id
stringlengths 40
40
| source
stringclasses 9
values | title
stringlengths 2
345
| clean_text
stringlengths 35
1.63M
| raw_text
stringlengths 4
1.63M
| url
stringlengths 4
498
| overview
stringlengths 0
10k
|
|---|---|---|---|---|---|---|
4ffe5b874a2007acd12154716cb9e6a539851e25 | wikidoc | Social work | Social work
# Overview
Social Workers are concerned with social problems, their causes, their solutions and their human impacts. Social workers work with individuals, families, groups, organizations and communities, as members of a profession which is committed to social justice and human rights. Their approach is to consider the whole individual (including their biological, psychological, sociological, familial, cultural, and spiritual subsystems) within the context of their current situation.
Social Work is the profession committed to the pursuit of social justice, to the enhancement of the quality of life, and to the development of the full potential of each individual, group and community in society.
# Origins
The concept of charity goes back to ancient times, and the practice of providing for the poor has roots in all major world religions. However, the practice and profession of social work has a relatively modern (19th century) and scientific origin . Charity in Europe was considered to be a responsibility and a sign of one’s piety. This charity was, generally, in the form of direct relief (i.e. money, food, etc.). After the end of feudalism, a need arose to have an organized system to care for the poor. In England, the Poor Law served this purpose. This system of laws sorted the poor and developed different remedies for these different groups.
The 19th century ushered in the Industrial Revolution. There was a great leap in technological and scientific achievement, but there was also a great migration to urban areas. This led to many social problems, which in turn led to an increase in social activism. Also with the dawn of the 19th century came a great “missionary” push from many Protestant denominations. Some of the mission efforts (urban missions), attempted to resolve the problems (poverty, prostitution, disease, etc.) inherent in large cities. These “friendly visitors”, stipended by church and other charitable bodies, worked through direct relief, prayer, and evangelism to alleviate these problems . In Europe, chaplains or almoners were appointed to administrate the church’s mission to the poor.
During this time, rescue societies were initiated to find more appropriate means of self-support for women involved in prostitution. Mental asylums grew to assist in taking care of the mentally ill. A new philosophy of "scientific charity" which stated charity should be "secular, rational and empirical as opposed to sectarian, sentimental, and dogmatic." (James Leiby) In the late 1880s, a new system to provide aid for social ills popped up, that would become known as the settlement movement . The settlement movement focused on the causes of poverty. They did this through the three "R's" - Research, Reform, and Residence. They provided a variety of services including educational, legal, and health services. These programs also advocated changes in social policy. Workers in the settlement movement immersed themselves in the culture of those they were helping.
In America, this led to a fundamental question – is social work a profession? This debate can be traced back to the early 20th century debate between Mary Richmond's Charity Organization Society (COS) and Jane Addams's Settlement House Movement. The essence of this debate was whether the problem should be approached from COS’ traditional, scientific method focused on efficiency and prevention or the Settlement House Movement’s immersion into the problem, blurring the lines of practitioner and client .
Schools of social work and formalized processes began to spring up. However, the question lingered. In 1915, at the National Conference of Charities and Corrections, Dr. Abraham Flexner spoke on the topic "Is Social Work a Profession?" He contended that it was not because it lacked specialized knowledge and specific application of theoretical and intellectual knowledge to solve human and social problems . This led to the professionalization of social work, concentrating on case work and the scientific method.
# Qualifications for social work
Lay practitioners, often referred to as SSA (Social Services Assistant) or Care Managers are unqualified and unregistered social workers. They are not professionally registered and often do not hold any formal social work qualification. Within the mental health sector, unqualified social workers (Social Service Assistants / Care Managers) are called Care Co-ordinators.
In a number of countries and jurisdictions where registration of people working as social workers is required there are mandated qualifications. In other places, the professional association sets academic and experiential requirements for admission to membership. The success of these professional bodies' effort to establish these requirements is demonstrated in the fact that these same requirements are recognised by many employers as necessary for employment.
# Role of the professional social worker
Professional social workers have a strong tradition of working for social justice and of refusing to recreate unequal social structures. The main tasks of professional social workers include case management (linking clients with agencies and programs that will meet their psychosocial needs), medical social work, counseling (psychotherapy), human services management, social welfare policy analysis, community organizing, advocacy, teaching (in schools of social work), and social science research. Professional social workers work in a variety of settings, including: non-profit or public social service agencies, grassroots advocacy organizations, hospitals, hospices, community health agencies, schools, faith-based organizations, and even the military. Some social workers work as psychotherapists, counselors, or mental health practitioners, normally working in coordination with psychiatrists, psychologists, or other medical professionals. Additionally, some social workers have chosen to focus their efforts on social policy or academic research into the practice or ethics of social work. The emphasis has varied among these task areas by historical era and country. Some of these areas have been the subject of controversy as to whether they are properly part of social work's mission.
A variety of settings employ social workers, including governmental departments (especially in the areas of child and family welfare, mental health, correctional services, and education departments), hospitals, non-government welfare agencies and private practice - working independently as counsellors, family therapists or researchers.
# Professional social work associations
There is a International Regulatory body for professional social workers, which is called International Federation of Social Workers(IFSW)
and International Association of Schools of Social Work
In the Country level, there are organizations regulating the profession.
USA - National Association of Social Workers
UK - British Association of Social Workers
India - Professional Social Workers' Association
Association for the Advancement of Social Work with Groups (aaswg.org)
# Social work knowledge building
The history of social work is a history plagued by a fundamental question – is social work a profession? This debate can be traced back to the early 20th century debate between Mary Richmond's Charity Organization Society (COS) and Jane Addams's Settlement House Movement. The essence of this debate was whether the problem should be approached from COS’ traditional, scientific method focused on efficiency and prevention or the Settlement House Movement’s immersion into the problem, blurring the lines of practitioner and client . The impetus for both movements was the glaring reality of social problems and the question over how to best attack them. This debate is arguably the earliest example of a larger debate within social work – how is knowledge acquired? This debate pits positivism against post-positivism in the pursuit of achieving respect as a profession.
The current state of social work knowledge building is characterized by two realities. There is a great deal of traditional research, both qualitative and quantitative being carried out, primarily by university-based researchers, but also in different fields, by researchers based in institutes, foundations, or social service agencies. Meanwhile, the majority of social work practitioners continue to look elsewhere for knowledge. This is a state of affairs that has persisted since the outset of the profession in the first decade of the twentieth century. One reason for the practice-research gap is that practitioners deal with situations that are unique and idiosyncratic, while research deals with regularities and aggregates. The translation between the two is often imperfect. A hopeful development for bridging this gap is the compilation in many practice fields of collections of "best practices," largely taken from research findings, but also distilled from the experience of respected practitioners.
# Types of professional social work intervention
There are three levels of intervention:
- Micro (individual & family)
- Mezzo (agency & small groups)
- Macro (societies, organizations & communities)
## Clinical or direct practice
## Community practice
# Fields of professional social work practice (both direct and community levels) | Social work
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Social Workers are concerned with social problems, their causes, their solutions and their human impacts. Social workers work with individuals, families, groups, organizations and communities, as members of a profession which is committed to social justice and human rights. Their approach is to consider the whole individual (including their biological, psychological, sociological, familial, cultural, and spiritual subsystems) within the context of their current situation.
Social Work is the profession committed to the pursuit of social justice, to the enhancement of the quality of life, and to the development of the full potential of each individual, group and community in society.
# Origins
The concept of charity goes back to ancient times, and the practice of providing for the poor has roots in all major world religions. However, the practice and profession of social work has a relatively modern (19th century) and scientific origin [1]. Charity in Europe was considered to be a responsibility and a sign of one’s piety. This charity was, generally, in the form of direct relief (i.e. money, food, etc.). After the end of feudalism, a need arose to have an organized system to care for the poor. In England, the Poor Law served this purpose. This system of laws sorted the poor and developed different remedies for these different groups.
The 19th century ushered in the Industrial Revolution. There was a great leap in technological and scientific achievement, but there was also a great migration to urban areas. This led to many social problems, which in turn led to an increase in social activism[2]. Also with the dawn of the 19th century came a great “missionary” push from many Protestant denominations. Some of the mission efforts (urban missions), attempted to resolve the problems (poverty, prostitution, disease, etc.) inherent in large cities. These “friendly visitors”, stipended by church and other charitable bodies, worked through direct relief, prayer, and evangelism to alleviate these problems [3]. In Europe, chaplains or almoners were appointed to administrate the church’s mission to the poor.
During this time, rescue societies were initiated to find more appropriate means of self-support for women involved in prostitution. Mental asylums grew to assist in taking care of the mentally ill. A new philosophy of "scientific charity" which stated charity should be "secular, rational and empirical as opposed to sectarian, sentimental, and dogmatic." (James Leiby) [4] In the late 1880s, a new system to provide aid for social ills popped up, that would become known as the settlement movement [5]. The settlement movement focused on the causes of poverty. They did this through the three "R's" - Research, Reform, and Residence. They provided a variety of services including educational, legal, and health services. These programs also advocated changes in social policy. Workers in the settlement movement immersed themselves in the culture of those they were helping.
In America, this led to a fundamental question – is social work a profession? This debate can be traced back to the early 20th century debate between Mary Richmond's Charity Organization Society (COS) and Jane Addams's Settlement House Movement. The essence of this debate was whether the problem should be approached from COS’ traditional, scientific method focused on efficiency and prevention or the Settlement House Movement’s immersion into the problem, blurring the lines of practitioner and client [6].
Schools of social work and formalized processes began to spring up. However, the question lingered. In 1915, at the National Conference of Charities and Corrections, Dr. Abraham Flexner spoke on the topic "Is Social Work a Profession?" He contended that it was not because it lacked specialized knowledge and specific application of theoretical and intellectual knowledge to solve human and social problems [7]. This led to the professionalization of social work, concentrating on case work and the scientific method.
# Qualifications for social work
Lay practitioners, often referred to as SSA (Social Services Assistant) or Care Managers are unqualified and unregistered social workers. They are not professionally registered and often do not hold any formal social work qualification. Within the mental health sector, unqualified social workers (Social Service Assistants / Care Managers) are called Care Co-ordinators.
In a number of countries and jurisdictions where registration of people working as social workers is required there are mandated qualifications[8]. In other places, the professional association sets academic and experiential requirements for admission to membership. The success of these professional bodies' effort to establish these requirements is demonstrated in the fact that these same requirements are recognised by many employers as necessary for employment[9].
# Role of the professional social worker
Professional social workers have a strong tradition of working for social justice and of refusing to recreate unequal social structures. The main tasks of professional social workers include case management (linking clients with agencies and programs that will meet their psychosocial needs), medical social work, counseling (psychotherapy), human services management, social welfare policy analysis, community organizing, advocacy, teaching (in schools of social work), and social science research. Professional social workers work in a variety of settings, including: non-profit or public social service agencies, grassroots advocacy organizations, hospitals, hospices, community health agencies, schools, faith-based organizations, and even the military. Some social workers work as psychotherapists, counselors, or mental health practitioners, normally working in coordination with psychiatrists, psychologists, or other medical professionals. Additionally, some social workers have chosen to focus their efforts on social policy or academic research into the practice or ethics of social work. The emphasis has varied among these task areas by historical era and country. Some of these areas have been the subject of controversy as to whether they are properly part of social work's mission.
A variety of settings employ social workers, including governmental departments (especially in the areas of child and family welfare, mental health, correctional services, and education departments), hospitals, non-government welfare agencies and private practice - working independently as counsellors, family therapists or researchers.
# Professional social work associations
There is a International Regulatory body for professional social workers, which is called International Federation of Social Workers(IFSW) [2]
and International Association of Schools of Social Work [3]
In the Country level, there are organizations regulating the profession.
USA - National Association of Social Workers [4]
UK - British Association of Social Workers [5]
India - Professional Social Workers' Association [6]
Association for the Advancement of Social Work with Groups (aaswg.org)
# Social work knowledge building
The history of social work is a history plagued by a fundamental question – is social work a profession? This debate can be traced back to the early 20th century debate between Mary Richmond's Charity Organization Society (COS) and Jane Addams's Settlement House Movement. The essence of this debate was whether the problem should be approached from COS’ traditional, scientific method focused on efficiency and prevention or the Settlement House Movement’s immersion into the problem, blurring the lines of practitioner and client [10]. The impetus for both movements was the glaring reality of social problems and the question over how to best attack them. This debate is arguably the earliest example of a larger debate within social work – how is knowledge acquired? This debate pits positivism against post-positivism in the pursuit of achieving respect as a profession.
The current state of social work knowledge building is characterized by two realities. There is a great deal of traditional research, both qualitative and quantitative being carried out, primarily by university-based researchers, but also in different fields, by researchers based in institutes, foundations, or social service agencies. Meanwhile, the majority of social work practitioners continue to look elsewhere for knowledge. This is a state of affairs that has persisted since the outset of the profession in the first decade of the twentieth century. One reason for the practice-research gap is that practitioners deal with situations that are unique and idiosyncratic, while research deals with regularities and aggregates. The translation between the two is often imperfect. A hopeful development for bridging this gap is the compilation in many practice fields of collections of "best practices," largely taken from research findings, but also distilled from the experience of respected practitioners.
# Types of professional social work intervention
There are three levels of intervention:
- Micro (individual & family)
- Mezzo (agency & small groups)
- Macro (societies, organizations & communities)
## Clinical or direct practice
## Community practice
# Fields of professional social work practice (both direct and community levels) | https://www.wikidoc.org/index.php/Social_Work | |
cf8c1b684e5641dd820cc6d73c6810cc24059d26 | wikidoc | Soda syphon | Soda syphon
The soda syphon, also known as the seltzer bottle or syphon seltzer bottle is a device for dispensing soda water.
As early as 1790, the concept of an "aerosol" was introduced in France with self-pressurized carbonated beverages,
but the modern syphon was created in 1829, when two Frenchmen patented a hollow corkscrew which could be inserted into a soda bottle and by use of a valve allowed a portion of the contents to be dispensed while maintaining the pressure on the inside of the bottle and hence preventing the remaining soda going flat.
Soda syphons were popular in the 1920s and 1930s but the rise of bottled carbonated beverages and the destruction of many of their manufacturers' plants in Eastern Europe during World War II lead to a decline in their popularity in the years after the war.
Commercial production and delivery of pre-filled bottles of seltzer continued in the New York, USA region into the 1980s.
The seltzer bottle is an indispensable prop in classic physical comedy.
# Notes
- ↑ Donald A. Bull (2001). "Cork Ejectors". Retrieved 2006-09-13..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}
- ↑ Jump up to: 2.0 2.1 Bryan Grapentine (1998-05). "Seltzer Bottles" (PDF). Bottles & Extras. Retrieved 2006-09-13. Check date values in: |date= (help) | Soda syphon
The soda syphon, also known as the seltzer bottle or syphon seltzer bottle is a device for dispensing soda water.
As early as 1790, the concept of an "aerosol" was introduced in France with self-pressurized carbonated beverages,[1]
but the modern syphon was created in 1829, when two Frenchmen patented a hollow corkscrew which could be inserted into a soda bottle and by use of a valve allowed a portion of the contents to be dispensed while maintaining the pressure on the inside of the bottle and hence preventing the remaining soda going flat.[2]
Soda syphons were popular in the 1920s and 1930s but the rise of bottled carbonated beverages and the destruction of many of their manufacturers' plants in Eastern Europe during World War II lead to a decline in their popularity in the years after the war.[2]
Commercial production and delivery of pre-filled bottles of seltzer continued in the New York, USA region into the 1980s.
The seltzer bottle is an indispensable prop in classic physical comedy.
# Notes
- ↑ Donald A. Bull (2001). "Cork Ejectors". Retrieved 2006-09-13..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}
- ↑ Jump up to: 2.0 2.1 Bryan Grapentine (1998-05). "Seltzer Bottles" (PDF). Bottles & Extras. Retrieved 2006-09-13. Check date values in: |date= (help) | https://www.wikidoc.org/index.php/Soda_syphon | |
8d2872bb19ca9fd38e8520ec87f57ff251f492a6 | wikidoc | Sole (foot) | Sole (foot)
# Overview
The sole is the bottom of the human foot. Anatomically, the sole of the foot is referred to as the plantar aspect. The equivalent surface in ungulates is the hoof.
# Description
The skin on the sole of the foot lacks the vellus hair and pigmentation found on the rest of the body, and has a high concentration of sweat pores. The soles are crossed by a set of creases that form during embryogenesis and contain the thickest layers of skin on the human body due to the weight that is continually placed on them. Like the palm, the sweat pores of the sole lack sebaceous glands.
## Innervation of the sole
The soles of the feet are extremely sensitive to touch due to a high concentration of nerve endings. This makes them sensitive to surfaces that are walked on, ticklish and some people find them to be erogenous zones. Medically, the soles are the site of the plantar reflex, the testing of which can be painful due to the sole's sensitivity. The feet can also be a used for torture.
## Arches
The sole of the adult foot is normally arched. Arches may fail to develop during childhood or may flatten during pregnancy and old age resulting in flat feet.
# The sole of the foot in culture
In the Middle East the sole of the foot is considered unclean and it is considered insulting or offensive to prominently display a barefoot. In Western culture the sensitivity of the sole makes it a target for tickling or sexual stimulation. | Sole (foot)
Template:Infobox Anatomy
# Overview
The sole is the bottom of the human foot. Anatomically, the sole of the foot is referred to as the plantar aspect. The equivalent surface in ungulates is the hoof.
# Description
The skin on the sole of the foot lacks the vellus hair and pigmentation found on the rest of the body, and has a high concentration of sweat pores. The soles are crossed by a set of creases that form during embryogenesis and contain the thickest layers of skin on the human body due to the weight that is continually placed on them. Like the palm, the sweat pores of the sole lack sebaceous glands.
## Innervation of the sole
The soles of the feet are extremely sensitive to touch due to a high concentration of nerve endings. This makes them sensitive to surfaces that are walked on, ticklish and some people find them to be erogenous zones.[1] Medically, the soles are the site of the plantar reflex, the testing of which can be painful due to the sole's sensitivity. The feet can also be a used for torture.
## Arches
The sole of the adult foot is normally arched. Arches may fail to develop during childhood or may flatten during pregnancy and old age resulting in flat feet.
# The sole of the foot in culture
In the Middle East the sole of the foot is considered unclean and it is considered insulting or offensive to prominently display a barefoot. In Western culture the sensitivity of the sole makes it a target for tickling or sexual stimulation.[2] | https://www.wikidoc.org/index.php/Sole | |
4b2ba2f756294330b2d831bf6394b3355eb95861 | wikidoc | Solifenacin | Solifenacin
# 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
Solifenacin is a muscarinic receptor antagonist that is FDA approved for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Common adverse reactions include constipation, Xerostomia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### urge urinary incontinence, Urgency, and Urinary frequency
- Dosing information
- Recommended dosage: 5 mg PO qd.
- If the 5 mg dose is well tolerated, the dose may be increased to 10 mg once daily.
- Solifenacin should be taken with water and swallowed whole. Solifenacin can be administered with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Solifenacin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Solifenacin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Solifenacin 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 Solifenacin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Solifenacin in pediatric patients.
# Contraindications
Solifenacin is contraindicated in patients with:
- urinary retention
- gastric retention
- uncontrolled narrow-angle glaucoma
- in patients who have demonstrated hypersensitivity to the drug
# Warnings
### Angioedema and Anaphylactic Reactions=
Angioedema of the face, lips, tongue, and/or larynx have been reported with solifenacin. In some cases angioedema occurred after the first dose. Cases of angioedema have been reported to occur hours after the first dose or after multiple doses. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, solifenacin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided. Anaphylactic reactions have been reported rarely in patients treated with solifenacin succinate. Solifenacin succinate should not be used in patients with a known or suspected hypersensitivity to solifenacin succinate. In patients who develop anaphylactic reactions, solifenacin succinate should be discontinued and appropriate therapy and/or measures should be taken.
### Urinary Retention
Solifenacin, like other anticholinergic drugs, should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.
### Gastrointestinal Disorders
Solifenacin, like other anticholinergics, should be used with caution in patients with decreased gastrointestinal motility.
### Central Nervous System Effects
Solifenacin is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Solifenacin affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
### Controlled Narrow-Angle Glaucoma
Solifenacin should be used with caution in patients being treated for narrow-angle glaucoma.
### Hepatic Impairment
Solifenacin should be used with caution in patients with hepatic impairment. Doses of Solifenacin greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh
# 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.
Solifenacin has been evaluated for safety in 1811 patients in randomized, placebo-controlled trials. Expected adverse reactions of antimuscarinic agents are dry mouth, constipation, blurred vision (accommodation abnormalities), urinary retention, and dry eyes. The incidence of dry mouth and constipation in patients treated with Solifenacin was higher in the 10 mg compared to the 5 mg dose group.
In the four 12-week double-blind clinical trials, severe fecal impaction, colonic obstruction, and intestinal obstruction were reported in one patient each, all in the Solifenacin 10 mg group. Angioneurotic edema has been reported in one patient taking Solifenacin 5 mg. Compared to 12 weeks of treatment with Solifenacin, the incidence and severity of adverse reactions were similar in patients who remained on drug for up to 12 months.
The most frequent adverse reaction leading to study discontinuation was dry mouth (1.5%). Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events, in randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Solifenacin 5 or 10 mg once daily for up to 12 weeks.
## Postmarketing Experience
Because these spontaneously reported events are from the worldwide postmarketing experience, the frequency of events and the role of solifenacin in their causation cannot be reliably determined.
The following events have been reported in association with solifenacin use in worldwide postmarketing experience:
General: peripheral edema, hypersensitivity reactions, including angioedema with airway obstruction, rash, pruritus, urticaria, and anaphylactic reaction;
Central Nervous: headache, confusion, hallucinations, delirium and somnolence;
Cardiovascular: QT prolongation; Torsade de Pointes, atrial fibrillation, tachycardia, palpitations;
Hepatic: liver disorders mostly characterized by abnormal liver function tests, AST (aspartate aminotransferase), ALT (alanine aminotransferase), GGT (gamma-glutamyl transferase);
Renal: renal impairment;
Metabolism and nutrition disorders: decreased appetite, hyperkalemia;
Dermatologic: exfoliative dermatitis and erythema multiforme;
Eye disorders:glaucoma;
Gastrointestinal disorders:gastroesophageal reflux disease and ileus;
Respiratory, thoracic and mediastinal disorders: dysphonia;
Musculoskeletal and connective tissue disorders: muscular weakness;
# Drug Interactions
### Potent CYP3A4 Inhibitors
Following the administration of 10 mg of Solifenacin in the presence of 400 mg of ketoconazole, a potent inhibitor of CYP3A4, the mean Cmax and AUC of solifenacin increased by 1.5 and 2.7-fold, respectively. Therefore, it is recommended not to exceed a 5 mg daily dose of Solifenacin when administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors . The effects of weak or moderate CYP3A4 inhibitors were not examined.
### CYP3A4 Inducers
There were no in vivo studies conducted to evaluate the effect of CYP3A4 inducers on Solifenacin. In vitro drug metabolism studies have shown that solifenacin is a substrate of CYP3A4. Therefore, inducers of CYP3A4 may decrease the concentration of solifenacin.
### Drugs Metabolized by Cytochrome P450
At therapeutic concentrations, solifenacin does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes.
### Warfarin
Solifenacin has no significant effect on the pharmacokinetics of R-warfarin or S-warfarin.
### Oral Contraceptives
In the presence of solifenacin there are no significant changes in the plasma concentrations of combined oral contraceptives (ethinyl estradiol/levonorgestrel).
### Digoxin
Solifenacin had no significant effect on the pharmacokinetics of digoxin (0.125 mg/day) in healthy subjects
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies in pregnant women.
Reproduction studies have been performed in mice, rats and rabbits. After oral administration of 14C-solifenacin succinate to pregnant mice, drug-related material was shown to cross the placental barrier. No embryotoxicity or teratogenicity was observed in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose of 10 mg. Administration of solifenacin succinate to pregnant mice at 3.6 times and greater (100 mg/kg/day and greater) the exposure at the MRHD, during the major period of organ development resulted in reduced fetal body weights. Administration of 7.9 times (250 mg/kg/day) the MRHD to pregnant mice resulted in an increased incidence of cleft palate. In utero and lactational exposures to maternal doses of solifenacin succinate of 3.6 times (100 mg/kg/day) the MRHD resulted in reduced peripartum and postnatal survival, reductions in body weight gain, and delayed physical development (eye opening and vaginal patency). An increase in the percentage of male offspring was also observed in litters from offspring exposed to maternal doses of 250 mg/kg/day. No embryotoxic effects were observed in rats at up to 50 mg/kg/day (<1 times the exposure at the MRHD) or in rabbits at up to 1.8 times (50 mg/kg/day) the exposure at the MRHD. Because animal reproduction studies are not always predictive of human response, Solifenacin 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 Solifenacin in women who are pregnant.
### Labor and Delivery
The effect of Solifenacin on labor and delivery in humans has not been studied.
There were no effects on natural delivery in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose of 10 mg. Administration of solifenacin succinate at 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater increased peripartum pup mortality.
### Nursing Mothers
After oral administration of 14C-solifenacin succinate to lactating mice, radioactivity was detected in maternal milk. There were no adverse observations in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose . Pups of female mice treated with 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater revealed reduced body weights, postpartum pup mortality or delays in the onset of reflex and physical development during the lactation period.
It is not known whether solifenacin is excreted in human milk. Because many drugs are excreted in human milk, Solifenacin should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue Solifenacin in nursing mothers.
### Pediatric Use
The safety and effectiveness of Solifenacin in pediatric patients have not been established.
### Geriatic Use
In placebo-controlled clinical studies, similar safety and effectiveness were observed between older (623 patients ≥ 65 years and 189 patients ≥ 75 years) and younger patients (1188 patients < 65 years) treated with Solifenacin.
Multiple dose studies of Solifenacin in elderly volunteers (65 to 80 years) showed that Cmax, AUC and t1/2 values were 20-25% higher as compared to the younger volunteers (18 to 55 years).
### Gender
The pharmacokinetics of solifenacin is not significantly influenced by gender.
### Race
There is no FDA guidance on the use of Solifenacin with respect to specific racial populations.
### Renal Impairment
Solifenacin should be used with caution in patients with renal impairment. There is a 2.1-fold increase in AUC and 1.6-fold increase in t1/2 of solifenacin in patients with severe renal impairment. Doses of Solifenacin greater than 5 mg are not recommended in patients with severe renal impairment (CLcr < 30 mL/min)
### Hepatic Impairment
Solifenacin should be used with caution in patients with reduced hepatic function. There is a 2-fold increase in the t1/2 and 35% increase in AUC of solifenacin in patients with moderate hepatic impairment. Doses of Solifenacin greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Solifenacin is not recommended for patients with severe hepatic impairment (Child-Pugh C)
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Solifenacin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Solifenacin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Solifenacin Monitoring in the drug label.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
Overdosage with Solifenacin can potentially result in severe anticholinergic effects and should be treated accordingly. The highest dose ingested in an accidental overdose of solifenacin succinate was 280 mg in a 5-hour period. This case was associated with mental status changes. Some cases reported a decrease in the level of consciousness.
Intolerable anticholinergic side effects (fixed and dilated pupils, blurred vision, failure of heel-to-toe exam, tremors and dry skin) occurred on day 3 in normal volunteers taking 50 mg daily (5 times the maximum recommended therapeutic dose) and resolved within 7 days following discontinuation of drug.
In the event of overdose with Solifenacin, treat with gastric lavage and appropriate supportive measures. ECG monitoring is also recommended.
# Pharmacology
## Mechanism of Action
Solifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle and stimulation of salivary secretion.
## Structure
Solifenacin® (solifenacin succinate) is a competitive muscarinic receptor antagonist. Chemically, solifenacin succinate is butanedioic acid, compounded with (1S)-(3R)-1-azabicyclooct-3-yl 3,4-dihydro-1-phenyl-2(1H)-iso-quinolinecarboxylate (1:1) having an empirical formula of C23H26N2O2C4H6O4, and a molecular weight of 480.55. The structural formula of solifenacin succinate is:
Solifenacin succinate is a white to pale-yellowish-white crystal or crystalline powder. It is freely soluble at room temperature in water, glacial acetic acid, dimethyl sulfoxide, and methanol. Each Solifenacin tablet contains 5 or 10 mg of solifenacin succinate and is formulated for oral administration. In addition to the active ingredient solifenacin succinate, each Solifenacin tablet also contains the following inert ingredients: lactose monohydrate, corn starch, hypromellose 2910, magnesium stearate, talc, polyethylene glycol 8000 and titanium dioxide with yellow ferric oxide (5 mg Solifenacin tablet) or red ferric oxide (10 mg Solifenacin tablet).
## Pharmacodynamics
Cardiac Electrophysiology
The effect of 10 mg and 30 mg solifenacin succinate on the QT interval was evaluated at the time of peak plasma concentration of solifenacin in a multi-dose, randomized, double-blind, placebo and positive-controlled (moxifloxacin 400 mg) trial. Subjects were randomized to one of two treatment groups after receiving placebo and moxifloxacin sequentially. One group (n=51) went on to complete 3 additional sequential periods of dosing with solifenacin 10, 20, and 30 mg while the second group (n=25) in parallel completed a sequence of placebo and moxifloxacin. Study subjects were female volunteers aged 19 to 79 years. The 30 mg dose of solifenacin succinate (three times the highest recommended dose) was chosen for use in this study because this dose results in a solifenacin exposure that covers those observed upon co-administration of 10 mg Solifenacin with potent CYP3A4 inhibitors (e.g. ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline EKG measurements were separated from the final QT assessment (of the 30 mg dose level) by 33 days.
The median difference from baseline in heart rate associated with the 10 and 30 mg doses of solifenacin succinate compared to placebo was -2 and 0 beats/minute, respectively. Because a significant period effect on QTc was observed, the QTc effects were analyzed utilizing the parallel placebo control arm rather than the pre-specified intra-patient analysis. Representative results are shown in Table 2.
Moxifloxacin was included as a positive control in this study and, given the length of the study, its effect on the QT interval was evaluated in 3 different sessions. The placebo subtracted mean changes (90% CI) in QTcF for moxifloxacin in the three sessions were 11 (7, 14), 12 (8, 17), and 16 (12, 21), respectively.
The QT interval prolonging effect appeared greater for the 30 mg compared to the 10 mg dose of solifenacin. Although the effect of the highest solifenacin dose (three times the maximum therapeutic dose) studied did not appear as large as that of the positive control moxifloxacin at its therapeutic dose, the confidence intervals overlapped. This study was not designed to draw direct statistical conclusions between the drugs or the dose levels.
## Pharmacokinetics
Absorption
After oral administration of Solifenacin to healthy volunteers, peak plasma levels (Cmax) of solifenacin are reached within 3 to 8 hours after administration, and at steady state ranged from 32.3 to 62.9 ng/mL for the 5 and 10 mg Solifenacin tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered.
Effect of food
Solifenacin may be administered without regard to meals. A single 10 mg dose administration of Solifenacin with food increased Cmax and AUC by 4% and 3%, respectively.
Distribution
Solifenacin is approximately 98% (in vivo) bound to human plasma proteins, principally to ∝1-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600L.
Metabolism
Solifenacin is extensively metabolized in the liver. The primary pathway for elimination is by way of CYP3A4; however, alternate metabolic pathways exist. The primary metabolic routes of solifenacin are through N-oxidation of the quinuclidin ring and 4R-hydroxylation of tetrahydroisoquinoline ring. One pharmacologically active metabolite (4R-hydroxy solifenacin), occurring at low concentrations and unlikely to contribute significantly to clinical activity, and three pharmacologically inactive metabolites (N-glucuronide and the N-oxide and 4R-hydroxy-N-oxide of solifenacin) have been found in human plasma after oral dosing.
Excretion
Following the administration of 10 mg of 14C-solifenacin succinate to healthy volunteers, 69.2% of the radioactivity was recovered in the urine and 22.5% in the feces over 26 days. Less than 15% (as mean value) of the dose was recovered in the urine as intact solifenacin. The major metabolites identified in urine were N-oxide of solifenacin, 4R-hydroxy solifenacin and 4R-hydroxy-N-oxide of solifenacin and in feces 4R-hydroxy solifenacin. The elimination half-life of solifenacin following chronic dosing is approximately 45-68 hours.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
No increase in tumors was found following the administration of solifenacin succinate to male and female mice for 104 weeks at doses up to 200 mg/kg/day (5 and 9 times, respectively, of the exposure at the maximum recommended human dose of 10 mg), and male and female rats for 104 weeks at doses up to 20 and 15 mg/kg/day, respectively (<1 times the exposure at the MRHD).
Solifenacin succinate was not mutagenic in the in vitro Salmonella typhimurium or Escherichia coli microbial mutagenicity test or chromosomal aberration test in human peripheral blood lymphocytes with or without metabolic activation, or in the in vivo micronucleus test in rats.
Solifenacin succinate had no effect on reproductive function, fertility or early embryonic development of the fetus in male and female mice treated with 250 mg/kg/day (13 times the exposure at the MRHD) of solifenacin succinate, and in male rats treated with 50 mg/kg/day (<1 times the exposure at the MRHD) and female rats treated with 100 mg/kg/day (1.7 times the exposure at the MRHD) of solifenacin succinate.
# Clinical Studies
Solifenacin was evaluated in four twelve-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials for the treatment of overactive bladder in patients having symptoms of urinary frequency, urgency, and/or urge or mixed incontinence (with a predominance of urge). Entry criteria required that patients have symptoms of overactive bladder for ≥ 3 months duration. These studies involved 3027 patients (1811 on Solifenacin and 1216 on placebo), and approximately 90% of these patients completed the 12-week studies. Two of the four studies evaluated the 5 and 10 mg Solifenacin doses and the other two evaluated only the 10 mg dose. All patients completing the 12-week studies were eligible to enter an open label, long term extension study and 81% of patients enrolling completed the additional 40-week treatment period. The majority of patients were Caucasian (93%) and female (80%) with a mean age of 58 years.
The primary endpoint in all four trials was the mean change from baseline to 12 weeks in number of micturitions/24 hours. Secondary endpoints included mean change from baseline to 12 weeks in number of incontinence episodes/24 hours, and mean volume voided per micturition. The efficacy of Solifenacin was similar across patient age and gender. The mean reduction in the number of micturitions per 24 hours was significantly greater with Solifenacin 5 mg (2.3; p<0.001) and Solifenacin 10 mg (2.7; p<0.001) compared to placebo, (1.4).
The mean reduction in the number of incontinence episodes per 24 hours was significantly greater with Solifenacin 5 mg (1.5; p<0.001) and Solifenacin 10 mg (1.8; p<0.001) treatment groups compared to placebo (1.1). The mean increase in the volume voided per micturition was significantly greater with Solifenacin 5 mg (32.3 mL; p<0.001) and Solifenacin 10 mg (42.5 mL; p<0.001) compared with placebo (8.5 mL).
The results for the primary and secondary endpoints in the four individual 12-week clinical studies of Solifenacin are reported in Table 3 through 6.
# How Supplied
Solifenacin is supplied as round, film-coated tablets, available in bottles and unit dose blister packages as follows:
Each 5 mg tablet is light yellow and debossed with a logo and “150” and is available as follows:
Each 10 mg tablet is light pink and debossed with a logo and “151” and is available as follows:
## Storage
Store at 25C (77F) with excursions permitted from 15C to 30C (59°F-86F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be informed that antimuscarinic agents such as Solifenacin have been associated with constipation and blurred vision. Patients should be advised to contact their physician if they experience severe abdominal pain or become constipated for 3 or more days. Because Solifenacin may cause blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug’s effect on the patient’s vision has been determined. Heat prostration (due to decreased sweating) can occur when anticholinergic drugs, such as Solifenacin, are used in a hot environment. Patients should read the patient leaflet entitled “Patient Information Solifenacin” before starting therapy with Solifenacin.
Patients should be informed that solifenacin may produce angioedema, which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue solifenacin therapy and seek immediate attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing.
FDA Approved Patient Labeling
Solifenacin® (VES-ih-care)
(solifenacin succinate)
Tablet
Read the Patient Information that comes with Solifenacin before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment.
What is Solifenacin?
Solifenacin is a prescription medicine for adults used to treat the following symptoms due to a condition called overactive bladder:
- Urge urinary incontinence: a strong need to urinate with leaking or wetting accidents
- Urgency: a strong need to urinate right away
- Frequency: urinating often
It is not known if Solifenacin is safe and effective in children.
Who should NOT take Solifenacin?
Do not take Solifenacin if you:
- are not able to empty your bladder (urinary retention)
- have delayed or slow emptying of your stomach (gastric retention)
- have an eye problem called “uncontrolled narrow-angle glaucoma”
- are allergic to solifenacin succinate or any of the ingredients in Solifenacin. See the end of this leaflet for a complete list of ingredients.
What should I tell my doctor before taking Solifenacin?
Before you take Solifenacin, tell your doctor if you:
- have any stomach or intestinal problems or problems with constipation
- have trouble emptying your bladder or you have a weak urine stream
- have an eye problem called "narrow angle glaucoma"
- have liver problems
- have kidney problems
- have a rare heart problem called "QT prolongation"
- are pregnant or plan to become pregnant. It is not known if Solifenacin will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
- are breastfeeding or plan to breastfeed. It is not known if Solifenacin passes into your breast milk. You and your doctor should decide if you will take Solifenacin or breastfeed. You should not do both.
Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Solifenacin may affect the way other medicines work, and other medicines may affect how Solifenacin works.
How should I take Solifenacin?
- Take Solifenacin exactly as your doctor tells you to take it.
- You should take 1 Solifenacin tablet 1 time a day.
- You should take Solifenacin with water and swallow the tablet whole.
- You can take Solifenacin with or without food.
- If you miss a dose of Solifenacin, begin taking Solifenacin again the next day. Do not take 2 doses of Solifenacin the same day.
- If you take too much Solifenacin, call your doctor or go to the nearest hospital emergency room right away.
What should I avoid while taking Solifenacin?
Solifenacin can cause blurred vision or drowsiness. Do not drive or operate heavy machinery until you know how Solifenacin affects you.
What are the possible side effects of Solifenacin?
Solifenacin may cause serious side effects including:
- Serious allergic reaction. Stop taking Solifenacin and get medical help right away if you have:
- hives, skin rash or swelling
- severe itching
- swelling of your face, mouth or tongue
- trouble breathing
The most common side effects of Solifenacin include:
- dry mouth
- constipation. Call your doctor if you get severe stomach area (abdominal) pain or become constipated for 3 or more days.
- urinary tract infection
- blurred vision
- heat exhaustion or heat-stroke. This can happen when Solifenacin is used in hot environments. Symptoms may include:
- decreased sweating
- dizziness
- tiredness
- nausea
- increase in body temperature
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Solifenacin. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Solifenacin?
- Store Solifenacin at 59°F to 86°F (15°C to 30°C). Keep the bottle closed.
- Safely throw away medicine that is out of date or that you no longer need.
Keep Solifenacin and all medicines out of the reach of children.
General information about Solifenacin.
Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Solifenacin for a condition for which it was not prescribed. Do not give Solifenacin to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Solifenacin. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Solifenacin that is written for health professionals.
For more information, go to www.Solifenacin.com or call (800) 727-7003.
What are the ingredients in Solifenacin?
Active ingredient: solifenacin succinate
Inactive ingredients: lactose monohydrate, corn starch, hypromellose 2910, magnesium stearate, talc, polyethylene glycol 8000 and titanium dioxide with yellow ferric oxide (5 mg Solifenacin tablet) or red ferric oxide (10 mg Solifenacin tablet)
What is overactive bladder?
Overactive bladder occurs when you cannot control your bladder contractions. When these muscle contractions happen too often or cannot be controlled you can get symptoms of overactive bladder, which are urinary frequency, urinary urgency, and urinary incontinence (leakage).
# Precautions with Alcohol
Alcohol-Solifenacin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
VESICARE
# Look-Alike Drug Names
Solifenacin - Vesanoid
# Drug Shortage Status
# Price | Solifenacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Adeel Jamil, M.D. [3]
# 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
Solifenacin is a muscarinic receptor antagonist that is FDA approved for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Common adverse reactions include constipation, Xerostomia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### urge urinary incontinence, Urgency, and Urinary frequency
- Dosing information
- Recommended dosage: 5 mg PO qd.
- If the 5 mg dose is well tolerated, the dose may be increased to 10 mg once daily.
- Solifenacin should be taken with water and swallowed whole. Solifenacin can be administered with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Solifenacin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Solifenacin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Solifenacin 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 Solifenacin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Solifenacin in pediatric patients.
# Contraindications
Solifenacin is contraindicated in patients with:
- urinary retention
- gastric retention
- uncontrolled narrow-angle glaucoma
- in patients who have demonstrated hypersensitivity to the drug
# Warnings
### Angioedema and Anaphylactic Reactions=
Angioedema of the face, lips, tongue, and/or larynx have been reported with solifenacin. In some cases angioedema occurred after the first dose. Cases of angioedema have been reported to occur hours after the first dose or after multiple doses. Angioedema associated with upper airway swelling may be life threatening. If involvement of the tongue, hypopharynx, or larynx occurs, solifenacin should be promptly discontinued and appropriate therapy and/or measures necessary to ensure a patent airway should be promptly provided. Anaphylactic reactions have been reported rarely in patients treated with solifenacin succinate. Solifenacin succinate should not be used in patients with a known or suspected hypersensitivity to solifenacin succinate. In patients who develop anaphylactic reactions, solifenacin succinate should be discontinued and appropriate therapy and/or measures should be taken.
### Urinary Retention
Solifenacin, like other anticholinergic drugs, should be administered with caution to patients with clinically significant bladder outflow obstruction because of the risk of urinary retention.
### Gastrointestinal Disorders
Solifenacin, like other anticholinergics, should be used with caution in patients with decreased gastrointestinal motility.
### Central Nervous System Effects
Solifenacin is associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, confusion, hallucinations and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment or increasing the dose. Advise patients not to drive or operate heavy machinery until they know how Solifenacin affects them. If a patient experiences anticholinergic CNS effects, dose reduction or drug discontinuation should be considered.
### Controlled Narrow-Angle Glaucoma
Solifenacin should be used with caution in patients being treated for narrow-angle glaucoma.
### Hepatic Impairment
Solifenacin should be used with caution in patients with hepatic impairment. Doses of Solifenacin greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh
# 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.
Solifenacin has been evaluated for safety in 1811 patients in randomized, placebo-controlled trials. Expected adverse reactions of antimuscarinic agents are dry mouth, constipation, blurred vision (accommodation abnormalities), urinary retention, and dry eyes. The incidence of dry mouth and constipation in patients treated with Solifenacin was higher in the 10 mg compared to the 5 mg dose group.
In the four 12-week double-blind clinical trials, severe fecal impaction, colonic obstruction, and intestinal obstruction were reported in one patient each, all in the Solifenacin 10 mg group. Angioneurotic edema has been reported in one patient taking Solifenacin 5 mg. Compared to 12 weeks of treatment with Solifenacin, the incidence and severity of adverse reactions were similar in patients who remained on drug for up to 12 months.
The most frequent adverse reaction leading to study discontinuation was dry mouth (1.5%). Table 1 lists the rates of identified adverse reactions, derived from all reported adverse events, in randomized, placebo-controlled trials at an incidence greater than placebo and in 1% or more of patients treated with Solifenacin 5 or 10 mg once daily for up to 12 weeks.
## Postmarketing Experience
Because these spontaneously reported events are from the worldwide postmarketing experience, the frequency of events and the role of solifenacin in their causation cannot be reliably determined.
The following events have been reported in association with solifenacin use in worldwide postmarketing experience:
General: peripheral edema, hypersensitivity reactions, including angioedema with airway obstruction, rash, pruritus, urticaria, and anaphylactic reaction;
Central Nervous: headache, confusion, hallucinations, delirium and somnolence;
Cardiovascular: QT prolongation; Torsade de Pointes, atrial fibrillation, tachycardia, palpitations;
Hepatic: liver disorders mostly characterized by abnormal liver function tests, AST (aspartate aminotransferase), ALT (alanine aminotransferase), GGT (gamma-glutamyl transferase);
Renal: renal impairment;
Metabolism and nutrition disorders: decreased appetite, hyperkalemia;
Dermatologic: exfoliative dermatitis and erythema multiforme;
Eye disorders:glaucoma;
Gastrointestinal disorders:gastroesophageal reflux disease and ileus;
Respiratory, thoracic and mediastinal disorders: dysphonia;
Musculoskeletal and connective tissue disorders: muscular weakness;
# Drug Interactions
### Potent CYP3A4 Inhibitors
Following the administration of 10 mg of Solifenacin in the presence of 400 mg of ketoconazole, a potent inhibitor of CYP3A4, the mean Cmax and AUC of solifenacin increased by 1.5 and 2.7-fold, respectively. Therefore, it is recommended not to exceed a 5 mg daily dose of Solifenacin when administered with therapeutic doses of ketoconazole or other potent CYP3A4 inhibitors . The effects of weak or moderate CYP3A4 inhibitors were not examined.
### CYP3A4 Inducers
There were no in vivo studies conducted to evaluate the effect of CYP3A4 inducers on Solifenacin. In vitro drug metabolism studies have shown that solifenacin is a substrate of CYP3A4. Therefore, inducers of CYP3A4 may decrease the concentration of solifenacin.
### Drugs Metabolized by Cytochrome P450
At therapeutic concentrations, solifenacin does not inhibit CYP1A1/2, 2C9, 2C19, 2D6, or 3A4 derived from human liver microsomes.
### Warfarin
Solifenacin has no significant effect on the pharmacokinetics of R-warfarin or S-warfarin.
### Oral Contraceptives
In the presence of solifenacin there are no significant changes in the plasma concentrations of combined oral contraceptives (ethinyl estradiol/levonorgestrel).
### Digoxin
Solifenacin had no significant effect on the pharmacokinetics of digoxin (0.125 mg/day) in healthy subjects
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
There are no adequate and well-controlled studies in pregnant women.
Reproduction studies have been performed in mice, rats and rabbits. After oral administration of 14C-solifenacin succinate to pregnant mice, drug-related material was shown to cross the placental barrier. No embryotoxicity or teratogenicity was observed in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate to pregnant mice at 3.6 times and greater (100 mg/kg/day and greater) the exposure at the MRHD, during the major period of organ development resulted in reduced fetal body weights. Administration of 7.9 times (250 mg/kg/day) the MRHD to pregnant mice resulted in an increased incidence of cleft palate. In utero and lactational exposures to maternal doses of solifenacin succinate of 3.6 times (100 mg/kg/day) the MRHD resulted in reduced peripartum and postnatal survival, reductions in body weight gain, and delayed physical development (eye opening and vaginal patency). An increase in the percentage of male offspring was also observed in litters from offspring exposed to maternal doses of 250 mg/kg/day. No embryotoxic effects were observed in rats at up to 50 mg/kg/day (<1 times the exposure at the MRHD) or in rabbits at up to 1.8 times (50 mg/kg/day) the exposure at the MRHD. Because animal reproduction studies are not always predictive of human response, Solifenacin 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 Solifenacin in women who are pregnant.
### Labor and Delivery
The effect of Solifenacin on labor and delivery in humans has not been studied.
There were no effects on natural delivery in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD] of 10 mg. Administration of solifenacin succinate at 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater increased peripartum pup mortality.
### Nursing Mothers
After oral administration of 14C-solifenacin succinate to lactating mice, radioactivity was detected in maternal milk. There were no adverse observations in mice treated with 1.2 times (30 mg/kg/day) the expected exposure at the maximum recommended human dose [MRHD]. Pups of female mice treated with 3.6 times (100 mg/kg/day) the exposure at the MRHD or greater revealed reduced body weights, postpartum pup mortality or delays in the onset of reflex and physical development during the lactation period.
It is not known whether solifenacin is excreted in human milk. Because many drugs are excreted in human milk, Solifenacin should not be administered during nursing. A decision should be made whether to discontinue nursing or to discontinue Solifenacin in nursing mothers.
### Pediatric Use
The safety and effectiveness of Solifenacin in pediatric patients have not been established.
### Geriatic Use
In placebo-controlled clinical studies, similar safety and effectiveness were observed between older (623 patients ≥ 65 years and 189 patients ≥ 75 years) and younger patients (1188 patients < 65 years) treated with Solifenacin.
Multiple dose studies of Solifenacin in elderly volunteers (65 to 80 years) showed that Cmax, AUC and t1/2 values were 20-25% higher as compared to the younger volunteers (18 to 55 years).
### Gender
The pharmacokinetics of solifenacin is not significantly influenced by gender.
### Race
There is no FDA guidance on the use of Solifenacin with respect to specific racial populations.
### Renal Impairment
Solifenacin should be used with caution in patients with renal impairment. There is a 2.1-fold increase in AUC and 1.6-fold increase in t1/2 of solifenacin in patients with severe renal impairment. Doses of Solifenacin greater than 5 mg are not recommended in patients with severe renal impairment (CLcr < 30 mL/min)
### Hepatic Impairment
Solifenacin should be used with caution in patients with reduced hepatic function. There is a 2-fold increase in the t1/2 and 35% increase in AUC of solifenacin in patients with moderate hepatic impairment. Doses of Solifenacin greater than 5 mg are not recommended in patients with moderate hepatic impairment (Child-Pugh B). Solifenacin is not recommended for patients with severe hepatic impairment (Child-Pugh C)
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Solifenacin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Solifenacin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
There is limited information regarding Solifenacin Monitoring in the drug label.
# IV Compatibility
There is limited information about the IV Compatibility.
# Overdosage
Overdosage with Solifenacin can potentially result in severe anticholinergic effects and should be treated accordingly. The highest dose ingested in an accidental overdose of solifenacin succinate was 280 mg in a 5-hour period. This case was associated with mental status changes. Some cases reported a decrease in the level of consciousness.
Intolerable anticholinergic side effects (fixed and dilated pupils, blurred vision, failure of heel-to-toe exam, tremors and dry skin) occurred on day 3 in normal volunteers taking 50 mg daily (5 times the maximum recommended therapeutic dose) and resolved within 7 days following discontinuation of drug.
In the event of overdose with Solifenacin, treat with gastric lavage and appropriate supportive measures. ECG monitoring is also recommended.
# Pharmacology
## Mechanism of Action
Solifenacin is a competitive muscarinic receptor antagonist. Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of urinary bladder smooth muscle and stimulation of salivary secretion.
## Structure
Solifenacin® (solifenacin succinate) is a competitive muscarinic receptor antagonist. Chemically, solifenacin succinate is butanedioic acid, compounded with (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)-iso-quinolinecarboxylate (1:1) having an empirical formula of C23H26N2O2C4H6O4, and a molecular weight of 480.55. The structural formula of solifenacin succinate is:
Solifenacin succinate is a white to pale-yellowish-white crystal or crystalline powder. It is freely soluble at room temperature in water, glacial acetic acid, dimethyl sulfoxide, and methanol. Each Solifenacin tablet contains 5 or 10 mg of solifenacin succinate and is formulated for oral administration. In addition to the active ingredient solifenacin succinate, each Solifenacin tablet also contains the following inert ingredients: lactose monohydrate, corn starch, hypromellose 2910, magnesium stearate, talc, polyethylene glycol 8000 and titanium dioxide with yellow ferric oxide (5 mg Solifenacin tablet) or red ferric oxide (10 mg Solifenacin tablet).
## Pharmacodynamics
Cardiac Electrophysiology
The effect of 10 mg and 30 mg solifenacin succinate on the QT interval was evaluated at the time of peak plasma concentration of solifenacin in a multi-dose, randomized, double-blind, placebo and positive-controlled (moxifloxacin 400 mg) trial. Subjects were randomized to one of two treatment groups after receiving placebo and moxifloxacin sequentially. One group (n=51) went on to complete 3 additional sequential periods of dosing with solifenacin 10, 20, and 30 mg while the second group (n=25) in parallel completed a sequence of placebo and moxifloxacin. Study subjects were female volunteers aged 19 to 79 years. The 30 mg dose of solifenacin succinate (three times the highest recommended dose) was chosen for use in this study because this dose results in a solifenacin exposure that covers those observed upon co-administration of 10 mg Solifenacin with potent CYP3A4 inhibitors (e.g. ketoconazole, 400 mg). Due to the sequential dose escalating nature of the study, baseline EKG measurements were separated from the final QT assessment (of the 30 mg dose level) by 33 days.
The median difference from baseline in heart rate associated with the 10 and 30 mg doses of solifenacin succinate compared to placebo was -2 and 0 beats/minute, respectively. Because a significant period effect on QTc was observed, the QTc effects were analyzed utilizing the parallel placebo control arm rather than the pre-specified intra-patient analysis. Representative results are shown in Table 2.
Moxifloxacin was included as a positive control in this study and, given the length of the study, its effect on the QT interval was evaluated in 3 different sessions. The placebo subtracted mean changes (90% CI) in QTcF for moxifloxacin in the three sessions were 11 (7, 14), 12 (8, 17), and 16 (12, 21), respectively.
The QT interval prolonging effect appeared greater for the 30 mg compared to the 10 mg dose of solifenacin. Although the effect of the highest solifenacin dose (three times the maximum therapeutic dose) studied did not appear as large as that of the positive control moxifloxacin at its therapeutic dose, the confidence intervals overlapped. This study was not designed to draw direct statistical conclusions between the drugs or the dose levels.
## Pharmacokinetics
Absorption
After oral administration of Solifenacin to healthy volunteers, peak plasma levels (Cmax) of solifenacin are reached within 3 to 8 hours after administration, and at steady state ranged from 32.3 to 62.9 ng/mL for the 5 and 10 mg Solifenacin tablets, respectively. The absolute bioavailability of solifenacin is approximately 90%, and plasma concentrations of solifenacin are proportional to the dose administered.
Effect of food
Solifenacin may be administered without regard to meals. A single 10 mg dose administration of Solifenacin with food increased Cmax and AUC by 4% and 3%, respectively.
Distribution
Solifenacin is approximately 98% (in vivo) bound to human plasma proteins, principally to ∝1-acid glycoprotein. Solifenacin is highly distributed to non-CNS tissues, having a mean steady-state volume of distribution of 600L.
Metabolism
Solifenacin is extensively metabolized in the liver. The primary pathway for elimination is by way of CYP3A4; however, alternate metabolic pathways exist. The primary metabolic routes of solifenacin are through N-oxidation of the quinuclidin ring and 4R-hydroxylation of tetrahydroisoquinoline ring. One pharmacologically active metabolite (4R-hydroxy solifenacin), occurring at low concentrations and unlikely to contribute significantly to clinical activity, and three pharmacologically inactive metabolites (N-glucuronide and the N-oxide and 4R-hydroxy-N-oxide of solifenacin) have been found in human plasma after oral dosing.
Excretion
Following the administration of 10 mg of 14C-solifenacin succinate to healthy volunteers, 69.2% of the radioactivity was recovered in the urine and 22.5% in the feces over 26 days. Less than 15% (as mean value) of the dose was recovered in the urine as intact solifenacin. The major metabolites identified in urine were N-oxide of solifenacin, 4R-hydroxy solifenacin and 4R-hydroxy-N-oxide of solifenacin and in feces 4R-hydroxy solifenacin. The elimination half-life of solifenacin following chronic dosing is approximately 45-68 hours.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
No increase in tumors was found following the administration of solifenacin succinate to male and female mice for 104 weeks at doses up to 200 mg/kg/day (5 and 9 times, respectively, of the exposure at the maximum recommended human dose [MRHD] of 10 mg), and male and female rats for 104 weeks at doses up to 20 and 15 mg/kg/day, respectively (<1 times the exposure at the MRHD).
Solifenacin succinate was not mutagenic in the in vitro Salmonella typhimurium or Escherichia coli microbial mutagenicity test or chromosomal aberration test in human peripheral blood lymphocytes with or without metabolic activation, or in the in vivo micronucleus test in rats.
Solifenacin succinate had no effect on reproductive function, fertility or early embryonic development of the fetus in male and female mice treated with 250 mg/kg/day (13 times the exposure at the MRHD) of solifenacin succinate, and in male rats treated with 50 mg/kg/day (<1 times the exposure at the MRHD) and female rats treated with 100 mg/kg/day (1.7 times the exposure at the MRHD) of solifenacin succinate.
# Clinical Studies
Solifenacin was evaluated in four twelve-week, double-blind, randomized, placebo-controlled, parallel group, multicenter clinical trials for the treatment of overactive bladder in patients having symptoms of urinary frequency, urgency, and/or urge or mixed incontinence (with a predominance of urge). Entry criteria required that patients have symptoms of overactive bladder for ≥ 3 months duration. These studies involved 3027 patients (1811 on Solifenacin and 1216 on placebo), and approximately 90% of these patients completed the 12-week studies. Two of the four studies evaluated the 5 and 10 mg Solifenacin doses and the other two evaluated only the 10 mg dose. All patients completing the 12-week studies were eligible to enter an open label, long term extension study and 81% of patients enrolling completed the additional 40-week treatment period. The majority of patients were Caucasian (93%) and female (80%) with a mean age of 58 years.
The primary endpoint in all four trials was the mean change from baseline to 12 weeks in number of micturitions/24 hours. Secondary endpoints included mean change from baseline to 12 weeks in number of incontinence episodes/24 hours, and mean volume voided per micturition. The efficacy of Solifenacin was similar across patient age and gender. The mean reduction in the number of micturitions per 24 hours was significantly greater with Solifenacin 5 mg (2.3; p<0.001) and Solifenacin 10 mg (2.7; p<0.001) compared to placebo, (1.4).
The mean reduction in the number of incontinence episodes per 24 hours was significantly greater with Solifenacin 5 mg (1.5; p<0.001) and Solifenacin 10 mg (1.8; p<0.001) treatment groups compared to placebo (1.1). The mean increase in the volume voided per micturition was significantly greater with Solifenacin 5 mg (32.3 mL; p<0.001) and Solifenacin 10 mg (42.5 mL; p<0.001) compared with placebo (8.5 mL).
The results for the primary and secondary endpoints in the four individual 12-week clinical studies of Solifenacin are reported in Table 3 through 6.
# How Supplied
Solifenacin is supplied as round, film-coated tablets, available in bottles and unit dose blister packages as follows:
Each 5 mg tablet is light yellow and debossed with a logo and “150” and is available as follows:
Each 10 mg tablet is light pink and debossed with a logo and “151” and is available as follows:
## Storage
Store at 25C (77F) with excursions permitted from 15C to 30C (59°F-86F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be informed that antimuscarinic agents such as Solifenacin have been associated with constipation and blurred vision. Patients should be advised to contact their physician if they experience severe abdominal pain or become constipated for 3 or more days. Because Solifenacin may cause blurred vision, patients should be advised to exercise caution in decisions to engage in potentially dangerous activities until the drug’s effect on the patient’s vision has been determined. Heat prostration (due to decreased sweating) can occur when anticholinergic drugs, such as Solifenacin, are used in a hot environment. Patients should read the patient leaflet entitled “Patient Information Solifenacin” before starting therapy with Solifenacin.
Patients should be informed that solifenacin may produce angioedema, which could result in life-threatening airway obstruction. Patients should be advised to promptly discontinue solifenacin therapy and seek immediate attention if they experience edema of the tongue or laryngopharynx, or difficulty breathing.
FDA Approved Patient Labeling
Solifenacin® (VES-ih-care)
(solifenacin succinate)
Tablet
Read the Patient Information that comes with Solifenacin before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your doctor about your medical condition or treatment.
What is Solifenacin?
Solifenacin is a prescription medicine for adults used to treat the following symptoms due to a condition called overactive bladder:
- Urge urinary incontinence: a strong need to urinate with leaking or wetting accidents
- Urgency: a strong need to urinate right away
- Frequency: urinating often
It is not known if Solifenacin is safe and effective in children.
Who should NOT take Solifenacin?
Do not take Solifenacin if you:
- are not able to empty your bladder (urinary retention)
- have delayed or slow emptying of your stomach (gastric retention)
- have an eye problem called “uncontrolled narrow-angle glaucoma”
- are allergic to solifenacin succinate or any of the ingredients in Solifenacin. See the end of this leaflet for a complete list of ingredients.
What should I tell my doctor before taking Solifenacin?
Before you take Solifenacin, tell your doctor if you:
- have any stomach or intestinal problems or problems with constipation
- have trouble emptying your bladder or you have a weak urine stream
- have an eye problem called "narrow angle glaucoma"
- have liver problems
- have kidney problems
- have a rare heart problem called "QT prolongation"
- are pregnant or plan to become pregnant. It is not known if Solifenacin will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
- are breastfeeding or plan to breastfeed. It is not known if Solifenacin passes into your breast milk. You and your doctor should decide if you will take Solifenacin or breastfeed. You should not do both.
Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Solifenacin may affect the way other medicines work, and other medicines may affect how Solifenacin works.
How should I take Solifenacin?
- Take Solifenacin exactly as your doctor tells you to take it.
- You should take 1 Solifenacin tablet 1 time a day.
- You should take Solifenacin with water and swallow the tablet whole.
- You can take Solifenacin with or without food.
- If you miss a dose of Solifenacin, begin taking Solifenacin again the next day. Do not take 2 doses of Solifenacin the same day.
- If you take too much Solifenacin, call your doctor or go to the nearest hospital emergency room right away.
What should I avoid while taking Solifenacin?
Solifenacin can cause blurred vision or drowsiness. Do not drive or operate heavy machinery until you know how Solifenacin affects you.
What are the possible side effects of Solifenacin?
Solifenacin may cause serious side effects including:
- Serious allergic reaction. Stop taking Solifenacin and get medical help right away if you have:
- hives, skin rash or swelling
- severe itching
- swelling of your face, mouth or tongue
- trouble breathing
The most common side effects of Solifenacin include:
- dry mouth
- constipation. Call your doctor if you get severe stomach area (abdominal) pain or become constipated for 3 or more days.
- urinary tract infection
- blurred vision
- heat exhaustion or heat-stroke. This can happen when Solifenacin is used in hot environments. Symptoms may include:
- decreased sweating
- dizziness
- tiredness
- nausea
- increase in body temperature
Tell your doctor if you have any side effect that bothers you or that does not go away.
These are not all the possible side effects of Solifenacin. For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store Solifenacin?
- Store Solifenacin at 59°F to 86°F (15°C to 30°C). Keep the bottle closed.
- Safely throw away medicine that is out of date or that you no longer need.
Keep Solifenacin and all medicines out of the reach of children.
General information about Solifenacin.
Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflets. Do not use Solifenacin for a condition for which it was not prescribed. Do not give Solifenacin to other people, even if they have the same symptoms you have. It may harm them.
This leaflet summarizes the most important information about Solifenacin. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Solifenacin that is written for health professionals.
For more information, go to www.Solifenacin.com or call (800) 727-7003.
What are the ingredients in Solifenacin?
Active ingredient: solifenacin succinate
Inactive ingredients: lactose monohydrate, corn starch, hypromellose 2910, magnesium stearate, talc, polyethylene glycol 8000 and titanium dioxide with yellow ferric oxide (5 mg Solifenacin tablet) or red ferric oxide (10 mg Solifenacin tablet)
What is overactive bladder?
Overactive bladder occurs when you cannot control your bladder contractions. When these muscle contractions happen too often or cannot be controlled you can get symptoms of overactive bladder, which are urinary frequency, urinary urgency, and urinary incontinence (leakage).
# Precautions with Alcohol
Alcohol-Solifenacin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
VESICARE
# Look-Alike Drug Names
Solifenacin - Vesanoid[1]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Solifenacin | |
fbfe224e6f00883d50289a4d5e2a2d3b7b0ea4a0 | wikidoc | Somatotrope | Somatotrope
Somatotropes are cells in the anterior pituitary which produce growth hormone. These cells constitute 40-50% of anterior pituitary cells. They respond by releasing HGH in response to GHRH (somatocrinin) or are inhibited by GHIH (somatostatin), both received from the hypothalamus via the hypophyseal portal system vein and the secondary plexus.
Somatotrope cells are classified as acidophilic cells. These cells take years to grow and mature very slowly. If these cells grow large enough they can impair vision, cause headaches or damage other pituitary functions.
These cells produce Growth Hormone in response to Growth hormone releasing hormone. If there is an excess of growth hormone it is usually because of over secretion of somatotrope cells in the anterior pituitary gland. This is what happens if you have a disease known as gigantism.
Bovine somatotropin occurs in the pituitary of cattle and differs in structure from human pituitary growth hormone and is biologically inactive in the human being. Bovine somatotropin aids in regulating the amount of milk produced. rbST is a hormone that is injected in cows that increases milk production.
When levels of somatotropin are low in the body it is possible to take a supplement known as Protropin. This is a man-made growth hormone that can be given to children who have diseases, or naturally occurring problems that limit the amount of hormone being produced. Examples of these diseases are human growth hormone deficiency, kidney’s disease, Turner’s syndrome or Prader-Willi Syndrome (PWS). It is also possible to be used in adults who are coping with weight loss from acquired immunodeficiency syndrome (AIDS). Protropin is illegal when used for athletic purposes.
Deficiency in somatotrope secretion before puberty, or before the end of new bone tissue growth, can lead to pituitary dwarfism. When growth hormone is deficient blood sugar is low because insulin is not opposed by normal amount of growth hormone. This can lead to diabetes in dwarfs. Dwarfs are usually well proportioned, but sometimes have a large head compared to the body. Treatment includes injections of somatotrope.
A significant amount of excess somatotrope secretion before puberty, or before the end of new bone tissue growth, can lead to gigantism. Gigantism is a disease that causes excess growth of body (eg. being over 7 ft. tall) and unusually long limbs. An excess of secretion of growth hormone after puberty can lead to acromegaly. This is a disease that causes abnormal growth in the hands, head, jaw, and tongue. Some symptoms associated with acromegaly include heavy sweating, oily skin, improper processing of sugars in the diet (diabetes), high blood pressure, increased calcium in urine and swelling of the thyroid gland and arthritis. | Somatotrope
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Phone:617-632-7753
Somatotropes are cells in the anterior pituitary which produce growth hormone. These cells constitute 40-50% of anterior pituitary cells. They respond by releasing HGH in response to GHRH (somatocrinin) or are inhibited by GHIH (somatostatin), both received from the hypothalamus via the hypophyseal portal system vein and the secondary plexus.
Somatotrope cells are classified as acidophilic cells. These cells take years to grow and mature very slowly. If these cells grow large enough they can impair vision, cause headaches or damage other pituitary functions.
These cells produce Growth Hormone in response to Growth hormone releasing hormone. If there is an excess of growth hormone it is usually because of over secretion of somatotrope cells in the anterior pituitary gland. This is what happens if you have a disease known as gigantism.
Bovine somatotropin occurs in the pituitary of cattle and differs in structure from human pituitary growth hormone and is biologically inactive in the human being. Bovine somatotropin aids in regulating the amount of milk produced. rbST is a hormone that is injected in cows that increases milk production.
When levels of somatotropin are low in the body it is possible to take a supplement known as Protropin. This is a man-made growth hormone that can be given to children who have diseases, or naturally occurring problems that limit the amount of hormone being produced. Examples of these diseases are human growth hormone deficiency, kidney’s disease, Turner’s syndrome or Prader-Willi Syndrome (PWS). It is also possible to be used in adults who are coping with weight loss from acquired immunodeficiency syndrome (AIDS). Protropin is illegal when used for athletic purposes.
Deficiency in somatotrope secretion before puberty, or before the end of new bone tissue growth, can lead to pituitary dwarfism. When growth hormone is deficient blood sugar is low because insulin is not opposed by normal amount of growth hormone. This can lead to diabetes in dwarfs. Dwarfs are usually well proportioned, but sometimes have a large head compared to the body. Treatment includes injections of somatotrope.
A significant amount of excess somatotrope secretion before puberty, or before the end of new bone tissue growth, can lead to gigantism. Gigantism is a disease that causes excess growth of body (eg. being over 7 ft. tall) and unusually long limbs. An excess of secretion of growth hormone after puberty can lead to acromegaly. This is a disease that causes abnormal growth in the hands, head, jaw, and tongue. Some symptoms associated with acromegaly include heavy sweating, oily skin, improper processing of sugars in the diet (diabetes), high blood pressure, increased calcium in urine and swelling of the thyroid gland and arthritis.
Template:Pituitary gland
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Somatotrope | |
2ec900501cd254adc996ef0702af1fb75006a05f | wikidoc | Spectrogram | Spectrogram
The spectrogram is the result of calculating the frequency spectrum of windowed frames of a compound signal. It is a three-dimensional plot of the energy of the frequency content of a signal as it changes over time.
Spectrograms are used to identify phonetic sounds, to analyse the cries of animals, and in the fields of music, sonar/radar, speech processing, etc. A spectrogram can also be called a spectral waterfall, sonogram, voiceprint, or voicegram. The instrument that generates a spectrogram is called a sonograph.
# Format
In the most usual format, the horizontal axis represents time, the vertical axis is frequency, and the intensity of each point in the image represents amplitude of a particular frequency at a particular time. Often the diagram is reduced to two dimensions by indicating the intensity with thicker lines, more intense colors or grey values.
There are many variations of format. Sometimes the vertical and horizontal axes are switched, so time runs up and down. Sometimes the amplitude is represented as the height of a 3D surface instead of color or intensity. The frequency and amplitude axes can be either linear or logarithmic, depending on what the graph is being used for. For instance, audio would usually be represented with a logarithmic amplitude axis (probably in dB), and frequency would be linear to emphasize harmonic relationships, or logarithmic to emphasize musical, tonal relationships.
# Generation
Spectrograms are usually created in one of two ways; either with a series of bandpass filters, or calculated from the time signal using the short-time Fourier transform (STFT).
The filter method is usually used in the analog, continuous version of measurement. The frequency range of the signal (an audio signal, for instance, would have frequencies in the range of 20 Hz - 20 kHz) is divided into equal sections, either linearly (0-100, 100-200, 200-300, ...), or logarithmically (10-100, 100-1000, 1000-10000, ...). The signal is input to a corresponding filter, which removes most of the signal that does not fall within its frequency band (imperfect window functions and limited frequency resolution will cause some "bleeding" between adjacent frequency bands). The magnitudes of each filter's output are recorded as functions of time. Each recording then corresponds to a horizontal line in the image; a measurement of magnitude versus time for a specific frequency band.
To calculate the spectrogram using the magnitude of the STFT is usually a digital process. Digitally sampled data, in the time domain, is broken up into chunks, which usually overlap, and Fourier transformed to calculate the magnitude of the frequency spectrum for each chunk. Each chunk then corresponds to a vertical line in the image; a measurement of magnitude versus frequency for a specific moment in time.
The spectrums or time plots are then "laid side by side" to form the image or a three-dimensional surface.
The spectrogram is given by the magnitude of the STFT of the function:
# Creating sound from a spectrogram
The above process can be reversed; some programs are available that turn a digital image into sound:
- MetaSynth for Macintosh;
- Coagula for Windows;
- Enscribe for Linux;
- ARSS, The Analysis & Resynthesis Sound Spectrograph, multi-platform;
- JavOICe, a Java applet.
- FL Studio's "BeepMap" additive synthesizer.
This technique allows electronic music artists to "hide" images in their music. Examples include:
- Aphex Twin hid an image of himself in a spectrogram. The image can be found on Track 2 of the Windowlicker EP as a nine-second sweeping section right at the end. (It is recognizable in an MP3, but the compression changes the spectrogram and it is not as clear as from the CD.) Aphex Twin also hid the image of a spiral shape in his first track from the "Windowlicker" EP.
- The song "Look" from Venetian Snares' album Songs About My Cats, contains several images of his cats.
- The song "3recurring" from Plaid on their album Rest Proof Clockwork contains the recurring 3s represented as a logo on the cover of the "Not for Threes" album.
- Nine Inch Nails has employed this technique on a few occasions as part of an ongoing Alternate Reality Game for their album Year Zero.
The MP3 version of "My Violent Heart" (deliberately leaked before Year Zero was released) contains a few brief moments of static at the end. When analyzed in a spectrogram, it reveals the image of a hand reaching down from the sky. This image echoes a similar theme seen throughout the alternate reality game viral marketing campaign launched for the album. On the official version of the album, the sound appears at the end of the song "The Warning."
Another new Nine Inch Nails track from Year Zero was also found on a flash drive in a bathroom stall on their current European tour. This time it was "Me, I'm Not." Along with the song, was an MP3 of "cricket chirping", which when put through a spectrogram revealed the number: 216.333.1810.
Using this method again to deliver clues as part of the Year Zero ARG, there were two extra audio files included in the Garageband Multitrack files for the song Capital G. The images in the sounds are of various avatars of user at the Nine Inch Nails oriented forum Echoing the Sound. The user names are used to form the title of a new site that is part of the ARG.
- The MP3 version of "My Violent Heart" (deliberately leaked before Year Zero was released) contains a few brief moments of static at the end. When analyzed in a spectrogram, it reveals the image of a hand reaching down from the sky. This image echoes a similar theme seen throughout the alternate reality game viral marketing campaign launched for the album. On the official version of the album, the sound appears at the end of the song "The Warning."
- Another new Nine Inch Nails track from Year Zero was also found on a flash drive in a bathroom stall on their current European tour. This time it was "Me, I'm Not." Along with the song, was an MP3 of "cricket chirping", which when put through a spectrogram revealed the number: 216.333.1810.
- Using this method again to deliver clues as part of the Year Zero ARG, there were two extra audio files included in the Garageband Multitrack files for the song Capital G. The images in the sounds are of various avatars of user at the Nine Inch Nails oriented forum Echoing the Sound. The user names are used to form the title of a new site that is part of the ARG.
- An untitled audio track by Treetops McPhoenix to accompany a video for the Stephen Moles Coma ARG on Facebook is made entirely from images of the Mona Lisa.
On spectrograms of the records of Mike Oldfield's song "Tubular Bells" signals from the Rugby VLF transmitter are found.
Some modern music is also created using spectrograms as an intermediate medium; changing the intensity of different frequencies over time, or even creating new ones, by drawing them and then inverse transforming. See Audio timescale-pitch modification and Phase vocoder.
# VLF-reception with the PC
Using spectrograms generated by audio-band FFT-software is a very convenient way to receive frequencies below 24 kHz. This technique allows wide-range reception of the VLF-range. | Spectrogram
The spectrogram is the result of calculating the frequency spectrum of windowed frames of a compound signal. It is a three-dimensional plot of the energy of the frequency content of a signal as it changes over time.
Spectrograms are used to identify phonetic sounds, to analyse the cries of animals, and in the fields of music, sonar/radar, speech processing, etc. A spectrogram can also be called a spectral waterfall, sonogram, voiceprint, or voicegram. The instrument that generates a spectrogram is called a sonograph.
# Format
In the most usual format, the horizontal axis represents time, the vertical axis is frequency, and the intensity of each point in the image represents amplitude of a particular frequency at a particular time. Often the diagram is reduced to two dimensions by indicating the intensity with thicker lines, more intense colors or grey values.
There are many variations of format. Sometimes the vertical and horizontal axes are switched, so time runs up and down. Sometimes the amplitude is represented as the height of a 3D surface instead of color or intensity. The frequency and amplitude axes can be either linear or logarithmic, depending on what the graph is being used for. For instance, audio would usually be represented with a logarithmic amplitude axis (probably in dB), and frequency would be linear to emphasize harmonic relationships, or logarithmic to emphasize musical, tonal relationships.
# Generation
Spectrograms are usually created in one of two ways; either with a series of bandpass filters, or calculated from the time signal using the short-time Fourier transform (STFT).
The filter method is usually used in the analog, continuous version of measurement. The frequency range of the signal (an audio signal, for instance, would have frequencies in the range of 20 Hz - 20 kHz) is divided into equal sections, either linearly (0-100, 100-200, 200-300, ...), or logarithmically (10-100, 100-1000, 1000-10000, ...). The signal is input to a corresponding filter, which removes most of the signal that does not fall within its frequency band (imperfect window functions and limited frequency resolution will cause some "bleeding" between adjacent frequency bands). The magnitudes of each filter's output are recorded as functions of time. Each recording then corresponds to a horizontal line in the image; a measurement of magnitude versus time for a specific frequency band.
To calculate the spectrogram using the magnitude of the STFT is usually a digital process. Digitally sampled data, in the time domain, is broken up into chunks, which usually overlap, and Fourier transformed to calculate the magnitude of the frequency spectrum for each chunk. Each chunk then corresponds to a vertical line in the image; a measurement of magnitude versus frequency for a specific moment in time.
The spectrums or time plots are then "laid side by side" to form the image or a three-dimensional surface.
The spectrogram is given by the magnitude of the STFT of the function:
# Creating sound from a spectrogram
The above process can be reversed; some programs are available that turn a digital image into sound:
- MetaSynth for Macintosh;
- Coagula for Windows;
- Enscribe for Linux;
- ARSS, The Analysis & Resynthesis Sound Spectrograph, multi-platform;
- JavOICe, a Java applet.
- FL Studio's "BeepMap" additive synthesizer.
This technique allows electronic music artists to "hide" images in their music. Examples include:
- Aphex Twin hid an image of himself in a spectrogram. The image can be found on Track 2 of the Windowlicker EP as a nine-second sweeping section right at the end. (It is recognizable in an MP3, but the compression changes the spectrogram and it is not as clear as from the CD.) Aphex Twin also hid the image of a spiral shape in his first track from the "Windowlicker" EP. [2]
- The song "Look" from Venetian Snares' album Songs About My Cats, contains several images of his cats.
- The song "3recurring" from Plaid on their album Rest Proof Clockwork contains the recurring 3s represented as a logo on the cover of the "Not for Threes" album.
- Nine Inch Nails has employed this technique on a few occasions as part of an ongoing Alternate Reality Game for their album Year Zero.
The MP3 version of "My Violent Heart" (deliberately leaked before Year Zero was released) contains a few brief moments of static at the end. When analyzed in a spectrogram, it reveals the image of a hand reaching down from the sky. This image echoes a similar theme seen throughout the alternate reality game viral marketing campaign launched for the album. On the official version of the album, the sound appears at the end of the song "The Warning."
Another new Nine Inch Nails track from Year Zero was also found on a flash drive in a bathroom stall on their current European tour. This time it was "Me, I'm Not." Along with the song, was an MP3 of "cricket chirping", which when put through a spectrogram revealed the number: 216.333.1810.
Using this method again to deliver clues as part of the Year Zero ARG, there were two extra audio files included in the Garageband Multitrack files for the song Capital G. The images in the sounds are of various avatars of user at the Nine Inch Nails oriented forum Echoing the Sound. The user names are used to form the title of a new site that is part of the ARG.
- The MP3 version of "My Violent Heart" (deliberately leaked before Year Zero was released) contains a few brief moments of static at the end. When analyzed in a spectrogram, it reveals the image of a hand reaching down from the sky. This image echoes a similar theme seen throughout the alternate reality game viral marketing campaign launched for the album. On the official version of the album, the sound appears at the end of the song "The Warning."
- Another new Nine Inch Nails track from Year Zero was also found on a flash drive in a bathroom stall on their current European tour. This time it was "Me, I'm Not." Along with the song, was an MP3 of "cricket chirping", which when put through a spectrogram revealed the number: 216.333.1810.
- Using this method again to deliver clues as part of the Year Zero ARG, there were two extra audio files included in the Garageband Multitrack files for the song Capital G. The images in the sounds are of various avatars of user at the Nine Inch Nails oriented forum Echoing the Sound. The user names are used to form the title of a new site that is part of the ARG.
- An untitled audio track by Treetops McPhoenix to accompany a video for the Stephen Moles Coma ARG on Facebook is made entirely from images of the Mona Lisa.
On spectrograms of the records of Mike Oldfield's song "Tubular Bells" signals from the Rugby VLF transmitter are found[citation needed].
Some modern music is also created using spectrograms as an intermediate medium; changing the intensity of different frequencies over time, or even creating new ones, by drawing them and then inverse transforming. See Audio timescale-pitch modification and Phase vocoder.
# VLF-reception with the PC
Using spectrograms generated by audio-band FFT-software is a very convenient way to receive frequencies below 24 kHz. This technique allows wide-range reception of the VLF-range. | https://www.wikidoc.org/index.php/Sonograph | |
92bb6a711291f5676d1598765827f3364555398e | wikidoc | Sonographer | Sonographer
Sonographers are medical professionals who operate ultrasonic imaging devices to produce diagnostic images and scans, videos, or 3D volumes of anatomy and diagnostic data. Sonography requires specialized education and skills to view, analyze and modify the scan to optimize the information in the image. Because of the high levels of decisional latitude and diagnostic responsibility sonographers have a high level of responsibility in the diagnostic process, certification in sonography is generally required. Sonographers require a high level of understanding in ultrasound physics, cross sectional anatomy, physiology, pathology and communication skills; as well as highly developed psycho-motor skills that are specific to the profession.
In the United States the most widely accepted sonographic education is provided by CAAHEP/JRC-DMS accredited programs. The profession is sub-divided in specialties such as cardiac, obstetrical, vascular, and general sonographers. General sonographers are registered in abdominal and/or obstetric and gynecologic sonography. There are two credentialing bodies in the United States for sonographers, the American Registry for Diagnostic Medical Sonography (ARDMS) and Cardiovascular Credentialing International.
The Australian Sonographers Association(ASA) was formed in 1992 in response to the desire of Sonographers across Australia for an organisation which had as its charter, to exclusively represent and consider the issues confronting and challenging sonographers in the Australian healthcare environment. The ASA now has a membership of more than 1,900 sonographers and about 40 corporate members. The ASA has pledged to pursue high standards within the practice of Medical Sonography. The ASA has a structure of a Board of Directors and multiple representative Branches in all Australian states.
Australian sonographers must be accredited by the Australasian Sonographers Accreditation Registry (ASAR). ASAR’s brief is to accredit and re-accredit on a regular basis, ultrasound programs offered by Australian Universities (and the DMU), and to establish the criteria against which those programs and any other future Australian and New Zealand programs are to be judged. In addition a register of accredited (AMS) and student (ASS) sonographers is maintained and their continuing professional development (CPD) activities monitored and recorded.
In the UK where sonographers are also responsible for the interpretation of the images and issue diagnostic reports; education is provided by the universities and overseen by the Consortium for Accrediation of Sonographic Education (CASE.)
Certifications in sonography after examinations administered by the ARDMS and Cardiovascular Credentialing International are recognized and administered in some countries outside the US. | Sonographer
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Sonographers are medical professionals who operate ultrasonic imaging devices to produce diagnostic images and scans, videos, or 3D volumes of anatomy and diagnostic data. Sonography requires specialized education and skills to view, analyze and modify the scan to optimize the information in the image. Because of the high levels of decisional latitude and diagnostic responsibility sonographers have a high level of responsibility in the diagnostic process, certification in sonography is generally required. Sonographers require a high level of understanding in ultrasound physics, cross sectional anatomy, physiology, pathology and communication skills; as well as highly developed psycho-motor skills that are specific to the profession.
In the United States the most widely accepted sonographic education is provided by CAAHEP/JRC-DMS accredited programs. The profession is sub-divided in specialties such as cardiac, obstetrical, vascular, and general sonographers. General sonographers are registered in abdominal and/or obstetric and gynecologic sonography. There are two credentialing bodies in the United States for sonographers, the American Registry for Diagnostic Medical Sonography (ARDMS) and Cardiovascular Credentialing International.
The Australian Sonographers Association(ASA) was formed in 1992 in response to the desire of Sonographers across Australia for an organisation which had as its charter, to exclusively represent and consider the issues confronting and challenging sonographers in the Australian healthcare environment. The ASA now has a membership of more than 1,900 sonographers and about 40 corporate members. The ASA has pledged to pursue high standards within the practice of Medical Sonography. The ASA has a structure of a Board of Directors and multiple representative Branches in all Australian states.
Australian sonographers must be accredited by the Australasian Sonographers Accreditation Registry (ASAR). ASAR’s brief is to accredit and re-accredit on a regular basis, ultrasound programs offered by Australian Universities (and the DMU), and to establish the criteria against which those programs and any other future Australian and New Zealand programs are to be judged. In addition a register of accredited (AMS) and student (ASS) sonographers is maintained and their continuing professional development (CPD) activities monitored and recorded.
In the UK where sonographers are also responsible for the interpretation of the images and issue diagnostic reports; education is provided by the universities and overseen by the Consortium for Accrediation of Sonographic Education (CASE.)
Certifications in sonography after examinations administered by the ARDMS and Cardiovascular Credentialing International are recognized and administered in some countries outside the US.
