks the T wave usually flips around V3.
The T wave angle is the result of small differences in the duration of the repolarisation between the endocardial and epicardial layers of the left ventricle. The endocardial myocytes need a little more time to repolarise (about 22 msec). This difference causes an electrical current from the endocardium to the epicardium, which reads as a positive signal on the ECG. [2]
# ST Segment Changes in Acute Myocardial Injury or Ischemia
EKG manifestations of acute myocardial injury or ischemia in absence of left ventricular hypertrophy and LBBB are as follow:[3] [4]
- ST segment elevation
In general, ST segment elevation reflects myocardial injury, which may be irreversible (unlike ischemia which may be reversible) and which is associated with a risk of necrosis. ST elevation is defined as new ST segment elevation at the J point in two contiguous leads with the cut off points ≥0.2 mV in men or ≥0.15 mV in women in V2-V3 and ≥0.1 mV in other leads.
- ST segment depression and T wave changes
In general, ST depresstion represents reversible ischemia (less likely to result in irreversible necorsis). One exception is the presence of ST depression in the anterior precordial leads that can reflect posterior injury rather than anterior ischemia. Ischemia is defined as new horizontal or downsloping ST segment changes as ≥0.05 mV in two contiguous leads and/or T wave inversion ≥0.1 mV in two contiguous leads with prominent R wave or in situations which R wave amplitude / S wave amplitude ratio is >1.
Althought it is not observed in women, the J point elevation in men decreases with increasing age.[5]
The term of contiguous lead represents lead groups such as anterior leads (V1-V6), inferior leads (II, III, and aVF), or lateral/apical leads (I and aVL).
Shown below is a table depicting the interpretation of ST elevation and ST depression by the involved contiguous leads.
# ST Depression
## Causes of ST Segment Depression
- Ischemia particularly if the ST segment is downsloping
- "Reciprocal changes" which are associated with a pattern of injury (ST segment elevation) in other leads. It is unclear if the ST depression is truly simply a reciprocal change which is a mirror image electrically of the injury in the other leads or if the ST depression is due to active ischemia in the other territory. Reciprocal changes are associated with a poorer prognosis. Reciprocal changes in the anterior precordial leads in association with an inferior MI are associated with slower flow in the LAD
- Digoxin effect (concave up;"reverse-checkmark")
- LV "strain"-associated with LVH (asymmetric ST depression, concave up, with slow downstroke and rapid upstroke, most often in I, aVL, V4-6)
- RV "strain"-associated with RVH (asymmetric ST depression, concave up, with slow downstroke and rapid upstroke, most often in V1-2)
- Hypokalemia (usually slight ST depression)
- Hypercalcemia
- Hypomagnesemia
- Heart rate-induced changes (post tachycardia)
- Neurologic events
Shown below is an ECG depicting ST depression in the precordial leads.
# ST Elevation
## Pathophysiology
ST segment corresponds to a period of ventrical systolic depolarization, when the cardiac muscle is contracted. Subsequent relaxation occurs during the diastolic repolarization phase. The normal course of ST segment reflects a certain sequence of muscular layers undergoing repolarization and certain timing of this activity. When the cardiac muscle is damaged or undergoes a pathological process (e.g. inflammation), its contractile and electrical properties change. Usually, this leads to early repolarization, or premature ending of the systole.
The exact topology and distribution of the affected areas depend on the underlying condition. Thus, ST elevation may be present on all or some leads of ECG.
## Measurement
The optimal time after the J point to measure ST elevation is debated. This example shows the technique of measuring the magnitude of ST elevation 60 milliseconds or 1.5 small boxes after the J point.[11]
## Causes
### Common Causes
- Acute MI or heart attack
- Early repolarization
- Left ventricular aneurysm
- Pericarditis[12][13]
### Causes in Alphabetical Order
- Acute MI or heart attack
- Brugada syndrome
- Coronary vasospasm
- Early repolarization
- Hyperkalemia and this is known as a dialyzable current of injury
- Intracranial hemorrhage
- Left bundle branch block
- Left ventricular aneurysm
- Pericardiocentesis with contact of the needle with the myocardium creating a current of injury
- Pericarditis[12][13]
- Prinzmetal's angina
- Pulmonary embolism
- Short QT syndrome (some variants)
- Vasospastic angina
## Differentiating the Causes of ST Segment Elevation
### Myocardial Injury
- The ST elevation is usually localized to an anatomic distribution that follows the coronary arteries (e.g. leads II,III, aVF).
- In the setting of myocardial injury, "reciprocal changes" representing ischemia in other leads or a mirror like effect of the ST elevation presenting as ST depression in other leads, may be present. For example, ST elevation in the anterior leads in acute MI may be accompanied by ST depression in the inferior leads.
- Prinzmetal's angina can cause transient ST elevation during chest pain.
- Contact of the needle can cause a "current of injury" and ST segment elevation during pericardiocentesis.
### Pericarditis
- There is diffuse ST segment elevation (usually flat or concave up) together with PR segment depression. ST elevation reflects inflammation of the ventricular subepicardial layer and PR segment depression reflects inflammation of the atrial subepicardial layer.
- T wave inversion can be seen in pericarditis but usually not until the ST elevation has resolved, so *T wave inversion accompanying ST elevation is probably not due to pericarditis
### Hyperkalemia
Hyperkalemia may not affect all leads.
### Ventricular Aneurysm
- Ventricular aneurysm should be suspected if the ST segment elevation persists > 6 weeks after acute MI and if there is a wall motion abnormality on echocardiography.
### Early Repolarization
- "J point" elevation aka "early repolarization" is a concave-upward ST segment deflection.
- Vaulting ST segment or J point elevation is a normal variant in leads V1-V3.
### Differentiating the Causes of ST Segment Elevation EKG Examples
Shown below is an example of EKG illustrating ST elevation in various pathological states.
Shown below is an example of an EKG showing early repolarization ST elevation and normal ST elevation variants.
Shown below is a example of an ECG demonstrating early repolarization ST changes. | https://www.wikidoc.org/index.php/ST | |
c31f55181ba2067d90a236ac72a590f7a89dd2a8 | wikidoc | SVG anatomy | SVG anatomy
The great saphenous vein (GSV) originates from where the dorsal vein of the first digit (the large toe) merges with the dorsal venous arch of the foot.
After passing anterior to the medial malleolus (where it often can be visualized and palpated), it runs up the medial side of the leg. At the knee, it runs over the posterior border of the medial epicondyle of the femur bone.
The great saphenous vein then courses laterally to lie on the anterior surface of the thigh before entering an opening in the fascia lata called the saphenous opening. It joins with the femoral vein in the region of the femoral triangle at the saphenofemoral junction.
The small saphenous vein (also lesser saphenous vein) is originated where the dorsal vein from the fifth digit (smallest toe) merges with the dorsal venous arch of the foot, which attaches to the great saphenous vein. It is considered a superficial vein and is subcutaneous (just under the skin). From its origin, it courses around the lateral aspect of the foot (inferior and posterior to the lateral malleolus) and runs along the posterior aspect of the leg (with the sural nerve), passes between the heads of the gastrocnemius muscle, and drains into the popliteal vein, approximately at or above the level of the knee joint.
- Cross-section through the middle of the thigh.
- Cross-section through middle of leg.
- The great saphenous vein and landmarks along its course
- The great saphenous vein and its tributaries at the fossa ovalis in the groin.
- Small saphenous vein and its tributaries. | SVG anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The great saphenous vein (GSV) originates from where the dorsal vein of the first digit (the large toe) merges with the dorsal venous arch of the foot.
After passing anterior to the medial malleolus (where it often can be visualized and palpated), it runs up the medial side of the leg. At the knee, it runs over the posterior border of the medial epicondyle of the femur bone.
The great saphenous vein then courses laterally to lie on the anterior surface of the thigh before entering an opening in the fascia lata called the saphenous opening. It joins with the femoral vein in the region of the femoral triangle at the saphenofemoral junction.
The small saphenous vein (also lesser saphenous vein) is originated where the dorsal vein from the fifth digit (smallest toe) merges with the dorsal venous arch of the foot, which attaches to the great saphenous vein. It is considered a superficial vein and is subcutaneous (just under the skin). From its origin, it courses around the lateral aspect of the foot (inferior and posterior to the lateral malleolus) and runs along the posterior aspect of the leg (with the sural nerve), passes between the heads of the gastrocnemius muscle, and drains into the popliteal vein, approximately at or above the level of the knee joint.
- Cross-section through the middle of the thigh.
- Cross-section through middle of leg.
- The great saphenous vein and landmarks along its course
- The great saphenous vein and its tributaries at the fossa ovalis in the groin.
- Small saphenous vein and its tributaries.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/SVG_anatomy | |
fc796727e4ff89c39dd28453a68ea3d0369431ee | wikidoc | Sacrosidase | Sacrosidase
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Sacrosidase is a gastrointestinal agent that is FDA approved for the treatment of of oral replacement therapy of the genetically determined sucrase deficiency, which is part of congenital sucrase-isomaltase deficiency (CSID).. Common adverse reactions include abdominal pain, constipation, diarrhea, nausea, vomiting, headache, insomnia, dehydration.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- sacrosidase oral solution is indicated as oral replacement therapy of the genetically determined sucrase deficiency, which is part of congenital sucrase-isomaltase deficiency (CSID).
- The recommended dosage is 1 or 2 mL (8,500 to 17,000 I.U.) or 1 or 2 full measuring scoops (each full measuring scoop equals 1mL; 28 drops from the sacrosidasecontainer tip equals 1mL) taken orally with each meal or snack diluted with 2 to 4 ounces of water, milk or infant formula. The beverage or infant formula should be served cold or at room temperature. The beverage or infant formula should not be warmed or heated before or after addition of sacrosidasebecause heating is likely to decrease potency. sacrosidaseshould not be reconstituted or consumed with fruit juice since its acidity may reduce the enzyme activity.
- It is recommended that approximately half of the dosage be taken at the beginning of the meal or snack and the remainder be taken during the meal or snack.
- The recommended dosage is as follows:
- 1 mL (8,500 I.U.) (one full measuring scoop or 28 drops) per meal or snack for patients up to 15 kg in body weight.
- 2mL (17,000 I.U.) (two full measuring scoops or 56 drops) per meal or snack for patients over 15 kg in body weight.
- Dosage may be measured with the 1 mL measuring scoop (provided) or by drop count method (1mL equals 28 drops from the sacrosidasecontainer tip).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sacrosidase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sacrosidase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Sacrosidase in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sacrosidase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sacrosidase in pediatric patients.
# Contraindications
- Patients known to be hypersensitive to yeast, yeast products, glycerin (glycerol), or papain.
# Warnings
- Severe wheezing, 90 minutes after a second dose of sacrosidase, necessitated admission into the ICU for a 4-year old boy. The wheezing was probably caused by sacrosidase. He had asthma and was being treated with steroids. A skin test for sacrosidase was positive.
- Other serious events have not been linked to sacrosidase.
### Precautions
- Care should be taken to administer initial doses of sacrosidasenear (within a few minutes’ travel) a facility where acute hypersensitivity reactions can be adequately treated. Alternatively, the patient may be tested for hypersensitivity to sacrosidase through skin abrasion testing. Should symptoms of hypersensitivity appear, discontinue medication and initiate symptomatic and supportive therapy.
- Skin testing as a rechallenge has been used to verify hypersensitivity in one asthmatic child who displayed wheezing after oral sacrosidase.
- Although sacrosidaseprovides replacement therapy for the deficient sucrase, it does not provide specific replacement therapy for the deficient isomaltase. Therefore, restricting starch in the diet may still be necessary to reduce symptoms as much as possible. The need for dietary starch restriction for patients using sacrosidaseshould be evaluated in each patient.
- It may sometimes be clinically inappropriate, difficult or inconvenient to perform a small bowel biopsy or breath hydrogen test to make a definitive diagnosis of CSID. If the diagnosis is in doubt, it may be warranted to conduct a short therapeutic trial (e.g. one week) with sacrosidaseto assess response in a patient suspected of sucrase deficiency.
- The effects of sacrosidasehave not been evaluated in patients with secondary (acquired) disaccharidase deficiencies
The use of sacrosidasewill enable the products of sucrose hydrolysis - glucose and fructose to be absorbed. This fact must be carefully considered in planning the diet of diabetic CSID patients using sacrosidase.
# Adverse Reactions
## Clinical Trials Experience
- Adverse experiences with sacrosidasein clinical trials were generally minor and were frequently associated with the underlying disease.
- In clinical studies of up to 54 months duration, physicians treated a total of 52 patients with sacrosidase. The adverse experiences and respective number of patients reporting each event (in parenthesis) were as follows: abdominal pain (4), vomiting (3), nausea (2), diarrhea (2), constipation (2), insomnia (1) headache (1) nervousness (1) and dehydration (1).
- Note: diarrhea and abdominal pain can be a part of the clinical presentation of the genetically determined sucrase deficiency, which is part of congenital sucrase-isomaltase deficiency (CSID).
- One asthmatic child experienced a serious hypersensitivity reaction (wheezing) probably related to sacrosidase . The event resulted in withdrawal of the patient from the trial but resolved with no sequelae.
## Postmarketing Experience
There is limited information regarding Sacrosidase Postmarketing Experience in the drug label.
# Drug Interactions
- Neither drug-drug nor drug-food interactions are expected or have been reported with the use of sacrosidase. However, sacrosidaseshould not be reconstituted or consumed with fruit juice, since its acidity may reduce the enzyme activity.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with sacrosidase. sacrosidaseis not expected to cause fetal harm when administered to a pregnant woman or to affect reproductive capacity. sacrosidaseshould be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sacrosidase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sacrosidase during labor and delivery.
### Nursing Mothers
- The sacrosidaseenzyme is broken down in the stomach and intestines and the component amino acids and peptides are then absorbed as nutrients.
### Pediatric Use
- sacrosidasehas been used in patients as young as 5 months of age. Evidence in one controlled trial in primarily pediatric patients shows that sacrosidaseis safe and effective for the treatment of the genetically acquired sucrase deficiency, which is part of CSID.
### Geriatic Use
There is no FDA guidance on the use of Sacrosidase with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Sacrosidase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sacrosidase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sacrosidase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sacrosidase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sacrosidase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sacrosidase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- The definitive test for diagnosis of CSID is the measurement of intestinal disaccharidases following small bowel biopsy.
- Other tests used alone may be inaccurate: for example, the breath hydrogen test (high incidence of false-negatives) or oral sucrose tolerance test (high incidence of false positives). Differential urinary disaccharide testing has been reported to show good agreement with small intestinal biopsy for diagnosis of CSID.
# IV Compatibility
There is limited information regarding IV Compatibility of Sacrosidase in the drug label.
# Overdosage
- Overdosage with sacrosidasehas not been reported.
# Pharmacology
## Mechanism of Action
- Congenital sucrase-isomaltase deficiency (CSID) is a chronic, autosomal recessive, inherited, phenotypically heterogeneous disease with very variable enzyme activity. CSID is usually characterized by a complete or almost complete lack of endogenous sucrase activity, a very marked reduction in isomaltase activity, a moderate decrease in maltase activity and normal lactase levels.
## Structure
- Sacrosidase oral solution is an enzyme replacement therapy for the treatment of genetically determined sucrase deficiency, which is part of congenital sucrase-isomaltase deficiency (CSID).
- sacrosidaseis a pale yellow, clear solution with a pleasant sweet taste. Each milliliter (mL) of sacrosidase contains 8,500 International Units (I.U.) of the enzyme sacrosidase, the active ingredient. The chemical name of this enzyme is ß,D-fructofuranoside fructohydrolase. The enzyme is derived from baker’s yeast (Saccharomyces cerevisiae).
- It has been reported that the primary amino acid structure of this protein consists of 513 amino acids with an apparent molecular weight of 100,000 g/mole for the glycosylated monomer (Range 66,000-116,000 g/mole). Reports also suggest that the protein exists in solution as a monomer, dimer, tetramer, and octomer ranging from 100,000 g/mole to 800,000 g/mole. It has an isoelectric point of 4 (pl=4.093).
- sacrosidasemay contain small amounts of papain. Papain is known to cause allergic reactions in some people. Papain is a protein-cleaving enzyme that is introduced in the manufacturing process to digest the cell wall of the yeast and may not be completely removed during subsequent process steps.
- sacrosidasealso contains 50% glycerol (w/w) in an aqueous solution. Glycerol (glycerin) in the amount consumed in the recommended doses of sacrosidasehas no expected toxicity.
- This enzyme preparation is fully soluble with water, milk, and infant formula (DO NOT HEAT SOLUTIONS CONTAINING sacrosidase). Do not put sacrosidasein warm or hot liquids.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Sacrosidase in the drug label.
## Pharmacokinetics
- Sucrase is naturally produced in the brush border of the small intestine, primarily the distal duodenum and jejunum. Sucrase hydrolyzes the disaccharide sucrose into its component monosaccharides, glucose and fructose. Isomaltase breaks down disaccharides from starch into simple sugars. sacrosidasedoes not contain isomaltase.
- In the absence of endogenous human sucrase, as in CSID, sucrose is not metabolized. Unhydrolyzed sucrose and starch are not absorbed from the intestine and their presence in the intestinal lumen may lead to osmotic retention of water. This may result in loose stools.
- Unabsorbed sucrose in the colon is fermented by bacterial flora to produce increased amounts of hydrogen, methane and water. As a consequence, excessive gas, bloating, abdominal cramps, nausea and vomiting may occur.
- Chronic malabsorption of disaccharides may result in malnutrition. Undiagnosed/untreated CSID patients often fail to thrive and fall behind in their expected growth and development curves. Previously, the treatment of CSID has required the continual use of a strict sucrose-free diet.
- CSID is often difficult to diagnose. Approximately 4% to 10% of pediatric patients with chronic diarrhea of unknown origin have CSID. Measurement of expired breath hydrogen under controlled conditions following a sucrose challenge (a measurement of excess hydrogen excreted in exhalation) in CSID patients has shown levels as great as 6 times that in normal subjects.
- A generally accepted clinical definition of CSID is a condition characterized by the following: stool pH 10ppm when challenged with sucrose after fasting and a negative lactose breath test. However, because of the difficulties in diagnosing CSID, it may be warranted to conduct a short therapeutic trial (e.g. one week) to assess response in patients suspected of having CSID.
## Nonclinical Toxicology
- Long-term studies in animals with sacrosidasehave not been performed to evaluate the carcinogenic potential. Studies to evaluate the effect of sacrosidaseon fertility or its mutagenic potential have not been performed.