# External links
- American Registry for Diagnostic Medical Sonography
- Australasian Sonographer Accreditation Registry
- Australian Sonographers Association
- Society of Diagnostic Medical Sonography
- CAAHEP
- Cardiovascular Credentialing International
- Sonographers Medical employment of Sonographers in Europe & Australasia
- British medical Ultrasound Society
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Sonographer | |
22dd4592265619ac13016655a806feeece4c8580 | wikidoc | Sorbic acid | Sorbic acid
Sorbic acid, or 2,4-hexadienoic acid, is a natural organic compound used as a food preservative. It has the chemical formula C6H8O2. It was first isolated from the unripe berries of the Rowan (Sorbus aucuparia), hence its name.
Sorbic acid and its mineral salts, such as sodium sorbate, potassium sorbate and calcium sorbate, are antimicrobial agents often used as preservatives in food and drinks to prevent the growth of mold, yeast and fungi. In general the salts are preferred over the acid form because they are more soluble in water. The optimal pH for the antimicrobial activity is below pH 6.5 and sorbates are generally used at concentrations of 0.025% to 0.10%. Adding sorbate salts to food will however raise the pH of the food slightly so the pH may need to be adjusted to assure safety.
Sorbic acid should not be confused with other chemically unrelated, but similarly named food additives sorbitol, polysorbate, and ascorbic acid (Vitamin C).
The E numbers are:
- E200 Sorbic acid
- E201 Sodium sorbate
- E202 Potassium sorbate
- E203 Calcium sorbate
Some molds (notably some Trichoderma and Penicillium strains) and yeasts are able to detoxify sorbates by decarboxylation, producing trans-1,3-pentadiene. The pentadiene manifests as a typical odor of kerosene or petroleum. Other detoxification reactions include reduction to 4-hexenol and 4-hexenoic acid. | Sorbic acid
Template:Chembox new
Sorbic acid, or 2,4-hexadienoic acid, is a natural organic compound used as a food preservative. It has the chemical formula C6H8O2. It was first isolated from the unripe berries of the Rowan (Sorbus aucuparia), hence its name.
Sorbic acid and its mineral salts, such as sodium sorbate, potassium sorbate and calcium sorbate, are antimicrobial agents often used as preservatives in food and drinks to prevent the growth of mold, yeast and fungi. In general the salts are preferred over the acid form because they are more soluble in water. The optimal pH for the antimicrobial activity is below pH 6.5 and sorbates are generally used at concentrations of 0.025% to 0.10%. Adding sorbate salts to food will however raise the pH of the food slightly so the pH may need to be adjusted to assure safety.
Sorbic acid should not be confused with other chemically unrelated, but similarly named food additives sorbitol, polysorbate, and ascorbic acid (Vitamin C).
The E numbers are:
- E200 Sorbic acid
- E201 Sodium sorbate
- E202 Potassium sorbate
- E203 Calcium sorbate
Some molds (notably some Trichoderma and Penicillium strains) and yeasts are able to detoxify sorbates by decarboxylation, producing trans-1,3-pentadiene. The pentadiene manifests as a typical odor of kerosene or petroleum. Other detoxification reactions include reduction to 4-hexenol and 4-hexenoic acid. [1] | https://www.wikidoc.org/index.php/Sorbic_acid | |
be747e761a1a8f8a6ae06b23ab560d39143e3413 | wikidoc | Soured milk | Soured milk
Soured milk is a general term for milk that has acquired a sour taste, either through the addition of an acid, such as lemon juice or vinegar, or through bacterial fermentation. The acid causes milk to coagulate and form a thicker consistency. Soured milk that is produced by bacterial fermentation is more specifically called fermented milk or cultured milk. Soured milk that is produced by the addition of an acid, with or without the addition of microbial organisms, is more specifically called acidified milk. In the US, the acids that may be used in the manufacture of acidified milk are acetic acid (commonly found in vinegar), adipic acid, citric acid (commonly found in lemon juice), fumaric acid, glucono-delta-lactone, hydrochloric acid, lactic acid, malic acid, phosphoric acid, succinic acid, and tartaric acid.
In recipes, soured milk created by the addition of an acid or by bacterial fermentation can often be used interchangeably. For example, 1 cup of cultured buttermilk, a soured milk produced by bacterial fermentation, can be substituted with 1 tablespoon of lemon juice or vinegar plus enough milk to make 1 cup. The chemically soured milk can be used after standing for 5 minutes.
# Sour Milk
Currently, sour milk commonly means (pasteurized) milk that has spoiled and is "in an unpalatable state". However, the meaning of sour milk can be ambiguous since it has been used in different contexts in different time periods.
In more recent years, sour milk has been used both for chemically and biologically soured milk.
Some older recipes use sour milk, but today it is unclear which dairy product was "sour milk". Pasteurized milk was not available in the US until the early 1900s. For example, the South Jersey Milk Company created a poster in 1930 entitled "What is pasteurized milk?" to educate the American public about the safety of its newly pasteurized milk. Thus, older recipes that use sour milk may have been written prior to the availability of pasteurized milk. Before pasteurized milk became widely available, sour milk may have been unpasteurized milk that had naturally acquired a sour taste through bacterial fermentation at room temperature.
At least until the 1920s, there was a clear distinction between sour milk and buttermilk, where buttermilk was the sour tasting thin liquid leftover from making butter. Today, in North America, either cultured buttermilk, also commonly known as buttermilk but not the same product as the aforementioned buttermilk, or milk soured by the addition of lemon juice or vinegar is often used when sour milk is needed in a recipe. | Soured milk
Soured milk is a general term for milk that has acquired a sour taste, either through the addition of an acid, such as lemon juice or vinegar, or through bacterial fermentation. The acid causes milk to coagulate and form a thicker consistency. Soured milk that is produced by bacterial fermentation is more specifically called fermented milk or cultured milk.[1] Soured milk that is produced by the addition of an acid, with or without the addition of microbial organisms, is more specifically called acidified milk.[2] In the US, the acids that may be used in the manufacture of acidified milk are acetic acid (commonly found in vinegar), adipic acid, citric acid (commonly found in lemon juice), fumaric acid, glucono-delta-lactone, hydrochloric acid, lactic acid, malic acid, phosphoric acid, succinic acid, and tartaric acid.
In recipes, soured milk created by the addition of an acid or by bacterial fermentation can often be used interchangeably. For example, 1 cup of cultured buttermilk, a soured milk produced by bacterial fermentation, can be substituted with 1 tablespoon of lemon juice or vinegar plus enough milk to make 1 cup. The chemically soured milk can be used after standing for 5 minutes.[3]
# Sour Milk
Currently, sour milk commonly means (pasteurized) milk that has spoiled and is "in an unpalatable state".[4] However, the meaning of sour milk can be ambiguous since it has been used in different contexts in different time periods.
In more recent years, sour milk has been used both for chemically and biologically soured milk.[5][6][7][8]
Some older recipes use sour milk, but today it is unclear which dairy product was "sour milk". Pasteurized milk was not available in the US until the early 1900s. For example, the South Jersey Milk Company created a poster in 1930 entitled "What is pasteurized milk?" to educate the American public about the safety of its newly pasteurized milk.[9] Thus, older recipes that use sour milk may have been written prior to the availability of pasteurized milk. Before pasteurized milk became widely available, sour milk may have been unpasteurized milk that had naturally acquired a sour taste through bacterial fermentation at room temperature.
At least until the 1920s, there was a clear distinction between sour milk and buttermilk,[10] where buttermilk was the sour tasting thin liquid leftover from making butter.[11] Today, in North America, either cultured buttermilk, also commonly known as buttermilk but not the same product as the aforementioned buttermilk, or milk soured by the addition of lemon juice or vinegar is often used when sour milk is needed in a recipe. | https://www.wikidoc.org/index.php/Soured_milk | |
33954ae04cf0eabc3a9573fbdbb63c6fc6246f7d | wikidoc | Soybean wax | Soybean wax
Soybean wax, often referred to simply as "soy wax," is produced with hydrogenated soybean oil. It was created by inventor Michael Richards in 1993, who was looking for a cheaper alternative to beeswax, thus becoming the first wax innovation in the candle industry for over a hundred years.
Its main disadvantage is lower melting point, resulting in candles which deform easily in hot weather and drip readily when burning.
It has not been documented that soy wax is a safer alternative to paraffin, but can be cheaper than beeswax. Template:WW
Because of the addition of chemicals to soy beans to make them into a viable wax, it is generally equal to paraffin and beeswax for biodegradable waxes.
Soy is listed as a major food allergen by the FDA. If a person has reactions to soy, paraffin can be a safe alternative. | Soybean wax
Soybean wax, often referred to simply as "soy wax," is produced with hydrogenated soybean oil. It was created by inventor Michael Richards in 1993, who was looking for a cheaper alternative to beeswax, thus becoming the first wax innovation in the candle industry for over a hundred years.
Its main disadvantage is lower melting point, resulting in candles which deform easily in hot weather and drip readily when burning.
It has not been documented that soy wax is a safer alternative to paraffin, but can be cheaper than beeswax. Template:WW
Because of the addition of chemicals to soy beans to make them into a viable wax, it is generally equal to paraffin and beeswax for biodegradable waxes.
Soy is listed as a major food allergen by the FDA.[1] If a person has reactions to soy, paraffin can be a safe alternative. | https://www.wikidoc.org/index.php/Soybean_wax | |
7f38797473c3ad5f23a70f849cf285c3c57c990c | wikidoc | Space group | Space group
The space group of a crystal or crystallographic group is a mathematical description of the symmetry inherent in the structure. The word 'group' in the name comes from the mathematical notion of a group, which is used to build the set of space groups.
# Crystallography
The space groups in three dimensions are made from combinations of the 32 crystallographic point groups with the 14 Bravais lattices which belong to one of 7 crystal systems. This results in a space group being some combination of the translational symmetry of a unit cell including lattice centering, and the point group symmetry operations of reflection, rotation and improper rotation (also called rotoinversion). Furthermore one must consider the screw axis and glide plane symmetry operations. These are called compound symmetry operations and are combinations of a rotation or reflection with a translation less than the unit cell size. The combination of all these symmetry operations results in a total of 230 unique space groups describing all possible crystal symmetries.
## Glide planes and screw axes
Two of the symmetry operations involved in the space groups are not contained in the corresponding point group or Bravais lattice. These are the compound symmetry operations called the glide plane and the screw axis.
A glide plane is a reflection in a plane, followed by a translation parallel with that plane. This is noted by a, b or c, depending on which axis the glide is along. There is also the n glide, which is a glide along the half of a diagonal of a face, and the d glide, which is a fourth of the way along either a face or space diagonal of the unit cell. The latter is often called the diamond glide plane as it features in the diamond structure.
A screw axis is a rotation about an axis, followed by a translation along the direction of the axis. These are noted by a number, n, to describe the degree of rotation, where the number is how many operations must be applied to complete a full rotation (e.g., 3 would mean a rotation one third of the way around the axis each time). The degree of translation is then added as a subscript showing how far along the axis the translation is, as a portion of the parallel lattice vector. So, 21 is a twofold rotation followed by a translation of 1/2 of the lattice vector.
## Notation
There are a number of methods of identifying space groups. The International Union of Crystallography publishes a table (more correctly, a hefty tome of tables) of all space groups, and assigns each a unique number. Other than this numbering scheme there are two main forms of notation, the Hermann-Mauguin notation and Schönflies notation.
The Hermann-Mauguin (or international) notation is the one most commonly used in crystallography, and consists of a set of four symbols. The first describes the centering of the Bravais lattice (P, A, B, C, I, R or F). The next three describe the most prominent symmetry operation visible when projected along one of the high symmetry directions of the crystal. These symbols are the same as used in point groups, with the addition of glide planes and screw axis, described above. By way of example, the space group of quartz is P3121, showing that it exhibits primitive centering of the motif (i.e., once per unit cell), with a threefold screw axis and a twofold rotation axis. Note that it does not explicitly contain the crystal system, although this is unique to each space group (in the case of P3121, it is trigonal).
In HM notation the first symbol (31 in this example) denotes the symmetry along the major axis (c-axis in trigonal cases), the second (2 in this case) along axes of secondary importance (a and b) and the third symbol the symmetry in another direction. In the trigonal case there also exists a space group P3112. In this space group the twofold axes are not along the a and b-axes but in a direction rotated by 30o.
# Group theory
Mathematically, a space group is a symmetry group or symmetry group type of n-dimensional structures with translational symmetry in n independent directions, such as, for n = 3, a crystal. Only discrete symmetry groups are included in the categorization; i.e., infinitely fine structure or homogeneity in one or more directions is excluded. This comes from the necessity to describe discrete sets of 'points' (i.e. atoms or ions in a crystal), as opposed to continuous media (see Symmetry in physics for the latter case). See the articles Bravais lattices, Crystals, and Translation (geometry) for a fuller discussion.
Two symmetry groups are of the same crystallographic space group type if they are the same up to an affine transformation of space that preserves orientation. Thus e.g. a change of angle between translation vectors does not affect the space group type if it does not add or remove any symmetry. A more formal definition involves conjugacy, see Symmetry group.
Two symmetry groups are of the same affine space group type if they are the same up to an affine transformation, even if that inverts orientation.
This can be expressed by saying that two symmetry groups which are chiral and each other's mirror image, are of different crystallographic space group type, but of the same affine space group type.
In 1D and 2D space groups of the same affine space group type are also of the same crystallographic space group type, but in 3D this need not be the case: in 2D, the mirror image of a rotation is a reversed rotation, which is in the group anyway, and the mirror image of a mirror is still a mirror, but the mirror image of a righthand screw operation is a lefthand one, not the inverse of the righthand screw operation.
The Bieberbach theorem states that in each dimension all affine space group types are different even as abstract groups (as opposed to e.g. Frieze groups, of which two are isomorphic with Z).
The term "space group" is often used for space group type. It is often clear from the context what is meant. However, when considering subgroup relationships a specific symmetry group should not be confused with the space group type.
## Various dimensions
In 1D there are two space group types: those with and without mirror image symmetry, see symmetry groups in one dimension.
In 2D there are 17; these 2D space groups are also called wallpaper groups or plane groups.
In 3D there are 230 crystallographic space group types, which reduces to 219 affine space group types because of some types being different from their mirror image; these are said to differ by "enantiomorphous character" (e.g. P3112 and P3212). Usually "space group" refers to 3D. They are by themselves purely mathematical, but play a large role in crystallography.
In 4 dimensions there are 4895 crystallographic space group types, or 4783 affine space group types.
The number of affine space group types in n dimensions is given by sequence A004029 in OEIS; the number of crystallographic space group types in n dimensions is given by A006227.
## Double groups and time reversal
In addition to crystallographic space groups there are also magnetic space groups or double groups. These symmetries contain an element known as time reversal. They are of importance in magnetic structures that contain ordered unpaired spins, i.e. ferro-, ferri- or antiferromagnetic structures as studied by neutron diffraction. The time reversal element flips a magnetic spin while leaving all other structure the same and it can be combined with a number of other symmetry elements. Including time reversal there are 1651 magnetic space groups in 3D.
## Grouping by point group
A symmetry group consists of isometric affine transformations; each is given by an orthogonal matrix and a translation vector (which may be the zero vector). Space groups can be grouped by the matrices involved, i.e. ignoring the translation vectors (see also Euclidean group). This corresponds to discrete symmetry groups with a fixed point: the point groups. However, not all point groups are compatible with translational symmetry; those that are compatible are called the crystallographic point groups. This is expressed in the crystallographic restriction theorem. (In spite of these names, this is a geometric limitation, not just a physical one.)
In 1D both space group types correspond to their own "crystallographic point group".
In 2D the 17 wallpaper groups are grouped according to 10 associated crystallographic point groups: 1-, 2-, 3-, 4-, and 6-fold rotational symmetry, each with or without reflections. Thus a wallpaper group with glide reflection axes is associated with the same point group as the wallpaper group with reflection axes parallel to these glide reflection axes.
In 3D this gives a grouping of the 230 space group types into 32 crystal classes, one for each associated crystallographic point group. A space group with a screw axis is in the same crystal class as one with a corresponding pure axis of rotation. Similarly a space group with a glide plane is in the same crystal class as one with a corresponding pure reflection.
In addition to translations, and the point operations of reflection, rotation and improper rotation, there are combinations of reflections and rotations with translation: the screw axis and the glide plane.
The number of crystallographic point groups in n dimensions is given by OEIS:A004028.
## Further categorizing
Space groups are categorized by Bravais lattice and crystal class. However, for some combinations there are multiple space groups, while other combinations are not possible.
The 230 space group types can be subdivided in two categories:
- 73 symmorphic space group types: a space group is symmorphic if all symmetries can be described in terms of rotation axes and reflection planes all through the same point (including rotoreflections), without screw axes and glide planes). Equivalently, a space group is symmorphic if it is equivalent to a semidirect product of its point group with its translation subgroup.
- 157 nonsymmorphic space group types.
Conway and Thurston gave another classification of the space groups, where they divided the 230 groups into reducible and irreducible groups. The reducible groups fall into 17 classes corresponding to the 17 wallpaper groups, and the remaining 35 irreducible groups are classified separately. | Space group
The space group of a crystal or crystallographic group is a mathematical description of the symmetry inherent in the structure. The word 'group' in the name comes from the mathematical notion of a group, which is used to build the set of space groups.
# Crystallography
The space groups in three dimensions are made from combinations of the 32 crystallographic point groups with the 14 Bravais lattices which belong to one of 7 crystal systems. This results in a space group being some combination of the translational symmetry of a unit cell including lattice centering, and the point group symmetry operations of reflection, rotation and improper rotation (also called rotoinversion). Furthermore one must consider the screw axis and glide plane symmetry operations. These are called compound symmetry operations and are combinations of a rotation or reflection with a translation less than the unit cell size. The combination of all these symmetry operations results in a total of 230 unique space groups describing all possible crystal symmetries.
## Glide planes and screw axes
Two of the symmetry operations involved in the space groups are not contained in the corresponding point group or Bravais lattice. These are the compound symmetry operations called the glide plane and the screw axis.
A glide plane is a reflection in a plane, followed by a translation parallel with that plane. This is noted by a, b or c, depending on which axis the glide is along. There is also the n glide, which is a glide along the half of a diagonal of a face, and the d glide, which is a fourth of the way along either a face or space diagonal of the unit cell. The latter is often called the diamond glide plane as it features in the diamond structure.
A screw axis is a rotation about an axis, followed by a translation along the direction of the axis. These are noted by a number, n, to describe the degree of rotation, where the number is how many operations must be applied to complete a full rotation (e.g., 3 would mean a rotation one third of the way around the axis each time). The degree of translation is then added as a subscript showing how far along the axis the translation is, as a portion of the parallel lattice vector. So, 21 is a twofold rotation followed by a translation of 1/2 of the lattice vector.
## Notation
There are a number of methods of identifying space groups. The International Union of Crystallography publishes a table (more correctly, a hefty tome of tables) of all space groups, and assigns each a unique number. Other than this numbering scheme there are two main forms of notation, the Hermann-Mauguin notation and Schönflies notation.
The Hermann-Mauguin (or international) notation is the one most commonly used in crystallography, and consists of a set of four symbols. The first describes the centering of the Bravais lattice (P, A, B, C, I, R or F). The next three describe the most prominent symmetry operation visible when projected along one of the high symmetry directions of the crystal. These symbols are the same as used in point groups, with the addition of glide planes and screw axis, described above. By way of example, the space group of quartz is P3121, showing that it exhibits primitive centering of the motif (i.e., once per unit cell), with a threefold screw axis and a twofold rotation axis. Note that it does not explicitly contain the crystal system, although this is unique to each space group (in the case of P3121, it is trigonal).
In HM notation the first symbol (31 in this example) denotes the symmetry along the major axis (c-axis in trigonal cases), the second (2 in this case) along axes of secondary importance (a and b) and the third symbol the symmetry in another direction. In the trigonal case there also exists a space group P3112. In this space group the twofold axes are not along the a and b-axes but in a direction rotated by 30o.
# Group theory
Mathematically, a space group is a symmetry group or symmetry group type of n-dimensional structures with translational symmetry in n independent directions, such as, for n = 3, a crystal. Only discrete symmetry groups are included in the categorization; i.e., infinitely fine structure or homogeneity in one or more directions is excluded. This comes from the necessity to describe discrete sets of 'points' (i.e. atoms or ions in a crystal), as opposed to continuous media (see Symmetry in physics for the latter case). See the articles Bravais lattices, Crystals, and Translation (geometry) for a fuller discussion.
Two symmetry groups are of the same crystallographic space group type if they are the same up to an affine transformation of space that preserves orientation. Thus e.g. a change of angle between translation vectors does not affect the space group type if it does not add or remove any symmetry. A more formal definition involves conjugacy, see Symmetry group.
Two symmetry groups are of the same affine space group type if they are the same up to an affine transformation, even if that inverts orientation.
This can be expressed by saying that two symmetry groups which are chiral and each other's mirror image, are of different crystallographic space group type, but of the same affine space group type.
In 1D and 2D space groups of the same affine space group type are also of the same crystallographic space group type, but in 3D this need not be the case: in 2D, the mirror image of a rotation is a reversed rotation, which is in the group anyway, and the mirror image of a mirror is still a mirror, but the mirror image of a righthand screw operation is a lefthand one, not the inverse of the righthand screw operation.
The Bieberbach theorem states that in each dimension all affine space group types are different even as abstract groups (as opposed to e.g. Frieze groups, of which two are isomorphic with Z).
The term "space group" is often used for space group type. It is often clear from the context what is meant. However, when considering subgroup relationships a specific symmetry group should not be confused with the space group type.
## Various dimensions
In 1D there are two space group types: those with and without mirror image symmetry, see symmetry groups in one dimension.
In 2D there are 17; these 2D space groups are also called wallpaper groups or plane groups.
In 3D there are 230 crystallographic space group types, which reduces to 219 affine space group types because of some types being different from their mirror image; these are said to differ by "enantiomorphous character" (e.g. P3112 and P3212). Usually "space group" refers to 3D. They are by themselves purely mathematical, but play a large role in crystallography.
In 4 dimensions there are 4895 crystallographic space group types, or 4783 affine space group types.[1]
The number of affine space group types in <math>n</math> dimensions is given by sequence A004029 in OEIS; the number of crystallographic space group types in <math>n</math> dimensions is given by A006227.
## Double groups and time reversal
In addition to crystallographic space groups there are also magnetic space groups or double groups. These symmetries contain an element known as time reversal. They are of importance in magnetic structures that contain ordered unpaired spins, i.e. ferro-, ferri- or antiferromagnetic structures as studied by neutron diffraction. The time reversal element flips a magnetic spin while leaving all other structure the same and it can be combined with a number of other symmetry elements. Including time reversal there are 1651 magnetic space groups in 3D. [2]
## Grouping by point group
A symmetry group consists of isometric affine transformations; each is given by an orthogonal matrix and a translation vector (which may be the zero vector). Space groups can be grouped by the matrices involved, i.e. ignoring the translation vectors (see also Euclidean group). This corresponds to discrete symmetry groups with a fixed point: the point groups. However, not all point groups are compatible with translational symmetry; those that are compatible are called the crystallographic point groups. This is expressed in the crystallographic restriction theorem. (In spite of these names, this is a geometric limitation, not just a physical one.)
In 1D both space group types correspond to their own "crystallographic point group".
In 2D the 17 wallpaper groups are grouped according to 10 associated crystallographic point groups: 1-, 2-, 3-, 4-, and 6-fold rotational symmetry, each with or without reflections. Thus a wallpaper group with glide reflection axes is associated with the same point group as the wallpaper group with reflection axes parallel to these glide reflection axes.
In 3D this gives a grouping of the 230 space group types into 32 crystal classes, one for each associated crystallographic point group. A space group with a screw axis is in the same crystal class as one with a corresponding pure axis of rotation. Similarly a space group with a glide plane is in the same crystal class as one with a corresponding pure reflection.
In addition to translations, and the point operations of reflection, rotation and improper rotation, there are combinations of reflections and rotations with translation: the screw axis and the glide plane.
The number of crystallographic point groups in n dimensions is given by OEIS:A004028.
## Further categorizing
Space groups are categorized by Bravais lattice and crystal class. However, for some combinations there are multiple space groups, while other combinations are not possible.
The 230 space group types can be subdivided in two categories:
- 73 symmorphic space group types: a space group is symmorphic if all symmetries can be described in terms of rotation axes and reflection planes all through the same point (including rotoreflections), without screw axes and glide planes). Equivalently, a space group is symmorphic if it is equivalent to a semidirect product of its point group with its translation subgroup.
- 157 nonsymmorphic space group types.
Conway and Thurston gave another classification of the space groups, where they divided the 230 groups into reducible and irreducible groups. The reducible groups fall into 17 classes corresponding to the 17 wallpaper groups, and the remaining 35 irreducible groups are classified separately. | https://www.wikidoc.org/index.php/Space_group | |
6ebd3d25580192e279f5f41862bebb327504f1db | wikidoc | Spanish fly | Spanish fly
The Spanish fly is an emerald-green beetle in the family Meloidae, Lytta vesicatoria. It is 15 mm to 22 mm long and 5 mm to 8 mm wide, and lives on plants in the families Caprifoliaceae and Oleaceae. The beetle contains up to 5% cantharidin which irritates animal tissues. The crushed powder of Spanish fly is of yellowish brown to brown-olive color with iridescent reflections, of disagreeable scent and bitter flavor.
Spanish fly, or cantharides as it is sometimes called, is often given to farm animals to incite them to mating. The cantharides excreted in the urine irritate the urethral passages, causing inflammation in the genitals and subsequent priapism. For this reason, Spanish fly has been given to humans for purposes of seduction. It is dangerous since the amount required is minuscule and the difference between the effective dose and the harmful dose is quite narrow. Cantharides cause painful urination, fever, and sometimes bloody discharge. They can cause permanent damage to the kidneys and genitals.
# History
Its medical use dates back to descriptions from Hippocrates. Plasters made from wings of these beetles have been used to raise blisters. In ancient China, cantharides beetles were mixed with human dung, arsenic and wolfsbane to make the world's first recorded stink bomb. It is also one of the world’s most well-known aphrodisiacs. In Roman times, Livia, the scheming wife of Augustus Caesar, would slip it into food hoping to inspire her guests to some indiscretion with which she could later blackmail them. Henry IV (1050-1106) is known to have consumed Spanish fly at the risk of his health. In 1572, the famous French surgeon Ambroise Paré wrote an account of a man suffering from "the most frightful satyriasis" after having taken a potion composed of nettles and cantharides. In the 1670s, Spanish fly was mixed with dried moles and bat's blood for a love charm made by the black magician La Voisin. It was slipped into the food of Louis XIV to secure the king's lust for Madame de Montespan. In the 18th century cantharides became fashionable, known as pastilles Richelieu in France. Marquis de Sade is claimed to have given aniseed-flavored pastilles that were laced with Spanish fly to prostitutes at an orgy in 1772. He was sentenced to death for poisoning and sodomy, but later reprieved on appeal.
Also it was used as an abortifacient, stimulant (since one of its effects was producing insomnia and nervous agitation), and as a poison; in powder, mixed with the food, it could go unnoticed. Aqua toffana, or aquetta di Napoli, was one of the poisons associated with the Medicis. Thought to be a mixture of arsenic and cantharides, it was reportedly created by an Italian countess, Toffana. Four to six drops of this poison in water or wine was enough to deliver a painless death in a few hours.
In order to determine if a death had taken place by the effects of Spanish fly they had to resort to the vesicación test. One of those test methods consisted of rubbing part of the internal organs of the deceased, dissolved in oil, on the shaved skin of a rabbit; the absorption of the cantharides and its blistering effect are such that they became visible on the skin of the rabbit.
In Santeria, catharides are used in incense.
# Commercial products
Cantharides are illegal in the United States, except for use in animal husbandry and by licensed physicians for the topical treatment of certain types of warts. Some internet or mail order suppliers of sex stimulants advertise such products like "Herbal Spanish fly", "Mexican Spanish Fly", or "Spanish Fly Potion". Most of these products are simply cayenne pepper in capsules, sometimes blended with the powder of ginseng, kelp, ginger or gotu kola. The products with the name "Spanische Fliege (Spanish fly)" that are available in Germany represent no danger with a normal application since they contain the active substance actually only in homeopathic dosage, diluted to be effectively non-existent.
# Culinary use
Dawamesk, a spread or jam made in North Africa and containing hashish, almond paste, pistachio nuts, sugar, orange or tamarind peel, cloves and other various spices, occasionally included Spanish fly.
In Morocco and other parts of North Africa, a spice blend called Ras el hanout included cantharides in its list of ingredients at one time. However, the sale of Spanish fly in the Moroccan spice markets was banned in the 1990s.
# Notes
- ↑ From Greek lytta, rage and Latin vesica, blister.
- ↑ Other species of blister beetle used in apothecary are often called by the same name. Lytta vesicatoria is sometimes called Cantharis vesicatoria, but the genus Cantharis is in an unrelated family, Cantharidae.
- ↑ Template:Harv
- ↑ Template:Harv
- ↑ James, Peter (1995). Ancient Inventions. Ballantine Books. pp. p. 177. ISBN 0345401026.CS1 maint: Extra text (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}
- ↑ Template:Harv
- ↑ Template:Harv
- ↑ Template:Harv
- ↑ Template:Harv
- ↑ Template:Harv | Spanish fly
Template:Otheruses2
Template:Wikispecies
The Spanish fly is an emerald-green beetle in the family Meloidae, Lytta vesicatoria.[1][2] It is 15 mm to 22 mm long and 5 mm to 8 mm wide, and lives on plants in the families Caprifoliaceae and Oleaceae. The beetle contains up to 5% cantharidin which irritates animal tissues. The crushed powder of Spanish fly is of yellowish brown to brown-olive color with iridescent reflections, of disagreeable scent and bitter flavor.
Spanish fly, or cantharides as it is sometimes called, is often given to farm animals to incite them to mating.[3] The cantharides excreted in the urine irritate the urethral passages, causing inflammation in the genitals and subsequent priapism. For this reason, Spanish fly has been given to humans for purposes of seduction. It is dangerous since the amount required is minuscule and the difference between the effective dose and the harmful dose is quite narrow. Cantharides cause painful urination, fever, and sometimes bloody discharge. They can cause permanent damage to the kidneys and genitals.
# History
Its medical use dates back to descriptions from Hippocrates. Plasters made from wings of these beetles have been used to raise blisters. In ancient China, cantharides beetles were mixed with human dung, arsenic and wolfsbane to make the world's first recorded stink bomb.[4] It is also one of the world’s most well-known aphrodisiacs. In Roman times, Livia, the scheming wife of Augustus Caesar, would slip it into food hoping to inspire her guests to some indiscretion with which she could later blackmail them.[5] Henry IV (1050-1106) is known to have consumed Spanish fly at the risk of his health. In 1572, the famous French surgeon Ambroise Paré wrote an account of a man suffering from "the most frightful satyriasis" after having taken a potion composed of nettles and cantharides.[6] In the 1670s, Spanish fly was mixed with dried moles and bat's blood for a love charm made by the black magician La Voisin.[7] It was slipped into the food of Louis XIV to secure the king's lust for Madame de Montespan. In the 18th century cantharides became fashionable, known as pastilles Richelieu in France. Marquis de Sade is claimed to have given aniseed-flavored pastilles that were laced with Spanish fly to prostitutes at an orgy in 1772. He was sentenced to death for poisoning and sodomy, but later reprieved on appeal.
Also it was used as an abortifacient, stimulant (since one of its effects was producing insomnia and nervous agitation), and as a poison; in powder, mixed with the food, it could go unnoticed. Aqua toffana, or aquetta di Napoli, was one of the poisons associated with the Medicis. Thought to be a mixture of arsenic and cantharides, it was reportedly created by an Italian countess, Toffana. Four to six drops of this poison in water or wine was enough to deliver a painless death in a few hours.[8]
In order to determine if a death had taken place by the effects of Spanish fly they had to resort to the vesicación test. One of those test methods consisted of rubbing part of the internal organs of the deceased, dissolved in oil, on the shaved skin of a rabbit; the absorption of the cantharides and its blistering effect are such that they became visible on the skin of the rabbit.
In Santeria, catharides are used in incense.[9]
# Commercial products
Cantharides are illegal in the United States, except for use in animal husbandry and by licensed physicians for the topical treatment of certain types of warts. Some internet or mail order suppliers of sex stimulants advertise such products like "Herbal Spanish fly", "Mexican Spanish Fly", or "Spanish Fly Potion". Most of these products are simply cayenne pepper in capsules, sometimes blended with the powder of ginseng, kelp, ginger or gotu kola.[10] The products with the name "Spanische Fliege (Spanish fly)" that are available in Germany represent no danger with a normal application since they contain the active substance actually only in homeopathic dosage, diluted to be effectively non-existent.
# Culinary use
Dawamesk, a spread or jam made in North Africa and containing hashish, almond paste, pistachio nuts, sugar, orange or tamarind peel, cloves and other various spices, occasionally included Spanish fly.
In Morocco and other parts of North Africa, a spice blend called Ras el hanout included cantharides in its list of ingredients at one time. However, the sale of Spanish fly in the Moroccan spice markets was banned in the 1990s.
# Notes
- ↑ From Greek lytta, rage and Latin vesica, blister.
- ↑ Other species of blister beetle used in apothecary are often called by the same name. Lytta vesicatoria is sometimes called Cantharis vesicatoria, but the genus Cantharis is in an unrelated family, Cantharidae.
- ↑ Template:Harv
- ↑ Template:Harv
- ↑ James, Peter (1995). Ancient Inventions. Ballantine Books. pp. p. 177. ISBN 0345401026.CS1 maint: Extra text (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}
- ↑ Template:Harv
- ↑ Template:Harv
- ↑ Template:Harv
- ↑ Template:Harv
- ↑ Template:Harv | https://www.wikidoc.org/index.php/Spanish_fly | |
32c2d22d0ed0513865c1491523b3015670f378c1 | wikidoc | Spinal fMRI | Spinal fMRI
# Overview
Functional magnetic resonance imaging (fMRI) of the spinal cord (spinal fMRI) is an adaptation of the fMRI method that has been developed for use in the brain (1). Although the basic principles underlying the methods are the same, spinal fMRI requires a number of specific adaptations to accommodate the periodic motion of the spinal cord, the small cross-sectional dimensions (roughly 8 mm x 15 mm at the largest region), the length (~45 cm in adult humans), and the fact that the magnetic field that is used for MRI varies with position in the spinal cord because of magnetic susceptibility differences between bone and tissues. Spinal fMRI has been used to produce maps of neuronal activity at most levels of the spinal cord in response to various stimuli, such as touch, vibration, and thermal changes, and with motor tasks. Research applications of spinal fMRI to date include studies of normal sensory and motor function, and studies of the effects of trauma to the spinal cord (1-3) and multiple sclerosis (4). Two different data acquisition methods have been applied, one based on the established BOLD (blood-oxygen-level dependent) fMRI methods used in the brain, and the other based on SEEP (signal enhancement by extravascular water protons) contrast with essentially proton-density weighted spin-echo imaging (see MRI). The majority of the studies published to date are based on the SEEP contrast method. Methods demonstrated to overcome the challenges listed above include using a recording of the heart-beat to account for the related time course of spinal cord motion, acquiring image data with relatively high (~ 1-2 mm) spatial resolution to detect fine structural details, and acquiring images in thin contiguous sagittal slices to span a large extent of the spinal cord. Methods based on BOLD contrast have employed parallel imaging techniques to accelerate data acquisition, and imaging slices transverse to the spinal cord, in order to reduce the effects of spatial magnetic field distortions (5). Methods based on SEEP contrast have been developed specifically because they have low sensitivity to magnetic field distortions while maintaining sensitivity to changes in neuronal activity.
References
1. Stroman PW. Magnetic resonance imaging of neuronal function in the spinal cord: spinal FMRI. Clin Med Res 2005;3(3):146-156.
2. Stroman PW, Kornelsen J, Bergman A, Krause V, Ethans K, Malisza KL, Tomanek B. Noninvasive assessment of the injured human spinal cord by means of functional magnetic resonance imaging. Spinal Cord 2004;42(2):59-66.
3. Kornelsen J, Stroman PW. fMRI of the lumbar spinal cord during a lower limb motor task. Magn Reson Med 2004;52(2):411-414.
4. Agosta F, Valsasina P, Caputo D, Stroman PW, Filippi M. Tactile-associated recruitment of the cervical cord is altered in patients with multiple sclerosis. Neuroimage 2008;39(4):1542-1548.
5. Maieron M, Iannetti GD, Bodurka J, Tracey I, Bandettini PA, Porro CA. Functional responses in the human spinal cord during willed motor actions: evidence for side- and rate-dependent activity. J Neurosci 2007;27(15):4182-4190. | Spinal fMRI
# Overview
Functional magnetic resonance imaging (fMRI) of the spinal cord (spinal fMRI) is an adaptation of the fMRI method that has been developed for use in the brain (1). Although the basic principles underlying the methods are the same, spinal fMRI requires a number of specific adaptations to accommodate the periodic motion of the spinal cord, the small cross-sectional dimensions (roughly 8 mm x 15 mm at the largest region), the length (~45 cm in adult humans), and the fact that the magnetic field that is used for MRI varies with position in the spinal cord because of magnetic susceptibility differences between bone and tissues. Spinal fMRI has been used to produce maps of neuronal activity at most levels of the spinal cord in response to various stimuli, such as touch, vibration, and thermal changes, and with motor tasks. Research applications of spinal fMRI to date include studies of normal sensory and motor function, and studies of the effects of trauma to the spinal cord (1-3) and multiple sclerosis (4). Two different data acquisition methods have been applied, one based on the established BOLD (blood-oxygen-level dependent) fMRI methods used in the brain, and the other based on SEEP (signal enhancement by extravascular water protons) contrast with essentially proton-density weighted spin-echo imaging (see MRI). The majority of the studies published to date are based on the SEEP contrast method. Methods demonstrated to overcome the challenges listed above include using a recording of the heart-beat to account for the related time course of spinal cord motion, acquiring image data with relatively high (~ 1-2 mm) spatial resolution to detect fine structural details, and acquiring images in thin contiguous sagittal slices to span a large extent of the spinal cord. Methods based on BOLD contrast have employed parallel imaging techniques to accelerate data acquisition, and imaging slices transverse to the spinal cord, in order to reduce the effects of spatial magnetic field distortions (5). Methods based on SEEP contrast have been developed specifically because they have low sensitivity to magnetic field distortions while maintaining sensitivity to changes in neuronal activity.
References
1. Stroman PW. Magnetic resonance imaging of neuronal function in the spinal cord: spinal FMRI. Clin Med Res 2005;3(3):146-156.
2. Stroman PW, Kornelsen J, Bergman A, Krause V, Ethans K, Malisza KL, Tomanek B. Noninvasive assessment of the injured human spinal cord by means of functional magnetic resonance imaging. Spinal Cord 2004;42(2):59-66.
3. Kornelsen J, Stroman PW. fMRI of the lumbar spinal cord during a lower limb motor task. Magn Reson Med 2004;52(2):411-414.
4. Agosta F, Valsasina P, Caputo D, Stroman PW, Filippi M. Tactile-associated recruitment of the cervical cord is altered in patients with multiple sclerosis. Neuroimage 2008;39(4):1542-1548.
5. Maieron M, Iannetti GD, Bodurka J, Tracey I, Bandettini PA, Porro CA. Functional responses in the human spinal cord during willed motor actions: evidence for side- and rate-dependent activity. J Neurosci 2007;27(15):4182-4190.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Spinal_fMRI | |
c9d6cf2b05a89638e96f368545b64eb625d0ff76 | wikidoc | Spirobolida | Spirobolida
The order Spirobolida is a species-rich (more than 900 described species) and important group of millipedes. Most spirobolids live in the tropics, and like the majority of millipedes, members of the order are all detritivores. Species are often large and conspicuous, and at least in the United States, are often used as classroom representatives for the class Diplopoda. Taxonomically, it is a relatively neglected group with only two revised families, and both revisions dating back more than 40 years.
Spirobolida is one of 11 helminthomorph diplopod orders. Helminthomorphs are typified by the modification of at least one pair of legs on the seventh segment of males into secondary sperm-transfer organs called gonopods. Gonopod morphology is usually species specific and of great taxonomic importance. Much of helminthomorph taxonomy is based almost entirely on gonopod structure (especially at lower taxonomic levels). Female sexual organs (cyphopods) are relatively understudied and underused in millipede taxonomy, with the unfortunate result that female specimens are often unidentifiable to species level.
Spirobolids have both pairs on legs of the seventh segment modified into gonopods, which are thus divided into an anterior pair, the coleopods, and a posterior pair, the phallopods. It is the phallopods that assume the most active role during sperm transfer. The coleopods seem to have a mostly protective function and usually envelope the phallopods. It is the phallopods that display the highest level of species specificity. Development in these animals is gradual and gonopods are first formed during several nymphal stages and molts preceding the final adult form. Growth, and therefore moulting, continues through adulthood, and their life span is typically several years.
# Species
- Narceus americanus | Spirobolida
The order Spirobolida is a species-rich (more than 900 described species) and important group of millipedes. Most spirobolids live in the tropics, and like the majority of millipedes, members of the order are all detritivores. Species are often large and conspicuous, and at least in the United States, are often used as classroom representatives for the class Diplopoda. Taxonomically, it is a relatively neglected group with only two revised families, and both revisions dating back more than 40 years.
Spirobolida is one of 11 helminthomorph diplopod orders. Helminthomorphs are typified by the modification of at least one pair of legs on the seventh segment of males into secondary sperm-transfer organs called gonopods. Gonopod morphology is usually species specific and of great taxonomic importance. Much of helminthomorph taxonomy is based almost entirely on gonopod structure (especially at lower taxonomic levels). Female sexual organs (cyphopods) are relatively understudied and underused in millipede taxonomy, with the unfortunate result that female specimens are often unidentifiable to species level.
Spirobolids have both pairs on legs of the seventh segment modified into gonopods, which are thus divided into an anterior pair, the coleopods, and a posterior pair, the phallopods. It is the phallopods that assume the most active role during sperm transfer. The coleopods seem to have a mostly protective function and usually envelope the phallopods. It is the phallopods that display the highest level of species specificity. Development in these animals is gradual and gonopods are first formed during several nymphal stages and molts preceding the final adult form. Growth, and therefore moulting, continues through adulthood, and their life span is typically several years.
# Species
- Narceus americanus
Template:WS | https://www.wikidoc.org/index.php/Spirobolida | |
9d99763d3ee9dde1ed7719fde681a3e1ab43d67d | wikidoc | Spirochaete | Spirochaete
# Overview
Spirochetes is a phylum of distinctive Gram-negative bacteria, which have long, helically coiled cells. Spirochetes are chemoheterotrophic in nature, with lengths between 5 and 250 µm and diameters around 0.1-0.6 µm.
Spriochetes are distinguished from other bacterial phyla by the presence of flagella, sometimes called axial filaments, running lengthwise between the cell membrane and outer membrane. These cause a twisting motion which allows the spirochaete to move about.
The spirochaetes are divided into three families (Brachyspiraceae, Leptospiraceae, and Spirochaetaceae), all placed within a single order (Spirochaetales).
- Leptospira species, which causes leptospirosis
- Borrelia burgdorferi, which causes Lyme disease
- Borrelia recurrentis, which causes relapsing fever
- Treponema pallidum, which causes syphilis
Most spirochaetes are free-living and anaerobic, but there are numerous exceptions, including the above.
Cavalier-Smith has postulated that the Spirochaetes belong in a larger clade called Gracilicutes.
# Historical
Salvarsan, the first antibiotic in medical history, was effective against spirochaetes only and was primarily used to cure syphilis.
It has been suggested by biologist Lynn Margulis that eukaryotic flagella were derived from symbiotic spirochaetes, but few biologists accept this, as there is no close structural similarity between the two.
# See Also
- Flagellum
- Treponema pallidum
- Lyme disease microbiology
- Borrelia
- Bacteriology
- Prokaryote | Spirochaete
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Spirochetes is a phylum of distinctive Gram-negative bacteria, which have long, helically coiled cells.[1] Spirochetes are chemoheterotrophic in nature, with lengths between 5 and 250 µm and diameters around 0.1-0.6 µm.[citation needed]
Spriochetes are distinguished from other bacterial phyla by the presence of flagella, sometimes called axial filaments, running lengthwise between the cell membrane and outer membrane. These cause a twisting motion which allows the spirochaete to move about.
The spirochaetes are divided into three families (Brachyspiraceae, Leptospiraceae, and Spirochaetaceae), all placed within a single order (Spirochaetales).
- Leptospira species, which causes leptospirosis[2]
- Borrelia burgdorferi, which causes Lyme disease
- Borrelia recurrentis, which causes relapsing fever[3]
- Treponema pallidum, which causes syphilis
Most spirochaetes are free-living and anaerobic, but there are numerous exceptions, including the above.
Cavalier-Smith has postulated that the Spirochaetes belong in a larger clade called Gracilicutes.[4]
# Historical
Salvarsan, the first antibiotic in medical history, was effective against spirochaetes only and was primarily used to cure syphilis.
It has been suggested by biologist Lynn Margulis that eukaryotic flagella were derived from symbiotic spirochaetes, but few biologists accept this, as there is no close structural similarity between the two.
# See Also
- Flagellum
- Treponema pallidum
- Lyme disease microbiology
- Borrelia
- Bacteriology
- Prokaryote | https://www.wikidoc.org/index.php/Spirochaeta | |
1f2914893f83f8dd2a1738bfa9b22f7444a6846d | wikidoc | Spirostomum | Spirostomum
Spirostomum is a member of the protist kingdom. It is an animal-like protist, or protozoan which feeds on bacteria. It is found in pond water. Spirostomum is a Ciliate, which use cilia to move through water.
Spirostomum is an unusual protozoan.
It is large for a protist. It can grow up to .17 in (3 mm) which is large enough to be seen with the naked eye.
Though a unicellular organism, it has multiple nuclei. Also, Spirostomum can contract it's body to 1/4 of it's length in 6-8 millisec which is the fastest contraction known in any living cell. | Spirostomum
Spirostomum is a member of the protist kingdom. It is an animal-like protist, or protozoan which feeds on bacteria. It is found in pond water. Spirostomum is a Ciliate, which use cilia to move through water.
Spirostomum is an unusual protozoan.
It is large for a protist. It can grow up to .17 in (3 mm) which is large enough to be seen with the naked eye.
Though a unicellular organism, it has multiple nuclei. Also, Spirostomum can contract it's body to 1/4 of it's length in 6-8 millisec which is the fastest contraction known in any living cell.[1] | https://www.wikidoc.org/index.php/Spirostomum | |
d8e91a5dcdffa6590d4c5fbc0a0db1afa1ef597a | wikidoc | Splenectomy | Splenectomy
A splenectomy is a procedure that involves the removal of the spleen by operative means.
# Indications
The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the destruction of old red blood cells and platelets, and the detection and fight against certain bacteria. It's also known to create new blood cells. The spleen is enlarged in a variety of conditions such as malaria, mononucleosis and most commonly in "cancers" of the lymphatics, such as lymphomas or the leukemia.
It is removed under the following circumstances:
- When it becomes very large such that it becomes destructive to platelets/red cells
- For diagnosing certain lymphomas
- When platelets are destroyed in the spleen as a result of an auto-immune process (see also idiopathic thrombocytopenic purpura)
- When the spleen bleeds following physical trauma
- Following spontaneous rupture
- For long-term treatment of congenital erythropoietic porphyria (CEP) if severe hemolytic anemia develops
The classical cause of traumatic damage to the spleen is a blow to the abdomen during a sporting event. In cases where the spleen is enlarged due to illness (mononucleosis), the smallest things such as leaning over a counter or straining at stool can cause it to rupture.
# Procedure
Vaccination for pneumococcus, H. influenza and meningococcus should be given pre-operatively if possible.
In general, spleens are removed by laparoscopy (minimal access surgery) when the spleen is not too large and when the procedure is elective. It is performed by open surgery for trauma or large spleens. Both methods are major surgeries, and are performed under general anesthesia. The spleen is located and disconnected from its arteries. The ligaments holding the spleen in place are dissected and the spleen is removed. When indicated a drain is left in place and the incision(s) is closed. If necessary, tissue samples are sent to a laboratory for analysis.
# Side effects
Because splenectomy causes an increased risk of overwhelming sepsis due to encapsulated organisms (such as S. pneumoniae and Haemophilus influenzae) the patient should be immunized, if possible, prior to removal of the spleen; see asplenia. An increase in blood leukocytes can occur following a splenectomy.
Failure to do so later puts the patient at risk of overwhelming post-splenectomy infection (OPSI), a potentially rapidly fatal septicaemia. These bacteria often cause a sore throat under normal circumstances but after splenectomy, when infecting bacteria cannot be adequately opsonized, the infection becomes more severe.
Following splenectomy, the platelet count may rise to high levels in blood leading to an increased risk of clot formation and death. | Splenectomy
Template:Interventions infobox
A splenectomy is a procedure that involves the removal of the spleen by operative means.
# Indications
The spleen, similar in structure to a large lymph node, acts as a blood filter. Current knowledge of its purpose includes the destruction of old red blood cells and platelets, and the detection and fight against certain bacteria. It's also known to create new blood cells. The spleen is enlarged in a variety of conditions such as malaria, mononucleosis and most commonly in "cancers" of the lymphatics, such as lymphomas or the leukemia.
It is removed under the following circumstances:
- When it becomes very large such that it becomes destructive to platelets/red cells
- For diagnosing certain lymphomas
- When platelets are destroyed in the spleen as a result of an auto-immune process (see also idiopathic thrombocytopenic purpura)
- When the spleen bleeds following physical trauma
- Following spontaneous rupture
- For long-term treatment of congenital erythropoietic porphyria (CEP) if severe hemolytic anemia develops[1]
The classical cause of traumatic damage to the spleen is a blow to the abdomen during a sporting event. In cases where the spleen is enlarged due to illness (mononucleosis), the smallest things such as leaning over a counter or straining at stool can cause it to rupture.
# Procedure
Vaccination for pneumococcus, H. influenza and meningococcus should be given pre-operatively if possible.
In general, spleens are removed by laparoscopy (minimal access surgery) when the spleen is not too large and when the procedure is elective. It is performed by open surgery for trauma or large spleens. Both methods are major surgeries, and are performed under general anesthesia. The spleen is located and disconnected from its arteries. The ligaments holding the spleen in place are dissected and the spleen is removed. When indicated a drain is left in place and the incision(s) is closed. If necessary, tissue samples are sent to a laboratory for analysis.
# Side effects
Because splenectomy causes an increased risk of overwhelming sepsis due to encapsulated organisms (such as S. pneumoniae and Haemophilus influenzae) the patient should be immunized, if possible, prior to removal of the spleen; see asplenia. An increase in blood leukocytes can occur following a splenectomy.[2][3]
Failure to do so later puts the patient at risk of overwhelming post-splenectomy infection (OPSI), a potentially rapidly fatal septicaemia. These bacteria often cause a sore throat under normal circumstances but after splenectomy, when infecting bacteria cannot be adequately opsonized, the infection becomes more severe.
Following splenectomy, the platelet count may rise to high levels in blood leading to an increased risk of clot formation and death. | https://www.wikidoc.org/index.php/Spleenectomy | |
8208e6e02e234de46a17a1ed8d1a04940eeccdb9 | wikidoc | Square root | Square root
In mathematics, a square root of a number x is a number r such that r2 = x, or in words, a number r whose square (the result of multiplying the number by itself) is x. Every non-negative real number x has a unique non-negative square root, called the principal square root and denoted with a radical symbol as √x. For example, the principal square root of 9 is 3, denoted √9 = 3, because 32 = 3 × 3 = 9. If otherwise unqualified, "the square root" of a number refers to the principal square root: the square root of 2 is approximately 1.4142.
Square roots often arise when solving quadratic equations, or equations of the form ax2 + bx + c = 0, due to the variable x being squared.
Every positive number x has two square roots. One of them is √x, which is positive, and the other −√x, which is negative. Together, these two roots are denoted ±√x. Square roots of negative numbers can be discussed within the framework of complex numbers. Square roots of objects other than numbers can also be defined.
Square roots of integers that are not perfect squares are always irrational numbers: numbers not expressible as a ratio of two integers. For example, √2 cannot be written exactly as m/n, where n and m are integers. Nonetheless, it is exactly the length of the diagonal of a square with side length 1. This has been known since ancient times, with the discovery that √2 is irrational attributed to Hipparchus, a disciple of Pythagoras. (See square root of 2 for proofs of the irrationality of this number.)
# Properties
The principal square root function f(x) = √x (usually just referred to as the "square root function") is a function which maps the set of non-negative real numbers R+ ∪ {0} onto itself, and, like all functions, always returns a unique value. The square root function also maps rational numbers into algebraic numbers (a superset of the rational numbers); √x is rational if and only if x is a rational number which can be represented as a ratio of two perfect squares. In geometrical terms, the square root function maps the area of a square to its side length.
- For all real numbers x,
\sqrt{x^2} = \left|x\right| =
\begin{cases}
\end{cases}
(see absolute value)
- For all non-negative real numbers x and y,
- The square root function is continuous for all non-negative x and differentiable for all positive x. Its derivative is given by
- The Taylor series of √1 + x about x = 0 converges for | x | < 1 and is given by
# Computation
Many methods of calculating square roots exist today, some meant to be done by hand and some meant to be done by machine.
Many, but not all pocket calculators have a square root key. Computer spreadsheets and other software are also frequently used to calculate square roots. Computer software programs typically implement good routines to compute the exponential function and the natural logarithm or logarithm, and then compute the square root of x using the identity
The same identity is exploited when computing square roots with logarithm tables or slide rules.
The most common method of square root calculation by hand is known as the "Babylonian method". It involves a simple algorithm, which results in a number closer to the actual square root each time it is repeated. To find r, the square root of a real number x:
- Start with an arbitrary positive start value r (the closer to the square root of x, the better).
- Replace r by the average between r and x/r. (It is sufficient to take an approximate value of the average, not too close to the previous value of r and x/r in order to ensure convergence.)
- Repeat step 2 until r and x/r are as close as desired.
The best known time complexity for computing a square root with n digits of precision is the same as that for multiplying two n-digit numbers.
# Square roots of negative and complex numbers
The square of any positive or negative number is positive, and the square of 0 is 0. Therefore, no negative number can have a real square root. However, it is possible to work with a larger set of numbers, called the complex numbers, that does contain solutions to the square root of a negative number. This is done by introducing a new number, denoted by i (sometimes j, especially in the context of electricity) and called the imaginary unit, which is defined such that i2 = −1. Using this notation, we can think of i as the square root of −1, but notice that we also have (−i)2 = i2 = −1 and so −i is also a square root of −1. Similarly to the real numbers, we say the principal square root of −1 is i, or more generally, if x is any positive number, then the principal square root of −x is
because
By the argument given above, i can be neither positive nor negative. This creates a problem: for the complex number z, we cannot define √z to be the "positive" square root of z.
For every non-zero complex number z there exist precisely two numbers w such that w2 = z. For example, the square roots of i are:
and
The usual definition of √z is by introducing the following branch cut: if z = r eiφ is represented in polar coordinates with −π < φ ≤ π, then we set the principal value to
Thus defined, the square root function is holomorphic everywhere except on the non-positive real numbers (where it isn't even continuous). The above Taylor series for √1 + x remains valid for complex numbers x with | x | < 1.
When the number is in rectangular form the following formula can be used for the principal value:
where
is the absolute value or modulus of the complex number, unless x = −r and y = 0. Notice that the sign of the imaginary part of the root is the same as the sign of the imaginary part of the original number. The real part of the principal value is always non-negative.
Note that because of the discontinuous nature of the square root function in the complex plane, the law √zw = √z√w is in general not true. (Equivalently, the problem occurs because of the freedom in the choice of branch. The chosen branch may or may not yield the equality; in fact, the choice of branch for the square root need not contain the value of √z√w at all, leading to the equality's failure. A similar problem appears with the complex logarithm and the relation log z + log w = log(zw).) Wrongly assuming this law underlies several faulty "proofs", for instance the following one showing that −1 = 1:
The third equality cannot be justified (see invalid proof). It can be made to hold by changing the meaning of √ so that this no longer represents the principal square root but selects a branch for the square root that contains \sqrt{-1} \cdot \sqrt{-1}. The left hand side becomes either
if the branch includes +i or
if the branch includes −i, while the right hand side becomes
where the last equality, \sqrt{1}=-1, is a consequence of the choice of branch in the redefinition of √.
# Square roots of matrices and operators
If A is a positive-definite matrix or operator, then there exists precisely one positive definite matrix or operator B with B2 = A; we then define √A = B.
More generally, to every normal matrix or operator A there exist normal operators B such that B2 = A. In general, there are several such operators B for every A and the square root function cannot be defined for normal operators in a satisfactory manner. Positive definite operators are akin to positive real numbers, and normal operators are akin to complex numbers.
# Principal square roots of the first 20 positive integers
## As decimal expansions
The square roots of the perfect squares (1, 4, 9, and 16) are integers. In all other cases, the square roots are irrational numbers, and therefore their decimal representations are non-repeating decimals.
## As periodic continued fractions
One of the most intriguing results from the study of irrational numbers as continued fractions was obtained by Joseph Louis Lagrange circa 1780. Lagrange found that the representation of the square root of any non-square positive integer as a continued fraction is periodic. That is, a certain pattern of partial denominators repeats indefinitely in the continued fraction. In a sense these square roots are the very simplest irrational numbers, because they can be represented with a simple repeating pattern of digits.
The square bracket notation used above is a sort of mathematical shorthand to conserve space. Written in more traditional notation the simple continued fraction for the square root of 11 – – looks like this:
\sqrt{11} = 3 + \cfrac{1}{3 + \cfrac{1}{6 + \cfrac{1}{3 + \cfrac{1}{6 + \cfrac{1}{\ddots}}}}}\,
where the two-digit pattern {3, 6} repeats over and over and over again in the partial denominators.
# Geometric construction of the square root
A square root can be constructed with a compass and straightedge. In his Elements, Euclid (fl. 300 BC) gave the construction of the geometric mean of two quantities in two different places: Proposition II.14 and Proposition VI.13. Since the geometric mean of a and b is √ab, one can construct √a simply by taking b = 1.
The construction is also given by Descartes in his La Géométrie, see figure 2 on page 2. However, Descartes made no claim to originality and his audience would have been quite familiar with Euclid.
Another method of geometric construction uses right triangles and induction: √1 can, of course, be constructed, and once √x has been constructed, the right triangle with 1 and √x for its legs has a hypotenuse of √x + 1.
# History
The Rhind Mathematical Papyrus is a copy from 1650 BC of an even earlier work and shows us how the Egyptians extracted square roots.
In Ancient India, the knowledge of theoretical and applied aspects of square and square root was at least as old as the Sulba Sutras, dated around 800-500 B.C. (possibly much earlier). A method for finding very good approximations to the square roots of 2 and 3 are given in the Baudhayana Sulba Sutra. Aryabhata in the Aryabhatiya (section 2.4), has given a method for finding the square root of numbers having many digits.
D.E. Smith in History of Mathematics, says, about the existing situation in Europe: "In Europe these methods (for finding out the square and square root) did not appear before Cataneo (1546). He gave the method of Aryabhata for determining the square root".
# Notes
- ↑ Anglin, W.S. (1994). Mathematics: A Concise History and Philosophy. New York: Springer-Verlag.
- ↑ Joseph, ch.8.
- ↑ Smith, p. 148. | Square root
In mathematics, a square root of a number x is a number r such that r2 = x, or in words, a number r whose square (the result of multiplying the number by itself) is x. Every non-negative real number x has a unique non-negative square root, called the principal square root and denoted with a radical symbol as √x. For example, the principal square root of 9 is 3, denoted √9 = 3, because 32 = 3 × 3 = 9. If otherwise unqualified, "the square root" of a number refers to the principal square root: the square root of 2 is approximately 1.4142.
Square roots often arise when solving quadratic equations, or equations of the form ax2 + bx + c = 0, due to the variable x being squared.
Every positive number x has two square roots. One of them is √x, which is positive, and the other −√x, which is negative. Together, these two roots are denoted ±√x. Square roots of negative numbers can be discussed within the framework of complex numbers. Square roots of objects other than numbers can also be defined.
Square roots of integers that are not perfect squares are always irrational numbers: numbers not expressible as a ratio of two integers. For example, √2 cannot be written exactly as m/n, where n and m are integers. Nonetheless, it is exactly the length of the diagonal of a square with side length 1. This has been known since ancient times, with the discovery that √2 is irrational attributed to Hipparchus, a disciple of Pythagoras. (See square root of 2 for proofs of the irrationality of this number.)
# Properties
The principal square root function f(x) = √x (usually just referred to as the "square root function") is a function which maps the set of non-negative real numbers R+ ∪ {0} onto itself, and, like all functions, always returns a unique value. The square root function also maps rational numbers into algebraic numbers (a superset of the rational numbers); √x is rational if and only if x is a rational number which can be represented as a ratio of two perfect squares. In geometrical terms, the square root function maps the area of a square to its side length.
- For all real numbers x,
\sqrt{x^2} = \left|x\right| =
\begin{cases}
\end{cases}
</math> (see absolute value)
- For all non-negative real numbers x and y,
- The square root function is continuous for all non-negative x and differentiable for all positive x. Its derivative is given by
- The Taylor series of √1 + x about x = 0 converges for | x | < 1 and is given by
# Computation
Many methods of calculating square roots exist today, some meant to be done by hand and some meant to be done by machine.
Many, but not all pocket calculators have a square root key. Computer spreadsheets and other software are also frequently used to calculate square roots. Computer software programs typically implement good routines to compute the exponential function and the natural logarithm or logarithm, and then compute the square root of x using the identity
The same identity is exploited when computing square roots with logarithm tables or slide rules.
The most common method of square root calculation by hand is known as the "Babylonian method". It involves a simple algorithm, which results in a number closer to the actual square root each time it is repeated. To find r, the square root of a real number x:
- Start with an arbitrary positive start value r (the closer to the square root of x, the better).
- Replace r by the average between r and x/r. (It is sufficient to take an approximate value of the average, not too close to the previous value of r and x/r in order to ensure convergence.)
- Repeat step 2 until r and x/r are as close as desired.
The best known time complexity for computing a square root with n digits of precision is the same as that for multiplying two n-digit numbers.
# Square roots of negative and complex numbers
Template:Seealso
The square of any positive or negative number is positive, and the square of 0 is 0. Therefore, no negative number can have a real square root. However, it is possible to work with a larger set of numbers, called the complex numbers, that does contain solutions to the square root of a negative number. This is done by introducing a new number, denoted by i (sometimes j, especially in the context of electricity) and called the imaginary unit, which is defined such that i2 = −1. Using this notation, we can think of i as the square root of −1, but notice that we also have (−i)2 = i2 = −1 and so −i is also a square root of −1. Similarly to the real numbers, we say the principal square root of −1 is i, or more generally, if x is any positive number, then the principal square root of −x is
because
By the argument given above, i can be neither positive nor negative. This creates a problem: for the complex number z, we cannot define √z to be the "positive" square root of z.
For every non-zero complex number z there exist precisely two numbers w such that w2 = z. For example, the square roots of i are:
and
The usual definition of √z is by introducing the following branch cut: if z = r eiφ is represented in polar coordinates with −π < φ ≤ π, then we set the principal value to
Thus defined, the square root function is holomorphic everywhere except on the non-positive real numbers (where it isn't even continuous). The above Taylor series for √1 + x remains valid for complex numbers x with | x | < 1.
When the number is in rectangular form the following formula can be used for the principal value:
where
is the absolute value or modulus of the complex number, unless x = −r and y = 0. Notice that the sign of the imaginary part of the root is the same as the sign of the imaginary part of the original number. The real part of the principal value is always non-negative.
Note that because of the discontinuous nature of the square root function in the complex plane, the law √zw = √z√w is in general not true. (Equivalently, the problem occurs because of the freedom in the choice of branch. The chosen branch may or may not yield the equality; in fact, the choice of branch for the square root need not contain the value of √z√w at all, leading to the equality's failure. A similar problem appears with the complex logarithm and the relation log z + log w = log(zw).) Wrongly assuming this law underlies several faulty "proofs", for instance the following one showing that −1 = 1:
The third equality cannot be justified (see invalid proof). It can be made to hold by changing the meaning of √ so that this no longer represents the principal square root but selects a branch for the square root that contains <math>\sqrt{-1} \cdot \sqrt{-1}</math>. The left hand side becomes either
if the branch includes +i or
if the branch includes −i, while the right hand side becomes
where the last equality, <math>\sqrt{1}=-1</math>, is a consequence of the choice of branch in the redefinition of √.
# Square roots of matrices and operators
If A is a positive-definite matrix or operator, then there exists precisely one positive definite matrix or operator B with B2 = A; we then define √A = B.
More generally, to every normal matrix or operator A there exist normal operators B such that B2 = A. In general, there are several such operators B for every A and the square root function cannot be defined for normal operators in a satisfactory manner. Positive definite operators are akin to positive real numbers, and normal operators are akin to complex numbers.
# Principal square roots of the first 20 positive integers
## As decimal expansions
The square roots of the perfect squares (1, 4, 9, and 16) are integers. In all other cases, the square roots are irrational numbers, and therefore their decimal representations are non-repeating decimals.
## As periodic continued fractions
One of the most intriguing results from the study of irrational numbers as continued fractions was obtained by Joseph Louis Lagrange circa 1780. Lagrange found that the representation of the square root of any non-square positive integer as a continued fraction is periodic. That is, a certain pattern of partial denominators repeats indefinitely in the continued fraction. In a sense these square roots are the very simplest irrational numbers, because they can be represented with a simple repeating pattern of digits.
The square bracket notation used above is a sort of mathematical shorthand to conserve space. Written in more traditional notation the simple continued fraction for the square root of 11 – [3; 3, 6, 3, 6, ...] – looks like this:
\sqrt{11} = 3 + \cfrac{1}{3 + \cfrac{1}{6 + \cfrac{1}{3 + \cfrac{1}{6 + \cfrac{1}{\ddots}}}}}\,
</math>
where the two-digit pattern {3, 6} repeats over and over and over again in the partial denominators.
# Geometric construction of the square root
A square root can be constructed with a compass and straightedge. In his Elements, Euclid (fl. 300 BC) gave the construction of the geometric mean of two quantities in two different places: Proposition II.14 and Proposition VI.13. Since the geometric mean of a and b is √ab, one can construct √a simply by taking b = 1.
The construction is also given by Descartes in his La Géométrie, see figure 2 on page 2. However, Descartes made no claim to originality and his audience would have been quite familiar with Euclid.
Another method of geometric construction uses right triangles and induction: √1 can, of course, be constructed, and once √x has been constructed, the right triangle with 1 and √x for its legs has a hypotenuse of √x + 1.
# History
The Rhind Mathematical Papyrus is a copy from 1650 BC of an even earlier work and shows us how the Egyptians extracted square roots.[1]
In Ancient India, the knowledge of theoretical and applied aspects of square and square root was at least as old as the Sulba Sutras, dated around 800-500 B.C. (possibly much earlier). A method for finding very good approximations to the square roots of 2 and 3 are given in the Baudhayana Sulba Sutra.[2] Aryabhata in the Aryabhatiya (section 2.4), has given a method for finding the square root of numbers having many digits.
D.E. Smith in History of Mathematics, says, about the existing situation in Europe: "In Europe these methods (for finding out the square and square root) did not appear before Cataneo (1546). He gave the method of Aryabhata for determining the square root".[3]
# Notes
- ↑ Anglin, W.S. (1994). Mathematics: A Concise History and Philosophy. New York: Springer-Verlag.
- ↑ Joseph, ch.8.
- ↑ Smith, p. 148. | https://www.wikidoc.org/index.php/Square_root | |
e29117d5cd347f6e282ce645a57b7226908970fb | wikidoc | Staple food | Staple food
A staple food is a food that forms the basis of a traditional diet. Staple foods vary from place to place, but are typically inexpensive starchy foods of vegetable origin that are high in food energy (Calories) and carbohydrate and that can be stored for use throughout the year. The staple food of a specific cuisine may commonly be served as part of every meal, and its name may be used synonymously with "food" in some contexts, such as the reference to "our daily bread" in The Lord's Prayer, and a common greeting of "Have you eaten rice?" denoting "How are you?" in certain cultures.
Most staple foods derive either from cereals such as wheat, barley, rye, maize, or rice, or starchy root vegetables such as potatoes, yams, taro, and cassava. Other staple foods include pulses (dried legumes), sago (derived from the pith of the sago palm tree), and fruits such as breadfruit and plantains.
Rice is most commonly eaten as cooked entire grains, but most other cereals are milled into flour or meal which is used to make bread; noodles or other pasta; and porridges and "mushes" such as polenta or mealie pap. Mashed root vegetables can be used to make similar porridge-like dishes, including poi and fufu. Pulses (particularly chickpeas) and starchy root vegetables, such as Canna, can also be made into flour.
Although nutritious, staple foods generally do not by themselves provide a full range of nutrients, so other foods need to be added to the diet to prevent malnutrition. For example, the deficiency disease pellagra is associated with a diet consisting primarily of maize, and beriberi with a diet of white (i.e. refined) rice.
It has been hypothesized that some staple foods may act as a Giffen good in conditions of extreme poverty. This was first noted by Robert Giffen who argued that potato demand actually rose during the Great Irish Famine (1845-1849). While theoretically possible, this is a controversial view among economists as studies have failed to find much evidence of Giffen good behaviour in actual markets. | Staple food
A staple food is a food that forms the basis of a traditional diet.[1] Staple foods vary from place to place, but are typically inexpensive starchy foods of vegetable origin that are high in food energy (Calories) and carbohydrate and that can be stored for use throughout the year. The staple food of a specific cuisine may commonly be served as part of every meal, and its name may be used synonymously with "food" in some contexts, such as the reference to "our daily bread" in The Lord's Prayer, and a common greeting of "Have you eaten rice?" denoting "How are you?" in certain cultures.
Most staple foods derive either from cereals such as wheat, barley, rye, maize, or rice, or starchy root vegetables such as potatoes, yams, taro, and cassava.[2] Other staple foods include pulses (dried legumes), sago (derived from the pith of the sago palm tree), and fruits such as breadfruit and plantains.[3]
Rice is most commonly eaten as cooked entire grains, but most other cereals are milled into flour or meal which is used to make bread; noodles or other pasta; and porridges and "mushes" such as polenta or mealie pap. Mashed root vegetables can be used to make similar porridge-like dishes, including poi and fufu. Pulses (particularly chickpeas) and starchy root vegetables, such as Canna, can also be made into flour.
Although nutritious, staple foods generally do not by themselves provide a full range of nutrients, so other foods need to be added to the diet to prevent malnutrition.[1] For example, the deficiency disease pellagra is associated with a diet consisting primarily of maize, and beriberi with a diet of white (i.e. refined) rice.[4]
It has been hypothesized that some staple foods may act as a Giffen good in conditions of extreme poverty. This was first noted by Robert Giffen who argued that potato demand actually rose during the Great Irish Famine (1845-1849). While theoretically possible, this is a controversial view among economists as studies have failed to find much evidence of Giffen good behaviour in actual markets.[5] | https://www.wikidoc.org/index.php/Staple_food | |
73c70ef8447617b579e4c916a63163187bfd0590 | wikidoc | Stereoscopy | Stereoscopy
Stereoscopy, stereoscopic imaging or 3-D (three-dimensional) imaging is any technique capable of recording three-dimensional visual information or creating the illusion of depth in an image. The illusion of depth in a photograph, movie, or other two-dimensional image is created by presenting a slightly different image to each eye. Many 3D displays use this method to convey images. It was first invented by Sir Charles Wheatstone in 1840. Stereoscopy is used in photogrammetry and also for entertainment through the production of stereograms. Stereoscopy is useful in viewing images rendered from large multi-dimensional data sets such as are produced by experimental data. Modern industrial three dimensional photography may use 3D scanners to detect and record 3 dimensional information. The three-dimensional depth information can be reconstructed from two images using a computer by corresponding the pixels in the left and right images. Solving the Correspondence problem in the field of Computer Vision aims to create meaningful depth information from two images.
Traditional stereoscopic photography consists of creating a 3-D illusion starting from a pair of 2-D images. The easiest way to create depth perception in the brain is to provide the eyes of the viewer with two different images, representing two perspectives of the same object, with a minor deviation similar to the perspectives that both eyes naturally receive in binocular vision.
If eyestrain and distortion are to be avoided, each of the two 2-D images preferably should be presented to each eye of the viewer so that any object at infinite distance seen by the viewer should be perceived by that eye while it is oriented straight ahead, the viewer's eyes being neither crossed nor diverging. When the picture contains no object at infinite distance, such as a horizon or a cloud, the pictures should be spaced correspondingly closer together.
# Side-by-side
## Characteristics
Little or no additional image processing is required. Under some circumstances, such as when a pair of images is presented for crossed or diverged eye viewing, no device or additional optical equipment is needed.
The principal advantages of side-by-side viewers is that there is no diminution of brightness so images may be presented at very high resolution and in full spectrum color. The ghosting associated
with polarized projection or when color filtering is used is totally eliminated. The images are
discretely presented to the eyes and visual center of the brain, with no co-mingling of the views.
The recent advent of wider HD and computer flat screens has made wider 3D digital images practical
in this side by side mode, which hitherto has been used mainly with paired photos or in print form.
## Stereographic cards and the stereoscope
Two separate images are printed side-by-side. When viewed without a stereoscopic viewer the user is required to force his eyes either to cross, or to diverge, so that the two images appear to be three. Then as each eye sees a different image, the effect of depth is achieved in the central image of the three.
The stereoscope offers several advantages:
- Using positive curvature (magnifying) lenses, the focus point of the image is changed from its short distance (about 30 to 40 cm) to a virtual distance at infinity. This allows the focus of the eyes to be consistent with the parallel lines of sight, greatly reducing eye strain.
- The card image is magnified, offering a wider field of view and the ability to examine the detail of the photograph.
- The viewer provides a partition between the images, avoiding a potential distraction to the user.
Stereograms cards are frequently used by orthoptists and vision therapists in the treatment of many binocular vision and accommodative disorders.
## Cross converged viewing, with new "masking" glasses
By exchanging the right and left views, and the opposite eye converged to the shifted images, it is possible to obtain a true color 3-D effect with some effort, without glasses or a viewer. Very recently, low cost glasses became available to aid the viewer in cross convergence viewing. An unusual effect of these optical glasses is to substantially widen the field of view to include a part of the peripheral area not visible to both eyes. There is a wrap-around effect produced, without the ghosting and the depth perspective can be greatly deepened. These new glasses provide acrylic lenses, plastic frames, that integrate a set of adjustable masking elements, that channel the view to only one image per eye. This allows full use of the screen width in the way that live vision treats stereo. The cross view image can easily fill any screen including 16 by 9 HDTV screens, working like a mirror to allow a dual perspective & wider view, as the images are mentally processed. Several non-commercial demonstration sites, such as bymal.com are showing extended 3D, sound, perfect color slide-shows, of subjects such as the Renaissance Pleasure Faire. They can be viewed with the glasses or without by masking with two hands turned upward, one per side. The technique is easily applied to full motion video as well. There are examples of the ultra wide aspect cross glasses images, as well as narrower "portrait" format, which fills a 4×3 computer screen efficiently.
## Cross viewing without glasses
To view the crossed-eye view shown here, the viewer should move slightly back from his or her normal viewing distance and place his viewpoint on a line perpendicular to the center of the image. A finger should be placed halfway between the eyes and the image, then the finger should be viewed. The three bright spots between the pictures should become four spots, and the two images become three. If the focus of the eyes is now allowed to drift to the surface of the screen without uncrossing the eyes, a three dimensional depth illusion will appear in the central image. The finger may now be removed from the view. A viewer may find that the extra side images become unimportant once in-depth view of the central image is stable. This is a popular way of presenting images on computers but it is difficult to learn and for many viewers the method produces substantial eye-strain, and is not comfortable enough for extended viewing. Another disadvantage is that after prolonged viewing, the eyes may become accustomed to "close-convergence", as it requires the ability to direct the eyes as if viewing an object about eight inches away. This very close angle may lead to momentary double-vision. It also offers few of the advantages enumerated above that are provided by the stereoscope or Pokescope. When images are presented as for the stereoscope, with the image to be viewed by the left eye on the left, they can be viewed by diverging the eyes. This gives a different kind of "naked eye stress" than crossing the eyes (known as "wall-eyed divergence") but may require a smaller adjustment of focus, but can be even harder to learn. Without the use of viewing equipment, the size of a stereoscopic image viewable is significantly limited by one's eye-spacing and the inability of one's eyes to diverge painlessly. The major advantage of cross-eye viewing is that the images can be more than twice the area, and no glasses are needed by those who have the viewing knack. Prismatic cross glasses, with built-in masking, make the convergence very easy for most people, but they tend to be expensive, something like 5 times the cost of the simpler arcylic masking glasses.
A printable cut and fold cross viewer can be used.
File:3dviewer.gif
## Transparency viewers
In the 1940s, a modified and miniaturized variation of this technology was introduced as the View-Master. Pairs of stereo views are printed on translucent film which is then mounted around the edge of a cardboard disk, images of each pair being diametrically opposite. A lever is used to move the disk so as to present the next image pair. A series of seven views can thus be seen on each card when it was inserted into the View-Master viewer. These viewers were available in many forms both non-lighted and self-lighted and may still be found today. One type of material presented is children's fairy tale story scenes or brief stories using popular cartoon characters. These use photographs of three dimensional model sets and characters. Another type of material is a series of scenic views associated with some tourist destination, typically sold at gift shops located at the attraction.
Another important development in the late 1940s was the introduction of the Stereo Realist camera and viewer system. Using color slide film, this equipment made stereo photography available to the masses and caused a surge in its popularity. The Stereo Realist and competing products can still be found (in estate sales and elsewhere) and utilized today.
Low-cost folding cardboard viewers with plastic lenses have been used to view images from a sliding card and have been used by computer technical groups as part of annual convention proceedings. These have been supplanted by the DVD recording and display on a television set. By exhibiting moving images of rotating objects a three dimensional effect is obtained through other than stereoscopic means.
An advantage offered by transparency viewing is that a wider field of view may be presented since images, being illuminated from the rear, may be placed much closer to the lenses. Note that with simple viewers the images are limited in size as they must be adjacent and so the field of view is determined by the distance between each lens and its corresponding image.
Good quality wide angle lenses are quite expensive and they are not found in most stereo viewers.
## Head-mounted displays
The user typically wears a helmet or glasses with two small LCD or OLED displays with magnifying lenses, one for each eye. The technology can be used to show stereo films, images or games, but it can also be used to create a virtual display. Head-mounted displays may also be coupled with head-tracking devices, allowing the user to "look around" the virtual world by moving their head, eliminating the need for a separate controller. Performing this update quickly enough to avoid inducing nausea in the user requires a great amount of computer image processing. If six axis position sensing (direction and position) is used then wearer may move about within the limitations of the equipment used. Owing to rapid advancements in computer graphics and the continuing miniaturization of video and other equipment these devices are beginning to become available at more reasonable cost.
Head-mounted or wearable glasses may be used to view a see-through image imposed upon the real world view, creating what is called augmented reality. This is done by reflecting the video images through partially reflective mirrors. The real world view is seen through the mirrors' reflective surface. Experimental systems have been used for gaming, where virtual opponents may peek from real windows as a player moves about. This type of system is expected to have wide application in the maintenance of complex systems, as it can give a technician what is effectively "x-ray vision" by combining computer graphics rendering of hidden elements with the technician's natural vision. Additionally, technical data and schematic diagrams may be delivered to this same equipment, eliminating the need to obtain and carry bulky paper documents.
Augmented stereoscopic vision is also expected to have applications in surgery, as it allows the combination of radiographic data (CAT scans and MRI imaging) with the surgeon's vision.
# 3D glasses
## Liquid Crystal shutter glasses
Glasses containing liquid crystal that will let light through in synchronization with the images on the computer display, using the concept of alternate-frame sequencing. See also Time-division multiplexing.
## Linearly polarized glasses
To present a stereoscopic motion picture, two images are projected superimposed onto the same screen through orthogonal polarizing filters. It is best to use a silver screen so that polarization is preserved. The projectors can receive their outputs from a computer with a dual-head graphics card. The viewer wears low-cost eyeglasses which also contain a pair of orthogonal polarizing filters. As each filter only passes light which is similarly polarized and blocks the orthogonally polarized light, each eye only sees one of the images, and the effect is achieved. Linearly polarized glasses require the viewer to keep his head level, as tilting of the viewing filters will cause the images of the left and right channels to bleed over to the opposite channel – on the other hand, viewers learn very quickly not to tilt their heads. In addition, since no head tracking is involved, several people can view the stereocopic images at the same time.
There are several commercial systems offering products like the above, and one can also put one together by oneself using instructions on the GeoWall Consortium site – they refer to such a system as a GeoWall.
## Circularly polarized glasses
To present a stereoscopic motion picture, two images are projected superimposed onto the same screen through circular polarizing filters of opposite handedness. The viewer wears low-cost eyeglasses which contain a pair of analyzing filters (circular polarizers mounted in reverse) of opposite handedness. Light that is left-circularly polarized is extinguished by the right-handed analyzer; while right-circularly polarized light is extinguished by the left-handed analyzer. The result is similar to that of steroscopic viewing using linearly polarized glasses; except the viewer can tilt his head and still maintain left/right separation.
Real D Cinema System (used recently with the sterescopic Disney movie, "Chicken Little 3D") uses electronically driven circular polarizers that alternate between left- and right- handedness, and does so in sync with the left or right image being displayed by the (digital) movie projector.
## Two-color anaglyph
Anaglyph images have seen a recent resurgence due to the presentation of images on the internet. Where traditionally, this has been a largely black & white format, recent digital camera and processing advances have brought very acceptable color images to the internet and DVD field. With the online availability of low cost paper glasses with improved red-cyan filters, and even better plastic framed glasses, the field is growing fast. Scientific images, where depth perception is useful, include the presentation of complex multi-dimensional data sets and stereographic images from (for example) the surface of Mars, but due to recent release of 3D DVDs, they are increasingly used for entertainment. Anaglyph images are much easier to view than either parallel sighting or crossed eye stereograms, although the latter types offer bright and accurate color rendering, which is not quite obtainable with even good color anaglyphs.
### Compensating anaglyph glasses
Simple sheet or uncorrected molded glasses do not compensate for the 250 nanometer difference in the wave lengths of the red-cyan filters. With simple glasses, the red filter image can be blurry when viewing a close computer screen or printed image since the retinal focus differs from the cyan filtered image, which dominates the eyes' focusing. Better quality molded plastic glasses employ a compensating differential diopter power to equalize the red filter focus shift relative to the cyan. The direct view focus on computer monitors has been recently improved by manufacturers providing secondary
paired lenses fitted and attached inside the red-cyan primary filters of some high end anaglyph glasses. They are used where very high resolution is required, including science, stereo macros, and animation studio applications.
They also use carefully balanced cyan (blue-green) acrylic lenses, which pass a minute percentage of red to improve skin tone perception. Simple red/blue glasses work well with black and white, but are very unsuitable for human skin in color.
## ColorCode 3-D
ColorCode 3-D is a new patented 3-D Stereo system. It is the only in the world to reproduce 3-dimensional images in a simple way with full color- and depth information on all display media. ColorCode 3-D is sometimes confused with anaglyph because of the colored filters in the ColorCodeViewer, but both the filters and the encoding process are entirely different from the more than 150 years old anaglyph system.
## Chromadepth method and glasses
The Chromadepth procedure of American Paper Optics is based on the fact that with a prism colors are separated by varying degrees. The ChromaDepth eyeglasses contain special view foils, which consist of microscopically small prisms. This causes the image to be translated a certain amount that depends on its color. If one uses a prism foil now with one eye but not on the other eye, then the two seen pictures – depending upon color – are more or less widely separated. The brain produces the spatial impression from this difference. The advantage of this technology consists above all of the fact that one can regard ChromaDepth pictures also without eyeglasses (thus two-dimensional) problem-free (unlike with two-color anaglyph). However the colors are only limitedly selectable, since they contain the depth information of the picture. If one changes the color of an object, then its observed distance will also be changed.