# Clinical Studies
- A two-phase (dose response preceded by a breath hydrogen phase) double-blind, multi-site, crossover trial was conducted in 28 patients (aged 4 months to 11.5 years) with confirmed CSID. During the dose response phase the patients were challenged with an ordinary sucrose containing diet while receiving each of four doses of sacrosidase; full strength (9000 I.U./mL) and three dilutions (1:10 , 1:100 , and 1:1000 ) in random order for a period of 10 days. Patients who weighed no more than 15 kg received 1 mL per meal; those weighing more than 15 kg received 2 mL per meal. The dose did not vary with age or sucrose intake.
- A dose-response relationship was shown between the two higher and the two lower doses. The two higher doses of sacrosidase were associated with significantly fewer total stools and higher proportions of patients having lower total symptom scores, the primary efficacy end-points. In addition, higher doses of sacrosidase were associated with a significantly greater number of hard and formed stools as well as with fewer watery and soft stools, the secondary efficacy end-points.
- Analysis of the overall symptomatic response as a function of age indicated that in CSID patients up to 3 years of age, 86% became asymptomatic. In patients over 3 years of age 77% became asymptomatic. Thus, the therapeutic response did not differ significantly according to age.
- A second study of similar design and execution as the first used 4 different dilutions of sacrosidase 1:100 (90 I.U./mL), 1:1000 (9 I.U./mL), 1:10,000 (0.9 I.U./mL), and 1:100,000 (0.09 I.U./mL). There were inconsistent results with regards to the primary efficacy parameters.
- In both trials however, patients showed a marked decrease in breath hydrogen output when they received sacrosidase in comparison to placebo.
# How Supplied
- sacrosidaseis available in 118 mL (4 fluid ounces) translucent plastic bottles, packaged two bottles per box. Each mL of solution contains 8,500 International Units (I.U.) of sacrosidase. A 1 mL measuring scoop is provided with each bottle. A full measuring scoop is 1 mL.
- Store in a refrigerator at 2°- 8°C (36°- 46°F). Product is sterile until opened. Discard four weeks after first opening due to the potential for bacterial growth. Protect from heat and light.
## Storage
There is limited information regarding Sacrosidase Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to discard bottles of sacrosidase4 weeks after opening due to the potential for bacterial growth. For the same reason, patients should be advised to rinse the measuring scoop with water after each use.
sacrosidaseis fully soluble with water, milk and infant formula, but it is important to note that this product is sensitive to heat. sacrosidaseshould not be reconstituted or consumed with fruit juice, since its acidity may reduce the enzyme activity.
# Precautions with Alcohol
- Alcohol-Sacrosidase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sacrosidase Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Sacrosidase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Sacrosidase
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
# Overview
Sacrosidase is a gastrointestinal agent that is FDA approved for the treatment of of oral replacement therapy of the genetically determined sucrase deficiency, which is part of congenital sucrase-isomaltase deficiency (CSID).. Common adverse reactions include abdominal pain, constipation, diarrhea, nausea, vomiting, headache, insomnia, dehydration.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- sacrosidase oral solution is indicated as oral replacement therapy of the genetically determined sucrase deficiency, which is part of congenital sucrase-isomaltase deficiency (CSID).
- The recommended dosage is 1 or 2 mL (8,500 to 17,000 I.U.) or 1 or 2 full measuring scoops (each full measuring scoop equals 1mL; 28 drops from the sacrosidasecontainer tip equals 1mL) taken orally with each meal or snack diluted with 2 to 4 ounces of water, milk or infant formula. The beverage or infant formula should be served cold or at room temperature. The beverage or infant formula should not be warmed or heated before or after addition of sacrosidasebecause heating is likely to decrease potency. sacrosidaseshould not be reconstituted or consumed with fruit juice since its acidity may reduce the enzyme activity.
- It is recommended that approximately half of the dosage be taken at the beginning of the meal or snack and the remainder be taken during the meal or snack.
- The recommended dosage is as follows:
- 1 mL (8,500 I.U.) (one full measuring scoop or 28 drops) per meal or snack for patients up to 15 kg in body weight.
- 2mL (17,000 I.U.) (two full measuring scoops or 56 drops) per meal or snack for patients over 15 kg in body weight.
- Dosage may be measured with the 1 mL measuring scoop (provided) or by drop count method (1mL equals 28 drops from the sacrosidasecontainer tip).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sacrosidase in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sacrosidase in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Sacrosidase in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sacrosidase in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sacrosidase in pediatric patients.
# Contraindications
- Patients known to be hypersensitive to yeast, yeast products, glycerin (glycerol), or papain.
# Warnings
- Severe wheezing, 90 minutes after a second dose of sacrosidase, necessitated admission into the ICU for a 4-year old boy. The wheezing was probably caused by sacrosidase. He had asthma and was being treated with steroids. A skin test for sacrosidase was positive.
- Other serious events have not been linked to sacrosidase.
### Precautions
- Care should be taken to administer initial doses of sacrosidasenear (within a few minutes’ travel) a facility where acute hypersensitivity reactions can be adequately treated. Alternatively, the patient may be tested for hypersensitivity to sacrosidase through skin abrasion testing. Should symptoms of hypersensitivity appear, discontinue medication and initiate symptomatic and supportive therapy.
- Skin testing as a rechallenge has been used to verify hypersensitivity in one asthmatic child who displayed wheezing after oral sacrosidase.
- Although sacrosidaseprovides replacement therapy for the deficient sucrase, it does not provide specific replacement therapy for the deficient isomaltase. Therefore, restricting starch in the diet may still be necessary to reduce symptoms as much as possible. The need for dietary starch restriction for patients using sacrosidaseshould be evaluated in each patient.
- It may sometimes be clinically inappropriate, difficult or inconvenient to perform a small bowel biopsy or breath hydrogen test to make a definitive diagnosis of CSID. If the diagnosis is in doubt, it may be warranted to conduct a short therapeutic trial (e.g. one week) with sacrosidaseto assess response in a patient suspected of sucrase deficiency.
- The effects of sacrosidasehave not been evaluated in patients with secondary (acquired) disaccharidase deficiencies
The use of sacrosidasewill enable the products of sucrose hydrolysis - glucose and fructose to be absorbed. This fact must be carefully considered in planning the diet of diabetic CSID patients using sacrosidase.
# Adverse Reactions
## Clinical Trials Experience
- Adverse experiences with sacrosidasein clinical trials were generally minor and were frequently associated with the underlying disease.
- In clinical studies of up to 54 months duration, physicians treated a total of 52 patients with sacrosidase. The adverse experiences and respective number of patients reporting each event (in parenthesis) were as follows: abdominal pain (4), vomiting (3), nausea (2), diarrhea (2), constipation (2), insomnia (1) headache (1) nervousness (1) and dehydration (1).
- Note: diarrhea and abdominal pain can be a part of the clinical presentation of the genetically determined sucrase deficiency, which is part of congenital sucrase-isomaltase deficiency (CSID).
- One asthmatic child experienced a serious hypersensitivity reaction (wheezing) probably related to sacrosidase . The event resulted in withdrawal of the patient from the trial but resolved with no sequelae.
## Postmarketing Experience
There is limited information regarding Sacrosidase Postmarketing Experience in the drug label.
# Drug Interactions
- Neither drug-drug nor drug-food interactions are expected or have been reported with the use of sacrosidase. However, sacrosidaseshould not be reconstituted or consumed with fruit juice, since its acidity may reduce the enzyme activity.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with sacrosidase. sacrosidaseis not expected to cause fetal harm when administered to a pregnant woman or to affect reproductive capacity. sacrosidaseshould be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sacrosidase in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sacrosidase during labor and delivery.
### Nursing Mothers
- The sacrosidaseenzyme is broken down in the stomach and intestines and the component amino acids and peptides are then absorbed as nutrients.
### Pediatric Use
- sacrosidasehas been used in patients as young as 5 months of age. Evidence in one controlled trial in primarily pediatric patients shows that sacrosidaseis safe and effective for the treatment of the genetically acquired sucrase deficiency, which is part of CSID.
### Geriatic Use
There is no FDA guidance on the use of Sacrosidase with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Sacrosidase with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sacrosidase with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sacrosidase in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sacrosidase in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sacrosidase in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sacrosidase in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- The definitive test for diagnosis of CSID is the measurement of intestinal disaccharidases following small bowel biopsy.
- Other tests used alone may be inaccurate: for example, the breath hydrogen test (high incidence of false-negatives) or oral sucrose tolerance test (high incidence of false positives). Differential urinary disaccharide testing has been reported to show good agreement with small intestinal biopsy for diagnosis of CSID.
# IV Compatibility
There is limited information regarding IV Compatibility of Sacrosidase in the drug label.
# Overdosage
- Overdosage with sacrosidasehas not been reported.
# Pharmacology
## Mechanism of Action
- Congenital sucrase-isomaltase deficiency (CSID) is a chronic, autosomal recessive, inherited, phenotypically heterogeneous disease with very variable enzyme activity. CSID is usually characterized by a complete or almost complete lack of endogenous sucrase activity, a very marked reduction in isomaltase activity, a moderate decrease in maltase activity and normal lactase levels.
## Structure
- Sacrosidase oral solution is an enzyme replacement therapy for the treatment of genetically determined sucrase deficiency, which is part of congenital sucrase-isomaltase deficiency (CSID).
- sacrosidaseis a pale yellow, clear solution with a pleasant sweet taste. Each milliliter (mL) of sacrosidase contains 8,500 International Units (I.U.) of the enzyme sacrosidase, the active ingredient. The chemical name of this enzyme is ß,D-fructofuranoside fructohydrolase. The enzyme is derived from baker’s yeast (Saccharomyces cerevisiae).
- It has been reported that the primary amino acid structure of this protein consists of 513 amino acids with an apparent molecular weight of 100,000 g/mole for the glycosylated monomer (Range 66,000-116,000 g/mole). Reports also suggest that the protein exists in solution as a monomer, dimer, tetramer, and octomer ranging from 100,000 g/mole to 800,000 g/mole. It has an isoelectric point of 4 (pl=4.093).
- sacrosidasemay contain small amounts of papain. Papain is known to cause allergic reactions in some people. Papain is a protein-cleaving enzyme that is introduced in the manufacturing process to digest the cell wall of the yeast and may not be completely removed during subsequent process steps.
- sacrosidasealso contains 50% glycerol (w/w) in an aqueous solution. Glycerol (glycerin) in the amount consumed in the recommended doses of sacrosidasehas no expected toxicity.
- This enzyme preparation is fully soluble with water, milk, and infant formula (DO NOT HEAT SOLUTIONS CONTAINING sacrosidase). Do not put sacrosidasein warm or hot liquids.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Sacrosidase in the drug label.
## Pharmacokinetics
- Sucrase is naturally produced in the brush border of the small intestine, primarily the distal duodenum and jejunum. Sucrase hydrolyzes the disaccharide sucrose into its component monosaccharides, glucose and fructose. Isomaltase breaks down disaccharides from starch into simple sugars. sacrosidasedoes not contain isomaltase.
- In the absence of endogenous human sucrase, as in CSID, sucrose is not metabolized. Unhydrolyzed sucrose and starch are not absorbed from the intestine and their presence in the intestinal lumen may lead to osmotic retention of water. This may result in loose stools.
- Unabsorbed sucrose in the colon is fermented by bacterial flora to produce increased amounts of hydrogen, methane and water. As a consequence, excessive gas, bloating, abdominal cramps, nausea and vomiting may occur.
- Chronic malabsorption of disaccharides may result in malnutrition. Undiagnosed/untreated CSID patients often fail to thrive and fall behind in their expected growth and development curves. Previously, the treatment of CSID has required the continual use of a strict sucrose-free diet.
- CSID is often difficult to diagnose. Approximately 4% to 10% of pediatric patients with chronic diarrhea of unknown origin have CSID. Measurement of expired breath hydrogen under controlled conditions following a sucrose challenge (a measurement of excess hydrogen excreted in exhalation) in CSID patients has shown levels as great as 6 times that in normal subjects.
- A generally accepted clinical definition of CSID is a condition characterized by the following: stool pH <6, an increase in breath hydrogen of > 10ppm when challenged with sucrose after fasting and a negative lactose breath test. However, because of the difficulties in diagnosing CSID, it may be warranted to conduct a short therapeutic trial (e.g. one week) to assess response in patients suspected of having CSID.
## Nonclinical Toxicology
- Long-term studies in animals with sacrosidasehave not been performed to evaluate the carcinogenic potential. Studies to evaluate the effect of sacrosidaseon fertility or its mutagenic potential have not been performed.
# Clinical Studies
- A two-phase (dose response preceded by a breath hydrogen phase) double-blind, multi-site, crossover trial was conducted in 28 patients (aged 4 months to 11.5 years) with confirmed CSID. During the dose response phase the patients were challenged with an ordinary sucrose containing diet while receiving each of four doses of sacrosidase; full strength (9000 I.U./mL) and three dilutions (1:10 [900 I.U./mL], 1:100 [90 I.U./mL], and 1:1000 [9 I.U./mL]) in random order for a period of 10 days. Patients who weighed no more than 15 kg received 1 mL per meal; those weighing more than 15 kg received 2 mL per meal. The dose did not vary with age or sucrose intake.
- A dose-response relationship was shown between the two higher and the two lower doses. The two higher doses of sacrosidase were associated with significantly fewer total stools and higher proportions of patients having lower total symptom scores, the primary efficacy end-points. In addition, higher doses of sacrosidase were associated with a significantly greater number of hard and formed stools as well as with fewer watery and soft stools, the secondary efficacy end-points.
- Analysis of the overall symptomatic response as a function of age indicated that in CSID patients up to 3 years of age, 86% became asymptomatic. In patients over 3 years of age 77% became asymptomatic. Thus, the therapeutic response did not differ significantly according to age.
- A second study of similar design and execution as the first used 4 different dilutions of sacrosidase 1:100 (90 I.U./mL), 1:1000 (9 I.U./mL), 1:10,000 (0.9 I.U./mL), and 1:100,000 (0.09 I.U./mL). There were inconsistent results with regards to the primary efficacy parameters.
- In both trials however, patients showed a marked decrease in breath hydrogen output when they received sacrosidase in comparison to placebo.
# How Supplied
- sacrosidaseis available in 118 mL (4 fluid ounces) translucent plastic bottles, packaged two bottles per box. Each mL of solution contains 8,500 International Units (I.U.) of sacrosidase. A 1 mL measuring scoop is provided with each bottle. A full measuring scoop is 1 mL.
- Store in a refrigerator at 2°- 8°C (36°- 46°F). Product is sterile until opened. Discard four weeks after first opening due to the potential for bacterial growth. Protect from heat and light.
## Storage
There is limited information regarding Sacrosidase Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be instructed to discard bottles of sacrosidase4 weeks after opening due to the potential for bacterial growth. For the same reason, patients should be advised to rinse the measuring scoop with water after each use.
sacrosidaseis fully soluble with water, milk and infant formula, but it is important to note that this product is sensitive to heat. sacrosidaseshould not be reconstituted or consumed with fruit juice, since its acidity may reduce the enzyme activity.
# Precautions with Alcohol
- Alcohol-Sacrosidase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Sacrosidase Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Sacrosidase Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Sacrosidase | |
a824fe7c306abea922df221fa6eed52e694d6741 | wikidoc | Salix nigra | Salix nigra
Salix nigra, commonly known as the black willow, is a tree species native to eastern North America. It is present from Nova Scotia and southern Ontario, west to Nebraska and southeastern Arizona and south to Florida and northeastern Mexico. The largest American species of willow, it is typically found along streams and in swamps, hence it is also known as the swamp willow (not to be confused with Salix myrtilloides). Goodding's willow (Salix gooddingii) is sometimes considered a variety of the black willow, which would extend its range to western North America.
# Description
It is a small to medium-sized deciduous tree, growing to 20-30 m in good conditions, exceptionally up to 40 m. It has long, thin leaves, 7-13 cm long and 1-2 cm broad, dark, shiny green color, with a lighter green underside. It is dioecious, with small, green flowers that are borne on catkins 2.5-7.5 cm long. The fruit is a 5 mm capsule which splits open when mature to release the numerous minute, down-covered seeds.
# Uses
Black Willow roots are very bitter, and have been used as a substitute for quinine in the past. | Salix nigra
Salix nigra, commonly known as the black willow, is a tree species native to eastern North America. It is present from Nova Scotia and southern Ontario, west to Nebraska and southeastern Arizona and south to Florida and northeastern Mexico. The largest American species of willow, it is typically found along streams and in swamps, hence it is also known as the swamp willow (not to be confused with Salix myrtilloides). Goodding's willow (Salix gooddingii) is sometimes considered a variety of the black willow, which would extend its range to western North America.
# Description
It is a small to medium-sized deciduous tree, growing to 20-30 m in good conditions, exceptionally up to 40 m. It has long, thin leaves, 7-13 cm long and 1-2 cm broad, dark, shiny green color, with a lighter green underside. It is dioecious, with small, green flowers that are borne on catkins 2.5-7.5 cm long. The fruit is a 5 mm capsule which splits open when mature to release the numerous minute, down-covered seeds.
# Uses
Black Willow roots are very bitter, and have been used as a substitute for quinine in the past. | https://www.wikidoc.org/index.php/Salix_nigra | |
71b633c2f0b14732240b7562b4d375f9ec29ecb8 | wikidoc | Salpingitis | Salpingitis
# Overview
Salpingitis is an infection and inflammation in the fallopian tubes. It is often used synonymously with PID, although PID lacks an accurate definition and can refer to several diseases of the female upper genital tract, such as endometritis, oophoritis, myometritis, parametritis and infection in the pelvic peritoneum
. In contrast, salpingitis only refers to infection and inflammation in the fallopian tubes.
# Epidemiology
Over one million cases of acute salpingitis are reported every year in the U.S., but the number of incidents is probably larger, due to incomplete and untimely reporting methods and that many cases are reported first when the illness has gone so far that it has developed chronic complications. For women aged 16-25, salpingitis is the most common serious infection. It affects approximately 11% of the female of reproductive age.
Salpingitis has a higher incidence among blacks and members of lower socioeconomic classes. However, this is thought of being an effect of earlier sex debut, multiple partners and decreased ability to receive proper health care rather than any independent risk factor for salpingitis.
As an effect of an increased risk due to multiple partners, the prevalence of salpingitis is highest for people aged 15-24 years. Decreased awareness of symptoms and less will to use contraceptives are also common in this group, raising the occurrence of salpingitis.
# Acute and chronic salpingitis
There are two types of salpingitis: Acute salpingitis and chronic salpingitis.
Acute salpingitis causes the fallopian types to become red and swollen. The inner walls get adhered to each other, causing a block in the tube. The fallopian tube can also get stuck to the surrounding intestine.