## Anachrome "compatible" color anaglyph method
A recent variation on the anaglyph technique is called "Anachrome method". This approach is an attempt to provide images that look fairly normal without glasses as 2D images to be "compatible" for posting in conventional websites or magazines. The 3D effect is generally more subtle, as the images are shot with a narrower stereo base, (the distance between the camera lenses). Pains are taken to adjust for a better overlay fit of the two images, which are layered one on top of another. Only a few pixels of non-registration give the depth cues. The range of color is perhaps three times wider in Anachrome due to the deliberate passage of a small amount of the red information through the cyan filter. Warmer tones can be boosted, and this provides warmer skin tones and vividness.
As of April 2007, more than 4,500 educational, or scientific images were offered on-line in this and similar "compatible" formats. More than 40 public photo groups on www.flickr.com, the free photo archive, accept or feature "compatible" or more conventional anaglyph photos.
- Full color AnachromeTemplate:3d glasses
Full color AnachromeTemplate:3d glasses
- 3-D view of an engine using the same technology.Template:3d glasses
3-D view of an engine using the same technology.Template:3d glasses
# Other display methods
## Autostereograms
More recently, random-dot autostereograms have been created using computers to hide the different images in a field of apparently random noise, so that until viewed by diverging the eyes, the subject of the image remains a mystery. A popular example of this is the Magic Eye series, a collection of stereograms based on distorted colorful and interesting patterns instead of random noise.
## Pulfrich effect
In the classic Pulfrich effect paradigm a subject views, binocularly, a pendulum swinging perpendicular to his line of sight. When a neutral density filter (e.g., a darkened lens -like from a pair of sunglasses) is placed in front of, say, the right eye the pendulum appears to take on an elliptical orbit, being closer as it swings toward the right and farther as it swings toward the left.
The widely accepted explanation of the apparent motion with depth is that a reduction in retinal illumination (relative to the fellow eye) yields a corresponding delay in signal transmission, imparting instantaneous spatial disparity to moving objects. This occurs because the eye, and hence the brain, respond more quickly to brighter objects than to dimmer ones.
So, if the brightness of the pendulum is greater in the left eye than in the right, the retinal signals from the left eye will reach the brain slightly ahead of those from the right eye making it seem like the pendulum seen by the right eye is lagging behind its counterpart in the left eye. This difference in position over time is interpreted by the brain as motion with depth: No motion, no depth.
The ultimate effect of this, with appropriate scene composition, is the illusion of motion with depth. Object motion must be maintained for most conditions and is effective only for very limited "real-world" scenes.
## Prismatic & self masking crossview glasses
"Naked-eye" cross viewing is a skill that must be learned to be used. New prismatic glasses now make cross-viewing easier, and also mask off the secondary non-3D images, that otherwise show up on either side of the 3D image. The most recent low-cost glasses mask the images down to one per eye using integrated baffles. Images or video frames can be displayed on a new widescreen HD or computer monitor with all available area used for display. HDTV wide format permits excellent color and sharpness. Cross viewing provides true "ghost-free 3D" with maximum clarity, brightness and color range, as does the stereopticon and stereoscope viewer with the parallel approach. The potential depth and brightness is maximized. A recent cross converged development, is a new variant wide format that uses a conjoining of visual information outside of the regular binocular stereo window. This allows an efficient seamless visual presentation in true wide-screen, more closely matching the focal range of the human eyes.
## Lenticular prints
Lenticular printing is a technique by which one places an array of lenses, with a texture much like corduroy, over a specially made and carefully aligned print such that different viewing angles will reveal different image slices to each eye, producing the illusion of three dimensions, over a certain limited viewing angle. This can be done cheaply enough that it is sometimes used on stickers, album covers, etc. It is the classic technique for 3D postcards.
## Displays with filter arrays
The LCD is covered with an array of prisms that divert the light from odd and even pixel columns to left and right eyes respectively. As of 2004, several manufacturers, including Sharp Corporation, offer this technology in their notebook and desktop computers. These displays usually cost upwards of 1000 dollars and are mainly targeted at science or medical professionals.
Another technique, for example used by the X3D company, is simply to cover the LCD with two layers, the first being closer to the LCD than the second, by some millimeters. The two layers are transparent with black strips, each strip about one millimeter wide. One layer has its strips about ten degrees to the left, the other to the right. This allows seeing different pixels depending on the viewer's position.
## Wiggle stereoscopy
This method, possibly the most simple stereogram viewing technique, is to simply alternate between the left and right images of a stereogram. In a web browser, this can easily be accomplished with an animated .gif image, flash applet or a specialized java applet. Most people can get a crude sense of dimensionality from such images, due to persistence of vision and parallax. Closing one eye and moving the head from side-to-side helps to understand why this works. Objects that are closer appear to move more than those further away.
This effect may also be observed by a passenger in a vehicle or low-flying aircraft, where distant hills or tall buildings appear in three-dimensional relief, a view not seen by a static observer as the distance is beyond the range of effective binocular vision.
Advantages of the wiggle viewing method include:
- No glasses or special hardware required
- Most people can "get" the effect much quicker than cross-eyed and parallel viewing techniques
- It is the only method of stereoscopic visualisation for people with limited or no vision in one eye
Disadvantages of the "wiggle" method:
- Does not provide true binocular stereoscopic depth perception
- Not suitable for print, limited to displays that can "wiggle" between the two images
- Difficult to appreciate details in images that are constantly "wiggling"
Most wiggle images use only two images, leading to an annoyingly jerky image. A smoother image, more akin to a motion picture image where the camera is moved back and forth, can be composed by using several intermediate images (perhaps with synthetic motion blur) and longer image residency at the end images to allow inspection of details.
Although the "wiggle" method is an excellent way of previewing stereoscopic images, it cannot actually be considered a true three-dimensional stereoscopic format. An individual looking at a wiggling image is not at all experiencing stereoscopic viewing, they are still only seeing a flat two-dimensional image that is "wiggling". To experience binocular depth perception as made possible with true stereoscopic formats, each eyeball must be presented with a different image at the same time – this is not the case with "wiggling" stereo. The "wiggle" effect is similar to walking around one's environment while blinking one eyes.
# Taking the pictures
When using two cameras there are two prime considerations to take into account when taking stereo pictures; How far the resulting image is to be viewed from and how far the subject in the scene is from the two cameras.
How far you are intending to view the pictures from requires a certain separation between the cameras. This sepearation is called stereo base or stereo base line and results from the ratio of the distance to the image to the distance between your eyes (close enough to 2.5 inches to always use 2.5 inches).
For example if you are going to view a stereo image on your computer monitor from a distance of 40 inches you will have a eye to view ratio of 40/2.5 or 16. To set your cameras the correct distance apart you take the distance to the subject (say a person at a distance from the cameras of 10 feet) and divide by 16 which gives you a stereo base of .625 feet or 7.5 inches between the cameras.
If however you are going to view the stereo image from a greater distance (say projected on a movie screen at a distance from the person viewing it of 10 feet) then your eye to view ratio will be 120/2.5 or 48. So even though your subject is the same distance from your cameras as in the previous example of 10 feet, when you divide 10 feet by 48 you will get .208 feet or 2.5 inches, a much smaller stereo base separation than when you are viewing the image from a closer distance.
In the 1950s, stereoscopic photography regained popularity when a number of manufacturers began introducing stereoscopic cameras to the public. The new cameras were developed to use 135 film, which had gained popularity after the close of World War II. Many of the conventional cameras used the film for 35mm transparency slides, and the new stereoscopic cameras utilized the film to make stereoscopic slides. The Stereo Realist camera was the most popular, and the 35mm picture format became the standard by which other stereo cameras were designed. The stereoscopic cameras were marketed with special viewers that allowed for the use of such slides, which were similar to View-Master reels but offered a much larger image. With these cameras the public could easily create their own stereoscopic memories. Although their popularity has waned somewhat, these cameras are still in use today.
The 1980s saw a minor revival of stereoscopic photography extent when point-and-shoot stereo cameras were introduced. These cameras suffered from poor optics and plastic construction, so they never gained the popularity of the 1950s stereo cameras. Over the last few years they have been improved upon and now produce good images.
The beginning of the 21st century marked the coming of the age of digital photography. Stereo lenses were introduced which could turn an ordinary film camera into a stereo camera by using a special double lens to take two images and direct them through a single lens to capture them side-by-side on the film. Although there are not any out-of-the-box digital stereocameras available, it is possible to create a twin camera rig, together with a "shepherd" device to synchronize the shutter and flash of the two cameras. (By mounting two cameras on a bracket, spaced a bit, with a mechanism to make both take pictures at the same time.) Newer cameras are even being used to shoot "step video" 3D slide shows with many pictures almost like a 3D motion picture if viewed properly. A modern camera can take 5 pictures per second, with images that greatly exceed HDTV resolution.
The side-by-side method is extremely simple to create, but it can be difficult or uncomfortable to view without optical aids. One such aid for non-crossed images is the modern Pokescope. Traditional stereoscopes such as the Holmes can be used as well. Cross view technique now has the simple Perfect-Chroma cross viewing glasses to facilitate viewing.
## Imaging methods
If anything is in motion within the field of view, it is necessary to take both images at once, either through use of a specialized two-lens camera, or by using two identical cameras, operated as close as possible to the same moment.
A single digital camera can also be used if the subject remains perfectly still (such as an object in a museum display). Two exposures are required. The camera can be moved on a sliding bar for offset, or with practice, the photographer can simply shift the camera while holding it straight and level. In practice the hand-held method works very well. This method of taking stereo photos is sometimes referred to as the "Cha-Cha" method.
A good rule of thumb is to shift sideways 1/30th of the distance to the closest subject for 'side by side' display, or just 1/60th if the image is to be also used for color anaglyph or anachrome image display. For example, if you are taking a photo of a person in front of a house, and the person is 30 feet away, then you should move the camera 1 foot between shots.
The stereo effect is not significantly diminished by slight pan or rotation between images. In fact slight rotation inwards (also called 'toe in') can be beneficial. Bear in mind that both images should show the same objects in the scene (just from different angles) - if a tree is on the edge of one image but out of view in the other image, then it will appear in a ghostly, semi-transparent way to the viewer, which is distracting and uncomfortable. Therefore, you can either crop the images so they completely overlap, or you can 'toe-in' the cameras so that the images completely overlap without having to discard any of the images. However, be a little cautious - too much 'toe-in' can cause eye strain for reasons best described here .
## Longer base line
For making stereo images of a distant object (e.g., a mountain with foothills), one can separate the camera positions by a larger distance than usual. This will enhance the depth perception of these distant objects, but is not suitable for use when foreground objects are present. In the red-cyan anaglyphed example at right, a ten-meter baseline atop the roof ridge of a house was used to image the mountain. The two foothill ridges are about 6.5 km (4 mi) distant and are separated in depth from each other and the background. The baseline is still too short to resolve the depth of the two more distant major peaks from each other. Owing to various trees that appeared in only one of the images the final image had to be severely cropped at each side and the bottom.
In the wider image, taken from a different location, a single camera was walked about 100 ft (30m) between pictures. The images were converted to monochrome before combination.
## Base line selection
There is a specific optimal distance for viewing of natural scenes (not stereograms), which has been estimated by some to have the closest object at a distance of about 30 times the distance between the eyes (when the scene extends to infinity). An object at this distance will appear on the picture plane, the apparent surface of the image. Objects closer than this will appear in front of the picture plane, or popping out of the image. All objects at greater distances appear behind the picture plane. This interpupillar or interocular distance will vary between individuals. If one assumes that it is 2.5 inches (about 6.5 cm), then the closest object in a natural scene by this criterion would be 30 × 2.5 = 75 inches (about 2 m). It is this ratio (1:30) that determines the inter-camera spacing appropriate to imaging scenes. Thus if the nearest object is 30 feet away, this ratio suggests an inter-camera distance of one foot. It may be that a more dramatic effect can be obtained with a lower ratio, say 1:20 (in other words, the cameras will be spaced further apart), but with some risk of having the overall scene appear less "natural". This unnaturalness can often be seen in old stereoscope cards, where a landscape will have the appearance of a stack of cardboard cutouts. Where images may also be used for anaglyph display a narrower base, say 1:50 or 1:60 will allow for less ghosting in the display. | Stereoscopy
Stereoscopy, stereoscopic imaging or 3-D (three-dimensional) imaging is any technique capable of recording three-dimensional visual information or creating the illusion of depth in an image. The illusion of depth in a photograph, movie, or other two-dimensional image is created by presenting a slightly different image to each eye. Many 3D displays use this method to convey images. It was first invented by Sir Charles Wheatstone in 1840.[1] Stereoscopy is used in photogrammetry and also for entertainment through the production of stereograms. Stereoscopy is useful in viewing images rendered from large multi-dimensional data sets such as are produced by experimental data. Modern industrial three dimensional photography may use 3D scanners to detect and record 3 dimensional information. The three-dimensional depth information can be reconstructed from two images using a computer by corresponding the pixels in the left and right images. Solving the Correspondence problem in the field of Computer Vision aims to create meaningful depth information from two images.
Traditional stereoscopic photography consists of creating a 3-D illusion starting from a pair of 2-D images. The easiest way to create depth perception in the brain is to provide the eyes of the viewer with two different images, representing two perspectives of the same object, with a minor deviation similar to the perspectives that both eyes naturally receive in binocular vision.
If eyestrain and distortion are to be avoided, each of the two 2-D images preferably should be presented to each eye of the viewer so that any object at infinite distance seen by the viewer should be perceived by that eye while it is oriented straight ahead, the viewer's eyes being neither crossed nor diverging. When the picture contains no object at infinite distance, such as a horizon or a cloud, the pictures should be spaced correspondingly closer together.
# Side-by-side
## Characteristics
Little or no additional image processing is required. Under some circumstances, such as when a pair of images is presented for crossed or diverged eye viewing, no device or additional optical equipment is needed.
The principal advantages of side-by-side viewers is that there is no diminution of brightness so images may be presented at very high resolution and in full spectrum color. The ghosting associated
with polarized projection or when color filtering is used is totally eliminated. The images are
discretely presented to the eyes and visual center of the brain, with no co-mingling of the views.
The recent advent of wider HD and computer flat screens has made wider 3D digital images practical
in this side by side mode, which hitherto has been used mainly with paired photos or in print form.
## Stereographic cards and the stereoscope
Two separate images are printed side-by-side. When viewed without a stereoscopic viewer the user is required to force his eyes either to cross, or to diverge, so that the two images appear to be three. Then as each eye sees a different image, the effect of depth is achieved in the central image of the three.
The stereoscope offers several advantages:
- Using positive curvature (magnifying) lenses, the focus point of the image is changed from its short distance (about 30 to 40 cm) to a virtual distance at infinity. This allows the focus of the eyes to be consistent with the parallel lines of sight, greatly reducing eye strain.
- The card image is magnified, offering a wider field of view and the ability to examine the detail of the photograph.
- The viewer provides a partition between the images, avoiding a potential distraction to the user.
Stereograms cards are frequently used by orthoptists and vision therapists in the treatment of many binocular vision and accommodative disorders.
## Cross converged viewing, with new "masking" glasses
By exchanging the right and left views, and the opposite eye converged to the shifted images, it is possible to obtain a true color 3-D effect with some effort, without glasses or a viewer. Very recently, low cost glasses became available to aid the viewer in cross convergence viewing. An unusual effect of these optical glasses is to substantially widen the field of view to include a part of the peripheral area not visible to both eyes. There is a wrap-around effect produced, without the ghosting and the depth perspective can be greatly deepened. These new glasses provide acrylic lenses, plastic frames, that integrate a set of adjustable masking elements, that channel the view to only one image per eye. This allows full use of the screen width in the way that live vision treats stereo. The cross view image can easily fill any screen including 16 by 9 HDTV screens, working like a mirror to allow a dual perspective & wider view, as the images are mentally processed. Several non-commercial demonstration sites, such as bymal.com[2] are showing extended 3D, sound, perfect color slide-shows, of subjects such as the Renaissance Pleasure Faire. They can be viewed with the glasses or without by masking with two hands turned upward, one per side. The technique is easily applied to full motion video as well. There are examples of the ultra wide aspect cross glasses images, as well as narrower "portrait" format, which fills a 4×3 computer screen efficiently.
## Cross viewing without glasses
Template:Howto
To view the crossed-eye view shown here, the viewer should move slightly back from his or her normal viewing distance and place his viewpoint on a line perpendicular to the center of the image. A finger should be placed halfway between the eyes and the image, then the finger should be viewed. The three bright spots between the pictures should become four spots, and the two images become three. If the focus of the eyes is now allowed to drift to the surface of the screen without uncrossing the eyes, a three dimensional depth illusion will appear in the central image. The finger may now be removed from the view. A viewer may find that the extra side images become unimportant once in-depth view of the central image is stable. This is a popular way of presenting images on computers but it is difficult to learn and for many viewers the method produces substantial eye-strain, and is not comfortable enough for extended viewing. Another disadvantage is that after prolonged viewing, the eyes may become accustomed to "close-convergence", as it requires the ability to direct the eyes as if viewing an object about eight inches away. This very close angle may lead to momentary double-vision. It also offers few of the advantages enumerated above that are provided by the stereoscope or Pokescope. When images are presented as for the stereoscope, with the image to be viewed by the left eye on the left, they can be viewed by diverging the eyes. This gives a different kind of "naked eye stress" than crossing the eyes (known as "wall-eyed divergence") but may require a smaller adjustment of focus, but can be even harder to learn. Without the use of viewing equipment, the size of a stereoscopic image viewable is significantly limited by one's eye-spacing and the inability of one's eyes to diverge painlessly. The major advantage of cross-eye viewing is that the images can be more than twice the area, and no glasses are needed by those who have the viewing knack. Prismatic cross glasses, with built-in masking, make the convergence very easy for most people, but they tend to be expensive, something like 5 times the cost of the simpler arcylic masking glasses.
A printable cut and fold cross viewer can be used.
File:3dviewer.gif
## Transparency viewers
In the 1940s, a modified and miniaturized variation of this technology was introduced as the View-Master. Pairs of stereo views are printed on translucent film which is then mounted around the edge of a cardboard disk, images of each pair being diametrically opposite. A lever is used to move the disk so as to present the next image pair. A series of seven views can thus be seen on each card when it was inserted into the View-Master viewer. These viewers were available in many forms both non-lighted and self-lighted and may still be found today. One type of material presented is children's fairy tale story scenes or brief stories using popular cartoon characters. These use photographs of three dimensional model sets and characters. Another type of material is a series of scenic views associated with some tourist destination, typically sold at gift shops located at the attraction.
Another important development in the late 1940s was the introduction of the Stereo Realist camera and viewer system. Using color slide film, this equipment made stereo photography available to the masses and caused a surge in its popularity. The Stereo Realist and competing products can still be found (in estate sales and elsewhere) and utilized today.
Low-cost folding cardboard viewers with plastic lenses have been used to view images from a sliding card and have been used by computer technical groups as part of annual convention proceedings. These have been supplanted by the DVD recording and display on a television set. By exhibiting moving images of rotating objects a three dimensional effect is obtained through other than stereoscopic means.
An advantage offered by transparency viewing is that a wider field of view may be presented since images, being illuminated from the rear, may be placed much closer to the lenses. Note that with simple viewers the images are limited in size as they must be adjacent and so the field of view is determined by the distance between each lens and its corresponding image.
Good quality wide angle lenses are quite expensive and they are not found in most stereo viewers.
## Head-mounted displays
The user typically wears a helmet or glasses with two small LCD or OLED displays with magnifying lenses, one for each eye. The technology can be used to show stereo films, images or games, but it can also be used to create a virtual display. Head-mounted displays may also be coupled with head-tracking devices, allowing the user to "look around" the virtual world by moving their head, eliminating the need for a separate controller. Performing this update quickly enough to avoid inducing nausea in the user requires a great amount of computer image processing. If six axis position sensing (direction and position) is used then wearer may move about within the limitations of the equipment used. Owing to rapid advancements in computer graphics and the continuing miniaturization of video and other equipment these devices are beginning to become available at more reasonable cost.
Head-mounted or wearable glasses may be used to view a see-through image imposed upon the real world view, creating what is called augmented reality. This is done by reflecting the video images through partially reflective mirrors. The real world view is seen through the mirrors' reflective surface. Experimental systems have been used for gaming, where virtual opponents may peek from real windows as a player moves about. This type of system is expected to have wide application in the maintenance of complex systems, as it can give a technician what is effectively "x-ray vision" by combining computer graphics rendering of hidden elements with the technician's natural vision. Additionally, technical data and schematic diagrams may be delivered to this same equipment, eliminating the need to obtain and carry bulky paper documents.
Augmented stereoscopic vision is also expected to have applications in surgery, as it allows the combination of radiographic data (CAT scans and MRI imaging) with the surgeon's vision.
# 3D glasses
## Liquid Crystal shutter glasses
Glasses containing liquid crystal that will let light through in synchronization with the images on the computer display, using the concept of alternate-frame sequencing. See also Time-division multiplexing.
## Linearly polarized glasses
To present a stereoscopic motion picture, two images are projected superimposed onto the same screen through orthogonal polarizing filters. It is best to use a silver screen so that polarization is preserved. The projectors can receive their outputs from a computer with a dual-head graphics card. The viewer wears low-cost eyeglasses which also contain a pair of orthogonal polarizing filters. As each filter only passes light which is similarly polarized and blocks the orthogonally polarized light, each eye only sees one of the images, and the effect is achieved. Linearly polarized glasses require the viewer to keep his head level, as tilting of the viewing filters will cause the images of the left and right channels to bleed over to the opposite channel – on the other hand, viewers learn very quickly not to tilt their heads. In addition, since no head tracking is involved, several people can view the stereocopic images at the same time.
There are several commercial systems offering products like the above, and one can also put one together by oneself using instructions on the GeoWall Consortium site – they refer to such a system as a GeoWall.
## Circularly polarized glasses
To present a stereoscopic motion picture, two images are projected superimposed onto the same screen through circular polarizing filters of opposite handedness. The viewer wears low-cost eyeglasses which contain a pair of analyzing filters (circular polarizers mounted in reverse) of opposite handedness. Light that is left-circularly polarized is extinguished by the right-handed analyzer; while right-circularly polarized light is extinguished by the left-handed analyzer. The result is similar to that of steroscopic viewing using linearly polarized glasses; except the viewer can tilt his head and still maintain left/right separation.
Real D Cinema System (used recently with the sterescopic Disney movie, "Chicken Little 3D") uses electronically driven circular polarizers that alternate between left- and right- handedness, and does so in sync with the left or right image being displayed by the (digital) movie projector.
## Two-color anaglyph
Anaglyph images have seen a recent resurgence due to the presentation of images on the internet. Where traditionally, this has been a largely black & white format, recent digital camera and processing advances have brought very acceptable color images to the internet and DVD field. With the online availability of low cost paper glasses with improved red-cyan filters, and even better plastic framed glasses, the field is growing fast. Scientific images, where depth perception is useful, include the presentation of complex multi-dimensional data sets and stereographic images from (for example) the surface of Mars, but due to recent release of 3D DVDs, they are increasingly used for entertainment. Anaglyph images are much easier to view than either parallel sighting or crossed eye stereograms, although the latter types offer bright and accurate color rendering, which is not quite obtainable with even good color anaglyphs.
### Compensating anaglyph glasses
Simple sheet or uncorrected molded glasses do not compensate for the 250 nanometer difference in the wave lengths of the red-cyan filters. With simple glasses, the red filter image can be blurry when viewing a close computer screen or printed image since the retinal focus differs from the cyan filtered image, which dominates the eyes' focusing. Better quality molded plastic glasses employ a compensating differential diopter power to equalize the red filter focus shift relative to the cyan. The direct view focus on computer monitors has been recently improved by manufacturers providing secondary
paired lenses fitted and attached inside the red-cyan primary filters of some high end anaglyph glasses. They are used where very high resolution is required, including science, stereo macros, and animation studio applications.
They also use carefully balanced cyan (blue-green) acrylic lenses, which pass a minute percentage of red to improve skin tone perception. Simple red/blue glasses work well with black and white, but are very unsuitable for human skin in color.
## ColorCode 3-D
ColorCode 3-D is a new patented 3-D Stereo system. It is the only in the world to reproduce 3-dimensional images in a simple way with full color- and depth information on all display media. ColorCode 3-D is sometimes confused with anaglyph because of the colored filters in the ColorCodeViewer, but both the filters and the encoding process are entirely different from the more than 150 years old anaglyph system.
## Chromadepth method and glasses
The Chromadepth procedure of American Paper Optics is based on the fact that with a prism colors are separated by varying degrees. The ChromaDepth eyeglasses contain special view foils, which consist of microscopically small prisms. This causes the image to be translated a certain amount that depends on its color. If one uses a prism foil now with one eye but not on the other eye, then the two seen pictures – depending upon color – are more or less widely separated. The brain produces the spatial impression from this difference. The advantage of this technology consists above all of the fact that one can regard ChromaDepth pictures also without eyeglasses (thus two-dimensional) problem-free (unlike with two-color anaglyph). However the colors are only limitedly selectable, since they contain the depth information of the picture. If one changes the color of an object, then its observed distance will also be changed.
## Anachrome "compatible" color anaglyph method
A recent variation on the anaglyph technique is called "Anachrome method".[3] This approach is an attempt to provide images that look fairly normal without glasses as 2D images to be "compatible" for posting in conventional websites or magazines. The 3D effect is generally more subtle, as the images are shot with a narrower stereo base, (the distance between the camera lenses). Pains are taken to adjust for a better overlay fit of the two images, which are layered one on top of another. Only a few pixels of non-registration give the depth cues. The range of color is perhaps three times wider in Anachrome due to the deliberate passage of a small amount of the red information through the cyan filter. Warmer tones can be boosted, and this provides warmer skin tones and vividness.
As of April 2007, more than 4,500 educational, or scientific images were offered on-line in this and similar "compatible" formats. More than 40 public photo groups on www.flickr.com, the free photo archive, accept or feature "compatible" or more conventional anaglyph photos.
- Full color AnachromeTemplate:3d glasses
Full color AnachromeTemplate:3d glasses
- 3-D view of an engine using the same technology.Template:3d glasses
3-D view of an engine using the same technology.Template:3d glasses
# Other display methods
## Autostereograms
More recently, random-dot autostereograms have been created using computers to hide the different images in a field of apparently random noise, so that until viewed by diverging the eyes, the subject of the image remains a mystery. A popular example of this is the Magic Eye series, a collection of stereograms based on distorted colorful and interesting patterns instead of random noise.
## Pulfrich effect
In the classic Pulfrich effect paradigm a subject views, binocularly, a pendulum swinging perpendicular to his line of sight. When a neutral density filter (e.g., a darkened lens -like from a pair of sunglasses) is placed in front of, say, the right eye the pendulum appears to take on an elliptical orbit, being closer as it swings toward the right and farther as it swings toward the left.
The widely accepted explanation of the apparent motion with depth is that a reduction in retinal illumination (relative to the fellow eye) yields a corresponding delay in signal transmission, imparting instantaneous spatial disparity to moving objects. This occurs because the eye, and hence the brain, respond more quickly to brighter objects than to dimmer ones.[4][5][6][7]
So, if the brightness of the pendulum is greater in the left eye than in the right, the retinal signals from the left eye will reach the brain slightly ahead of those from the right eye making it seem like the pendulum seen by the right eye is lagging behind its counterpart in the left eye. This difference in position over time is interpreted by the brain as motion with depth: No motion, no depth.
The ultimate effect of this, with appropriate scene composition, is the illusion of motion with depth. Object motion must be maintained for most conditions and is effective only for very limited "real-world" scenes.
## Prismatic & self masking crossview glasses
"Naked-eye" cross viewing is a skill that must be learned to be used. New prismatic glasses now make cross-viewing easier, and also mask off the secondary non-3D images, that otherwise show up on either side of the 3D image. The most recent low-cost glasses mask the images down to one per eye using integrated baffles. Images or video frames can be displayed on a new widescreen HD or computer monitor with all available area used for display. HDTV wide format permits excellent color and sharpness. Cross viewing provides true "ghost-free 3D" with maximum clarity, brightness and color range, as does the stereopticon and stereoscope viewer with the parallel approach. The potential depth and brightness is maximized. A recent cross converged development, is a new variant wide format that uses a conjoining of visual information outside of the regular binocular stereo window. This allows an efficient seamless visual presentation in true wide-screen, more closely matching the focal range of the human eyes.
## Lenticular prints
Lenticular printing is a technique by which one places an array of lenses, with a texture much like corduroy, over a specially made and carefully aligned print such that different viewing angles will reveal different image slices to each eye, producing the illusion of three dimensions, over a certain limited viewing angle. This can be done cheaply enough that it is sometimes used on stickers, album covers, etc. It is the classic technique for 3D postcards.
## Displays with filter arrays
The LCD is covered with an array of prisms that divert the light from odd and even pixel columns to left and right eyes respectively. As of 2004, several manufacturers, including Sharp Corporation, offer this technology in their notebook and desktop computers. These displays usually cost upwards of 1000 dollars and are mainly targeted at science or medical professionals.
Another technique, for example used by the X3D company,[citation needed] is simply to cover the LCD with two layers, the first being closer to the LCD than the second, by some millimeters. The two layers are transparent with black strips, each strip about one millimeter wide. One layer has its strips about ten degrees to the left, the other to the right. This allows seeing different pixels depending on the viewer's position.
## Wiggle stereoscopy
This method, possibly the most simple stereogram viewing technique, is to simply alternate between the left and right images of a stereogram. In a web browser, this can easily be accomplished with an animated .gif image, flash applet or a specialized java applet. Most people can get a crude sense of dimensionality from such images, due to persistence of vision and parallax. Closing one eye and moving the head from side-to-side helps to understand why this works. Objects that are closer appear to move more than those further away.
This effect may also be observed by a passenger in a vehicle or low-flying aircraft, where distant hills or tall buildings appear in three-dimensional relief, a view not seen by a static observer as the distance is beyond the range of effective binocular vision.
Advantages of the wiggle viewing method include:
- No glasses or special hardware required
- Most people can "get" the effect much quicker than cross-eyed and parallel viewing techniques
- It is the only method of stereoscopic visualisation for people with limited or no vision in one eye
Disadvantages of the "wiggle" method:
- Does not provide true binocular stereoscopic depth perception
- Not suitable for print, limited to displays that can "wiggle" between the two images
- Difficult to appreciate details in images that are constantly "wiggling"
Most wiggle images use only two images, leading to an annoyingly jerky image. A smoother image, more akin to a motion picture image where the camera is moved back and forth, can be composed by using several intermediate images (perhaps with synthetic motion blur) and longer image residency at the end images to allow inspection of details.
Although the "wiggle" method is an excellent way of previewing stereoscopic images, it cannot actually be considered a true three-dimensional stereoscopic format. An individual looking at a wiggling image is not at all experiencing stereoscopic viewing, they are still only seeing a flat two-dimensional image that is "wiggling". To experience binocular depth perception as made possible with true stereoscopic formats, each eyeball must be presented with a different image at the same time – this is not the case with "wiggling" stereo. The "wiggle" effect is similar to walking around one's environment while blinking one eyes.
# Taking the pictures
When using two cameras there are two prime considerations to take into account when taking stereo pictures; How far the resulting image is to be viewed from and how far the subject in the scene is from the two cameras.
How far you are intending to view the pictures from requires a certain separation between the cameras. This sepearation is called stereo base or stereo base line and results from the ratio of the distance to the image to the distance between your eyes (close enough to 2.5 inches to always use 2.5 inches).
For example if you are going to view a stereo image on your computer monitor from a distance of 40 inches you will have a eye to view ratio of 40/2.5 or 16. To set your cameras the correct distance apart you take the distance to the subject (say a person at a distance from the cameras of 10 feet) and divide by 16 which gives you a stereo base of .625 feet or 7.5 inches between the cameras.
If however you are going to view the stereo image from a greater distance (say projected on a movie screen at a distance from the person viewing it of 10 feet) then your eye to view ratio will be 120/2.5 or 48. So even though your subject is the same distance from your cameras as in the previous example of 10 feet, when you divide 10 feet by 48 you will get .208 feet or 2.5 inches, a much smaller stereo base separation than when you are viewing the image from a closer distance.
In the 1950s, stereoscopic photography regained popularity when a number of manufacturers began introducing stereoscopic cameras to the public. The new cameras were developed to use 135 film, which had gained popularity after the close of World War II. Many of the conventional cameras used the film for 35mm transparency slides, and the new stereoscopic cameras utilized the film to make stereoscopic slides. The Stereo Realist camera was the most popular, and the 35mm picture format became the standard by which other stereo cameras were designed. The stereoscopic cameras were marketed with special viewers that allowed for the use of such slides, which were similar to View-Master reels but offered a much larger image. With these cameras the public could easily create their own stereoscopic memories. Although their popularity has waned somewhat, these cameras are still in use today.
The 1980s saw a minor revival of stereoscopic photography extent when point-and-shoot stereo cameras were introduced. These cameras suffered from poor optics and plastic construction, so they never gained the popularity of the 1950s stereo cameras. Over the last few years they have been improved upon and now produce good images.
The beginning of the 21st century marked the coming of the age of digital photography. Stereo lenses were introduced which could turn an ordinary film camera into a stereo camera by using a special double lens to take two images and direct them through a single lens to capture them side-by-side on the film. Although there are not any out-of-the-box digital stereocameras available, it is possible to create a twin camera rig, together with a "shepherd" device to synchronize the shutter and flash of the two cameras. (By mounting two cameras on a bracket, spaced a bit, with a mechanism to make both take pictures at the same time.) Newer cameras are even being used to shoot "step video" 3D slide shows with many pictures almost like a 3D motion picture if viewed properly. A modern camera can take 5 pictures per second, with images that greatly exceed HDTV resolution.
The side-by-side method is extremely simple to create, but it can be difficult or uncomfortable to view without optical aids. One such aid for non-crossed images is the modern Pokescope. Traditional stereoscopes such as the Holmes can be used as well. Cross view technique now has the simple Perfect-Chroma cross viewing glasses to facilitate viewing.
## Imaging methods
If anything is in motion within the field of view, it is necessary to take both images at once, either through use of a specialized two-lens camera, or by using two identical cameras, operated as close as possible to the same moment.
A single digital camera can also be used if the subject remains perfectly still (such as an object in a museum display). Two exposures are required. The camera can be moved on a sliding bar for offset, or with practice, the photographer can simply shift the camera while holding it straight and level. In practice the hand-held method works very well. This method of taking stereo photos is sometimes referred to as the "Cha-Cha" method.
A good rule of thumb is to shift sideways 1/30th of the distance to the closest subject for 'side by side' display, or just 1/60th if the image is to be also used for color anaglyph or anachrome image display. For example, if you are taking a photo of a person in front of a house, and the person is 30 feet away, then you should move the camera 1 foot between shots.
The stereo effect is not significantly diminished by slight pan or rotation between images. In fact slight rotation inwards (also called 'toe in') can be beneficial. Bear in mind that both images should show the same objects in the scene (just from different angles) - if a tree is on the edge of one image but out of view in the other image, then it will appear in a ghostly, semi-transparent way to the viewer, which is distracting and uncomfortable. Therefore, you can either crop the images so they completely overlap, or you can 'toe-in' the cameras so that the images completely overlap without having to discard any of the images. However, be a little cautious - too much 'toe-in' can cause eye strain for reasons best described here [1].
## Longer base line
For making stereo images of a distant object (e.g., a mountain with foothills), one can separate the camera positions by a larger distance than usual. This will enhance the depth perception of these distant objects, but is not suitable for use when foreground objects are present. In the red-cyan anaglyphed example at right, a ten-meter baseline atop the roof ridge of a house was used to image the mountain. The two foothill ridges are about 6.5 km (4 mi) distant and are separated in depth from each other and the background. The baseline is still too short to resolve the depth of the two more distant major peaks from each other. Owing to various trees that appeared in only one of the images the final image had to be severely cropped at each side and the bottom.
In the wider image, taken from a different location, a single camera was walked about 100 ft (30m) between pictures. The images were converted to monochrome before combination.
## Base line selection
There is a specific optimal distance for viewing of natural scenes (not stereograms), which has been estimated by some to have the closest object at a distance of about 30 times the distance between the eyes (when the scene extends to infinity). An object at this distance will appear on the picture plane, the apparent surface of the image. Objects closer than this will appear in front of the picture plane, or popping out of the image. All objects at greater distances appear behind the picture plane. This interpupillar or interocular distance will vary between individuals. If one assumes that it is 2.5 inches (about 6.5 cm), then the closest object in a natural scene by this criterion would be 30 × 2.5 = 75 inches (about 2 m). It is this ratio (1:30) that determines the inter-camera spacing appropriate to imaging scenes. Thus if the nearest object is 30 feet away, this ratio suggests an inter-camera distance of one foot. It may be that a more dramatic effect can be obtained with a lower ratio, say 1:20 (in other words, the cameras will be spaced further apart), but with some risk of having the overall scene appear less "natural". This unnaturalness can often be seen in old stereoscope cards, where a landscape will have the appearance of a stack of cardboard cutouts. Where images may also be used for anaglyph display a narrower base, say 1:50 or 1:60 will allow for less ghosting in the display. | https://www.wikidoc.org/index.php/Stereoscopy | |
35998e0003a9bba4ff7c5f252fb3ced92edbccab | wikidoc | Steri strip | Steri strip
# Overview
Steri strips are surgical strips of adhesive backed paper tape that are placed across an incision or minor cut. They keep the edges of a wound together as it heals. The Steri-Strip was invented by the company 3M.
Steri strips may be used instead of sutures (stitches) in some injuries, because they lessen scarring and are easier to care for.
The precursor to the steri-strip, was Micropore Surgical Tape. Reports of dramatic cases where Micropore Surgical tape alone was used to hold large abdominal incisions together when the skin was too fragile to accommodate sutures and another where one patient's abdominal wall was literally rebuilt with the tape and his life saved when sutures on the patient's compromised skin failed to hold the wound closed prompted 3M to cut Micropore Surgical Tape into one-eighth inch, one-fourth inch and one-half inch strips, sterilise and package it as primary surface closures for incisions.
# Usage
They are inappropriate over joints, but useful for areas where skin is thin and sutures are likely to 'cut out', to make Steristrips stickier, tincture of benzoin could be applied to the dry skin around the wound. | Steri strip
# Overview
Steri strips are surgical strips of adhesive backed paper tape that are placed across an incision or minor cut. They keep the edges of a wound together as it heals. The Steri-Strip was invented by the company 3M.
Steri strips may be used instead of sutures (stitches) in some injuries, because they lessen scarring and are easier to care for.
The precursor to the steri-strip, was Micropore Surgical Tape. Reports of dramatic cases where Micropore Surgical tape alone was used to hold large abdominal incisions together when the skin was too fragile to accommodate sutures and another where one patient's abdominal wall was literally rebuilt with the tape and his life saved when sutures on the patient's compromised skin failed to hold the wound closed prompted 3M to cut Micropore Surgical Tape into one-eighth inch, one-fourth inch and one-half inch strips, sterilise and package it as primary surface closures for incisions. [1]
# Usage
They are inappropriate over joints, but useful for areas where skin is thin and sutures are likely to 'cut out', to make Steristrips stickier, tincture of benzoin could be applied to the dry skin around the wound. | https://www.wikidoc.org/index.php/Steri_strip | |
f65c114547d9417d82ef5d4e8cdde9cafdada5dd | wikidoc | Stethoscope | Stethoscope
The stethoscope (Greek στηθοσκόπιο, of στήθος, stéthos - chest and σκοπή, skopé - examination) is an acoustic medical device for auscultation, or listening, to internal sounds in a human or animal body. It is most often used to listen to heart sounds and breathing. It is also used to listen to intestines and blood flow in arteries and veins. Less commonly, "mechanic's stethosopes" are used to listen to internal sounds made by machines, such as diagnosing a malfunctioning automobile engine by listening to the sounds of its internal parts.
# History
The stethoscope was invented in France in 1816 by René-Théophile-Hyacinthe Laennec. It consisted of a wooden tube and was monaural. His device was similar to the common ear trumpet; indeed, his invention was almost indistinguishable in structure and function from the trumpet, which was commonly called a "microphone." In 1851 Arthur Leared invented a binaural stethoscope, and in 1852 George Cammann perfected the design of the instrument for commercial production, which has become the standard ever since. Cammann also authored a major treatise on diagnosis by auscultation, which the refined binaural stethoscope made possible. By 1873, there were descriptions of a differential stethoscope that could connect to slightly different locations to create a slight stereo effect, though this did not become a standard tool in clinical practise.
Rappaport and Sprague designed a new stethoscope in the 1940's which became the standard by which other stethoscopes are measured. The Rappaport-Sprague was later made by Hewlett-Packard, later Philips, and today there are still cardiologists who consider it to be the finest acoustic stethoscope. Several other minor refinements were made to stethoscopes until in the early 1960's Dr. Littmann, a Harvard Medical School professor, created a new stethoscope that was lighter than previous models.
# Current practice
The stethoscope is used in aid of diagnosing certain diseases and conditions. The stethoscope is able to transmit certain sounds and exclude others. Before the stethoscope was invented, doctors placed their ear next to the patient's body in hopes of hearing something.
Stethoscopes are often considered as a symbol of the doctor's profession, as doctors are often seen or depicted with a stethoscope hanging around their neck.
Stethoscopes are also used by mechanics to isolate sounds of a particular moving engine part for diagnosis.
Stethoscopes are sometimes used by safe-crackers to hear the tumblers inside the combination, to ultimately learn the combination to a safe.
## Types of stethoscopes
### Acoustic
Acoustic stethoscopes are familiar to most people, and operate on the transmission of sound from the chestpiece, via air-filled hollow tubes, to the listener's ears. The chestpiece usually consists of two sides that can be placed against the patient for sensing sound — a diaphragm (plastic disc) or bell (hollow cup). If the diaphragm is placed on the patient, body sounds vibrate the diaphragm, creating acoustic pressure waves which travel up the tubing to the listener's ears. If the bell is placed on the patient, the vibrations of the skin directly produce acoustic pressure waves traveling up to the listener's ears. The bell transmits low frequency sounds, while the diaphragm transmits higher frequency sounds. This 2-sided stethoscope was invented by Rappaport and Sprague in the early part of the 20th century. One problem with acoustic stethoscopes is that the sound level is extremely low. They are the most commonly used.
### Electronic
Electronic stethoscopes overcome the low sound levels by amplifiying body sounds. Currently, a number of companies offer electronic stethoscopes, and it can be expected that within a few years, the electronic stethoscope will have eclipsed acoustic devices.
Electronic stethoscopes require conversion of acoustic sound waves to electrical signals which can then be amplified and processed for optimal listening. Unlike acoustic stethoscopes, which are all based on the same physics, transducers in electronic stethoscopes vary widely. The simplest and least effective method of sound detection is achieved by placing a microphone in the chestpiece. This method suffers from ambient noise interference and has fallen out of favor. Another method, used in Welch-Allyn's Meditron stethoscope, comprises placement of a piezoelectric crystal at the head of a metal shaft, the bottom of the shaft making contact with a diaphragm. 3M also uses a piezo-electric crystal placed within foam behind a thick rubber-like diaphragm. Thinklabs uses a stethoscope diaphragm with an electrically conductive inner surface to form a capacitive sensor. This diaphragm responds to sound waves identically to a conventional acoustic stethoscope, with changes in an electric field replacing changes in air pressure. This preserves the sound of an acoustic stethoscope with the benefits of amplification.
More recently, ambient noise filtering has become available in electronic stethoscopes, with 3M's Littmann 3000 and Thinklabs ds32a offering methods for eliminating ambient noise. | Stethoscope
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The stethoscope (Greek στηθοσκόπιο, of στήθος, stéthos - chest and σκοπή, skopé - examination) is an acoustic medical device for auscultation, or listening, to internal sounds in a human or animal body. It is most often used to listen to heart sounds and breathing. It is also used to listen to intestines and blood flow in arteries and veins. Less commonly, "mechanic's stethosopes" are used to listen to internal sounds made by machines, such as diagnosing a malfunctioning automobile engine by listening to the sounds of its internal parts.
# History
The stethoscope was invented in France in 1816 by René-Théophile-Hyacinthe Laennec. It consisted of a wooden tube and was monaural. His device was similar to the common ear trumpet; indeed, his invention was almost indistinguishable in structure and function from the trumpet, which was commonly called a "microphone." In 1851 Arthur Leared invented a binaural stethoscope, and in 1852 George Cammann perfected the design of the instrument for commercial production, which has become the standard ever since. Cammann also authored a major treatise on diagnosis by auscultation, which the refined binaural stethoscope made possible. By 1873, there were descriptions of a differential stethoscope that could connect to slightly different locations to create a slight stereo effect, though this did not become a standard tool in clinical practise.
Rappaport and Sprague designed a new stethoscope in the 1940's which became the standard by which other stethoscopes are measured. The Rappaport-Sprague was later made by Hewlett-Packard, later Philips, and today there are still cardiologists who consider it to be the finest acoustic stethoscope. Several other minor refinements were made to stethoscopes until in the early 1960's Dr. Littmann, a Harvard Medical School professor, created a new stethoscope that was lighter than previous models.
# Current practice
The stethoscope is used in aid of diagnosing certain diseases and conditions. The stethoscope is able to transmit certain sounds and exclude others. Before the stethoscope was invented, doctors placed their ear next to the patient's body in hopes of hearing something.
Stethoscopes are often considered as a symbol of the doctor's profession, as doctors are often seen or depicted with a stethoscope hanging around their neck.
Stethoscopes are also used by mechanics to isolate sounds of a particular moving engine part for diagnosis.
Stethoscopes are sometimes used by safe-crackers to hear the tumblers inside the combination, to ultimately learn the combination to a safe.
## Types of stethoscopes
### Acoustic
Acoustic stethoscopes are familiar to most people, and operate on the transmission of sound from the chestpiece, via air-filled hollow tubes, to the listener's ears. The chestpiece usually consists of two sides that can be placed against the patient for sensing sound — a diaphragm (plastic disc) or bell (hollow cup). If the diaphragm is placed on the patient, body sounds vibrate the diaphragm, creating acoustic pressure waves which travel up the tubing to the listener's ears. If the bell is placed on the patient, the vibrations of the skin directly produce acoustic pressure waves traveling up to the listener's ears. The bell transmits low frequency sounds, while the diaphragm transmits higher frequency sounds. This 2-sided stethoscope was invented by Rappaport and Sprague in the early part of the 20th century. One problem with acoustic stethoscopes is that the sound level is extremely low. They are the most commonly used.
### Electronic
Electronic stethoscopes overcome the low sound levels by amplifiying body sounds. Currently, a number of companies offer electronic stethoscopes, and it can be expected that within a few years, the electronic stethoscope will have eclipsed acoustic devices.
Electronic stethoscopes require conversion of acoustic sound waves to electrical signals which can then be amplified and processed for optimal listening. Unlike acoustic stethoscopes, which are all based on the same physics, transducers in electronic stethoscopes vary widely. The simplest and least effective method of sound detection is achieved by placing a microphone in the chestpiece. This method suffers from ambient noise interference and has fallen out of favor. Another method, used in Welch-Allyn's Meditron stethoscope, comprises placement of a piezoelectric crystal at the head of a metal shaft, the bottom of the shaft making contact with a diaphragm. 3M also uses a piezo-electric crystal placed within foam behind a thick rubber-like diaphragm. Thinklabs uses a stethoscope diaphragm with an electrically conductive inner surface to form a capacitive sensor. This diaphragm responds to sound waves identically to a conventional acoustic stethoscope, with changes in an electric field replacing changes in air pressure. This preserves the sound of an acoustic stethoscope with the benefits of amplification.
More recently, ambient noise filtering has become available in electronic stethoscopes, with 3M's Littmann 3000 and Thinklabs ds32a offering methods for eliminating ambient noise. | https://www.wikidoc.org/index.php/Stethescope | |
2bc1daf6a9a153fce3483a1e070625a212342dc5 | wikidoc | Stinky tofu | Stinky tofu
Stinky tofu is a form of fermented tofu, which, as the name suggests, has a strong odor. It is a popular snack in East and Southeast Asia, particularly China, Taiwan, and Indonesia where it is usually found at night markets or roadside stands, or as a side dish in lunch bars.
# Preparation
Wide regional and individual variations exist in manufacture and preparation. Most typically, it consists of tofu, which has been marinated in a brine made from fermented vegetables for as long as several months. The brine can also include dried shrimp, amaranth greens, mustard greens, bamboo shoots, and Chinese herbs.
Stinky tofu can be eaten cold, steamed, stewed, or most commonly, fried. It is often accompanied by chili sauce. The color varies from the golden fried Zhejiang-style to the black typical of Hunan-style stinky tofu .
From a distance, the odor of stinky tofu is said to resemble that of rotten garbage or manure, even by its enthusiasts. In spite of stinky tofu's smell, the flavor is surprisingly mild. Some have compared it to the taste of blue cheese. It is said the more it smells, the better its flavor. Many foreigners, and even many Chinese and Taiwanese people detest stinky tofu, particularly on first encountering it.
# Regional
## China
Stinky tofu is made and consumed in different ways in various areas of China. For example, the types of dried stinky tofu made in Changsha and Shaoxing are both very popular, but they are made with different methods, and the resulting flavors are very different. The most famous shop for stinky tofu in Changsha makes the tofu with yellow soybeans marinated in seasoning. The stinky tofu sold in Tianjin is mostly made in the Nanjing style, with a mild aroma.
## Hong Kong
This has been another one of the street trademark food along with fishball and beef ball. The street style is rather plain. It is deep fried fresh at street hawker stalls and sometimes dai pai dong. It is purchased by the bag, and is well known for the grease and oil. It goes with hoisin sauce as the tradition.
## Taiwan
In Taiwan, stinky tofu is also served with goose blood in a Sichuan mala soup. | Stinky tofu
Template:Chinese
Stinky tofu is a form of fermented tofu, which, as the name suggests, has a strong odor. It is a popular snack in East and Southeast Asia, particularly China, Taiwan, and Indonesia where it is usually found at night markets or roadside stands, or as a side dish in lunch bars.
# Preparation
Wide regional and individual variations exist in manufacture and preparation. Most typically, it consists of tofu, which has been marinated in a brine made from fermented vegetables for as long as several months. The brine can also include dried shrimp, amaranth greens, mustard greens, bamboo shoots, and Chinese herbs.[1]
Stinky tofu can be eaten cold, steamed, stewed, or most commonly, fried. It is often accompanied by chili sauce. The color varies from the golden fried Zhejiang-style to the black typical of Hunan-style stinky tofu .[1]
From a distance, the odor of stinky tofu is said to resemble that of rotten garbage or manure, even by its enthusiasts. In spite of stinky tofu's smell, the flavor is surprisingly mild. Some have compared it to the taste of blue cheese. It is said the more it smells, the better its flavor. Many foreigners, and even many Chinese and Taiwanese people detest stinky tofu, particularly on first encountering it.[citation needed]
# Regional
## China
Stinky tofu is made and consumed in different ways in various areas of China. For example, the types of dried stinky tofu made in Changsha and Shaoxing are both very popular, but they are made with different methods, and the resulting flavors are very different. The most famous shop for stinky tofu in Changsha makes the tofu with yellow soybeans marinated in seasoning. The stinky tofu sold in Tianjin is mostly made in the Nanjing style, with a mild aroma.
## Hong Kong
This has been another one of the street trademark food along with fishball and beef ball. The street style is rather plain. It is deep fried fresh at street hawker stalls and sometimes dai pai dong. It is purchased by the bag, and is well known for the grease and oil. It goes with hoisin sauce as the tradition.
## Taiwan
In Taiwan, stinky tofu is also served with goose blood in a Sichuan mala soup. | https://www.wikidoc.org/index.php/Stinky_tofu | |
29c17b7d7de81b29172f93ae6b2ff51025a0ee8c | wikidoc | Stiripentol | Stiripentol
# Overview
Stiripentol (marketed as Diacomit by Laboratoires BIOCODEX) is an anticonvulsant drug used in the treatment of epilepsy.
It is unrelated to other anticonvulsants and belongs to the group of aromatic allylic alcohols.
# Mechanism of action
As with most anticonvulsants, the precise mechanism is unknown. It has been shown to have anticonvulsant effects on its own. It can prevent the reuptake of GABA and inhibit its metabolism.
It also improves the effectiveness of many other anticonvulsants, possibly due to it inhibiting certain enzymes. This slows the drug's metabolism, increasing blood plasma levels.
# Approval history
## E.U.
- December 2001 - Treatment of severe myoclonic epilepsy in infancy (SMEI). EU orphan designation number EU/3/01/071.
Stiripentol has very limited availability.
# Indications and usage
It is indicated as an adjunctive therapy with sodium valproate and clobazam for treating severe myoclonic epilepsy in infancy (SMEI, also know as Dravet's syndrome). Children with SMEI develop often intractable seizures during their first year of life and mental retardation follows. Small-scale trials have show remarkably high response rates, with a significant minority of those treated becoming seizure free.
In addition, it may be used to treat refractory childhood epilepsy in conjunction with carbamazepine. It appears to be less effective in adolescents and adults.
# Dosing
Stiripentol is available as a gelatine capsule (250mg, 500mg) and as a sachet of powder to make a drinkable suspension (250mg, 500mg).
Initial dose is 50 mg/kg per day. This may be increased up to 100 mg/kg per day, with a maximum of 4g. The dose to be divided into two or three with meals. The does of other anticonvulsants may have to be reduced (possibly up to 50%).
# Side effects
Side effects are largely due to the increase in plasma concentrations of other anticonvulsants and can be reduced by lowering the does of those drugs. Nausea and vomiting are particularly noted when used in combination with sodium valproate.
# Drug interactions
Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines. This is both a strength and weakness. It appears to increase the potency of phenobarbital, primidone, phenytoin, carbamazepine, clobazam and diazepam. For example, blood levels of carbamazepine can be maintained whist reducing the dose by 50%. | Stiripentol
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Stiripentol (marketed as Diacomit by Laboratoires BIOCODEX) is an anticonvulsant drug used in the treatment of epilepsy.
It is unrelated to other anticonvulsants and belongs to the group of aromatic allylic alcohols.
# Mechanism of action
As with most anticonvulsants, the precise mechanism is unknown. It has been shown to have anticonvulsant effects on its own. It can prevent the reuptake of GABA and inhibit its metabolism.
It also improves the effectiveness of many other anticonvulsants, possibly due to it inhibiting certain enzymes. This slows the drug's metabolism, increasing blood plasma levels.
# Approval history
## E.U.
- December 2001 - Treatment of severe myoclonic epilepsy in infancy (SMEI). EU orphan designation number EU/3/01/071.
Stiripentol has very limited availability.
# Indications and usage
It is indicated as an adjunctive therapy with sodium valproate and clobazam for treating severe myoclonic epilepsy in infancy (SMEI, also know as Dravet's syndrome). Children with SMEI develop often intractable seizures during their first year of life and mental retardation follows. Small-scale trials have show remarkably high response rates, with a significant minority of those treated becoming seizure free.
In addition, it may be used to treat refractory childhood epilepsy in conjunction with carbamazepine. It appears to be less effective in adolescents and adults.
# Dosing
Stiripentol is available as a gelatine capsule (250mg, 500mg) and as a sachet of powder to make a drinkable suspension (250mg, 500mg).
Initial dose is 50 mg/kg per day. This may be increased up to 100 mg/kg per day, with a maximum of 4g. The dose to be divided into two or three with meals. The does of other anticonvulsants may have to be reduced (possibly up to 50%).
# Side effects
Side effects are largely due to the increase in plasma concentrations of other anticonvulsants and can be reduced by lowering the does of those drugs. Nausea and vomiting are particularly noted when used in combination with sodium valproate.
# Drug interactions
Stiripentol inhibits several cytochrome P450 isoenzymes and so interacts with many anticonvulsants and other medicines. This is both a strength and weakness. It appears to increase the potency of phenobarbital, primidone, phenytoin, carbamazepine, clobazam and diazepam. For example, blood levels of carbamazepine can be maintained whist reducing the dose by 50%. | https://www.wikidoc.org/index.php/Stiripentol | |
9ca3f48fb0c281fef5190dfee88c3ae95e96957d | wikidoc | Stomatology | Stomatology
# Overview
Stomatology is an international training course in specialised medicine recognised in the European Union relating to the mouth and its diseases. It requires a minimum of 3 years' university training beyond the medical degree (MD), and it also generally forms part of a dental degree. The specialty is defined within Europe under the Medical Directive 2001/19/EC.
# Focus
The study of stomatology includes, but is not limited to, the following:
1.1. At the sickness of parodentium:
a)extraction of a dental deposit of over gingival and sub gingival
Manual
Piezon-master
b) teaching of hygiene of the oral cavity
c) Hygiene control
d) medial treatment of gingival periodontal canal
e) Flap operation
f) application of medical – protective band
g) selective filing
h) temporary splinting
2. At the disease of mucous membrane.
2.1. Take material for oral cavity:
- Cytological analysis
- diorrological analysis
- bacterioscopic analysis
2.2. Application irrigation by medicinal agent has done:
- anaesthetization
- anti-infective agent anaesthetization
- enzyme anaesthetization
- by keratoplasty
2.3. Injections Done:
- by pharmaceutical composition
- blockades
- preventive/initial/teeth handling by anticarious agent
- cutter choice
2.3 Preparation of carious cavity of different appearance
- by Bleck
- for composite materials
- tooth stopping with amalgam
- composite material of chemical rejection and light rejection
- glass ionomers cement – 20 teeth and glass ionomers inset
- polish and burnish the stopping
- utilization of modern matrix and retainer during the stopping
- utilization of light reflector wedges during the polymnerization of composites
- gluing up by fissure hermetics
- utilization of temporary filing materials, insulating liners
- treatment of deep caries with utilization of modern liners
- sandwich – technics
- make insets direct method
- utilization of parapulpal nail for the renewal of the crown of tooth
- during the trauma and caries of 4 class by Bleck
2.4. Pulpitis treated by:
- pulp devitalization -
- preservation of viable pulp
- utilize the endodontic handpiece
- extract the coronal pulp and root pulp
- determine the (active) length of teeth canals
2.5. Root canals with
- antibacterial preparations
- chemical preparations | Stomatology
# Overview
Stomatology is an international training course in specialised medicine recognised in the European Union relating to the mouth and its diseases. It requires a minimum of 3 years' university training beyond the medical degree (MD), and it also generally forms part of a dental degree. The specialty is defined within Europe under the Medical Directive 2001/19/EC.
# Focus
The study of stomatology includes, but is not limited to, the following:
1.1. At the sickness of parodentium:
a)extraction of a dental deposit of over gingival and sub gingival
Manual
Piezon-master
b) teaching of hygiene of the oral cavity
c) Hygiene control
d) medial treatment of gingival periodontal canal
e) Flap operation
f) application of medical – protective band
g) selective filing
h) temporary splinting
2. At the disease of mucous membrane.
2.1. Take material for oral cavity:
- Cytological analysis
- diorrological analysis
- bacterioscopic analysis
2.2. Application irrigation by medicinal agent has done:
- anaesthetization
- anti-infective agent anaesthetization
- enzyme anaesthetization
- by keratoplasty
2.3. Injections Done:
- by pharmaceutical composition
- blockades
- preventive/initial/teeth handling by anticarious agent
- cutter choice
2.3 Preparation of carious cavity of different appearance
- by Bleck
- for composite materials
- tooth stopping with amalgam
- composite material of chemical rejection and light rejection
- glass ionomers cement – 20 teeth and glass ionomers inset
- polish and burnish the stopping
- utilization of modern matrix and retainer during the stopping
- utilization of light reflector wedges during the polymnerization of composites
- gluing up by fissure hermetics
- utilization of temporary filing materials, insulating liners
- treatment of deep caries with utilization of modern liners
- sandwich – technics
- make insets direct method
- utilization of parapulpal nail for the renewal of the crown of tooth
- during the trauma and caries of 4 class by Bleck
2.4. Pulpitis treated by:
- pulp devitalization -
- preservation of viable pulp
- utilize the endodontic handpiece
- extract the coronal pulp and root pulp
- determine the (active) length of teeth canals
2.5. Root canals with
- antibacterial preparations
- chemical preparations
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Stomatological | |
c770e45f8cdc2d51c5043fc89b841912ad4bfdd8 | wikidoc | String sign | String sign
# Overview
String sign is a medical term used in diagnosing Hypertrophic Pyloric Stenosis (HPS). Specifically, it is a radiographic finding on an Upper GI series in which the infant is given a radio-opaque material, such as barium, to drink. X-rays are then taken of the infant's stomach and intestines.
If the infant has pyloric stenosis, the pylorus is narrowed and the barium will take on the appearance of a thin string as it passes through this narrowed channel. Often, there are several of these strings seen (called the "railroad track sign"). The use of the Upper GI series for the diagnosis of HPS, which was the primary diagnostic tool for this condition in the 1980's and 1990's, has been largely replaced by the use of ultrasound, which is less invasive and can visualize the thickened pylorus, giving actual measurements of this thickening.
String sign is also used to describe a narrowed segment in regional ileitis. Among the inflammatory bowel disease, string sign appears in Crohn disease and not Ulcerative colitis making this sign of significance. | String sign
# Overview
String sign is a medical term used in diagnosing Hypertrophic Pyloric Stenosis (HPS). Specifically, it is a radiographic finding on an Upper GI series in which the infant is given a radio-opaque material, such as barium, to drink. X-rays are then taken of the infant's stomach and intestines.
If the infant has pyloric stenosis, the pylorus is narrowed and the barium will take on the appearance of a thin string as it passes through this narrowed channel. Often, there are several of these strings seen (called the "railroad track sign"). The use of the Upper GI series for the diagnosis of HPS, which was the primary diagnostic tool for this condition in the 1980's and 1990's, has been largely replaced by the use of ultrasound, which is less invasive and can visualize the thickened pylorus, giving actual measurements of this thickening.
String sign is also used to describe a narrowed segment in regional ileitis. Among the inflammatory bowel disease, string sign appears in Crohn disease and not Ulcerative colitis making this sign of significance. | https://www.wikidoc.org/index.php/String_sign | |
38334cc5c1a2d8c6f2dbeb61e3d2504972fc04bd | wikidoc | Strong acid | Strong acid
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
A strong acid is an acid that ionizes completely in an aqueous solution (not in the case of sulphuric acid as it is diprotic), or in other terms, with a pKa < −1.74. This generally means that in aqueous solution at standard temperature and pressure, the concentration of hydronium ions is equal to the concentration of strong acid introduced to the solution. While strong acids are generally assumed to be the most corrosive, this is not always true. The carborane superacid (H(CHB11Cl11), which is one million times stronger than sulfuric acid, is entirely non-corrosive, whereas the weak acid hydrofluoric acid (HF) is extremely corrosive and can dissolve, among other things, glass and all metals except iridium. The equation for complete dissociation of an acid in aqueous solution is as follows:
In all other acid-water reactions, dissociation is not complete, so will be represented as an equilibrium, not a completed reaction. The typical definition of a weak acid is any acid that does not dissociate completely. The difference separating the acid dissociation constants of strong acids from all other acids is so small that this is a reasonable demarcation.
Due to the complete dissociation of strong acids in aqueous solution, the concentration of hydronium ions in the water is equal to the re-duplication of the acid introduced to solution: = = ; pH = −log.
# Determining Acid Strength
The strength of an acid, in comparison to other acids, can be determined without the use of pH calculations by observing the following characteristics:
1. Electronegativity: The higher the EN of a conjugate base in the same period, the more acidic.
2. Atomic Radius: With increasing atomic radius, acidity also increases. For example, HCl and HI, both strong acids, ionize 100% in water to become their respective ionic constituents. However, HI is stronger than HCl. This is because the atomic radius of an atom of iodine is much larger than that of a chlorine atom. As a result, the negative charge over the I- anion is dispersed over a larger electron cloud and its attraction for the proton (H+) is not as strong as the same attraction in HCl. Therefore, HI is ionized (deprotonated) more readily.
3. Charge: The more positively charged a species is, the more acidic (neutral molecules can be stripped of protons more easily than anions, and cations are more acidic than comparable molecules).
# Some Common Strong Acids (As Ionizers)
(Strongest to the weakest)
- Perchloric acid HClO4
- Hydroiodic acid HI
- Hydrobromic acid HBr
- Hydrochloric acid HCl
- Sulfuric acid H2SO4 (Ka1/first dissociation only)
- Nitric acid HNO3
- Hydronium ion H3O+ or H+. For purposes of simplicity, H3O+ is often replaced in a chemical equation with H+. However, it should be noted that a bare proton simply does not exist in water but instead is bound to one of the lone pairs of electrons on the H2O molecule. This creates the hydronium ion and gives its single O atom a formal charge of +1.
- Some chemists include chloric acid (HClO3), bromic acid (HBrO3), perbromic acid (HBrO4), iodic acid (HIO3), and periodic acid (HIO4) as strong acids, although these are not universally accepted.
## Extremely Strong Acids (As Ionizers)
(Strongest to weakest)
- Fluoroantimonic acid HFSbF5
- Magic acid FSO3HSbF5
- Carborane superacid H(CHB11Cl11)
- Fluorosulfuric acid FSO3H
- Triflic acid CF3SO3H | Strong acid
- Acid-base extraction
- Acid-base reaction
- Acid-base physiology
- Acid-base homeostasis
- Dissociation constant
- Acidity function
- Buffer solutions
- pH
- Proton affinity
- Self-ionization of water
- Acids:
Lewis acids
Mineral acids
Organic acids
Strong acids
Superacids
Weak acids
- Lewis acids
- Mineral acids
- Organic acids
- Strong acids
- Superacids
- Weak acids
- Bases:
Lewis bases
Organic bases
Strong bases
Superbases
Non-nucleophilic bases
Weak bases
- Lewis bases
- Organic bases
- Strong bases
- Superbases
- Non-nucleophilic bases
- Weak bases
A strong acid is an acid that ionizes completely in an aqueous solution (not in the case of sulphuric acid as it is diprotic), or in other terms, with a pKa < −1.74. This generally means that in aqueous solution at standard temperature and pressure, the concentration of hydronium ions is equal to the concentration of strong acid introduced to the solution. While strong acids are generally assumed to be the most corrosive, this is not always true. The carborane superacid (H(CHB11Cl11), which is one million times stronger than sulfuric acid, is entirely non-corrosive, whereas the weak acid hydrofluoric acid (HF) is extremely corrosive and can dissolve, among other things, glass and all metals except iridium. The equation for complete dissociation of an acid in aqueous solution is as follows:
In all other acid-water reactions, dissociation is not complete, so will be represented as an equilibrium, not a completed reaction. The typical definition of a weak acid is any acid that does not dissociate completely. The difference separating the acid dissociation constants of strong acids from all other acids is so small that this is a reasonable demarcation.
Due to the complete dissociation of strong acids in aqueous solution, the concentration of hydronium ions in the water is equal to the re-duplication of the acid introduced to solution: [HA] = [H+] = [A−]; pH = −log[H+].
# Determining Acid Strength
The strength of an acid, in comparison to other acids, can be determined without the use of pH calculations by observing the following characteristics:
1. Electronegativity: The higher the EN of a conjugate base in the same period, the more acidic.
2. Atomic Radius: With increasing atomic radius, acidity also increases. For example, HCl and HI, both strong acids, ionize 100% in water to become their respective ionic constituents. However, HI is stronger than HCl. This is because the atomic radius of an atom of iodine is much larger than that of a chlorine atom. As a result, the negative charge over the I- anion is dispersed over a larger electron cloud and its attraction for the proton (H+) is not as strong as the same attraction in HCl. Therefore, HI is ionized (deprotonated) more readily.
3. Charge: The more positively charged a species is, the more acidic (neutral molecules can be stripped of protons more easily than anions, and cations are more acidic than comparable molecules).
# Some Common Strong Acids (As Ionizers)
(Strongest to the weakest)
- Perchloric acid HClO4
- Hydroiodic acid HI
- Hydrobromic acid HBr
- Hydrochloric acid HCl
- Sulfuric acid H2SO4 (Ka1/first dissociation only)
- Nitric acid HNO3
- Hydronium ion H3O+ or H+. For purposes of simplicity, H3O+ is often replaced in a chemical equation with H+. However, it should be noted that a bare proton simply does not exist in water but instead is bound to one of the lone pairs of electrons on the H2O molecule. This creates the hydronium ion and gives its single O atom a formal charge of +1.
- Some chemists include chloric acid (HClO3), bromic acid (HBrO3), perbromic acid (HBrO4), iodic acid (HIO3), and periodic acid (HIO4) as strong acids, although these are not universally accepted.
## Extremely Strong Acids (As Ionizers)
(Strongest to weakest)
- Fluoroantimonic acid HFSbF5
- Magic acid FSO3HSbF5
- Carborane superacid H(CHB11Cl11)
- Fluorosulfuric acid FSO3H
- Triflic acid CF3SO3H | https://www.wikidoc.org/index.php/Strong_acid | |
b21fa5cc52ad30362fabe2eee1a8a537b60d4008 | wikidoc | Strongylida | Strongylida
The order Strongylida includes many of the important nematodes found in the gastrointestinal tracts of ruminants, horses, and swine, as well as the lungworms of ruminants and, the hookworms of dogs and cats.
This order includes:
- Amidostomatidae
- Ancylostomidae
- Cloacinidae
- Diaphanocephalidae
- Dictyocaulidae
- Globocephalidae
- Heligosomatidae
- Metastrongylidae
- Ollulanidae
- Strongylidae
- Strongylacanthidae
- Syngamidae
- Trichostrongylidae
- Uncinariidae
# Major Families
## Diaphanocepaloidea
These are parasites of lizards and snakes. They have a direct life cycle in soil.
## Ancylostomatoidea
These have very large buccal vavities. They infect the small intestine of mammal carnivores by skin penetration.
## Strongyloidea
These have large buccal capsules with corona radiata. Most of them infect the large intestine by oral ingestion of the larva.
## Trichostrongyloidea
These worms have very small mouths and are found in a large number of hosts
## Metastrongyloidea
All of these parasites go through a snail to infect the lungs or vascular system of mammals, artiodactyls, carnivores, marsupials, and cetacea. | Strongylida
The order Strongylida includes many of the important nematodes found in the gastrointestinal tracts of ruminants, horses, and swine, as well as the lungworms of ruminants and, the hookworms of dogs and cats.
This order includes:
- Amidostomatidae
- Ancylostomidae
- Cloacinidae
- Diaphanocephalidae
- Dictyocaulidae
- Globocephalidae
- Heligosomatidae
- Metastrongylidae
- Ollulanidae
- Strongylidae
- Strongylacanthidae
- Syngamidae
- Trichostrongylidae
- Uncinariidae
# Major Families
## Diaphanocepaloidea
These are parasites of lizards and snakes. They have a direct life cycle in soil.
## Ancylostomatoidea
These have very large buccal vavities. They infect the small intestine of mammal carnivores by skin penetration.
## Strongyloidea
These have large buccal capsules with corona radiata. Most of them infect the large intestine by oral ingestion of the larva.
## Trichostrongyloidea
These worms have very small mouths and are found in a large number of hosts
## Metastrongyloidea
All of these parasites go through a snail to infect the lungs or vascular system of mammals, artiodactyls, carnivores, marsupials, and cetacea.
Template:Nematode-stub
Template:Parasite-stub
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Strongylida | |
f9a97b450104d1be17771bacde7976166070d040 | wikidoc | Study phase | Study phase
# Phase I Trials
These are initial studies to determine the metabolism and pharmacologic actions of drugs in humans (what are called PK/PD studies or pharmacokinetic / pharmacodynamic studies), the side effects associated with increasing doses (a dose response curve or dose response relationship), and to gain early evidence of effectiveness; may include healthy participants and/or patients. These are sometimes called a first in man study.
# Phase II Trials
Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks. Sometimes multiple doses will be studied in these trials to select the appropriate dose for further testing in phase III. These are sometimes called a dose finding study.
# Phase III Trials
Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling. These are also called pivotal trials.
# Phase IV Trials
After the drug has been approved by a regulatory agency, these are post-marketing studies to delineate additional information including the drug's risks,benefits, and optimal use in a broader group of real world patients. | Study phase
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Phase I Trials
These are initial studies to determine the metabolism and pharmacologic actions of drugs in humans (what are called PK/PD studies or pharmacokinetic / pharmacodynamic studies), the side effects associated with increasing doses (a dose response curve or dose response relationship), and to gain early evidence of effectiveness; may include healthy participants and/or patients. These are sometimes called a first in man study.
# Phase II Trials
Controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks. Sometimes multiple doses will be studied in these trials to select the appropriate dose for further testing in phase III. These are sometimes called a dose finding study.
# Phase III Trials
Expanded controlled and uncontrolled trials after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling. These are also called pivotal trials.
# Phase IV Trials
After the drug has been approved by a regulatory agency, these are post-marketing studies to delineate additional information including the drug's risks,benefits, and optimal use in a broader group of real world patients.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Study_phase | |
2bd0d50794ada4029996629bc24186c9b1e19c2b | wikidoc | Subluxation | Subluxation
# Overview
A subluxation may have different meanings, depending on the profession or specialty involved. It implies the presence of an incomplete or partial dislocation (Latin: luxatio) of a joint or organ
# Medicine
A medical subluxation is an incomplete or partial dislocation of a joint or organ. The World Health Organization (WHO) considers a subluxation to be a "significant structural displacement, and therefore visible on static imaging studies." In the spine, such a displacement may be caused by a spondylolisthesis.
## Orthopedics
An orthopedic dislocation of any joint will usually need medical attention to help relocate or reduce the joint. Nursemaid's elbow is the subluxation of the head of the radius from the annular ligament. Other joints that are prone to subluxations are the shoulders, fingers, kneecaps, and hips affected by hip dysplasia. A spinal subluxation is relatively rare, but can sometimes impinge on spinal nerve roots causing symptoms in the areas served by those roots.
## Ophthalmology
An ophthalmologic subluxation is called ectopia lentis, an ocular condition characterized by a displaced or malpositioned lens within the eye. Although a relatively rare disorder, subluxated lenses are frequently found in those who have had ocular trauma and those with certain systemic disorders, such as Marfan syndrome, Ehlers-Danlos syndrome and homocystinuria. Some subluxated lenses may require removal, as in the case of those that float freely or those that have opacified to form cataracts.
# Chiropractic
A chiropractic subluxation is called a vertebral subluxation, which is an historical concept defined by chiropractors as a relatively common condition in which a spinal vertebra has lost its proper juxtaposition with one or both of its neighboring vertebrae. While not as extreme as a luxation, chiropractors believe they interfere with the nervous system. The WHO considers the degree of structural displacement to not necessarily be "visible on static imaging studies." Although research into the significance of the chiropractic vertebral subluxation is ongoing in chiropractic circles, the concept is rejected by mainstream medicine and progressive chiropractors. Campbel et. al. considered that the disease is the result of spinal nerve dysfunction caused by misplaced (subluxated) vertebrae. Although rejected by medical science, this concept is still accepted by a minority of chiropractors.... Indeed, many progressive chiropractors have rejected the historical concept of the chiropractic subluxation in favor of ones that more accurately describe the nature of the complex joint dysfunctions they treat. | Subluxation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A subluxation may have different meanings, depending on the profession or specialty involved. It implies the presence of an incomplete or partial dislocation (Latin: luxatio)[1] of a joint or organ
# Medicine
A medical subluxation is an incomplete or partial dislocation of a joint or organ.[2] The World Health Organization (WHO) considers a subluxation to be a "significant structural displacement, and therefore visible on static imaging studies."[3] In the spine, such a displacement may be caused by a spondylolisthesis.
## Orthopedics
An orthopedic dislocation of any joint will usually need medical attention to help relocate or reduce the joint. Nursemaid's elbow is the subluxation of the head of the radius from the annular ligament. Other joints that are prone to subluxations are the shoulders, fingers, kneecaps, and hips affected by hip dysplasia. A spinal subluxation is relatively rare, but can sometimes impinge on spinal nerve roots causing symptoms in the areas served by those roots.
## Ophthalmology
An ophthalmologic subluxation is called ectopia lentis, an ocular condition characterized by a displaced or malpositioned lens within the eye.[4] Although a relatively rare disorder, subluxated lenses are frequently found in those who have had ocular trauma and those with certain systemic disorders, such as Marfan syndrome, Ehlers-Danlos syndrome and homocystinuria. Some subluxated lenses may require removal, as in the case of those that float freely or those that have opacified to form cataracts.
# Chiropractic
A chiropractic subluxation is called a vertebral subluxation, which is an historical concept defined by chiropractors as a relatively common condition in which a spinal vertebra has lost its proper juxtaposition with one or both of its neighboring vertebrae. While not as extreme as a luxation, chiropractors believe they interfere with the nervous system. The WHO considers the degree of structural displacement to not necessarily be "visible on static imaging studies."[3] Although research into the significance of the chiropractic vertebral subluxation is ongoing in chiropractic circles, the concept is rejected by mainstream medicine and progressive chiropractors. Campbel et. al. considered that the disease is the result of spinal nerve dysfunction caused by misplaced (subluxated) vertebrae. Although rejected by medical science, this concept is still accepted by a minority of chiropractors.... Indeed, many progressive chiropractors have rejected the historical concept of the chiropractic subluxation in favor of ones that more accurately describe the nature of the complex joint dysfunctions they treat. [5] | https://www.wikidoc.org/index.php/Subluxate | |
a40a28f69b94be31bdfc31c9762a358b497c7265 | wikidoc | Substance D | Substance D
Substance D (also called Death, Slow Death, D) is a fictional recreational drug used by characters in the Philip K. Dick novel, A Scanner Darkly.
# Composition of Substance D
Not much is said about the drug's chemical makeup, except that it is synthesised in a laboratory in an unknown location. It is derived from a small, blue flower grown primarily in the Anaheim, California area in a large produce farm. Substance D can be cut with meth, cocaine, or seemingly any stimulant drug. ,
# Effects of Substance D
If taken in large enough amounts (and in a high enough frequency) Substance D can cause hallucinations, paranoia (if taken in in increased levels) psychosis (permanent, usually; exempli gratia: Charles Freck , Jerry Fabin ) and, in a few cases, death (hence its street name). ,
It is implied multiple times in Dick's novel that Substance D induces lethargy, indicating that Substance D is not a stimulant. As is shown in the novel when Freck's ability to operate a car properly was hindered, Substance D apparently also impairs one's judgement (much like grain alcohol). ,
All throughout the novel, it is shown that long-term use of Substance D causes the two cerebral hemispheres of the brain to separate. "Death" also inhibits the ability of the two halves of the brain to 'communicate' with each other. This splitting of the brain (literally, right down the middle) ultimately causes a form of drug-induced Dissociative identity disorder (DID). The main character in the novel, Robert Arctor (played by Keanu Reeves in the 2006 film), had his mind divided into one side that became "Bob Arctor" and the other side that became Fred (his identity as an undercover narc in the Anaheim Police Force).
# People who use Substance D
Those who regularly use Substance D (which appears to be most of Anaheim, California) are referred to as heads. Those who don't, the users and addicts call straights. , ,
Philip K. Dick seems to separate the "straights" from the "heads," but makes it very nebulous as to who is dealing the drug. According to the novel's assertion of it, the straights don't use Substance D, but may deal it, and the heads don't usually deal, but they do use it (and buy from other heads or even straights).
# The legality of Substance D
Substance D is illegal for anyone to have and/or sell, but not to produce. This is evidenced by the fact that the California Police will set up an undercover sting operation to catch the dealers and those who possess it, but never go after the lab that manufactures it or the company that runs the lab.
Dick also mentions in A Scanner Darkly that the police don't often arrest "small-time local dealer," such as Donna Hawthorne (played by Winona Ryder in the 2006 film). However, despite all this, the police will " such persons automatically."
From the character of Charles Freck's view-point, California is a "fascist police state."
# Forms in which Substance D is sold
Substance D is sold in the following forms:
- "Tabs" (tablets)
- Liquid (for injection, via hypodermic needle)
Substance D (in the book) is only bought over the phone (called "buy calls") by way of a payphone, since the California Police bug everyone's phone lines.
One would call their dealer to arrange a meeting-spot to buy the drug, but even the pay phones are tapped.
In the film, Substance D is purchased in the same way, only with a cellular phone (since the film was set in the year 2013; the book was set in 1994). Cell-phone calls were monitored, so buyers kept their 'drug-talk' discrete. | Substance D
Substance D (also called Death, Slow Death, D) is a fictional recreational drug used by characters in the Philip K. Dick novel, A Scanner Darkly.
# Composition of Substance D
Not much is said about the drug's chemical makeup, except that it is synthesised in a laboratory in an unknown location. It is derived from a small, blue flower grown primarily in the Anaheim, California area in a large produce farm. Substance D can be cut with meth, cocaine, or seemingly any stimulant drug. [CH.2; PG.32], [CH.2; PG.31]
# Effects of Substance D
If taken in large enough amounts (and in a high enough frequency) Substance D can cause hallucinations, paranoia (if taken in in increased levels) psychosis (permanent, usually; exempli gratia: Charles Freck [played by Rory Cochrane in the 2006 film], Jerry Fabin [not present in film: combined into 'Charles Freck' character]) and, in a few cases, death (hence its street name). [CH.1; PG.1], [CH.4; PG.65]
It is implied multiple times in Dick's novel that Substance D induces lethargy, indicating that Substance D is not a stimulant. As is shown in the novel when Freck's ability to operate a car properly was hindered, Substance D apparently also impairs one's judgement (much like grain alcohol). [CH.1; PG.10], [CH.1; PG.9]
All throughout the novel, it is shown that long-term use of Substance D causes the two cerebral hemispheres of the brain to separate. "Death" also inhibits the ability of the two halves of the brain to 'communicate' with each other. This splitting of the brain (literally, right down the middle) ultimately causes a form of drug-induced Dissociative identity disorder (DID). The main character in the novel, Robert Arctor (played by Keanu Reeves in the 2006 film), had his mind divided into one side that became "Bob Arctor" and the other side that became Fred (his identity as an undercover narc in the Anaheim Police Force).
# People who use Substance D
Those who regularly use Substance D (which appears to be most of Anaheim, California) are referred to as heads. Those who don't, the users and addicts call straights. [CH.1; PG.9], [CH.1; PG10], [CH.1; PG.12]
Philip K. Dick seems to separate the "straights" from the "heads," but makes it very nebulous as to who is dealing the drug. According to the novel's assertion of it, the straights don't use Substance D, but may deal it, and the heads don't usually deal, but they do use it (and buy from other heads or even straights).
# The legality of Substance D
Substance D is illegal for anyone to have and/or sell, but not to produce. This is evidenced by the fact that the California Police will set up an undercover sting operation to catch the dealers and those who possess it, but never go after the lab that manufactures it or the company that runs the lab. [CH.3; PG.49]
Dick also mentions in A Scanner Darkly that the police don't often arrest "small-time local dealer[s]," such as Donna Hawthorne (played by Winona Ryder in the 2006 film). [CH.2; PG.31] However, despite all this, the police will "[hassle] such persons automatically."
From the character of Charles Freck's view-point, California is a "fascist police state."
# Forms in which Substance D is sold
Substance D is sold in the following forms:
- "Tabs" (tablets) [CH.1; PG.7]
- Liquid (for injection, via hypodermic needle) [CH.1; PG.14]
Substance D (in the book) is only bought over the phone (called "buy calls") by way of a payphone, since the California Police bug everyone's phone lines.
One would call their dealer to arrange a meeting-spot to buy the drug, but even the pay phones are tapped. [CH.2; PG.33]
In the film, Substance D is purchased in the same way, only with a cellular phone (since the film was set in the year 2013; the book was set in 1994). Cell-phone calls were monitored, so buyers kept their 'drug-talk' discrete. | https://www.wikidoc.org/index.php/Substance_D | |
8c722ba100a17bb0b2cacdec0919eef27e589eaa | wikidoc | Substance P | Substance P
Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:
- Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met (RPKPQQFFGLM)
with an amidation at the C-terminus.
Substance P is released from the terminals of specific sensory nerves. It is found in the brain and spinal cord and is associated with inflammatory processes and pain.
# Discovery
The original discovery of Substance P (SP) was in 1931 by Ulf von Euler and John H. Gaddum as a tissue extract that caused intestinal contraction in vitro. Its tissue distribution and biologic actions were further investigated over the following decades. The eleven-amino-acid structure of the peptide was determined by Chang, et. al in 1971.<Jul 21, 1971 ·
Amino-acid Sequence of Substance P. MICHAEL M. CHANG; , SUSAN E. LEEMAN; & HUGH D. NIALL. Nature New Biology ...