In contrast, the chronic salpingitis is milder, showing lesser symptoms. It often comes after an attack of acute salpingitis, and lasts longer than the former. Chronic salpingitis may result in a hydrosalpinx.
# Causes and pathophysiology
The infection usually has its origin in the vagina, and ascends to the fallopian tube from there. Because the infection can spread via the lymph vessels, infection in one fallopian tube usually leads to infection of the other.
# Differential diagnosis
- Salpingitis must be differentiated from other diseases that cause lower abdominal pain and fever like appendicitis, diverticulitis, inflammatory bowel disease, cystitis, colorectal cancer and endometritis. | Salpingitis
For patient information, click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Salpingitis is an infection and inflammation in the fallopian tubes. It is often used synonymously with PID, although PID lacks an accurate definition and can refer to several diseases of the female upper genital tract, such as endometritis, oophoritis, myometritis, parametritis and infection in the pelvic peritoneum[1]
. In contrast, salpingitis only refers to infection and inflammation in the fallopian tubes.
[1]
# Epidemiology
Over one million cases of acute salpingitis are reported every year in the U.S., but the number of incidents is probably larger, due to incomplete and untimely reporting methods and that many cases are reported first when the illness has gone so far that it has developed chronic complications. For women aged 16-25, salpingitis is the most common serious infection. It affects approximately 11% of the female of reproductive age.[1]
Salpingitis has a higher incidence among blacks and members of lower socioeconomic classes. However, this is thought of being an effect of earlier sex debut, multiple partners and decreased ability to receive proper health care rather than any independent risk factor for salpingitis.
As an effect of an increased risk due to multiple partners, the prevalence of salpingitis is highest for people aged 15-24 years. Decreased awareness of symptoms and less will to use contraceptives are also common in this group, raising the occurrence of salpingitis.
# Acute and chronic salpingitis
There are two types of salpingitis: Acute salpingitis and chronic salpingitis.
Acute salpingitis causes the fallopian types to become red and swollen. The inner walls get adhered to each other, causing a block in the tube. The fallopian tube can also get stuck to the surrounding intestine.
In contrast, the chronic salpingitis is milder, showing lesser symptoms. It often comes after an attack of acute salpingitis, and lasts longer than the former. [2] Chronic salpingitis may result in a hydrosalpinx.
# Causes and pathophysiology
The infection usually has its origin in the vagina, and ascends to the fallopian tube from there. Because the infection can spread via the lymph vessels, infection in one fallopian tube usually leads to infection of the other. [2]
# Differential diagnosis
- Salpingitis must be differentiated from other diseases that cause lower abdominal pain and fever like appendicitis, diverticulitis, inflammatory bowel disease, cystitis, colorectal cancer and endometritis.[3][4][5][6][7][8] | https://www.wikidoc.org/index.php/Salpingitis | |
9a13f6f5b5d93d49613ef8a846c1f9fac6d6d8a2 | wikidoc | Sample size | Sample size
# Overview
The sample size of a statistical sample is the number of repeated measurements that constitute it. It is typically denoted n, and is a non-negative integer (natural number).
Typically, different sample sizes lead to different accuracies of measurement. This can be seen in such statistical rules as the law of large numbers and the central limit theorem. All else being equal, a larger sample size n leads to increased precision in estimates of various properties of the population.
A typical example would be when a statistician wishes to estimate the arithmetic mean of a continuous random variable (for example, the height of a person). Assuming that they have a random sample with independent observations, then if the variability of the population (as measured by the standard deviation σ) is known, then the standard error of the sample mean is given by the formula:
It is easy to show that as n becomes large, this variability becomes very small. This yields to more sensitive hypothesis tests with greater Statistical power and smaller confidence intervals.
With more complicated sampling techniques, such as Stratified sampling, the sample can often be split up into sub-samples. Typically, if there are k such sub-samples (from k different strata) then each of them will have a sample size ni, i = 1, 2, ..., k. These ni must conform to the rule that n1 + n2 + ... + nk = n (i.e. that the total sample size is given by the sum of the sub-sample sizes). Selecting these ni optimally can be done in various ways, using (for example) Neyman's optimal allocation.
# Further examples
# Central limit theorem
The central limit theorem is a significant result which depends on sample size.
# Estimating proportions
A typical statistical aim is to demonstrate with 95% certainty that the true value of a parameter is within a distance B of the estimate: B is an error range that decreases with increasing sample size (n). The value of B generated is referred to as the 95% confidence interval.
For example, a simple situation is estimating a proportion in a population. To do so, a statistician will estimate the bounds of a 95% confidence interval for an unknown proportion.
The rule of thumb for (a maximum or 'conservative') B for a proportion derives from the fact the estimator of a proportion, \hat p = X/n, (where X is the number of 'positive' observations) has a (scaled) binomial distribution and is also a form of sample mean (from a Bernoulli distribution which has a maximum variance of 0.25 for parameter p = 0.5). So, the sample mean X/n has maximum variance 0.25/n. For sufficiently large n (usually this means that we need to have observed at least 10 positive and 10 negative responses), this distribution will be closely approximated by a normal distribution with the same mean and variance.
Using this approximation, it can be shown that ~95% of this distribution's probability lies within 2 standard deviations of the mean. Because of this, an interval of the form
will form a 95% confidence interval for the true proportion.
If we require the sampling error ε to be no larger than some bound B, we can solve the equation
to give us
So, n = 100 B = 10%, n = 400 B = 5%, n = 1000 B = ~3%, and n = 10000 B = 1%. One sees these numbers quoted often in news reports of opinion polls and other sample surveys.
## Extension to other cases
In general, if a population mean is estimated using the sample mean from n observations from a distribution with variance σ², then if n is large enough (typically >30) the central limit theorem can be applied to obtain an approximate 95% confidence interval of the form
If the sampling error ε is required to be no larger than bound B, as above, then
Note, if the mean is to be estimated using P parameters that must first be estimated themselves from the same sample, then to preserve sufficient "degrees of freedom," the sample size should be at least n + P.
# Required sample sizes for hypothesis tests
A common problem facing statisticians is calculating the sample size required to yield a certain power for a test, given a predetermined Type I error rate α. A typical example for this is as follows:
Let X i , i = 1, 2, ..., n be independent observations taken from a normal distribution with mean μ and variance σ2 . Let us consider two hypotheses, a null hypothesis:
and an alternative hypothesis:
for some 'smallest significant difference' μ- >0. This is the smallest value for which we care about observing a difference. Now, if we wish to (1) reject H0 with a probability of at least 1-β when
Ha is true (i.e. a power of 1-β), and (2) reject H0 with probability α when H0 is true, then we need the following:
If zα is the upper α percentage point of the standard normal distribution, then
and so
is a decision rule which satisfies (2). (Note, this is a 2-tailed test)
Now we wish for this to happen with a probability at least 1-β when
Ha is true. In this case, our sample average will come from a Normal distribution with mean μ*. Therefore we require
Through careful manipulation, this can be shown to happen when
where \Phi is the normal cumulative distribution function. | Sample size
# Overview
The sample size of a statistical sample is the number of repeated measurements that constitute it. It is typically denoted n, and is a non-negative integer (natural number).
Typically, different sample sizes lead to different accuracies of measurement. This can be seen in such statistical rules as the law of large numbers and the central limit theorem. All else being equal, a larger sample size n leads to increased precision in estimates of various properties of the population.
A typical example would be when a statistician wishes to estimate the arithmetic mean of a continuous random variable (for example, the height of a person). Assuming that they have a random sample with independent observations, then if the variability of the population (as measured by the standard deviation σ) is known, then the standard error of the sample mean is given by the formula:
It is easy to show that as n becomes large, this variability becomes very small. This yields to more sensitive hypothesis tests with greater Statistical power and smaller confidence intervals.
With more complicated sampling techniques, such as Stratified sampling, the sample can often be split up into sub-samples. Typically, if there are k such sub-samples (from k different strata) then each of them will have a sample size ni, i = 1, 2, ..., k. These ni must conform to the rule that n1 + n2 + ... + nk = n (i.e. that the total sample size is given by the sum of the sub-sample sizes). Selecting these ni optimally can be done in various ways, using (for example) Neyman's optimal allocation.
# Further examples
# Central limit theorem
The central limit theorem is a significant result which depends on sample size.
# Estimating proportions
A typical statistical aim is to demonstrate with 95% certainty that the true value of a parameter is within a distance B of the estimate: B is an error range that decreases with increasing sample size (n). The value of B generated is referred to as the 95% confidence interval.
For example, a simple situation is estimating a proportion in a population. To do so, a statistician will estimate the bounds of a 95% confidence interval for an unknown proportion.
The rule of thumb for (a maximum or 'conservative') B for a proportion derives from the fact the estimator of a proportion, <math> \hat p = X/n</math>, (where X is the number of 'positive' observations) has a (scaled) binomial distribution and is also a form of sample mean (from a Bernoulli distribution [0,1] which has a maximum variance of 0.25 for parameter p = 0.5). So, the sample mean X/n has maximum variance 0.25/n. For sufficiently large n (usually this means that we need to have observed at least 10 positive and 10 negative responses), this distribution will be closely approximated by a normal distribution with the same mean and variance.
Using this approximation, it can be shown that ~95% of this distribution's probability lies within 2 standard deviations of the mean. Because of this, an interval of the form
will form a 95% confidence interval for the true proportion.
If we require the sampling error ε to be no larger than some bound B, we can solve the equation
to give us
So, n = 100 <=> B = 10%, n = 400 <=> B = 5%, n = 1000 <=> B = ~3%, and n = 10000 <=> B = 1%. One sees these numbers quoted often in news reports of opinion polls and other sample surveys.
## Extension to other cases
In general, if a population mean is estimated using the sample mean from n observations from a distribution with variance σ², then if n is large enough (typically >30) the central limit theorem can be applied to obtain an approximate 95% confidence interval of the form
If the sampling error ε is required to be no larger than bound B, as above, then
Note, if the mean is to be estimated using P parameters that must first be estimated themselves from the same sample, then to preserve sufficient "degrees of freedom," the sample size should be at least n + P.
# Required sample sizes for hypothesis tests
A common problem facing statisticians is calculating the sample size required to yield a certain power for a test, given a predetermined Type I error rate α. A typical example for this is as follows:
Let X i , i = 1, 2, ..., n be independent observations taken from a normal distribution with mean μ and variance σ2 . Let us consider two hypotheses, a null hypothesis:
and an alternative hypothesis:
for some 'smallest significant difference' μ* >0. This is the smallest value for which we care about observing a difference. Now, if we wish to (1) reject H0 with a probability of at least 1-β when
Ha is true (i.e. a power of 1-β), and (2) reject H0 with probability α when H0 is true, then we need the following:
If zα is the upper α percentage point of the standard normal distribution, then
and so
is a decision rule which satisfies (2). (Note, this is a 2-tailed test)
Now we wish for this to happen with a probability at least 1-β when
Ha is true. In this case, our sample average will come from a Normal distribution with mean μ*. Therefore we require
Through careful manipulation, this can be shown to happen when
where <math>\Phi</math> is the normal cumulative distribution function. | https://www.wikidoc.org/index.php/Sample_size | |
38e3d1fbd1d7059b7c35d603a4bc61378bc009ea | wikidoc | Sandbox/HCM | Sandbox/HCM
# Overview
Hypertrophic cardiomyopathy (HCM), is a heterogeneous cardiac muscle disease characterized by unexplained LV hypertrophy associated with nondilated ventricular chambers in the absence any underlying disease that is capable of producing hypertrophy, or without overt hypertrophy in the presence of the HCM genetic substrate (genotype positive/phenotype negative or subclinical HCM). HCM is caused by autosomal dominant mutations in sarcomere genes which encode components of the contractile apparatus of the heart. The clinical manifestations of HCM individuals depends upon the site and extent of cardiac hypertrophy, having asymptomatic normal life expectancy without disability to severe symptomatic presentation due to LV outflow obstruction, heart failure, myocardial ischemia, arrhythmia, mitral regurgitation or sudden cardiac death. The diagnosis of HCM is made with cardiac imaging (echocardiography or cardiac MRI), showing maximal LV wall thickness ≥ 15 mm in adults or thickness ≥ 2 SD above the mean for age, sex, body size in children and with genetic testing. The management of HCM involves risk stratification to ascertain which patients are at risk for sudden cardiac death, treatment of comorbidities, ICDs for secondary or primary prevention, pharmacological therapy to control heart failure, surgical options for progressive and drug-refractory heart failure symptoms due to LV outflow tract (LVOT) obstruction and heart transplantation for systolic dysfunction with severe unrelenting symptoms.
# Classification
## Obstructive form of HCM
Defined when peak instantaneous LV outflow gradient ≥30 mm Hg under basal (resting) conditions. or with physiologic provocation.
## Non-obstructive form of HCM
Defined when peak instantaneous LV outflow gradient <30 mm Hg at rest and with provocation.
# Causes
## Life Threatening Causes
Hypertrophic cardiomyopathy can be a life-threatening condition and must be treated as such irrespective of the underlying cause.
## Common Causes
- Congenital: Autosomal dominant mutation in genes that encode sarcomere proteins or sarcomere-associated proteins.
Beta myosin heavy chain
Myosin binding protein C
Troponin T
Troponin I
Alpha tropomyosin
Actin
Regulatory light chain
Essential light chain
Actinin
Myozenin
- Beta myosin heavy chain
- Myosin binding protein C
- Troponin T
- Troponin I
- Alpha tropomyosin
- Actin
- Regulatory light chain
- Essential light chain
- Actinin
- Myozenin
# FIRE: Focused Initial Rapid Evaluation
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.
Boxes in red color signify that an urgent management is needed.
# Complete Diagnostic Approach to Hypertrophic Obstructive Cardiomyopathy
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.
# Treatment
# Complete Diagnostic Approach to Mitral Regurgitation
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.
Abbreviations: EKG: Electrocardiogram; LVOT: Left ventricle outflow tract;
# Treatment
# Do's
However in equivocal cases, cardiac catheterization with isoproterenol infusion may further aid in eliciting a provocable gradient (82). Otherwise, routine invasive cardiac catheterization to document outflow gradients is necessary only when there are discordant data from Doppler echocardiography and the physical examination
# Don'ts
Provocation with dobutamine infusion during Doppler echocardiography is no longer recommended as a strategy to induce outflow gradients in HCM.
- Don't perform genetic testing for relatives when the index patient does not have a definitive pathogenic mutation (Class IIb Level of Evidence:B). | Sandbox/HCM
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mugilan Poongkunran M.B.B.S [2]
# Overview
Hypertrophic cardiomyopathy (HCM), is a heterogeneous cardiac muscle disease characterized by unexplained LV hypertrophy associated with nondilated ventricular chambers in the absence any underlying disease that is capable of producing hypertrophy, or without overt hypertrophy in the presence of the HCM genetic substrate (genotype positive/phenotype negative or subclinical HCM). HCM is caused by autosomal dominant mutations in sarcomere genes which encode components of the contractile apparatus of the heart. The clinical manifestations of HCM individuals depends upon the site and extent of cardiac hypertrophy, having asymptomatic normal life expectancy without disability to severe symptomatic presentation due to LV outflow obstruction, heart failure, myocardial ischemia, arrhythmia, mitral regurgitation or sudden cardiac death. The diagnosis of HCM is made with cardiac imaging (echocardiography or cardiac MRI), showing maximal LV wall thickness ≥ 15 mm in adults or thickness ≥ 2 SD above the mean for age, sex, body size in children and with genetic testing. The management of HCM involves risk stratification to ascertain which patients are at risk for sudden cardiac death, treatment of comorbidities, ICDs for secondary or primary prevention, pharmacological therapy to control heart failure, surgical options for progressive and drug-refractory heart failure symptoms due to LV outflow tract (LVOT) obstruction and heart transplantation for systolic dysfunction with severe unrelenting symptoms.
# Classification
## Obstructive form of HCM
Defined when peak instantaneous LV outflow gradient ≥30 mm Hg under basal (resting) conditions. or with physiologic provocation.
## Non-obstructive form of HCM
Defined when peak instantaneous LV outflow gradient <30 mm Hg at rest and with provocation.
# Causes
## Life Threatening Causes
Hypertrophic cardiomyopathy can be a life-threatening condition and must be treated as such irrespective of the underlying cause.
## Common Causes
- Congenital: Autosomal dominant mutation in genes that encode sarcomere proteins or sarcomere-associated proteins.
Beta myosin heavy chain
Myosin binding protein C
Troponin T
Troponin I
Alpha tropomyosin
Actin
Regulatory light chain
Essential light chain
Actinin
Myozenin
- Beta myosin heavy chain
- Myosin binding protein C
- Troponin T
- Troponin I
- Alpha tropomyosin
- Actin
- Regulatory light chain
- Essential light chain
- Actinin
- Myozenin
# FIRE: Focused Initial Rapid Evaluation
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.
Boxes in red color signify that an urgent management is needed.
# Complete Diagnostic Approach to Hypertrophic Obstructive Cardiomyopathy
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.
# Treatment
# Complete Diagnostic Approach to Mitral Regurgitation
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.
Abbreviations: EKG: Electrocardiogram; LVOT: Left ventricle outflow tract;
# Treatment
# Do's
However in equivocal cases, cardiac catheterization with isoproterenol infusion may further aid in eliciting a provocable gradient (82). Otherwise, routine invasive cardiac catheterization to document outflow gradients is necessary only when there are discordant data from Doppler echocardiography and the physical examination
# Don'ts
Provocation with dobutamine infusion during Doppler echocardiography is no longer recommended as a strategy to induce outflow gradients in HCM.