In 1983, NKA (previously known as substance K or neuromedin L) was isolated from porcine spinal cord and was also found to stimulate intestinal contraction.
# Receptor
The endogenous receptor for substance P is neurokinin 1 receptor (NK1-receptor, NK1R). It belongs to the tachykinin receptor sub-family of GPCRs. Other neurokinin subtypes and neurokinin receptors that interact with SP have been reported as well. Amino acid residues that are responsible for the binding of SP and its antagonists are present in the extracellular loops and transmembrane regions of NK-1. Binding of SP to NK-1 results in internalization by the clathrin-dependent mechanism to the acidified endosomes where the complex disassociates. Subsequently, SP is degraded and NK-1 is re-expressed on the cell surface.
Substance P and the NK1 receptor are widely distributed in the brain and are found in brain regions that are specific to regulating emotion (hypothalamus, amygdala, and the periaqueductal gray). They are found in close association with serotonin (5-HT) and neurons containing norepinephrine that are targeted by the currently used antidepressant drugs. The SP receptor promoter contains regions that are sensitive to cAMP, AP-1, AP-4, CEBPB, and epidermal growth factor. Because these regions are related to complexed signal transduction pathways mediated by cytokines, it has been proposed that cytokines and neurotropic factors can induce NK-1. Also, SP can induce the cytokines that are capable of inducing NK-1 transcription factors.
# Function
## Overview
Substance P ("P" standing for "Preparation" or "Powder") is a neuropeptide – but only nominally so, as it is ubiquitous. Its receptor – the neurokinin type 1 – is distributed over cytoplasmic membranes of many cell types (neurons, glia, endothelia of capillaries and lymphatics, fibroblasts, stem cells, white blood cells) in many tissues and organs. SP amplifies or excites most cellular processes.
Substance P is a key first responder to most noxious/extreme stimuli (stressors), i.e., those with a potential to compromise biological integrity. SP is thus regarded as an immediate defense, stress, repair, survival system. The molecule, which is rapidly inactivated (or at times further activated by peptidases) is rapidly released – repetitively and chronically, as warranted, in the presence of a stressor. Unique among biological processes, SP release (and expression of its NK1 Receptor (through autocrine, paracrine, and endocrine-like processes)) may not naturally subside in diseases marked by chronic inflammation (including cancer). The SP or its NK1R, as well as similar neuropeptides, appear to be vital targets capable of satisfying many unmet medical needs. The failure of clinical proof of concept studies, designed to confirm various preclinical predictions of efficacy, is currently a source of frustration and confusion among biomedical researchers.
### Vasodilation
Substance P is a potent vasodilator. Substance P-induced vasodilatation is dependent on nitric oxide release. Substance P is involved in the axon reflex-mediated vasodilatation to local heating and wheal and flare reaction. It has been shown that vasodilatation to substance P is dependent on the NK1 receptor located on the endothelium. In contrast to other neuropeptides studied in human skin, substance P-induced vasodilatation has been found to decline during continuous infusion. This possibly suggests an internalization of neurokinin-1 (NK1). As is typical with many vasodilators, it also has bronchoconstrictive properties, administered through the non-adrenergic, non-cholinergic nervous system (branch of the vagal system).
### Inflammation
SP initiates expression of almost all known immunological chemical messengers (cytokines). Also, most of the cytokines, in turn, induce SP and the NK1 receptor. SP is particularly excitatory to cell growth and multiplication. via usual, as well as oncogenic driver. SP is a trigger for nausea and emesis, Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibers in the skin, muscle, and joints. It is proposed that this release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infection or injury.
### Pain
Preclinical data support the notion that Substance P is an important element in pain perception. The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system. Substance P coexists with the excitatory neurotransmitter glutamate in primary afferents that respond to painful stimulation. Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibers in the skin, muscle, and joints. It is proposed that this release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infection or injury. Unfortunately, the reasons why NK1RAs have failed as efficacious analgesics in well-conducted clinical proof of concept studies have not yet been persuasively elucidated.
### Mood, anxiety, learning
Substance P has been associated with the regulation of mood disorders, anxiety, stress, reinforcement, neurogenesis, respiratory rhythm, neurotoxicity, pain, and nociception. In 2014, it was found that substance P played a role in male fruit fly aggression.
### Vomiting
The vomiting center in the medulla called the Area Postrema, contains high concentrations of substance P and its receptor, in addition to other neurotransmitters such as choline, histamine, dopamine, serotonin, and opioids. Their activation stimulates the vomiting reflex. Different emetic pathways exist, and substance P/NK1R appears to be within the final common pathway to regulate vomiting.
### Cell growth, proliferation, angiogenesis, and migration
The above processes are part and parcel to tissue integrity and repair. Substance P has been known to stimulate cell growth in normal and cancer cell line cultures, and it was shown that substance P could promote wound healing of non-healing ulcers in humans. SP and its induced cytokines promote multiplication of cells required for repair or replacement, growth of new blood vessels ., and "leg-like pods" on cells (including cancer cells) bestowing upon them mobility. and metastasis. It has been suggested that cancer exploits the SP-NK1R to progress and metastasize, and that NK1RAs may be useful in the treatment of several cancer types.
# Clinical significance of the SP-NK1R
## Quantification in disease
Elevation of serum, plasma, or tissue SP and/or its receptor (NK1R) has been associated with many diseases: sickle cell crisis; inflammatory bowel disease; major depression and related disorders; fibromyalgia; rheumatological; and infections such as HIV/AIDS and respiratory syncytial virus, as well as in cancer.
When assayed in the human, the observed variability of the SP concentrations are large, and in some cases the assay methodology is questionable. SP concentrations cannot yet be used to diagnose disease clinically or gauge disease severity. It is not yet known whether changes in concentration of SP or density of its receptors is the cause of any given disease, or an effect.
## Blockade for diseases with a chronic immunological component
As increasingly documented, the SP-NK1R system induces or modulates many aspects of the immune response, including WBC production and activation, and cytokine expression, Reciprocally, cytokines may induce expression of SP and its NK1R. In this sense, for diseases in which a pro-inflammatory component has been identified or strongly suspected, and for which current treatments are absent or in need of improvement, abrogation of the SP-NK1 system continues to receive focus as a treatment strategy. Currently, the only completely developed method available in that regard is antagonism (blockade, inhibition) of the SP preferring receptor, i.e., by drugs known as neurokinin type 1 antagonists (also termed: SP antagonists, or tachykinin antagonists.) One such drug is aprepitant to prevent the nausea and vomiting that accompanies chemotherapy, typically for cancer.
With the exception of chemotherapy-induced nausea and vomiting, the patho-physiological basis of many of the disease groups listed below, for which NK1RAs have been studied as a therapeutic intervention, are to varying extents hypothesized to be initiated or advanced by a chronic non-homeostatic inflammatory response.
### Dermatological disorders: eczema/psoriasis, chronic pruritus
High levels of BDNF and substance P have been found associated with increased itching in eczema.
### Mood disorders, major depressive disorder, anxiety disorders
To be populated re IL6, immunology of depression/anxiety, psycho-immune interface.
### Arthritis
To be populated.
### Cancer
To be populated. 20 years of research findings.
### Mood disorders, major depressive disorder, anxiety disorders
To be populated.
### Infections: HIV-AIDS, Measles, RSV, others
The role of SP in HIV-AIDS has been well-documented. Doses of aprepitant greater than those tested to date are required for demonstration of full efficacy. Respiratory syncytial and related viruses appear to upregulate SP receptors, and rat studies suggest that NK1RAs may be useful in treating or limiting long term sequelae from such infections.
Entamoeba histolytica is a unicellular parasitic protozoan that infects the lower gastrointestinal tract of humans. The symptoms of infection are diarrhea, constipation, and abdominal pain. This protozoan was found to secrete serotonin as well as substance P and neurotensin.
### Inflammatory bowel disease (IBD)/cystitis
Despite strong preclinical rationale, efforts to demonstrate efficacy of SP antagonists in inflammatory disease have been unproductive. A study in women with IBS confirmed that an NK1RAs antagonist was anxiolytic.
## Chemotherapy induced nausea and vomiting
In line with its role as a first line defense system, SP is released when toxicants or poisons come into contact with a range of receptors on cellular elements in the chemoreceptor trigger zone, located in the floor of the fourth ventricle of the brain, the (area postrema). Presumably, SP is released in or around the nucleus of the solitary tract upon integrated activity of dopamine, serotonin, opioid, and/or acetylcholine receptor signaling. NK1Rs are stimulated. In turn, a fairly complex reflex is triggered involving cranial nerves sub-serving respiration, retroperistalsis, and general autonomic discharge. The actions of aprepitant are said to be entirely central, thus requiring passage of the drug into the central nervous system. However, given that NK1Rs are unprotected by a blood brain barrier in the area postrema just adjacent to neuronal structures in the medulla, and the activity of sendide (the peptide based NK1RA) against cisplatin-induced emesis in the ferret. It is likely that some peripheral exposure contributes to antiemetic effects, even if through vagal terminals in the clinical setting.
## Other findings
### Denervation supersensitivity
When the innervation to substance P nerve terminals is lost, post-synaptic cells compensate for the loss of adequate neurotransmitter by increasing the expression of post-synaptic receptors. This, ultimately, leads to a condition known as denervation supersensitivity as the post-synaptic nerves will become hypersensitive to any release of substance P into the synaptic cleft.
### Male aggression
A suggestion of a link to male aggression was made in 2014. One research team found a correlation in male fruit flies and discussed it as a possibility in other species, even humans. Clues found in the brains of fruit flies might lead to further research that reveals the role of substance P in similar behaviour in those other species. | Substance P
Substance P (SP) is an undecapeptide (a peptide composed of a chain of 11 amino acid residues) member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator.[1][2] Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:[3]
- Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met (RPKPQQFFGLM)
with an amidation at the C-terminus.[4]
Substance P is released from the terminals of specific sensory nerves. It is found in the brain and spinal cord and is associated with inflammatory processes and pain.
# Discovery
The original discovery of Substance P (SP) was in 1931 by Ulf von Euler and John H. Gaddum as a tissue extract that caused intestinal contraction in vitro.[5] Its tissue distribution and biologic actions were further investigated over the following decades.[1] The eleven-amino-acid structure of the peptide was determined by Chang, et. al in 1971.<Jul 21, 1971 ·
Amino-acid Sequence of Substance P. MICHAEL M. CHANG; , SUSAN E. LEEMAN; & HUGH D. NIALL. Nature New Biology ...
>
In 1983, NKA (previously known as substance K or neuromedin L) was isolated from porcine spinal cord and was also found to stimulate intestinal contraction.[6]
# Receptor
The endogenous receptor for substance P is neurokinin 1 receptor (NK1-receptor, NK1R).[7] It belongs to the tachykinin receptor sub-family of GPCRs.[8] Other neurokinin subtypes and neurokinin receptors that interact with SP have been reported as well. Amino acid residues that are responsible for the binding of SP and its antagonists are present in the extracellular loops and transmembrane regions of NK-1. Binding of SP to NK-1 results in internalization by the clathrin-dependent mechanism to the acidified endosomes where the complex disassociates. Subsequently, SP is degraded and NK-1 is re-expressed on the cell surface.[9]
Substance P and the NK1 receptor are widely distributed in the brain and are found in brain regions that are specific to regulating emotion (hypothalamus, amygdala, and the periaqueductal gray).[10] They are found in close association with serotonin (5-HT) and neurons containing norepinephrine that are targeted by the currently used antidepressant drugs.[11] The SP receptor promoter contains regions that are sensitive to cAMP, AP-1, AP-4, CEBPB,[12] and epidermal growth factor. Because these regions are related to complexed signal transduction pathways mediated by cytokines, it has been proposed that cytokines and neurotropic factors can induce NK-1. Also, SP can induce the cytokines that are capable of inducing NK-1 transcription factors.[13]
# Function
## Overview
Substance P ("P" standing for "Preparation" or "Powder") is a neuropeptide – but only nominally so, as it is ubiquitous. Its receptor – the neurokinin type 1 – is distributed over cytoplasmic membranes of many cell types (neurons, glia, endothelia of capillaries and lymphatics, fibroblasts, stem cells, white blood cells) in many tissues and organs. SP amplifies or excites most cellular processes.[14][15]
Substance P is a key first responder to most noxious/extreme stimuli (stressors), i.e., those with a potential to compromise biological integrity. SP is thus regarded as an immediate defense, stress, repair, survival system. The molecule, which is rapidly inactivated (or at times further activated by peptidases) is rapidly released – repetitively and chronically, as warranted, in the presence of a stressor. Unique among biological processes, SP release (and expression of its NK1 Receptor (through autocrine, paracrine, and endocrine-like processes)) may not naturally subside in diseases marked by chronic inflammation (including cancer). The SP or its NK1R, as well as similar neuropeptides, appear to be vital targets capable of satisfying many unmet medical needs. The failure of clinical proof of concept studies, designed to confirm various preclinical predictions of efficacy, is currently a source of frustration and confusion among biomedical researchers.
### Vasodilation
Substance P is a potent vasodilator. Substance P-induced vasodilatation is dependent on nitric oxide release.[16] Substance P is involved in the axon reflex-mediated vasodilatation to local heating and wheal and flare reaction. It has been shown that vasodilatation to substance P is dependent on the NK1 receptor located on the endothelium. In contrast to other neuropeptides studied in human skin, substance P-induced vasodilatation has been found to decline during continuous infusion. This possibly suggests an internalization of neurokinin-1 (NK1).[17] As is typical with many vasodilators, it also has bronchoconstrictive properties, administered through the non-adrenergic, non-cholinergic nervous system (branch of the vagal system).
### Inflammation
SP initiates expression of almost all known immunological chemical messengers (cytokines).[18][19][20] Also, most of the cytokines, in turn, induce SP and the NK1 receptor.[21][22] SP is particularly excitatory to cell growth and multiplication.[23] via usual,[24] as well as oncogenic driver.[25] SP is a trigger for nausea and emesis,[26] Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibers in the skin, muscle, and joints. It is proposed that this release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infection or injury.[27]
### Pain
Preclinical data support the notion that Substance P is an important element in pain perception. The sensory function of substance P is thought to be related to the transmission of pain information into the central nervous system. Substance P coexists with the excitatory neurotransmitter glutamate in primary afferents that respond to painful stimulation.[28] Substance P and other sensory neuropeptides can be released from the peripheral terminals of sensory nerve fibers in the skin, muscle, and joints. It is proposed that this release is involved in neurogenic inflammation, which is a local inflammatory response to certain types of infection or injury.[27] Unfortunately, the reasons why NK1RAs have failed as efficacious analgesics in well-conducted clinical proof of concept studies have not yet been persuasively elucidated.
### Mood, anxiety, learning
Substance P has been associated with the regulation of mood disorders, anxiety, stress,[29] reinforcement,[30] neurogenesis,[31] respiratory rhythm,[32] neurotoxicity, pain, and nociception.[33] In 2014, it was found that substance P played a role in male fruit fly aggression.[34]
### Vomiting
The vomiting center in the medulla called the Area Postrema, contains high concentrations of substance P and its receptor, in addition to other neurotransmitters such as choline, histamine, dopamine, serotonin, and opioids. Their activation stimulates the vomiting reflex. Different emetic pathways exist, and substance P/NK1R appears to be within the final common pathway to regulate vomiting.[35]
### Cell growth, proliferation, angiogenesis, and migration
The above processes are part and parcel to tissue integrity and repair. Substance P has been known to stimulate cell growth in normal and cancer cell line cultures,[36] and it was shown that substance P could promote wound healing of non-healing ulcers in humans.[37] SP and its induced cytokines promote multiplication of cells required for repair or replacement, growth of new blood vessels .,[38] and "leg-like pods" on cells (including cancer cells) bestowing upon them mobility.[39] and metastasis.[40] It has been suggested that cancer exploits the SP-NK1R to progress and metastasize, and that NK1RAs may be useful in the treatment of several cancer types.[41][42][43][44]
# Clinical significance of the SP-NK1R
## Quantification in disease
Elevation of serum, plasma, or tissue SP and/or its receptor (NK1R) has been associated with many diseases: sickle cell crisis;[45] inflammatory bowel disease;[46][47] major depression and related disorders;[48][49][50] fibromyalgia;[51] rheumatological;[52] and infections such as HIV/AIDS and respiratory syncytial virus,[53] as well as in cancer.[54][55]
When assayed in the human, the observed variability of the SP concentrations are large, and in some cases the assay methodology is questionable.[56] SP concentrations cannot yet be used to diagnose disease clinically or gauge disease severity. It is not yet known whether changes in concentration of SP or density of its receptors is the cause of any given disease, or an effect.
## Blockade for diseases with a chronic immunological component
As increasingly documented, the SP-NK1R system induces or modulates many aspects of the immune response, including WBC production and activation, and cytokine expression,[57] Reciprocally, cytokines may induce expression of SP and its NK1R.[58][59] In this sense, for diseases in which a pro-inflammatory component has been identified or strongly suspected, and for which current treatments are absent or in need of improvement, abrogation of the SP-NK1 system continues to receive focus as a treatment strategy. Currently, the only completely developed method available in that regard is antagonism (blockade, inhibition) of the SP preferring receptor, i.e., by drugs known as neurokinin type 1 antagonists (also termed: SP antagonists, or tachykinin antagonists.) One such drug is aprepitant to prevent the nausea and vomiting that accompanies chemotherapy, typically for cancer.
With the exception of chemotherapy-induced nausea and vomiting, the patho-physiological basis of many of the disease groups listed below, for which NK1RAs have been studied as a therapeutic intervention, are to varying extents hypothesized to be initiated or advanced by a chronic non-homeostatic inflammatory response.[15][60][61][62]
### Dermatological disorders: eczema/psoriasis, chronic pruritus
High levels of BDNF and substance P have been found associated with increased itching in eczema.[63][64]
### Mood disorders, major depressive disorder, anxiety disorders
To be populated re IL6, immunology of depression/anxiety, psycho-immune interface.
### Arthritis
To be populated.
### Cancer
To be populated. 20 years of research findings.
### Mood disorders, major depressive disorder, anxiety disorders
To be populated.
### Infections: HIV-AIDS, Measles, RSV, others
The role of SP in HIV-AIDS has been well-documented.[57] Doses of aprepitant greater than those tested to date are required for demonstration of full efficacy. Respiratory syncytial and related viruses appear to upregulate SP receptors, and rat studies suggest that NK1RAs may be useful in treating or limiting long term sequelae from such infections.[65][66]
Entamoeba histolytica is a unicellular parasitic protozoan that infects the lower gastrointestinal tract of humans. The symptoms of infection are diarrhea, constipation, and abdominal pain.[67][68] This protozoan was found to secrete serotonin[69] as well as substance P and neurotensin.[70]
### Inflammatory bowel disease (IBD)/cystitis
Despite strong preclinical rationale,[71] efforts to demonstrate efficacy of SP antagonists in inflammatory disease have been unproductive. A study in women with IBS confirmed that an NK1RAs antagonist was anxiolytic.[72]
## Chemotherapy induced nausea and vomiting
In line with its role as a first line defense system, SP is released when toxicants or poisons come into contact with a range of receptors on cellular elements in the chemoreceptor trigger zone, located in the floor of the fourth ventricle of the brain, the (area postrema). Presumably, SP is released in or around the nucleus of the solitary tract upon integrated activity of dopamine, serotonin, opioid, and/or acetylcholine receptor signaling. NK1Rs are stimulated. In turn, a fairly complex reflex is triggered involving cranial nerves sub-serving respiration, retroperistalsis, and general autonomic discharge. The actions of aprepitant are said to be entirely central, thus requiring passage of the drug into the central nervous system.[73] However, given that NK1Rs are unprotected by a blood brain barrier in the area postrema just adjacent to neuronal structures in the medulla, and the activity of sendide (the peptide based NK1RA) against cisplatin-induced emesis in the ferret.[74] It is likely that some peripheral exposure contributes to antiemetic effects, even if through vagal terminals in the clinical setting.
## Other findings
### Denervation supersensitivity
When the innervation to substance P nerve terminals is lost, post-synaptic cells compensate for the loss of adequate neurotransmitter by increasing the expression of post-synaptic receptors. This, ultimately, leads to a condition known as denervation supersensitivity as the post-synaptic nerves will become hypersensitive to any release of substance P into the synaptic cleft.
### Male aggression
A suggestion of a link to male aggression was made in 2014. One research team found a correlation in male fruit flies and discussed it as a possibility in other species, even humans.[34] Clues found in the brains of fruit flies might lead to further research that reveals the role of substance P in similar behaviour in those other species. | https://www.wikidoc.org/index.php/Substance_P | |
76ba2a0555746e3990e62483b9e6862dbdb3468a | wikidoc | Sudan stain | Sudan stain
Sudan staining is the use of Sudan dyes to stain sudanophilic substances, usually lipids. Sudan lysochromes (Sudan II, Sudan III, Sudan IV, Oil Red O, and Sudan Black B) are used.
Sudan dyes have high affinity to fats, therefore they are used to demonstrate triglycerides, lipids, and lipoproteins.
Alcoholic solutions of Sudan dyes are usually used, however pyridine solutions can be used in some situations as well.
Sudan stain test is often used to determine the level of fecal fat to diagnose steatorrhea. Small sample is dissolved in water or saline, glacial acetic acid is added to hydrolyze the insoluble salts of fatty acids, few drops of alcoholic solution of Sudan III are added, the sample is spread on a microscopic slide, and heated twice to boil. Normally, a stool sample should show only a few drops of red-orange stained fat under the microscope. The method is only semiquantitative, however due to its simplicity it is used for screening. | Sudan stain
Sudan staining is the use of Sudan dyes to stain sudanophilic substances, usually lipids. Sudan lysochromes (Sudan II, Sudan III, Sudan IV, Oil Red O, and Sudan Black B) are used.
Sudan dyes have high affinity to fats, therefore they are used to demonstrate triglycerides, lipids, and lipoproteins.
Alcoholic solutions of Sudan dyes are usually used, however pyridine solutions can be used in some situations as well.
Sudan stain test is often used to determine the level of fecal fat to diagnose steatorrhea. Small sample is dissolved in water or saline, glacial acetic acid is added to hydrolyze the insoluble salts of fatty acids, few drops of alcoholic solution of Sudan III are added, the sample is spread on a microscopic slide, and heated twice to boil. Normally, a stool sample should show only a few drops of red-orange stained fat under the microscope. The method is only semiquantitative, however due to its simplicity it is used for screening.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Sudan_stain | |
b5be8cf7b7214bb9c0f3b26aedcf1003b6477df9 | wikidoc | Sugar-apple | Sugar-apple
In some regions of the world, the sugar-apple is also known as custard-apple, a different plant in the same genus.
Annona squamosa (Sugar-apple, Sweetsop or Custard Apple) is a species of Annona native to the tropical Americas. Its exact native range is unknown due to extensive cultivation, but thought to be in the Caribbean; the species was described from Jamaica.
It is a semi-evergreen shrub or small tree reaching 6-8 m tall. The leaves are alternate, simple, oblong-lanceolate, 5-17 cm long and 2-5 cm broad. The flowers are produced in clusters of 3-4, each flower 1.5-3 cm across, with six petals, yellow-green spotted purple at the base.
The fruit is usually round or oval, slightly pine cone-like, 6-10 cm diameter and weighing 100-230 g, with a scaly or lumpy skin. The fruit flesh is edible, white to light yellow, and resembles and tastes like custard. The seeds are scattered through the fruit flesh; they are blackish-brown, 12-18 mm long, and hard and shiny.
# Nomenclature
Different cultures have many names for the species. In English it is most widely known as Sugar-apple or Sweetsop, also sometimes custard-apple (especially in India) though technically incorrectly, as this name usually refers to another closely related species. In Latin America regional names include anón, anón de azucar, anona blanca, fruta do conde, cachiman, saramuyo, and many others. In India it is known as aarticum, "shareefa", sitaphal or seethaphal (literally meaning "sita fruit" as it resembles the head of Sita), and in Indonesia, srimatikiya or mostly people call it as "srikaya". The Taiwanese call it Sakya (Template:Zh-tp; Taiwanese: suck-khia, suck-kia) because one cultivar resembles the top part of Sakyamuni's (釋迦牟尼) head; it is also known as Buddha Head in Taiwan. Its name in Burmese is aajaa thee. In the Philippines it is called atis. In Thailand it is called Noi-Na (น้อยหน่า) which is also the common name for a hand-grenade because of its appearance. In Vietnam, it is called trái mãng cầu ta or na. In Brazil, it is called fruta do conde, pinha or ata.
# Cultivation and uses
Sugar-apple fruit is high in calories and is a good source of iron. It is the most widely cultivated of all the species of Annona, being grown widely throughout the tropics and warmer subtropics; it was introduced to southern Asia before 1590. It is naturalized north to southern Florida in the United States and south to Bahia in Brazil, and is an invasive species in some areas.
Like most species of Annona, it requires a tropical or subtropical climate with summer temperatures from 25 ° to 41 °C, and mean winter temperatures above 15 °C. It is sensitive to cold and frost, being defoliated below 10 °C and killed by temperatures of a few degrees below freezing. It is only moderately drought-tolerant, requiring rainfall above 700 mm, and not producing fruit well during droughts.
It is quite a prolific bearer and will produce fruit in as little as two to three years. A tree five years old may have produce as much as 50 fruit. Poor fruit production has been reported in Florida because there are few natural pollinators (honeybees have a difficult time penetrating the tightly closed female flowers); however hand pollination with a natural fiber brush is effective in increasing yield.
In the Philippines, the fruit is commonly eaten by the Philippine Fruit Bat (Kabag or Kabog) which then spreads the seeds from island to island.
In the Philippines there is a company that produces Sugar apple wine.
It is a host plant for larvae of the butterfly Graphium agamemnon (Tailed Jay).
It is used by some societies in India to prepare a hair tonic. The seeds are also ground and applied to rid the hair of lice. | Sugar-apple
In some regions of the world, the sugar-apple is also known as custard-apple, a different plant in the same genus.
Annona squamosa (Sugar-apple, Sweetsop or Custard Apple) is a species of Annona native to the tropical Americas. Its exact native range is unknown due to extensive cultivation, but thought to be in the Caribbean; the species was described from Jamaica.
It is a semi-evergreen shrub or small tree reaching 6-8 m tall. The leaves are alternate, simple, oblong-lanceolate, 5-17 cm long and 2-5 cm broad. The flowers are produced in clusters of 3-4, each flower 1.5-3 cm across, with six petals, yellow-green spotted purple at the base.
The fruit is usually round or oval, slightly pine cone-like, 6-10 cm diameter and weighing 100-230 g, with a scaly or lumpy skin. The fruit flesh is edible, white to light yellow, and resembles and tastes like custard. The seeds are scattered through the fruit flesh; they are blackish-brown, 12-18 mm long, and hard and shiny.
# Nomenclature
Different cultures have many names for the species. In English it is most widely known as Sugar-apple or Sweetsop, also sometimes custard-apple (especially in India) though technically incorrectly, as this name usually refers to another closely related species. In Latin America regional names include anón, anón de azucar, anona blanca, fruta do conde, cachiman, saramuyo, and many others. In India it is known as aarticum, "shareefa", sitaphal or seethaphal (literally meaning "sita fruit" as it resembles the head of Sita), and in Indonesia, srimatikiya or mostly people call it as "srikaya". The Taiwanese call it Sakya (Template:Zh-tp; Taiwanese: suck-khia, suck-kia) because one cultivar resembles the top part of Sakyamuni's (釋迦牟尼) head; it is also known as Buddha Head in Taiwan. Its name in Burmese is aajaa thee. In the Philippines it is called atis. In Thailand it is called Noi-Na (น้อยหน่า) which is also the common name for a hand-grenade because of its appearance. In Vietnam, it is called trái mãng cầu ta or na. In Brazil, it is called fruta do conde, pinha or ata.
# Cultivation and uses
Sugar-apple fruit is high in calories and is a good source of iron. It is the most widely cultivated of all the species of Annona, being grown widely throughout the tropics and warmer subtropics; it was introduced to southern Asia before 1590. It is naturalized north to southern Florida in the United States and south to Bahia in Brazil, and is an invasive species in some areas.
Like most species of Annona, it requires a tropical or subtropical climate with summer temperatures from 25 ° to 41 °C, and mean winter temperatures above 15 °C. It is sensitive to cold and frost, being defoliated below 10 °C and killed by temperatures of a few degrees below freezing. It is only moderately drought-tolerant, requiring rainfall above 700 mm, and not producing fruit well during droughts.
It is quite a prolific bearer and will produce fruit in as little as two to three years. A tree five years old may have produce as much as 50 fruit. Poor fruit production has been reported in Florida because there are few natural pollinators (honeybees have a difficult time penetrating the tightly closed female flowers); however hand pollination with a natural fiber brush is effective in increasing yield.
In the Philippines, the fruit is commonly eaten by the Philippine Fruit Bat (Kabag or Kabog) which then spreads the seeds from island to island.
In the Philippines there is a company that produces Sugar apple wine.
It is a host plant for larvae of the butterfly Graphium agamemnon (Tailed Jay).
It is used by some societies in India to prepare a hair tonic. The seeds are also ground and applied to rid the hair of lice. | https://www.wikidoc.org/index.php/Sugar-apple | |
b441f26a0db86819e5c8a9648dcd1bf0a8b527ea | wikidoc | Sulconazole | Sulconazole
# 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
Sulconazole is an antifungal that is FDA approved for the treatment of tinea pedis (athlete’s foot), tinea cruris, tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis and tinea versicolor. Common adverse reactions include pruritus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Sulconazole nitrate, 1.0% is an antifungal agent indicated for the treatment of tinea pedis (athlete’s foot), tinea cruris, and tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis, and for the treatment of tinea versicolor.
- A small amount of cream should be gently massaged into the affected and surrounding skin areas once or twice daily, except in tinea pedis, where administration should be twice daily.
- Early relief of symptoms is experienced by the majority of patients and clinical improvement may be seen fairly soon after treatment is begun; however, tinea corporis/cruris and tinea versicolor should be treated for 3 weeks and tinea pedis for 4 weeks to reduce the possibility of recurrence.
- If significant clinical improvement is not seen after 4 to 6 weeks of treatment, an alternate diagnosis should be considered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sulconazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulconazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Sulconazole in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sulconazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulconazole in pediatric patients.
# Contraindications
- Sulconazole nitrate, 1.0% is contraindicated in patients who have a history of hypersensitivity to any of its ingredients.
# Warnings
- Sulconazole nitrate, 1.0% is for external use only. Avoid contact with the eyes. If irritation develops, the cream should be discontinued and appropriate therapy instituted.
- Patients should be told to use sulconazole nitrate as directed by the physician, to use it externally only, and to avoid contact with the eyes.
- Long-term animal studies to determine carcinogenic potential have not been performed. In vitro studies have shown no mutagenic activity.
- Efficacy for this organism in the organ system was studied in fewer than ten infections.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Sulconazole in the drug label.
## Postmarketing Experience
- There were no systemic effects and only infrequent cutaneous adverse reactions in 1185 patients treated with sulconazole nitrate cream in controlled clinical trials. Approximately 3% of these patients reported itching, 3% burning or stinging, and 1% redness. These complaints did not usually interfere with treatment.
# Drug Interactions
There is limited information regarding Sulconazole Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well controlled studies in pregnant women. Sulconazole nitrate should be used during pregnancy only if clearly needed. Sulconazole nitrate has been shown to be embryotoxic in rats when given in doses of 125 times the adult human dose (in mg/kg). The drug was not teratogenic in rats or rabbits at oral doses of 50 mg/kg/day.
- Sulconazole nitrate given orally to rats at a dose 125 times the human dose resulted in prolonged gestation and dystocia. Several females died during the prenatal period, most likely due to labor complications.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sulconazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sulconazole during labor and delivery.
### Nursing Mothers
It is not known whether sulconazole nitrate is excreted in human milk. Caution should be exercised when sulconazole nitrate is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in children have not been established.
- Efficacy for this organism in the organ system was studied in fewer than ten infections.
### Geriatic Use
- Clinical studies of sulconazole nitrate, 1.0%, did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Sulconazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sulconazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sulconazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sulconazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sulconazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sulconazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Topical
### Monitoring
There is limited information regarding Monitoring of Sulconazole in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Sulconazole in the drug label.
# Overdosage
There is limited information regarding Sulconazole overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
There is limited information regarding Sulconazole Mechanism of Action in the drug label.
## Structure
- Sulconazole nitrate, 1.0% is a broad-spectrum antifungal agent intended for topical application. Sulconazole nitrate, USP the active ingredient in sulconazole nitrate, is an imidazole derivative with in vitro antifungal and antiyeast activity. Its chemical name is (±)-1-phenethyl]imidazole mononitrate and it has the following chemical structure:
- Sulconazole nitrate, USP is a white to off-white crystalline powder with a molecular weight of 460.77. It is freely soluble in pyridine; slightly soluble in ethanol, acetone, and chloroform; and very slightly soluble in water. It has a melting point of about 130°C.
- Sulconazole nitrate contains sulconazole nitrate 10 mg/g in an emollient cream base consisting of propylene glycol, stearyl alcohol, isopropyl myristate, cetyl alcohol, polysorbate 60, sorbitan monostearate, glyceryl stearate (and) PEG-100 stearate, ascorbyl palmitate, and purified water, with sodium hydroxide and/or nitric acid added to adjust the pH.
## Pharmacodynamics
There is limited information regarding Sulconazole Pharmacodynamics in the drug label.
## Pharmacokinetics
- Sulconazole nitrate is an imidazole derivative with broad-spectrum antifungal activity that inhibits the growth in vitro of the common pathogenic dermatophytes including Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum and Microsporum canis. It also inhibits (in vitro) the organism responsible for tinea versicolor, Malassezia furfur. Sulconazole nitrate has been shown to be active in vitro against the following microorganisms, although clinical efficacy has not been established: Candida albicans and certain gram positive bacteria.
- A modified Draize test showed no allergic contact dermatitis and a phototoxicity study showed no phototoxic or photoallergic reaction to sulconazole nitrate cream. Maximization tests with sulconazole nitrate cream showed no evidence of contact sensitization or irritation.
## Nonclinical Toxicology
There is limited information regarding Sulconazole Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Sulconazole Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Sulconazole How Supplied in the drug label.
## Storage
There is limited information regarding Sulconazole Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Sulconazole Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Sulconazole 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 Sulconazole Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Sulconazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Sulconazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [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
Sulconazole is an antifungal that is FDA approved for the treatment of tinea pedis (athlete’s foot), tinea cruris, tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis and tinea versicolor. Common adverse reactions include pruritus.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Sulconazole nitrate, 1.0% is an antifungal agent indicated for the treatment of tinea pedis (athlete’s foot), tinea cruris, and tinea corporis caused by Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum, and Microsporum canis, and for the treatment of tinea versicolor.
- A small amount of cream should be gently massaged into the affected and surrounding skin areas once or twice daily, except in tinea pedis, where administration should be twice daily.
- Early relief of symptoms is experienced by the majority of patients and clinical improvement may be seen fairly soon after treatment is begun; however, tinea corporis/cruris and tinea versicolor should be treated for 3 weeks and tinea pedis for 4 weeks to reduce the possibility of recurrence.
- If significant clinical improvement is not seen after 4 to 6 weeks of treatment, an alternate diagnosis should be considered.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sulconazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulconazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Sulconazole in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Sulconazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Sulconazole in pediatric patients.
# Contraindications
- Sulconazole nitrate, 1.0% is contraindicated in patients who have a history of hypersensitivity to any of its ingredients.
# Warnings
- Sulconazole nitrate, 1.0% is for external use only. Avoid contact with the eyes. If irritation develops, the cream should be discontinued and appropriate therapy instituted.
- Patients should be told to use sulconazole nitrate as directed by the physician, to use it externally only, and to avoid contact with the eyes.
- Long-term animal studies to determine carcinogenic potential have not been performed. In vitro studies have shown no mutagenic activity.
- Efficacy for this organism in the organ system was studied in fewer than ten infections.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Sulconazole in the drug label.
## Postmarketing Experience
- There were no systemic effects and only infrequent cutaneous adverse reactions in 1185 patients treated with sulconazole nitrate cream in controlled clinical trials. Approximately 3% of these patients reported itching, 3% burning or stinging, and 1% redness. These complaints did not usually interfere with treatment.
# Drug Interactions
There is limited information regarding Sulconazole Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well controlled studies in pregnant women. Sulconazole nitrate should be used during pregnancy only if clearly needed. Sulconazole nitrate has been shown to be embryotoxic in rats when given in doses of 125 times the adult human dose (in mg/kg). The drug was not teratogenic in rats or rabbits at oral doses of 50 mg/kg/day.
- Sulconazole nitrate given orally to rats at a dose 125 times the human dose resulted in prolonged gestation and dystocia. Several females died during the prenatal period, most likely due to labor complications.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sulconazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Sulconazole during labor and delivery.
### Nursing Mothers
It is not known whether sulconazole nitrate is excreted in human milk. Caution should be exercised when sulconazole nitrate is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness in children have not been established.
- Efficacy for this organism in the organ system was studied in fewer than ten infections.
### Geriatic Use
- Clinical studies of sulconazole nitrate, 1.0%, did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Sulconazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Sulconazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Sulconazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Sulconazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Sulconazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Sulconazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Topical
### Monitoring
There is limited information regarding Monitoring of Sulconazole in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Sulconazole in the drug label.
# Overdosage
There is limited information regarding Sulconazole overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
There is limited information regarding Sulconazole Mechanism of Action in the drug label.
## Structure
- Sulconazole nitrate, 1.0% is a broad-spectrum antifungal agent intended for topical application. Sulconazole nitrate, USP the active ingredient in sulconazole nitrate, is an imidazole derivative with in vitro antifungal and antiyeast activity. Its chemical name is (±)-1-[2,4-Dichloro-β-[(pchlorobenzyl)thio]phenethyl]imidazole mononitrate and it has the following chemical structure:
- Sulconazole nitrate, USP is a white to off-white crystalline powder with a molecular weight of 460.77. It is freely soluble in pyridine; slightly soluble in ethanol, acetone, and chloroform; and very slightly soluble in water. It has a melting point of about 130°C.
- Sulconazole nitrate contains sulconazole nitrate 10 mg/g in an emollient cream base consisting of propylene glycol, stearyl alcohol, isopropyl myristate, cetyl alcohol, polysorbate 60, sorbitan monostearate, glyceryl stearate (and) PEG-100 stearate, ascorbyl palmitate, and purified water, with sodium hydroxide and/or nitric acid added to adjust the pH.
## Pharmacodynamics
There is limited information regarding Sulconazole Pharmacodynamics in the drug label.
## Pharmacokinetics
- Sulconazole nitrate is an imidazole derivative with broad-spectrum antifungal activity that inhibits the growth in vitro of the common pathogenic dermatophytes including Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophyton floccosum and Microsporum canis. It also inhibits (in vitro) the organism responsible for tinea versicolor, Malassezia furfur. Sulconazole nitrate has been shown to be active in vitro against the following microorganisms, although clinical efficacy has not been established: Candida albicans and certain gram positive bacteria.
- A modified Draize test showed no allergic contact dermatitis and a phototoxicity study showed no phototoxic or photoallergic reaction to sulconazole nitrate cream. Maximization tests with sulconazole nitrate cream showed no evidence of contact sensitization or irritation.
## Nonclinical Toxicology
There is limited information regarding Sulconazole Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Sulconazole Clinical Studies in the drug label.
# How Supplied
There is limited information regarding Sulconazole How Supplied in the drug label.
## Storage
There is limited information regarding Sulconazole Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Sulconazole Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Sulconazole 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 Sulconazole Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Sulconazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Sulconazole | |
323f69a91a4a5fb1e97e4bf39be98266511b49c8 | wikidoc | Sulcus sign | Sulcus sign
# Overview
The Sulcus sign is an orthopedic evaluation test for glenohumeral instability of the shoulder (glenohumeral joint).
# Physical examination technique
This test can be administered with the patient either seated or standing with his arm relaxed at her side. The examiner palpates the shoulder by placing her thumb and fingers on the anterior and posterior aspects of the humeral head.
The examiner grasps the patient's elbow with her other hand and applies a downward distraction force. With excessive inferior translation, a depression occurs just below the acromion. A positive test will result in a sulcus being formed between the acromion and the humeral head as the humeral head moves inferiorly while the force is being applied. | Sulcus sign
Template:Search infobox
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The Sulcus sign is an orthopedic evaluation test for glenohumeral instability of the shoulder (glenohumeral joint).
# Physical examination technique
This test can be administered with the patient either seated or standing with his arm relaxed at her side. The examiner palpates the shoulder by placing her thumb and fingers on the anterior and posterior aspects of the humeral head.
The examiner grasps the patient's elbow with her other hand and applies a downward distraction force. With excessive inferior translation, a depression occurs just below the acromion. A positive test will result in a sulcus being formed between the acromion and the humeral head as the humeral head moves inferiorly while the force is being applied.
Template:Skin and subcutaneous tissue symptoms and signs
Template:Nervous and musculoskeletal system symptoms and signs
Template:Urinary system symptoms and signs
Template:Cognition, perception, emotional state and behaviour symptoms and signs
Template:Speech and voice symptoms and signs
Template:General symptoms and signs
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Sulcus_sign | |
bf7f69c27e3f59f1a8f03789f81e8ec6687425c2 | wikidoc | Sulfadoxine | Sulfadoxine
# Overview
Sulfadoxine (also spelled sulphadoxine) is an ultra-long-lasting sulfonamide previously used in combination with pyrimethamine to treat or prevent malaria. Due to high levels of resistance, its use is no longer recommended routinely.
It is also used, usually in combination with other drugs, to treat or prevent various infections in livestock.
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.
# Mechanism of action
Sulfadoxine competitively inhibits dihydropteroate synthase, interfering with folate synthesis.
# Synthesis | Sulfadoxine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sulfadoxine (also spelled sulphadoxine) is an ultra-long-lasting sulfonamide previously used in combination with pyrimethamine to treat or prevent malaria.[1] Due to high levels of resistance, its use is no longer recommended routinely.[2]
It is also used, usually in combination with other drugs, to treat or prevent various infections in livestock.[3]
It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[4]
# Mechanism of action
Sulfadoxine competitively inhibits dihydropteroate synthase, interfering with folate synthesis.
# Synthesis | https://www.wikidoc.org/index.php/Sulfadoxine | |
3db6b11de9c2d8bc470f144df53d215d240cf82f | wikidoc | Sun tanning | Sun tanning
# Overview
Sun tanning describes a darkening of the skin (especially of fair-skinned individuals) in a natural physiological response stimulated by exposure to ultraviolet radiation from sunshine (or a sunbed). With excess exposure to the sun, a suntanned area can also develop sunburn.
# Cause and effect
Darkening of the skin is caused by an increased release of the pigment melanin into the skin's cells after exposure to ultraviolet radiation. Melanin is produced by cells called melanocytes and protects the body from absorbing an excess of solar radiation, which can be harmful. Depending on genetics, some people can darken quickly and deeply whereas others do not darken much at all.
The ultraviolet frequencies responsible for tanning are often divided into the UVA (315 to 400nm wavelength) and UVB (280 to 315nm wavelength) ranges. UVB have higher energy than UVA waves and are therefore more damaging and more carcinogenic.
## UVB
- triggers creation and secretion of new melanin into the skin
- is thought to cause the formation of moles and some types of skin cancer (but not melanoma)
- causes skin aging (but at a far slower rate than UVA.)
- produces Vitamin D in human skin
- is more likely to cause a sunburn than UVA as a result of overexposure
- reduced by virtually all sunscreens in accordance with their SPF
## UVA
- causes release of preexisting melanin from the melanocytes
- causes the melanin to combine with oxygen (oxidize), which creates the actual tan color in the skin
- seems to cause cancer less than UVB, but causes melanoma, a far more dangerous type of skin cancer than other types
- is blocked less than UVB by many sunscreens but is blocked to some degree by clothing
- is present more uniformly throughout the day, and throughout the seasons than UVB
# Cultural history
Culturally, a suntan may be regarded as attractive, although this is susceptible to the whims of fashion. In ancient Rome, women deliberately lightened their skin with lead based cosmetics. At the time of Shakespeare, before the industrial revolution, untanned skin signified higher status, and Elizabeth I died from the white lead cosmetics; in Much Ado About Nothing, Act II, Scene I, Beatrice observes of her self-perceived unattractiveness and her consequent lack of marriage prospects:
In Europe, during much of the 18th and 19th centuries, fair, freckleless skin was considered attractive, especially in women, since tanned skin was associated with manual labour such as on a farm or in the outdoor employ of a wealthier person. Having fair skin signified that one was wealthy enough to hire other people to do manual labour. In 18th-century France, members of the royal court emphasized this point by powdering their faces to look as white as possible. As labour patterns shifted during the early 20th century, with indoor work becoming the norm, tanned skin came to be seen as a credential for membership of the leisured classes. When famous fashion designer Coco Chanel accidentally acquired a dark tan during a vacation on the French Riviera in the 1920's, she ignited a fad among whites for tanned skin. By the 1960s, a tan's earlier social significance had been reversed and bronzed skin among whites often signified social status, wealth and health, possibly for the opposite reason. Now that most jobs are done inside, tans among whites signify the wealth required to have the leisure time to acquire one.
# Health benefits
The skin produces vitamin D in response to sun exposure, which can be a health benefit for those with vitamin D deficiency. In 2002, Dr. William B. Grant published an article in the claiming that 23,800 premature deaths occur in the US annually from cancer due to insufficient UVB exposures (apparently via vitamin D deficiency). This is higher than 8,800 deaths occurred from melanoma or squamous cell carcinoma, so the overall effect of sun tanning might be beneficial. Another research estimates that 50,000–63,000 individuals in the United States and 19,000 - 25,000 in the UK die prematurely from cancer annually due to insufficient vitamin D.
Another effect of vitamin D deficiency is osteomalacia, which can result in bone pain, difficulty in weight bearing and sometimes fractures. This work has been updated in Grant et al. 2005 and Grant and Garland, 2006
In addition, it was reported that in Spain, risk of non-melanoma skin cancer is balanced by reduced risk of 16 types of cancer
According to a 2007 research of Islam, Gauderman, Cozen, and Mack , sun exposure during childhood prevents multiple sclerosis later in life.
Ultraviolet radiation has other medical applications, in the treatment of skin conditions such as psoriasis and vitiligo. Sunshine is informally used as a short term way to treat or hide acne, but research shows that in the long term, acne worsens with sunlight exposure and safer treatments now exist (see phototherapy).
# Social Context
Intentionally darkening one's skin did not become a socially desirable phenomenon in the West until the mid-20th century. For centuries, sharp divisions existed in most societies between the upper classes, whose members held positions of power and leisure indoors, and the commonfolk who typically led agrarian lives toiling outside. As a result, wealthier people tended to be fairer-skinned and this correlation made pale skin more desirable. Hence, the word "fair" came to mean "beautiful". The Industrial Revolution brought poor laborers and wealthy industrialists alike inside under the same roofs and this distinction began to evaporate. By the end of World War II, the economic boom the United States experienced gave middle class citizens more time and money to devote to leisurely pursuits. Vacations became standard practice and the advent of air travel made warmer, tropical destinations a more realistic possibility for average people. Tanned skin became associated not with a hard life of labor in the fields, but with swimming pools, backyard barbecues, dinner parties, and exotic vacations. In this context, tanned skin took on a feature of attractiveness as a signal of being well-traveled, cultured, and supposed evidence of leisure wealth. It also became a signal of health and strength as the bodybuilding and fitness industries increasingly promoted tanning to highlight muscle tone and definition.
In some other parts of the world, fair skin remains the standard of beauty. The geisha of Japan were renowned for their brilliant white painted faces, and the appeal of the
# Prevention
To avoid sunburn or excess tanning, covering up skin, wearing hats and staying out of direct sunlight is the primary defense.
If long sun exposure cannot be avoided or is desired one may use sunscreen or various over-the-counter creams to reduce sun exposure. The SPF (Sun Protection Factor) number on a sunscreen product shows its rated effectiveness. Products with a higher SPF number are those designed to provide more defense for the skin against the effects of solar radiation. However in 1998, the Annual Meeting of the American Association for the Advancement of Science reported that some sunscreens advertising UVA and UVB protection do not provide adequate safety from UVA radiation and could give sun tanners a false sense of protection.
Tanning oils or creams, when applied, are usually thicker on some parts of skin than on others. This causes some parts of skin to get more UVA and UVB than others and thus get sunburns. For this reason, improper application of tanning oils or creams may increase the occurrence of skin cancer and other skin diseases.
For those who choose to tan, some dermatologists recommend the following preventative measures:
- Make sure the sunscreen blocks both UVA and UVB rays. These types of sunscreens, called broad-spectrum sunscreens, contain more active ingredients. Ideally a sunscreen should also be hypoallergenic and noncomedogenic so it doesn't cause a rash or clog the pores, which can cause acne.
- Sunscreen needs to be applied thickly enough to make a difference. People often do not put on enough sunscreen to get the full SPF protection. In case of uncertainty about how much product to use, or discomfort with the amount applied, switching to a sunscreen with a higher SPF may help.
- Reapply sunscreen every 2 to 3 hours and after swimming or sweating. In direct sun, wear a sunscreen with a higher SPF (such as SPF 30). For playing sports the sunscreen should also be waterproof and sweatproof.
- The rays of the sun are strongest between 10 a.m. and 4 p.m (see ), so frequent shade breaks are recommended during these hours. Sun rays are stronger at higher elevations (mountains) and lower latitudes (near the equator). One way to deal with time zones, daylight saving time (summer time) and latitude is to check shadow length. If a person's shadow is shorter than their actual height, the risk of sunburn is much higher.
- Wear a hat with a brim and anti-UV sunglasses which can provide almost 100% protection against ultraviolet radiation entering the eyes.
- Be aware that reflective surfaces like snow and water can greatly increase the amount of UV radiation to which the skin is exposed.
The American Academy of Dermatology recommends the use of sunscreens, wearing sun protective clothing and avoiding the sun altogether. | Sun tanning
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Sun tanning describes a darkening of the skin (especially of fair-skinned individuals) in a natural physiological response stimulated by exposure to ultraviolet radiation from sunshine (or a sunbed). With excess exposure to the sun, a suntanned area can also develop sunburn.
# Cause and effect
Darkening of the skin is caused by an increased release of the pigment melanin into the skin's cells after exposure to ultraviolet radiation. Melanin is produced by cells called melanocytes and protects the body from absorbing an excess of solar radiation, which can be harmful. Depending on genetics, some people can darken quickly and deeply whereas others do not darken much at all.
The ultraviolet frequencies responsible for tanning are often divided into the UVA (315 to 400nm wavelength) and UVB (280 to 315nm wavelength) ranges. UVB have higher energy than UVA waves and are therefore more damaging and more carcinogenic.
## UVB
- triggers creation and secretion of new melanin into the skin
- is thought to cause the formation of moles and some types of skin cancer (but not melanoma)
- causes skin aging (but at a far slower rate than UVA.)
- produces Vitamin D in human skin
- is more likely to cause a sunburn than UVA as a result of overexposure
- reduced by virtually all sunscreens in accordance with their SPF
## UVA
- causes release of preexisting melanin from the melanocytes
- causes the melanin to combine with oxygen (oxidize), which creates the actual tan color in the skin
- seems to cause cancer less than UVB, but causes melanoma, a far more dangerous type of skin cancer than other types
- is blocked less than UVB by many sunscreens but is blocked to some degree by clothing
- is present more uniformly throughout the day, and throughout the seasons than UVB
# Cultural history
Culturally, a suntan may be regarded as attractive, although this is susceptible to the whims of fashion. In ancient Rome, women deliberately lightened their skin with lead based cosmetics. At the time of Shakespeare, before the industrial revolution, untanned skin signified higher status, and Elizabeth I died from the white lead cosmetics; in Much Ado About Nothing, Act II, Scene I, Beatrice observes of her self-perceived unattractiveness and her consequent lack of marriage prospects:
In Europe, during much of the 18th and 19th centuries, fair, freckleless skin was considered attractive, especially in women, since tanned skin was associated with manual labour such as on a farm or in the outdoor employ of a wealthier person. Having fair skin signified that one was wealthy enough to hire other people to do manual labour. In 18th-century France, members of the royal court emphasized this point by powdering their faces to look as white as possible. As labour patterns shifted during the early 20th century, with indoor work becoming the norm, tanned skin came to be seen as a credential for membership of the leisured classes. When famous fashion designer Coco Chanel accidentally acquired a dark tan during a vacation on the French Riviera in the 1920's, she ignited a fad among whites for tanned skin. By the 1960s, a tan's earlier social significance had been reversed and bronzed skin among whites often signified social status, wealth and health, possibly for the opposite reason. Now that most jobs are done inside, tans among whites signify the wealth required to have the leisure time to acquire one.
# Health benefits
The skin produces vitamin D in response to sun exposure, which can be a health benefit for those with vitamin D deficiency. In 2002, Dr. William B. Grant published an article in the claiming that 23,800 premature deaths occur in the US annually from cancer due to insufficient UVB exposures (apparently via vitamin D deficiency).[1] This is higher than 8,800 deaths occurred from melanoma or squamous cell carcinoma, so the overall effect of sun tanning might be beneficial. Another research[2][3] estimates that 50,000–63,000 individuals in the United States and 19,000 - 25,000 in the UK die prematurely from cancer annually due to insufficient vitamin D.
Another effect of vitamin D deficiency is osteomalacia, which can result in bone pain, difficulty in weight bearing and sometimes fractures. This work has been updated in Grant et al. 2005[4] and Grant and Garland, 2006[5]
In addition, it was reported that in Spain, risk of non-melanoma skin cancer is balanced by reduced risk of 16 types of cancer [Grant, 2006][6]
According to a 2007 research of Islam, Gauderman, Cozen, and Mack [7] [8], sun exposure during childhood prevents multiple sclerosis later in life.
Ultraviolet radiation has other medical applications, in the treatment of skin conditions such as psoriasis and vitiligo. Sunshine is informally used as a short term way to treat or hide acne, but research shows that in the long term, acne worsens with sunlight exposure and safer treatments now exist (see phototherapy).
# Social Context
Intentionally darkening one's skin did not become a socially desirable phenomenon in the West until the mid-20th century. For centuries, sharp divisions existed in most societies between the upper classes, whose members held positions of power and leisure indoors, and the commonfolk who typically led agrarian lives toiling outside. As a result, wealthier people tended to be fairer-skinned and this correlation made pale skin more desirable. Hence, the word "fair" came to mean "beautiful". The Industrial Revolution brought poor laborers and wealthy industrialists alike inside under the same roofs and this distinction began to evaporate. By the end of World War II, the economic boom the United States experienced gave middle class citizens more time and money to devote to leisurely pursuits. Vacations became standard practice and the advent of air travel made warmer, tropical destinations a more realistic possibility for average people. Tanned skin became associated not with a hard life of labor in the fields, but with swimming pools, backyard barbecues, dinner parties, and exotic vacations. In this context, tanned skin took on a feature of attractiveness as a signal of being well-traveled, cultured, and supposed evidence of leisure wealth. It also became a signal of health and strength as the bodybuilding and fitness industries increasingly promoted tanning to highlight muscle tone and definition.
In some other parts of the world, fair skin remains the standard of beauty. The geisha of Japan were renowned for their brilliant white painted faces, and the appeal of the
Template:Nihongo, or "beautiful white", ideal leads many Japanese women to avoid any form of tanning[9], and the color white is associated with purity and divinity in many Eastern religions. In post-colonial Africa and India, dark skin is heavily associated with a lower class status, and some people resort to skin bleaching to achieve a skin color they view as more socially acceptable.
# Prevention
To avoid sunburn or excess tanning, covering up skin, wearing hats and staying out of direct sunlight is the primary defense.
If long sun exposure cannot be avoided or is desired one may use sunscreen or various over-the-counter creams to reduce sun exposure. The SPF (Sun Protection Factor) number on a sunscreen product shows its rated effectiveness. Products with a higher SPF number are those designed to provide more defense for the skin against the effects of solar radiation. However in 1998, the Annual Meeting of the American Association for the Advancement of Science reported that some sunscreens advertising UVA and UVB protection do not provide adequate safety from UVA radiation and could give sun tanners a false sense of protection.
Tanning oils or creams, when applied, are usually thicker on some parts of skin than on others. This causes some parts of skin to get more UVA and UVB than others and thus get sunburns. For this reason, improper application of tanning oils or creams may increase the occurrence of skin cancer and other skin diseases.
For those who choose to tan, some dermatologists recommend the following preventative measures:
- Make sure the sunscreen blocks both UVA and UVB rays. These types of sunscreens, called broad-spectrum sunscreens, contain more active ingredients. Ideally a sunscreen should also be hypoallergenic and noncomedogenic so it doesn't cause a rash or clog the pores, which can cause acne.
- Sunscreen needs to be applied thickly enough to make a difference. People often do not put on enough sunscreen to get the full SPF protection. In case of uncertainty about how much product to use, or discomfort with the amount applied, switching to a sunscreen with a higher SPF may help.
- Reapply sunscreen every 2 to 3 hours and after swimming or sweating. In direct sun, wear a sunscreen with a higher SPF (such as SPF 30). For playing sports the sunscreen should also be waterproof and sweatproof.
- The rays of the sun are strongest between 10 a.m. and 4 p.m (see http://www.epa.gov/sunwise/actionsteps.html), so frequent shade breaks are recommended during these hours. Sun rays are stronger at higher elevations (mountains) and lower latitudes (near the equator). One way to deal with time zones, daylight saving time (summer time) and latitude is to check shadow length. If a person's shadow is shorter than their actual height, the risk of sunburn is much higher.
- Wear a hat with a brim and anti-UV sunglasses which can provide almost 100% protection against ultraviolet radiation entering the eyes.
- Be aware that reflective surfaces like snow and water can greatly increase the amount of UV radiation to which the skin is exposed.
The American Academy of Dermatology recommends the use of sunscreens, wearing sun protective clothing and avoiding the sun altogether. | https://www.wikidoc.org/index.php/Sun_tanning | |
a8b99267c9f84e8df5e0362e39d9a1581beaa3f5 | wikidoc | Suppository | Suppository
A suppository is a drug delivery system that is inserted either into the rectum (rectal suppository), vagina (vaginal suppository) or urethra (urethral suppository) where it dissolves. They are used to deliver both systemically-acting and locally-acting medications. The alternative term for delivery of medicine via such routes, is known as a pharmaceutical pessary.
The general principle is that the suppository is inserted as a solid, and will dissolve inside the body to deliver the medicine. (The phrase liquid suppository is also sometimes applied to small syringes injecting a liquid, typically a laxative, into the rectum.)
Vaginal suppositories are commonly used to treat gynaecological ailments, including vaginal infections such as candidiasis.
Rectal suppositories are commmonly used for:
- For laxative purposes, with chemicals such as glycerin or bisacodyl.
- To treat a hemorrhoid by delivering a moisturizer or vasoconstrictor.
- Delivery of many other systemically-acting medications, such as promethazine or aspirin.
- For general medical administration purposes: the substance crosses the rectal mucosa into the bloodstream; examples include paracetamol (acetaminophen), opiates, and eucalyptol suppositories.
Non-laxative rectal suppositories are to be used after defecation, so as not to be expelled before they are fully dissolved and the substance is absorbed.
Alprostadil pellets are urethral suppositories used for the treatment of severe erectile dysfunction. They are marketed under the name Muse in the United States. Its use has diminished since the development of oral impotence medications, but is still on the market.
Some suppositories are made from a greasy base, such as cocoa butter, in which the active ingredient and other excipients are dissolved; this grease will melt at body temperature (this may be a source of discomfort for the patient, as the melted grease may pass the anus during flatulences). Other suppositories are made from a water soluble base, such as polyethylene glycol. Suppositories made from polyethylene glycol are commonly used in vaginal and urethral suppositories. Glycerin suppositories are made of glycerol and gelatin.
Suppositories may be used for patients in the event it may be easier to administer than tablets or syrups. Suppositories may also be used when a patient has a stomach virus, and oral medication can be thrown up. | Suppository
A suppository is a drug delivery system that is inserted either into the rectum (rectal suppository), vagina (vaginal suppository) or urethra (urethral suppository) where it dissolves. They are used to deliver both systemically-acting and locally-acting medications. The alternative term for delivery of medicine via such routes, is known as a pharmaceutical pessary.
The general principle is that the suppository is inserted as a solid, and will dissolve inside the body to deliver the medicine. (The phrase liquid suppository is also sometimes applied to small syringes injecting a liquid, typically a laxative, into the rectum.)
Vaginal suppositories are commonly used to treat gynaecological ailments, including vaginal infections such as candidiasis.
Rectal suppositories are commmonly used for:
- For laxative purposes, with chemicals such as glycerin or bisacodyl.
- To treat a hemorrhoid by delivering a moisturizer or vasoconstrictor.
- Delivery of many other systemically-acting medications, such as promethazine or aspirin.
- For general medical administration purposes: the substance crosses the rectal mucosa into the bloodstream; examples include paracetamol (acetaminophen), opiates, and eucalyptol suppositories.
Non-laxative rectal suppositories are to be used after defecation, so as not to be expelled before they are fully dissolved and the substance is absorbed.
Alprostadil pellets are urethral suppositories used for the treatment of severe erectile dysfunction. They are marketed under the name Muse in the United States.[1] Its use has diminished since the development of oral impotence medications, but is still on the market.
Some suppositories are made from a greasy base, such as cocoa butter, in which the active ingredient and other excipients are dissolved; this grease will melt at body temperature (this may be a source of discomfort for the patient[citation needed], as the melted grease may pass the anus during flatulences). Other suppositories are made from a water soluble base, such as polyethylene glycol. Suppositories made from polyethylene glycol are commonly used in vaginal and urethral suppositories. Glycerin suppositories are made of glycerol and gelatin.
Suppositories may be used for patients in the event it may be easier to administer than tablets or syrups. Suppositories may also be used when a patient has a stomach virus, and oral medication can be thrown up. | https://www.wikidoc.org/index.php/Suppositories | |
2e2fbc9ec3517cb2f4b689b4eff711f3b38c26ee | wikidoc | Sweet Birch | Sweet Birch
Sweet Birch (Betula lenta), also known as Black Birch, Cherry Birch, Mahogany Birch, River Birch, or Spice Birch is a species of birch native to eastern North America, from southern Maine west to southernmost Ontario and southern Michigan, and south in the Appalachian Mountains to northern Georgia.
It is a medium-sized deciduous tree reaching 20 m tall with a trunk up to 60 cm diameter. The bark is (unlike most birches) rough, dark blackish-brown, cracking into irregular scaly plates. The twigs, when scraped, have a strong scent of oil of wintergreen. The leaves are alternate, ovate, 5-10 cm long and 4-8 cm broad, with a finely serrated margin. The flowers are wind-pollinated catkins 3-6 cm long, the male catkins pendulous, the female catkins erect. The fruit, maturing in fall, is composed of numerous tiny winged seeds packed between the catkin bracts.
Sweet Birch was used commercially in the past for production of oil of wintergreen before modern industrial synthesis; the tree's name reflects this scent of the shoots.
The sap flows about a month later than maple sap, and much faster. The trees can be tapped in a similar fashion, but must be gathered about three times more often. Birch sap can be boiled the same as maple sap, but its syrup is stronger (like molasses).
The Sweet Birch's leaves serve as food for some lepidopteran caterpillars. See List of Lepidoptera which feed on Birches.
# Gallery
- File:Betula lenta subsps lenta 01-10-2005 14.54.08.JPG
- Birch bark
Birch bark
- 19th century illustration
19th century illustration | Sweet Birch
Sweet Birch (Betula lenta), also known as Black Birch, Cherry Birch, Mahogany Birch, River Birch, or Spice Birch is a species of birch native to eastern North America, from southern Maine west to southernmost Ontario and southern Michigan, and south in the Appalachian Mountains to northern Georgia.
It is a medium-sized deciduous tree reaching 20 m tall with a trunk up to 60 cm diameter. The bark is (unlike most birches) rough, dark blackish-brown, cracking into irregular scaly plates. The twigs, when scraped, have a strong scent of oil of wintergreen. The leaves are alternate, ovate, 5-10 cm long and 4-8 cm broad, with a finely serrated margin. The flowers are wind-pollinated catkins 3-6 cm long, the male catkins pendulous, the female catkins erect. The fruit, maturing in fall, is composed of numerous tiny winged seeds packed between the catkin bracts.
Sweet Birch was used commercially in the past for production of oil of wintergreen before modern industrial synthesis; the tree's name reflects this scent of the shoots.
The sap flows about a month later than maple sap, and much faster. The trees can be tapped in a similar fashion, but must be gathered about three times more often. Birch sap can be boiled the same as maple sap, but its syrup is stronger (like molasses).
The Sweet Birch's leaves serve as food for some lepidopteran caterpillars. See List of Lepidoptera which feed on Birches.
# Gallery
- File:Betula lenta subsps lenta 01-10-2005 14.54.08.JPG
- Birch bark
Birch bark
- 19th century illustration
19th century illustration
# External links
- Flora of North America: Betula lenta RangeMap:
- Betula lenta images at bioimages.vanderbilt.edu
nl:Suikerberk | https://www.wikidoc.org/index.php/Sweet_Birch | |
3fc9fe65bc293aa6a1927448c9cb9c11b20e0417 | wikidoc | Systematics | Systematics
# Overview
Biological systematics is the study of the diversity of life on the planet Earth, both past and present, and the relationships among living things through time. Relationships are visualized as evolutionary trees (synonyms: cladograms, phylogenetic trees, phylogenies). Phylogenies have two components, branching order (showing group relationships) and branch length (showing amount of evolution). Phylogenetic trees of species and higher taxa are used to study the evolution of traits (e.g., anatomical or molecular characteristics) and the distribution of organisms (biogeography). Systematics, in other words, is used to understand the evolutionary history of life on Earth.
The term "systematics" is sometimes used synonymously with "taxonomy" and may be confused with "scientific classification." However, taxonomy is properly the describing, identifying, classifying, and naming of organisms, while "classification" is focused on placing organisms within groups that show their relationships to other organisms. All of these biological disciplines can be involved with extinct and extant organisms. However, systematics alone deals specifically with relationships through time, requiring recognition of the fossil record when dealing with the systematics of organisms.
Systematics uses taxonomy as a primary tool in understanding organisms, as nothing about an organism's relationships with other living things can be understood without it first being properly studied and described in sufficient detail to identify and classify it correctly. Scientific classifications are aids in recording and reporting information to other scientists and to laymen. The systematist, a scientist who specializes in systematics, must, therefore, be able to use existing classification systems, or at least know them well enough to skillfully justify not using them.
Phenetic systematics was an attempt to determine the relationships of organisms through a measure of similarity, considering plesiomorphies (ancestral traits) and apomorphies (derived traits) to be equally informative. From the 20th century onwards, it was superseded by cladistics, which considers plesiomorphies to be uninformative for an attempt to resolve the phylogeny of Earth's various organisms through time. Today's systematists generally make extensive use of molecular biology and computer programs to study organisms.
Systematics is fundamental to biology because it is the foundation for all studies of organisms, by showing how any organism relates to other living things.
Systematics is also of major importance in understanding conservation issues because it attempts to explain the Earth's biodiversity and could be used to assist in allocating limited means to preserve and protect endangered species, by looking at, for example, the genetic diversity among various taxa of plants or animals and deciding how much of that it is necessary to preserve. | Systematics
# Overview
Biological systematics is the study of the diversity of life on the planet Earth, both past and present, and the relationships among living things through time. Relationships are visualized as evolutionary trees (synonyms: cladograms, phylogenetic trees, phylogenies). Phylogenies have two components, branching order (showing group relationships) and branch length (showing amount of evolution). Phylogenetic trees of species and higher taxa are used to study the evolution of traits (e.g., anatomical or molecular characteristics) and the distribution of organisms (biogeography). Systematics, in other words, is used to understand the evolutionary history of life on Earth.
The term "systematics" is sometimes used synonymously with "taxonomy" and may be confused with "scientific classification." However, taxonomy is properly the describing, identifying, classifying, and naming of organisms, while "classification" is focused on placing organisms within groups that show their relationships to other organisms. All of these biological disciplines can be involved with extinct and extant organisms. However, systematics alone deals specifically with relationships through time, requiring recognition of the fossil record when dealing with the systematics of organisms.
Systematics uses taxonomy as a primary tool in understanding organisms, as nothing about an organism's relationships with other living things can be understood without it first being properly studied and described in sufficient detail to identify and classify it correctly. Scientific classifications are aids in recording and reporting information to other scientists and to laymen. The systematist, a scientist who specializes in systematics, must, therefore, be able to use existing classification systems, or at least know them well enough to skillfully justify not using them.
Phenetic systematics was an attempt to determine the relationships of organisms through a measure of similarity, considering plesiomorphies (ancestral traits) and apomorphies (derived traits) to be equally informative. From the 20th century onwards, it was superseded by cladistics, which considers plesiomorphies to be uninformative for an attempt to resolve the phylogeny of Earth's various organisms through time. Today's systematists generally make extensive use of molecular biology and computer programs to study organisms.
Systematics is fundamental to biology because it is the foundation for all studies of organisms, by showing how any organism relates to other living things.
Systematics is also of major importance in understanding conservation issues because it attempts to explain the Earth's biodiversity and could be used to assist in allocating limited means to preserve and protect endangered species, by looking at, for example, the genetic diversity among various taxa of plants or animals and deciding how much of that it is necessary to preserve. | https://www.wikidoc.org/index.php/Systematics | |
96837c558b4230f7218fbc6bfa9bf71284c56d02 | wikidoc | T-complex 1 | T-complex 1
T-complex protein 1 subunit alpha is a protein that in humans is encoded by the TCP1 gene.
# Function
This gene encodes a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT), also known as the TCP1 ring complex (TRiC). This complex consists of two identical stacked rings, each containing eight different proteins. Unfolded polypeptides enter the central cavity of the complex and are folded in an ATP-dependent manner. The complex folds various proteins, including actin and tubulin. Alternate transcriptional splice variants of this gene, encoding different isoforms, have been characterized.
# Interactions
T-complex 1 has been shown to interact with PPP4C and HDAC3. CCT also directly interacts with lectin type oxidized LDL receptor-1 (LOX-1) while its ligand oxidized low density lipoprotein (OxLDL) disassociates CCT from LOX-1. | T-complex 1
T-complex protein 1 subunit alpha is a protein that in humans is encoded by the TCP1 gene.[1][2][3]
# Function
This gene encodes a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT), also known as the TCP1 ring complex (TRiC). This complex consists of two identical stacked rings, each containing eight different proteins. Unfolded polypeptides enter the central cavity of the complex and are folded in an ATP-dependent manner. The complex folds various proteins, including actin and tubulin. Alternate transcriptional splice variants of this gene, encoding different isoforms, have been characterized.[3]
# Interactions
T-complex 1 has been shown to interact with PPP4C[4][5] and HDAC3.[6] CCT also directly interacts with lectin type oxidized LDL receptor-1 (LOX-1) while its ligand oxidized low density lipoprotein (OxLDL) disassociates CCT from LOX-1.[7] | https://www.wikidoc.org/index.php/T-complex_1 | |
73a4ba25aa93db4be5b05bdf522d7365ba83e875 | wikidoc | T. S. Wiley | T. S. Wiley
T.S. Wiley is the author of Lights Out: Sleep, Sugar and Survival, and Sex, Lies and Menopause. She writes about women's health, particularly sleep and hormonal issues, hormone replacement therapy and bioidentical hormone replacement therapy. Wiley has developed her own version of BHRT known as the Wiley Protocol which uses compounding to provide estrogen and progesterone creams, dosed in a manner to create a monthly cycle mimicking that of a pre-menopausal woman.
# Writings and beliefs
Wiley's main thesis in Lights Out is that light is a physiological trigger that controls dopamine and hormones like cortisol. Wiley posits that with the extension of the natural day through artificial lighting, rest at the hormonal level is rarely adequate for optimum biological needs of the body. In her view, this results in both fatigue and unnatural appetite, which leads to weight gain, exhaustion and disease. Wiley theorizes that the body's responses are cyclical, reflecting the seasons of the year, and that the body's needs vary seasonally. According to Wiley, during the winter months the body needs more sleep, and carbohydrates should be restricted as they would have been naturally during hunter-gatherer times.
## The Wiley Protocol
In her follow-up book, Sex, Lies and Menopause, Wiley theorizes that imbalances in hormones such as estrogen, progesterone, insulin, cortisol, and prolactin, among others, are the root cause of age-related diseases including cancer, heart disease, diabetes mellitus, stroke, and Alzheimer's. These imbalances, Wiley claims, can be attributed to deviations from humankind's natural state—artificial light, sleeping too much in the summer and not enough during winter, and eating fruit during winter months—and indirectly to women's liberation, insofar as it has led to the increased use of contraceptives, deferral of child bearing into the 20s and 30s, less frequent childbirth, and reduced breastfeeding. Wiley's Protocol attempts to mimic the youthful levels and cycles of estrogen and progesterone in order to prevent or treat age-related diseases. Wiley believes conventional hormone replacement therapy is ineffective and dangerous, advocating instead rhythmic, cyclical dosing of bioidential hormones.
Subsequent to the book's publication, her hormone regimen became known as "The Wiley Protocol." Wiley created a registered pharmacy program to ensure the consistency of the compounded products. Pharmacists enter a contract stipulating compounding methods, materials, testing, packaging and recommended pricing while Wiley's company provides the packaging materials bearing the Wiley Protocol trademark. Training for pharmacists is handled by a third party. Wiley offers educational courses for physicians for which they receive CME credits. Suzanne Somers advocates the Wiley Protocol in her book Ageless: The Naked Truth About Bioidentical Hormones and acts as a spokesperson for the treatment.
# Controversy
Wiley has been criticized for promoting her version of BHRT without proper qualifications or scientific evidence. On October 11, 2006, Erika Schwartz, Diana Schwarzbein, and five other MDs who have worked with BHRT during their careers issued a public letter to Suzanne Somers and her publisher, Crown, criticizing Somers' endorsement of Wiley's protocol. In the letter they alleged that the Wiley Protocol is "scientifically unproven and dangerous" and that Wiley has no medical or clinical qualifications. Wiley has claimed on her website and in speaking engagements that she earned a B.A. in anthropology from Webster University in 1975. On November 27, 2006, Newsweek reported that Webster has no record of this degree. Wiley's bio page was then changed to "Pending B.A. in Anthropology, Webster University, 1975" and then again to "Attended the B.A. Program in Anthropology, Webster University, 1970-1975". ABC News reported on February 16, 2007, that, according to Webster, she received only a blank diploma.
## Publications
Wiley is listed as co-author of three scientific journal articles along with Dr. Bent Formby between 1998 and 2001.
# Senate testimony
On April 19, 2007, Wiley appeared as a witness before the Senate Special Committee on Aging to give testimony at a hearing in which the safety and oversight of BHRT and compounding pharmacy were discussed. | T. S. Wiley
T.S. Wiley is the author of Lights Out: Sleep, Sugar and Survival,[1] and Sex, Lies and Menopause.[2] She writes about women's health, particularly sleep and hormonal issues, hormone replacement therapy and bioidentical hormone replacement therapy. Wiley has developed her own version of BHRT known as the Wiley Protocol which uses compounding to provide estrogen and progesterone creams, dosed in a manner to create a monthly cycle mimicking that of a pre-menopausal woman.
# Writings and beliefs
Wiley's main thesis in Lights Out is that light is a physiological trigger that controls dopamine and hormones like cortisol. Wiley posits that with the extension of the natural day through artificial lighting, rest at the hormonal level is rarely adequate for optimum biological needs of the body. In her view, this results in both fatigue and unnatural appetite, which leads to weight gain, exhaustion and disease. Wiley theorizes that the body's responses are cyclical, reflecting the seasons of the year, and that the body's needs vary seasonally. According to Wiley, during the winter months the body needs more sleep, and carbohydrates should be restricted as they would have been naturally during hunter-gatherer times.
## The Wiley Protocol
In her follow-up book, Sex, Lies and Menopause, Wiley theorizes that imbalances in hormones such as estrogen, progesterone, insulin, cortisol, and prolactin, among others, are the root cause of age-related diseases including cancer, heart disease, diabetes mellitus, stroke, and Alzheimer's. These imbalances, Wiley claims, can be attributed to deviations from humankind's natural state—artificial light, sleeping too much in the summer and not enough during winter, and eating fruit during winter months—and indirectly to women's liberation, insofar as it has led to the increased use of contraceptives, deferral of child bearing into the 20s and 30s, less frequent childbirth, and reduced breastfeeding. Wiley's Protocol attempts to mimic the youthful levels and cycles of estrogen and progesterone in order to prevent or treat age-related diseases.[2] Wiley believes conventional hormone replacement therapy is ineffective and dangerous, advocating instead rhythmic, cyclical dosing of bioidential hormones.
Subsequent to the book's publication, her hormone regimen became known as "The Wiley Protocol." Wiley created a registered pharmacy program to ensure the consistency of the compounded products. Pharmacists enter a contract stipulating compounding methods, materials, testing, packaging and recommended pricing while Wiley's company provides the packaging materials bearing the Wiley Protocol trademark. Training for pharmacists is handled by a third party. Wiley offers educational courses for physicians for which they receive CME credits. Suzanne Somers advocates the Wiley Protocol in her book Ageless: The Naked Truth About Bioidentical Hormones[3] and acts as a spokesperson for the treatment.
# Controversy
Wiley has been criticized for promoting her version of BHRT without proper qualifications or scientific evidence. On October 11, 2006, Erika Schwartz, Diana Schwarzbein, and five other MDs who have worked with BHRT during their careers issued a public letter to Suzanne Somers and her publisher, Crown, criticizing Somers' endorsement of Wiley's protocol. In the letter they alleged that the Wiley Protocol is "scientifically unproven and dangerous" and that Wiley has no medical or clinical qualifications.[4][5] Wiley has claimed on her website and in speaking engagements that she earned a B.A. in anthropology from Webster University in 1975.[citation needed] On November 27, 2006, Newsweek reported that Webster has no record of this degree.[6] Wiley's bio page was then changed to "Pending B.A. in Anthropology, Webster University, 1975" and then again to "Attended the B.A. Program in Anthropology, Webster University, 1970-1975". ABC News reported on February 16, 2007, that, according to Webster, she received only a blank diploma.[7]
## Publications
Wiley is listed as co-author of three scientific journal articles along with Dr. Bent Formby between 1998 and 2001.[8][9][10]
# Senate testimony
On April 19, 2007, Wiley appeared as a witness before the Senate Special Committee on Aging to give testimony at a hearing in which the safety and oversight of BHRT and compounding pharmacy were discussed.[11] | https://www.wikidoc.org/index.php/T._S._Wiley | |
2f1d846d4849bf9eaacf402838473b5bacaf78bd | wikidoc | TANK (gene) | TANK (gene)
TRAF family member-associated NF-kappa-B activator is a protein that in humans is encoded by the TANK gene.
# Function
The TRAF (tumor necrosis factor receptor-associated factor) family of proteins associate with and transduce signals from members of the tumor necrosis factor receptor superfamily. The protein encoded by this gene is found in the cytoplasm and can bind to TRAF1, TRAF2, or TRAF3, thereby inhibiting TRAF function by sequestering the TRAFs in a latent state in the cytoplasm. For example, the protein encoded by this gene can block TRAF2 binding to LMP1, the Epstein-Barr virus transforming protein, and inhibit LMP1-mediated NF-kappa-B activation. Two transcript variants encoding different isoforms have been found for this gene.
# Interactions
TANK (gene) has been shown to interact with TANK-binding kinase 1, IKBKE, TRAF2, IKBKG and TRAF3. | TANK (gene)
TRAF family member-associated NF-kappa-B activator is a protein that in humans is encoded by the TANK gene.[1][2][3]
# Function
The TRAF (tumor necrosis factor receptor-associated factor) family of proteins associate with and transduce signals from members of the tumor necrosis factor receptor superfamily. The protein encoded by this gene is found in the cytoplasm and can bind to TRAF1, TRAF2, or TRAF3, thereby inhibiting TRAF function by sequestering the TRAFs in a latent state in the cytoplasm. For example, the protein encoded by this gene can block TRAF2 binding to LMP1, the Epstein-Barr virus transforming protein, and inhibit LMP1-mediated NF-kappa-B activation. Two transcript variants encoding different isoforms have been found for this gene.[3]
# Interactions
TANK (gene) has been shown to interact with TANK-binding kinase 1,[4][5] IKBKE,[6] TRAF2,[1][4][5][6] IKBKG[7] and TRAF3.[1][4] | https://www.wikidoc.org/index.php/TANK_(gene) | |
3b18477dc8ff86f573c3b322583be46a6b9f734a | wikidoc | TBX5 (gene) | TBX5 (gene)
T-box transcription factor TBX5 is a protein that in humans is encoded by the TBX5 gene.
This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is closely linked to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12.
Tbx5 is a gene that is located on the long arm of chromosome 12. Tbx5 produces a protein called T-box 5 that acts as a transcription factor. The Tbx5 gene is involved with forelimb and heart development. This gene impacts the early development of the forelimb by triggering fibroblast growth factor, FGF10.
# Function
Tbx5 is involved with the development of the four chambers in the heart, the electrical conducting system, and the septum separating the right and left sides of the heart.
# Clinical significance
The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs. Skeletally there may be abnormally bent fingers, sloping shoulders, and phocomelia. Cardiac defects include ventral and atrial septation and problems with the conduction system. Several transcript variants encoding different isoforms have been described for this gene.
In studies done in mutant mice without the TBX5 gene it has been shown that the homozygous mice did not survive gestation due to the heart not developing past embryonic day E9.5. Also the heterozygous mice were born with morphological problems such as enlarged hearts, atrial and ventral septum defects, and limb malformations similar to those found in the Holt-Oram Syndrome. Supporting the essential role of TBX5 in the heart development.
The encoded protein plays a major role in limb development, specifically during limb bud initiation. For instance, in chickens Tbx5 specifies forelimb status. The activation of Tbx5 and other T-box proteins by Hox genes activates signaling cascades that involve the Wnt signaling pathway and FGF signals in limb buds. Ultimately, Tbx5 leads to the development of apical ectodermal ridge (AER) and zone of polarizing activity (ZPA) signaling centers in the developing limb bud, which specify the orientation growth of the developing limb. Together with Tbx4, Tbx5 plays a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.
A mutation in this gene can cause Holt-Oram syndrome or Amelia syndrome. Holt-Oram syndrome can cause several different defects. One effect of Holt-Oram syndrome is a hole in the septum. Another symptom of this syndrome is bone abnormalities in the fingers, wrists, or arms. An additional defect that Holt-Oram syndrome can cause is a conduction disease leading to abnormal heart rates and arrhythmias. Amelia syndrome is a condition where forelimb malformation occurs because FGF-10 is not triggered due to Tbx5 mutations. This condition can lead to the absence of one or both forelimbs.
# Interactions
TBX5 (gene) has been shown to interact with:
- GATA4 and
- NKX2-5. | TBX5 (gene)
T-box transcription factor TBX5 is a protein that in humans is encoded by the TBX5 gene.[1][2][3]
This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is closely linked[clarification needed] to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12.
Tbx5 is a gene that is located on the long arm of chromosome 12.[4] Tbx5 produces a protein called T-box 5 that acts as a transcription factor.[5] The Tbx5 gene is involved with forelimb and heart development.[6] This gene impacts the early development of the forelimb by triggering fibroblast growth factor, FGF10.[7]
# Function
Tbx5 is involved with the development of the four chambers in the heart, the electrical conducting system, and the septum separating the right and left sides of the heart.[8]
# Clinical significance
The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs.[6][9] Skeletally there may be abnormally bent fingers, sloping shoulders, and phocomelia. Cardiac defects include ventral and atrial septation and problems with the conduction system.[10] Several transcript variants encoding different isoforms have been described for this gene.[3]
In studies done in mutant mice without the TBX5 gene it has been shown that the homozygous mice did not survive gestation due to the heart not developing past embryonic day E9.5. Also the heterozygous mice were born with morphological problems such as enlarged hearts, atrial and ventral septum defects, and limb malformations similar to those found in the Holt-Oram Syndrome.[11] Supporting the essential role of TBX5 in the heart development.
The encoded protein plays a major role in limb development, specifically during limb bud initiation.[12] For instance, in chickens Tbx5 specifies forelimb status.[13] The activation of Tbx5 and other T-box proteins by Hox genes activates signaling cascades that involve the Wnt signaling pathway and FGF signals in limb buds.[12] Ultimately, Tbx5 leads to the development of apical ectodermal ridge (AER) and zone of polarizing activity (ZPA) signaling centers in the developing limb bud, which specify the orientation growth of the developing limb.[12] Together with Tbx4, Tbx5 plays a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.[14]
A mutation in this gene can cause Holt-Oram syndrome or Amelia syndrome.[6] Holt-Oram syndrome can cause several different defects. One effect of Holt-Oram syndrome is a hole in the septum.[15] Another symptom of this syndrome is bone abnormalities in the fingers, wrists, or arms.[16] An additional defect that Holt-Oram syndrome can cause is a conduction disease leading to abnormal heart rates and arrhythmias.[17] Amelia syndrome is a condition where forelimb malformation occurs because FGF-10 is not triggered due to Tbx5 mutations.[18] This condition can lead to the absence of one or both forelimbs.
# Interactions
TBX5 (gene) has been shown to interact with:
- GATA4[19] and
- NKX2-5.[19][20] | https://www.wikidoc.org/index.php/TBX5 | |
2d7c659f704fb9972de377c6c1b3cea5f9d29fb0 | wikidoc | TB Alliance | TB Alliance
The Global Alliance for TB Drug Development (TB Alliance) is a non-profit organization dedicated to the discovery and development of new, faster-acting and affordable tuberculosis medicines.
The TB Alliance expects to register a new anti-TB regimen that could cut the duration of tuberculosis treatment one-third by 2010. In the long-term, the TB Alliance’s goal is to develop a drug regimen that will reduce TB treatment to 10 doses from 130; be effective against drug resistant strains of TB; work with the antiretroviral drugs used to treat HIV; and improve the treatment of latent TB infection.
# Background
Tuberculosis infects one third of the world’s population, kills two million people each year, and costs the global economy $16 billion annually. However, research and development for new TB drugs came to a virtual standstill after the 1960s. Today, a four drug combination therapy exists, but it takes six months or more to be effective. This requires a degree of monitoring (See Direct Observational Therapy, Shortcourse) beyond the capacity of the health infrastructure in many countries; adequate TB treatment is available to less than half of the most infectious cases. This can inhibit control of the disease and fuel the rise of drug resistance. TB is also the number one killer of AIDS patients, but it is generally agreed that current TB treatments do not work well with the antiretroviral drugs used to treat HIV.
The TB drug market lacks sufficient financial incentives to stimulate a single private pharmaceutical company to invest in the new research required to sustain a treatment pipeline. The TB epidemic is concentrated in developing countries where drugs must be low in cost to remain accessible. It does not generate the kind of revenue streams that private companies usually deem necessary to justify the research costs and strategic risks involved in pharmaceuticals. The TB Alliance was designed to be the primary instrument to fill this vacuum and to ensure that new anti-TB drugs are affordable and accessible in endemic countries.
# History
The TB Alliance was conceived at a February 2000 meeting in Cape Town, South Africa, where 120 representatives from academia, industry, major government agencies, non-governmental organizations and donors gathered to discuss the problems of tuberculosis treatment. Participants stressed the need for faster-acting, novel TB drugs and highlighted the scientific opportunities involved. The resulting "Declaration of Cape Town" provided a road map for TB drug development and outlined the need for creation of the TB Alliance.
# Program
The TB Alliance is a non-profit public-private partnership. It operates like a virtual biotechnology firm, collaborating with research institutions and pharmaceutical companies so that risks and incentives are shared. While retaining management oversight of its drug development projects, the TB Alliance out-sources the development of potential drugs to public and private partners, providing funding and scientific guidance. Depending on the project, the TB Alliance either co-invests and co-develops a project, funds and manages it directly, or in-licenses the technology or intellectual property involved. Project diversity is a stated goal, with potentials compounds selected from a variety of chemical classes, with a wide-range of targets within the TB organism, Mycobacterium tuberculosis.
As of May, 2006, the TB Alliance has 11 drug projects underway, either in development or in human testing. Part of the TB Alliance’s stated mission is to ensure that any new treatments are affordable and accessible in the developing world, and that they are adopted as soon as they become available. Pricing terms are included in all licensing contracts and end products are designed to be easy to take. The TB Alliance also collaborates with national and international partners, working to ensure that new therapies are adopted and accessible to healthcare providers and patients via local channels. | TB Alliance
The Global Alliance for TB Drug Development (TB Alliance) is a non-profit organization dedicated to the discovery and development of new, faster-acting and affordable tuberculosis medicines.
The TB Alliance expects to register a new anti-TB regimen that could cut the duration of tuberculosis treatment one-third by 2010. In the long-term, the TB Alliance’s goal is to develop a drug regimen that will reduce TB treatment to 10 doses from 130; be effective against drug resistant strains of TB; work with the antiretroviral drugs used to treat HIV; and improve the treatment of latent TB infection.
# Background
Tuberculosis infects one third of the world’s population, kills two million people each year, and costs the global economy $16 billion annually. However, research and development for new TB drugs came to a virtual standstill after the 1960s. Today, a four drug combination therapy exists, but it takes six months or more to be effective. This requires a degree of monitoring (See Direct Observational Therapy, Shortcourse) beyond the capacity of the health infrastructure in many countries; adequate TB treatment is available to less than half of the most infectious cases. This can inhibit control of the disease and fuel the rise of drug resistance. TB is also the number one killer of AIDS patients, but it is generally agreed that current TB treatments do not work well with the antiretroviral drugs used to treat HIV.
The TB drug market lacks sufficient financial incentives to stimulate a single private pharmaceutical company to invest in the new research required to sustain a treatment pipeline. The TB epidemic is concentrated in developing countries where drugs must be low in cost to remain accessible. It does not generate the kind of revenue streams that private companies usually deem necessary to justify the research costs and strategic risks involved in pharmaceuticals. The TB Alliance was designed to be the primary instrument to fill this vacuum and to ensure that new anti-TB drugs are affordable and accessible in endemic countries.
# History
The TB Alliance was conceived at a February 2000 meeting in Cape Town, South Africa, where 120 representatives from academia, industry, major government agencies, non-governmental organizations and donors gathered to discuss the problems of tuberculosis treatment. Participants stressed the need for faster-acting, novel TB drugs and highlighted the scientific opportunities involved. The resulting "Declaration of Cape Town" provided a road map for TB drug development and outlined the need for creation of the TB Alliance.
# Program
The TB Alliance is a non-profit public-private partnership. It operates like a virtual biotechnology firm, collaborating with research institutions and pharmaceutical companies so that risks and incentives are shared. While retaining management oversight of its drug development projects, the TB Alliance out-sources the development of potential drugs to public and private partners, providing funding and scientific guidance. Depending on the project, the TB Alliance either co-invests and co-develops a project, funds and manages it directly, or in-licenses the technology or intellectual property involved. Project diversity is a stated goal, with potentials compounds selected from a variety of chemical classes, with a wide-range of targets within the TB organism, Mycobacterium tuberculosis.
As of May, 2006, the TB Alliance has 11 drug projects underway, either in development or in human testing. Part of the TB Alliance’s stated mission is to ensure that any new treatments are affordable and accessible in the developing world, and that they are adopted as soon as they become available. Pricing terms are included in all licensing contracts and end products are designed to be easy to take. The TB Alliance also collaborates with national and international partners, working to ensure that new therapies are adopted and accessible to healthcare providers and patients via local channels. | https://www.wikidoc.org/index.php/TB_Alliance | |
c140b77ad7fb8096829e9329470558983e3fe068 | wikidoc | Tecovirimat | Tecovirimat
# 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
Tecovirimat is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein that is FDA approved for the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg. Common adverse reactions include headache, nausea, abdominal pain, and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Tecovirimat is indicated for the treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 13 kg.
Limitations of Use
- The effectiveness of tecovirimat for treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical.
- Tecovirimat efficacy may be reduced in immunocompromised patients based on studies demonstrating reduced efficacy in immunocompromised animal models.
Dosage
- The recommended dosage of tecovirimat in adults and pediatric patients weighing at least 40 kg is 600 mg (three 200 mg capsules) taken twice daily orally for 14 days. Tecovirimat should be taken within 30 minutes after a full meal of moderate or high fat.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding tecovirimat Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tecovirimat Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Indication
- Tecovirimat is indicated for the treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 13 kg.
Limitations of Use
- The effectiveness of tecovirimat for treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical.
- Tecovirimat efficacy may be reduced in immunocompromised patients based on studies demonstrating reduced efficacy in immunocompromised animal models.
Dosage
- The recommended dosage of tecovirimat in adults and pediatric patients weighing at least 40 kg is 600 mg (three 200 mg capsules) taken twice daily orally for 14 days. Tecovirimat should be taken within 30 minutes after a full meal of moderate or high fat.
- The recommended dosage for pediatric patients is based on weight starting at 13 kg as shown in TABLE 1 (see ). The dose should be given twice daily orally for 14 days and should be taken within 30 minutes after a full meal of moderate or high fat.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding tecovirimat Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tecovirimat Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
None.
# Warnings
- Co-administration of repaglinide and tecovirimat may cause mild to moderate hypoglycemia. Monitor blood glucose and monitor for hypoglycemic symptoms when administering tecovirimat with repaglinide.
- In a drug interaction study, 10 of 30 healthy subjects experienced mild (6 subjects) or moderate (4 subjects) hypoglycemia following co-administration of repaglinide (2 mg) and tecovirimat. Symptoms resolved in all subjects after intake of food and/or oral glucose.
# 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.
- The safety of tecovirimat has not been studied in patients with smallpox disease.
- The safety of tecovirimat was evaluated in 359 healthy adult subjects ages 18-79 years in a Phase 3 clinical trial. Of the subjects who received at least one 600 mg dose of tecovirimat, 59% were female, 69% were White, 28% were Black/African American, 1% were Asian, and 12% were Hispanic or Latino. Ten percent of the subjects who participated in the study were age 65 or older. Of these 359 subjects, 336 subjects received at least 23 of 28 doses of 600 mg tecovirimat in a twice daily regimen for 14 days.
Most Frequently Reported Adverse Reactions
- The most frequently reported adverse reactions were headache and nausea. Adverse reactions that occurred in at least 2% of subjects in the tecovirimat treatment group are shown in TABLE 2.
Adverse Reactions Leading to Discontinuation of Tecovirimat
- Six subjects (2%) had their treatment with tecovirimat discontinued due to adverse reactions. Each of these subject’s adverse reactions (with severity) is listed below:
EEG change, abnormal
Mild upset stomach, dry mouth, decreased concentration and dysphoria
Mild nausea and fever, moderate diarrhea, severe headache
Mild palpable purpura
Mild nausea, fever and chills
Mild facial redness, facial swelling and pruritus
- EEG change, abnormal
- Mild upset stomach, dry mouth, decreased concentration and dysphoria
- Mild nausea and fever, moderate diarrhea, severe headache
- Mild palpable purpura
- Mild nausea, fever and chills
- Mild facial redness, facial swelling and pruritus
Less Common Adverse Reactions
- Clinically significant adverse reactions that were reported in < 2% of subjects exposed to tecovirimat and at rates higher than subjects who received placebo are listed below:
Gastrointestinal: dry mouth, chapped lips, dyspepsia, eructation, oral paresthesia
General and administration site: pyrexia, pain, chills, malaise, thirst
Investigations: abnormal electroencephalogram, hematocrit decreased, hemoglobin decreased, heart rate increased
Musculoskeletal and connective tissue: arthralgia, osteoarthritis
Nervous system: migraine, disturbance in attention, dysgeusia, paresthesia
Psychiatric: depression, dysphoria, irritability, panic attack
Respiratory, Thoracic and Mediastinal Disorders: oropharyngeal pain
Skin and subcutaneous tissue: palpable purpura, rash, pruritic rash, facial redness, facial swelling, pruritus
- Gastrointestinal: dry mouth, chapped lips, dyspepsia, eructation, oral paresthesia
- General and administration site: pyrexia, pain, chills, malaise, thirst
- Investigations: abnormal electroencephalogram, hematocrit decreased, hemoglobin decreased, heart rate increased
- Musculoskeletal and connective tissue: arthralgia, osteoarthritis
- Nervous system: migraine, disturbance in attention, dysgeusia, paresthesia
- Psychiatric: depression, dysphoria, irritability, panic attack
- Respiratory, Thoracic and Mediastinal Disorders: oropharyngeal pain
- Skin and subcutaneous tissue: palpable purpura, rash, pruritic rash, facial redness, facial swelling, pruritus
## Postmarketing Experience
There is limited information regarding Tecovirimat Postmarketing Experience in the drug label.
# Drug Interactions
- Tecovirimat is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C8 and CYP2C19. However, the effects are not expected to be clinically relevant for most substrates of those enzymes based on the magnitude of interactions and the duration of treatment of tecovirimat. See TABLE 3 for clinical recommendations for select sensitive substrates.
- TABLE 3 provides a listing of established or significant drug interactions.
- Based on a drug interaction study, no clinically significant drug interactions have been observed when tecovirimat is co-administered with bupropion, flurbiprofen, or omeprazole.
- No vaccine-drug interaction studies have been performed in human subjects. Some animal studies have indicated that co-administration of tecovirimat at the same time as live smallpox vaccine (vaccinia virus) may reduce the immune response to the vaccine. The clinical impact of this interaction on vaccine efficacy is unknown.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- No adequate and well-controlled studies in pregnant women were conducted; therefore there are no human data to establish the presence or absence of tecovirimat associated risk.
- In animal reproduction studies, no embryofetal developmental toxicity was observed in mice during the period of organogenesis at tecovirimat exposures (area under the curve ) up to 23 times higher than human exposure at the recommended human dose (RHD). In rabbits, no embryofetal developmental toxicity was observed during organogenesis at tecovirimat exposures (AUC) less than human exposures at the RHD. In a mouse pre-/post-natal development study, no toxicities were observed at maternal tecovirimat exposures up to 24 times higher than human exposure at the RHD.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. 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.
Animal Data
- Tecovirimat was administered orally to pregnant mice at doses up to 1,000 mg/kg/day from gestation Days 6-15. No embryofetal toxicities were observed at doses up to 1,000 mg/kg/day (approximately 23 times higher than human exposure at the RHD).
- Tecovirimat was administered orally to pregnant rabbits at doses up to 100 mg/kg/day from gestation Days 6-19. No embryofetal toxicities were observed at doses up to 100 mg/kg/day (0.4 times the human exposure at the RHD).
- In the pre-/post-natal development study, tecovirimat was administered orally to pregnant mice at doses up to 1,000 mg/kg/day from gestation Day 6 to post-natal Day 20. No toxicities were observed at doses up to 1,000 mg/kg/day (approximately 24 times higher than human exposure at the RHD).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tecovirimat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tecovirimat during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data to assess the effect on milk production, the presence of the drug in human milk, and/or the effects on the breastfed child. When administered to lactating mice, tecovirimat was present in the milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tecovirimat and any potential adverse effects on the breastfed child from tecovirimat or from the underlying maternal condition.
Data
- In a lactation study at doses up to 1,000 mg/kg/day, mean tecovirimat milk to plasma ratios up to approximately 0.8 were observed at 6 and 24 hours post-dose when administered orally to mice on lactation Day 10 or 11.
### Pediatric Use
- As in adults, the effectiveness of tecovirimat in pediatric patients is based solely on efficacy studies in animal models of orthopoxvirus disease. As exposure of healthy pediatric subjects to tecovirimat with no potential for direct clinical benefit is not ethical, pharmacokinetic simulation was used to derive dosing regimens that are predicted to provide pediatric patients with exposures comparable to the observed exposure in adults receiving 600 mg twice daily. The dosage for pediatric patients is based on weight.
### Geriatic Use
- Clinical studies of tecovirimat did not include sufficient numbers of subjects aged 65 and over to determine whether the safety profile of tecovirimat is different in this population compared to younger subjects. Of the 359 subjects in the clinical study of tecovirimat, 10% (36/359) were ≥ 65 years of age, and 1% (4/359) were ≥ 75 years of age. No alteration of dosing is needed for patients ≥ 65 years of age.
### Gender
There is no FDA guidance on the use of Tecovirimat with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tecovirimat with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is required for patients with mild, moderate or severe renal impairment or patients with end stage renal disease (ESRD) requiring hemodialysis
### Hepatic Impairment
- No dosage adjustment is required for patients with mild, moderate or severe hepatic impairment (Child Pugh Class A, B, or C).
### Females of Reproductive Potential and Males
Infertility
- There are no data on the effect of tecovirimat on female and male reproductive potential in humans. Decreased fertility due to testicular toxicity was observed in male mice.
### Immunocompromised Patients
There is no FDA guidance one the use of Tecovirimat in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The recommended dosage of tecovirimat in adults and pediatric patients weighing at least 40 kg is 600 mg (three 200 mg capsules) taken twice daily orally for 14 days. Tecovirimat should be taken within 30 minutes after a full meal of moderate or high fat.
- The recommended dosage for pediatric patients is based on weight starting at 13 kg as shown in TABLE 1. The dose should be given twice daily orally for 14 days and should be taken within 30 minutes after a full meal of moderate or high fat.
- Tecovirimat capsules can be administered by carefully opening the capsule and mixing the entire contents in 30 mL of liquid (e.g., milk, chocolate milk) or soft food (e.g., apple sauce, yogurt). The entire mixture should be administered within 30 minutes of its preparation.
### Monitoring
There is limited information regarding Tecovirimat Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tecovirimat and IV administrations.
# Overdosage
- There is no clinical experience with overdosage of tecovirimat. In case of overdosage, monitor patients for any signs or symptoms of adverse effects. Hemodialysis will not significantly remove tecovirimat in overdosed patients.
# Pharmacology
## Mechanism of Action
- Tecovirimat is an antiviral drug against variola (smallpox) virus
## Structure
- The chemical formula is C19H15F3N2O3·H2O representing a molecular weight of 394.35 g/moL. The molecular structure is as follows:
## Pharmacodynamics
Cardiac Electrophysiology
- Tecovirimat does not prolong the QT interval to any clinically relevant extent at the anticipated therapeutic exposure.
## Pharmacokinetics
- At the approved recommended dosage, the mean steady-state values of tecovirimat AUC0-24hr, Cmax, and Cmin are 28791 hr·ng/mL (CV: 35%), 2106 ng/mL (CV: 33%), and 587 ng/mL (CV: 38%), respectively. Tecovirimat steady-state AUC is achieved by Day 6. Refer to TABLE 4 for pharmacokinetic parameters of tecovirimat.
Comparison of Animal and Human PK Data to Support Effective Human Dose Selection
- Because the effectiveness of tecovirimat cannot be tested in humans, a comparison of tecovirimat exposures achieved in healthy human subjects to those observed in animal models of orthopoxvirus infection (nonhuman primates and rabbits infected with monkeypox virus and rabbitpox virus, respectively) in therapeutic efficacy studies was necessary to support the dosage regimen of 600 mg twice daily for treatment of smallpox disease in humans. Humans achieve greater systemic exposure (AUC, Cmax, and Cmin) of tecovirimat following a twice daily dose of 600 mg when compared to the therapeutic exposures in these animal models.
Specific Populations
- No clinically significant differences in the pharmacokinetics of tecovirimat were observed based on age, sex, ethnicity, renal impairment (based on estimated GFR), or hepatic impairment (Child Pugh Scores A, B or C).
Pediatric Patients
- Tecovirimat pharmacokinetics has not been evaluated in pediatric patients. The recommended pediatric dosing regimen is expected to produce tecovirimat exposures that are comparable to those in adult subjects based on a population pharmacokinetic modeling and simulation approach.
Drug Interaction Studies
- The effect of tecovirimat on the exposure of co-administered drugs are shown in TABLE 5.
- No pharmacokinetic changes were observed for the following drug when co-administered with tecovirimat: flurbiprofen.
- Cytochrome P450 (CYP) Enzymes: Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19, and a weak inducer of CYP3A4. Tecovirimat is not an inhibitor or an inducer of CYP2B6 or CYP2C9.
In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically
- CYP Enzymes: Tecovirimat is not an inhibitor of CYP1A2, CYP2D6, CYP2E1 or CYP3A4, and is not an inducer of CYP1A2. Tecovirimat is not a substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.
- UGT Enzymes: Tecovirimat is a substrate of UGT1A1 and UGT1A4.
- Transporter Systems: Tecovirimat inhibited Breast Cancer Resistance Protein (BCRP) in vitro.
- Tecovirimat is not an inhibitor of P-glycoprotein (P-gp), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), organic anion transporter 1 (OAT1), OAT3, and organic cation transporter 2 (OCT2). Tecovirimat is not a substrate for P-gp, BCRP, OATP1B1, and OATP1B3.
## Microbiology
Mechanism of Action
- Tecovirimat targets and inhibits the activity of the orthopoxvirus VP37 protein (encoded by and highly conserved in all members of the orthopoxvirus genus) and blocks its interaction with cellular Rab9 GTPase and TIP47, which prevents the formation of egress-competent enveloped virions necessary for cell-to-cell and long-range dissemination of virus.
Activity in Cell Culture
- In cell culture assays, the effective concentrations of tecovirimat resulting in a 50% reduction in virus-induced cytopathic effect (EC50), were 0.016-0.067 µM, 0.014-0.039 µM, 0.015 µM, and 0.009 µM, for variola, monkeypox, rabbitpox, and vaccinia viruses, respectively. Ranges given for variola and monkeypox viruses are reflective of results from multiple strains assayed.
Resistance
- There are no known instances of naturally occurring tecovirimat resistant orthopoxviruses, although tecovirimat resistance may develop under drug selection. Tecovirimat has a relatively low resistance barrier, and certain amino acid substitutions in the target VP37 protein can confer large reductions in tecovirimat antiviral activity. The possibility of resistance to tecovirimat should be considered in patients who either fail to respond to therapy or who develop recrudescence of disease after an initial period of responsiveness.
- Cross Resistance: There are no other antiviral drugs approved for the treatment of variola (smallpox) virus infection.
## Nonclinical Toxicology
Carcinogenesis and Mutagenesis
- Carcinogenicity studies have not been conducted with tecovirimat.
- Tecovirimat was not genotoxic in in vitro or in vivo assays, including a bacterial reverse mutation assay, a mammalian mutagenicity assay in mouse lymphoma L5178Y/TK± cells, and in an in vivo mouse micronucleus study.
Impairment of Fertility
- In a fertility and early embryonic development study in mice, no effects of tecovirimat on female fertility were observed at tecovirimat exposures (AUC) approximately 24 times higher than human exposure at the RHD. In male mice, decreased male fertility associated with testicular toxicity (increased percent abnormal sperm and decreased sperm motility) was observed at 1,000 mg/kg/day (approximately 24 times the human exposure at the RHD).
- In a repeat-dose toxicology study in dogs, convulsions (tonic and clonic) were observed in one animal within 6 hours of a single dose of 300 mg/kg (approximately 4 times higher than the highest observed human exposure at the RHD based on Cmax). Electroencephalography (EEG) findings in this animal were consistent with seizure activity during the observed convulsions. Tremors, which were considered non-adverse, were observed at 100 mg/kg/dose (similar to the highest observed human exposure at the RHD based on Cmax), although no convulsions or EEG findings were observed at this dose.
# Clinical Studies
Overview
- The effectiveness of tecovirimat for treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical. Therefore, the effectiveness of tecovirimat for treatment of smallpox disease was established based on results of adequate and well-controlled animal efficacy studies of non-human primates and rabbits infected with non-variola orthopoxviruses. Survival rates observed in the animal studies may not be predictive of survival rates in clinical practice.
Study Design
- Efficacy studies were conducted in cynomolgus macaques infected with monkeypox virus, and New Zealand white (NZW) rabbits infected with rabbitpox virus. The primary efficacy endpoint for these studies was survival. In non-human primate studies, cynomolgus macaques were lethally challenged intravenously with 5 x 107 plaque-forming units of monkeypox virus; tecovirimat was administered orally once daily at a dose level of 10 mg/kg for 14 days, starting at Day 4, 5 or 6 post-challenge. In rabbit studies, NZW rabbits were lethally challenged intradermally with 1,000 plaque-forming units of rabbitpox virus; tecovirimat was administered orally once daily for 14 days at a dose level of 40 mg/kg, starting at Day 4 post-challenge. The timing of tecovirimat dosing in these studies was intended to assess efficacy when treatment is initiated after animals have developed clinical signs of disease, specifically dermal pox lesions in cynomolgus macaques, and fever in rabbits. Clinical signs of disease were evident in some animals at Day 2-3 post-challenge but were evident in all animals by Day 4 post-challenge. Survival was monitored for 3-6 times the mean time to death for untreated animals in each model.
Study Results
- Treatment with tecovirimat for 14 days resulted in statistically significant improvement in survival relative to placebo, except when given to cynomolgus macaques starting at Day 6 post-challenge (TABLE 6).
# How Supplied
- Each tecovirimat capsule contains 200 mg of tecovirimat. Tecovirimat capsules are hard gelatin with an opaque orange body imprinted in white ink with “SIGA” followed by the SIGA logo followed by “®”, and an opaque black cap imprinted in white ink with "ST-246®", containing white to off-white powder. Each bottle contains 42 capsules (NDC 50072-200-42) with an induction seal and child-resistant cap.
## Storage
- Store capsules in the original bottle at 20°C to 25°C (68°F to 77°F); excursions permitted 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
Efficacy Based on Animal Models Alone
- Inform patients that the efficacy of tecovirimat is based solely on efficacy studies demonstrating a survival benefit in animals and that the effectiveness of tecovirimat has not been tested in humans with smallpox disease.
Important Dosage and Administration Information
- Advise patients to take tecovirimat as directed within 30 minutes of eating a full meal of moderate or high fat. Inform patients to take tecovirimat for the entire duration without missing or skipping a dose.
Drug Interactions
- Inform patients that tecovirimat may interact with other drugs. Advise patients to report to their healthcare provider the use of other prescription drugs. Co-administration of tecovirimat with repaglinide may cause hypoglycemia.
# Precautions with Alcohol
Alcohol-Tecovirimat interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
TPOXX
# Look-Alike Drug Names
There is limited information regarding Tecovirimat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tecovirimat
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [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
Tecovirimat is an inhibitor of the orthopoxvirus VP37 envelope wrapping protein that is FDA approved for the treatment of human smallpox disease in adults and pediatric patients weighing at least 13 kg. Common adverse reactions include headache, nausea, abdominal pain, and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Indication
- Tecovirimat is indicated for the treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 13 kg.
Limitations of Use
- The effectiveness of tecovirimat for treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical.
- Tecovirimat efficacy may be reduced in immunocompromised patients based on studies demonstrating reduced efficacy in immunocompromised animal models.
Dosage
- The recommended dosage of tecovirimat in adults and pediatric patients weighing at least 40 kg is 600 mg (three 200 mg capsules) taken twice daily orally for 14 days. Tecovirimat should be taken within 30 minutes after a full meal of moderate or high fat.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding tecovirimat Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tecovirimat Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Indication
- Tecovirimat is indicated for the treatment of human smallpox disease caused by variola virus in adults and pediatric patients weighing at least 13 kg.
Limitations of Use
- The effectiveness of tecovirimat for treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical.
- Tecovirimat efficacy may be reduced in immunocompromised patients based on studies demonstrating reduced efficacy in immunocompromised animal models.
Dosage
- The recommended dosage of tecovirimat in adults and pediatric patients weighing at least 40 kg is 600 mg (three 200 mg capsules) taken twice daily orally for 14 days. Tecovirimat should be taken within 30 minutes after a full meal of moderate or high fat.
- The recommended dosage for pediatric patients is based on weight starting at 13 kg as shown in TABLE 1 (see [Administration & Monitoring]). The dose should be given twice daily orally for 14 days and should be taken within 30 minutes after a full meal of moderate or high fat.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding tecovirimat Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding tecovirimat Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
None.
# Warnings
- Co-administration of repaglinide and tecovirimat may cause mild to moderate hypoglycemia. Monitor blood glucose and monitor for hypoglycemic symptoms when administering tecovirimat with repaglinide.
- In a drug interaction study, 10 of 30 healthy subjects experienced mild (6 subjects) or moderate (4 subjects) hypoglycemia following co-administration of repaglinide (2 mg) and tecovirimat. Symptoms resolved in all subjects after intake of food and/or oral glucose.
# 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.
- The safety of tecovirimat has not been studied in patients with smallpox disease.
- The safety of tecovirimat was evaluated in 359 healthy adult subjects ages 18-79 years in a Phase 3 clinical trial. Of the subjects who received at least one 600 mg dose of tecovirimat, 59% were female, 69% were White, 28% were Black/African American, 1% were Asian, and 12% were Hispanic or Latino. Ten percent of the subjects who participated in the study were age 65 or older. Of these 359 subjects, 336 subjects received at least 23 of 28 doses of 600 mg tecovirimat in a twice daily regimen for 14 days.
Most Frequently Reported Adverse Reactions
- The most frequently reported adverse reactions were headache and nausea. Adverse reactions that occurred in at least 2% of subjects in the tecovirimat treatment group are shown in TABLE 2.
Adverse Reactions Leading to Discontinuation of Tecovirimat
- Six subjects (2%) had their treatment with tecovirimat discontinued due to adverse reactions. Each of these subject’s adverse reactions (with severity) is listed below:
EEG change, abnormal
Mild upset stomach, dry mouth, decreased concentration and dysphoria
Mild nausea and fever, moderate diarrhea, severe headache
Mild palpable purpura
Mild nausea, fever and chills
Mild facial redness, facial swelling and pruritus
- EEG change, abnormal
- Mild upset stomach, dry mouth, decreased concentration and dysphoria
- Mild nausea and fever, moderate diarrhea, severe headache
- Mild palpable purpura
- Mild nausea, fever and chills
- Mild facial redness, facial swelling and pruritus
Less Common Adverse Reactions
- Clinically significant adverse reactions that were reported in < 2% of subjects exposed to tecovirimat and at rates higher than subjects who received placebo are listed below:
Gastrointestinal: dry mouth, chapped lips, dyspepsia, eructation, oral paresthesia
General and administration site: pyrexia, pain, chills, malaise, thirst
Investigations: abnormal electroencephalogram, hematocrit decreased, hemoglobin decreased, heart rate increased
Musculoskeletal and connective tissue: arthralgia, osteoarthritis
Nervous system: migraine, disturbance in attention, dysgeusia, paresthesia
Psychiatric: depression, dysphoria, irritability, panic attack
Respiratory, Thoracic and Mediastinal Disorders: oropharyngeal pain
Skin and subcutaneous tissue: palpable purpura, rash, pruritic rash, facial redness, facial swelling, pruritus
- Gastrointestinal: dry mouth, chapped lips, dyspepsia, eructation, oral paresthesia
- General and administration site: pyrexia, pain, chills, malaise, thirst
- Investigations: abnormal electroencephalogram, hematocrit decreased, hemoglobin decreased, heart rate increased
- Musculoskeletal and connective tissue: arthralgia, osteoarthritis
- Nervous system: migraine, disturbance in attention, dysgeusia, paresthesia
- Psychiatric: depression, dysphoria, irritability, panic attack
- Respiratory, Thoracic and Mediastinal Disorders: oropharyngeal pain
- Skin and subcutaneous tissue: palpable purpura, rash, pruritic rash, facial redness, facial swelling, pruritus
## Postmarketing Experience
There is limited information regarding Tecovirimat Postmarketing Experience in the drug label.
# Drug Interactions
- Tecovirimat is a weak inducer of cytochrome P450 (CYP)3A and a weak inhibitor of CYP2C8 and CYP2C19. However, the effects are not expected to be clinically relevant for most substrates of those enzymes based on the magnitude of interactions and the duration of treatment of tecovirimat. See TABLE 3 for clinical recommendations for select sensitive substrates.
- TABLE 3 provides a listing of established or significant drug interactions.
- Based on a drug interaction study, no clinically significant drug interactions have been observed when tecovirimat is co-administered with bupropion, flurbiprofen, or omeprazole.
- No vaccine-drug interaction studies have been performed in human subjects. Some animal studies have indicated that co-administration of tecovirimat at the same time as live smallpox vaccine (vaccinia virus) may reduce the immune response to the vaccine. The clinical impact of this interaction on vaccine efficacy is unknown.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- No adequate and well-controlled studies in pregnant women were conducted; therefore there are no human data to establish the presence or absence of tecovirimat associated risk.
- In animal reproduction studies, no embryofetal developmental toxicity was observed in mice during the period of organogenesis at tecovirimat exposures (area under the curve [AUC]) up to 23 times higher than human exposure at the recommended human dose (RHD). In rabbits, no embryofetal developmental toxicity was observed during organogenesis at tecovirimat exposures (AUC) less than human exposures at the RHD. In a mouse pre-/post-natal development study, no toxicities were observed at maternal tecovirimat exposures up to 24 times higher than human exposure at the RHD.
- The background risk of major birth defects and miscarriage for the indicated population is unknown. 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.
Animal Data
- Tecovirimat was administered orally to pregnant mice at doses up to 1,000 mg/kg/day from gestation Days 6-15. No embryofetal toxicities were observed at doses up to 1,000 mg/kg/day (approximately 23 times higher than human exposure at the RHD).
- Tecovirimat was administered orally to pregnant rabbits at doses up to 100 mg/kg/day from gestation Days 6-19. No embryofetal toxicities were observed at doses up to 100 mg/kg/day (0.4 times the human exposure at the RHD).
- In the pre-/post-natal development study, tecovirimat was administered orally to pregnant mice at doses up to 1,000 mg/kg/day from gestation Day 6 to post-natal Day 20. No toxicities were observed at doses up to 1,000 mg/kg/day (approximately 24 times higher than human exposure at the RHD).
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tecovirimat in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tecovirimat during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data to assess the effect on milk production, the presence of the drug in human milk, and/or the effects on the breastfed child. When administered to lactating mice, tecovirimat was present in the milk (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tecovirimat and any potential adverse effects on the breastfed child from tecovirimat or from the underlying maternal condition.
Data
- In a lactation study at doses up to 1,000 mg/kg/day, mean tecovirimat milk to plasma ratios up to approximately 0.8 were observed at 6 and 24 hours post-dose when administered orally to mice on lactation Day 10 or 11.
### Pediatric Use
- As in adults, the effectiveness of tecovirimat in pediatric patients is based solely on efficacy studies in animal models of orthopoxvirus disease. As exposure of healthy pediatric subjects to tecovirimat with no potential for direct clinical benefit is not ethical, pharmacokinetic simulation was used to derive dosing regimens that are predicted to provide pediatric patients with exposures comparable to the observed exposure in adults receiving 600 mg twice daily. The dosage for pediatric patients is based on weight.
### Geriatic Use
- Clinical studies of tecovirimat did not include sufficient numbers of subjects aged 65 and over to determine whether the safety profile of tecovirimat is different in this population compared to younger subjects. Of the 359 subjects in the clinical study of tecovirimat, 10% (36/359) were ≥ 65 years of age, and 1% (4/359) were ≥ 75 years of age. No alteration of dosing is needed for patients ≥ 65 years of age.
### Gender
There is no FDA guidance on the use of Tecovirimat with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tecovirimat with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is required for patients with mild, moderate or severe renal impairment or patients with end stage renal disease (ESRD) requiring hemodialysis
### Hepatic Impairment
- No dosage adjustment is required for patients with mild, moderate or severe hepatic impairment (Child Pugh Class A, B, or C).
### Females of Reproductive Potential and Males
Infertility
- There are no data on the effect of tecovirimat on female and male reproductive potential in humans. Decreased fertility due to testicular toxicity was observed in male mice.
### Immunocompromised Patients
There is no FDA guidance one the use of Tecovirimat in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- The recommended dosage of tecovirimat in adults and pediatric patients weighing at least 40 kg is 600 mg (three 200 mg capsules) taken twice daily orally for 14 days. Tecovirimat should be taken within 30 minutes after a full meal of moderate or high fat.
- The recommended dosage for pediatric patients is based on weight starting at 13 kg as shown in TABLE 1. The dose should be given twice daily orally for 14 days and should be taken within 30 minutes after a full meal of moderate or high fat.
- Tecovirimat capsules can be administered by carefully opening the capsule and mixing the entire contents in 30 mL of liquid (e.g., milk, chocolate milk) or soft food (e.g., apple sauce, yogurt). The entire mixture should be administered within 30 minutes of its preparation.
### Monitoring
There is limited information regarding Tecovirimat Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tecovirimat and IV administrations.
# Overdosage
- There is no clinical experience with overdosage of tecovirimat. In case of overdosage, monitor patients for any signs or symptoms of adverse effects. Hemodialysis will not significantly remove tecovirimat in overdosed patients.
# Pharmacology
## Mechanism of Action
- Tecovirimat is an antiviral drug against variola (smallpox) virus
## Structure
- The chemical formula is C19H15F3N2O3·H2O representing a molecular weight of 394.35 g/moL. The molecular structure is as follows:
## Pharmacodynamics
Cardiac Electrophysiology
- Tecovirimat does not prolong the QT interval to any clinically relevant extent at the anticipated therapeutic exposure.
## Pharmacokinetics
- At the approved recommended dosage, the mean steady-state values of tecovirimat AUC0-24hr, Cmax, and Cmin are 28791 hr·ng/mL (CV: 35%), 2106 ng/mL (CV: 33%), and 587 ng/mL (CV: 38%), respectively. Tecovirimat steady-state AUC is achieved by Day 6. Refer to TABLE 4 for pharmacokinetic parameters of tecovirimat.
Comparison of Animal and Human PK Data to Support Effective Human Dose Selection
- Because the effectiveness of tecovirimat cannot be tested in humans, a comparison of tecovirimat exposures achieved in healthy human subjects to those observed in animal models of orthopoxvirus infection (nonhuman primates and rabbits infected with monkeypox virus and rabbitpox virus, respectively) in therapeutic efficacy studies was necessary to support the dosage regimen of 600 mg twice daily for treatment of smallpox disease in humans. Humans achieve greater systemic exposure (AUC, Cmax, and Cmin) of tecovirimat following a twice daily dose of 600 mg when compared to the therapeutic exposures in these animal models.
Specific Populations
- No clinically significant differences in the pharmacokinetics of tecovirimat were observed based on age, sex, ethnicity, renal impairment (based on estimated GFR), or hepatic impairment (Child Pugh Scores A, B or C).
Pediatric Patients
- Tecovirimat pharmacokinetics has not been evaluated in pediatric patients. The recommended pediatric dosing regimen is expected to produce tecovirimat exposures that are comparable to those in adult subjects based on a population pharmacokinetic modeling and simulation approach.
Drug Interaction Studies
- The effect of tecovirimat on the exposure of co-administered drugs are shown in TABLE 5.
- No pharmacokinetic changes were observed for the following drug when co-administered with tecovirimat: flurbiprofen.
- Cytochrome P450 (CYP) Enzymes: Tecovirimat is a weak inhibitor of CYP2C8 and CYP2C19, and a weak inducer of CYP3A4. Tecovirimat is not an inhibitor or an inducer of CYP2B6 or CYP2C9.
In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically
- CYP Enzymes: Tecovirimat is not an inhibitor of CYP1A2, CYP2D6, CYP2E1 or CYP3A4, and is not an inducer of CYP1A2. Tecovirimat is not a substrate for CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4.
- UGT Enzymes: Tecovirimat is a substrate of UGT1A1 and UGT1A4.
- Transporter Systems: Tecovirimat inhibited Breast Cancer Resistance Protein (BCRP) in vitro.
- Tecovirimat is not an inhibitor of P-glycoprotein (P-gp), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), organic anion transporter 1 (OAT1), OAT3, and organic cation transporter 2 (OCT2). Tecovirimat is not a substrate for P-gp, BCRP, OATP1B1, and OATP1B3.
## Microbiology
Mechanism of Action
- Tecovirimat targets and inhibits the activity of the orthopoxvirus VP37 protein (encoded by and highly conserved in all members of the orthopoxvirus genus) and blocks its interaction with cellular Rab9 GTPase and TIP47, which prevents the formation of egress-competent enveloped virions necessary for cell-to-cell and long-range dissemination of virus.
Activity in Cell Culture
- In cell culture assays, the effective concentrations of tecovirimat resulting in a 50% reduction in virus-induced cytopathic effect (EC50), were 0.016-0.067 µM, 0.014-0.039 µM, 0.015 µM, and 0.009 µM, for variola, monkeypox, rabbitpox, and vaccinia viruses, respectively. Ranges given for variola and monkeypox viruses are reflective of results from multiple strains assayed.
Resistance
- There are no known instances of naturally occurring tecovirimat resistant orthopoxviruses, although tecovirimat resistance may develop under drug selection. Tecovirimat has a relatively low resistance barrier, and certain amino acid substitutions in the target VP37 protein can confer large reductions in tecovirimat antiviral activity. The possibility of resistance to tecovirimat should be considered in patients who either fail to respond to therapy or who develop recrudescence of disease after an initial period of responsiveness.
- Cross Resistance: There are no other antiviral drugs approved for the treatment of variola (smallpox) virus infection.
## Nonclinical Toxicology
Carcinogenesis and Mutagenesis
- Carcinogenicity studies have not been conducted with tecovirimat.
- Tecovirimat was not genotoxic in in vitro or in vivo assays, including a bacterial reverse mutation assay, a mammalian mutagenicity assay in mouse lymphoma L5178Y/TK± cells, and in an in vivo mouse micronucleus study.
Impairment of Fertility
- In a fertility and early embryonic development study in mice, no effects of tecovirimat on female fertility were observed at tecovirimat exposures (AUC) approximately 24 times higher than human exposure at the RHD. In male mice, decreased male fertility associated with testicular toxicity (increased percent abnormal sperm and decreased sperm motility) was observed at 1,000 mg/kg/day (approximately 24 times the human exposure at the RHD).
- In a repeat-dose toxicology study in dogs, convulsions (tonic and clonic) were observed in one animal within 6 hours of a single dose of 300 mg/kg (approximately 4 times higher than the highest observed human exposure at the RHD based on Cmax). Electroencephalography (EEG) findings in this animal were consistent with seizure activity during the observed convulsions. Tremors, which were considered non-adverse, were observed at 100 mg/kg/dose (similar to the highest observed human exposure at the RHD based on Cmax), although no convulsions or EEG findings were observed at this dose.
# Clinical Studies
Overview
- The effectiveness of tecovirimat for treatment of smallpox disease has not been determined in humans because adequate and well-controlled field trials have not been feasible, and inducing smallpox disease in humans to study the drug’s efficacy is not ethical. Therefore, the effectiveness of tecovirimat for treatment of smallpox disease was established based on results of adequate and well-controlled animal efficacy studies of non-human primates and rabbits infected with non-variola orthopoxviruses. Survival rates observed in the animal studies may not be predictive of survival rates in clinical practice.
Study Design
- Efficacy studies were conducted in cynomolgus macaques infected with monkeypox virus, and New Zealand white (NZW) rabbits infected with rabbitpox virus. The primary efficacy endpoint for these studies was survival. In non-human primate studies, cynomolgus macaques were lethally challenged intravenously with 5 x 107 plaque-forming units of monkeypox virus; tecovirimat was administered orally once daily at a dose level of 10 mg/kg for 14 days, starting at Day 4, 5 or 6 post-challenge. In rabbit studies, NZW rabbits were lethally challenged intradermally with 1,000 plaque-forming units of rabbitpox virus; tecovirimat was administered orally once daily for 14 days at a dose level of 40 mg/kg, starting at Day 4 post-challenge. The timing of tecovirimat dosing in these studies was intended to assess efficacy when treatment is initiated after animals have developed clinical signs of disease, specifically dermal pox lesions in cynomolgus macaques, and fever in rabbits. Clinical signs of disease were evident in some animals at Day 2-3 post-challenge but were evident in all animals by Day 4 post-challenge. Survival was monitored for 3-6 times the mean time to death for untreated animals in each model.
Study Results
- Treatment with tecovirimat for 14 days resulted in statistically significant improvement in survival relative to placebo, except when given to cynomolgus macaques starting at Day 6 post-challenge (TABLE 6).
# How Supplied
- Each tecovirimat capsule contains 200 mg of tecovirimat. Tecovirimat capsules are hard gelatin with an opaque orange body imprinted in white ink with “SIGA” followed by the SIGA logo followed by “®”, and an opaque black cap imprinted in white ink with "ST-246®", containing white to off-white powder. Each bottle contains 42 capsules (NDC 50072-200-42) with an induction seal and child-resistant cap.
## Storage
- Store capsules in the original bottle at 20°C to 25°C (68°F to 77°F); excursions permitted 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
Efficacy Based on Animal Models Alone
- Inform patients that the efficacy of tecovirimat is based solely on efficacy studies demonstrating a survival benefit in animals and that the effectiveness of tecovirimat has not been tested in humans with smallpox disease.
Important Dosage and Administration Information
- Advise patients to take tecovirimat as directed within 30 minutes of eating a full meal of moderate or high fat. Inform patients to take tecovirimat for the entire duration without missing or skipping a dose.
Drug Interactions
- Inform patients that tecovirimat may interact with other drugs. Advise patients to report to their healthcare provider the use of other prescription drugs. Co-administration of tecovirimat with repaglinide may cause hypoglycemia.
# Precautions with Alcohol
Alcohol-Tecovirimat interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
TPOXX
# Look-Alike Drug Names
There is limited information regarding Tecovirimat Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/TPOXX | |
a854bbb53f3069e5333f86964b51fdbcf7ddcb0d | wikidoc | TRIL (gene) | TRIL (gene)
KIAA0644, also known as TRIL or TLR4 interactor with leucine rich repeats, is a protein that in humans is encoded by the KIAA0644 gene.
# Function
The exact function of KIAA0644 is not known. It is, however, a member of the leucine-rich repeat family of proteins, which are known to be involved in protein-protein interactions. This protein is known to interact with the TLR4 protein.
TRIL is a component of the TLR4 complex and is induced in a number of cell types by lipopolysaccharide (LPS).
# Protein sequence
The main isoform of the human protein is 811 amino long and is composed primarily of leucine (17%), alanine and arginine (~10%), and glycine (~ 8.5%) residues. The protein sequence is predicted to consists mostly of α-helices and a few β-sheet
# Homology
KIAA0644 is conserved well among mammals but can be found in all chordates with lower sequence identities.
# Gene neighborhood
The KIAA0644 gene is neighbors to mRNA-cAMP responsive element binding gene downstream and mRNA carboxypeptidase and serine carboxypeptidase gene upstream | TRIL (gene)
KIAA0644, also known as TRIL or TLR4 interactor with leucine rich repeats, is a protein that in humans is encoded by the KIAA0644 gene.[1]
# Function
The exact function of KIAA0644 is not known. It is, however, a member of the leucine-rich repeat family of proteins, which are known to be involved in protein-protein interactions. This protein is known to interact with the TLR4 protein.
TRIL is a component of the TLR4 complex and is induced in a number of cell types by lipopolysaccharide (LPS).[2]
# Protein sequence
The main isoform of the human protein is 811 amino long and is composed primarily of leucine (17%), alanine and arginine (~10%), and glycine (~ 8.5%) residues. The protein sequence is predicted to consists mostly of α-helices and a few β-sheet
# Homology
KIAA0644 is conserved well among mammals but can be found in all chordates with lower sequence identities.
# Gene neighborhood
The KIAA0644 gene is neighbors to mRNA-cAMP responsive element binding gene downstream and mRNA carboxypeptidase and serine carboxypeptidase gene upstream [3][4] | https://www.wikidoc.org/index.php/TRIL_(gene) | |
658755f0418c1ed41f80e2cdcfb4ae20e4ec60e4 | wikidoc | Tak Wah Mak | Tak Wah Mak
# Overview
Tak Wah Mak, (born 1946 in China) is an award-winning Canadian researcher who has worked in a variety of areas including biochemistry, immunology, and cancergenetics. He first became widely known for his pioneering work in the genetics of immunology.
Born in southern China in 1946 and raised in Hong Kong, Mak studied biochemistry and biophysics at the University of Wisconsin. In the early 1970s, he earned his PhD in biochemistry from the University of Alberta, in Edmonton. After he obtained his degree, Dr. Mak moved to Toronto and became a Canadian citizen.
In 1984, Dr. Mak published his work on the cloning of T-cell receptor genes; as of 2005, that article has been cited nearly 1200 times. Dr. Mak’s role in advancing the use of genetically-altered mice in scientific study has led to important breakthroughs in immunology and understanding cancer at the cellular level. The basic research in breast cancer.conducted by Dr. Mak has been published in top international scientific journals and he has given several keynote addresses at breast cancer symposia across Canada and the United States.
In spite of offers from prestigious institutions around the world, Dr. Mak remained committed to Canada’s scientific community. In 1993, Dr. Mak received support to establish the AMGEN Research Institute in Toronto. As of 2005, AMGEN-produced papers have been cited more than 40,000 times.
Dr. Mak holds Honorary Doctoral Degrees from numerous universities in North America and Europe. He is an Officer of the Order of Canada and has been elected a Foreign Associate of the National Academy of Sciences (USA) as well as a Fellow of the Royal Society of London (UK.) He has won international recognition in the forms of the Emil von Behring Prize, the King Faisal Prize for Medicine, the Gairdner Foundation International Award, the Sloan Prize of the General Motors Cancer Foundation, the Paul Ehrlich Prize and the Novartis Prize in Immunology.
In 2004 Mak became the director of the Advanced Medical Discovery Institute and the Campbell Family Institute for Breast Cancer Research. He is also the senior scientist, division of Stem Cell and Developmental Biology, Advanced Medical Discovery Institute/Ontario Cancer Institute. Since 1984, he has been a Professor in the Departments of Medical Biophysics and Immunology at the University of Toronto.
# Honours
- 1986, elected a Fellow of the Royal Society of Canada
- 1989, awarded the Gairdner Foundation International Award
- 1990, awarded the Royal Society of Canada's McLaughlin Medal
- 1994, made a Fellow of the Royal Society
- 1996, awarded the Robert L. Noble Prize by the National Cancer Institute of Canada
- 2000, made an Officer of the Order of Canada
- 2002, elected as a foreign associate to the National Academy of Sciences in the discipline of immunology
- 2003, awarded the Killam Prize by the Canada Council for the Arts. | Tak Wah Mak
# Overview
Tak Wah Mak, (born 1946 in China) is an award-winning Canadian researcher who has worked in a variety of areas including biochemistry, immunology, and cancergenetics. He first became widely known for his pioneering work in the genetics of immunology.
Born in southern China in 1946 and raised in Hong Kong, Mak studied biochemistry and biophysics at the University of Wisconsin. In the early 1970s, he earned his PhD in biochemistry from the University of Alberta, in Edmonton. After he obtained his degree, Dr. Mak moved to Toronto and became a Canadian citizen.
In 1984, Dr. Mak published his work on the cloning of T-cell receptor genes; as of 2005, that article has been cited nearly 1200 times. Dr. Mak’s role in advancing the use of genetically-altered mice in scientific study has led to important breakthroughs in immunology and understanding cancer at the cellular level. The basic research in breast cancer.conducted by Dr. Mak has been published in top international scientific journals and he has given several keynote addresses at breast cancer symposia across Canada and the United States.
In spite of offers from prestigious institutions around the world, Dr. Mak remained committed to Canada’s scientific community. In 1993, Dr. Mak received support to establish the AMGEN Research Institute in Toronto. As of 2005, AMGEN-produced papers have been cited more than 40,000 times.
Dr. Mak holds Honorary Doctoral Degrees from numerous universities in North America and Europe. He is an Officer of the Order of Canada and has been elected a Foreign Associate of the National Academy of Sciences (USA) as well as a Fellow of the Royal Society of London (UK.) He has won international recognition in the forms of the Emil von Behring Prize, the King Faisal Prize for Medicine, the Gairdner Foundation International Award, the Sloan Prize of the General Motors Cancer Foundation, the Paul Ehrlich Prize and the Novartis Prize in Immunology.
In 2004 Mak became the director of the Advanced Medical Discovery Institute and the Campbell Family Institute for Breast Cancer Research. He is also the senior scientist, division of Stem Cell and Developmental Biology, Advanced Medical Discovery Institute/Ontario Cancer Institute. Since 1984, he has been a Professor in the Departments of Medical Biophysics and Immunology at the University of Toronto.
# Honours
- 1986, elected a Fellow of the Royal Society of Canada
- 1989, awarded the Gairdner Foundation International Award
- 1990, awarded the Royal Society of Canada's McLaughlin Medal
- 1994, made a Fellow of the Royal Society
- 1996, awarded the Robert L. Noble Prize by the National Cancer Institute of Canada
- 2000, made an Officer of the Order of Canada
- 2002, elected as a foreign associate to the National Academy of Sciences in the discipline of immunology
- 2003, awarded the Killam Prize by the Canada Council for the Arts.
# External links
- University of Toronto biography
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Tak_Wah_Mak | |
42c71e71bf7ebe4a6a11f8685a5fb4fdf277cfc0 | wikidoc | Taoist diet | Taoist diet
While there are many different historical and modern schools of Taoism, with different teachings on the subject, it is safe to say that many Taoists regard their diet as extremely important to their physical, mental and spiritual health in one way or another, especially where the amount of qi in the food is concerned.
# History
Early Taoist diets were very different from present-day ones. While present-day Taoist diets call for eating lots of grains, ancient diets called for the eating of no grains at all. This was because early Taoists believed the rotting of the grains in the intestines attracted demonic creatures known as the 'three worms.' These demons loved eating decaying matter in the intestines in the hope that they could kill the person and devour his corpse. In fact, early Taoists advocated eliminating most foods from their diet. An early Taoist text, the Taipingjing, suggests that people "live on air", and that is best to be satiated without eating solid food. In effect, it suggests that people eat non-corporeal food such as qi.
# Present Day
## Basic Guidelines
A Taoist diet could focus on:
### Increase intake of the following:
- Whole grains and products made with them
- Vegetables (ideally organic and seasonal)
- Fruit (not tropical; dried fruit is very good, and only what is in season)
- Seeds and nuts
- Tofu and soy
- Herbs (although herbal usage is normally carefully prescribed)
- Tea
### Decrease intake of the following:
- Red meat (which can be difficult to digest)
- Refined products (such as white sugar, flour, and bread)
- Artificial additives/preservatives of any kind
- Dairy products (such as cheese, yogurt and cream, with the exception of the milk of running animals, in the winter)
- Cold drinks and foods (outside consumption in the summer months)
## Everyday Meals
For regular eating Taoists believe in eating a frugal diet that is based primarily on cereals. Meals are served in order of seniority, with the elders being served first, and the youngest last. Every three, five, ten or fifteen days, some families will also observe a periodic vegetarian feast.
## Festivals
The regular diet is enhanced by the frequency of festivals which take place at least every ten to fifteen days. Each festival was associated with a certain kind of food. For example, the New Year’s festival’s special food is rice cake. During the Dragon Boat festival, it is steamed dumplings and glutinous rice packed in bamboo leaves, and during the Mid-Autumn Festival the special food is mooncakes. These festivals also give Taoists the opportunity to eat far more than their diet usually proscribes. Rich food such as meat and wine is also a part of these festivals.
## Herbs
Some Taoists practice herbalism in their diets. Taoists believe that using different herbs in their food can help increase the positive energy in their bodies, and that by mixing two herbs with opposite effects they can decrease the negative energy and increase the positive energy (see Yin and Yang). | Taoist diet
While there are many different historical and modern schools of Taoism, with different teachings on the subject, it is safe to say that many Taoists regard their diet as extremely important to their physical, mental and spiritual health in one way or another, especially where the amount of qi in the food is concerned.
# History
Early Taoist diets were very different from present-day ones. While present-day Taoist diets call for eating lots of grains, ancient diets called for the eating of no grains at all. This was because early Taoists believed the rotting of the grains in the intestines attracted demonic creatures known as the 'three worms.' These demons loved eating decaying matter in the intestines in the hope that they could kill the person and devour his corpse.[1] In fact, early Taoists advocated eliminating most foods from their diet. An early Taoist text, the Taipingjing, suggests that people "live on air", and that is best to be satiated without eating solid food. In effect, it suggests that people eat non-corporeal food such as qi.[2]
# Present Day
## Basic Guidelines
A Taoist diet could focus on:
### Increase intake of the following:
- Whole grains and products made with them
- Vegetables (ideally organic and seasonal)
- Fruit (not tropical; dried fruit is very good, and only what is in season)
- Seeds and nuts
- Tofu and soy
- Herbs (although herbal usage is normally carefully prescribed)
- Tea
### Decrease intake of the following:
- Red meat (which can be difficult to digest)
- Refined products (such as white sugar, flour, and bread)
- Artificial additives/preservatives of any kind
- Dairy products (such as cheese, yogurt and cream, with the exception of the milk of running animals, in the winter)
- Cold drinks and foods (outside consumption in the summer months)
## Everyday Meals
For regular eating Taoists believe in eating a frugal diet that is based primarily on cereals. Meals are served in order of seniority, with the elders being served first, and the youngest last. Every three, five, ten or fifteen days, some families will also observe a periodic vegetarian feast.[3]
## Festivals
The regular diet is enhanced by the frequency of festivals which take place at least every ten to fifteen days. Each festival was associated with a certain kind of food. For example, the New Year’s festival’s special food is rice cake. During the Dragon Boat festival, it is steamed dumplings and glutinous rice packed in bamboo leaves, and during the Mid-Autumn Festival the special food is mooncakes. These festivals also give Taoists the opportunity to eat far more than their diet usually proscribes. Rich food such as meat and wine is also a part of these festivals.[4]
## Herbs
Some Taoists practice herbalism in their diets. Taoists believe that using different herbs in their food can help increase the positive energy in their bodies, and that by mixing two herbs with opposite effects they can decrease the negative energy and increase the positive energy (see Yin and Yang). | https://www.wikidoc.org/index.php/Taoist_diet | |
56ddae70f3714e7e415e251ee3bebfb697cfaa99 | wikidoc | Target cell | Target cell
Target cell is a term given to one of three different concepts in medicine.
- In hematology, target cells are abnormal red blood cells, that have a bullseye appearance. (See main article: codocyte)
- In endocrinology, target cells can refer to the cells where hormones have their effect. Target cells are capable of responding to hormones because they bear receptors to which the hormone can bind. Hormones will float along the bloodstream until they find an appropriate target cell.
- In immunology, target cells are the direct recipient of a T cell's effector functions, and are therefore targeted for cytotoxic destruction.
# Diagnosis
## Pathology | Target cell
Target cell is a term given to one of three different concepts in medicine.
- In hematology, target cells are abnormal red blood cells, that have a bullseye appearance. (See main article: codocyte)
- In endocrinology, target cells can refer to the cells where hormones have their effect. Target cells are capable of responding to hormones because they bear receptors to which the hormone can bind. Hormones will float along the bloodstream until they find an appropriate target cell.
- In immunology, target cells are the direct recipient of a T cell's effector functions, and are therefore targeted for cytotoxic destruction.
# Diagnosis
## Pathology
Template:WikiDoc Sources
- ↑ http://picasaweb.google.com/mcmumbi/USMLEIIImages | https://www.wikidoc.org/index.php/Target_cell | |
0e4ce44d97e8e74eead31a665f4a2f8543f463fd | wikidoc | Taribavirin | Taribavirin
Taribavirin (rINN; also known as viramidine, codenamed ICN 3142) is an antiviral drug in Phase III human trials, but not yet approved for pharmaceutical use. It is a prodrug of ribavirin, active against a number of DNA and RNA viruses. Taribavirin has better liver-targeting than ribavirin, and has a shorter life in the body due to less penetration and storage in red blood cells. It is expected eventually to be the drug of choice for viral hepatitis syndromes in which ribavirin is active. These include hepatitis C and perhaps also hepatitis B and yellow fever.
Taribavirin is as active against influenza as ribavirin in animal models, with slightly less toxicity, so it may also eventually replace ribavirin as an anti-influenza agent.
Taribavirin is being developed by Valeant Pharmaceuticals International, the parent company of Ribapharm, the company which first reported synthesis and testing of the drug in 1973. Valeant is testing the drug as a treatment for chronic hepatitis C.
Note on formulas: The carboxamidine group of this molecule is somewhat basic, and therefore this drug is also known and administered as the hydrochloride salt (with a corresponding .HCl chemical formula and different ChemID / PubChem number). At physiologic pH, the positive charge on the molecule from partial protonation of the carboximide group contributes to the relative slowness with which the drug crosses cell membranes (such as in red blood cells) until it has been metabolized into ribavirin. In the liver, however, the transformation from carboxamidine to carboxamide happens on first-pass metabolism and contributes to the higher levels of ribavirin found in liver cells and bile when viramidine is administered. | Taribavirin
Taribavirin (rINN; also known as viramidine, codenamed ICN 3142) is an antiviral drug in Phase III human trials, but not yet approved for pharmaceutical use. It is a prodrug of ribavirin, active against a number of DNA and RNA viruses. Taribavirin has better liver-targeting than ribavirin, and has a shorter life in the body due to less penetration and storage in red blood cells. It is expected eventually to be the drug of choice for viral hepatitis syndromes in which ribavirin is active. These include hepatitis C and perhaps also hepatitis B and yellow fever.
Taribavirin is as active against influenza as ribavirin in animal models, with slightly less toxicity, so it may also eventually replace ribavirin as an anti-influenza agent.
Taribavirin is being developed by Valeant Pharmaceuticals International, the parent company of Ribapharm, the company which first reported synthesis and testing of the drug in 1973. Valeant is testing the drug as a treatment for chronic hepatitis C.
Note on formulas: The carboxamidine group of this molecule is somewhat basic, and therefore this drug is also known and administered as the hydrochloride salt (with a corresponding .HCl chemical formula and different ChemID / PubChem number). At physiologic pH, the positive charge on the molecule from partial protonation of the carboximide group contributes to the relative slowness with which the drug crosses cell membranes (such as in red blood cells) until it has been metabolized into ribavirin. In the liver, however, the transformation from carboxamidine to carboxamide happens on first-pass metabolism and contributes to the higher levels of ribavirin found in liver cells and bile when viramidine is administered. | https://www.wikidoc.org/index.php/Taribavirin | |
9dde0adf0aa6d5fe90db7bddecd2a16adbe826eb | wikidoc | Tasimelteon | Tasimelteon
# 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
Tasimelteon is a central nervous system agent that is FDA approved for the treatment of non-24-hour sleep-wake disorder. Common adverse reactions include headache, urinary tract infection, upper respiratory tract infection, abnormal dreams, increased liver enzymes.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- HETLIOZ is indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24).
# Dosage
- The recommended dosage of HETLIOZ is 20 mg per day taken before bedtime, at the same time every night.
- Because of individual differences in circadian rhythms, drug effect may not occur for weeks or months.
# DOSAGE FORMS AND STRENGTHS
- Capsules: 20 mg size 1 dark blue opaque, hard gelatin capsules printed with “VANDA 20 mg” in white.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Tasimelteon in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Tasimelteon in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Tasimelteon in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Tasimelteon in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Tasimelteon in pediatric patients.
# Contraindications
- None
# Warnings
Somnolence
- After taking HETLIOZ, patients should limit their activity to preparing for going to bed. HETLIOZ can potentially impair the performance of activities requiring complete mental alertness.
# 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 clinical practice.
- A total of 1346 subjects were treated with at least one dose of HETLIOZ, of which 139 were treated for > 26 weeks and 93 were treated for > 1 year.
- A 26-week, parallel-arm placebo-controlled study (Study 1) evaluated HETLIOZ (n=42) compared to placebo (n=42) in patients with Non-24. A randomized-withdrawal, placebo- controlled study of 8 weeks duration (Study 2) also evaluated HETLIOZ (n=10), compared to placebo (n=10), in patients with Non-24.
- In placebo-controlled studies, 6% of patients exposed to HETLIOZ discontinued treatment due to an adverse event, compared with 4% of patients who received placebo.
- TABLE 1 shows the incidence of adverse reactions from Study 1.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Tasimelteon in the drug label.
# Drug Interactions
Strong CYP1A2 Inhibitors (e.g., fluvoxamine)
- Avoid use of HETLIOZ in combination with fluvoxamine or other strong CYP1A2 inhibitors because of a potentially large increase in tasimelteon exposure and greater risk of adverse reactions .
Strong CYP3A4 Inducers (e.g., rifampin)
- Avoid use of HETLIOZ in combination with rifampin or other CYP3A4 inducers because of a potentially large decrease in tasimelteon exposure with reduced efficacy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- There are no adequate and well-controlled studies of HETLIOZ in pregnant women. In animal studies, administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofetal mortality, neurobehavioral impairment, and decreased growth and development in offspring) at doses greater than those used clinically. HETLIOZ should be used during pregnancy only if the potential benefit justifies the potential risks.
- In pregnant rats administered tasimelteon at oral doses of 5, 50, or 500 mg/kg/day during the period of organogenesis, there were no effects on embryofetal development. The highest dose tested is approximately 240 times the recommended human dose (RHD) of 20 mg/day, on a mg/m2 basis.
- In pregnant rabbits administered tasimelteon at oral doses of 5, 30, or 200 mg/kg/day during the period of organogenesis, embryolethality and embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. The highest dose not associated with adverse effects (30 mg/kg/day) is approximately 30 times the RHD on a mg/m2 basis.
- Oral administration of tasimelteon (50, 150, or 450 mg/kg/day) to rats throughout organogenesis and lactation resulted in persistent reductions in body weight, delayed sexual maturation and physical development, and neurobehavioral impairment in offspring at the highest dose tested. Reduced body weight in offspring was also observed at the mid-dose. The no effect dose (50 mg/kg/day) is approximately 25 times the RHD on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tasimelteon in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tasimelteon 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 HETLIOZ is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- The risk of adverse reactions may be greater in elderly (>65 years) patients than younger patients because exposure to tasimelteon is increased by approximately 2-fold compared with younger patients.
### Gender
There is no FDA guidance on the use of Tasimelteon with respect to specific racial populations.
### Race
There is no FDA guidance on the use of Tasimelteon with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tasimelteon in patients with renal impairment.
### Hepatic Impairment
- Dose adjustment is not necessary in patients with mild or moderate hepatic impairment. HETLIOZ has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, HETLIOZ is not recommended for use in patients with severe hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tasimelteon in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tasimelteon in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Tasimelteon in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tasimelteon in the drug label.
# Overdosage
- There is limited premarketing clinical experience with the effects of an overdosage of HETLIOZ.
- As with the management of any overdose, general symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Respiration, pulse, blood pressure, and other appropriate vital signs should be monitored, and general supportive measures employed.
- While hemodialysis was effective at clearing HETLIOZ and the majority of its major metabolites in patients with renal impairment, it is not known if hemodialysis will effectively reduce exposure in the case of overdose.
- As with the management of any overdose, the possibility of multiple drug ingestion should be considered. Contact a poison control center for current information on the management of overdose.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which tasimelteon exerts its therapeutic effect in patients with Non-24 is not known. Tasimelteon is an agonist at melatonin MT1 and MT2 receptors. These receptors are thought to be involved in the control of circadian rhythms.
## Structure
HETLIOZ (tasimelteon) is a melatonin receptor agonist, chemically designated as (1R, 2R)-N-propanamide, containing two chiral centers. The molecular formula is C15H19NO2, and the molecular weight is 245.32. The structural formula is:
- Tasimelteon is a white to off-white crystalline powder. It is very slightly soluble in cyclohexane, slightly soluble in water and 0.1 N hydrochloric acid, and freely soluble or very soluble in methanol, 95% ethanol, acetonitrile, isopropanol, polyethylene glycol 300, propylene glycol and ethyl acetate.
- HETLIOZ is available in 20 mg strength capsules for oral administration. Inactive ingredients are: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. Each hard gelatin capsule consists of gelatin, titanium dioxide, FD&C Blue #1, FD&C Red #3, and FD&C Yellow #6.
## Pharmacodynamics
- HETLIOZ is an agonist at MT1 and MT2 receptors. HETLIOZ exhibits a greater affinity for the MT2 as compared to the MT1 receptor. The most abundant metabolites of HETLIOZ have less than one-tenth of the binding affinity of the parent molecule for both the MT1 and MT2 receptors.
## Pharmacokinetics
- The pharmacokinetics of HETLIOZ is linear over doses ranging from 3 to 300 mg (0.15 to 15 times the recommended daily dosage). The pharmacokinetics of HETLIOZ and its metabolites did not change with repeated daily dosing.
Absorption
- The absolute oral bioavailability is 38.3%. The peak concentration (Tmax) of tasimelteon occurred approximately 0.5 to 3 hours after fasted oral administration.
- When administered with a high-fat meal, the Cmax of tasimelteon was 44% lower than when given in a fasted state, and the median Tmax was delayed by approximately 1.75 hours. Therefore, HETLIOZ should be taken without food.
Distribution
- The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 59 - 126 L. At therapeutic concentrations, tasimelteon is about 90% bound to proteins.
Metabolism
- Tasimelteon is extensively metabolized. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon.
- Phenolic glucuronidation is the major phase II metabolic route.
- Major metabolites had 13-fold or less activity at melatonin receptors compared to tasimelteon.
Elimination
- Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 84%. Less than 1% of the dose was excreted in urine as the parent compound.
- The observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 hours. The mean terminal elimination half-life ± standard deviation of the main metabolites ranges from 1.3 ± 0.5 to 3.7 ± 2.2.
- Repeated once daily dosing with HETLIOZ does not result in changes in pharmacokinetic parameters or significant accumulation of tasimelteon.
Studies in Specific Populations
Elderly
- In elderly subjects, tasimelteon exposure increased by approximately two-fold compared with non-elderly adults.
Gender
- The mean overall exposure of tasimelteon was approximately 20-30% greater in female than in male subjects.
Race
- The effect of race on exposure of HETLIOZ was not evaluated.
Hepatic Impairment
- The pharmacokinetic profile of a 20 mg dose of HETLIOZ was compared among eight subjects with mild hepatic impairment (Child-Pugh Score ≥5 and ≤6 points), eight subjects with moderate hepatic impairment (Child-Pugh Score ≥7 and ≤9 points), and 13 healthy matched controls. Tasimelteon exposure was increased less than two-fold in subjects with moderate hepatic impairment. Therefore, no dose adjustment is needed in patients with mild or moderate hepatic impairment. HETLIOZ has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and is not recommended in these patients.
Renal Impairment
- The pharmacokinetic profile of a 20 mg dose of HETLIOZ was compared among eight subjects with severe renal impairment (estimated glomerular filtration rate ≤ 29 mL/min/1.73m 2), eight subjects with end-stage renal disease (ESRD) (GFR < 15 mL/min/1.73m 2) requiring hemodialysis, and sixteen healthy matched controls. There was no apparent relationship between tasimelteon CL/F and renal function, as measured by either estimated creatinine clearance or eGFR. Subjects with severe renal impairment had a 30% lower clearance, and clearance in subjects with ESRD was comparable to that of healthy subjects. No dose adjustment is necessary for patients with renal impairment.
Smokers (smoking is a moderate CYP1A2 inducer)
- Tasimelteon exposure decreased by approximately 40% in smokers, compared to non- smokers.
Drug Interaction Studies
- No potential drug interactions were identified in in vitro studies with CYP inducers or inhibitors of CYP1A1, CYP1A2, CYP2B6, CYP2C9/2C19, CYP2E1, CYP2D6 and transporters including P-glycoprotein, OATP1B1, OATP1B3, OCT2, OAT1 and OAT3.
Effect of Other Drugs on HETLIOZ
- Drugs that inhibit CYP1A2 and CYP3A4 are expected to alter the metabolism of tasimelteon.
- Fluvoxamine (strong CYP1A2 inhibitor): the AUC 0-inf and C max of tasimelteon increased by 7-fold and 2-fold, respectively, when co-administered with fluvoxamine 50 mg (after 6 days of fluvoxamine 50 mg per day).
- Ketoconazole (strong CYP3A4 inhibitor): tasimelteon exposure increased by approximately 50% when co-administered with ketoconazole 400 mg (after 5 days of ketoconazole 400 mg per day).
- Rifampin (strong CYP3A4 and moderate CYP2C19 inducer): the exposure of tasimelteon decreased by approximately 90% when co-administered with rifampin 600 mg (after 11 days of rifampin 600 mg per day). Efficacy may be reduced when HETLIOZ is used in combination with strong CYP3A4 inducers, such as rifampin.
Effect of HETLIOZ on Other Drugs
- Midazolam (CYP3A4 substrate): Administration of HETLIOZ 20 mg once a day for 14 days did not produce any significant changes in the T max, C max, or AUC of midazolam or 1-OH midazolam. This indicates there is no induction of CYP3A4 by tasimelteon at this dose.
- Rosiglitazone (CYP2C8 substrate): Administration of HETLIOZ 20 mg once a day for 16 days did not produce any clinically significant changes in the T max, C max, or AUC of rosiglitazone after oral administration of 4 mg. This indicates that there is no induction of CYP2C8 by tasimelteon at this dose.
Effect of Alcohol on HETLIOZ
- In a study of 28 healthy volunteers, a single dose of ethanol (0.6 g/kg for women and 0.7 g/kg for men) was co-administered with a 20 mg dose of HETLIOZ. There was a trend for an additive effect of HETLIOZ and ethanol on some psychomotor tests.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- Tasimelteon was administered orally for up to two years to mice (30, 100, and 300 mg/kg/day) and rats (20, 100, and 250 mg/kg/day). No evidence of carcinogenic potential was observed in mice; the highest dose tested is approximately 75 times the recommended human dose (RHD) of 20 mg/day, on a mg/m2 basis. In rats, the incidence of liver tumors was increased in males (adenoma and carcinoma) and females (adenoma) at 100 and 250 mg/kg/day; the incidence of tumors of the uterus (endometrial adenocarcinoma) and uterus and cervix (squamous cell carcinoma) were increased at 250 mg/kg/day. There was no increase in tumors at the lowest dose tested in rats, which is approximately 10 times the RHD on a mg/m2 basis.
Mutagenesis
- Tasimelteon was negative in an in vitro bacterial reverse mutation (Ames) assay, an in vitro cytogenetics assay in primary human lymphocytes, and an in vivo micronucleus assay in rats.
Impairment of Fertility
- When male and female rats were given tasimelteon at oral doses of 5, 50, or 500 mg/kg/day prior to and throughout mating and continuing in females to gestation day 7, estrus cycle disruption and decreased fertility were observed at all but the lowest dose tested. The no-effect dose for effects on female reproduction (5 mg/kg/day) is approximately 2 times the RHD on a mg/m2 basis.
# Clinical Studies
- The effectiveness of HETLIOZ in the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) was established in two randomized double-masked, placebo-controlled, multicenter, parallel-group studies (Studies 1 and 2) in totally blind patients with Non-24.
- In study 1, 84 patients with Non-24 (median age 54 years) were randomized to receive HETLIOZ 20 mg or placebo, one hour prior to bedtime, at the same time every night for up to 6 months.
- Study 2 was a randomized withdrawal trial in 20 patients with Non-24 (median age 55 years) that was designed to evaluate the maintenance of efficacy of HETLIOZ after 12-weeks. Patients were treated for approximately 12 weeks with HETLIOZ 20 mg one hour prior to bedtime, at the same time every night. Patients in whom the calculated time of peak melatonin level (melatonin acrophase) occurred at approximately the same time of day (in contrast to the expected daily delay) during the run-in phase were randomized to receive placebo or continue treatment with HETLIOZ 20 mg for 8 weeks.
- Study 1 and Study 2 evaluated the duration and timing of nighttime sleep and daytime naps via patient-recorded diaries. During Study 1, patient diaries were recorded for an average of 88 days during screening, and 133 days during randomization. During Study 2, patient diaries were recorded for an average of 57 days during the run-in phase, and 59 days during the randomized-withdrawal phase.
- Because symptoms of nighttime sleep disruption and daytime sleepiness are cyclical in patients with Non-24, with severity varying according to the state of alignment of the individual patient’s circadian rhythm with the 24-hour day (least severe when fully aligned, most severe when 12 hours out of alignment), efficacy endpoints for nighttime total sleep time and daytime nap duration were based on the 25% of nights with the least nighttime sleep, and the 25% of days with the most daytime nap time. In Study 1, patients in the HETLIOZ group had, at baseline, an average 195 minutes of nighttime sleep and 137 minutes of daytime nap time on the 25% of most symptomatic nights and days, respectively. Treatment with HETLIOZ resulted in a significant improvement, compared with placebo, for both of these endpoints in Study 1 and Study 2.
- A responder analysis of patients with both ≥ 45 minutes increase in nighttime sleep and ≥ 45 minutes decrease in daytime nap time was conducted in Study 1: 29% (n=12) of patients treated with HETLIOZ, compared with 12% (n=5) of patients treated with placebo met the responder criteria.
- The efficacy of HETLIOZ in treating Non-24 may be reduced in subjects with concomitant administration of beta adrenergic receptor antagonists.
# How Supplied
- HETLIOZ 20 mg capsules are available as size 1, dark blue opaque, hard gelatin capsules printed with “VANDA 20 mg” in white, containing 20 mg of tasimelteon per capsule.
- NDC 43068-220-01 Bottles of 30
## Storage
- Store HETLIOZ 20 mg capsules at controlled room temperature, 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect HETLIOZ 20 mg capsules from exposure to light and moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise patients
- To take HETLIOZ before bedtime at the same time every night.
- To skip the dose that night if they cannot take HETLIOZ at approximately the same time on a given night.
- To limit their activities to preparing for going to bed after taking HETLIOZ because HETLIOZ can potentially impair the performance of activities requiring complete mental alertness.
- That because of individual differences in circadian rhythms, daily use for several weeks or months may be necessary before benefit from HETLIOZ is observed.
- To swallow the capsule whole.
# Precautions with Alcohol
- Alcohol-Tasimelteon interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- HETLIOZ ®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Tasimelteon
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [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
Tasimelteon is a central nervous system agent that is FDA approved for the treatment of non-24-hour sleep-wake disorder. Common adverse reactions include headache, urinary tract infection, upper respiratory tract infection, abnormal dreams, increased liver enzymes.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- HETLIOZ is indicated for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24).
# Dosage
- The recommended dosage of HETLIOZ is 20 mg per day taken before bedtime, at the same time every night.
- Because of individual differences in circadian rhythms, drug effect may not occur for weeks or months.
# DOSAGE FORMS AND STRENGTHS
- Capsules: 20 mg size 1 dark blue opaque, hard gelatin capsules printed with “VANDA 20 mg” in white.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Tasimelteon in adult patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Tasimelteon in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- There is limited information regarding FDA-Labeled Use of Tasimelteon in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- There is limited information regarding Off-Label Guideline-Supported Use of Tasimelteon in pediatric patients.
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Tasimelteon in pediatric patients.
# Contraindications
- None
# Warnings
Somnolence
- After taking HETLIOZ, patients should limit their activity to preparing for going to bed. HETLIOZ can potentially impair the performance of activities requiring complete mental alertness.
# 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 clinical practice.
- A total of 1346 subjects were treated with at least one dose of HETLIOZ, of which 139 were treated for > 26 weeks and 93 were treated for > 1 year.
- A 26-week, parallel-arm placebo-controlled study (Study 1) evaluated HETLIOZ (n=42) compared to placebo (n=42) in patients with Non-24. A randomized-withdrawal, placebo- controlled study of 8 weeks duration (Study 2) also evaluated HETLIOZ (n=10), compared to placebo (n=10), in patients with Non-24.
- In placebo-controlled studies, 6% of patients exposed to HETLIOZ discontinued treatment due to an adverse event, compared with 4% of patients who received placebo.
- TABLE 1 shows the incidence of adverse reactions from Study 1.
## Postmarketing Experience
- There is limited information regarding Postmarketing Experience of Tasimelteon in the drug label.
# Drug Interactions
Strong CYP1A2 Inhibitors (e.g., fluvoxamine)
- Avoid use of HETLIOZ in combination with fluvoxamine or other strong CYP1A2 inhibitors because of a potentially large increase in tasimelteon exposure and greater risk of adverse reactions [see Clinical Pharmacology (12.3)].
Strong CYP3A4 Inducers (e.g., rifampin)
- Avoid use of HETLIOZ in combination with rifampin or other CYP3A4 inducers because of a potentially large decrease in tasimelteon exposure with reduced efficacy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category C
- There are no adequate and well-controlled studies of HETLIOZ in pregnant women. In animal studies, administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofetal mortality, neurobehavioral impairment, and decreased growth and development in offspring) at doses greater than those used clinically. HETLIOZ should be used during pregnancy only if the potential benefit justifies the potential risks.
- In pregnant rats administered tasimelteon at oral doses of 5, 50, or 500 mg/kg/day during the period of organogenesis, there were no effects on embryofetal development. The highest dose tested is approximately 240 times the recommended human dose (RHD) of 20 mg/day, on a mg/m2 basis.
- In pregnant rabbits administered tasimelteon at oral doses of 5, 30, or 200 mg/kg/day during the period of organogenesis, embryolethality and embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. The highest dose not associated with adverse effects (30 mg/kg/day) is approximately 30 times the RHD on a mg/m2 basis.
- Oral administration of tasimelteon (50, 150, or 450 mg/kg/day) to rats throughout organogenesis and lactation resulted in persistent reductions in body weight, delayed sexual maturation and physical development, and neurobehavioral impairment in offspring at the highest dose tested. Reduced body weight in offspring was also observed at the mid-dose. The no effect dose (50 mg/kg/day) is approximately 25 times the RHD on a mg/m2 basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tasimelteon in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tasimelteon 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 HETLIOZ is administered to a nursing woman.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
- The risk of adverse reactions may be greater in elderly (>65 years) patients than younger patients because exposure to tasimelteon is increased by approximately 2-fold compared with younger patients.
### Gender
There is no FDA guidance on the use of Tasimelteon with respect to specific racial populations.
### Race
There is no FDA guidance on the use of Tasimelteon with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tasimelteon in patients with renal impairment.
### Hepatic Impairment
- Dose adjustment is not necessary in patients with mild or moderate hepatic impairment. HETLIOZ has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, HETLIOZ is not recommended for use in patients with severe hepatic impairment
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tasimelteon in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tasimelteon in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Tasimelteon in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tasimelteon in the drug label.
# Overdosage
- There is limited premarketing clinical experience with the effects of an overdosage of HETLIOZ.
- As with the management of any overdose, general symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Respiration, pulse, blood pressure, and other appropriate vital signs should be monitored, and general supportive measures employed.
- While hemodialysis was effective at clearing HETLIOZ and the majority of its major metabolites in patients with renal impairment, it is not known if hemodialysis will effectively reduce exposure in the case of overdose.
- As with the management of any overdose, the possibility of multiple drug ingestion should be considered. Contact a poison control center for current information on the management of overdose.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which tasimelteon exerts its therapeutic effect in patients with Non-24 is not known. Tasimelteon is an agonist at melatonin MT1 and MT2 receptors. These receptors are thought to be involved in the control of circadian rhythms.
## Structure
HETLIOZ (tasimelteon) is a melatonin receptor agonist, chemically designated as (1R, 2R)-N-[2-(2,3-dihydrobenzofuran-4-yl)cyclopropylmethyl]propanamide, containing two chiral centers. The molecular formula is C15H19NO2, and the molecular weight is 245.32. The structural formula is:
- Tasimelteon is a white to off-white crystalline powder. It is very slightly soluble in cyclohexane, slightly soluble in water and 0.1 N hydrochloric acid, and freely soluble or very soluble in methanol, 95% ethanol, acetonitrile, isopropanol, polyethylene glycol 300, propylene glycol and ethyl acetate.
- HETLIOZ is available in 20 mg strength capsules for oral administration. Inactive ingredients are: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. Each hard gelatin capsule consists of gelatin, titanium dioxide, FD&C Blue #1, FD&C Red #3, and FD&C Yellow #6.
## Pharmacodynamics
- HETLIOZ is an agonist at MT1 and MT2 receptors. HETLIOZ exhibits a greater affinity for the MT2 as compared to the MT1 receptor. The most abundant metabolites of HETLIOZ have less than one-tenth of the binding affinity of the parent molecule for both the MT1 and MT2 receptors.
## Pharmacokinetics
- The pharmacokinetics of HETLIOZ is linear over doses ranging from 3 to 300 mg (0.15 to 15 times the recommended daily dosage). The pharmacokinetics of HETLIOZ and its metabolites did not change with repeated daily dosing.
Absorption
- The absolute oral bioavailability is 38.3%. The peak concentration (Tmax) of tasimelteon occurred approximately 0.5 to 3 hours after fasted oral administration.