- Don't perform genetic testing for relatives when the index patient does not have a definitive pathogenic mutation (Class IIb Level of Evidence:B). | https://www.wikidoc.org/index.php/Sandbox/HCM | |
1879569fbf728a7137b604515bd0865c479ce774 | wikidoc | Sandbox/HIV | Sandbox/HIV
- ↑ Cain KP, McCarthy KD, Heilig CM, Monkongdee P, Tasaneeyapan T, Kanara N; et al. (2010). "An algorithm for tuberculosis screening and diagnosis in people with HIV". N Engl J Med. 362 (8): 707–16. doi:10.1056/NEJMoa0907488. PMID . 20181972 . Check |pmid= value (help).CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Batungwanayo J, Taelman H, Dhote R, Bogaerts J, Allen S, Van de Perre P (1992). "Pulmonary tuberculosis in Kigali, Rwanda. Impact of human immunodeficiency virus infection on clinical and radiographic presentation". Am Rev Respir Dis. 146 (1): 53–6. doi:10.1164/ajrccm/146.1.53. PMID 1626814.CS1 maint: Multiple names: authors list (link)
- ↑ Jones BE, Young SM, Antoniskis D, Davidson PT, Kramer F, Barnes PF (1993). "Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection". Am Rev Respir Dis. 148 (5): 1292–7. doi:10.1164/ajrccm/148.5.1292. PMID . 7902049 . Check |pmid= value (help).CS1 maint: Multiple names: authors list (link)
- ↑ Perlman DC, el-Sadr WM, Nelson ET, Matts JP, Telzak EE, Salomon N; et al. (1997). "Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). The AIDS Clinical Trials Group (ACTG)". Clin Infect Dis. 25 (2): 242–6. PMID . 9332519 . Check |pmid= value (help).CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Tedla Z, Nyirenda S, Peeler C, Agizew T, Sibanda T, Motsamai O; et al. (2010). "Isoniazid-associated hepatitis and antiretroviral drugs during tuberculosis prophylaxis in hiv-infected adults in Botswana". Am J Respir Crit Care Med. 182 (2): 278–85. doi:10.1164/rccm.200911-1783OC. PMID 20378730.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Hoffmann CJ, Charalambous S, Thio CL, Martin DJ, Pemba L, Fielding KL; et al. (2007). "Hepatotoxicity in an African antiretroviral therapy cohort: the effect of tuberculosis and hepatitis B." AIDS. 21 (10): 1301–8. doi:10.1097/QAD.0b013e32814e6b08. PMID 17545706.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Osato T (1988). "". Nihon Naika Gakkai Zasshi. 77 (9): 1355–7. PMID 2854545.
- ↑ Narayanan S, Swaminathan S, Supply P, Shanmugam S, Narendran G, Hari L; et al. (2010). "Impact of HIV infection on the recurrence of tuberculosis in South India". J Infect Dis. 201 (5): 691–703. doi:10.1086/650528. PMID 20121433.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | Sandbox/HIV
- ↑ Cain KP, McCarthy KD, Heilig CM, Monkongdee P, Tasaneeyapan T, Kanara N; et al. (2010). "An algorithm for tuberculosis screening and diagnosis in people with HIV". N Engl J Med. 362 (8): 707–16. doi:10.1056/NEJMoa0907488. PMID . 20181972 . Check |pmid= value (help).CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Batungwanayo J, Taelman H, Dhote R, Bogaerts J, Allen S, Van de Perre P (1992). "Pulmonary tuberculosis in Kigali, Rwanda. Impact of human immunodeficiency virus infection on clinical and radiographic presentation". Am Rev Respir Dis. 146 (1): 53–6. doi:10.1164/ajrccm/146.1.53. PMID 1626814.CS1 maint: Multiple names: authors list (link)
- ↑ Jones BE, Young SM, Antoniskis D, Davidson PT, Kramer F, Barnes PF (1993). "Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection". Am Rev Respir Dis. 148 (5): 1292–7. doi:10.1164/ajrccm/148.5.1292. PMID . 7902049 . Check |pmid= value (help).CS1 maint: Multiple names: authors list (link)
- ↑ Perlman DC, el-Sadr WM, Nelson ET, Matts JP, Telzak EE, Salomon N; et al. (1997). "Variation of chest radiographic patterns in pulmonary tuberculosis by degree of human immunodeficiency virus-related immunosuppression. The Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA). The AIDS Clinical Trials Group (ACTG)". Clin Infect Dis. 25 (2): 242–6. PMID . 9332519 . Check |pmid= value (help).CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Tedla Z, Nyirenda S, Peeler C, Agizew T, Sibanda T, Motsamai O; et al. (2010). "Isoniazid-associated hepatitis and antiretroviral drugs during tuberculosis prophylaxis in hiv-infected adults in Botswana". Am J Respir Crit Care Med. 182 (2): 278–85. doi:10.1164/rccm.200911-1783OC. PMID 20378730.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Hoffmann CJ, Charalambous S, Thio CL, Martin DJ, Pemba L, Fielding KL; et al. (2007). "Hepatotoxicity in an African antiretroviral therapy cohort: the effect of tuberculosis and hepatitis B." AIDS. 21 (10): 1301–8. doi:10.1097/QAD.0b013e32814e6b08. PMID 17545706.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Osato T (1988). "[Viral infections in medicine. 5. EB virus, cytomegalovirus, herpesvirus infections diseases]". Nihon Naika Gakkai Zasshi. 77 (9): 1355–7. PMID 2854545.
- ↑ Narayanan S, Swaminathan S, Supply P, Shanmugam S, Narendran G, Hari L; et al. (2010). "Impact of HIV infection on the recurrence of tuberculosis in South India". J Infect Dis. 201 (5): 691–703. doi:10.1086/650528. PMID 20121433.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Sandbox/HIV | |
163a43818f04500ec35b05758755ca43d463731f | wikidoc | Sandbox/JRH | Sandbox/JRH
# 1.- Substance/Medication-Induced Psychotic Disorder
Synonyms and keywords: Medication induced psychotic disorder; substance induced psychotic disorder; substance-medication induced psychotic disorder;
# Differential Diagnosis
- Alcohol withdrawal
- Brief psychotic disorder
- Cannabis intoxication
- Delusional disorder
- Flashback hallucinations
- Intoxication with stimulants
- Phencyclidine
- Schizophrenia
- Schizoaffective disorder
- Schizophrenia spectrum
- Delusional disorder
- Opioid meperidine
# Epidemiology and Demographics
## Prevalence
The prevalence of substance/medication-induced psychotic disorder is unknown of the overall population.
# Risk Factors
- Cocaine usage
- Heavy and constant ingestion of alcohol
- History of psychopathic disorder
# Natural History, Complications and Prognosis
Poor prognosis factors include:
- Depersonalization
- Flashbacks
- Hallucinations
- Marked anxiety
- Persecutory delusions
# Diagnostic Criteria
- A. Presence of one or both of the following symptoms:
AND
- B. There is evidence from the history, physical examination, or laboratory findings of both (1) and (2):
AND
- C. The disturbance is not better explained by a psychotic disorder that is not substance/medication-induced. Such evidence of an independent psychotic disorder could include the following:
The symptoms preceded the onset of the substance/medication use; the symptoms persist for a substantial period of time (e.g., about 1 month) after the cessation of acute withdrawal or severe intoxication: or there is other evidence of an independent non-substance/medication-induced psychotic disorder (e.g., a history of recurrent non-substance/medication-related episodes).
AND
- D. The disturbance does not occur exclusively during the course of a delirium.
AND
- E. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
Note: This diagnosis should be made instead of a diagnosis of substance intoxication or substance withdrawal only when the symptoms in Criterion A predominate in the clinical picture and when they are sufficiently severe to warrant clinical attention. | Sandbox/JRH
# 1.- Substance/Medication-Induced Psychotic Disorder
Synonyms and keywords: Medication induced psychotic disorder; substance induced psychotic disorder; substance-medication induced psychotic disorder;
# Differential Diagnosis
- Alcohol withdrawal
- Brief psychotic disorder
- Cannabis intoxication
- Delusional disorder
- Flashback hallucinations
- Intoxication with stimulants
- Phencyclidine
- Schizophrenia
- Schizoaffective disorder
- Schizophrenia spectrum
- Delusional disorder
- Opioid meperidine[1]
# Epidemiology and Demographics
## Prevalence
The prevalence of substance/medication-induced psychotic disorder is unknown of the overall population.[1]
# Risk Factors
- Cocaine usage
- Heavy and constant ingestion of alcohol
- History of psychopathic disorder [1]
# Natural History, Complications and Prognosis
Poor prognosis factors include:
- Depersonalization
- Flashbacks
- Hallucinations
- Marked anxiety
- Persecutory delusions[1]
# Diagnostic Criteria
- A. Presence of one or both of the following symptoms:
AND
- B. There is evidence from the history, physical examination, or laboratory findings of both (1) and (2):
AND
- C. The disturbance is not better explained by a psychotic disorder that is not substance/medication-induced. Such evidence of an independent psychotic disorder could include the following:
The symptoms preceded the onset of the substance/medication use; the symptoms persist for a substantial period of time (e.g., about 1 month) after the cessation of acute withdrawal or severe intoxication: or there is other evidence of an independent non-substance/medication-induced psychotic disorder (e.g., a history of recurrent non-substance/medication-related episodes).
AND
- D. The disturbance does not occur exclusively during the course of a delirium.
AND
- E. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning.
Note: This diagnosis should be made instead of a diagnosis of substance intoxication or substance withdrawal only when the symptoms in Criterion A predominate in the clinical picture and when they are sufficiently severe to warrant clinical attention. | https://www.wikidoc.org/index.php/Sandbox/JRH | |
64d4672fb14f2dc6f2d071c8c28a339c49d18636 | wikidoc | Sandbox/NCT | Sandbox/NCT
# Overview
Narrow complex tachycardia (NCT) is characterized by heart rate > 100 beats per minute and QRS complex of duration < 120 milliseconds. The NCT may originate in the sinus node, the atria, the AV node, the His bundle, or combination of these tissues causing rapid activation of the ventricles. Diagnosis of NCT is established by surface ECG in correlation with history and physical examination. Hemodynamically unstable patients should receive urgent cardioversion.
# Causes
## Life Threatening Causes
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.
- Wolff-Parkinson-White syndrome
- VT
## Common Causes
- Atrial fibrillation
- Atrial flutter
- Atrial tachycardia
- AVNRT
- AVRT
# Diagnosis
Shown below is an algorithm summarizing the approach for diagnosing narrow complex tachycardia according to the 2003 ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias.