- When administered with a high-fat meal, the Cmax of tasimelteon was 44% lower than when given in a fasted state, and the median Tmax was delayed by approximately 1.75 hours. Therefore, HETLIOZ should be taken without food.
Distribution
- The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 59 - 126 L. At therapeutic concentrations, tasimelteon is about 90% bound to proteins.
Metabolism
- Tasimelteon is extensively metabolized. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon.
- Phenolic glucuronidation is the major phase II metabolic route.
- Major metabolites had 13-fold or less activity at melatonin receptors compared to tasimelteon.
Elimination
- Following oral administration of radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 84%. Less than 1% of the dose was excreted in urine as the parent compound.
- The observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 hours. The mean terminal elimination half-life ± standard deviation of the main metabolites ranges from 1.3 ± 0.5 to 3.7 ± 2.2.
- Repeated once daily dosing with HETLIOZ does not result in changes in pharmacokinetic parameters or significant accumulation of tasimelteon.
Studies in Specific Populations
Elderly
- In elderly subjects, tasimelteon exposure increased by approximately two-fold compared with non-elderly adults.
Gender
- The mean overall exposure of tasimelteon was approximately 20-30% greater in female than in male subjects.
Race
- The effect of race on exposure of HETLIOZ was not evaluated.
Hepatic Impairment
- The pharmacokinetic profile of a 20 mg dose of HETLIOZ was compared among eight subjects with mild hepatic impairment (Child-Pugh Score ≥5 and ≤6 points), eight subjects with moderate hepatic impairment (Child-Pugh Score ≥7 and ≤9 points), and 13 healthy matched controls. Tasimelteon exposure was increased less than two-fold in subjects with moderate hepatic impairment. Therefore, no dose adjustment is needed in patients with mild or moderate hepatic impairment. HETLIOZ has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and is not recommended in these patients.
Renal Impairment
- The pharmacokinetic profile of a 20 mg dose of HETLIOZ was compared among eight subjects with severe renal impairment (estimated glomerular filtration rate [eGFR] ≤ 29 mL/min/1.73m 2), eight subjects with end-stage renal disease (ESRD) (GFR < 15 mL/min/1.73m 2) requiring hemodialysis, and sixteen healthy matched controls. There was no apparent relationship between tasimelteon CL/F and renal function, as measured by either estimated creatinine clearance or eGFR. Subjects with severe renal impairment had a 30% lower clearance, and clearance in subjects with ESRD was comparable to that of healthy subjects. No dose adjustment is necessary for patients with renal impairment.
Smokers (smoking is a moderate CYP1A2 inducer)
- Tasimelteon exposure decreased by approximately 40% in smokers, compared to non- smokers.
Drug Interaction Studies
- No potential drug interactions were identified in in vitro studies with CYP inducers or inhibitors of CYP1A1, CYP1A2, CYP2B6, CYP2C9/2C19, CYP2E1, CYP2D6 and transporters including P-glycoprotein, OATP1B1, OATP1B3, OCT2, OAT1 and OAT3.
Effect of Other Drugs on HETLIOZ
- Drugs that inhibit CYP1A2 and CYP3A4 are expected to alter the metabolism of tasimelteon.
- Fluvoxamine (strong CYP1A2 inhibitor): the AUC 0-inf and C max of tasimelteon increased by 7-fold and 2-fold, respectively, when co-administered with fluvoxamine 50 mg (after 6 days of fluvoxamine 50 mg per day).
- Ketoconazole (strong CYP3A4 inhibitor): tasimelteon exposure increased by approximately 50% when co-administered with ketoconazole 400 mg (after 5 days of ketoconazole 400 mg per day).
- Rifampin (strong CYP3A4 and moderate CYP2C19 inducer): the exposure of tasimelteon decreased by approximately 90% when co-administered with rifampin 600 mg (after 11 days of rifampin 600 mg per day). Efficacy may be reduced when HETLIOZ is used in combination with strong CYP3A4 inducers, such as rifampin.
Effect of HETLIOZ on Other Drugs
- Midazolam (CYP3A4 substrate): Administration of HETLIOZ 20 mg once a day for 14 days did not produce any significant changes in the T max, C max, or AUC of midazolam or 1-OH midazolam. This indicates there is no induction of CYP3A4 by tasimelteon at this dose.
- Rosiglitazone (CYP2C8 substrate): Administration of HETLIOZ 20 mg once a day for 16 days did not produce any clinically significant changes in the T max, C max, or AUC of rosiglitazone after oral administration of 4 mg. This indicates that there is no induction of CYP2C8 by tasimelteon at this dose.
Effect of Alcohol on HETLIOZ
- In a study of 28 healthy volunteers, a single dose of ethanol (0.6 g/kg for women and 0.7 g/kg for men) was co-administered with a 20 mg dose of HETLIOZ. There was a trend for an additive effect of HETLIOZ and ethanol on some psychomotor tests.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
- Tasimelteon was administered orally for up to two years to mice (30, 100, and 300 mg/kg/day) and rats (20, 100, and 250 mg/kg/day). No evidence of carcinogenic potential was observed in mice; the highest dose tested is approximately 75 times the recommended human dose (RHD) of 20 mg/day, on a mg/m2 basis. In rats, the incidence of liver tumors was increased in males (adenoma and carcinoma) and females (adenoma) at 100 and 250 mg/kg/day; the incidence of tumors of the uterus (endometrial adenocarcinoma) and uterus and cervix (squamous cell carcinoma) were increased at 250 mg/kg/day. There was no increase in tumors at the lowest dose tested in rats, which is approximately 10 times the RHD on a mg/m2 basis.
Mutagenesis
- Tasimelteon was negative in an in vitro bacterial reverse mutation (Ames) assay, an in vitro cytogenetics assay in primary human lymphocytes, and an in vivo micronucleus assay in rats.
Impairment of Fertility
- When male and female rats were given tasimelteon at oral doses of 5, 50, or 500 mg/kg/day prior to and throughout mating and continuing in females to gestation day 7, estrus cycle disruption and decreased fertility were observed at all but the lowest dose tested. The no-effect dose for effects on female reproduction (5 mg/kg/day) is approximately 2 times the RHD on a mg/m2 basis.
# Clinical Studies
- The effectiveness of HETLIOZ in the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24) was established in two randomized double-masked, placebo-controlled, multicenter, parallel-group studies (Studies 1 and 2) in totally blind patients with Non-24.
- In study 1, 84 patients with Non-24 (median age 54 years) were randomized to receive HETLIOZ 20 mg or placebo, one hour prior to bedtime, at the same time every night for up to 6 months.
- Study 2 was a randomized withdrawal trial in 20 patients with Non-24 (median age 55 years) that was designed to evaluate the maintenance of efficacy of HETLIOZ after 12-weeks. Patients were treated for approximately 12 weeks with HETLIOZ 20 mg one hour prior to bedtime, at the same time every night. Patients in whom the calculated time of peak melatonin level (melatonin acrophase) occurred at approximately the same time of day (in contrast to the expected daily delay) during the run-in phase were randomized to receive placebo or continue treatment with HETLIOZ 20 mg for 8 weeks.
- Study 1 and Study 2 evaluated the duration and timing of nighttime sleep and daytime naps via patient-recorded diaries. During Study 1, patient diaries were recorded for an average of 88 days during screening, and 133 days during randomization. During Study 2, patient diaries were recorded for an average of 57 days during the run-in phase, and 59 days during the randomized-withdrawal phase.
- Because symptoms of nighttime sleep disruption and daytime sleepiness are cyclical in patients with Non-24, with severity varying according to the state of alignment of the individual patient’s circadian rhythm with the 24-hour day (least severe when fully aligned, most severe when 12 hours out of alignment), efficacy endpoints for nighttime total sleep time and daytime nap duration were based on the 25% of nights with the least nighttime sleep, and the 25% of days with the most daytime nap time. In Study 1, patients in the HETLIOZ group had, at baseline, an average 195 minutes of nighttime sleep and 137 minutes of daytime nap time on the 25% of most symptomatic nights and days, respectively. Treatment with HETLIOZ resulted in a significant improvement, compared with placebo, for both of these endpoints in Study 1 and Study 2.
- A responder analysis of patients with both ≥ 45 minutes increase in nighttime sleep and ≥ 45 minutes decrease in daytime nap time was conducted in Study 1: 29% (n=12) of patients treated with HETLIOZ, compared with 12% (n=5) of patients treated with placebo met the responder criteria.
- The efficacy of HETLIOZ in treating Non-24 may be reduced in subjects with concomitant administration of beta adrenergic receptor antagonists.
# How Supplied
- HETLIOZ 20 mg capsules are available as size 1, dark blue opaque, hard gelatin capsules printed with “VANDA 20 mg” in white, containing 20 mg of tasimelteon per capsule.
- NDC 43068-220-01 Bottles of 30
## Storage
- Store HETLIOZ 20 mg capsules at controlled room temperature, 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect HETLIOZ 20 mg capsules from exposure to light and moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise patients
- To take HETLIOZ before bedtime at the same time every night.
- To skip the dose that night if they cannot take HETLIOZ at approximately the same time on a given night.
- To limit their activities to preparing for going to bed after taking HETLIOZ because HETLIOZ can potentially impair the performance of activities requiring complete mental alertness.
- That because of individual differences in circadian rhythms, daily use for several weeks or months may be necessary before benefit from HETLIOZ is observed.
- To swallow the capsule whole.
# Precautions with Alcohol
- Alcohol-Tasimelteon interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- HETLIOZ ®[2]
# Look-Alike Drug Names
- A® — B®[3]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tasimelteon | |
bf82c2befc55805a222ee9156b61e4d93f38e890 | wikidoc | Tau protein | Tau protein
Tau proteins (or τ proteins, after the Greek letter with that name) are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes. Pathologies and dementias of the nervous system such as Alzheimer's disease and Parkinson's disease are associated with tau proteins that have become defective and no longer stabilize microtubules properly.
The tau proteins are the product of alternative splicing from a single gene that in humans is designated MAPT (microtubule-associated protein tau) and is located on chromosome 17.
The tau proteins were identified in 1975 as heat-stable proteins essential for microtubule assembly and since then, they have been characterized as intrinsically disordered proteins.
# Function
Tau protein is a highly soluble microtubule-associated protein tau (MAPT). In humans, these proteins are found mostly in neurons compared to non-neuronal cells. One of tau's main functions is to modulate the stability of axonal microtubules. Other nervous system MAPs may perform similar functions, as suggested by tau knock out mice that did not show abnormalities in brain development - possibly because of compensation in tau deficiency by other MAPs. Tau is not present in dendrites and is active primarily in the distal portions of axons where it provides microtubule stabilization but also flexibility as needed. This contrasts with MAP6 (STOP) proteins in the proximal portions of axons, which, in essence, lock down the microtubules and MAP2 that stabilizes microtubules in dendrites. In addition to their microtubule stabilizing functions, MAPTs have also been found to recruit signaling proteins and regulation of microtubule-mediated transport.
Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules. Tau has two ways of controlling microtubule stability: isoforms and phosphorylation.
# Genetics
In humans, the MAPT gene for encoding tau protein is located on chromosome 17q21, containing 16 exons. The major tau protein in the human brain is encoded by 11 exons. Exons 2, 3 and 10 are alternatively spliced that lead to formation of six tau isoforms. In human brain, tau proteins constitute a family of six isoforms with a range of 352-441 amino acids. Tau isoforms are different in either zero, one, or two inserts of 29 amino acids at the N-terminal part (exon 2 and 3), and three or four repeat-regions at the C-terminal part (exon 10). Thus, the longest isoform in the CNS has four repeats (R1, R2, R3 and R4) and two inserts (441 amino acids total), while the shortest isoform has three repeats (R1, R3 and R4) and no insert (352 amino acids total).
The MAPT gene has two haplogroups, H1 and H2, in which the gene appears in inverted orientations. Haplogroup H2 is common only in Europe and in people with European ancestry. Haplogroup H1 appears to be associated with increased probability of certain dementias, such as Alzheimer's disease. The presence of both haplogroups in Europe means that recombination between inverted haplotypes can result in the lack of one of the functioning copy of the gene, resulting in congenital defects.
# Structure
Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding domains. Three isoforms have three binding domains and the other three have four binding domains. The binding domains are located in the carboxy-terminus of the protein and are positively charged (allowing it to bind to the negatively charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. The isoforms are a result of alternative splicing in exons 2, 3, and 10 of the tau gene. Tau is a phosphoprotein with 79 potential Serine (Ser) and Threonine (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been reported on approximately 30 of these sites in normal tau proteins.
Phosphorylation of tau is regulated by a host of kinases, including PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization. Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau. The degree of phosphorylation in all six isoforms decreases with age due to the activation of phosphatases. Like kinases, phosphatases too play a role in regulating the phosphorylation of tau. For example, PP2A and PP2B are both present in human brain tissue and have the ability to dephosphorylate Ser396. The binding of these phosphatases to tau affects tau's association with MTs.
# Tau Mechanism
The accumulation of hyperphosphorylated tau in neurons will lead to the neurofibrillary degeneration. The actual mechanism of how tau propagate from one cell to another is not well identified. Also, other mechanisms including tau release and toxicity are unclear. As tau aggregates, it replaces tubulin which in turn enhance fibrilization of tau. Several propagation methods have been proposed which occur by synaptic contact such as synaptic cell adhesion proteins and neuronal activity and other synaptic and non-synaptic mechanisms. The mechanism of tau aggregation is still not completely elucidated still there are several factors that favorize this process, including Tau phosphorylation and zinc ions.
## Tau release
Tau involves in uptake and release process, which is known as seeding. Uptake of tau protein mechanism requires the presence of heparan sulfate proteoglycans at the cell surface which happen by macropinocytosis. On the other hand, tau release depends on neuronal activity. Many factors influence tau release, for example, type of isoforms or MAPT mutations which change the extracellular level of tau. According to Asai and his colleagues, spreading of tau protein occurs from entorhinal cortex to the hippocampal region in the early stages of the disease. They also suggested that microglia were also involved in the transport process and their actual rule is still unknown.
## Tau toxicity
Tau causes toxic effects through its accumulation inside cells. Many enzymes involved in toxicity mechanism such as PAR-1 kinase. This enzyme stimulates phosphorylation of serine 262 and 356, which in turn lead to activate other kinases (GSK-3 and Cdk5) that cause disease-associated phophoepitopes. The degree of toxicity is affected by different factors such as the degree of microtubule binding. Toxicity could also happen by NFTs which lead to cell death and cognitive decline.
# Clinical significance
Hyperphosphorylation of the tau protein (tau inclusions, pTau) can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer's disease, frontotemporal dementia, and other tauopathies.
All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments from Alzheimer's disease brain. In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases.
Tau protein has a direct effect on the breakdown of a living cell caused by tangles that form and block nerve synapses. Tangles are clumps of Tau protein that stick together and block essential nutrients that need to be distributed to cells in the brain, causing the cells to die.
Recent research suggests that tau may be released extracellularly by an exosome-based mechanism in Alzheimer's disease.
Gender-specific tau gene expression across different regions of the human brain has recently been implicated in gender differences in the manifestations and risk for tauopathies.
Some aspects of how the disease functions also suggest that it has some similarities to prion proteins.
# Traumatic brain injury
Repetitive mild traumatic brain injury (TBI) is now recognized as a central component of brain injury in contact sports, especially American football, and the concussive force of military blasts. It can lead to chronic traumatic encephalopathy (CTE) that is characterized by fibrillar tangles of hyperphosphorylated tau.
High levels of tau protein in fluid bathing the brain are linked to poor recovery after head trauma.
Concussions increase the speed of cognitive decline which is caused by a degradation in the brain from the Tau protein.
# Tau hypothesis of Alzheimer's disease
The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs (neurofibrillary tangles) . The stage of the disease determines NFTs phosphorylation. In AD, at least 19 amino acids are phosphorylated such as pre-NFTs phosphorylation occurs at serine 119, 202, and 409. While intra-NFT phosphorylation happens at serine 396 and threonine 231. Tau protein is a highly soluble microtubule-associated protein tau (MAPT). Through its isoforms and phosphorylation tau protein interacts with tubulin to stabilize microtubule assembly. All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments from AD.
Tau mutations have many consequences such as changing the expression level of tau isoforms or lead to MTs dysfunction. Mutations that alter function and isoform expression of tau lead to hyperphosphorylation. The process of tau aggregation in the absence of mutations is not known but might result from increased phosphorylation, protease action or exposure to polyanions, such as glycosaminoglycans. Hyperphosphorylated tau disassembles microtubules and sequesters normal tau, MAPT 1(microtubule associated protein tau1), MAPT 2, and ubiquitin into tangles of PHFs. This insoluble structure damages cytoplasmic functions and interferes with axonal transport, which can lead to cell death.
Vaccines have been found that attack the Tau protein, one of the leading causes of Alzheimer's. This would reduce symptoms for those with Alzheimer's disease and could eventually lead to a cure.
# Interactions
Tau protein has been shown to interact with proto-oncogene tyrosine-protein kinase:
- Alpha-synuclein,
- FYN,
- S100B, and
- YWHAZ. | Tau protein
Tau proteins (or τ proteins, after the Greek letter with that name) are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.[1] Pathologies and dementias of the nervous system such as Alzheimer's disease and Parkinson's disease[2] are associated with tau proteins that have become defective and no longer stabilize microtubules properly.
The tau proteins are the product of alternative splicing from a single gene that in humans is designated MAPT (microtubule-associated protein tau) and is located on chromosome 17.[3][4]
The tau proteins were identified in 1975 as heat-stable proteins essential for microtubule assembly [5][6] and since then, they have been characterized as intrinsically disordered proteins.[7]
# Function
Tau protein is a highly soluble microtubule-associated protein tau (MAPT). In humans, these proteins are found mostly in neurons compared to non-neuronal cells. One of tau's main functions is to modulate the stability of axonal microtubules. Other nervous system MAPs may perform similar functions, as suggested by tau knock out mice that did not show abnormalities in brain development - possibly because of compensation in tau deficiency by other MAPs.[8] Tau is not present in dendrites and is active primarily in the distal portions of axons where it provides microtubule stabilization but also flexibility as needed. This contrasts with MAP6 (STOP) proteins in the proximal portions of axons, which, in essence, lock down the microtubules and MAP2 that stabilizes microtubules in dendrites. In addition to their microtubule stabilizing functions, MAPTs have also been found to recruit signaling proteins and regulation of microtubule-mediated transport.[9]
Tau proteins interact with tubulin to stabilize microtubules and promote tubulin assembly into microtubules.[6] Tau has two ways of controlling microtubule stability: isoforms and phosphorylation.
# Genetics
In humans, the MAPT gene for encoding tau protein is located on chromosome 17q21, containing 16 exons.[10] The major tau protein in the human brain is encoded by 11 exons. Exons 2, 3 and 10 are alternatively spliced that lead to formation of six tau isoforms.[11] In human brain, tau proteins constitute a family of six isoforms with a range of 352-441 amino acids. Tau isoforms are different in either zero, one, or two inserts of 29 amino acids at the N-terminal part (exon 2 and 3), and three or four repeat-regions at the C-terminal part (exon 10). Thus, the longest isoform in the CNS has four repeats (R1, R2, R3 and R4) and two inserts (441 amino acids total), while the shortest isoform has three repeats (R1, R3 and R4) and no insert (352 amino acids total).
The MAPT gene has two haplogroups, H1 and H2, in which the gene appears in inverted orientations. Haplogroup H2 is common only in Europe and in people with European ancestry. Haplogroup H1 appears to be associated with increased probability of certain dementias, such as Alzheimer's disease. The presence of both haplogroups in Europe means that recombination between inverted haplotypes can result in the lack of one of the functioning copy of the gene, resulting in congenital defects.[12][13][14][15]
# Structure
Six tau isoforms exist in human brain tissue, and they are distinguished by their number of binding domains. Three isoforms have three binding domains and the other three have four binding domains. The binding domains are located in the carboxy-terminus of the protein and are positively charged (allowing it to bind to the negatively charged microtubule). The isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains. The isoforms are a result of alternative splicing in exons 2, 3, and 10 of the tau gene. Tau is a phosphoprotein with 79 potential Serine (Ser) and Threonine (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been reported on approximately 30 of these sites in normal tau proteins.[16]
Phosphorylation of tau is regulated by a host of kinases, including PKN, a serine/threonine kinase. When PKN is activated, it phosphorylates tau, resulting in disruption of microtubule organization.[17] Phosphorylation of tau is also developmentally regulated. For example, fetal tau is more highly phosphorylated in the embryonic CNS than adult tau.[18] The degree of phosphorylation in all six isoforms decreases with age due to the activation of phosphatases.[19] Like kinases, phosphatases too play a role in regulating the phosphorylation of tau. For example, PP2A and PP2B are both present in human brain tissue and have the ability to dephosphorylate Ser396.[20] The binding of these phosphatases to tau affects tau's association with MTs.
# Tau Mechanism
The accumulation of hyperphosphorylated tau in neurons will lead to the neurofibrillary degeneration.[21] The actual mechanism of how tau propagate from one cell to another is not well identified. Also, other mechanisms including tau release and toxicity are unclear. As tau aggregates, it replaces tubulin which in turn enhance fibrilization of tau.[22] Several propagation methods have been proposed which occur by synaptic contact such as synaptic cell adhesion proteins and neuronal activity and other synaptic and non-synaptic mechanisms.[23] The mechanism of tau aggregation is still not completely elucidated still there are several factors that favorize this process, including Tau phosphorylation and zinc ions.[24]
## Tau release
Tau involves in uptake and release process, which is known as seeding. Uptake of tau protein mechanism requires the presence of heparan sulfate proteoglycans at the cell surface which happen by macropinocytosis.[25] On the other hand, tau release depends on neuronal activity. Many factors influence tau release, for example, type of isoforms or MAPT mutations which change the extracellular level of tau.[26] According to Asai and his colleagues, spreading of tau protein occurs from entorhinal cortex to the hippocampal region in the early stages of the disease. They also suggested that microglia were also involved in the transport process and their actual rule is still unknown.[27]
## Tau toxicity
Tau causes toxic effects through its accumulation inside cells. Many enzymes involved in toxicity mechanism such as PAR-1 kinase. This enzyme stimulates phosphorylation of serine 262 and 356, which in turn lead to activate other kinases (GSK-3 and Cdk5) that cause disease-associated phophoepitopes.[28] The degree of toxicity is affected by different factors such as the degree of microtubule binding.[29][30] Toxicity could also happen by NFTs which lead to cell death and cognitive decline.
# Clinical significance
Hyperphosphorylation of the tau protein (tau inclusions, pTau) can result in the self-assembly of tangles of paired helical filaments and straight filaments, which are involved in the pathogenesis of Alzheimer's disease, frontotemporal dementia, and other tauopathies.[31]
All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments from Alzheimer's disease brain. In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. When misfolded, this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases.
Tau protein has a direct effect on the breakdown of a living cell caused by tangles that form and block nerve synapses. Tangles are clumps of Tau protein that stick together and block essential nutrients that need to be distributed to cells in the brain, causing the cells to die.[32]
Recent research suggests that tau may be released extracellularly by an exosome-based mechanism in Alzheimer's disease.[33][34]
Gender-specific tau gene expression across different regions of the human brain has recently been implicated in gender differences in the manifestations and risk for tauopathies.[35]
Some aspects of how the disease functions also suggest that it has some similarities to prion proteins.[36]
# Traumatic brain injury
Repetitive mild traumatic brain injury (TBI) is now recognized as a central component of brain injury in contact sports, especially American football,[37][38] and the concussive force of military blasts.[39] It can lead to chronic traumatic encephalopathy (CTE) that is characterized by fibrillar tangles of hyperphosphorylated tau.[40]
High levels of tau protein in fluid bathing the brain are linked to poor recovery after head trauma.[41]
Concussions increase the speed of cognitive decline which is caused by a degradation in the brain from the Tau protein.[42]
# Tau hypothesis of Alzheimer's disease
The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs (neurofibrillary tangles) [43]. The stage of the disease determines NFTs phosphorylation. In AD, at least 19 amino acids are phosphorylated such as pre-NFTs phosphorylation occurs at serine 119, 202, and 409. While intra-NFT phosphorylation happens at serine 396 and threonine 231.[44] Tau protein is a highly soluble microtubule-associated protein tau (MAPT).[6] Through its isoforms and phosphorylation tau protein interacts with tubulin to stabilize microtubule assembly. All of the six tau isoforms are present in an often hyperphosphorylated state in paired helical filaments from AD.
Tau mutations have many consequences such as changing the expression level of tau isoforms or lead to MTs dysfunction.[45] Mutations that alter function and isoform expression of tau lead to hyperphosphorylation. The process of tau aggregation in the absence of mutations is not known but might result from increased phosphorylation, protease action or exposure to polyanions, such as glycosaminoglycans.[6] Hyperphosphorylated tau disassembles microtubules and sequesters normal tau, MAPT 1(microtubule associated protein tau1), MAPT 2, and ubiquitin into tangles of PHFs. This insoluble structure damages cytoplasmic functions and interferes with axonal transport, which can lead to cell death.[46]
Vaccines have been found that attack the Tau protein, one of the leading causes of Alzheimer's. This would reduce symptoms for those with Alzheimer's disease and could eventually lead to a cure.[47]
# Interactions
Tau protein has been shown to interact with proto-oncogene tyrosine-protein kinase:
- Alpha-synuclein,[48][49]
- FYN,[50]
- S100B,[51][52] and
- YWHAZ.[53] | https://www.wikidoc.org/index.php/Tau_protein | |
8aab56897286000081c29b3dffb7828557030440 | wikidoc | Taurolidine | Taurolidine
# Overview
Taurolidine (
Taurolidine has been used to treat patients with peritonitis and as an antiendoxic agent in patients with systemic inflammatory response syndrome. It is a live-saving antimicrobial for severe abdominal sepsis and peritonitis.
For severe surgical infections and use in surgical oncology
Taurolidine is active against a wide range of micro- organisms that include gram positive bacteria, gram negative bacteria, fungi, mycobateria and also bacteria that are resistant to various antibiotics such as MRSA, VISA VRSA ORSA VRE. Additionally, taurolidine demonstrates some anti-tumor properties, with positive results seen in early-stage clinical investigations using the drug to treat gastrointestinal malignancies and tumors of the central nervous system.
Taurolidine is the active ingredient of anti-microbial catheter lock solutions for the prevention and treatment of catheter related blood stream infections (CRBSIs) and is suitable for use in all catheter based vascular access devices.
Bacterial resistance against taurolidine has never been observed in various studies.
Taurolidine acts by a non selective chemical reaction.
In aqueous solution, the parent molecule taurolidine forms equilibrium with taurultam and N-hydroxymethyl taurultam, with taurinamide being a downstream derivative.
The active principle of taurolidine are N-methylol derivatives of taurultam and taurinamide, which react with the bacterial cell wall, cell membrane, proteins as well as with the primary amino groups of endo- and exotoxins. Microbes are killed and the resulting toxins are inactivated; the destruction time in vitro is 30 minutes.
Pro-inflammatory cytokines and enhanced TNF-α levels are reduced when used as a catheter lock solution.
Taurolidine decreases the adherence of bacteria and fungi to host cells by destructing the fimbriae and flagella and thus prevent the biofilm formation.
Dose of 5g over 2 hours every 4 hours for at least 48 hours were given intravenously for the treatment of various sepsis condition.
# Pharmacokinetic properties
Absorption is rapid, with maximum concentrations of taurultam occurring between 10 and 15 minutes, and the half-life being less than one hour.
Maximum plasma taurinamide concentration occurs between 0.5 and 2 hours, and the
Taurolidine is metabolised with a short half-life to taurine, carbon dioxide and water.
Elimination half-life lies between 5 and 5.5 hours.
Urinary estimations show excretion of taurinamide accounts for 25% of the Taurolidine dose.
# Pharmacodynamic properties
Following administration of taurolidine, the bactericidal and antiendotoxin activity of the taurolidine molecule is conferred by the release of three active methylol (hydroxymethyl) groups as taurolidine is rapidly metabolized by hydrolysis via taurultam and methylol taurultam to methylol taurinamide and taurine. These labile methylol groups react with the bacterial cell-wall resulting in lysis of the bacteria, and by inter- and intramolecular cross-linking of the lipopolysaccharide-protein complex, neutralization of the bacterial endotoxins which is enhanced by enzymatic activation. This mechanism of action is accelerated and maximised when Taurolidine is pre-warmed to 37 °C. Taurolidine inhibits the formation of postoperative adhesions, and in vitro has been shown to reduce the adherence of micro-organisms to mucosal epithelium.
The chemical mode of action of taurolidine via its reactive methylol groups confers greater potency in vivo than indicated by in vitroMIC (minimum inhibitory concentration) values, and also appears to preclude susceptibility to resistance mechanisms.
Taurolidine is highly active against the common infecting pathogens associated with peritonitis, this activity extends across a wide-spectrum of aerobic/anaerobic bacteria and fungi (with no diminution of effect in the presence of biological fluids, e.g. blood, serum, pus.
Gram positive bacteria (MIC/MBC 1 - 2 mg/mL): Staphylococci (including multiple-antibiotic resistant coagulase negative strains, Methicillin-resistant Staph. aureus), streptococci, enterococci, pneumococci.
Gram negative bacteria (MIC/MBC 0.5 - 5 mg/mL): Aerobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Proteus species (indole negative), Proteus mirabilis, Pseudomonas species (including Ps. aeruginosa), Salmonella species, Serratia marcescans, Klebsiella species.
Anaerobes (MIC/MBC 0.03 - 0.3 mg/mL): Bacteroides species (including Bact. fragilis), Fusobacteria, Clostridium species, Peptostreptococcus anaerobius.
Fungi (MIC 0.3 - 5 mg/mL): Candida albicans, Cryptococcus neoformans, Aspergillus species, Trichophyton rubrum, Epidermophyton floccosum, Pitosporom ovale.
# Contraindications
Taurolidine should not be used systemically in neonates, infants and children under 10 years of age.
Taurolidine should be used with caution in patients with renal impairment for systemic use.
## Pregnancy and Breastfeeding
Taurolidine has shown no evidence of teratogenicity in animal studies, but administration to pregnant women should only be undertaken if the clinician considers it essential.
# Side effects
No systemic side effects have been identified. The safety of taurolidine has also been confirmed in clinical studies with long-term intravenous administration of high doses (up to 20 g daily).
In the body, taurolidine is metabolized rapidly via the metabolites taurultam and methylol taurinamide, which also have a bactericidal action, to taurine, an endogenous aminosulphonic acid, CO2 and H2O. Therefore, no toxic effects are known or expected in the event of accidental injection.
# Catheter lock solution in hemodialysis (HD)
The combination of taurolidine with the anticoagulant citrate (4%) and heparin (500IU/mL) may help to decrease the incidence and occurrence of catheter-related blood stream infections (CRBSI) in hemodialysis patients (HD).
# Catheter lock solution in oncology
Catheter-or port-a-cath-related bloodstream infections are a common problem in cancer patients. The use of taurolidine/citrate lock solution is associated with a significant reduction in bloodstream infections in immune compromised (pediatric) patients.
# Catheter lock solution in home parenteral nutrition (HPN) / total parenteral nutrition (TPN)
CRBSI remains the most common serious complication associated with long-term parenteral nutrition HPN/TPN. The use of taurolidine/citrate as a catheter lock solution shows a significant reduction of CRBSI in adult patients and in pediatric patients. | Taurolidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Taurolidine ([bis(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)-methane) is an active pharmaceutical ingredient (API) with antimicrobial and anti-lipopolysaccharide properties. Derived from the amino acid taurine, its immuno modulatory action is reported to be mediated with priming and activation of macrophages and polymorphonuclear leukocytes.[1]
Taurolidine has been used to treat patients with peritonitis and as an antiendoxic agent in patients with systemic inflammatory response syndrome. It is a live-saving antimicrobial for severe abdominal sepsis and peritonitis.
For severe surgical infections and use in surgical oncology
Taurolidine is active against a wide range of micro- organisms that include gram positive bacteria, gram negative bacteria, fungi, mycobateria and also bacteria that are resistant to various antibiotics such as MRSA, VISA VRSA ORSA VRE.[2] Additionally, taurolidine demonstrates some anti-tumor properties, with positive results seen in early-stage clinical investigations using the drug to treat gastrointestinal malignancies and tumors of the central nervous system.[3]
Taurolidine is the active ingredient of anti-microbial catheter lock solutions for the prevention and treatment of catheter related blood stream infections (CRBSIs)[4][5][6][7][8][9] and is suitable for use in all catheter based vascular access devices.
Bacterial resistance against taurolidine has never been observed in various studies.[10]
Taurolidine acts by a non selective chemical reaction.
In aqueous solution, the parent molecule taurolidine forms equilibrium with taurultam and N-hydroxymethyl taurultam, with taurinamide being a downstream derivative.
The active principle of taurolidine are N-methylol derivatives of taurultam and taurinamide, which react with the bacterial cell wall, cell membrane, proteins as well as with the primary amino groups of endo- and exotoxins. Microbes are killed and the resulting toxins are inactivated; the destruction time in vitro is 30 minutes.
Pro-inflammatory cytokines and enhanced TNF-α levels are reduced when used as a catheter lock solution.[11]
Taurolidine decreases the adherence of bacteria and fungi to host cells by destructing the fimbriae and flagella and thus prevent the biofilm formation.
Dose of 5g over 2 hours every 4 hours for at least 48 hours were given intravenously for the treatment of various sepsis condition.[12]
# Pharmacokinetic properties
Absorption is rapid, with maximum concentrations of taurultam occurring between 10 and 15 minutes, and the half-life being less than one hour.
Maximum plasma taurinamide concentration occurs between 0.5 and 2 hours, and the
Taurolidine is metabolised with a short half-life to taurine, carbon dioxide and water.
Elimination half-life lies between 5 and 5.5 hours.
Urinary estimations show excretion of taurinamide accounts for 25% of the Taurolidine dose.
# Pharmacodynamic properties
Following administration of taurolidine, the bactericidal and antiendotoxin activity of the taurolidine molecule is conferred by the release of three active methylol (hydroxymethyl) groups as taurolidine is rapidly metabolized by hydrolysis via taurultam and methylol taurultam to methylol taurinamide and taurine. These labile methylol groups react with the bacterial cell-wall resulting in lysis of the bacteria, and by inter- and intramolecular cross-linking of the lipopolysaccharide-protein complex, neutralization of the bacterial endotoxins which is enhanced by enzymatic activation.[13] This mechanism of action is accelerated and maximised when Taurolidine is pre-warmed to 37 °C. Taurolidine inhibits the formation of postoperative adhesions, and in vitro has been shown to reduce the adherence of micro-organisms to mucosal epithelium.
The chemical mode of action of taurolidine via its reactive methylol groups confers greater potency in vivo than indicated by in vitroMIC (minimum inhibitory concentration) values, and also appears to preclude susceptibility to resistance mechanisms.
Taurolidine is highly active against the common infecting pathogens associated with peritonitis, this activity extends across a wide-spectrum of aerobic/anaerobic bacteria and fungi (with no diminution of effect in the presence of biological fluids, e.g. blood, serum, pus.
Gram positive bacteria (MIC/MBC 1 - 2 mg/mL): Staphylococci (including multiple-antibiotic resistant coagulase negative strains, Methicillin-resistant Staph. aureus), streptococci, enterococci, pneumococci.
Gram negative bacteria (MIC/MBC 0.5 - 5 mg/mL): Aerobacter species, Citrobacter species, Enterobacter species, Escherichia coli, Proteus species (indole negative), Proteus mirabilis, Pseudomonas species (including Ps. aeruginosa), Salmonella species, Serratia marcescans, Klebsiella species.
Anaerobes (MIC/MBC 0.03 - 0.3 mg/mL): Bacteroides species (including Bact. fragilis), Fusobacteria, Clostridium species, Peptostreptococcus anaerobius.
Fungi (MIC 0.3 - 5 mg/mL): Candida albicans, Cryptococcus neoformans, Aspergillus species, Trichophyton rubrum, Epidermophyton floccosum, Pitosporom ovale.
# Contraindications
Taurolidine should not be used systemically in neonates, infants and children under 10 years of age.
Taurolidine should be used with caution in patients with renal impairment for systemic use.
## Pregnancy and Breastfeeding
Taurolidine has shown no evidence of teratogenicity in animal studies, but administration to pregnant women should only be undertaken if the clinician considers it essential.
# Side effects
No systemic side effects have been identified. The safety of taurolidine has also been confirmed in clinical studies with long-term intravenous administration of high doses (up to 20 g daily).
In the body, taurolidine is metabolized rapidly via the metabolites taurultam and methylol taurinamide, which also have a bactericidal action, to taurine, an endogenous aminosulphonic acid, CO2 and H2O. Therefore, no toxic effects are known or expected in the event of accidental injection.[14]
# Catheter lock solution in hemodialysis (HD)
The combination of taurolidine with the anticoagulant citrate (4%) and heparin (500IU/mL) may help to decrease the incidence and occurrence of catheter-related blood stream infections (CRBSI) in hemodialysis patients (HD).[15][16][17][18][19]
# Catheter lock solution in oncology
Catheter-or port-a-cath-related bloodstream infections are a common problem in cancer patients. The use of taurolidine/citrate lock solution is associated with a significant reduction in bloodstream infections in immune compromised (pediatric) patients.[20][21][22][23][24]
# Catheter lock solution in home parenteral nutrition (HPN) / total parenteral nutrition (TPN)
CRBSI remains the most common serious complication associated with long-term parenteral nutrition HPN/TPN. The use of taurolidine/citrate as a catheter lock solution shows a significant reduction of CRBSI in adult patients and in pediatric patients.[25][26][27][28][29][30][31][32][33] | https://www.wikidoc.org/index.php/Taurolidine | |
c478fa1607c9a57557ddbfa65ad5f247302686e6 | wikidoc | Taylor cone | Taylor cone
A Taylor cone refers to the cone observed in electrospray and hydrodynamic spray processes from which a jet of charged particles emanates above a threshold voltage. Aside from electrospray ionization in mass spectrometry the Taylor cone is important in colloid thrusters used in fine control and high efficiency (low power) thrust of spacecraft.
# History
This cone was described by Sir Geoffrey Ingram Taylor in 1964 before electrospray was "discovered". This work followed on the work of Zeleny where in 1917 he photographed a cone-jet of glycerine under high electric field and the work of several others, Wilson & Taylor (1925), Nolan (1926) and Macky (1931). Taylor was primarily interested in the behavior of water droplets in strong electric fields, such as in thunderstorms.
# Taylor cone formation
When a small volume of electrically conductive liquid is exposed to an electric field the shape of liquid starts to deform from the shape caused by surface tension alone. As the voltage is increased the effect of the electric field becomes more prominent and as it approaches exerting a similar amount of force on the droplet as the surface tension does a cone shape begins to form with convex sides and a rounded tip. This approaches the shape of a straight generatrix (cone) with a whole angle (width) of 98.6°. When a certain threshold voltage has been reached the slightly rounded tip inverts and emits a jet of liquid. This is called a cone-jet and is the beginning of the electrospray process in which ions may be transferred to the gas phase. It is generally found that in order to achieve a stable cone-jet a slightly higher than threshold voltage must be used. As the voltage is increased even more other modes of droplet disintegration are found. The term Taylor cone can specifically refer to the theoretical limit of a perfect cone of exactly the predicted angle or generally refer to the approximately conical portion of a cone-jet after the electrospray process has begun.
# Theory
Sir Geoffrey Ingram Taylor in 1964 described this phenomenon, theoretically derived based on general assumptions that the requirements to form a perfect cone under such conditions required a semi-vertical angle of 49.3° (a whole angle of 98.6°) and demonstrated that the shape of such a cone approached the theoretical shape just before jet formation. This angle is known as the Taylor angle. This angle is more precisely \pi-\theta _0\, where \theta _0\, is the first zero of P _{1/2} (\cos\theta _0)\, (the Legendre polynomial of order 1/2).
Taylor's derivation is based on two assumptions: (1) that the surface of the cone is an equipotential surface and (2) that the cone exists in a steady state equilibrium. To meet both of these criteria the electric field must have azimuthal symmetry and have \sqrt{R}\, dependence to counter the surface tension to produce the cone. The solution to this problem is:
where V=V_0\, (equipotential surface) exists at a value of \theta _0 (regardless of R) producing an equipotential cone. The magic angle necessary for V=V_0\, for all R is a zero of P _{1/2} (\cos\theta _0)\, between 0 and \pi\, which there is only one at 130.7099°. The complement of this angle is the Taylor angle. | Taylor cone
A Taylor cone refers to the cone observed in electrospray and hydrodynamic spray processes from which a jet of charged particles emanates above a threshold voltage. Aside from electrospray ionization in mass spectrometry the Taylor cone is important in colloid thrusters used in fine control and high efficiency (low power) thrust of spacecraft.
# History
This cone was described by Sir Geoffrey Ingram Taylor in 1964 before electrospray was "discovered".[1] This work followed on the work of Zeleny[2] where in 1917 he photographed a cone-jet of glycerine under high electric field and the work of several others, Wilson & Taylor (1925),[3] Nolan (1926)[4] and Macky (1931).[5] Taylor was primarily interested in the behavior of water droplets in strong electric fields, such as in thunderstorms.
# Taylor cone formation
When a small volume of electrically conductive liquid is exposed to an electric field the shape of liquid starts to deform from the shape caused by surface tension alone. As the voltage is increased the effect of the electric field becomes more prominent and as it approaches exerting a similar amount of force on the droplet as the surface tension does a cone shape begins to form with convex sides and a rounded tip. This approaches the shape of a straight generatrix (cone) with a whole angle (width) of 98.6°. When a certain threshold voltage has been reached the slightly rounded tip inverts and emits a jet of liquid. This is called a cone-jet and is the beginning of the electrospray process in which ions may be transferred to the gas phase. It is generally found that in order to achieve a stable cone-jet a slightly higher than threshold voltage must be used. As the voltage is increased even more other modes of droplet disintegration are found. The term Taylor cone can specifically refer to the theoretical limit of a perfect cone of exactly the predicted angle or generally refer to the approximately conical portion of a cone-jet after the electrospray process has begun.
# Theory
Sir Geoffrey Ingram Taylor in 1964 described this phenomenon, theoretically derived based on general assumptions that the requirements to form a perfect cone under such conditions required a semi-vertical angle of 49.3° (a whole angle of 98.6°) and demonstrated that the shape of such a cone approached the theoretical shape just before jet formation. This angle is known as the Taylor angle. This angle is more precisely <math>\pi-\theta _0\,</math> where <math>\theta _0\,</math> is the first zero of <math>P _{1/2} (\cos\theta _0)\,</math> (the Legendre polynomial of order 1/2).
Taylor's derivation is based on two assumptions: (1) that the surface of the cone is an equipotential surface and (2) that the cone exists in a steady state equilibrium. To meet both of these criteria the electric field must have azimuthal symmetry and have <math>\sqrt{R}\,</math> dependence to counter the surface tension to produce the cone. The solution to this problem is:
where <math>V=V_0\,</math> (equipotential surface) exists at a value of <math>\theta _0</math> (regardless of R) producing an equipotential cone. The magic angle necessary for <math>V=V_0\,</math> for all R is a zero of <math>P _{1/2} (\cos\theta _0)\,</math> between 0 and <math>\pi\,</math> which there is only one at 130.7099°. The complement of this angle is the Taylor angle. | https://www.wikidoc.org/index.php/Taylor_cone | |
9614fa3df81714f1b4b7945c2d1b54d34917eadd | wikidoc | Teduglutide | Teduglutide
# 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
Teduglutide is a glucagon-like peptide-2 (GLP-2) analog that is FDA approved for the treatment of short bowel syndrome (SBS) who are dependent on parenteral support. Common adverse reactions include abdominal pain, injection site reactions, nausea, headaches, abdominal distension, upper respiratory tract infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended daily dose of GATTEX is 0.05 mg/kg body weight administered by subcutaneous injection once daily. Alternation of sites for subcutaneous injection is recommended, and can include the thighs, arms, and the quadrants of the abdomen. GATTEX should not be administered intravenously or intramuscularly. If a dose is missed, that dose should be taken as soon as possible on that day. Do not take 2 doses on the same day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teduglutide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teduglutide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy 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 Teduglutide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teduglutide in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Acceleration of Neoplastic Growth
- Based on the pharmacologic activity and findings in animals, GATTEX has the potential to cause hyperplastic changes including neoplasia. In patients at increased risk for malignancy, the clinical decision to use GATTEX should be considered only if the benefits outweigh the risks. In patients with active gastrointestinal malignancy (GI tract, hepatobiliary, pancreatic), GATTEX therapy should be discontinued. In patients with active non-gastrointestinal malignancy, the clinical decision to continue GATTEX should be made based on risk-benefit considerations.
- Colorectal Polyps
- Colorectal polyps were identified during the clinical trials. Colonoscopy of the entire colon with removal of polyps should be done within 6 months prior to starting treatment with GATTEX. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. Subsequent colonoscopies should be done every 5 years or more often as needed. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. In case of diagnosis of colorectal cancer, GATTEX therapy should be discontinued.
- Small Bowel Neoplasia
- Based on benign tumor findings in the rat carcinogenicity study, patients should be monitored clinically for small bowel neoplasia. If a benign neoplasm is found, it should be removed. In case of small bowel cancer, GATTEX therapy should be discontinued.
- Intestinal Obstruction
- Intestinal obstruction has been reported in clinical trials. In patients who develop intestinal or stomal obstruction, GATTEX should be temporarily discontinued while the patient is clinically managed. GATTEX may be restarted when the obstructive presentation resolves, if clinically indicated.
- Biliary and Pancreatic Disease
- Gallbladder and Biliary Tract Disease
- Cholecystitis, cholangitis, and cholelithiasis, have been reported in clinical studies. For identification of the onset or worsening of gallbladder/biliary disease, patients should undergo laboratory assessment of bilirubin and alkaline phosphatase within 6 months prior to starting GATTEX, and at least every 6 months while on GATTEX; or more frequently if needed. If clinically meaningful changes are seen, further evaluation including imaging of the gallbladder and/or biliary tract is recommended; and the need for continued GATTEX treatment should be reassessed.
- Pancreatic Disease
- Pancreatitis has been reported in clinical studies. For identification of onset or worsening of pancreatic disease, patients should undergo laboratory assessment of lipase and amylase within 6 months prior to starting GATTEX, and at least every 6 months while on GATTEX; or more frequently if needed. If clinically meaningful changes are seen, further evaluation such as imaging of the pancreas is recommended; and the need for continued GATTEX treatment should be reassessed.
- Fluid Overload
- Fluid overload and congestive heart failure have been observed in clinical trials, which were felt to be related to enhanced fluid absorption associated with GATTEX. If fluid overload occurs, parenteral support should be adjusted and GATTEX treatment should be reassessed, especially in patients with underlying cardiovascular disease. If significant cardiac deterioration develops while on GATTEX, the need for continued GATTEX treatment should be reassessed.
- Increased Absorption of Concomitant Oral Medication
- Altered mental status in association with GATTEX has been observed in patients on benzodiazepines in clinical trials. Patients on concomitant oral drugs (e.g., benzodiazepines, phenothiazines) requiring titration or with a narrow therapeutic index may require dose adjustment while on GATTEX.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
- Across all clinical studies, 566 subjects were exposed to at least one dose of GATTEX (190 patient-years of exposure; mean duration of exposure was 17 weeks). Of the 566 subjects, 173 subjects were treated in Phase 3 SBS studies (134/173 at the dose of 0.05 mg/kg/day and 39/173 at the dose of 0.10 mg/kg/day).
- The most commonly reported (≥ 10%) adverse reactions in patients treated with GATTEX across all clinical studies (n = 566) were: abdominal pain (30.0%); injection site reactions (22.4%); nausea (18.2%); headaches (15.9%); abdominal distension (13.8%); upper respiratory tract infection (11.8%).
- The rates of adverse reactions in subjects with SBS participating in two randomized, placebo-controlled, 24-week, double-blind clinical studies (Study 1 and Study 3) are summarized in Table 1. Only those reactions with a rate of at least 5% in the GATTEX group, and greater than placebo group, are summarized in Table 1. The majority of these reactions were mild or moderate. Of subjects receiving GATTEX at the recommended dose of 0.05 mg/kg/day, 88.3% (N=68/77) experienced an adverse reaction, as compared to 83.1% (49/59) for placebo. Many of these adverse reactions have been reported in association with the underlying disease and/or parenteral nutrition.
- In placebo-controlled Studies 1 and 3, 12% of patients in each of the placebo and GATTEX study groups experienced an injection site reaction.
- Malignancy. Three subjects were diagnosed with malignancy in the clinical studies, all of whom were male and had received GATTEX 0.05 mg/kg/day in Study 2. One subject had a history of abdominal radiation for Hodgkin's disease two decades prior to receiving GATTEX and prior liver lesion on CT scan, and was diagnosed with metastatic adenocarcinoma of unconfirmed origin after 11 months of exposure to GATTEX. Two subjects had extensive smoking histories, and were diagnosed with lung cancers (squamous and non-small cell) after 12 months and 3 months of GATTEX exposure, respectively.
- Colorectal Polyps. In the clinical studies, 6 subjects were diagnosed with polyps of the G.I. tract after initiation of study treatment. In the SBS placebo-controlled studies, 1/59 (1.7%) of subjects on placebo and 1/109 (0.9%) of subjects on GATTEX 0.05 mg/kg/day were diagnosed with intestinal polyps (inflammatory stomal and hyperplastic sigmoidal after 3 and 5 months, respectively). The remaining 4 polyp cases occurred in the extension studies – two colorectal villous adenomas (onset at 6 and 7 months in GATTEX 0.10 and 0.05 mg/kg/day dose groups, respectively), one hyperplastic polyp (onset 6 months in GATTEX 0.10 mg/kg/day dose group), and one small duodenal polyp (onset at 3 months in GATTEX 0.05 mg/kg/day dose group).
- Gastrointestinal Obstruction. Overall, 12 subjects experienced one or more episodes of intestinal obstruction/stenosis: 6 in SBS placebo-controlled studies and 6 in the extension studies. The 6 subjects in the placebo-controlled trials were all on GATTEX: 3/77 (3.9%) on GATTEX 0.05 mg/kg/day and 3/32 (9.4%) on GATTEX 0.10 mg/kg/day. No cases of intestinal obstruction occurred in the placebo group. Onsets ranged from 1 day to 6 months. In the extension studies, 6 additional subjects (all on GATTEX 0.05 mg/kg/day) were diagnosed with intestinal obstruction/stenosis with onsets ranging from 6 days to 7 months. Two of the 6 subjects from the placebo-controlled trials experienced recurrence of obstruction in the extension studies. Of all 8 subjects with an episode of intestinal obstruction/stenosis in these extension studies, 1 subject required endoscopic dilation and none required surgical intervention.
- Gallbladder, Biliary and Pancreatic Disease. For gallbladder and biliary disease in the placebo-controlled studies, 3 subjects were diagnosed with cholecystitis, all of whom had a prior history of gallbladder disease and were in the GATTEX 0.05 mg/kg/day dose group. No cases were reported in the placebo group. One of these 3 cases had gallbladder perforation and underwent cholecystectomy the next day. The remaining 2 cases underwent elective cholecystectomy at a later date. In the extension studies, 3 subjects had an episode of acute cholecystitis; 2 subjects had new-onset cholelithiasis; and 1 subject experienced cholestasis secondary to an obstructed biliary stent. For pancreatic disease in the placebo-controlled studies, 1 subject (GATTEX 0.05 mg/kg/day dose group) had a pancreatic pseudocyst diagnosed after 4 months of GATTEX. In the extension studies, 1 subject was diagnosed with chronic pancreatitis; and 1 subject was diagnosed with acute pancreatitis.
- Fluid Overload. In the placebo-controlled trials, fluid overload was reported in 4/59 (6.8%) of subjects on placebo and 9/77 (11.7%) subjects on GATTEX 0.05 mg/kg/day. Of the 9 cases in the GATTEX group, there were 2 cases of congestive heart failure (CHF), 1 of whom was reported as a serious adverse event and the other as non-serious. The serious case had onset at 6 months, and was possibly associated with previously undiagnosed hypothyroidism and/or cardiac dysfunction.
- Concomitant Oral Medication. GATTEX can increase the absorption of concomitant oral medications such as benzodiazepines and psychotropic agents. In the placebo-controlled trials, an analysis of episodes of cognition and attention disturbances was performed for subjects on benzodiazepines. One of the subjects in the GATTEX 0.05 mg/kg/day group (on prazepam) experienced dramatic deterioration in mental status progressing to coma during her first week of GATTEX therapy. She was admitted to the ICU where her benzodiazepine level was >300 mcg/L. GATTEX and prazepam were discontinued, and coma resolved 5 days later.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Teduglutide in the drug label.
# Drug Interactions
- Potential for Increased Absorption of Oral Medications
- Based upon the pharmacodynamic effect of GATTEX, there is a potential for increased absorption of concomitant oral medications, which should be considered if these drugs require titration or have a narrow therapeutic index.
- Concomitant Drug Therapy
- Clinical interaction studies were not performed. No inhibition or induction of the cytochrome P450 enzyme system has been observed based on in vitro studies although the relevance of in vitro studies to an in vivo setting is unknown.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies with teduglutide have been performed in pregnant rats at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg) and in rabbits at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to teduglutide. A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg). There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, teduglutide 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 Teduglutide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Teduglutide during labor and delivery.
### Nursing Mothers
- It is unknown whether teduglutide is excreted in human milk. Teduglutide is excreted in the milk of lactating rats, and the highest concentration in the milk was 2.9% of the plasma concentration following a single subcutaneous injection of 25 mg/kg. Because many drugs are excreted in human milk; because of the potential for serious adverse reactions to nursing infants from teduglutide and because of the potential for tumorigenicity shown for teduglutide in rats, 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 efficacy in pediatric patients have not been established.
### Geriatic Use
- No dose adjustment is necessary in patients above the age of 65 years. Of the 566 subjects treated with teduglutide, 43 subjects were 65 years or older, whereas 6 subjects were 75 years of age or older. In the SBS studies, no overall differences in safety or efficacy 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.
### Gender
There is no FDA guidance on the use of Teduglutide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Teduglutide with respect to specific racial populations.
### Renal Impairment
- Reduce the dose of GATTEX by 50% in patients with moderate and severe renal impairment (creatinine clearance less than 50 mL/min) and end-stage renal disease (ESRD).
### Hepatic Impairment
- GATTEX has not been formally studied in subjects with severe hepatic impairment. No dosage adjustment is necessary for patients with mild and moderate hepatic impairment based on a study conducted in Child-Pugh grade B subjects.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Teduglutide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Teduglutide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Teduglutide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Teduglutide in the drug label.
# Overdosage
## Acute Overdose
- The maximum dose of GATTEX studied during clinical development was 80 mg/day for 8 days. In the event of overdose, the patient should be carefully monitored by the medical professional.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Teduglutide in the drug label.
# Pharmacology
## Mechanism of Action
- Teduglutide is an analog of naturally occurring human glucagon-like peptide-2 (GLP-2), a peptide secreted by L-cells of the distal intestine. GLP-2 is known to increase intestinal and portal blood flow, and inhibit gastric acid secretion. Teduglutide binds to the glucagon-like peptide-2 receptors located in intestinal subpopulations of enteroendocrine cells, subepithelial myofibroblasts and enteric neurons of the submucosal and myenteric plexus. Activation of these receptors results in the local release of multiple mediators including insulin-like growth factor (IGF)-1, nitric oxide and keratinocyte growth factor (KGF).
## Structure
- The active ingredient in GATTEX (teduglutide ) for injection is teduglutide (rDNA origin), which is a 33 amino acid glucagon-like peptide-2 (GLP-2) analog manufactured using a strain of Escherichia coli modified by recombinant DNA technology. The chemical name of teduglutide is L-histidyl-L-glycyl-L-aspartyl-L-glycyl-L-seryl-L-phenylalanyl-L-seryl-L-aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-L-isoleucyl-L-leucyl-L-aspartyl-L-asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L-aspartyl-L-phenylalanyl-L-isoleucyl-L-asparaginyl-L-tryptophanyl-L-leucyl-L-isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L-isoleucyl-L-threonyl-L-aspartic acid. The structural formula is:
- Teduglutide has a molecular weight of 3752 Daltons. Teduglutide drug substance is a clear, colorless to light-straw–colored liquid.
- Each single-use vial of GATTEX contains 5 mg of teduglutide as a white lyophilized powder for solution for subcutaneous injection. In addition to the active pharmaceutical ingredient (teduglutide), each vial of GATTEX contains 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg monobasic sodium phosphate monohydrate, 3.434 mg dibasic sodium phosphate heptahydrate as excipients. No preservatives are present.
- At the time of administration the lyophilized powder is reconstituted with 0.5 mL of Sterile Water for Injection, which is provided in a prefilled syringe. A 10 mg/mL sterile solution is obtained after reconstitution. Up to 0.38 mL of the reconstituted solution which contains 3.8 mg of teduglutide can be withdrawn for subcutaneous injection upon reconstitution.
## Pharmacodynamics
- The ability of GATTEX to improve intestinal absorption was studied in 17 adult subjects with Short Bowel Syndrome using daily doses of 0.03, 0.10, 0.15 mg/kg (N=2-3 per dose group) in a 21-day, open-label, multi-center, dose-ranging study. All subcutaneous (abdomen) doses studied, except 0.03 mg/kg once daily, resulted in enhanced gastrointestinal fluid (wet weight) absorption of approximately 750-1000 mL/day, and increased villus height and crypt depth of the intestinal mucosa.
- At a dose 5 times the maximum recommended dose, teduglutide did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- Absorption:
- In healthy subjects, GATTEX administered subcutaneously had an absolute bioavailability of 88% and reached maximum plasma teduglutide concentrations at 3-5 hours after administration. Following a 0.05 mg/kg subcutaneous dose in SBS subjects, the median peak teduglutide concentration (Cmax) was 36 ng/mL and the median area under the curve (AUC0-inf) was 0.15 µghr/mL. No accumulation of teduglutide was observed following repeated subcutaneous administrations.
- Distribution:
- In healthy subjects, teduglutide has a volume of distribution (103 mL/kg) similar to blood volume.
- Metabolism:
- The metabolic pathway of teduglutide was not investigated in humans. However, teduglutide is expected to be degraded into small peptides and amino acids via catabolic pathways, similar to the catabolism of endogenous GLP-2.
- Elimination:
- In healthy subjects, teduglutide plasma clearance was approximately 123 mL/hr/kg which is similar to the GFR suggesting that teduglutide is primarily cleared by the kidney. Teduglutide has a mean terminal half-life (t1/2) of approximately 2 hours in healthy subjects and 1.3 hours in SBS subjects.
- Dose Linearity:
- The Cmax and AUC of teduglutide was dose proportional over the dose range of 0.05 to 0.4 mg/kg GATTEX.
- Hepatic Impairment:
- Subjects with moderate hepatic impairment had lower teduglutide Cmax and AUC (10 ~15%) compared to healthy matched control subjects after a single subcutaneous dose of 20 mg GATTEX. Teduglutide PK was not assessed in subjects with severe hepatic impairment.
- Renal Impairment:
- In subjects with moderate to severe renal impairment or end stage renal disease (ESRD), teduglutide Cmax and AUC0-inf increased with the degree of renal impairment following a single subcutaneous administration of 10 mg teduglutide. Teduglutide exposure increased by a factor of 2.1 (Cmax) and 2.6 (AUC0-inf) in ESRD subjects compared to healthy subjects.
- Geriatric Patients:
- No differences were observed between healthy subjects younger than 65 years and those older than 65 years. Experience in subjects 75 years and above is limited.
- Gender:
- No clinically relevant gender differences were observed.
## Nonclinical Toxicology
- In a 2-year carcinogenicity study in Wistar Han rats at subcutaneous doses of 3, 10 and 35 mg/kg/day (about 60, 200 and 700 times the recommended daily human dose of 0.05 mg/kg, respectively), teduglutide caused statistically significant increases in the incidences of adenomas in the bile duct and jejunum of male rats.
- Teduglutide was negative in the Ames test, chromosomal aberration test in Chinese hamster ovary cells, and in vivo mouse micronucleus assay.
- Teduglutide at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg) was found to have no adverse effect on fertility and reproductive performance of male and female rats.
# Clinical Studies
- Study 1. The efficacy, safety, and tolerability of GATTEX was evaluated in a randomized, double-blind, placebo-controlled, parallel-group, multi-national, multi-center clinical trial (Study 1) in adults with SBS who were dependent on parenteral nutrition/intravenous (PN/I.V.) support for at least 12 months and required PN at least 3 times per week. For 8 weeks (or less) prior to randomization, investigators optimized the PN/I.V. volume of all subjects. Optimization was followed by a 4-week to 8-week period of fluid stabilization. Subjects then were randomized (1:1) to placebo (n=43) or GATTEX 0.05 mg/kg/day (n=43). Study treatment was administered subcutaneously once daily for 24 weeks. PN/I.V. volume adjustments (up to 30% decrease) and clinical assessments were made at 2, 4, 8, 12, 20, and 24 weeks.
- The primary efficacy endpoint was based on a clinical response, defined as a subject achieving at least 20% reduction in weekly PN/I.V. volume from Baseline (immediately before randomization) to both Weeks 20 and 24.
- The mean age of subjects was 50.3 years. Mean duration of PN/I.V. dependency prior to enrollment was 6.25 years (range 1-25.8 years). The most common reasons for intestinal resection leading to SBS were vascular disease (34.1%, 29/85), Crohn's Disease (21.2%, 18/85), and "other" (21.2%, 18/85). Stoma was present in 44.7% (38/85) of subjects, and the most common type was jejunostomy/ileostomy (81.6%, 31/38). The mean length of remaining small intestine was 77.3±64.4 cm (range: 5 to 343 cm). The colon was not in continuity in 43.5% (37/85) subjects. At baseline, the mean (± SD) prescribed days per week for PN/I.V. infusion was 5.73 (±1.59) days.
- The percentages of treatment group responders were compared in the intent-to-treat population of this study which was defined as all randomized patients. 63% (27/43) of GATTEX-treated subjects versus 30% (13/43) of placebo-treated subjects were considered responders (p=0.002).
- At Week 24, the mean reduction in weekly PN/I.V. volume was 4.4 Liters for GATTEX-treated subjects (from pre-treatment baseline of 12.9 Liters) versus 2.3 Liters for placebo-treated subjects (from pre-treatment baseline of 13.2 Liters/week) (p<0.001).
- Twenty-one subjects on GATTEX (53.8%) versus 9 on placebo (23.1%) achieved at least a one-day reduction in PN/I.V. support.
- The mean changes from Baseline in PN/I.V. volume by visit are shown in Figure 2.
- Study 2. Study 2 is an ongoing two-year open-label extension of Study 1 in which 88 subjects receive GATTEX 0.05 mg/kg/day. Ninety-seven percent (76/78) of subjects from Study 1 elected to enroll in Study 2. An additional 12 subjects entered Study 2, who had been optimized and stabilized but not randomized in Study 1 because of closed enrollment. Of responders in Study 1 who entered Study 2, 100% (25/25) sustained their response to GATTEX after one year of continuous treatment. A 20% or greater reduction of parenteral support was achieved in 72% (31/43) of subjects after an additional 28 weeks of continuous GATTEX treatment. The mean reduction of weekly PN/I.V. volume was 5.2 L/week after one year of continuous GATTEX treatment. Six subjects in Study 2 were weaned off their PN/I.V. support while on GATTEX. Subjects were maintained on GATTEX even if no longer requiring PN/I.V. support. These 6 subjects had required PN/I.V. support for 3 to 18 years, and prior to GATTEX had required between 4 L/week and 13 L/week of PN/I.V. support.
- Study 3. Study 3 was a randomized, double-blind, placebo-controlled, three parallel-group, multinational study in adults with Short Bowel Syndrome who were dependent on parenteral nutrition/intravenous (PN/I.V.) support for at least 12 months and required PN at least 3 times per week. After a period of optimization and stabilization similar to Study 1, subjects were randomized to receive 24 weeks of one of the following treatment regimens: GATTEX 0.05 mg/kg/day (n=35), GATTEX 0.10 mg/kg/day dose (n=33), or placebo (n=16). The treatment groups were compared using the intent-to-treat population of this study which was defined as all randomized patients who were administered at least one dose of study drug. This population contained one less patient in the 0.10 mg/kg/day dose group hence n=32 in this group for all analyses. The primary efficacy endpoint was a graded categorical score that did not achieve statistical significance for the high dose. Further evaluation of PN/I.V. volume reduction using the endpoint of response (defined as at least 20% reduction in PN/I.V. fluid from Baseline to Weeks 20 and 24) showed that 46% of subjects on GATTEX 0.05 mg/kg/day responded versus 6% on placebo. Subjects on GATTEX at both dose levels experienced a 2.5 L/week reduction in parenteral support requirements versus 0.9 L/week for placebo at 24 weeks. Two subjects in the GATTEX 0.05 mg/kg/day dose group were weaned off parenteral support by Week 24.
- Study 4. Study 4 was a blinded, uncontrolled extension of Study 3, in which 65 subjects from Study 3 received GATTEX for up to an additional 28 weeks of treatment. Of responders in Study 3 who entered Study 4, 75% sustained response on GATTEX after one year of treatment. In the GATTEX 0.05 mg/kg/day dose group, a 20% or greater reduction of parenteral support was achieved in 68% (17/25) of subjects. The mean reduction of weekly PN/I.V. volume was 4.9 L/week (52% reduction from baseline) after one year of continuous GATTEX treatment. The subjects who had been completely weaned off PN/I.V. support in Study 3 remained off parenteral support through Study 4. During Study 4, an additional subject from Study 3 was weaned off parenteral support.
# How Supplied
- GATTEX® (teduglutide ) for injection is supplied in a sterile, single-use glass vial containing 5 mg of teduglutide as a white, lyophilized powder to be reconstituted with 0.5 mL Sterile Water for Injection. The product to be dispensed is either a one-vial kit or a 30-vial kit. The one-vial kit is pre-assembled and ready to be used. The 30-vial kit is to be assembled by a pharmacist with the following two cartons:
- Carton of Drug Vials (NDC 68875-0101-2):
- Thirty single-use vials of drug (NDC 68875-0101-1)
- Carton of Ancillary Supplies:
- Thirty disposable prefilled syringes containing diluent (0.5 mL Sterile Water for Injection USP) for reconstitution
- Thirty separate needles (22G x 1½ in) to attach to the syringes for reconstitution
- Thirty sterile disposable 1-mL syringes with needle (26G x 5/8 in)
- Sixty alcohol swabs
- The pharmacist in a dispensing pharmacy will assemble a 30-vial kit by transferring the trays containing 30 vials from a Carton of Drug Vials into a Carton of Ancillary Supplies. The final patient kits should contain the items listed as follows:
- 30-vial kit (NDC 68875-0102-1):
- Thirty single-use vials of drug (NDC 68875-0101-1)
- Thirty disposable prefilled syringes containing 0.5 mL Sterile Water for Injection USP for reconstitution, with 30 separate needles (22G x 1½ in) to attach to the syringes
- Thirty sterile disposable 1-mL syringes with needle (26G x 5/8 in) for dosing
- Sixty alcohol swabs
- One-vial kit (NDC 68875-0103-1):
- One single-use vial of drug (NDC 68875-0101-1)
- One disposable prefilled syringe containing 0.5 mL Sterile Water for Injection USP for reconstitution, with a separate needle (22G x 1½ in) to attach to the syringe
- One sterile disposable 1-mL syringe with needle (26G x 5/8 in) for dosing
- Four alcohol swabs
- Reconstitution with 0.5 mL of preservative-free Sterile Water for Injection, provided in a prefilled syringe, is required prior to subcutaneous administration of the drug. Reconstituted GATTEX is a sterile, clear, colorless to light straw-colored 10 mg/mL solution, which should be free from particulates. Upon reconstitution with the 0.5 mL Sterile Water for Injection provided in the prefilled syringe, a maximum of 0.38 mL of the reconstituted solution which contains 3.8 mg of teduglutide can be withdrawn from the vial for dosing.
- Storage and Handling
- Prior to Dispensing: Store refrigerated at 2°C to 8°C (36°F to 46°F) for Cartons of Drug Vials and the One-vial kits. Do not freeze. Do not use beyond the expiration date on the label. Store at room temperature up to 25°C (77°F) for the Cartons of Ancillary Supplies.
- Instruction for the Pharmacist:
- Prior to Dispensing: Store at 2°C to 8°C (36°F to 46°F) for Cartons of Drug Vials and the One-vial kits. Do not freeze.
- Dispensing Instructions: Dispense with a 90-day "use by" dating and specify "Store at room temperature up to 25°C (77°F). Do not freeze." Dispense Medication Guide to each patient.
- Reconstituted GATTEX is a sterile, clear, colorless to light straw-colored solution, which should be free from particulates. The drug should be completely dissolved before the solution is withdrawn from the vial. Do not shake or freeze the reconstituted solution. If the product remains undissolved after the second attempt, do not use. GATTEX does not contain any preservatives and is for single-use only. Any unused portion should be discarded. The product should be used within 3 hrs after reconstitution.
## Storage
There is limited information regarding Teduglutide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- General Counseling Information
- Prior to treatment, patients should fully understand the risks and benefits of GATTEX. Ensure that all patients receive the Medication Guide prior to initiating GATTEX therapy.
- Acceleration of Neoplastic Growth
- Advise patients with active gastrointestinal malignancy (GI tract, hepatobiliary, pancreatic), that GATTEX therapy should be discontinued. In patients with active non-gastrointestinal malignancy, the clinical decision to continue GATTEX should be discussed with patients and be made based on risk-benefit considerations.
- Colorectal polyps.
- Advise patients that colonoscopy of the entire colon with removal of polyps should be done within 6 months prior to starting treatment with GATTEX. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. Subsequent colonoscopies should be done every 5 years or more often as needed. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. In case of diagnosis of colorectal cancer, GATTEX therapy should be discontinued.
- Small Bowel Neoplasia.
- Advise patients that they should be monitored clinically for small bowel neoplasia. If a benign neoplasm is found, it should be removed. In case of small bowel cancer, GATTEX therapy should be discontinued.
- Intestinal Obstruction
- Advise patients to tell their physician if they experience any signs or symptoms suggestive of intestinal obstruction. If obstruction is present, the physician may temporarily discontinue GATTEX.
- Gallbladder and Bile Duct Disease
- Advise patients that laboratory assessments should be done before and then every 6 months while on GATTEX to monitor gallbladder and biliary function. If clinically significant change occurs, further evaluation (i.e., imaging studies or other) may be necessary. Advise patients to report to their physician all signs and symptoms suggestive of cholecystitis, cholangitis, or cholelithiasis while on GATTEX.
- Pancreatic Disease
- Advise patients that laboratory assessments should be done before and then every 6 months while on GATTEX. If clinically significant change occurs, further evaluation (i.e., imaging studies or other) may be necessary. Advise patients to report to their physician all signs and symptoms suggestive of pancreatic disease while on GATTEX.
- Cardiovascular Disease
- Advise patients with cardiovascular disease to report to their physician any signs of fluid overload or cardiac decompensation while on GATTEX.
- Risks Resulting from Increased Absorption of Concomitant Oral Medication
- Instruct patients to report to all of their physicians any concomitant oral medications that they are taking in order to assess any potential for increased absorption during GATTEX treatment of those oral medications requiring titration or with a narrow therapeutic index.
- Instructions
- Inform patients that GATTEX should not be administered intravenously or intramuscularly. The drug should be used for subcutaneous injection within 3 hours after reconstitution. Advise patients that subcutaneous administration has been associated with injection site reactions, but if they experience a severe reaction including severe rash, they should contact their physician.
- Advise patients that while they may experience abdominal pain and swelling of their stoma especially when starting therapy with GATTEX, if they experience symptoms of intestinal obstruction, they should contact their physician.
- Instruct patients to read the Medication Guide as they are starting GATTEX therapy and to re-read it each time their prescription is renewed.
# Precautions with Alcohol
- Alcohol-Teduglutide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- GATTEX®
# Look-Alike Drug Names
There is limited information regarding Teduglutide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Teduglutide
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
Teduglutide is a glucagon-like peptide-2 (GLP-2) analog that is FDA approved for the treatment of short bowel syndrome (SBS) who are dependent on parenteral support. Common adverse reactions include abdominal pain, injection site reactions, nausea, headaches, abdominal distension, upper respiratory tract infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- The recommended daily dose of GATTEX is 0.05 mg/kg body weight administered by subcutaneous injection once daily. Alternation of sites for subcutaneous injection is recommended, and can include the thighs, arms, and the quadrants of the abdomen. GATTEX should not be administered intravenously or intramuscularly. If a dose is missed, that dose should be taken as soon as possible on that day. Do not take 2 doses on the same day.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Teduglutide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teduglutide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy 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 Teduglutide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Teduglutide in pediatric patients.
# Contraindications
- None.
# Warnings
### Precautions
- Acceleration of Neoplastic Growth
- Based on the pharmacologic activity and findings in animals, GATTEX has the potential to cause hyperplastic changes including neoplasia. In patients at increased risk for malignancy, the clinical decision to use GATTEX should be considered only if the benefits outweigh the risks. In patients with active gastrointestinal malignancy (GI tract, hepatobiliary, pancreatic), GATTEX therapy should be discontinued. In patients with active non-gastrointestinal malignancy, the clinical decision to continue GATTEX should be made based on risk-benefit considerations.
- Colorectal Polyps
- Colorectal polyps were identified during the clinical trials. Colonoscopy of the entire colon with removal of polyps should be done within 6 months prior to starting treatment with GATTEX. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. Subsequent colonoscopies should be done every 5 years or more often as needed. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. In case of diagnosis of colorectal cancer, GATTEX therapy should be discontinued.
- Small Bowel Neoplasia
- Based on benign tumor findings in the rat carcinogenicity study, patients should be monitored clinically for small bowel neoplasia. If a benign neoplasm is found, it should be removed. In case of small bowel cancer, GATTEX therapy should be discontinued.
- Intestinal Obstruction
- Intestinal obstruction has been reported in clinical trials. In patients who develop intestinal or stomal obstruction, GATTEX should be temporarily discontinued while the patient is clinically managed. GATTEX may be restarted when the obstructive presentation resolves, if clinically indicated.
- Biliary and Pancreatic Disease
- Gallbladder and Biliary Tract Disease
- Cholecystitis, cholangitis, and cholelithiasis, have been reported in clinical studies. For identification of the onset or worsening of gallbladder/biliary disease, patients should undergo laboratory assessment of bilirubin and alkaline phosphatase within 6 months prior to starting GATTEX, and at least every 6 months while on GATTEX; or more frequently if needed. If clinically meaningful changes are seen, further evaluation including imaging of the gallbladder and/or biliary tract is recommended; and the need for continued GATTEX treatment should be reassessed.
- Pancreatic Disease
- Pancreatitis has been reported in clinical studies. For identification of onset or worsening of pancreatic disease, patients should undergo laboratory assessment of lipase and amylase within 6 months prior to starting GATTEX, and at least every 6 months while on GATTEX; or more frequently if needed. If clinically meaningful changes are seen, further evaluation such as imaging of the pancreas is recommended; and the need for continued GATTEX treatment should be reassessed.
- Fluid Overload
- Fluid overload and congestive heart failure have been observed in clinical trials, which were felt to be related to enhanced fluid absorption associated with GATTEX. If fluid overload occurs, parenteral support should be adjusted and GATTEX treatment should be reassessed, especially in patients with underlying cardiovascular disease. If significant cardiac deterioration develops while on GATTEX, the need for continued GATTEX treatment should be reassessed.
- Increased Absorption of Concomitant Oral Medication
- Altered mental status in association with GATTEX has been observed in patients on benzodiazepines in clinical trials. Patients on concomitant oral drugs (e.g., benzodiazepines, phenothiazines) requiring titration or with a narrow therapeutic index may require dose adjustment while on GATTEX.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.
- Across all clinical studies, 566 subjects were exposed to at least one dose of GATTEX (190 patient-years of exposure; mean duration of exposure was 17 weeks). Of the 566 subjects, 173 subjects were treated in Phase 3 SBS studies (134/173 [77%] at the dose of 0.05 mg/kg/day and 39/173 [23%] at the dose of 0.10 mg/kg/day).
- The most commonly reported (≥ 10%) adverse reactions in patients treated with GATTEX across all clinical studies (n = 566) were: abdominal pain (30.0%); injection site reactions (22.4%); nausea (18.2%); headaches (15.9%); abdominal distension (13.8%); upper respiratory tract infection (11.8%).
- The rates of adverse reactions in subjects with SBS participating in two randomized, placebo-controlled, 24-week, double-blind clinical studies (Study 1 and Study 3) are summarized in Table 1. Only those reactions with a rate of at least 5% in the GATTEX group, and greater than placebo group, are summarized in Table 1. The majority of these reactions were mild or moderate. Of subjects receiving GATTEX at the recommended dose of 0.05 mg/kg/day, 88.3% (N=68/77) experienced an adverse reaction, as compared to 83.1% (49/59) for placebo. Many of these adverse reactions have been reported in association with the underlying disease and/or parenteral nutrition.
- In placebo-controlled Studies 1 and 3, 12% of patients in each of the placebo and GATTEX study groups experienced an injection site reaction.
- Malignancy. Three subjects were diagnosed with malignancy in the clinical studies, all of whom were male and had received GATTEX 0.05 mg/kg/day in Study 2. One subject had a history of abdominal radiation for Hodgkin's disease two decades prior to receiving GATTEX and prior liver lesion on CT scan, and was diagnosed with metastatic adenocarcinoma of unconfirmed origin after 11 months of exposure to GATTEX. Two subjects had extensive smoking histories, and were diagnosed with lung cancers (squamous and non-small cell) after 12 months and 3 months of GATTEX exposure, respectively.
- Colorectal Polyps. In the clinical studies, 6 subjects were diagnosed with polyps of the G.I. tract after initiation of study treatment. In the SBS placebo-controlled studies, 1/59 (1.7%) of subjects on placebo and 1/109 (0.9%) of subjects on GATTEX 0.05 mg/kg/day were diagnosed with intestinal polyps (inflammatory stomal and hyperplastic sigmoidal after 3 and 5 months, respectively). The remaining 4 polyp cases occurred in the extension studies – two colorectal villous adenomas (onset at 6 and 7 months in GATTEX 0.10 and 0.05 mg/kg/day dose groups, respectively), one hyperplastic polyp (onset 6 months in GATTEX 0.10 mg/kg/day dose group), and one small duodenal polyp (onset at 3 months in GATTEX 0.05 mg/kg/day dose group).
- Gastrointestinal Obstruction. Overall, 12 subjects experienced one or more episodes of intestinal obstruction/stenosis: 6 in SBS placebo-controlled studies and 6 in the extension studies. The 6 subjects in the placebo-controlled trials were all on GATTEX: 3/77 (3.9%) on GATTEX 0.05 mg/kg/day and 3/32 (9.4%) on GATTEX 0.10 mg/kg/day. No cases of intestinal obstruction occurred in the placebo group. Onsets ranged from 1 day to 6 months. In the extension studies, 6 additional subjects (all on GATTEX 0.05 mg/kg/day) were diagnosed with intestinal obstruction/stenosis with onsets ranging from 6 days to 7 months. Two of the 6 subjects from the placebo-controlled trials experienced recurrence of obstruction in the extension studies. Of all 8 subjects with an episode of intestinal obstruction/stenosis in these extension studies, 1 subject required endoscopic dilation and none required surgical intervention.
- Gallbladder, Biliary and Pancreatic Disease. For gallbladder and biliary disease in the placebo-controlled studies, 3 subjects were diagnosed with cholecystitis, all of whom had a prior history of gallbladder disease and were in the GATTEX 0.05 mg/kg/day dose group. No cases were reported in the placebo group. One of these 3 cases had gallbladder perforation and underwent cholecystectomy the next day. The remaining 2 cases underwent elective cholecystectomy at a later date. In the extension studies, 3 subjects had an episode of acute cholecystitis; 2 subjects had new-onset cholelithiasis; and 1 subject experienced cholestasis secondary to an obstructed biliary stent. For pancreatic disease in the placebo-controlled studies, 1 subject (GATTEX 0.05 mg/kg/day dose group) had a pancreatic pseudocyst diagnosed after 4 months of GATTEX. In the extension studies, 1 subject was diagnosed with chronic pancreatitis; and 1 subject was diagnosed with acute pancreatitis.
- Fluid Overload. In the placebo-controlled trials, fluid overload was reported in 4/59 (6.8%) of subjects on placebo and 9/77 (11.7%) subjects on GATTEX 0.05 mg/kg/day. Of the 9 cases in the GATTEX group, there were 2 cases of congestive heart failure (CHF), 1 of whom was reported as a serious adverse event and the other as non-serious. The serious case had onset at 6 months, and was possibly associated with previously undiagnosed hypothyroidism and/or cardiac dysfunction.
- Concomitant Oral Medication. GATTEX can increase the absorption of concomitant oral medications such as benzodiazepines and psychotropic agents. In the placebo-controlled trials, an analysis of episodes of cognition and attention disturbances was performed for subjects on benzodiazepines. One of the subjects in the GATTEX 0.05 mg/kg/day group (on prazepam) experienced dramatic deterioration in mental status progressing to coma during her first week of GATTEX therapy. She was admitted to the ICU where her benzodiazepine level was >300 mcg/L. GATTEX and prazepam were discontinued, and coma resolved 5 days later.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Teduglutide in the drug label.
# Drug Interactions
- Potential for Increased Absorption of Oral Medications
- Based upon the pharmacodynamic effect of GATTEX, there is a potential for increased absorption of concomitant oral medications, which should be considered if these drugs require titration or have a narrow therapeutic index.
- Concomitant Drug Therapy
- Clinical interaction studies were not performed. No inhibition or induction of the cytochrome P450 enzyme system has been observed based on in vitro studies although the relevance of in vitro studies to an in vivo setting is unknown.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Reproduction studies with teduglutide have been performed in pregnant rats at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg) and in rabbits at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg). These studies did not reveal any evidence of impaired fertility or harm to the fetus due to teduglutide. A pre- and postnatal development study in rats showed no evidence of any adverse effect on pre- and postnatal development at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg). There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, teduglutide 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 Teduglutide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Teduglutide during labor and delivery.
### Nursing Mothers
- It is unknown whether teduglutide is excreted in human milk. Teduglutide is excreted in the milk of lactating rats, and the highest concentration in the milk was 2.9% of the plasma concentration following a single subcutaneous injection of 25 mg/kg. Because many drugs are excreted in human milk; because of the potential for serious adverse reactions to nursing infants from teduglutide and because of the potential for tumorigenicity shown for teduglutide in rats, 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 efficacy in pediatric patients have not been established.
### Geriatic Use
- No dose adjustment is necessary in patients above the age of 65 years. Of the 566 subjects treated with teduglutide, 43 subjects were 65 years or older, whereas 6 subjects were 75 years of age or older. In the SBS studies, no overall differences in safety or efficacy 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.
### Gender
There is no FDA guidance on the use of Teduglutide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Teduglutide with respect to specific racial populations.
### Renal Impairment
- Reduce the dose of GATTEX by 50% in patients with moderate and severe renal impairment (creatinine clearance less than 50 mL/min) and end-stage renal disease (ESRD).
### Hepatic Impairment
- GATTEX has not been formally studied in subjects with severe hepatic impairment. No dosage adjustment is necessary for patients with mild and moderate hepatic impairment based on a study conducted in Child-Pugh grade B subjects.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Teduglutide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Teduglutide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Teduglutide in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Teduglutide in the drug label.
# Overdosage
## Acute Overdose
- The maximum dose of GATTEX studied during clinical development was 80 mg/day for 8 days. In the event of overdose, the patient should be carefully monitored by the medical professional.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Teduglutide in the drug label.
# Pharmacology
## Mechanism of Action
- Teduglutide is an analog of naturally occurring human glucagon-like peptide-2 (GLP-2), a peptide secreted by L-cells of the distal intestine. GLP-2 is known to increase intestinal and portal blood flow, and inhibit gastric acid secretion. Teduglutide binds to the glucagon-like peptide-2 receptors located in intestinal subpopulations of enteroendocrine cells, subepithelial myofibroblasts and enteric neurons of the submucosal and myenteric plexus. Activation of these receptors results in the local release of multiple mediators including insulin-like growth factor (IGF)-1, nitric oxide and keratinocyte growth factor (KGF).