ECG: electrocardiogram; SVT: supraventricular tachycardia; ms: Milliseconds; bpm: beats per minute; NCT: Narrow complex tachycardia; AV: atrioventricular; AVNRT: atrioventricular nodal reciprocating tachycardia; MAT: multifocal atrial tachycardia; ms: milliseconds; PJRT: permanent form of junctional reciprocating tachycardia
# Treatment
## Initial Approach
## Short Term Treatment of SVT in a Hemodynamically Stable Patient
Shown below is an algorithm summarizing the management of narrow complex tachycardia according to the 2003 ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias.
AF: atrial fibrillation; AV: atrioventricular; AVNRT: atrioventricular nodal reciprocating tachycardia; AVRT: atrioventricular reciprocating tachycardia; BBB: bundle-branch block; ECG: electrocardiography; IV: intravenous; LV: left ventricle; SVT: supraventricular tachycardia; VT: ventricular tachycardia
† Adenosine should be used cautiously in patients with severe coronary artery disease and may produce AF.
‡ Ibutilide is especially indicated for patients with atrial flutter but should not be used in patients with ejection fraction less than 30% as it increases risk of polymorphic VT.
† EKG strips are a courtesy from ECGpedia.
## Treatment of Specific Supraventricular Arrhythmias | Sandbox/NCT
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Hilda Mahmoudi M.D., M.P.H.[2]; Twinkle Singh, M.B.B.S. [3]; Rim Halaby, M.D. [4]; Amr Marawan, M.D. [5]
# Overview
Narrow complex tachycardia (NCT) is characterized by heart rate > 100 beats per minute and QRS complex of duration < 120 milliseconds. The NCT may originate in the sinus node, the atria, the AV node, the His bundle, or combination of these tissues causing rapid activation of the ventricles. Diagnosis of NCT is established by surface ECG in correlation with history and physical examination. Hemodynamically unstable patients should receive urgent cardioversion.
# Causes
## Life Threatening Causes
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.
- Wolff-Parkinson-White syndrome
- VT
## Common Causes
- Atrial fibrillation
- Atrial flutter
- Atrial tachycardia
- AVNRT
- AVRT
# Diagnosis
Shown below is an algorithm summarizing the approach for diagnosing narrow complex tachycardia according to the 2003 ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias.[1]
ECG: electrocardiogram; SVT: supraventricular tachycardia; ms: Milliseconds; bpm: beats per minute; NCT: Narrow complex tachycardia; AV: atrioventricular; AVNRT: atrioventricular nodal reciprocating tachycardia; MAT: multifocal atrial tachycardia; ms: milliseconds; PJRT: permanent form of junctional reciprocating tachycardia
# Treatment
## Initial Approach
## Short Term Treatment of SVT in a Hemodynamically Stable Patient
Shown below is an algorithm summarizing the management of narrow complex tachycardia according to the 2003 ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias.[1]
AF: atrial fibrillation; AV: atrioventricular; AVNRT: atrioventricular nodal reciprocating tachycardia; AVRT: atrioventricular reciprocating tachycardia; BBB: bundle-branch block; ECG: electrocardiography; IV: intravenous; LV: left ventricle; SVT: supraventricular tachycardia; VT: ventricular tachycardia
† Adenosine should be used cautiously in patients with severe coronary artery disease and may produce AF.
‡ Ibutilide is especially indicated for patients with atrial flutter but should not be used in patients with ejection fraction less than 30% as it increases risk of polymorphic VT.
† EKG strips are a courtesy from ECGpedia.
## Treatment of Specific Supraventricular Arrhythmias | https://www.wikidoc.org/index.php/Sandbox/NCT | |
0cde0be0e9e044c97bc44f323805137e729f266b | wikidoc | Sandbox/WCT | Sandbox/WCT
For the mobile version, click here
# Overview
Wide complex tachycardia is characterized by a heart rate more than 100 beats per minute associated with a QRS interval of more than 120 ms. When wide complex tachycardia is present, it is important to determine whether the tachycardia is of a supraventricular or a ventricular origin. The diagnosis of wide complex tachycardia is very challenging as there is no fixed criteria to accurately determine the cause and type of the WCT. Hemodynamically unstable patients should receive urgent synchronized cardioversion. If the QRS complex and the T wave can't be distinguished in unstable patients, then we proceed with unsynchronized cardioversion.
# Causes
## Life Threatening Causes
Wide complex tachycardia may be a life-threatening condition and must be treated as such irrespective of the causes.
## Common Causes
- Atrial fibrillation with aberrancy
- Atrial fibrillation with pre-excitation
- Supraventricular tachycardia (SVT) with aberrancy
- Ventricular tachycardia
# FIRE: Focused Initial Rapid Evaluation
A Focused Initial Rapid Evaluation (FIRE) as shown below should be performed to identify patients in need of immediate intervention.
Boxes in salmon signify that an urgent management is needed.
# Complete Diagnostic Approach
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.
Abbreviations: ECG: electrocardiogram; VT: ventricular tachycardia; VF: ventricular fibrillation; ICD: implantable cardioverter-defibrillator; BPM: beat per minute
The above algorithm is adapted from the 2003 American College of Cardiology.
# Treatment
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.
ABC: Air, breathing and circulation; Afib: Atrial fibrillation; BBB: Bundle branch block; LV: Left ventricle; SVT: Supraventricular tachycardia; VT: Ventricular tachycardia; WPW: Wold Parkinson White
## Differentiating SVT from VT
Shown below is a table summarizing some clues that help differentiate SVT from VT.
For more details about differentiating VT from SVT, click here
## Antiarrhythmics
Shown below is a table summarizing the choices of the antiarrhythmic drugs for the different types of tachycardia according to the 2003 ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias.
BBB: Bundle branch block; LV: Left ventricle; SVT: Supraventricular tachycardia
# Do's
- Refer the patient to an arrhythmia specialist when the tachycardia causes syncope or dyspnea as well as when the wide complex tachycardia is of unknown cause.
- Place an ambulatory 24 hour Holter when the tachycardia is frequent and transient.
- Treat the patient as having a ventricular tachycardia when the diagnosis of supraventricular tachycardia can not be made.
- Suspect ventricular tachycardia in a patient with wide complex tachycardia and previous myocardial infarction or a history of structural heart disease.
- Use beta blockers with caution in pulmonary diseases or congestive heart failure.
# Dont's
- Don't rely on the hemodynamic status of the patient and the heart rate to differenciate SVT from VT. | Sandbox/WCT
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]
For the mobile version, click here
# Overview
Wide complex tachycardia is characterized by a heart rate more than 100 beats per minute associated with a QRS interval of more than 120 ms. When wide complex tachycardia is present, it is important to determine whether the tachycardia is of a supraventricular or a ventricular origin. The diagnosis of wide complex tachycardia is very challenging as there is no fixed criteria to accurately determine the cause and type of the WCT. Hemodynamically unstable patients should receive urgent synchronized cardioversion. If the QRS complex and the T wave can't be distinguished in unstable patients, then we proceed with unsynchronized cardioversion.[1]
# Causes
## Life Threatening Causes
Wide complex tachycardia may be a life-threatening condition and must be treated as such irrespective of the causes.
## Common Causes
- Atrial fibrillation with aberrancy
- Atrial fibrillation with pre-excitation
- Supraventricular tachycardia (SVT) with aberrancy
- Ventricular tachycardia
Click here for the complete list of causes.
# FIRE: Focused Initial Rapid Evaluation
A Focused Initial Rapid Evaluation (FIRE) as shown below should be performed to identify patients in need of immediate intervention.[1][2]
Boxes in salmon signify that an urgent management is needed.
# Complete Diagnostic Approach
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.[1][2]
Abbreviations: ECG: electrocardiogram; VT: ventricular tachycardia; VF: ventricular fibrillation; ICD: implantable cardioverter-defibrillator; BPM: beat per minute
The above algorithm is adapted from the 2003 American College of Cardiology.[1]
# Treatment
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.[1][2]
ABC: Air, breathing and circulation; Afib: Atrial fibrillation; BBB: Bundle branch block; LV: Left ventricle; SVT: Supraventricular tachycardia; VT: Ventricular tachycardia; WPW: Wold Parkinson White
## Differentiating SVT from VT
Shown below is a table summarizing some clues that help differentiate SVT from VT.[1]
For more details about differentiating VT from SVT, click here
## Antiarrhythmics
Shown below is a table summarizing the choices of the antiarrhythmic drugs for the different types of tachycardia according to the 2003 ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias.[1]
BBB: Bundle branch block; LV: Left ventricle; SVT: Supraventricular tachycardia
# Do's
- Refer the patient to an arrhythmia specialist when the tachycardia causes syncope or dyspnea as well as when the wide complex tachycardia is of unknown cause.[1]
- Place an ambulatory 24 hour Holter when the tachycardia is frequent and transient.[1]
- Treat the patient as having a ventricular tachycardia when the diagnosis of supraventricular tachycardia can not be made.[1]
- Suspect ventricular tachycardia in a patient with wide complex tachycardia and previous myocardial infarction or a history of structural heart disease.[1]
- Use beta blockers with caution in pulmonary diseases or congestive heart failure.
# Dont's
- Don't rely on the hemodynamic status of the patient and the heart rate to differenciate SVT from VT. | https://www.wikidoc.org/index.php/Sandbox/WCT |
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