## Structure
- The active ingredient in GATTEX (teduglutide [rDNA origin]) for injection is teduglutide (rDNA origin), which is a 33 amino acid glucagon-like peptide-2 (GLP-2) analog manufactured using a strain of Escherichia coli modified by recombinant DNA technology. The chemical name of teduglutide is L-histidyl-L-glycyl-L-aspartyl-L-glycyl-L-seryl-L-phenylalanyl-L-seryl-L-aspartyl-L-glutamyl-L-methionyl-L-asparaginyl-L-threonyl-L-isoleucyl-L-leucyl-L-aspartyl-L-asparaginyl-L-leucyl-L-alanyl-L-alanyl-L-arginyl-L-aspartyl-L-phenylalanyl-L-isoleucyl-L-asparaginyl-L-tryptophanyl-L-leucyl-L-isoleucyl-L-glutaminyl-L-threonyl-L-lysyl-L-isoleucyl-L-threonyl-L-aspartic acid. The structural formula is:
- Teduglutide has a molecular weight of 3752 Daltons. Teduglutide drug substance is a clear, colorless to light-straw–colored liquid.
- Each single-use vial of GATTEX contains 5 mg of teduglutide as a white lyophilized powder for solution for subcutaneous injection. In addition to the active pharmaceutical ingredient (teduglutide), each vial of GATTEX contains 3.88 mg L-histidine, 15 mg mannitol, 0.644 mg monobasic sodium phosphate monohydrate, 3.434 mg dibasic sodium phosphate heptahydrate as excipients. No preservatives are present.
- At the time of administration the lyophilized powder is reconstituted with 0.5 mL of Sterile Water for Injection, which is provided in a prefilled syringe. A 10 mg/mL sterile solution is obtained after reconstitution. Up to 0.38 mL of the reconstituted solution which contains 3.8 mg of teduglutide can be withdrawn for subcutaneous injection upon reconstitution.
## Pharmacodynamics
- The ability of GATTEX to improve intestinal absorption was studied in 17 adult subjects with Short Bowel Syndrome using daily doses of 0.03, 0.10, 0.15 mg/kg (N=2-3 per dose group) in a 21-day, open-label, multi-center, dose-ranging study. All subcutaneous (abdomen) doses studied, except 0.03 mg/kg once daily, resulted in enhanced gastrointestinal fluid (wet weight) absorption of approximately 750-1000 mL/day, and increased villus height and crypt depth of the intestinal mucosa.
- At a dose 5 times the maximum recommended dose, teduglutide did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
- Absorption:
- In healthy subjects, GATTEX administered subcutaneously had an absolute bioavailability of 88% and reached maximum plasma teduglutide concentrations at 3-5 hours after administration. Following a 0.05 mg/kg subcutaneous dose in SBS subjects, the median peak teduglutide concentration (Cmax) was 36 ng/mL and the median area under the curve (AUC0-inf) was 0.15 µg•hr/mL. No accumulation of teduglutide was observed following repeated subcutaneous administrations.
- Distribution:
- In healthy subjects, teduglutide has a volume of distribution (103 mL/kg) similar to blood volume.
- Metabolism:
- The metabolic pathway of teduglutide was not investigated in humans. However, teduglutide is expected to be degraded into small peptides and amino acids via catabolic pathways, similar to the catabolism of endogenous GLP-2.
- Elimination:
- In healthy subjects, teduglutide plasma clearance was approximately 123 mL/hr/kg which is similar to the GFR suggesting that teduglutide is primarily cleared by the kidney. Teduglutide has a mean terminal half-life (t1/2) of approximately 2 hours in healthy subjects and 1.3 hours in SBS subjects.
- Dose Linearity:
- The Cmax and AUC of teduglutide was dose proportional over the dose range of 0.05 to 0.4 mg/kg GATTEX.
- Hepatic Impairment:
- Subjects with moderate hepatic impairment had lower teduglutide Cmax and AUC (10 ~15%) compared to healthy matched control subjects after a single subcutaneous dose of 20 mg GATTEX. Teduglutide PK was not assessed in subjects with severe hepatic impairment.
- Renal Impairment:
- In subjects with moderate to severe renal impairment or end stage renal disease (ESRD), teduglutide Cmax and AUC0-inf increased with the degree of renal impairment following a single subcutaneous administration of 10 mg teduglutide. Teduglutide exposure increased by a factor of 2.1 (Cmax) and 2.6 (AUC0-inf) in ESRD subjects compared to healthy subjects.
- Geriatric Patients:
- No differences were observed between healthy subjects younger than 65 years and those older than 65 years. Experience in subjects 75 years and above is limited.
- Gender:
- No clinically relevant gender differences were observed.
## Nonclinical Toxicology
- In a 2-year carcinogenicity study in Wistar Han rats at subcutaneous doses of 3, 10 and 35 mg/kg/day (about 60, 200 and 700 times the recommended daily human dose of 0.05 mg/kg, respectively), teduglutide caused statistically significant increases in the incidences of adenomas in the bile duct and jejunum of male rats.
- Teduglutide was negative in the Ames test, chromosomal aberration test in Chinese hamster ovary cells, and in vivo mouse micronucleus assay.
- Teduglutide at subcutaneous doses up to 50 mg/kg/day (about 1000 times the recommended daily human dose of 0.05 mg/kg) was found to have no adverse effect on fertility and reproductive performance of male and female rats.
# Clinical Studies
- Study 1. The efficacy, safety, and tolerability of GATTEX was evaluated in a randomized, double-blind, placebo-controlled, parallel-group, multi-national, multi-center clinical trial (Study 1) in adults with SBS who were dependent on parenteral nutrition/intravenous (PN/I.V.) support for at least 12 months and required PN at least 3 times per week. For 8 weeks (or less) prior to randomization, investigators optimized the PN/I.V. volume of all subjects. Optimization was followed by a 4-week to 8-week period of fluid stabilization. Subjects then were randomized (1:1) to placebo (n=43) or GATTEX 0.05 mg/kg/day (n=43). Study treatment was administered subcutaneously once daily for 24 weeks. PN/I.V. volume adjustments (up to 30% decrease) and clinical assessments were made at 2, 4, 8, 12, 20, and 24 weeks.
- The primary efficacy endpoint was based on a clinical response, defined as a subject achieving at least 20% reduction in weekly PN/I.V. volume from Baseline (immediately before randomization) to both Weeks 20 and 24.
- The mean age of subjects was 50.3 years. Mean duration of PN/I.V. dependency prior to enrollment was 6.25 years (range 1-25.8 years). The most common reasons for intestinal resection leading to SBS were vascular disease (34.1%, 29/85), Crohn's Disease (21.2%, 18/85), and "other" (21.2%, 18/85). Stoma was present in 44.7% (38/85) of subjects, and the most common type was jejunostomy/ileostomy (81.6%, 31/38). The mean length of remaining small intestine was 77.3±64.4 cm (range: 5 to 343 cm). The colon was not in continuity in 43.5% (37/85) subjects. At baseline, the mean (± SD) prescribed days per week for PN/I.V. infusion was 5.73 (±1.59) days.
- The percentages of treatment group responders were compared in the intent-to-treat population of this study which was defined as all randomized patients. 63% (27/43) of GATTEX-treated subjects versus 30% (13/43) of placebo-treated subjects were considered responders (p=0.002).
- At Week 24, the mean reduction in weekly PN/I.V. volume was 4.4 Liters for GATTEX-treated subjects (from pre-treatment baseline of 12.9 Liters) versus 2.3 Liters for placebo-treated subjects (from pre-treatment baseline of 13.2 Liters/week) (p<0.001).
- Twenty-one subjects on GATTEX (53.8%) versus 9 on placebo (23.1%) achieved at least a one-day reduction in PN/I.V. support.
- The mean changes from Baseline in PN/I.V. volume by visit are shown in Figure 2.
- Study 2. Study 2 is an ongoing two-year open-label extension of Study 1 in which 88 subjects receive GATTEX 0.05 mg/kg/day. Ninety-seven percent (76/78) of subjects from Study 1 elected to enroll in Study 2. An additional 12 subjects entered Study 2, who had been optimized and stabilized but not randomized in Study 1 because of closed enrollment. Of responders in Study 1 who entered Study 2, 100% (25/25) sustained their response to GATTEX after one year of continuous treatment. A 20% or greater reduction of parenteral support was achieved in 72% (31/43) of subjects after an additional 28 weeks of continuous GATTEX treatment. The mean reduction of weekly PN/I.V. volume was 5.2 L/week after one year of continuous GATTEX treatment. Six subjects in Study 2 were weaned off their PN/I.V. support while on GATTEX. Subjects were maintained on GATTEX even if no longer requiring PN/I.V. support. These 6 subjects had required PN/I.V. support for 3 to 18 years, and prior to GATTEX had required between 4 L/week and 13 L/week of PN/I.V. support.
- Study 3. Study 3 was a randomized, double-blind, placebo-controlled, three parallel-group, multinational study in adults with Short Bowel Syndrome who were dependent on parenteral nutrition/intravenous (PN/I.V.) support for at least 12 months and required PN at least 3 times per week. After a period of optimization and stabilization similar to Study 1, subjects were randomized to receive 24 weeks of one of the following treatment regimens: GATTEX 0.05 mg/kg/day (n=35), GATTEX 0.10 mg/kg/day dose (n=33), or placebo (n=16). The treatment groups were compared using the intent-to-treat population of this study which was defined as all randomized patients who were administered at least one dose of study drug. This population contained one less patient in the 0.10 mg/kg/day dose group hence n=32 in this group for all analyses. The primary efficacy endpoint was a graded categorical score that did not achieve statistical significance for the high dose. Further evaluation of PN/I.V. volume reduction using the endpoint of response (defined as at least 20% reduction in PN/I.V. fluid from Baseline to Weeks 20 and 24) showed that 46% of subjects on GATTEX 0.05 mg/kg/day responded versus 6% on placebo. Subjects on GATTEX at both dose levels experienced a 2.5 L/week reduction in parenteral support requirements versus 0.9 L/week for placebo at 24 weeks. Two subjects in the GATTEX 0.05 mg/kg/day dose group were weaned off parenteral support by Week 24.
- Study 4. Study 4 was a blinded, uncontrolled extension of Study 3, in which 65 subjects from Study 3 received GATTEX for up to an additional 28 weeks of treatment. Of responders in Study 3 who entered Study 4, 75% sustained response on GATTEX after one year of treatment. In the GATTEX 0.05 mg/kg/day dose group, a 20% or greater reduction of parenteral support was achieved in 68% (17/25) of subjects. The mean reduction of weekly PN/I.V. volume was 4.9 L/week (52% reduction from baseline) after one year of continuous GATTEX treatment. The subjects who had been completely weaned off PN/I.V. support in Study 3 remained off parenteral support through Study 4. During Study 4, an additional subject from Study 3 was weaned off parenteral support.
# How Supplied
- GATTEX® (teduglutide [rDNA origin]) for injection is supplied in a sterile, single-use glass vial containing 5 mg of teduglutide as a white, lyophilized powder to be reconstituted with 0.5 mL Sterile Water for Injection. The product to be dispensed is either a one-vial kit or a 30-vial kit. The one-vial kit is pre-assembled and ready to be used. The 30-vial kit is to be assembled by a pharmacist with the following two cartons:
- Carton of Drug Vials (NDC 68875-0101-2):
- Thirty single-use vials of drug (NDC 68875-0101-1)
- Carton of Ancillary Supplies:
- Thirty disposable prefilled syringes containing diluent (0.5 mL Sterile Water for Injection USP) for reconstitution
- Thirty separate needles (22G x 1½ in) to attach to the syringes for reconstitution
- Thirty sterile disposable 1-mL syringes with needle (26G x 5/8 in)
- Sixty alcohol swabs
- The pharmacist in a dispensing pharmacy will assemble a 30-vial kit by transferring the trays containing 30 vials from a Carton of Drug Vials into a Carton of Ancillary Supplies. The final patient kits should contain the items listed as follows:
- 30-vial kit (NDC 68875-0102-1):
- Thirty single-use vials of drug (NDC 68875-0101-1)
- Thirty disposable prefilled syringes containing 0.5 mL Sterile Water for Injection USP for reconstitution, with 30 separate needles (22G x 1½ in) to attach to the syringes
- Thirty sterile disposable 1-mL syringes with needle (26G x 5/8 in) for dosing
- Sixty alcohol swabs
- One-vial kit (NDC 68875-0103-1):
- One single-use vial of drug (NDC 68875-0101-1)
- One disposable prefilled syringe containing 0.5 mL Sterile Water for Injection USP for reconstitution, with a separate needle (22G x 1½ in) to attach to the syringe
- One sterile disposable 1-mL syringe with needle (26G x 5/8 in) for dosing
- Four alcohol swabs
- Reconstitution with 0.5 mL of preservative-free Sterile Water for Injection, provided in a prefilled syringe, is required prior to subcutaneous administration of the drug. Reconstituted GATTEX is a sterile, clear, colorless to light straw-colored 10 mg/mL solution, which should be free from particulates. Upon reconstitution with the 0.5 mL Sterile Water for Injection provided in the prefilled syringe, a maximum of 0.38 mL of the reconstituted solution which contains 3.8 mg of teduglutide can be withdrawn from the vial for dosing.
- Storage and Handling
- Prior to Dispensing: Store refrigerated at 2°C to 8°C (36°F to 46°F) for Cartons of Drug Vials and the One-vial kits. Do not freeze. Do not use beyond the expiration date on the label. Store at room temperature up to 25°C (77°F) for the Cartons of Ancillary Supplies.
- Instruction for the Pharmacist:
- Prior to Dispensing: Store at 2°C to 8°C (36°F to 46°F) for Cartons of Drug Vials and the One-vial kits. Do not freeze.
- Dispensing Instructions: Dispense with a 90-day "use by" dating and specify "Store at room temperature up to 25°C (77°F). Do not freeze." Dispense Medication Guide to each patient.
- Reconstituted GATTEX is a sterile, clear, colorless to light straw-colored solution, which should be free from particulates. The drug should be completely dissolved before the solution is withdrawn from the vial. Do not shake or freeze the reconstituted solution. If the product remains undissolved after the second attempt, do not use. GATTEX does not contain any preservatives and is for single-use only. Any unused portion should be discarded. The product should be used within 3 hrs after reconstitution.
## Storage
There is limited information regarding Teduglutide Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- General Counseling Information
- Prior to treatment, patients should fully understand the risks and benefits of GATTEX. Ensure that all patients receive the Medication Guide prior to initiating GATTEX therapy.
- Acceleration of Neoplastic Growth
- Advise patients with active gastrointestinal malignancy (GI tract, hepatobiliary, pancreatic), that GATTEX therapy should be discontinued. In patients with active non-gastrointestinal malignancy, the clinical decision to continue GATTEX should be discussed with patients and be made based on risk-benefit considerations.
- Colorectal polyps.
- Advise patients that colonoscopy of the entire colon with removal of polyps should be done within 6 months prior to starting treatment with GATTEX. A follow-up colonoscopy (or alternate imaging) is recommended at the end of 1 year of GATTEX. Subsequent colonoscopies should be done every 5 years or more often as needed. If a polyp is found, adherence to current polyp follow-up guidelines is recommended. In case of diagnosis of colorectal cancer, GATTEX therapy should be discontinued.
- Small Bowel Neoplasia.
- Advise patients that they should be monitored clinically for small bowel neoplasia. If a benign neoplasm is found, it should be removed. In case of small bowel cancer, GATTEX therapy should be discontinued.
- Intestinal Obstruction
- Advise patients to tell their physician if they experience any signs or symptoms suggestive of intestinal obstruction. If obstruction is present, the physician may temporarily discontinue GATTEX.
- Gallbladder and Bile Duct Disease
- Advise patients that laboratory assessments should be done before and then every 6 months while on GATTEX to monitor gallbladder and biliary function. If clinically significant change occurs, further evaluation (i.e., imaging studies or other) may be necessary. Advise patients to report to their physician all signs and symptoms suggestive of cholecystitis, cholangitis, or cholelithiasis while on GATTEX.
- Pancreatic Disease
- Advise patients that laboratory assessments should be done before and then every 6 months while on GATTEX. If clinically significant change occurs, further evaluation (i.e., imaging studies or other) may be necessary. Advise patients to report to their physician all signs and symptoms suggestive of pancreatic disease while on GATTEX.
- Cardiovascular Disease
- Advise patients with cardiovascular disease to report to their physician any signs of fluid overload or cardiac decompensation while on GATTEX.
- Risks Resulting from Increased Absorption of Concomitant Oral Medication
- Instruct patients to report to all of their physicians any concomitant oral medications that they are taking in order to assess any potential for increased absorption during GATTEX treatment of those oral medications requiring titration or with a narrow therapeutic index.
- Instructions
- Inform patients that GATTEX should not be administered intravenously or intramuscularly. The drug should be used for subcutaneous injection within 3 hours after reconstitution. Advise patients that subcutaneous administration has been associated with injection site reactions, but if they experience a severe reaction including severe rash, they should contact their physician.
- Advise patients that while they may experience abdominal pain and swelling of their stoma especially when starting therapy with GATTEX, if they experience symptoms of intestinal obstruction, they should contact their physician.
- Instruct patients to read the Medication Guide as they are starting GATTEX therapy and to re-read it each time their prescription is renewed.
# Precautions with Alcohol
- Alcohol-Teduglutide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- GATTEX®[1]
# Look-Alike Drug Names
There is limited information regarding Teduglutide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Teduglutide | |
aa8063deddd516767553be435e905206e616bce8 | wikidoc | Teicoplanin | Teicoplanin
# Overview
Teicoplanin is an antibiotic used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. It is a semisynthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Its mechanism of action is to inhibit bacterial cell wall synthesis.
Teicoplanin is marketed by Sanofi-Aventis under the trade name Targocid. Other trade names include Teconin marketed by Biocon ltd (India).
Oral teicoplanin has been demonstrated to be effective in the treatment of pseudomembranous colitis and Clostridium difficile-associated diarrhoea, with comparable efficacy with vancomycin.
Its strength is considered to be due to the length of the hydrocarbon chain.
# Susceptibility data
Teicoplanin targets peptidoglycan synthesis making it an effective antimicrobial against Gram-positive bacteria including Staphylococci and Clostridium spp. The following represents MIC susceptibility data for a few medically significant pathogens:
- Clostridium difficile: 0.06 μg/ml - 0.5 μg/ml
- Staphylococcus aureus: ≤0.06 μg/ml - ≥128 μg/ml
- Staphylococcus epidermidis: ≤0.06 μg/ml - 32 μg/ml
# Chemistry
Teicoplanin (TARGOCID, marketed by Sanofi Aventis Ltd) is actually a mixture of several compounds, five major (named teicoplanin A2-1 through A2-5) and four minor (named teicoplanin RS-1 through RS-4).
All teicoplanins share a same glycopeptide core, termed teicoplanin A3-1 — a fused ring structure to which two carbohydrates (mannose and N-acetylglucosamine) are attached. The major and minor components also contain a third carbohydrate moiety — β-D-glucosamine — and differ only by the length and conformation of a side-chain attached to it.
The structures of the teicoplanin core and the side-chains that characterize the five major teicoplanin compounds are shown below.
# Biosynthesis
Teicoplanin refers to a complex of related natural products isolated from the fermentation broth of a strain of Actinoplanes teichomyceticus, consisting of a group of five structures. These structures possess a common aglycone, or core, consisting of seven amino acids bound by peptide and ether bonds to form a four-ring system. These five structures differ by the identity of the fatty acyl side-chain attached to the sugar. The origin of these seven amino acids in the biosynthesis of teicoplanin was studied by 1H and 13C nuclear magnetic resonance. The studies indicate amino acids AA1, AA2, AA4, AA5, and AA6 are derived from tyrosine, and amino acids AA3 and AA7 are derived from acetate. To be specific, teicoplanin contains 4-hydroxyphenylglycine and 3,5-dihydroxyphenylglycine residues, a chlorine atom attached on each of the tyrosine residues, and three sugar moieties, N-fatty acyl-β-D-glucosamine, N-acetyl-β-D-glucosamine, and D-mannose.
## Gene cluster
The study of the genetic cluster encoding the biosynthesis of teicoplanin identified 49 putative open reading frames (ORFs) involved in the compound's biosynthesis, export, resistance, and regulation. Thirty-five of these ORFs are similar to those found in other glycopeptide gene clusters. The function of each of these genes is described by Li and co-workers. A summary of the gene layout and purpose is shown below.
Gene layout. The genes are numbered. The letters L and R designate transcriptional direction. The presence of the - symbol means a gene is found after NRPs, which are represented by A, B, C, and D. Based on the figure from: Li, T-L.; Huang, F.; Haydock, S. F.; Mironenko, T.; Leadlay, P. F.; Spencer, J. B. Chemistry & Biology. 2004, 11, p. 109.
## Heptapeptide backbone synthesis
Analysis indicated tyrosine and three types of nonproteinogenic amino acids, (S)-4-hydroxyphenylglycine, 3,5-dihydroxyphenylglycine, and β-hydroxytyrosine as the building blocks of the teicoplanin group of glycopeptides. In all, six of the seven total amino acids of the teicoplanin backbone are composed of nonproteinogenic or modified amino acids. Eleven enzymes are coordinatively induced to produce these six required residues. Teicoplanin contains two chlorinated positions, 2 (3-Cl-Tyr) and 6 (3-Cl-β-Hty). The putative halogenase Orf8- has been proposed to catalyze the halogenation on both amino acids. Chlorination is thought to occur at a very early point in the biosynthesis prior to phenolic oxidative coupling, with the possibility of tyrosine or β-hydroxytyrosine being the substrate of chlorination.
The biosynthesis of the heptapeptide backbone is carried out by four nonribosomal peptide synthetases designated TeiA, TeiB, TeiC, and TeiD. Each of the modules has a domain for amino acid selection and activation as the aminoacyl-AMP. The catalytic domains in modules one and three of the nonribosomal peptide synthetase assembly line select and activate (S)-4-hydroxyphenylglycine and 3,5-dihydroxyphenylglycine. In addition to these modules for amino acid selection and activation, each module has a thiolation domain modified with phosphopantetheine to provide a thiol for covalent aminoacyl-S-enzyme formation.
## Modification after heptapeptide backbone formation
Once the heptapeptide backbone has been formed, the cyclization of the linear structure is begun. Gene disruption studies indicate a cytochrome P450 oxygenase as the enzyme that performs the coupling reactions. OxyB has been suggested to form the first ring by coupling residues 4 and 6. OxyA then couples residues 2 and 4, followed by the formation of a C-C bond between residues 5 and 7 by OxyC. A fourth enzyme catalyzes the coupling of residues 1 and 3, although where this coupling fits into the OxyB/OxyA/OxyC order is not known. The regioselectivity and atropisomer selectivity of these probable one-electron coupling reactions has been suggested to be due to the folding and orientation requirements of the partially crossed-linked substrates in the enzyme active site. The coupling reactions are shown below.
Specific glycosylation has been shown to occur after the formation of the heptpeptide aglycone. Data suggest three separate glycosyl transferases are required for the glycosylation of the teicoplanin aglycone. Two of these glycosyl transferases are involved in the addition of the N-fatty acyl-β-D-glucosamine and N-acetyl-β-D-glucosamine units. A third mannosyl transferase is responsible for the addition of the D-mannose unit onto residue 7. The fatty acyl chain is connected by amide bond to the glucosamine moiety by the action of an acyl transferase. In addition to glycosylation, some genes have been suggested to code for deacetylases. In addition to the ability to salvage portions of the molecular structure, it provides a way to protect/deprotect the molecule. | Teicoplanin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Teicoplanin is an antibiotic used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. It is a semisynthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Its mechanism of action is to inhibit bacterial cell wall synthesis.
Teicoplanin is marketed by Sanofi-Aventis under the trade name Targocid. Other trade names include Teconin marketed by Biocon ltd (India).
Oral teicoplanin has been demonstrated to be effective in the treatment of pseudomembranous colitis and Clostridium difficile-associated diarrhoea, with comparable efficacy with vancomycin.[1]
Its strength is considered to be due to the length of the hydrocarbon chain.[dead link][2]
# Susceptibility data
Teicoplanin targets peptidoglycan synthesis making it an effective antimicrobial against Gram-positive bacteria including Staphylococci and Clostridium spp. The following represents MIC susceptibility data for a few medically significant pathogens:
- Clostridium difficile: 0.06 μg/ml - 0.5 μg/ml
- Staphylococcus aureus: ≤0.06 μg/ml - ≥128 μg/ml
- Staphylococcus epidermidis: ≤0.06 μg/ml - 32 μg/ml
[3]
# Chemistry
Teicoplanin (TARGOCID, marketed by Sanofi Aventis Ltd) is actually a mixture of several compounds, five major (named teicoplanin A2-1 through A2-5) and four minor (named teicoplanin RS-1 through RS-4).[4]
All teicoplanins share a same glycopeptide core, termed teicoplanin A3-1 — a fused ring structure to which two carbohydrates (mannose and N-acetylglucosamine) are attached. The major and minor components also contain a third carbohydrate moiety — β-D-glucosamine — and differ only by the length and conformation of a side-chain attached to it.
The structures of the teicoplanin core and the side-chains that characterize the five major teicoplanin compounds are shown below.
# Biosynthesis
Teicoplanin refers to a complex of related natural products isolated from the fermentation broth of a strain of Actinoplanes teichomyceticus,[5] consisting of a group of five structures. These structures possess a common aglycone, or core, consisting of seven amino acids bound by peptide and ether bonds to form a four-ring system. These five structures differ by the identity of the fatty acyl side-chain attached to the sugar. The origin of these seven amino acids in the biosynthesis of teicoplanin was studied by 1H and 13C nuclear magnetic resonance.[6] The studies indicate amino acids AA1, AA2, AA4, AA5, and AA6 are derived from tyrosine, and amino acids AA3 and AA7 are derived from acetate. To be specific, teicoplanin contains 4-hydroxyphenylglycine and 3,5-dihydroxyphenylglycine residues, a chlorine atom attached on each of the tyrosine residues, and three sugar moieties, N-fatty acyl-β-D-glucosamine, N-acetyl-β-D-glucosamine, and D-mannose.
## Gene cluster
The study of the genetic cluster encoding the biosynthesis of teicoplanin identified 49 putative open reading frames (ORFs) involved in the compound's biosynthesis, export, resistance, and regulation. Thirty-five of these ORFs are similar to those found in other glycopeptide gene clusters. The function of each of these genes is described by Li and co-workers.[7] A summary of the gene layout and purpose is shown below.
Gene layout. The genes are numbered. The letters L and R designate transcriptional direction. The presence of the * symbol means a gene is found after NRPs, which are represented by A, B, C, and D. Based on the figure from: Li, T-L.; Huang, F.; Haydock, S. F.; Mironenko, T.; Leadlay, P. F.; Spencer, J. B. Chemistry & Biology. 2004, 11, p. 109.
[11-L] [10-L] [9-R] [8-R] [7-R] [6-R] [5-R] [4-L][3-L] [2-L] [1-R]
[A-R] [B-R] [C-R]
[D-R] [1*-R] [2*-R] [3*-R] [4*-R]
[5*-R] [6*-R] [7*-R] [8*-R] [9*-R] [10*-R] [11*-R] [12*-R] [13*-R]
[14*-R] [15*-R] [16*-R] [17*-R] [18*-R] [19*-R] [20*-R] [21*-R] [22*-R] [23*-R] [24*-R]
[25*-L] [26*-L] [27*-R] [28*-R] [29*-R] [30*-R][31*-R] [32*-L] [33*-L] [34*-R]
## Heptapeptide backbone synthesis
Analysis indicated tyrosine and three types of nonproteinogenic amino acids, (S)-4-hydroxyphenylglycine, 3,5-dihydroxyphenylglycine, and β-hydroxytyrosine as the building blocks of the teicoplanin group of glycopeptides. In all, six of the seven total amino acids of the teicoplanin backbone are composed of nonproteinogenic or modified amino acids. Eleven enzymes are coordinatively induced to produce these six required residues.[8] Teicoplanin contains two chlorinated positions, 2 (3-Cl-Tyr) and 6 (3-Cl-β-Hty). The putative halogenase Orf8* has been proposed to catalyze the halogenation on both amino acids. Chlorination is thought to occur at a very early point in the biosynthesis prior to phenolic oxidative coupling, with the possibility of tyrosine or β-hydroxytyrosine being the substrate of chlorination.
The biosynthesis of the heptapeptide backbone is carried out by four nonribosomal peptide synthetases designated TeiA, TeiB, TeiC, and TeiD. Each of the modules has a domain for amino acid selection and activation as the aminoacyl-AMP. The catalytic domains in modules one and three of the nonribosomal peptide synthetase assembly line select and activate (S)-4-hydroxyphenylglycine and 3,5-dihydroxyphenylglycine.[8] In addition to these modules for amino acid selection and activation, each module has a thiolation domain modified with phosphopantetheine to provide a thiol for covalent aminoacyl-S-enzyme formation.
## Modification after heptapeptide backbone formation
Once the heptapeptide backbone has been formed, the cyclization of the linear structure is begun.[9] Gene disruption studies indicate a cytochrome P450 oxygenase as the enzyme that performs the coupling reactions. OxyB has been suggested to form the first ring by coupling residues 4 and 6. OxyA then couples residues 2 and 4, followed by the formation of a C-C bond between residues 5 and 7 by OxyC. A fourth enzyme catalyzes the coupling of residues 1 and 3, although where this coupling fits into the OxyB/OxyA/OxyC order is not known. The regioselectivity and atropisomer selectivity of these probable one-electron coupling reactions has been suggested to be due to the folding and orientation requirements of the partially crossed-linked substrates in the enzyme active site.[9] The coupling reactions are shown below.
Specific glycosylation has been shown to occur after the formation of the heptpeptide aglycone.[10] Data suggest three separate glycosyl transferases are required for the glycosylation of the teicoplanin aglycone. Two of these glycosyl transferases are involved in the addition of the N-fatty acyl-β-D-glucosamine and N-acetyl-β-D-glucosamine units. A third mannosyl transferase is responsible for the addition of the D-mannose unit onto residue 7. The fatty acyl chain is connected by amide bond to the glucosamine moiety by the action of an acyl transferase. In addition to glycosylation, some genes have been suggested to code for deacetylases.[11] In addition to the ability to salvage portions of the molecular structure, it provides a way to protect/deprotect the molecule. | https://www.wikidoc.org/index.php/Teicoplanin | |
8bae677b5ec66b5937e5be24fe99b96ab6cc1e5c | wikidoc | Telbivudine | Telbivudine
# 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
Telbivudine is an HBV nucleoside analogue reverse transcriptase inhibitor that is FDA approved for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include fatigue, increased creatine kinase (CK), headache, cough, diarrhea, abdominal pain, nausea, pharyngolaryngeal pain, arthralgia, pyrexia, rash, back pain, dizziness, myalgia, ALT increased, dyspepsia, insomnia, and abdominal distension.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Due to higher rates of resistance that may develop with longer term treatment among patients with incomplete viral suppression, treatment should only be initiated, if pre-treatment HBV DNA and ALT measurements are known, in the following patient populations:
- For HBeAg-positive patients, HBV DNA should be less than 9 log10 copies per mL and ALT should be greater than or equal to 2x ULN prior to treatment with Tyzeka.
- For HBeAg-negative patients, HBV DNA should be less than 7 log10 copies per mL prior to treatment with Tyzeka.
- HBV DNA levels should be monitored at 24 weeks of treatment to assure complete viral suppression (HBV DNA less than 300 copies per mL). Alternate therapy should be initiated for patients who have detectable HBV DNA after 24 weeks of treatment. Optimal therapy should be guided by further resistance testing.
- The recommended dose of Tyzeka for the treatment of chronic hepatitis B is 600 mg once daily, taken orally, with or without food.
- Tyzeka oral solution (30 mL) may be considered for patients who have difficulty with swallowing tablets.
- Duration of Therapy
- For patients with incomplete viral suppression (HBV DNA greater than or equal to 300 copies per mL) after 24 weeks of treatment, alternate therapy should be instituted. HBV DNA should be monitored every 6 months to assure continued response. If patients test positive for HBV DNA at any time after their initial response, alternate treatment should be instituted. Optimal therapy should be guided by resistance testing.
- The optimal duration of therapy with Tyzeka for patients with chronic hepatitis B is unknown.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Telbivudine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Telbivudine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Telbivudine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Telbivudine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Telbivudine in pediatric patients.
# Contraindications
- Combination of Tyzeka with pegylated interferon alfa-2a is contraindicated because of increased risk of peripheral neuropathy.
# Warnings
### Precautions
- Lactic Acidosis
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering HBV nucleoside analogue reverse transcriptase inhibitors to patients with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Tyzeka should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
- Exacerbations of Hepatitis B after Discontinuation of Treatment
- Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including Tyzeka. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
- Myopathy
- Cases of myopathy/myositis have been reported with Tyzeka use several weeks to months after starting therapy. Myopathy has also been reported with some other drugs in this class. Rhabdomyolysis has been reported during postmarketing use of Tyzeka.
- Uncomplicated myalgia has been reported in Tyzeka-treated patients. Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness in conjunction with increases in creatine kinase (CK) values, should be considered in any patient with diffuse myalgias, muscle tenderness, or muscle weakness. Among patients with Tyzeka-associated myopathy, no pattern with regard to the degree or timing of CK elevations has been observed. In addition, the predisposing factors for the development of myopathy among Tyzeka recipients are unknown. Patients should be advised to report promptly unexplained muscle aches, pain, tenderness, or weakness. Tyzeka therapy should be interrupted if myopathy is suspected, and discontinued if myopathy is confirmed. It is unknown whether the risk of myopathy during treatment with drugs in this class is increased with concurrent administration of other drugs associated with myopathy, including but not limited to: corticosteroids, chloroquine, hydroxychloroquine, certain HMGCoA reductase inhibitors, fibric acid derivatives, penicillamine, zidovudine, cyclosporine, erythromycin, niacin, and certain azole antifungals. Physicians initiating concomitant treatment with any drug associated with myopathy should monitor patients closely for any signs or symptoms of unexplained muscle pain, tenderness, or weakness.
- Peripheral Neuropathy
- Peripheral neuropathy has been reported with Tyzeka alone or in combination with pegylated interferon alfa-2a and other interferons. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of Tyzeka 600mg daily and pegylated interferon alfa-2a 180 micrograms once weekly compared to Tyzeka or pegylated interferon alfa-2a alone. Such risk cannot be excluded for other dose regimens of pegylated interferon alfa-2a, or other alfa interferons (pegylated or standard). The safety and efficacy of Tyzeka in combination with pegylated interferons or other interferons for the treatment of chronic hepatitis B have not been demonstrated. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Tyzeka therapy should be interrupted if peripheral neuropathy is suspected, and discontinued if peripheral neuropathy is confirmed.
# 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 the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Assessment of adverse reactions is primarily based on two trials (007 GLOBE and NV-02B-015) in which 1,699 subjects with chronic hepatitis B received double-blind treatment with Tyzeka 600 mg per day (n=847 subjects) or lamivudine (n=852 subjects) for 104 weeks. The median duration of therapy was 104 weeks for both treatment groups.
- In the 104 week clinical trials, most adverse experiences reported with Tyzeka were classified as mild or moderate in severity and were not attributed to Tyzeka. Selected adverse events of any severity which were reported in greater than or equal to 3% of Tyzeka and lamivudine recipients are shown in Table 2. With the exception of increased creatine kinase (CK), which was reported more frequently among Tyzeka recipients, the adverse event profile was similar for the two drugs.
- Moderate to severe (Grade 2-4) adverse events were reported in 239/847 (28%) of Tyzeka recipients and 229/852 (27%) of lamivudine recipients. The profile of adverse events of moderate to severe intensity was similar in both treatment groups and no individual adverse event was reported in greater than 2% of subjects in either treatment group.
- Discontinuations due to adverse events were reported in 4% of Tyzeka recipients and 4% of lamivudine recipients. The most common adverse events resulting in Tyzeka discontinuation included increased CK, nausea, diarrhea, fatigue, myalgia, and myopathy.
- Peripheral neuropathy was reported as an adverse event in less than 1% (2/847) of subjects receiving Tyzeka monotherapy. Of Tyzeka-treated subjects less than 1% (5/847) were diagnosed with myopathy/myositis (presenting with muscular weakness).
- Laboratory Abnormalities
- Frequencies of selected treatment-emergent laboratory abnormalities in the 007 GLOBE and NV-02B-015 trials are listed in Table 3.
- Creatine Kinase (CK) Elevations
- Creatine kinase (CK) elevations were more frequent among subjects on Tyzeka treatment. By 104 weeks of treatment, Grade 1-4 CK elevations occurred in 79% of Tyzeka-treated subjects and 47% of lamivudine-treated subjects. Grade 3 or 4 CK elevations occurred in 13% of Tyzeka-treated subjects and 4% of lamivudine-treated subjects. Most CK elevations were asymptomatic, but the mean recovery time was longer for subjects on Tyzeka than subjects on lamivudine.
- Among Tyzeka-treated subjects with Grade 1-4 CK elevations, 10% developed a musculoskeletal adverse event compared to 5% of lamivudine-treated subjects. A total of 2% (13/847) Tyzeka-treated subjects interrupted or discontinued trial drug due to CK elevation or musculoskeletal adverse events1.
- 1 Includes the Preferred Terms: back pain, chest wall pain, non-cardiac chest pain, chest discomfort, flank pain, muscle cramp, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, myofascial pain syndrome, myopathy, myositis, neck pain, and pain in extremity.
- ALT Flares During Treatment
- The incidence of ALT flares, defined as ALT greater than 10 x ULN and greater than 2 x baseline, was similar in the two treatment arms (3%) in the first six months. After week 24, ALT flares were reported less frequently in the Tyzeka arm (2%) compared to the lamivudine arm (5%). Periodic monitoring of hepatic function is recommended during chronic hepatitis B treatment.
- Exacerbations of Hepatitis after Discontinuation of Treatment
- In the subset of subjects who discontinued treatment prematurely for reasons other than efficacy, or who elected not to continue Tyzeka in another clinical trial, 9/154 (6%) Tyzeka-treated and 10/180 (6%) lamivudine-treated subjects experienced an exacerbation of hepatitis (ALT elevation greater than 2 x baseline and greater than 10 x ULN) in the 4-month post-treatment period.
- Results at 208 Weeks
- After 104 weeks of blinded therapy in trials 007 GLOBE and NV-02B-015, 667 subjects received Tyzeka in an open-label extension trial, CLDT600A2303. Of those initially randomized to Tyzeka therapy, 78% of subjects (530/680) from trial 007 GLOBE and 82% (137/167) of subjects from trial NV-02B-015 enrolled into the extension trial and continued Tyzeka treatment for up to 208 weeks. The long-term Tyzeka safety population in trial CLDT600A2303 consisted of 655 subjects, including 518 subjects from trial 007 GLOBE and 137 subjects from trial NV-02B-015.
- The overall safety profile from the pooled analysis up to 104 and 208 weeks was similar. Grade 3/4 CK elevations occurred in 16% of subjects (104/655) treated with Tyzeka in trial CLDT600A2303. Most grade 3/4 CK elevations were asymptomatic (74% of subjects without any muscle related adverse reaction) and transient (98% of episodes lasted one or two visits (visit interval 2 - 12 weeks) and 87% of subjects had one or two episodes). Most grade 3/4 CK elevations (93%) resolved spontaneously or returned to baseline levels. Two cases of myopathy and two cases of myositis were reported in the 655 Tyzeka-treated subjects.
- Among the cohort of 655 subjects continuing Tyzeka for up to 208 weeks in trial CLDT600A2303, including the subgroup of patients (n=223) with mild renal impairment (eGFR 60-90 mL per min) at baseline, mean estimated GFR assessed by MDRD did not decline.
## Postmarketing Experience
- The following adverse reactions have been reported during post approval use of Tyzeka. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
### Musculoskeletal and Connective Tissue Disorders=
Rhabdomyolysis
Paraesthesia, hypoaesthesia
Lactic acidosis
# Drug Interactions
- Tyzeka is excreted mainly by passive diffusion so the potential for interactions between Tyzeka and other drugs eliminated by renal excretion is low. However, because Tyzeka is eliminated primarily by renal excretion, coadministration of Tyzeka with drugs that alter renal function may alter plasma concentrations of Tyzeka.
- A clinical trial investigating the combination of Tyzeka, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of peripheral neuropathy occurrence and severity, in comparison to Tyzeka or pegylated interferon alfa-2a alone.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Telbivudine is not teratogenic and has shown no adverse effects in developing embryos and fetuses in preclinical studies. Studies in pregnant rats and rabbits showed that telbivudine crosses the placenta. Developmental toxicity studies revealed no evidence of harm to the fetus in rats and rabbits at doses up to 1000 mg per kg per day, providing exposure levels 6- and 37-times higher, respectively, than those observed with the 600 mg per day dose in humans.
- There are no adequate and well-controlled trials of Tyzeka in pregnant women. Because animal reproductive toxicity studies are not always predictive of human response, Tyzeka should be used during pregnancy only if potential benefits outweigh the risks.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Telbivudine in women who are pregnant.
### Labor and Delivery
- There are no trials in pregnant women and no data on the effect of Tyzeka on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV infection.
### Nursing Mothers
- Telbivudine is excreted in the milk of rats. It is not known whether Tyzeka is excreted in human milk. Mothers should be instructed not to breast-feed if they are receiving Tyzeka.
### Pediatric Use
- Safety and effectiveness of Tyzeka in pediatric patients have not been established.
### Geriatic Use
- Clinical trials of Tyzeka did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised when prescribing Tyzeka to elderly patients, considering the greater frequency of decreased renal function due to concomitant disease or other drug therapy. Renal function should be monitored in elderly patients, and dosage adjustments should be made accordingly.
### Gender
There is no FDA guidance on the use of Telbivudine with respect to specific gender populations.
### Race
- The safety and efficacy of Tyzeka have not been evaluated in Black/African American or Hispanic patients. It is not known if safety and efficacy can be extrapolated from studied populations.
### Renal Impairment
- Tyzeka is eliminated primarily by renal excretion, therefore dose regimen adjustment is recommended in patients with creatinine clearance less than 50 mL per min, including patients with ESRD requiring hemodialysis.
### Hepatic Impairment
There is no FDA guidance on the use of Telbivudine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Telbivudine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Telbivudine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Telbivudine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Telbivudine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is no information on intentional overdose of Tyzeka, but one subject experienced an unintentional and asymptomatic overdose. Healthy subjects who received Tyzeka doses up to 1800 mg per day for 4 days had no increase in or unexpected adverse events. A maximum tolerated dose for Tyzeka has not been determined. In the event of an overdose, Tyzeka should be discontinued, the patient must be monitored for evidence of toxicity, and appropriate general supportive treatment applied as necessary.
### Management
- In case of overdosage, hemodialysis may be considered. Within 2 hours, following a single 200 mg dose of telbivudine, a 4-hour hemodialysis session removed approximately 23% of the telbivudine dose.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Telbivudine in the drug label.
# Pharmacology
## Mechanism of Action
- Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. It is phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. Telbivudine 5'-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of telbivudine 5'-triphosphate into viral DNA causes DNA chain termination. Telbivudine is an inhibitor of both HBV first strand (EC50 value = 1.3 ± 1.6 micromolar) and second strand synthesis (EC50 value = 0.2 ± 0.2 micromolar). Telbivudine 5'-triphosphate at concentrations up to 100 micromolar did not inhibit human cellular DNA polymerases α, β, or γ. No appreciable mitochondrial toxicity was observed in HepG2 cells treated with telbivudine at concentrations up to 10 micromolar.
## Structure
- Tyzeka is the trade name for telbivudine, a synthetic thymidine nucleoside analogue with activity against hepatitis B virus (HBV). The chemical name for telbivudine is 1-((2S,4R,5S)-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-y1)-5-methyl-1H-pyrimidine-2,4-dione, or 1-(2-deoxy-β-L-ribofuranosyl)-5-methyluracil. Telbivudine is the unmodified β-L enantiomer of the naturally occurring nucleoside, thymidine. Its molecular formula is C10H14N2O5, which corresponds to a molecular weight of 242.23. Telbivudine has the following structural formula:
- Telbivudine is a white to slightly yellowish powder. Telbivudine is sparingly soluble in water (greater than 20 mg per mL), and very slightly soluble in absolute ethanol (0.7 mg per mL) and n-octanol (0.1 mg per mL).
- Tyzeka film-coated tablets are available for oral administration in 600 mg strength. Tyzeka 600 mg film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet coating contains titanium dioxide, polyethylene glycol, talc, and hypromellose.
- Tyzeka oral solution is available for oral administration in 100 mg per 5 mL strength. Tyzeka oral solution contains the following inactive ingredients: citric acid anhydrous, benzoic acid, passion fruit flavor, sodium saccharin, sodium hydroxide, and purified water. A 600 mg dose (30 mL) of Tyzeka oral solution contains approximately 47 mg of sodium.
## Pharmacodynamics
- In a randomized, partially single-blinded, placebo and active-controlled, four-period crossover trial, 53 healthy subjects were administered Tyzeka 600 mg, a supratherapeutic Tyzeka 1800 mg dose, placebo, and moxifloxacin 400 mg. After 7 days of dosing, Tyzeka did not prolong the QT interval. The maximum placebo-adjusted mean (upper 1-side 95% CI) change from baseline in QTcF on day 7 were 3.4 msec (5.9 msec) for the 600 mg and 4.4 msec (6.9 msec) for the 1800 mg dosing regimens.
## Pharmacokinetics
- The single- and multiple-dose pharmacokinetics of Tyzeka were evaluated in healthy subjects and in patients with chronic hepatitis B. Tyzeka pharmacokinetics are similar between both populations.
- Absorption and Bioavailability
- Following oral administration of Tyzeka 600 mg once-daily in healthy subjects (n=12), steady state peak plasma concentration (Cmax) was 3.69 ± 1.25 microgram per mL (mean ± SD) which occurred between 1 and 4 hours (median 2 hours), AUC was 26.1 ± 7.2 microgram - hour per mL (mean ± SD), and trough plasma concentrations (Ctrough) were approximately 0.2-0.3 microgram per mL. Steady state was achieved after approximately 5 to 7 days of once-daily administration with ~1.5-fold accumulation, suggesting an effective half-life of ~15 hours.
- Effects of Food on Oral Absorption
- Tyzeka absorption and exposure were unaffected when a single 600 mg dose was administered with a high-fat (~55 g), high-calorie (~950 kcal) meal. Tyzeka may be taken with or without food.
- Distribution
- n vitro binding of telbivudine to human plasma proteins is low (3.3%). After oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that telbivudine is widely distributed into tissues. Telbivudine was equally partitioned between plasma and blood cells.
- Metabolism and Elimination
- No metabolites of telbivudine were detected following administration of -telbivudine in humans. Telbivudine is not a substrate, or inhibitor of the cytochrome P450 (CYP450) enzyme system.
- After reaching the peak concentration, plasma concentrations of Tyzeka declined in a biexponential manner with a terminal elimination half-life (T1/2) of 40-49 hours. Tyzeka is eliminated primarily by urinary excretion of unchanged drug. The renal clearance of Tyzeka approaches normal glomerular filtration rate suggesting that passive diffusion is the main mechanism of excretion. Approximately 42% of the dose is recovered in the urine over 7 days following a single 600 mg oral dose of Tyzeka. Because renal excretion is the predominant route of elimination, patients with moderate to severe renal dysfunction and those undergoing hemodialysis require a dose regimen adjustment.
- Special Populations
- Gender: There are no significant gender-related differences in Tyzeka pharmacokinetics.
- Race: There are no significant race-related differences in Tyzeka pharmacokinetics.
- Pediatrics and Geriatrics: Pharmacokinetic studies have not been conducted in children or elderly subjects.
- Renal Impairment: Single-dose pharmacokinetics of Tyzeka have been evaluated in subjects (without chronic hepatitis B) with various degrees of renal impairment (as assessed by creatinine clearance). Based on the results shown in Table 4, adjustment of the dose regimen for Tyzeka is recommended in patients with creatinine clearance of less than 50 mL per min.
- Renally Impaired Subjects on Hemodialysis: Hemodialysis (up to 4 hours) reduces systemic Tyzeka exposure by approximately 23%. Following dose regimen adjustment for creatinine clearance, no additional dose modification is necessary during routine hemodialysis. When administered on hemodialysis days, Tyzeka should be administered after hemodialysis.
- Hepatic Impairment: The pharmacokinetics of Tyzeka following a single 600 mg dose have been studied in subjects (without chronic hepatitis B) with various degrees of hepatic impairment. There were no changes in Tyzeka pharmacokinetics in hepatically impaired subjects compared to unimpaired subjects. Results of these studies indicate that no dosage adjustment is necessary for patients with hepatic impairment.
- Drug Interactions
- Drug-drug interaction studies show that lamivudine, adefovir dipivoxil, cyclosporine, pegylated interferon alfa-2a, and tenofovir disoproxil fumarate do not alter Tyzeka pharmacokinetics. In addition, Tyzeka does not alter the pharmacokinetics of lamivudine, adefovir dipivoxil, cyclosporine, or tenofovir disoproxil fumarate. No definitive conclusion could be drawn regarding the effects of Tyzeka on the pharmacokinetics of pegylated interferon alfa-2a due to the high inter-individual variability of pegylated interferon alfa-2a concentrations. At concentrations up to 12 times that in humans, telbivudine did not inhibit in vitro metabolism mediated by any of the following human hepatic microsomal cytochrome P450 (CYP) isoenzymes known to be involved in human medicinal product metabolism: 1A2, 2C9, 2C19, 2D26, 2E1, and 3A4. Based on the above results and the known elimination pathway of telbivudine, the potential for CYP450-mediated interactions involving telbivudine with other medicinal products is low.
## Nonclinical Toxicology
- Telbivudine has shown no carcinogenic potential. Long term oral carcinogenicity studies with telbivudine were negative in mice and rats at exposures up to 14 times those observed in humans at the therapeutic dose of 600 mg per day.
- There was no evidence of genotoxicity based on in vitro or in vivo tests. Telbivudine was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains with or without metabolic activation. Telbivudine was not clastogenic in mammalian-cell gene mutation assays, including human lymphocyte cultures and an assay with Chinese hamster ovary cells with or without metabolic activation. Furthermore, telbivudine showed no effect in an in vivo micronucleus study in mice.
- Effects on fertility were studied in rats administered telbivudine as juveniles or adults. Juvenile rats were treated with telbivudine at doses of 0, 250, 1000, and 2000 mg per kg per day from post natal days 14 to 70. These rats were mated following a 5 week drug-free recovery period. Up to 50% reduction of fertility was associated with doses 1000 mg per kg per day and higher, which was equivalent to a systemic exposure approximately 7.5 times that achieved in humans at the therapeutic dose. The no observed adverse effect level (NOAEL) for effects on fertility or mating parameters was 250 mg per kg per day, which was equivalent to systemic exposure levels 2.5 to 2.8 times that achieved in humans at the therapeutic dose. In contrast, such reduction of fertility was absent in adult rats treated with telbivudine at doses up to 2000 mg per kg per day, equivalent to a systemic exposure approximately 14 times that achieved in humans at the therapeutic dose.
# Clinical Studies
- The safety and efficacy of long-term (104-week) Tyzeka treatment were evaluated in one active-controlled, clinical trial (NV-02B-007 GLOBE Trial) that included 1,367 subjects with chronic hepatitis B and a smaller supportive trial (NV-02B-015) that included 332 subjects. Subjects were 16 years of age or older, with chronic hepatitis B, evidence of HBV infection with viral replication (HBsAg-positive, HBeAg-positive or HBeAg-negative, HBV DNA detectable by a PCR assay), and elevated ALT levels greater than or equal to 1.3 x ULN, no evidence of hepatic decompensation, and chronic inflammation on liver biopsy compatible with chronic viral hepatitis.
- NV-02B-007 GLOBE Trial
- The Week 52 and Week 104 results of the 007 GLOBE trial are summarized below.
- The 007 GLOBE trial was a Phase III, randomized, double-blind, multinational trial of Tyzeka 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 1,367 (n= 680 Tyzeka; n=687 lamivudine) nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative subjects. The primary data analysis was conducted after all subjects had reached Week 52.
- HBeAg-positive Subjects: (n= 458 Tyzeka; n= 463 lamivudine) The mean age of subjects was 32 years, 74% were male, 82% were Asian, 12% were Caucasian, and 6% had previously received alfa-interferon therapy. At baseline, subjects had a mean Knodell Necroinflammatory Score greater than or equal to 7; mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 9.52 log10 copies per mL; and mean serum ALT was 153 IU per L. Pre- and post-liver biopsy samples were adequate for 86% of subjects.
- HBeAg-negative Subjects: (n=222 Tyzeka; n= 224 lamivudine)The mean age of subjects was 43 years, 77% were male, 65% were Asian, 23% were Caucasian, and 11% had previously received alfa-interferon therapy. At baseline, subjects had a mean Knodell Necroinflammatory Score greater than or equal to 7; mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 7.54 log10 copies per mL; and mean serum ALT was 140 IU per L. Pre- and post-liver biopsy samples were adequate for 92% of subjects.
- Clinical Results
- Clinical and virologic efficacy endpoints were evaluated separately in the HBeAg-positive and HBeAg-negative subject populations.
- The primary endpoint of Therapeutic Response at Week 52 was a composite endpoint requiring suppression of HBV DNA to less than 5 log10 copies per mL in conjunction with either loss of serum HBeAg or ALT normalization. Key secondary endpoints included histologic response, ALT normalization, and measures of virologic response.
- At Week 52, in HBeAg-positive subjects, 75% of Tyzeka subjects and 67% of lamivudine subjects had a Therapeutic Response; in HBeAg-negative subjects, 75% of Tyzeka subjects and 77% of lamivudine subjects had a Therapeutic Response.
- Analysis of the histological response at Week 52 is shown in Table 6.
- Subjects were eligible to continue blinded treatment to Week 104. In the ITT population, 624/680 (92%) Tyzeka recipients and 599/687 (87%) lamivudine recipients completed trial treatment to Week 104. At Week 104, in HBeAg-positive subjects, 63% of Tyzeka subjects and 48% of lamivudine subjects had a Therapeutic Response, while in HBeAg-negative subjects 78% of Tyzeka subjects and 66% of lamivudine subjects had a Therapeutic Response.
- Selected virologic, biochemical, and serologic outcome measures at Weeks 52 and 104 are shown in Table 7.
- Subjects who achieved non-detectable HBV DNA levels at 24 weeks were more likely to undergo e-antigen seroconversion, achieve undetectable levels of HBV DNA, normalize ALT, and were less likely to develop resistance at one and two years.
- NV-02B-015 Trial
- The efficacy results of the 007 GLOBE trial were supported by results of trial NV-02B-015. This was a Phase III, randomized, double-blind, trial of Tyzeka 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 332 (n=167 Tyzeka; n=165 lamivudine) nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative Chinese subjects. The primary efficacy endpoint was serum HBV DNA reduction from baseline. In this trial, the composite endpoint Therapeutic Response was a key secondary endpoint. Histological response was not assessed as an outcome measure in this trial.
- Clinical Results
- Among HBeAg-positive subjects (n=147 Tyzeka; n=143 lamivudine) results for key endpoints at Week 104 included Therapeutic Response (66% vs. 41%), mean HBV DNA reduction (-5.47 vs. -3.97 log10 copies per mL), HBV DNA PCR negativity (58% vs. 34%), ALT normalization (73% vs. 59%), HBeAg loss (40% vs. 28%) and HBeAg seroconversion (29% vs. 20%), for Tyzeka and lamivudine, respectively. Because the number of HBeAg-negative subjects in this trial was small (n=42), definitive conclusions could not be drawn regarding efficacy outcomes in this subpopulation.
# How Supplied
- Tablets
- Tyzeka 600 mg tablets are white to slightly yellowish film-coated, ovaloid-shaped tablets, imprinted with “LDT” on one side.
- tle of 30 tablets (NDC 0078-0538-15) with child-resistant closure.
- Store Tyzeka tablets in original container at 25ºC (77ºF), excursions permitted to 15-30ºC (59-86ºF).
- Oral Solution
- Tyzeka (telbivudine) oral solution is a clear, colorless to pale yellow, passion fruit flavored liquid. Tyzeka oral solution contains 100 mg of telbivudine per 5 milliliters.
- Bottle containing 300 mL oral solution (NDC 0078-0539-85) with child-resistant closure and embossed dosing cup. The dosing cup is intended for measurement of Tyzeka oral solution only.
- Store Tyzeka oral solution in original container at 25ºC (77ºF), excursions permitted to 15-30ºC (59-86ºF). Use within two months after opening the bottle. Do not freeze.
- For all medical inquiries call: 1-877-8-Tyzeka (1-877-889-9352).
- Keep this and all drugs out of the reach of children.
## Storage
There is limited information regarding Telbivudine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should remain under the care of a physician while taking Tyzeka. They should discuss any new symptoms or concurrent medications with their physician.
- Patients should be advised to report promptly unexplained muscle weakness, tenderness, or pain.
- Patients should be advised to report promptly any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without difficulty walking.
- Patients should be advised that Tyzeka is not a cure for hepatitis B, that the long-term treatment benefits of Tyzeka are unknown at this time. In particular, the relationship of initial treatment response to outcomes such as hepatocellular carcinoma and decompensated cirrhosis is unknown.
- Patients should be informed that deterioration of liver disease may occur in some cases if treatment is discontinued, and that they should discuss any change in regimen with their physician.
- Patients should be advised that treatment with Tyzeka has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination. HBV prevention strategies should be discussed with patients, including safe sexual practices, and avoidance of needle sharing or sharing any personal items which may contain residual blood or body fluids, such as razor blades or toothbrushes. Additionally, a vaccine is available for prevention of hepatitis B infection in susceptible individuals.
- Patients on a low sodium diet should be advised that Tyzeka oral solution contains approximately 47 mg of sodium per 600 mg dose (30 mL).
- Patients should be advised to dispose of unused or expired Tyzeka by using a community pharmaceutical take-back disposal program, or by placing unused Tyzeka in a closed container, such as a sealed bag, into household trash. All identifying information should be removed from the original Tyzeka container prior to disposal.
# Precautions with Alcohol
- Alcohol-Telbivudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TYZEKA®
# Look-Alike Drug Names
There is limited information regarding Telbivudine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Telbivudine
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.
# Black Box Warning
# Overview
Telbivudine is an HBV nucleoside analogue reverse transcriptase inhibitor that is FDA approved for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include fatigue, increased creatine kinase (CK), headache, cough, diarrhea, abdominal pain, nausea, pharyngolaryngeal pain, arthralgia, pyrexia, rash, back pain, dizziness, myalgia, ALT increased, dyspepsia, insomnia, and abdominal distension.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Due to higher rates of resistance that may develop with longer term treatment among patients with incomplete viral suppression, treatment should only be initiated, if pre-treatment HBV DNA and ALT measurements are known, in the following patient populations:
- For HBeAg-positive patients, HBV DNA should be less than 9 log10 copies per mL and ALT should be greater than or equal to 2x ULN prior to treatment with Tyzeka.
- For HBeAg-negative patients, HBV DNA should be less than 7 log10 copies per mL prior to treatment with Tyzeka.
- HBV DNA levels should be monitored at 24 weeks of treatment to assure complete viral suppression (HBV DNA less than 300 copies per mL). Alternate therapy should be initiated for patients who have detectable HBV DNA after 24 weeks of treatment. Optimal therapy should be guided by further resistance testing.
- The recommended dose of Tyzeka for the treatment of chronic hepatitis B is 600 mg once daily, taken orally, with or without food.
- Tyzeka oral solution (30 mL) may be considered for patients who have difficulty with swallowing tablets.
- Duration of Therapy
- For patients with incomplete viral suppression (HBV DNA greater than or equal to 300 copies per mL) after 24 weeks of treatment, alternate therapy should be instituted. HBV DNA should be monitored every 6 months to assure continued response. If patients test positive for HBV DNA at any time after their initial response, alternate treatment should be instituted. Optimal therapy should be guided by resistance testing.
- The optimal duration of therapy with Tyzeka for patients with chronic hepatitis B is unknown.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Telbivudine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Telbivudine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Telbivudine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Telbivudine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Telbivudine in pediatric patients.
# Contraindications
- Combination of Tyzeka with pegylated interferon alfa-2a is contraindicated because of increased risk of peripheral neuropathy.
# Warnings
### Precautions
- Lactic Acidosis
- Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. Female gender, obesity, and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering HBV nucleoside analogue reverse transcriptase inhibitors to patients with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with Tyzeka should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
- Exacerbations of Hepatitis B after Discontinuation of Treatment
- Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including Tyzeka. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
- Myopathy
- Cases of myopathy/myositis have been reported with Tyzeka use several weeks to months after starting therapy. Myopathy has also been reported with some other drugs in this class. Rhabdomyolysis has been reported during postmarketing use of Tyzeka.
- Uncomplicated myalgia has been reported in Tyzeka-treated patients. Myopathy, defined as persistent unexplained muscle aches and/or muscle weakness in conjunction with increases in creatine kinase (CK) values, should be considered in any patient with diffuse myalgias, muscle tenderness, or muscle weakness. Among patients with Tyzeka-associated myopathy, no pattern with regard to the degree or timing of CK elevations has been observed. In addition, the predisposing factors for the development of myopathy among Tyzeka recipients are unknown. Patients should be advised to report promptly unexplained muscle aches, pain, tenderness, or weakness. Tyzeka therapy should be interrupted if myopathy is suspected, and discontinued if myopathy is confirmed. It is unknown whether the risk of myopathy during treatment with drugs in this class is increased with concurrent administration of other drugs associated with myopathy, including but not limited to: corticosteroids, chloroquine, hydroxychloroquine, certain HMGCoA reductase inhibitors, fibric acid derivatives, penicillamine, zidovudine, cyclosporine, erythromycin, niacin, and certain azole antifungals. Physicians initiating concomitant treatment with any drug associated with myopathy should monitor patients closely for any signs or symptoms of unexplained muscle pain, tenderness, or weakness.
- Peripheral Neuropathy
- Peripheral neuropathy has been reported with Tyzeka alone or in combination with pegylated interferon alfa-2a and other interferons. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of Tyzeka 600mg daily and pegylated interferon alfa-2a 180 micrograms once weekly compared to Tyzeka or pegylated interferon alfa-2a alone. Such risk cannot be excluded for other dose regimens of pegylated interferon alfa-2a, or other alfa interferons (pegylated or standard). The safety and efficacy of Tyzeka in combination with pegylated interferons or other interferons for the treatment of chronic hepatitis B have not been demonstrated. Patients should be advised to report any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without gait disturbance. Tyzeka therapy should be interrupted if peripheral neuropathy is suspected, and discontinued if peripheral neuropathy is confirmed.
# 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 the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
- Assessment of adverse reactions is primarily based on two trials (007 GLOBE and NV-02B-015) in which 1,699 subjects with chronic hepatitis B received double-blind treatment with Tyzeka 600 mg per day (n=847 subjects) or lamivudine (n=852 subjects) for 104 weeks. The median duration of therapy was 104 weeks for both treatment groups.
- In the 104 week clinical trials, most adverse experiences reported with Tyzeka were classified as mild or moderate in severity and were not attributed to Tyzeka. Selected adverse events of any severity which were reported in greater than or equal to 3% of Tyzeka and lamivudine recipients are shown in Table 2. With the exception of increased creatine kinase (CK), which was reported more frequently among Tyzeka recipients, the adverse event profile was similar for the two drugs.
- Moderate to severe (Grade 2-4) adverse events were reported in 239/847 (28%) of Tyzeka recipients and 229/852 (27%) of lamivudine recipients. The profile of adverse events of moderate to severe intensity was similar in both treatment groups and no individual adverse event was reported in greater than 2% of subjects in either treatment group.
- Discontinuations due to adverse events were reported in 4% of Tyzeka recipients and 4% of lamivudine recipients. The most common adverse events resulting in Tyzeka discontinuation included increased CK, nausea, diarrhea, fatigue, myalgia, and myopathy.
- Peripheral neuropathy was reported as an adverse event in less than 1% (2/847) of subjects receiving Tyzeka monotherapy. Of Tyzeka-treated subjects less than 1% (5/847) were diagnosed with myopathy/myositis (presenting with muscular weakness).
- Laboratory Abnormalities
- Frequencies of selected treatment-emergent laboratory abnormalities in the 007 GLOBE and NV-02B-015 trials are listed in Table 3.
- Creatine Kinase (CK) Elevations
- Creatine kinase (CK) elevations were more frequent among subjects on Tyzeka treatment. By 104 weeks of treatment, Grade 1-4 CK elevations occurred in 79% of Tyzeka-treated subjects and 47% of lamivudine-treated subjects. Grade 3 or 4 CK elevations occurred in 13% of Tyzeka-treated subjects and 4% of lamivudine-treated subjects. Most CK elevations were asymptomatic, but the mean recovery time was longer for subjects on Tyzeka than subjects on lamivudine.
- Among Tyzeka-treated subjects with Grade 1-4 CK elevations, 10% developed a musculoskeletal adverse event compared to 5% of lamivudine-treated subjects. A total of 2% (13/847) Tyzeka-treated subjects interrupted or discontinued trial drug due to CK elevation or musculoskeletal adverse events1.
- 1 Includes the Preferred Terms: back pain, chest wall pain, non-cardiac chest pain, chest discomfort, flank pain, muscle cramp, muscular weakness, musculoskeletal pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal stiffness, myalgia, myofascial pain syndrome, myopathy, myositis, neck pain, and pain in extremity.
- ALT Flares During Treatment
- The incidence of ALT flares, defined as ALT greater than 10 x ULN and greater than 2 x baseline, was similar in the two treatment arms (3%) in the first six months. After week 24, ALT flares were reported less frequently in the Tyzeka arm (2%) compared to the lamivudine arm (5%). Periodic monitoring of hepatic function is recommended during chronic hepatitis B treatment.
- Exacerbations of Hepatitis after Discontinuation of Treatment
- In the subset of subjects who discontinued treatment prematurely for reasons other than efficacy, or who elected not to continue Tyzeka in another clinical trial, 9/154 (6%) Tyzeka-treated and 10/180 (6%) lamivudine-treated subjects experienced an exacerbation of hepatitis (ALT elevation greater than 2 x baseline and greater than 10 x ULN) in the 4-month post-treatment period.
- Results at 208 Weeks
- After 104 weeks of blinded therapy in trials 007 GLOBE and NV-02B-015, 667 subjects received Tyzeka in an open-label extension trial, CLDT600A2303. Of those initially randomized to Tyzeka therapy, 78% of subjects (530/680) from trial 007 GLOBE and 82% (137/167) of subjects from trial NV-02B-015 enrolled into the extension trial and continued Tyzeka treatment for up to 208 weeks. The long-term Tyzeka safety population in trial CLDT600A2303 consisted of 655 subjects, including 518 subjects from trial 007 GLOBE and 137 subjects from trial NV-02B-015.
- The overall safety profile from the pooled analysis up to 104 and 208 weeks was similar. Grade 3/4 CK elevations occurred in 16% of subjects (104/655) treated with Tyzeka in trial CLDT600A2303. Most grade 3/4 CK elevations were asymptomatic (74% of subjects without any muscle related adverse reaction) and transient (98% of episodes lasted one or two visits (visit interval 2 - 12 weeks) and 87% of subjects had one or two episodes). Most grade 3/4 CK elevations (93%) resolved spontaneously or returned to baseline levels. Two cases of myopathy and two cases of myositis were reported in the 655 Tyzeka-treated subjects.
- Among the cohort of 655 subjects continuing Tyzeka for up to 208 weeks in trial CLDT600A2303, including the subgroup of patients (n=223) with mild renal impairment (eGFR 60-90 mL per min) at baseline, mean estimated GFR assessed by MDRD did not decline.
## Postmarketing Experience
- The following adverse reactions have been reported during post approval use of Tyzeka. Because these reactions were reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
### Musculoskeletal and Connective Tissue Disorders=
Rhabdomyolysis
Paraesthesia, hypoaesthesia
Lactic acidosis
# Drug Interactions
- Tyzeka is excreted mainly by passive diffusion so the potential for interactions between Tyzeka and other drugs eliminated by renal excretion is low. However, because Tyzeka is eliminated primarily by renal excretion, coadministration of Tyzeka with drugs that alter renal function may alter plasma concentrations of Tyzeka.
- A clinical trial investigating the combination of Tyzeka, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of peripheral neuropathy occurrence and severity, in comparison to Tyzeka or pegylated interferon alfa-2a alone.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- Telbivudine is not teratogenic and has shown no adverse effects in developing embryos and fetuses in preclinical studies. Studies in pregnant rats and rabbits showed that telbivudine crosses the placenta. Developmental toxicity studies revealed no evidence of harm to the fetus in rats and rabbits at doses up to 1000 mg per kg per day, providing exposure levels 6- and 37-times higher, respectively, than those observed with the 600 mg per day dose in humans.
- There are no adequate and well-controlled trials of Tyzeka in pregnant women. Because animal reproductive toxicity studies are not always predictive of human response, Tyzeka should be used during pregnancy only if potential benefits outweigh the risks.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Telbivudine in women who are pregnant.
### Labor and Delivery
- There are no trials in pregnant women and no data on the effect of Tyzeka on transmission of HBV from mother to infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV infection.
### Nursing Mothers
- Telbivudine is excreted in the milk of rats. It is not known whether Tyzeka is excreted in human milk. Mothers should be instructed not to breast-feed if they are receiving Tyzeka.
### Pediatric Use
- Safety and effectiveness of Tyzeka in pediatric patients have not been established.
### Geriatic Use
- Clinical trials of Tyzeka did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised when prescribing Tyzeka to elderly patients, considering the greater frequency of decreased renal function due to concomitant disease or other drug therapy. Renal function should be monitored in elderly patients, and dosage adjustments should be made accordingly.
### Gender
There is no FDA guidance on the use of Telbivudine with respect to specific gender populations.
### Race
- The safety and efficacy of Tyzeka have not been evaluated in Black/African American or Hispanic patients. It is not known if safety and efficacy can be extrapolated from studied populations.
### Renal Impairment
- Tyzeka is eliminated primarily by renal excretion, therefore dose regimen adjustment is recommended in patients with creatinine clearance less than 50 mL per min, including patients with ESRD requiring hemodialysis.
### Hepatic Impairment
There is no FDA guidance on the use of Telbivudine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Telbivudine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Telbivudine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Telbivudine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Telbivudine in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There is no information on intentional overdose of Tyzeka, but one subject experienced an unintentional and asymptomatic overdose. Healthy subjects who received Tyzeka doses up to 1800 mg per day for 4 days had no increase in or unexpected adverse events. A maximum tolerated dose for Tyzeka has not been determined. In the event of an overdose, Tyzeka should be discontinued, the patient must be monitored for evidence of toxicity, and appropriate general supportive treatment applied as necessary.
### Management
- In case of overdosage, hemodialysis may be considered. Within 2 hours, following a single 200 mg dose of telbivudine, a 4-hour hemodialysis session removed approximately 23% of the telbivudine dose.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Telbivudine in the drug label.
# Pharmacology
## Mechanism of Action
- Telbivudine is a synthetic thymidine nucleoside analogue with activity against HBV DNA polymerase. It is phosphorylated by cellular kinases to the active triphosphate form, which has an intracellular half-life of 14 hours. Telbivudine 5'-triphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate, thymidine 5'-triphosphate. Incorporation of telbivudine 5'-triphosphate into viral DNA causes DNA chain termination. Telbivudine is an inhibitor of both HBV first strand (EC50 value = 1.3 ± 1.6 micromolar) and second strand synthesis (EC50 value = 0.2 ± 0.2 micromolar). Telbivudine 5'-triphosphate at concentrations up to 100 micromolar did not inhibit human cellular DNA polymerases α, β, or γ. No appreciable mitochondrial toxicity was observed in HepG2 cells treated with telbivudine at concentrations up to 10 micromolar.
## Structure
- Tyzeka is the trade name for telbivudine, a synthetic thymidine nucleoside analogue with activity against hepatitis B virus (HBV). The chemical name for telbivudine is 1-((2S,4R,5S)-4-hydroxy-5-hydroxymethyltetrahydrofuran-2-y1)-5-methyl-1H-pyrimidine-2,4-dione, or 1-(2-deoxy-β-L-ribofuranosyl)-5-methyluracil. Telbivudine is the unmodified β-L enantiomer of the naturally occurring nucleoside, thymidine. Its molecular formula is C10H14N2O5, which corresponds to a molecular weight of 242.23. Telbivudine has the following structural formula:
- Telbivudine is a white to slightly yellowish powder. Telbivudine is sparingly soluble in water (greater than 20 mg per mL), and very slightly soluble in absolute ethanol (0.7 mg per mL) and n-octanol (0.1 mg per mL).
- Tyzeka film-coated tablets are available for oral administration in 600 mg strength. Tyzeka 600 mg film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet coating contains titanium dioxide, polyethylene glycol, talc, and hypromellose.
- Tyzeka oral solution is available for oral administration in 100 mg per 5 mL strength. Tyzeka oral solution contains the following inactive ingredients: citric acid anhydrous, benzoic acid, passion fruit flavor, sodium saccharin, sodium hydroxide, and purified water. A 600 mg dose (30 mL) of Tyzeka oral solution contains approximately 47 mg of sodium.
## Pharmacodynamics
- In a randomized, partially single-blinded, placebo and active-controlled, four-period crossover trial, 53 healthy subjects were administered Tyzeka 600 mg, a supratherapeutic Tyzeka 1800 mg dose, placebo, and moxifloxacin 400 mg. After 7 days of dosing, Tyzeka did not prolong the QT interval. The maximum placebo-adjusted mean (upper 1-side 95% CI) change from baseline in QTcF on day 7 were 3.4 msec (5.9 msec) for the 600 mg and 4.4 msec (6.9 msec) for the 1800 mg dosing regimens.
## Pharmacokinetics
- The single- and multiple-dose pharmacokinetics of Tyzeka were evaluated in healthy subjects and in patients with chronic hepatitis B. Tyzeka pharmacokinetics are similar between both populations.
- Absorption and Bioavailability
- Following oral administration of Tyzeka 600 mg once-daily in healthy subjects (n=12), steady state peak plasma concentration (Cmax) was 3.69 ± 1.25 microgram per mL (mean ± SD) which occurred between 1 and 4 hours (median 2 hours), AUC was 26.1 ± 7.2 microgram * hour per mL (mean ± SD), and trough plasma concentrations (Ctrough) were approximately 0.2-0.3 microgram per mL. Steady state was achieved after approximately 5 to 7 days of once-daily administration with ~1.5-fold accumulation, suggesting an effective half-life of ~15 hours.
- Effects of Food on Oral Absorption
- Tyzeka absorption and exposure were unaffected when a single 600 mg dose was administered with a high-fat (~55 g), high-calorie (~950 kcal) meal. Tyzeka may be taken with or without food.
- Distribution
- n vitro binding of telbivudine to human plasma proteins is low (3.3%). After oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that telbivudine is widely distributed into tissues. Telbivudine was equally partitioned between plasma and blood cells.
- Metabolism and Elimination
- No metabolites of telbivudine were detected following administration of [14C]-telbivudine in humans. Telbivudine is not a substrate, or inhibitor of the cytochrome P450 (CYP450) enzyme system.
- After reaching the peak concentration, plasma concentrations of Tyzeka declined in a biexponential manner with a terminal elimination half-life (T1/2) of 40-49 hours. Tyzeka is eliminated primarily by urinary excretion of unchanged drug. The renal clearance of Tyzeka approaches normal glomerular filtration rate suggesting that passive diffusion is the main mechanism of excretion. Approximately 42% of the dose is recovered in the urine over 7 days following a single 600 mg oral dose of Tyzeka. Because renal excretion is the predominant route of elimination, patients with moderate to severe renal dysfunction and those undergoing hemodialysis require a dose regimen adjustment.
- Special Populations
- Gender: There are no significant gender-related differences in Tyzeka pharmacokinetics.
- Race: There are no significant race-related differences in Tyzeka pharmacokinetics.
- Pediatrics and Geriatrics: Pharmacokinetic studies have not been conducted in children or elderly subjects.
- Renal Impairment: Single-dose pharmacokinetics of Tyzeka have been evaluated in subjects (without chronic hepatitis B) with various degrees of renal impairment (as assessed by creatinine clearance). Based on the results shown in Table 4, adjustment of the dose regimen for Tyzeka is recommended in patients with creatinine clearance of less than 50 mL per min.
- Renally Impaired Subjects on Hemodialysis: Hemodialysis (up to 4 hours) reduces systemic Tyzeka exposure by approximately 23%. Following dose regimen adjustment for creatinine clearance, no additional dose modification is necessary during routine hemodialysis. When administered on hemodialysis days, Tyzeka should be administered after hemodialysis.
- Hepatic Impairment: The pharmacokinetics of Tyzeka following a single 600 mg dose have been studied in subjects (without chronic hepatitis B) with various degrees of hepatic impairment. There were no changes in Tyzeka pharmacokinetics in hepatically impaired subjects compared to unimpaired subjects. Results of these studies indicate that no dosage adjustment is necessary for patients with hepatic impairment.
- Drug Interactions
- Drug-drug interaction studies show that lamivudine, adefovir dipivoxil, cyclosporine, pegylated interferon alfa-2a, and tenofovir disoproxil fumarate do not alter Tyzeka pharmacokinetics. In addition, Tyzeka does not alter the pharmacokinetics of lamivudine, adefovir dipivoxil, cyclosporine, or tenofovir disoproxil fumarate. No definitive conclusion could be drawn regarding the effects of Tyzeka on the pharmacokinetics of pegylated interferon alfa-2a due to the high inter-individual variability of pegylated interferon alfa-2a concentrations. At concentrations up to 12 times that in humans, telbivudine did not inhibit in vitro metabolism mediated by any of the following human hepatic microsomal cytochrome P450 (CYP) isoenzymes known to be involved in human medicinal product metabolism: 1A2, 2C9, 2C19, 2D26, 2E1, and 3A4. Based on the above results and the known elimination pathway of telbivudine, the potential for CYP450-mediated interactions involving telbivudine with other medicinal products is low.
## Nonclinical Toxicology
- Telbivudine has shown no carcinogenic potential. Long term oral carcinogenicity studies with telbivudine were negative in mice and rats at exposures up to 14 times those observed in humans at the therapeutic dose of 600 mg per day.
- There was no evidence of genotoxicity based on in vitro or in vivo tests. Telbivudine was not mutagenic in the Ames bacterial reverse mutation assay using S. typhimurium and E. coli strains with or without metabolic activation. Telbivudine was not clastogenic in mammalian-cell gene mutation assays, including human lymphocyte cultures and an assay with Chinese hamster ovary cells with or without metabolic activation. Furthermore, telbivudine showed no effect in an in vivo micronucleus study in mice.
- Effects on fertility were studied in rats administered telbivudine as juveniles or adults. Juvenile rats were treated with telbivudine at doses of 0, 250, 1000, and 2000 mg per kg per day from post natal days 14 to 70. These rats were mated following a 5 week drug-free recovery period. Up to 50% reduction of fertility was associated with doses 1000 mg per kg per day and higher, which was equivalent to a systemic exposure approximately 7.5 times that achieved in humans at the therapeutic dose. The no observed adverse effect level (NOAEL) for effects on fertility or mating parameters was 250 mg per kg per day, which was equivalent to systemic exposure levels 2.5 to 2.8 times that achieved in humans at the therapeutic dose. In contrast, such reduction of fertility was absent in adult rats treated with telbivudine at doses up to 2000 mg per kg per day, equivalent to a systemic exposure approximately 14 times that achieved in humans at the therapeutic dose.
# Clinical Studies
- The safety and efficacy of long-term (104-week) Tyzeka treatment were evaluated in one active-controlled, clinical trial (NV-02B-007 GLOBE Trial) that included 1,367 subjects with chronic hepatitis B and a smaller supportive trial (NV-02B-015) that included 332 subjects. Subjects were 16 years of age or older, with chronic hepatitis B, evidence of HBV infection with viral replication (HBsAg-positive, HBeAg-positive or HBeAg-negative, HBV DNA detectable by a PCR assay), and elevated ALT levels greater than or equal to 1.3 x ULN, no evidence of hepatic decompensation, and chronic inflammation on liver biopsy compatible with chronic viral hepatitis.
- NV-02B-007 GLOBE Trial
- The Week 52 and Week 104 results of the 007 GLOBE trial are summarized below.
- The 007 GLOBE trial was a Phase III, randomized, double-blind, multinational trial of Tyzeka 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 1,367 (n= 680 Tyzeka; n=687 lamivudine) nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative subjects. The primary data analysis was conducted after all subjects had reached Week 52.
- HBeAg-positive Subjects: (n= 458 Tyzeka; n= 463 lamivudine) The mean age of subjects was 32 years, 74% were male, 82% were Asian, 12% were Caucasian, and 6% had previously received alfa-interferon therapy. At baseline, subjects had a mean Knodell Necroinflammatory Score greater than or equal to 7; mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 9.52 log10 copies per mL; and mean serum ALT was 153 IU per L. Pre- and post-liver biopsy samples were adequate for 86% of subjects.
- HBeAg-negative Subjects: (n=222 Tyzeka; n= 224 lamivudine)The mean age of subjects was 43 years, 77% were male, 65% were Asian, 23% were Caucasian, and 11% had previously received alfa-interferon therapy. At baseline, subjects had a mean Knodell Necroinflammatory Score greater than or equal to 7; mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 7.54 log10 copies per mL; and mean serum ALT was 140 IU per L. Pre- and post-liver biopsy samples were adequate for 92% of subjects.
- Clinical Results
- Clinical and virologic efficacy endpoints were evaluated separately in the HBeAg-positive and HBeAg-negative subject populations.
- The primary endpoint of Therapeutic Response at Week 52 was a composite endpoint requiring suppression of HBV DNA to less than 5 log10 copies per mL in conjunction with either loss of serum HBeAg or ALT normalization. Key secondary endpoints included histologic response, ALT normalization, and measures of virologic response.
- At Week 52, in HBeAg-positive subjects, 75% of Tyzeka subjects and 67% of lamivudine subjects had a Therapeutic Response; in HBeAg-negative subjects, 75% of Tyzeka subjects and 77% of lamivudine subjects had a Therapeutic Response.
- Analysis of the histological response at Week 52 is shown in Table 6.
- Subjects were eligible to continue blinded treatment to Week 104. In the ITT population, 624/680 (92%) Tyzeka recipients and 599/687 (87%) lamivudine recipients completed trial treatment to Week 104. At Week 104, in HBeAg-positive subjects, 63% of Tyzeka subjects and 48% of lamivudine subjects had a Therapeutic Response, while in HBeAg-negative subjects 78% of Tyzeka subjects and 66% of lamivudine subjects had a Therapeutic Response.
- Selected virologic, biochemical, and serologic outcome measures at Weeks 52 and 104 are shown in Table 7.
- Subjects who achieved non-detectable HBV DNA levels at 24 weeks were more likely to undergo e-antigen seroconversion, achieve undetectable levels of HBV DNA, normalize ALT, and were less likely to develop resistance at one and two years.
- NV-02B-015 Trial
- The efficacy results of the 007 GLOBE trial were supported by results of trial NV-02B-015. This was a Phase III, randomized, double-blind, trial of Tyzeka 600 mg once daily compared to lamivudine 100 mg once daily for a treatment period of 104 weeks in 332 (n=167 Tyzeka; n=165 lamivudine) nucleoside-naïve chronic hepatitis B HBeAg-positive and HBeAg-negative Chinese subjects. The primary efficacy endpoint was serum HBV DNA reduction from baseline. In this trial, the composite endpoint Therapeutic Response was a key secondary endpoint. Histological response was not assessed as an outcome measure in this trial.
- Clinical Results
- Among HBeAg-positive subjects (n=147 Tyzeka; n=143 lamivudine) results for key endpoints at Week 104 included Therapeutic Response (66% vs. 41%), mean HBV DNA reduction (-5.47 vs. -3.97 log10 copies per mL), HBV DNA PCR negativity (58% vs. 34%), ALT normalization (73% vs. 59%), HBeAg loss (40% vs. 28%) and HBeAg seroconversion (29% vs. 20%), for Tyzeka and lamivudine, respectively. Because the number of HBeAg-negative subjects in this trial was small (n=42), definitive conclusions could not be drawn regarding efficacy outcomes in this subpopulation.
# How Supplied
- Tablets
- Tyzeka 600 mg tablets are white to slightly yellowish film-coated, ovaloid-shaped tablets, imprinted with “LDT” on one side.
- tle of 30 tablets (NDC 0078-0538-15) with child-resistant closure.
- Store Tyzeka tablets in original container at 25ºC (77ºF), excursions permitted to 15-30ºC (59-86ºF).
- Oral Solution
- Tyzeka (telbivudine) oral solution is a clear, colorless to pale yellow, passion fruit flavored liquid. Tyzeka oral solution contains 100 mg of telbivudine per 5 milliliters.
- Bottle containing 300 mL oral solution (NDC 0078-0539-85) with child-resistant closure and embossed dosing cup. The dosing cup is intended for measurement of Tyzeka oral solution only.
- Store Tyzeka oral solution in original container at 25ºC (77ºF), excursions permitted to 15-30ºC (59-86ºF). Use within two months after opening the bottle. Do not freeze.
- For all medical inquiries call: 1-877-8-Tyzeka (1-877-889-9352).
- Keep this and all drugs out of the reach of children.
## Storage
There is limited information regarding Telbivudine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should remain under the care of a physician while taking Tyzeka. They should discuss any new symptoms or concurrent medications with their physician.
- Patients should be advised to report promptly unexplained muscle weakness, tenderness, or pain.
- Patients should be advised to report promptly any numbness, tingling, and/or burning sensations in the arms and/or legs, with or without difficulty walking.
- Patients should be advised that Tyzeka is not a cure for hepatitis B, that the long-term treatment benefits of Tyzeka are unknown at this time. In particular, the relationship of initial treatment response to outcomes such as hepatocellular carcinoma and decompensated cirrhosis is unknown.
- Patients should be informed that deterioration of liver disease may occur in some cases if treatment is discontinued, and that they should discuss any change in regimen with their physician.
- Patients should be advised that treatment with Tyzeka has not been shown to reduce the risk of transmission of HBV to others through sexual contact or blood contamination. HBV prevention strategies should be discussed with patients, including safe sexual practices, and avoidance of needle sharing or sharing any personal items which may contain residual blood or body fluids, such as razor blades or toothbrushes. Additionally, a vaccine is available for prevention of hepatitis B infection in susceptible individuals.
- Patients on a low sodium diet should be advised that Tyzeka oral solution contains approximately 47 mg of sodium per 600 mg dose (30 mL).
- Patients should be advised to dispose of unused or expired Tyzeka by using a community pharmaceutical take-back disposal program, or by placing unused Tyzeka in a closed container, such as a sealed bag, into household trash. All identifying information should be removed from the original Tyzeka container prior to disposal.
# Precautions with Alcohol
- Alcohol-Telbivudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TYZEKA®[1]
# Look-Alike Drug Names
There is limited information regarding Telbivudine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Telbivudine | |
36c6ea26b10f784f61817cd7d852f29db8eaf05d | wikidoc | Tenomodulin | Tenomodulin
Tenomodulin (also referred to as tendin, myodulin, Tnmd and TeM) is a protein encoded by the TNMD (Tnmd) gene and was discovered independently by Brandau and Shukunami in 2001 as a gene sharing high similarity with the already known chondromodulin-1 (Chm1). It is a tendon-specific gene marker known to be important for tendon maturation with key implications for the residing tendon stem/progenitor cells (TSPCs) as well as for the regulation of endothelial cell migration in chordae tendineae cordis in the heart and in experimental tumour models. It is highly expressed in tendons, explaining the rationale behind its name and the establishment as being marker gene for tendinous and ligamentous lineages.
# Gene and protein structure
TNMD belongs to the new family of type II transmembrane glycoproteins. The gene is localized on the X chromosome and accounts for an approximately 1.4 kb transcript and a predicted protein consisting of 317 amino acids. The gene is composed of seven exons. The second exon encodes the transmembrane domain (amino acid position 31-49) and no signal peptide. TNMD contains a putative protease recognition sequence (Arg-Xxx-Xxx-Arg) identified at the position 233-236. Unlike chondromodulin-1, TNMD does not have a processing signal for furin protease. The extracellular part, prior the putative cleavage site, contains a BRICHOS extracellular domain found also in several other unrelated proteins. This domain consists of a homologous sequence of approximately 100 amino acids containing a pair of conserved cysteine residues. It has been suggested that BRICHOS participates in the protein post-translational processing, however the exact function remains unclear. TNMD contains two N-glycosylation sites at position 94 and 180. Protein analyses in eye and periodontal ligament revealed full length TNMD protein as a double band of 40 and 45 kDa. It has been experimentally proven that the 45 kDa band corresponds to glycosylated TNMD, while 40 kDa band is non-glycosylated TNMD. The last exon of TNMD gene encodes the conserved C-terminal cysteine-rich domain, which makes up the part of the protein sharing highest resemblance to chondromodulin-I (77% similarity/66% identity). This domain contains C-terminal hydrophobic tail with eight Cys residues forming four disulphide-bridges, which are well conserved across vertebrate species. A smaller cyclic structure forming by single Cys280-Cys292 disulphide bridge in TNMD has been shown to exert an anti-angiogenic function, while the other three disulphide-bridges are speculated to hold this cyclic structure and C-terminal hydrophobic tail separated from each other to avoid the formation of intramolecular aggregates. In certain tendon tissues such as Achilles tendon and chordae tendineae cordis, 16 kDa cleaved C-terminal part of TNMD was detected in the collagenous extracellular matrix.
# Expression pattern
TNMD is highly expressed on messenger and protein levels in tendons and ligaments, but has also been found in other tissues.
- In tendon development first signals are detectable as early as E9.5, but upregulated from E14.5 onwards, marking the differentiated stage of tendon progenitors.
- Mouse periodontal ligaments demonstrated tenomodulin protein expression at 3 and 4 weeks postnatal, a time period corresponding to molar eruptive and post-eruptive phases when the teeth become functional.
- Other tendinous tissues known to express Tnmd are the diaphragm and chordae tendineae cordis.
- Masseter muscle is compartmentalized by a laminar structure, which was shown to elevate Tnmd mRNA in mouse embryos between E12.5 to E17.5, which further decreased after birth. The epimysium of skeletal muscle is also TNMD -positive.
- Tnmd mRNA was detected in eyes, more specifically in the sclerocornea, tendon of the extraocular muscle and the retinal ganglion cell layer, lens fibre cells, inner nuclear layer cells and pigment epithelium.
- Tnmd mRNA was detected in mouse skin at E15.5 and in human subcutaneous adipose tissue and adipocytes.
- In situ hybridization revealed Tnmd expression in various parts of the adult mouse brain such as the dentate gyrus, CA regions of the hippocampus, neurons in the cerebral nuclei, cerebellum, Purkinje cells and neuronal cells in the cerebellar nucleus.
- Rat mandibular condylar cartilage is positive for Tnmd mRNA at 1 week and is downregulated after 5 weeks.
# Putative signalling pathway
The putative signalling pathway of TNMD is largely unknown due to unidentified direct binding partners. Many knockout mouse models with tendon phenotypes have helped in understanding which upstream factors or pathways affect Tnmd expression. Similarly, the generation of Tnmd knockout mouse model allowed the suggestion of possible downstream effectors. It is important to emphasize that most of the below studies show correlations between Tnmd expression or function to other genes and not a direct link in a common signalling cascade.
Regarding upstream regulators of Tnmd expression the description of the scleraxis (Scx) knockout mouse line suggested that Scx can directly drive Tnmd transcription, because Scx deletion led to complete elimination of Tnmd expression. Overexpression of scleraxis in cultured tenocytes or in mesenchymal stem cells significantly upregulated Tnmd expression. The deletion of myostatin in mice resulted in a parallel decrease in Scx and Tnmd mRNA levels, while myostatin stimulation of fibroblasts led to their upregulation, suggesting myostatin as an upstream factor in the Tnmd pathway. Egr1/2 transcription factors can induce Scx and collagen I gene expression, hence it would be interesting to investigate if Egr1 or 2 also can affect Tnmd expression. The absence of the Mohawk (Mkx) gene led to significantly lower Tnmd expression as well as collagen I and fibromodulin. A significant loss of Tnmd was noticeable in Mkx knockouts at E16.5, while Scx expression was unchanged , suggesting that Mkx can also directly affect Tnmd expression. Activation of the Wnt/β-catenin signalling pathway in bone marrow-derived stem cells resulted in Tnmd upregulation. Scx and Mkx expression were unaffected, suggesting the Wnt/ β-catenin signalling works independent from these transcription factors.
Regarding downstream factors, the Tnmd knockout mouse model suggested correlation to collagen I based on the observed abnormal collagen fibrillogenesis resulting in pathologically thicker fibres. The lower cellular density and proliferation in the mutant tendons, as well as the reduced self-renewal and earlier senescence of Tnmd-deficient tendon stem/progenitor cells was coupled with downregulation of the proliferative marker Cyclin D1 and upregulation of the senescent marker p53. A study analysing ruptures of human chordae tendineae cordis revealed loss of Tnmd expression in the affected area coupled with upregulation of VEGF-A and MMP1, 2 and 13.
# Function and correlation to disease
In the last decade major breakthroughs in understanding the roles of TNMD in tendons and other tissues and cells have been made. The exact TNMD functions vary according to the type of cell and tissue, and in great extent they remain still not fully deciphered. Also how precisely TNMD contributes to pathophysiology of some correlated diseases is still unclear.
- In tendons it proves to have beneficial functions for the maintenance of the tissue because its loss results in premature tendon ageing characterized with dysregulated collagen fibrillogenesis and reduced cell density and proliferation. Tnmd exerts a positive effect on tendon-derived stem/progenitor cells by supporting self-renewal and preventing senescence, actions in which the C-terminal cysteine-rich domain alone is sufficient. The first studies on Tnmd expression during tendon healing suggested a time-dependent role, which needs to be further elucidated.
- In periodontal ligaments mediating the teeth connection to the jaw bones, Tnmd contributes to proper fibroblast adhesion.
- In tendinous structures chordae tendineae cordis, which connect papillary muscle to the atrioventricular valves in the heart, local absence of Tnmd leads to enhanced angiogenesis, VEGF-A production and MMPs activation. This is followed by cordis ruptures which can cause mitral regurgitation and cardiac valvular diseases.
- With respect to Tnmd anti-angiogenic function in vivo, no major abnormalities in vessel formation and density were detected during tendon and retina development in the knockout mouse model. The latter finding is open for discussion because a study with recombinant tenomodulin has shown an obliterating vessel effect in retina when injected in vivo in the vitreous body.
- In ectopic tumour in vivo models, induced expression of TNMD in mouse melanoma cells resulted in suppression of tumour growth due to reduced vessel density.
- TNMD transduction in human retinal and umbilical vein endothelial cells resulted in reduced cell proliferation or migration, correspondingly.
- Multiple research studies on cell phenotypisation after gene overexpression, stimulation with growth factors or mechanical stress, tissue engineering and biomaterial evaluation utilize Tnmd expression as marker for tendinous and ligamentous cell lineage.
- Research conducted on a genomic level by single nucleotide polymorphism has presented interesting correlations between Tnmd and a variety of diseases namely obesity, type 2 diabetes, metabolic syndrome, Alzheimer's disease and age-related macular degeneration. How exactly these SNPs affect Tnmd transcription, splicing or protein amino acid sequence remains still unknown.
- A strong correlation between Tnmd mRNA expression and the progression of several diseases such as obesity, metabolic syndrome and juvenile dermatomyositis has been shown. Generally, in all these cases higher tenomodulin levels corresponded to advanced disease state.
# Notes | Tenomodulin
Tenomodulin (also referred to as tendin, myodulin, Tnmd and TeM) [1] is a protein encoded by the TNMD (Tnmd) gene and was discovered independently by Brandau and Shukunami in 2001 as a gene sharing high similarity with the already known chondromodulin-1 (Chm1).[2][3] It is a tendon-specific gene marker known to be important for tendon maturation with key implications for the residing tendon stem/progenitor cells (TSPCs) as well as for the regulation of endothelial cell migration in chordae tendineae cordis in the heart and in experimental tumour models. It is highly expressed in tendons, explaining the rationale behind its name and the establishment as being marker gene for tendinous and ligamentous lineages.[4]
# Gene and protein structure
TNMD belongs to the new family of type II transmembrane glycoproteins. The gene is localized on the X chromosome and accounts for an approximately 1.4 kb transcript and a predicted protein consisting of 317 amino acids.[2][3] The gene is composed of seven exons. The second exon encodes the transmembrane domain (amino acid position 31-49) and no signal peptide. TNMD contains a putative protease recognition sequence (Arg-Xxx-Xxx-Arg) identified at the position 233-236.[5][6][7] Unlike chondromodulin-1, TNMD does not have a processing signal for furin protease. The extracellular part, prior the putative cleavage site, contains a BRICHOS extracellular domain found also in several other unrelated proteins. This domain consists of a homologous sequence of approximately 100 amino acids containing a pair of conserved cysteine residues. It has been suggested that BRICHOS participates in the protein post-translational processing, however the exact function remains unclear.[8] TNMD contains two N-glycosylation sites at position 94 and 180.[3] Protein analyses in eye and periodontal ligament revealed full length TNMD protein as a double band of 40 and 45 kDa.[5][9] It has been experimentally proven that the 45 kDa band corresponds to glycosylated TNMD, while 40 kDa band is non-glycosylated TNMD.[9] The last exon of TNMD gene encodes the conserved C-terminal cysteine-rich domain, which makes up the part of the protein sharing highest resemblance to chondromodulin-I (77% similarity/66% identity).[3] This domain contains C-terminal hydrophobic tail with eight Cys residues forming four disulphide-bridges, which are well conserved across vertebrate species.[5][10] A smaller cyclic structure forming by single Cys280-Cys292 disulphide bridge in TNMD has been shown to exert an anti-angiogenic function,[11] while the other three disulphide-bridges are speculated to hold this cyclic structure and C-terminal hydrophobic tail separated from each other to avoid the formation of intramolecular aggregates.[11] In certain tendon tissues such as Achilles tendon and chordae tendineae cordis, 16 kDa cleaved C-terminal part of TNMD was detected in the collagenous extracellular matrix.[12][13]
# Expression pattern
TNMD is highly expressed on messenger and protein levels in tendons and ligaments, but has also been found in other tissues.
- In tendon development first signals are detectable as early as E9.5,[3] but upregulated from E14.5 onwards, marking the differentiated stage of tendon progenitors.[14]
- Mouse periodontal ligaments demonstrated tenomodulin protein expression at 3 and 4 weeks postnatal, a time period corresponding to molar eruptive and post-eruptive phases when the teeth become functional.[9]
- Other tendinous tissues known to express Tnmd are the diaphragm[3] and chordae tendineae cordis.[13]
- Masseter muscle is compartmentalized by a laminar structure, which was shown to elevate Tnmd mRNA in mouse embryos between E12.5 to E17.5, which further decreased after birth.[15] The epimysium of skeletal muscle is also TNMD -positive.[2][3]
- Tnmd mRNA was detected in eyes, more specifically in the sclerocornea, tendon of the extraocular muscle and the retinal ganglion cell layer, lens fibre cells, inner nuclear layer cells and pigment epithelium.[16]
- Tnmd mRNA was detected in mouse skin at E15.5 and in human subcutaneous adipose tissue and adipocytes.[17]
- In situ hybridization revealed Tnmd expression in various parts of the adult mouse brain such as the dentate gyrus, CA regions of the hippocampus, neurons in the cerebral nuclei, cerebellum, Purkinje cells and neuronal cells in the cerebellar nucleus.[3]
- Rat mandibular condylar cartilage is positive for Tnmd mRNA at 1 week and is downregulated after 5 weeks.[18]
# Putative signalling pathway
The putative signalling pathway of TNMD is largely unknown due to unidentified direct binding partners. Many knockout mouse models with tendon phenotypes have helped in understanding which upstream factors or pathways affect Tnmd expression. Similarly, the generation of Tnmd knockout mouse model allowed the suggestion of possible downstream effectors. It is important to emphasize that most of the below studies show correlations between Tnmd expression or function to other genes and not a direct link in a common signalling cascade.
Regarding upstream regulators of Tnmd expression the description of the scleraxis (Scx) knockout mouse line suggested that Scx can directly drive Tnmd transcription, because Scx deletion led to complete elimination of Tnmd expression.[19] Overexpression of scleraxis in cultured tenocytes[4] or in mesenchymal stem cells significantly upregulated Tnmd expression.[20] The deletion of myostatin in mice resulted in a parallel decrease in Scx and Tnmd mRNA levels,[21] while myostatin stimulation of fibroblasts led to their upregulation, suggesting myostatin as an upstream factor in the Tnmd pathway. Egr1/2 transcription factors can induce Scx and collagen I gene expression,[22] hence it would be interesting to investigate if Egr1 or 2 also can affect Tnmd expression. The absence of the Mohawk (Mkx) gene led to significantly lower Tnmd expression as well as collagen I and fibromodulin.[23] A significant loss of Tnmd was noticeable in Mkx knockouts at E16.5, while Scx expression was unchanged [22], suggesting that Mkx can also directly affect Tnmd expression. Activation of the Wnt/β-catenin signalling pathway in bone marrow-derived stem cells resulted in Tnmd upregulation. Scx and Mkx expression were unaffected, suggesting the Wnt/ β-catenin signalling works independent from these transcription factors.[24]
Regarding downstream factors, the Tnmd knockout mouse model suggested correlation to collagen I based on the observed abnormal collagen fibrillogenesis resulting in pathologically thicker fibres.[12] The lower cellular density and proliferation in the mutant tendons,[12] as well as the reduced self-renewal and earlier senescence of Tnmd-deficient tendon stem/progenitor cells was coupled with downregulation of the proliferative marker Cyclin D1 and upregulation of the senescent marker p53.[25] A study analysing ruptures of human chordae tendineae cordis revealed loss of Tnmd expression in the affected area coupled with upregulation of VEGF-A and MMP1, 2 and 13.[13]
# Function and correlation to disease
In the last decade major breakthroughs in understanding the roles of TNMD in tendons and other tissues and cells have been made. The exact TNMD functions vary according to the type of cell and tissue, and in great extent they remain still not fully deciphered. Also how precisely TNMD contributes to pathophysiology of some correlated diseases is still unclear.
- In tendons it proves to have beneficial functions for the maintenance of the tissue because its loss results in premature tendon ageing characterized with dysregulated collagen fibrillogenesis and reduced cell density and proliferation.[12] Tnmd exerts a positive effect on tendon-derived stem/progenitor cells by supporting self-renewal and preventing senescence, actions in which the C-terminal cysteine-rich domain alone is sufficient.[25] The first studies on Tnmd expression during tendon healing suggested a time-dependent role, which needs to be further elucidated.[26][27]
- In periodontal ligaments mediating the teeth connection to the jaw bones, Tnmd contributes to proper fibroblast adhesion.[9]
- In tendinous structures chordae tendineae cordis, which connect papillary muscle to the atrioventricular valves in the heart, local absence of Tnmd leads to enhanced angiogenesis, VEGF-A production and MMPs activation. This is followed by cordis ruptures which can cause mitral regurgitation and cardiac valvular diseases.[13][28]
- With respect to Tnmd anti-angiogenic function in vivo, no major abnormalities in vessel formation and density were detected during tendon and retina development in the knockout mouse model.[12] The latter finding is open for discussion because a study with recombinant tenomodulin has shown an obliterating vessel effect in retina when injected in vivo in the vitreous body.[29]
- In ectopic tumour in vivo models, induced expression of TNMD in mouse melanoma cells resulted in suppression of tumour growth due to reduced vessel density.[30]
- TNMD transduction in human retinal and umbilical vein endothelial cells resulted in reduced cell proliferation or migration, correspondingly.[30]
- Multiple research studies on cell phenotypisation after gene overexpression, stimulation with growth factors or mechanical stress, tissue engineering and biomaterial evaluation utilize Tnmd expression as marker for tendinous and ligamentous cell lineage.
- Research conducted on a genomic level by single nucleotide polymorphism has presented interesting correlations between Tnmd and a variety of diseases namely obesity,[31] type 2 diabetes,[31] metabolic syndrome,[32] Alzheimer's disease[33] and age-related macular degeneration.[34] How exactly these SNPs affect Tnmd transcription, splicing or protein amino acid sequence remains still unknown.
- A strong correlation between Tnmd mRNA expression and the progression of several diseases such as obesity,[17][35] metabolic syndrome[36] and juvenile dermatomyositis[37] has been shown. Generally, in all these cases higher tenomodulin levels corresponded to advanced disease state.
# Notes | https://www.wikidoc.org/index.php/Tenomodulin | |
1655edca8e310e18bb42d983f1aae962890d2e32 | wikidoc | Terconazole | Terconazole
# 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
Terconazole is an antifungal that is FDA approved for the treatment of vulvovaginal candidiasis (moniliasis). Common adverse reactions include vulvovaginal burning, itching, headache, dysmenorrhea, abdominal pain, asthenia, Influenza-Like Illness consisting of multiple listed reactions including fever and chills, nausea, vomiting, myalgia, arthralgia, malaise, hypersensitivity, anaphylaxis, face edema, bronchospasm, rash, toxic epidermal necrolysis, urticaria.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- One full applicator (5 g) of Terconazole Vaginal Cream (20 mg terconazole) should be administered intravaginally once daily at bedtime for seven consecutive days.
- One full applicator (5 g) of Terconazole Vaginal Cream (40 mg terconazole) should be administered intravaginally once daily at bedtime for three consecutive days.
- Before prescribing another course of therapy, the diagnosis should be reconfirmed by smears and/or cultures and other pathogens commonly associated with vulvovaginitis ruled out. The therapeutic effect of these products is not affected by menstruation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Terconazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Terconazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Terconazole 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 Terconazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Terconazole in pediatric patients.
# Contraindications
Patients known to be hypersensitive to terconazole or to any of the components of the cream.
# Warnings
- Anaphylaxis and toxic epidermal necrolysis have been reported during terconazole therapy. Terconazole therapy should be discontinued if anaphylaxis or toxic epidermal necrolysis develops.
# 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 clinical practice.
- During controlled clinical studies conducted in the United States, 521 patients with vulvovaginal candidiasis were treated with terconazole 0.4% vaginal cream.
- Based on comparative analyses with placebo, the adverse experiences considered most likely related to terconazole 0.4% vaginal cream were headache (26% vs. 17% with placebo) and body pain (2.1% vs. 0% with placebo). Fever (1.7% vs. 0.5% with placebo) and chills (0.4% vs. 0.0% with placebo), vulvovaginal burning, itching and irritation have also been reported.
- The adverse drug experience on terconazole most frequently causing discontinuation was vulvovaginal itching.
- During controlled clinical studies conducted in the United States, patients with vulvovaginal candidiasis were treated with terconazole 0.8% vaginal cream for three days.
- Based on comparative analyses with placebo and a standard agent, the adverse experiences considered most likely related to terconazole 0.8% vaginal cream were headache (21% vs. 16% with placebo) and dysmenorrhea (6% vs. 2% with placebo).
- Other adverse experiences reported with terconazole 0.8% vaginal cream were abdominal pain (3.4% vs. 1% with placebo) and fever (1% vs. 0.3% with placebo).
- The adverse drug experience most frequently causing discontinuation of therapy was vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3% with the placebo group.
## Postmarketing Experience
- The following adverse drug reactions have been first identified during post-marketing experience with terconazole.
- 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.
- Asthenia, Influenza-Like Illness consisting of multiple listed reactions including fever and chills, nausea, vomiting, myalgia, arthralgia, malaise
- Hypersensitivity, Anaphylaxis, Face Edema
- Dizziness
- Bronchospasm
- Rash, Toxic Epidermal Necrolysis, Urticaria
# Drug Interactions
There is limited information regarding Terconazole Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Terconazole in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Terconazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Terconazole during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Terconazole in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Terconazole in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Terconazole in geriatric settings.
### Gender
There is no FDA guidance on the use of Terconazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Terconazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Terconazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Terconazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Terconazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Terconazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Terconazole Administration in the drug label.
### Monitoring
There is limited information regarding Terconazole Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Terconazole and IV administrations.
# Overdosage
- In the rat, the oral LD 50 values were found to be 1741 and 849 mg/kg for the male and female, respectively. The oral LD 50 values for the male and female dog were ≅1280 and ≥640 mg/kg, respectively.
- In the event of oral ingestion of cream, supportive and symptomatic measures should be carried out. If the cream is accidentally applied to the eyes, wash with clean water or saline and seek medical attention if symptoms persist.
# Pharmacology
## Mechanism of Action
- Terconazole, an azole antifungal agent, inhibits fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylase enzyme. This enzyme functions to convert lanosterol to ergosterol.
- The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of terconazole. Mammalian cell demethylation is less sensitive to terconazole inhibition.
- Terconazole exhibits antifungal activity in vitro against Candida albicans and other Candida species. The MIC values of terconazole against most Lactobacillus spp. typically found in the human vagina were ≥128 mcg/mL; therefore these beneficial bacteria are not affected by drug treatment.
## Structure
There is limited information regarding Terconazole Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Terconazole Pharmacodynamics in the drug label.
## Pharmacokinetics
- Following a single intravaginal application of a suppository containing 240 mg 14C-terconazole to healthy women, approximately 70% (range: 64–76%) of terconazole remains in the vaginal area during the suppository retention period (16 hours); approximately 10% (range: 5–16%) of the administered radioactivity was absorbed systemically over 7 days.
- Maximum plasma concentrations of terconazole occur 5 to 10 hours after intravaginal application of the cream or suppository. Systemic exposure to terconazole is approximately proportional to the applied dose, whether as the cream or suppository.
- The rate and extent of absorption of terconazole are similar in patients with vulvovaginal candidiasis (pregnant or non-pregnant) and healthy subjects.
- Terconazole is highly protein bound (94.9%) in human plasma and the degree of binding is independent of drug concentration over the range of 0.01 to 5.0 mcg/mL.
- Systemically absorbed terconazole is extensively metabolized (>95%).
- Across various studies in healthy women, after single or multiple intravaginal administration of terconazole as the cream or suppository/ovule, the mean elimination half-life of unchanged terconazole ranged from 6.4 to 8.5 hours.
- Following a single intravaginal administration of a suppository containing 240 mg 14C-terconazole to hysterectomized or tubal ligated women, approximately 3 to 10% (mean ± SD: 5.7 ± 3.0%) of the administered radioactivity was eliminated in the urine and 2 to 6% (mean ± SD: 4.2 ± 1.6%) was eliminated in the feces during the 7-day collection period.
- There is no significant increase in maximum plasma concentration or overall exposure (AUC) after multiple daily applications of the cream for 7 days or suppositories for 3 days.
- Photosensitivity reactions were observed in some normal volunteers following repeated dermal application of terconazole 2.0% and 0.8% creams under conditions of filtered artificial ultraviolet light.
- Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in patients who were treated with terconazole suppositories or vaginal cream (0.4% and 0.8%).
## Nonclinical Toxicology
There is limited information regarding Terconazole Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Terconazole Clinical Studies in the drug label.
# How Supplied
- Terconazole Vaginal Cream 0.4% is available in 45 g (NDC 0591-3196-89) tubes with a measured-dose applicator. Store at Controlled Room Temperature 15°–30°C (59°–86°F).
- Terconazole Vaginal Cream 0.8% is available in 20 g (NDC 0591-3197-52) tubes with a measured-dose applicator.
## Storage
- Store at Controlled Room Temperature 15°–30°C (59°–86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- For best results, be sure to use the medication as prescribed by your doctor, even if you feel better quickly.
- Avoid sexual intercourse, if your doctor advises you to do so.
- If your partner has any penile itching, redness, or discomfort, he should consult his physician and mention that you are being treated for a yeast infection.
- You can use the medication even if you are having your menstrual period.
- However, you should not use tampons because they may absorb the medication. - Instead, use external pads or napkins until you have finished your medication. You may also wish to wear a sanitary napkin if the vaginal medication leaks.
- Dry the genital area thoroughly after showering, bathing, or swimming.
- Change out of a wet bathing suit or damp exercise clothes as soon as possible.
- A dry environment is less likely to encourage the growth of yeast.
Wipe from front to rear (away from the vagina) after a bowel movement.
- Don't douche unless your doctor specifically tells you to do so. Douching may disturb the vaginal balance.
- Don't scratch if you can help it. Scratching can cause more irritation and spread the infection.
- Discuss with your physician any medication you are already taking. Certain types of medication can make your vagina more susceptible to infection.
- Eat nutritious meals to promote your general health.
# Precautions with Alcohol
Alcohol-Terconazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TERCONAZOLE®
# Look-Alike Drug Names
There is limited information regarding Terconazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Terconazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [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
Terconazole is an antifungal that is FDA approved for the treatment of vulvovaginal candidiasis (moniliasis). Common adverse reactions include vulvovaginal burning, itching, headache, dysmenorrhea, abdominal pain, asthenia, Influenza-Like Illness consisting of multiple listed reactions including fever and chills, nausea, vomiting, myalgia, arthralgia, malaise, hypersensitivity, anaphylaxis, face edema, bronchospasm, rash, toxic epidermal necrolysis, urticaria.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- One full applicator (5 g) of Terconazole Vaginal Cream (20 mg terconazole) should be administered intravaginally once daily at bedtime for seven consecutive days.
- One full applicator (5 g) of Terconazole Vaginal Cream (40 mg terconazole) should be administered intravaginally once daily at bedtime for three consecutive days.
- Before prescribing another course of therapy, the diagnosis should be reconfirmed by smears and/or cultures and other pathogens commonly associated with vulvovaginitis ruled out. The therapeutic effect of these products is not affected by menstruation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Terconazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Terconazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Terconazole 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 Terconazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Terconazole in pediatric patients.
# Contraindications
Patients known to be hypersensitive to terconazole or to any of the components of the cream.
# Warnings
- Anaphylaxis and toxic epidermal necrolysis have been reported during terconazole therapy. Terconazole therapy should be discontinued if anaphylaxis or toxic epidermal necrolysis develops.
# 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 clinical practice.
- During controlled clinical studies conducted in the United States, 521 patients with vulvovaginal candidiasis were treated with terconazole 0.4% vaginal cream.
- Based on comparative analyses with placebo, the adverse experiences considered most likely related to terconazole 0.4% vaginal cream were headache (26% vs. 17% with placebo) and body pain (2.1% vs. 0% with placebo). Fever (1.7% vs. 0.5% with placebo) and chills (0.4% vs. 0.0% with placebo), vulvovaginal burning, itching and irritation have also been reported.
- The adverse drug experience on terconazole most frequently causing discontinuation was vulvovaginal itching.
- During controlled clinical studies conducted in the United States, patients with vulvovaginal candidiasis were treated with terconazole 0.8% vaginal cream for three days.
- Based on comparative analyses with placebo and a standard agent, the adverse experiences considered most likely related to terconazole 0.8% vaginal cream were headache (21% vs. 16% with placebo) and dysmenorrhea (6% vs. 2% with placebo).
- Other adverse experiences reported with terconazole 0.8% vaginal cream were abdominal pain (3.4% vs. 1% with placebo) and fever (1% vs. 0.3% with placebo).
- The adverse drug experience most frequently causing discontinuation of therapy was vulvovaginal itching, 0.7% with the terconazole 0.8% vaginal cream group and 0.3% with the placebo group.
## Postmarketing Experience
- The following adverse drug reactions have been first identified during post-marketing experience with terconazole.
- 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.
- Asthenia, Influenza-Like Illness consisting of multiple listed reactions including fever and chills, nausea, vomiting, myalgia, arthralgia, malaise
- Hypersensitivity, Anaphylaxis, Face Edema
- Dizziness
- Bronchospasm
- Rash, Toxic Epidermal Necrolysis, Urticaria
# Drug Interactions
There is limited information regarding Terconazole Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Terconazole in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Terconazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Terconazole during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Terconazole in women who are nursing.
### Pediatric Use
There is no FDA guidance on the use of Terconazole in pediatric settings.
### Geriatic Use
There is no FDA guidance on the use of Terconazole in geriatric settings.
### Gender
There is no FDA guidance on the use of Terconazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Terconazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Terconazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Terconazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Terconazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Terconazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Terconazole Administration in the drug label.
### Monitoring
There is limited information regarding Terconazole Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Terconazole and IV administrations.
# Overdosage
- In the rat, the oral LD 50 values were found to be 1741 and 849 mg/kg for the male and female, respectively. The oral LD 50 values for the male and female dog were ≅1280 and ≥640 mg/kg, respectively.
- In the event of oral ingestion of cream, supportive and symptomatic measures should be carried out. If the cream is accidentally applied to the eyes, wash with clean water or saline and seek medical attention if symptoms persist.
# Pharmacology
## Mechanism of Action
- Terconazole, an azole antifungal agent, inhibits fungal cytochrome P-450-mediated 14 alpha-lanosterol demethylase enzyme. This enzyme functions to convert lanosterol to ergosterol.
- The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell wall and may be responsible for the antifungal activity of terconazole. Mammalian cell demethylation is less sensitive to terconazole inhibition.
- Terconazole exhibits antifungal activity in vitro against Candida albicans and other Candida species. The MIC values of terconazole against most Lactobacillus spp. typically found in the human vagina were ≥128 mcg/mL; therefore these beneficial bacteria are not affected by drug treatment.
## Structure
There is limited information regarding Terconazole Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Terconazole Pharmacodynamics in the drug label.
## Pharmacokinetics
- Following a single intravaginal application of a suppository containing 240 mg 14C-terconazole to healthy women, approximately 70% (range: 64–76%) of terconazole remains in the vaginal area during the suppository retention period (16 hours); approximately 10% (range: 5–16%) of the administered radioactivity was absorbed systemically over 7 days.
- Maximum plasma concentrations of terconazole occur 5 to 10 hours after intravaginal application of the cream or suppository. Systemic exposure to terconazole is approximately proportional to the applied dose, whether as the cream or suppository.
- The rate and extent of absorption of terconazole are similar in patients with vulvovaginal candidiasis (pregnant or non-pregnant) and healthy subjects.
- Terconazole is highly protein bound (94.9%) in human plasma and the degree of binding is independent of drug concentration over the range of 0.01 to 5.0 mcg/mL.
- Systemically absorbed terconazole is extensively metabolized (>95%).
- Across various studies in healthy women, after single or multiple intravaginal administration of terconazole as the cream or suppository/ovule, the mean elimination half-life of unchanged terconazole ranged from 6.4 to 8.5 hours.
- Following a single intravaginal administration of a suppository containing 240 mg 14C-terconazole to hysterectomized or tubal ligated women, approximately 3 to 10% (mean ± SD: 5.7 ± 3.0%) of the administered radioactivity was eliminated in the urine and 2 to 6% (mean ± SD: 4.2 ± 1.6%) was eliminated in the feces during the 7-day collection period.
- There is no significant increase in maximum plasma concentration or overall exposure (AUC) after multiple daily applications of the cream for 7 days or suppositories for 3 days.
- Photosensitivity reactions were observed in some normal volunteers following repeated dermal application of terconazole 2.0% and 0.8% creams under conditions of filtered artificial ultraviolet light.
- Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in patients who were treated with terconazole suppositories or vaginal cream (0.4% and 0.8%).
## Nonclinical Toxicology
There is limited information regarding Terconazole Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Terconazole Clinical Studies in the drug label.
# How Supplied
- Terconazole Vaginal Cream 0.4% is available in 45 g (NDC 0591-3196-89) tubes with a measured-dose applicator. Store at Controlled Room Temperature 15°–30°C (59°–86°F).
- Terconazole Vaginal Cream 0.8% is available in 20 g (NDC 0591-3197-52) tubes with a measured-dose applicator.
## Storage
- Store at Controlled Room Temperature 15°–30°C (59°–86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- For best results, be sure to use the medication as prescribed by your doctor, even if you feel better quickly.
- Avoid sexual intercourse, if your doctor advises you to do so.
- If your partner has any penile itching, redness, or discomfort, he should consult his physician and mention that you are being treated for a yeast infection.
- You can use the medication even if you are having your menstrual period.
- However, you should not use tampons because they may absorb the medication. * Instead, use external pads or napkins until you have finished your medication. You may also wish to wear a sanitary napkin if the vaginal medication leaks.
- Dry the genital area thoroughly after showering, bathing, or swimming.
- Change out of a wet bathing suit or damp exercise clothes as soon as possible.
- A dry environment is less likely to encourage the growth of yeast.
Wipe from front to rear (away from the vagina) after a bowel movement.
- Don't douche unless your doctor specifically tells you to do so. Douching may disturb the vaginal balance.
- Don't scratch if you can help it. Scratching can cause more irritation and spread the infection.
- Discuss with your physician any medication you are already taking. Certain types of medication can make your vagina more susceptible to infection.
- Eat nutritious meals to promote your general health.
# Precautions with Alcohol
Alcohol-Terconazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- TERCONAZOLE®[1]
# Look-Alike Drug Names
There is limited information regarding Terconazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Terconazole | |
f20a837306fdb7c6d3814b4f75c7e4ac053efd89 | wikidoc | Tesamorelin | Tesamorelin
# 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
Tesamorelin is a Growth hormone secretagogues that is FDA approved for the treatment of reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. Common adverse reactions include arthralgia, injection site erythema, injection site pruritis, pain in extremity, peripheral edema, myalgia..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Tesamorelin® (tesamorelin for injection) is indicated for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy.
Limitations of Use:
- Since the long-term cardiovascular safety and potential long-term cardiovascular benefit of tesamorelin treatment have not been studied and are not known, careful consideration should be given whether to continue tesamorelin treatment in patients who do not show a clear efficacy response as judged by the degree of reduction in visceral adipose tissue measured by waist circumference or CT scan.
- Tesamorelin is not indicated for weight loss management (weight neutral effect).
- There are no data to support improved compliance with anti-retroviral therapies in HIV-positive patients taking tesamorelin.
# Dosage
General Dosing Information
- The recommended dose of tesamorelin is 2 mg injected subcutaneously once a day.
- The recommended injection site is the abdomen. Injection sites should be rotated to different areas of the abdomen. Do not inject into scar tissue, bruises or the navel.
# DOSAGE FORMS AND STRENGTHS
- Tesamorelin (tesamorelin for injection) is supplied in a vial containing 2 mg of tesamorelin as a lyophilized powder. The diluent (Sterile Water for Injection, USP 10 mL) is provided in a separate bottle.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tesamorelin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tesamorelin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tesamorelin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tesamorelin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tesamorelin in pediatric patients.
# Contraindications
Disruption of the Hypothalamic-pituitary Axis
- Tesamorelin is contraindicated in patients with disruption of the hypothalamic-pituitary axis due to hypophysectomy, hypopituitarism, pituitary tumor/surgery, head irradiation or head trauma.
Active Malignancy
- Tesamorelin is contraindicated in patients with active malignancy (either newly diagnosed or recurrent). Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with tesamorelin.
Hypersensitivity
- Tesamorelin is contraindicated in patients with known hypersensitivity to tesamorelin and/or mannitol (an excipient).
Pregnancy
- Tesamorelin is contraindicated in pregnant women. During pregnancy, visceral adipose tissue increases due to normal metabolic and hormonal changes. Modifying this physiologic change of pregnancy with tesamorelin offers no known benefit and could result in fetal harm. Tesamorelin acetate administration to rats during organogenesis and lactation resulted in hydrocephalus in offspring at a dose approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). If pregnancy occurs, discontinue tesamorelin therapy. 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 the fetus
# Warnings
Neoplasms
- Tesamorelin induces the release of endogenous growth hormone (GH), a known growth factor. Thus, patients with active malignancy should not be treated with tesamorelin.
- For patients with a history of non-malignant neoplasms, tesamorelin therapy should be initiated after careful evaluation of the potential benefit of treatment. For patients with a history of treated and stable malignancies, tesamorelin therapy should be initiated only after careful evaluation of the potential benefit of treatment relative to the risk of re-activation of the underlying malignancy.
- In addition, the decision to start treatment with tesamorelin should be considered carefully based on the increased background risk of malignancies in HIV-positive patients.
Elevated IGF-1
- Tesamorelin stimulates GH production and increases serum IGF-1. Given that IGF-1 is a growth factor and the effect of prolonged elevations in IGF-1 levels on the development or progression of malignancies is unknown, IGF-1 levels should be monitored closely during tesamorelin therapy. Careful consideration should be given to discontinuing tesamorelin in patients with persistent elevations of IGF-1 levels (e.g., >3 SDS), particularly if the efficacy response is not robust (e.g., based on visceral adipose tissue changes measured by waist circumference or CT scan).
- During the clinical trials, patients were monitored every three months. Among patients who received tesamorelin for 26 weeks, 47.4% had IGF-1 levels greater than 2 standard deviation scores (SDS), and 35.6% had SDS >3, with this effect seen as early as 13 weeks of treatment. Among those patients who remained on tesamorelin for a total of 52 weeks, at the end of treatment 33.7% had IGF-1 SDS >2 and 22.6% had IGF-1 SDS >3.
Fluid Retention
- Fluid retention may occur during tesamorelin therapy and is thought to be related to the induction of GH secretion. It manifests as increased tissue turgor and musculoskeletal discomfort resulting in a variety of adverse reactions (e.g. edema, arthralgia, carpal tunnel syndrome) which are either transient or resolve with discontinuation of treatment.
Glucose Intolerance
- Tesamorelin treatment may result in glucose intolerance. During the Phase 3 clinical trials, the percentages of patients with elevated HbA1c (≥ 6.5%) from baseline to Week 26 were 4.5% and 1.3% in the tesamorelin and placebo groups, respectively. An increased risk of developing diabetes with tesamorelin (HbA1c level ≥ 6.5%) relative to placebo was observed . Therefore, glucose status should be carefully evaluated prior to initiating tesamorelin treatment. In addition, all patients treated with tesamorelin should be monitored periodically for changes in glucose metabolism to diagnose those who develop impaired glucose tolerance or diabetes. Diabetes is a known cardiovascular risk factor and patients who develop glucose intolerance have an elevated risk for developing diabetes. Caution should be exercised in treating HIV-positive patients with lipodystrophy with tesamorelin if they develop glucose intolerance or diabetes, and careful consideration should be given to discontinuing tesamorelin treatment in patients who do not show a clear efficacy response as judged by the degree of reduction in visceral adipose tissue by waist circumference or CT scan measurements.
- Since tesamorelin increases IGF-1, patients with diabetes who are receiving ongoing treatment with tesamorelin should be monitored at regular intervals for potential development or worsening of retinopathy.
Hypersensitivity Reactions
- Hypersensitivity reactions may occur in patients treated with tesamorelin. Hypersensitivity reactions occurred in 3.6% of patients with HIV-associated lipodystrophy treated with tesamorelin in the Phase 3 clinical trials. These reactions included pruritus, erythema, flushing, urticaria, and other rash. In cases of suspected hypersensitivity reactions, patients should be advised to seek prompt medical attention and treatment with tesamorelin should be discontinued immediately.
Injection Site Reactions
- Tesamorelin treatment may cause injection site reactions, including injection site erythema, pruritus, pain, irritation, and bruising. The incidence of injection site reactions was 24.5% in tesamorelin-treated patients and 14.4% in placebo-treated patients during the first 26 weeks of treatment in the Phase 3 clinical trials. For patients who continued tesamorelin® for an additional 26 weeks, the incidence of injection site reactions was 6.1%. In order to reduce the incidence of injection site reactions, it is recommended to rotate the site of injection to different areas of the abdomen.
Acute Critical Illness
- Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of growth hormone. tesamorelin® has not been studied in patients with acute critical illness. Since tesamorelin® stimulates growth hormone production, careful consideration should be given to discontinuing tesamorelin® in critically ill patients.
# Adverse Reactions
## Clinical Trials Experience
- The most commonly reported adverse reactions are hypersensitivity (e.g., rash, urticaria) reactions due to the effect of GH (e.g., arthralgia, extremity pain, peripheral edema, hyperglycemia, carpal tunnel syndrome), injection site reactions (injection site erythema, pruritis, pain, urticaria, irritation, swelling, hemorrhage).
- During the first 26 weeks of treatment (main phase), discontinuations as a result of adverse reactions occurred in 9.6% of patients receiving tesamorelin® and 6.8% of patients receiving placebo. Apart from patients with hypersensitivity reactions identified during the studies and who were discontinued per protocol (2.2%), the most common reasons for discontinuation of tesamorelin® treatment were adverse reactions due to the effect of GH (4.2%) and local injection site reactions (4.6%).
- During the following 26 weeks of treatment (extension phase), discontinuations as a result of adverse events occurred in 2.4% of patients in the T-T group (patients treated with tesamorelin for Week 0-26 and with tesamorelin for Week 26-52) and 5.2% of patients in the T-P group (patients treated with tesamorelin for Week 0-26 and with placebo for Week 26-52).
Clinical Trial 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.
- Seven hundred and forty HIV-infected patients with lipodystrophy and excess abdominal fat were exposed to tesamorelin® in the Phase 3 clinical trials; of these 543 received tesamorelin® during the initial 26-week placebo-controlled phase.
- Adverse reactions that occurred more frequently with tesamorelin® relative to placebo and had an incidence ≥1% during the first 26 weeks across all studies are presented in Table 1.
- Mean levels of fasting blood glucose and fasting insulin were not significantly different between tesamorelin® -treated and placebo-treated patients after 26 weeks of treatment.
- In the tesamorelin Phase 3 clinical trials, mean baseline (Week 0) HbA1c was 5.26% among patients in the tesamorelin® group and 5.28% among those in the placebo group. At Week 26, mean HbA1c was higher among patients treated with tesamorelin® compared with placebo (5.39% vs. 5.28% for the tesamorelin® and placebo groups, respectively, mean treatment difference of 0.12%, p=0.0004). Patients receiving tesamorelin® had an increased risk of developing diabetes (HbA1c level ≥ 6.5%) compared with placebo (4.5% vs. 1.3%), with a hazard ratio of 3.3 (CI 1.4, 9.6).
- Adverse reactions observed during Week 26 to 52 of the Phase 3 clinical trials which had an incidence of ≥1% and were seen more frequently with tesamorelin® relative to placebo are presented in Table 2:
- For patients who continued from Week 26-52, mean levels of fasting blood glucose, fasting insulin, and HbA1c were not different between the T-T and T-P groups.
Immunogenicity
- As with all therapeutic proteins and peptides, there is a potential for in vivo development of anti- tesamorelin® antibodies. In the combined Phase 3 clinical trials anti-tesamorelin IgG antibodies were detected in 49.5% of patients treated with tesamorelin® for 26 weeks and 47.4% of patients who received tesamorelin® for 52 weeks. In the subset of patients with hypersensitivity reactions, anti-tesamorelin IgG antibodies were detected in 85.2%. Cross-reactivity to endogenous growth hormone-releasing hormone (GHRH) was observed in approximately 60% of patients who developed anti-tesamorelin antibodies. Patients with and without anti-tesamorelin IgG antibodies had similar mean reductions in visceral adipose tissue (VAT) and IGF-1 response suggesting that the presence of antibodies did not alter the efficacy of tesamorelin®. In a group of patients who had antibodies to tesamorelin after 26 weeks of treatment (56%) and were re-assessed 6 months later, after stopping tesamorelin® treatment, 18% were still antibody positive.
- Neutralizing antibodies to tesamorelin and hGHRH were detected in vitro at Week 52 in 10% and 5% of tesamorelin®-treated patients, respectively. They did not appear to have an impact on efficacy, as evidenced by comparable changes in VAT and IGF-1 level in patients with or without in vitro neutralizing antibodies.
- The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, methodology, sample handling, timing of sample collection, concomitant medication and underlying disease. For these reasons, comparison of the incidence of antibodies to tesamorelin® with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tesamorelin in the drug label.
# Drug Interactions
Cytochrome P450-Metabolized Drugs
- Co-administration of tesamorelin® with simvastatin, a sensitive CYP3A substrate, showed that tesamorelin® had no significant impact on the pharmacokinetics profiles of simvastatin in healthy subjects. This result suggests that tesamorelin® may not significantly affect CYP3A activity. Other isoenzymes of CYP450 have not been evaluated with tesamorelin®. Published data, however, indicate that GH may modulate cytochrome P450 (CYP450) mediated antipyrine clearance in man. These data suggest that GH may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Because tesamorelin stimulates GH production, careful monitoring is advisable when tesamorelin® is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes.
11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1)
- GH is known to inhibit 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1), a microsomal enzyme required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Because tesamorelin stimulates GH production, patients receiving glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in maintenance or stress doses following initiation of tesamorelin®, particularly in patients treated with cortisone acetate and prednisone because conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category X
- Tesamorelin is contraindicated in pregnant women. During pregnancy, visceral adipose tissue increases due to normal metabolic and hormonal changes. Modifying this physiologic change of pregnancy with tesamorelin® offers no known benefit and could result in fetal harm. Tesamorelin acetate administration to rats during organogenesis and lactation resulted in hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). If pregnancy occurs, discontinue tesamorelin® therapy. 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 the fetus.
- Tesamorelin acetate administration to rats during organogenesis and lactation produced hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). Actual animal dose was 1.2 mg/kg. During organogenesis, lower doses approximately 0.1 to 1 times the clinical dose caused delayed skull ossification in rats. Actual animal doses were 0.1 to 0.6 mg/kg. No adverse developmental effects occurred in rabbits using doses up to approximately 500 times the clinical dose.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tesamorelin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tesamorelin during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States not human milk-feed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 infection transmission and serious adverse reactions in nursing infants, mothers receiving tesamorelin® should be instructed not to human milk-feed.
- It is not known whether tesamorelin® is excreted in human milk. Tesamorelin acetate administration to rats during organogenesis and lactation resulted in hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). Actual animal dose was 1.2 mg/kg.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. Tesamorelin® should not be used in children with open epiphyses, among whom excess GH and IGF-1 may result in linear growth acceleration and excessive growth.
### Geriatic Use
- There is no information on the use of tesamorelin® in patients greater than 65 years of age with HIV and lipodystrophy
### Gender
There is no FDA guidance on the use of Tesamorelin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tesamorelin with respect to specific racial populations.
### Renal Impairment
Safety, efficacy, and pharmacokinetics of tesamorelin® in patients with renal impairment have not been established.
### Hepatic Impairment
- Safety, efficacy, and pharmacokinetics of tesamorelin® in patients with hepatic impairment have not been established.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tesamorelin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tesamorelin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Reconstituted tesamorelin® solution should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. tesamorelin® must be injected only if the solution is clear, colorless and without particulate matter.
- Tesamorelin® should be injected subcutaneously into the skin on the abdomen. Injection sites should be rotated to different areas of the abdomen. Do not inject into scar tissue, bruises or the navel.
### Monitoring
There is limited information regarding Monitoring of Tesamorelin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tesamorelin in the drug label.
# Overdosage
- No data are available on overdosage.
# Pharmacology
## Mechanism of Action
- In vitro, tesamorelin binds and stimulates human GRF receptors with similar potency as the endogenous GRF.
- Growth Hormone-Releasing Factor (GRF), also known as growth hormone-releasing hormone (GHRH), is a hypothalamic peptide that acts on the pituitary somatotroph cells to stimulate the synthesis and pulsatile release of endogenous growth hormone (GH), which is both anabolic and lipolytic. GH exerts its effects by interacting with specific receptors on a variety of target cells, including chondrocytes, osteoblasts, myocytes, hepatocytes, and adipocytes, resulting in a host of pharmacodynamic effects. Some, but not all these effects, are primarily mediated by IGF-1 produced in the liver and in peripheral tissues.
## Structure
- Patients treated with tesamorelin® for 52 weeks (T-T group) showed no change between Weeks 26 and 52 in mean trunk fat (increase of 0.1 kg in Study 1 and decrease of 0.5 kg in Study 2, respectively, compared with an increase of 1.4 kg in patients in the T-P group in Study 1 and an increase of 1.09 kg in Study 2, respectively) nor was there a change from Week 26 baseline in mean lean body mass (decrease of 0.1 kg in Study 1 and increase of 0.1 kg in Study 2, respectively, compared with a decrease of 1.8 kg in patients in the T-P group in Study 1 and a decrease of 1.7 kg in Study 2, respectively).
- There was no adverse effect of tesamorelin® on lipids or subcutaneous adipose tissue (SAT). tesamorelin® did not adversely alter antiretroviral effectiveness, such as mean circulating levels of CD4 counts or HIV-1 RNA (viral load).
- Tesamorelin® is a sterile, white to off-white, preservative-free lyophilized powder for subcutaneous injection. After reconstitution with the supplied diluent (Sterile Water for Injection, USP), a solution of tesamorelin® is clear and colorless. Each single-use vial of tesamorelin® contains 2 mg of tesamorelin as the free base (2.2 mg tesamorelin acetate, anhydrous) and the following inactive ingredient: 100 mg mannitol, US
## Pharmacodynamics
Effects on IGF-1 and IGFBP-3 levels
- Tesamorelin stimulates growth hormone secretion, and subsequently increases IGF-1 and IGFBP-3 levels.
Other Pituitary Hormones
- No clinically significant changes in the levels of other pituitary hormones, including thyroid-stimulating hormone (TSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH) and prolactin, were observed in subjects receiving tesamorelin® in Phase 3 clinical trials.
## Pharmacokinetics
Absorption
- The absolute bioavailability of tesamorelin® after subcutaneous administration of a 2 mg dose was determined to be less than 4% in healthy adult subjects. Single and multiple dose pharmacokinetics of tesamorelin® have been characterized in healthy subjects and HIV-infected patients without lipodystrophy following 2 mg subcutaneous administration.
- The mean values of the extent of absorption (AUC) for tesamorelin were 634.6 (72.4) and 852.8 (91.9) pg.h/mL in healthy subjects and HIV-infected patients, respectively, after a single subcutaneous administration of a 2 mg tesamorelin® dose. The mean (CV) peak tesamorelin concentration (Cmax) values were 2874.6 (43.9) pg/mL in healthy subjects and 2822.3 (48.9) pg/mL in HIV-infected patients. The median peak plasma tesamorelin concentration (Tmax) was 0.15 h in both populations.
Distribution
- The mean volume of distribution (±SD) of tesamorelin following a single subcutaneous administration was 9.4±3.1 L/kg in healthy subjects and 10.5±6.1 L/kg in HIV-infected patients.
Metabolism
- No formal metabolism studies have been performed in humans.
Elimination
- Mean elimination half-life (T1/2) of tesamorelin was 26 and 38 minutes in healthy subjects and HIV-infected patients, respectively, after subcutaneous administration for 14 consecutive days.
Drug Interactions
Simvastatin
- The effect of multiple dose administration of tesamorelin® (2 mg) on the pharmacokinetics of simvastatin and simvastatin acid was evaluated in healthy subjects. Co-administration of tesamorelin® and simvastatin (a sensitive CYP3A substrate) resulted in 8% decrease in extent of absorption (AUCinf) and 5% increase in rate of absorption (Cmax) of simvastatin. For simvastatin acid there was a 15% decrease in AUCinf and 1% decrease in Cmax.
Ritonavir
- The effect of multiple dose administration of tesamorelin® (2 mg) on the pharmacokinetics of ritonavir was evaluated in healthy subjects. Co-administration of tesamorelin® with ritonavir resulted in 9% decrease in AUCinf and 11% decrease in Cmax of ritonavir.
Specific Populations
- Pharmacokinetics of tesamorelin in patients with renal or hepatic impairment, in pediatric patients, or in elderly patients has not been established.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Life-time carcinogenicity studies in rodents have not been conducted with tesamorelin acetate. No potential mutagenicity of tesamorelin acetate was revealed in a battery of tests including induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (hamster CHOK1 cells), and chromosomal damage in intact animals (bone marrow cells in mice). There was no effect on fertility in male or female rats following administration of tesamorelin acetate at doses up to 0.6 mg/kg (approximately equal to clinical exposure) for 28 days in males or 14 days in females. In the 26-week toxicity study in rats, females given approximately 16 and 25 times the clinical dose were more likely to be in diestrus.
# Clinical Studies
- Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in HIV-infected patients with lipodystrophy and excess abdominal fat (abdominal lipohypertrophy). Both studies (Study 1 and 2) consisted of a 26-week Main Phase and a 26-week Extension Phase. Main inclusion criteria were age 18-65 years, a waist circumference ≥95 cm (37.4 inches) and a waist-to-hip ratio ≥0.94 for men and ≥94 cm (37.0 inches) and ≥0.88 for women, respectively, and fasting blood glucose (FBG) <150 mg/dL (8.33 mmol/L). Main exclusion criteria included BMI ≤ 20 kg/m2, type 1 diabetes, type 2 diabetes, if previously treated with insulin or with oral hypoglycemic or insulin-sensitizing agents, history of malignancy, and hypopituitarism. Patients were on a stable anti-retroviral regimen for at least 8 weeks prior to randomization. Patients meeting the inclusion/exclusion criteria were randomized in a 2:1 ratio to receive 2 mg tesamorelin® or placebo subcutaneously daily for 26 weeks. The primary efficacy assessment for each of these studies was the percent change from baseline to Week 26 (Main Phase) in visceral adipose tissue (VAT), as assessed by computed tomography (CT) scan at L4-L5 vertebral level. Secondary endpoints included changes from baseline in patient-reported outcomes related to body image, triglycerides, ratio of total cholesterol to HDL cholesterol, IGF-1 levels, and safety parameters. Other endpoints included changes from baseline in waist circumference, abdominal subcutaneous tissue (SAT), trunk fat, and lean body mass. In both studies, tesamorelin®-treated patients completing the 26-week treatment period were re-randomized to blinded therapy with either daily placebo or 2 mg tesamorelin® for an additional 26-week treatment period (Extension Phase) in order to assess maintenance of VAT reduction and to gather long-term safety data. For inclusion in the Extension Phase studies, subjects must have completed the Main Phase with FBG ≤ 150 mg/dL.
Main Phase (Baseline to Week 26):
Study 1
- This study randomized 412 HIV-infected patients with lipodystrophy and excess abdominal fat to receive either tesamorelin® (N=273) or placebo (N=137). At baseline for the two groups combined, mean age was 48 years; 86% were male; 75% were white, 14% were Black/African American, and 8% were Hispanic; mean weight was 90 kg; mean BMI was 29 kg/m2; mean waist circumference was 104 cm; mean hip circumference was 100 cm; mean VAT was 176 cm2; mean CD4 cell count was 606 cells/mm3; 69% had undetectable viral load (<50 copies/mL); and 33.7% randomized to tesamorelin® and 36.6% randomized to placebo had impaired glucose tolerance, while 5.6% randomized to tesamorelin® and 6.7% randomized to placebo had diet-controlled diabetes mellitus. The twenty-six week completion rate in Study 1 was 80%.
Study 2
- This study randomized 404 HIV-infected patients with lipodystrophy and excess abdominal fat to receive either tesamorelin® (N=270) or placebo (N=126). At baseline for the two groups combined, mean age was 48 years; 84% were male; 77% were white, 12% were Black/African American, and 9% were Hispanic; mean weight was 88 kg; mean BMI was 29 kg/m2; mean waist circumference was 105 cm; mean hip circumference was 100 cm; mean VAT was 189 cm2; mean CD4 cell count was 592 cells/mm3; 83% had undetectable viral load (<50 copies/mL); and 44.1% randomized to tesamorelin® and 39.7% randomized to placebo had impaired glucose tolerance, while 9.3% randomized to tesamorelin® and 9.5% randomized to placebo had diet-controlled diabetes mellitus. The twenty-six week completion rate in Study 2 was 74%.
- Results for the Main Phases of Studies 1 and 2 are presented in Tables 3 and 4.
- A subgroup analysis by gender showed that there were no statistical differences in the percent change from baseline in visceral adipose tissue (VAT) and IGF-1 responses, respectively, between males and females.
- At Week 26, treatment with tesamorelin® resulted in a reduction from baseline in mean trunk fat of 1.0 kg in Study 1 and 0.8 kg in Study 2, respectively (compared with an increase of 0.4 kg in Study 1 and of 0.2 kg in Study 2, respectively, in patients receiving placebo). Treatment with tesamorelin® resulted in an increase from baseline in mean lean body mass of 1.3 kg in Study 1 and of 1.2 kg in Study 2, respectively (compared with a decrease of 0.2 kg in Study 1 and of 0.03 kg in Study 2, respectively, in patients receiving placebo).
- On average, there were no adverse effects of tesamorelin® on lipids or subcutaneous adipose tissue (SAT). tesamorelin® did not adversely alter antiretroviral effectiveness, such as mean circulating levels of CD4 counts or HIV-1 RNA (viral load).
Patient Reported Outcomes
- Patients rated the degree of distress associated with their belly appearance on a 9-point rating scale that was then transformed to a score from 0 (extremely upsetting and distressing) to 100 (extremely encouraging). A score of 50 indicated neutral (no feeling either way). A positive change from baseline score indicated improvement, i.e., less distress.
- The cumulative distribution of response (change from baseline to 26 weeks) is shown in Figure 1 for both treatment groups. A curve shifted to the right on this scale indicates a greater percentage of patients reporting improvement.
Extension Phase (Weeks 26-52):
- In the double-blind Extension Phase, patients on tesamorelin® completing the 26-week Main Phase were re-randomized to receive 2 mg tesamorelin® or placebo.
Study 1
- This study re-randomized 207 HIV-infected patients with lipodystrophy who completed tesamorelin® treatment in the Main Phase to receive either tesamorelin® (N=154) or placebo (N=50) for an additional 26-week duration (3:1 randomization ratio). At baseline (Week 26) for the two groups combined, mean age was 48 years; 88% were male; 78% were white, 12% were Black/African American, and 8% were Hispanic; mean weight was 90 kg; mean BMI was 29 kg/m2; mean waist circumference was 102 cm; mean hip circumference was 100 cm; mean VAT was 145 cm2; mean CD4 cell count was 639 cells/mm3; 68% had undetectable viral load (<50 copies/mL); and for those tesamorelin®-treated patients completing the 26-week treatment period that were re-randomized to tesamorelin® (T-T group) or re-randomized to placebo, 36.6% and 32.0%, respectively, had impaired glucose tolerance, while 2.0% re-randomized to tesamorelin® and 6.0% re-randomized to placebo had diet-controlled diabetes mellitus. The completion rate for patients randomized into the extension phase of Study 1 was 83%.
Study 2
- This study re-randomized 177 HIV-infected patients with lipodystrophy who completed tesamorelin® treatment in the Main Phase to receive either tesamorelin® (N=92) or placebo (N=85) for an additional 26-week duration (1:1 randomization ratio). At baseline (Week 26) for the two groups combined, mean age was 48 years; 90% were male; 84% were white, 9% were Black/African American, and 7% were Hispanic; mean weight was 89 kg; mean BMI was 28 kg/m2; mean waist circumference was 105 cm; mean hip circumference was 100 cm; mean VAT was 172 cm2; mean CD4 cell count was 579 cells/mm3; 82% had undetectable viral load (<50 copies/mL); and for those tesamorelin®-treated patients completing the 26-week treatment period that were re-randomized to tesamorelin® (T-T group) or re-randomized to placebo, 48.9% and 50.6%, respectively, had impaired glucose tolerance, while 4.3% re-randomized to tesamorelin® and 12.9% re-randomized to placebo had diet-controlled diabetes mellitus. The completion rate for patients randomized into the extension phase of Study 2 was 81%.
- Results for the Extension Phases of Studies 1 and 2 are presented in Tables 5 and 6.
- Figure 2. shows the percent change in VAT from baseline (Week 0) over time until 52 weeks in completer patients.
- Data in Figure 2 are expressed as mean values. T-T (tesamorelin to tesamorelin) refers to the group of patients who received tesamorelin for Weeks 0-26 and were re-randomized to tesamorelin for Weeks 26-52. T-P (tesamorelin to placebo) refers to the group of patients who received tesamorelin for Weeks 0-26 and were re-randomized to placebo for Weeks 26-52. P-T (placebo to tesamorelin) refers to the group of patients who received placebo for Weeks 0-26 and were switched to tesamorelin (treated open label) for Weeks 26-52.
- Patients treated with tesamorelin® for 52 weeks (T-T group) showed no change between Weeks 26 and 52 in mean trunk fat (increase of 0.1 kg in Study 1 and decrease of 0.5 kg in Study 2, respectively, compared with an increase of 1.4 kg in patients in the T-P group in Study 1 and an increase of 1.09 kg in Study 2, respectively) nor was there a change from Week 26 baseline in mean lean body mass (decrease of 0.1 kg in Study 1 and increase of 0.1 kg in Study 2, respectively, compared with a decrease of 1.8 kg in patients in the T-P group in Study 1 and a decrease of 1.7 kg in Study 2, respectively).
- There was no adverse effect of tesamorelin® on lipids or subcutaneous adipose tissue (SAT). tesamorelin® did not adversely alter antiretroviral effectiveness, such as mean circulating levels of CD4 counts or HIV-1 RNA (viral load).
# How Supplied
- Tesamorelin (tesamorelin for injection) is supplied as a sterile, white to off-white lyophilized powder. Each single-use vial of tesamorelin® contains 2 mg of tesamorelin as the free base (2.2 mg tesamorelin acetate, anhydrous) and the following inactive ingredient: 100 mg mannitol, USP.
- tesamorelin® is available in a package comprised of two boxes. One box contains 30 vials of tesamorelin® and a second box contains 30 single-use 10 mL bottles of reconstitution diluent (Sterile Water for Injection, USP), disposable syringes, and needles sufficient for a 30 day supply.
- After reconstitution with Sterile Water for Injection, USP the reconstituted solution concentration is 1 mg/mL and should be injected immediately.
## Storage
- Tesamorelin vials should be protected from light and be kept in the original box until time of use. Non-reconstituted tesamorelin® must be stored at refrigerated temperature, between 2°C and 8°C (36°F and 46°F) until dispensed. Upon dispensing, the patient may store non-reconstituted tesamorelin® at refrigerated temperature until the expiration date, or at or below 25°C (77°F) for 3 months or until the expiration date, whichever occurs first. The reconstitution diluent (Sterile Water for Injection, USP), syringes and needles should be stored at controlled room temperature of 20ºC to 25ºC (68°F to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Fluid retention – Advise patients that treatment with tesamorelin may cause symptoms consistent with fluid retention, including edema, arthralgia, and carpal tunnel syndrome. These reactions are either transient or resolve with discontinuation of treatment.
- Hypersensitivity Reactions – Advise patients that hypersensitivity reactions (e.g., rash, urticaria) may occur during treatment with tesamorelin®. Advise patients to seek prompt medical attention and to immediately discontinue treatment with tesamorelin®.
Injection Site Reactions – Advise patients of possible injection site reactions, including injection site erythema, pruritus, pain, irritation, and bruising. To reduce the incidence of injection site reactions, advise patients to rotate the site of injection.
- Counsel patients that they should never share an tesamorelin® syringe with another person, even if the needle is changed. Sharing of syringes or needles between patients may pose a risk of transmission of infection.
Pregnancy
- Advise women to discontinue tesamorelin® if pregnancy occurs, as the drug offers no known benefit to pregnant women and could result in fetal harm.
Nursing Mothers
- Because of both the potential for HIV-1 infection transmission and serious adverse reactions in nursing infants, mothers receiving tesamorelin® should be instructed not to human milk-feed
# Precautions with Alcohol
- Alcohol-Tesamorelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tesamorelin
# Look-Alike Drug Names
# Drug Shortage Status
# Price | Tesamorelin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [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
Tesamorelin is a Growth hormone secretagogues that is FDA approved for the treatment of reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. Common adverse reactions include arthralgia, injection site erythema, injection site pruritis, pain in extremity, peripheral edema, myalgia..
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Tesamorelin® (tesamorelin for injection) is indicated for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy.
Limitations of Use:
- Since the long-term cardiovascular safety and potential long-term cardiovascular benefit of tesamorelin treatment have not been studied and are not known, careful consideration should be given whether to continue tesamorelin treatment in patients who do not show a clear efficacy response as judged by the degree of reduction in visceral adipose tissue measured by waist circumference or CT scan.
- Tesamorelin is not indicated for weight loss management (weight neutral effect).
- There are no data to support improved compliance with anti-retroviral therapies in HIV-positive patients taking tesamorelin.
# Dosage
General Dosing Information
- The recommended dose of tesamorelin is 2 mg injected subcutaneously once a day.
- The recommended injection site is the abdomen. Injection sites should be rotated to different areas of the abdomen. Do not inject into scar tissue, bruises or the navel.
# DOSAGE FORMS AND STRENGTHS
- Tesamorelin (tesamorelin for injection) is supplied in a vial containing 2 mg of tesamorelin as a lyophilized powder. The diluent (Sterile Water for Injection, USP 10 mL) is provided in a separate bottle.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tesamorelin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tesamorelin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tesamorelin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tesamorelin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tesamorelin in pediatric patients.
# Contraindications
Disruption of the Hypothalamic-pituitary Axis
- Tesamorelin is contraindicated in patients with disruption of the hypothalamic-pituitary axis due to hypophysectomy, hypopituitarism, pituitary tumor/surgery, head irradiation or head trauma.
Active Malignancy
- Tesamorelin is contraindicated in patients with active malignancy (either newly diagnosed or recurrent). Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with tesamorelin.
Hypersensitivity
- Tesamorelin is contraindicated in patients with known hypersensitivity to tesamorelin and/or mannitol (an excipient).
Pregnancy
- Tesamorelin is contraindicated in pregnant women. During pregnancy, visceral adipose tissue increases due to normal metabolic and hormonal changes. Modifying this physiologic change of pregnancy with tesamorelin offers no known benefit and could result in fetal harm. Tesamorelin acetate administration to rats during organogenesis and lactation resulted in hydrocephalus in offspring at a dose approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). If pregnancy occurs, discontinue tesamorelin therapy. 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 the fetus
# Warnings
Neoplasms
- Tesamorelin induces the release of endogenous growth hormone (GH), a known growth factor. Thus, patients with active malignancy should not be treated with tesamorelin.
- For patients with a history of non-malignant neoplasms, tesamorelin therapy should be initiated after careful evaluation of the potential benefit of treatment. For patients with a history of treated and stable malignancies, tesamorelin therapy should be initiated only after careful evaluation of the potential benefit of treatment relative to the risk of re-activation of the underlying malignancy.
- In addition, the decision to start treatment with tesamorelin should be considered carefully based on the increased background risk of malignancies in HIV-positive patients.
Elevated IGF-1
- Tesamorelin stimulates GH production and increases serum IGF-1. Given that IGF-1 is a growth factor and the effect of prolonged elevations in IGF-1 levels on the development or progression of malignancies is unknown, IGF-1 levels should be monitored closely during tesamorelin therapy. Careful consideration should be given to discontinuing tesamorelin in patients with persistent elevations of IGF-1 levels (e.g., >3 SDS), particularly if the efficacy response is not robust (e.g., based on visceral adipose tissue changes measured by waist circumference or CT scan).
- During the clinical trials, patients were monitored every three months. Among patients who received tesamorelin for 26 weeks, 47.4% had IGF-1 levels greater than 2 standard deviation scores (SDS), and 35.6% had SDS >3, with this effect seen as early as 13 weeks of treatment. Among those patients who remained on tesamorelin for a total of 52 weeks, at the end of treatment 33.7% had IGF-1 SDS >2 and 22.6% had IGF-1 SDS >3.
Fluid Retention
- Fluid retention may occur during tesamorelin therapy and is thought to be related to the induction of GH secretion. It manifests as increased tissue turgor and musculoskeletal discomfort resulting in a variety of adverse reactions (e.g. edema, arthralgia, carpal tunnel syndrome) which are either transient or resolve with discontinuation of treatment.
Glucose Intolerance
- Tesamorelin treatment may result in glucose intolerance. During the Phase 3 clinical trials, the percentages of patients with elevated HbA1c (≥ 6.5%) from baseline to Week 26 were 4.5% and 1.3% in the tesamorelin and placebo groups, respectively. An increased risk of developing diabetes with tesamorelin (HbA1c level ≥ 6.5%) relative to placebo was observed [intent-to-treat hazard odds ratio of 3.3 (CI 1.4, 9.6)]. Therefore, glucose status should be carefully evaluated prior to initiating tesamorelin treatment. In addition, all patients treated with tesamorelin should be monitored periodically for changes in glucose metabolism to diagnose those who develop impaired glucose tolerance or diabetes. Diabetes is a known cardiovascular risk factor and patients who develop glucose intolerance have an elevated risk for developing diabetes. Caution should be exercised in treating HIV-positive patients with lipodystrophy with tesamorelin if they develop glucose intolerance or diabetes, and careful consideration should be given to discontinuing tesamorelin treatment in patients who do not show a clear efficacy response as judged by the degree of reduction in visceral adipose tissue by waist circumference or CT scan measurements.
- Since tesamorelin increases IGF-1, patients with diabetes who are receiving ongoing treatment with tesamorelin should be monitored at regular intervals for potential development or worsening of retinopathy.
Hypersensitivity Reactions
- Hypersensitivity reactions may occur in patients treated with tesamorelin. Hypersensitivity reactions occurred in 3.6% of patients with HIV-associated lipodystrophy treated with tesamorelin in the Phase 3 clinical trials. These reactions included pruritus, erythema, flushing, urticaria, and other rash. In cases of suspected hypersensitivity reactions, patients should be advised to seek prompt medical attention and treatment with tesamorelin should be discontinued immediately.
Injection Site Reactions
- Tesamorelin treatment may cause injection site reactions, including injection site erythema, pruritus, pain, irritation, and bruising. The incidence of injection site reactions was 24.5% in tesamorelin-treated patients and 14.4% in placebo-treated patients during the first 26 weeks of treatment in the Phase 3 clinical trials. For patients who continued tesamorelin® for an additional 26 weeks, the incidence of injection site reactions was 6.1%. In order to reduce the incidence of injection site reactions, it is recommended to rotate the site of injection to different areas of the abdomen.
Acute Critical Illness
- Increased mortality in patients with acute critical illness due to complications following open heart surgery, abdominal surgery or multiple accidental trauma, or those with acute respiratory failure has been reported after treatment with pharmacologic amounts of growth hormone. tesamorelin® has not been studied in patients with acute critical illness. Since tesamorelin® stimulates growth hormone production, careful consideration should be given to discontinuing tesamorelin® in critically ill patients.
# Adverse Reactions
## Clinical Trials Experience
- The most commonly reported adverse reactions are hypersensitivity (e.g., rash, urticaria) reactions due to the effect of GH (e.g., arthralgia, extremity pain, peripheral edema, hyperglycemia, carpal tunnel syndrome), injection site reactions (injection site erythema, pruritis, pain, urticaria, irritation, swelling, hemorrhage).
- During the first 26 weeks of treatment (main phase), discontinuations as a result of adverse reactions occurred in 9.6% of patients receiving tesamorelin® and 6.8% of patients receiving placebo. Apart from patients with hypersensitivity reactions identified during the studies and who were discontinued per protocol (2.2%), the most common reasons for discontinuation of tesamorelin® treatment were adverse reactions due to the effect of GH (4.2%) and local injection site reactions (4.6%).
- During the following 26 weeks of treatment (extension phase), discontinuations as a result of adverse events occurred in 2.4% of patients in the T-T group (patients treated with tesamorelin for Week 0-26 and with tesamorelin for Week 26-52) and 5.2% of patients in the T-P group (patients treated with tesamorelin for Week 0-26 and with placebo for Week 26-52).
Clinical Trial 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.
- Seven hundred and forty HIV-infected patients with lipodystrophy and excess abdominal fat were exposed to tesamorelin® in the Phase 3 clinical trials; of these 543 received tesamorelin® during the initial 26-week placebo-controlled phase.
- Adverse reactions that occurred more frequently with tesamorelin® relative to placebo and had an incidence ≥1% during the first 26 weeks across all studies are presented in Table 1.
- Mean levels of fasting blood glucose and fasting insulin were not significantly different between tesamorelin® -treated and placebo-treated patients after 26 weeks of treatment.
- In the tesamorelin Phase 3 clinical trials, mean baseline (Week 0) HbA1c was 5.26% among patients in the tesamorelin® group and 5.28% among those in the placebo group. At Week 26, mean HbA1c was higher among patients treated with tesamorelin® compared with placebo (5.39% vs. 5.28% for the tesamorelin® and placebo groups, respectively, mean treatment difference of 0.12%, p=0.0004). Patients receiving tesamorelin® had an increased risk of developing diabetes (HbA1c level ≥ 6.5%) compared with placebo (4.5% vs. 1.3%), with a hazard ratio of 3.3 (CI 1.4, 9.6).
- Adverse reactions observed during Week 26 to 52 of the Phase 3 clinical trials which had an incidence of ≥1% and were seen more frequently with tesamorelin® relative to placebo are presented in Table 2:
- For patients who continued from Week 26-52, mean levels of fasting blood glucose, fasting insulin, and HbA1c were not different between the T-T and T-P groups.
Immunogenicity
- As with all therapeutic proteins and peptides, there is a potential for in vivo development of anti- tesamorelin® antibodies. In the combined Phase 3 clinical trials anti-tesamorelin IgG antibodies were detected in 49.5% of patients treated with tesamorelin® for 26 weeks and 47.4% of patients who received tesamorelin® for 52 weeks. In the subset of patients with hypersensitivity reactions, anti-tesamorelin IgG antibodies were detected in 85.2%. Cross-reactivity to endogenous growth hormone-releasing hormone (GHRH) was observed in approximately 60% of patients who developed anti-tesamorelin antibodies. Patients with and without anti-tesamorelin IgG antibodies had similar mean reductions in visceral adipose tissue (VAT) and IGF-1 response suggesting that the presence of antibodies did not alter the efficacy of tesamorelin®. In a group of patients who had antibodies to tesamorelin after 26 weeks of treatment (56%) and were re-assessed 6 months later, after stopping tesamorelin® treatment, 18% were still antibody positive.
- Neutralizing antibodies to tesamorelin and hGHRH were detected in vitro at Week 52 in 10% and 5% of tesamorelin®-treated patients, respectively. They did not appear to have an impact on efficacy, as evidenced by comparable changes in VAT and IGF-1 level in patients with or without in vitro neutralizing antibodies.
- The observed incidence of antibody positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, methodology, sample handling, timing of sample collection, concomitant medication and underlying disease. For these reasons, comparison of the incidence of antibodies to tesamorelin® with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tesamorelin in the drug label.
# Drug Interactions
Cytochrome P450-Metabolized Drugs
- Co-administration of tesamorelin® with simvastatin, a sensitive CYP3A substrate, showed that tesamorelin® had no significant impact on the pharmacokinetics profiles of simvastatin in healthy subjects. This result suggests that tesamorelin® may not significantly affect CYP3A activity. Other isoenzymes of CYP450 have not been evaluated with tesamorelin®. Published data, however, indicate that GH may modulate cytochrome P450 (CYP450) mediated antipyrine clearance in man. These data suggest that GH may alter the clearance of compounds known to be metabolized by CYP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine). Because tesamorelin stimulates GH production, careful monitoring is advisable when tesamorelin® is administered in combination with other drugs known to be metabolized by CYP450 liver enzymes.
11β-Hydroxysteroid Dehydrogenase Type 1 (11βHSD-1)
- GH is known to inhibit 11β-hydroxysteroid dehydrogenase type 1 (11βHSD-1), a microsomal enzyme required for conversion of cortisone to its active metabolite, cortisol, in hepatic and adipose tissue. Because tesamorelin stimulates GH production, patients receiving glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in maintenance or stress doses following initiation of tesamorelin®, particularly in patients treated with cortisone acetate and prednisone because conversion of these drugs to their biologically active metabolites is dependent on the activity of 11βHSD-1.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Pregnancy Category X
- Tesamorelin is contraindicated in pregnant women. During pregnancy, visceral adipose tissue increases due to normal metabolic and hormonal changes. Modifying this physiologic change of pregnancy with tesamorelin® offers no known benefit and could result in fetal harm. Tesamorelin acetate administration to rats during organogenesis and lactation resulted in hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). If pregnancy occurs, discontinue tesamorelin® therapy. 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 the fetus.
- Tesamorelin acetate administration to rats during organogenesis and lactation produced hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). Actual animal dose was 1.2 mg/kg. During organogenesis, lower doses approximately 0.1 to 1 times the clinical dose caused delayed skull ossification in rats. Actual animal doses were 0.1 to 0.6 mg/kg. No adverse developmental effects occurred in rabbits using doses up to approximately 500 times the clinical dose.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tesamorelin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tesamorelin during labor and delivery.
### Nursing Mothers
- The Centers for Disease Control and Prevention recommend that HIV-infected mothers in the United States not human milk-feed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of both the potential for HIV-1 infection transmission and serious adverse reactions in nursing infants, mothers receiving tesamorelin® should be instructed not to human milk-feed.
- It is not known whether tesamorelin® is excreted in human milk. Tesamorelin acetate administration to rats during organogenesis and lactation resulted in hydrocephaly in offspring at a dose of approximately two and four times the clinical dose, respectively, based on measured drug exposure (AUC). Actual animal dose was 1.2 mg/kg.
### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established. Tesamorelin® should not be used in children with open epiphyses, among whom excess GH and IGF-1 may result in linear growth acceleration and excessive growth.
### Geriatic Use
- There is no information on the use of tesamorelin® in patients greater than 65 years of age with HIV and lipodystrophy
### Gender
There is no FDA guidance on the use of Tesamorelin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tesamorelin with respect to specific racial populations.
### Renal Impairment
Safety, efficacy, and pharmacokinetics of tesamorelin® in patients with renal impairment have not been established.
### Hepatic Impairment
- Safety, efficacy, and pharmacokinetics of tesamorelin® in patients with hepatic impairment have not been established.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tesamorelin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tesamorelin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Reconstituted tesamorelin® solution should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. tesamorelin® must be injected only if the solution is clear, colorless and without particulate matter.
- Tesamorelin® should be injected subcutaneously into the skin on the abdomen. Injection sites should be rotated to different areas of the abdomen. Do not inject into scar tissue, bruises or the navel.
### Monitoring
There is limited information regarding Monitoring of Tesamorelin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tesamorelin in the drug label.
# Overdosage
- No data are available on overdosage.
# Pharmacology
-
## Mechanism of Action
- In vitro, tesamorelin binds and stimulates human GRF receptors with similar potency as the endogenous GRF.
- Growth Hormone-Releasing Factor (GRF), also known as growth hormone-releasing hormone (GHRH), is a hypothalamic peptide that acts on the pituitary somatotroph cells to stimulate the synthesis and pulsatile release of endogenous growth hormone (GH), which is both anabolic and lipolytic. GH exerts its effects by interacting with specific receptors on a variety of target cells, including chondrocytes, osteoblasts, myocytes, hepatocytes, and adipocytes, resulting in a host of pharmacodynamic effects. Some, but not all these effects, are primarily mediated by IGF-1 produced in the liver and in peripheral tissues.
## Structure
- Patients treated with tesamorelin® for 52 weeks (T-T group) showed no change between Weeks 26 and 52 in mean trunk fat (increase of 0.1 kg in Study 1 and decrease of 0.5 kg in Study 2, respectively, compared with an increase of 1.4 kg in patients in the T-P group in Study 1 and an increase of 1.09 kg in Study 2, respectively) nor was there a change from Week 26 baseline in mean lean body mass (decrease of 0.1 kg in Study 1 and increase of 0.1 kg in Study 2, respectively, compared with a decrease of 1.8 kg in patients in the T-P group in Study 1 and a decrease of 1.7 kg in Study 2, respectively).
- There was no adverse effect of tesamorelin® on lipids or subcutaneous adipose tissue (SAT). tesamorelin® did not adversely alter antiretroviral effectiveness, such as mean circulating levels of CD4 counts or HIV-1 RNA (viral load).
- Tesamorelin® is a sterile, white to off-white, preservative-free lyophilized powder for subcutaneous injection. After reconstitution with the supplied diluent (Sterile Water for Injection, USP), a solution of tesamorelin® is clear and colorless. Each single-use vial of tesamorelin® contains 2 mg of tesamorelin as the free base (2.2 mg tesamorelin acetate, anhydrous) and the following inactive ingredient: 100 mg mannitol, US
## Pharmacodynamics
Effects on IGF-1 and IGFBP-3 levels
- Tesamorelin stimulates growth hormone secretion, and subsequently increases IGF-1 and IGFBP-3 levels.
Other Pituitary Hormones
- No clinically significant changes in the levels of other pituitary hormones, including thyroid-stimulating hormone (TSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH) and prolactin, were observed in subjects receiving tesamorelin® in Phase 3 clinical trials.
## Pharmacokinetics
Absorption
- The absolute bioavailability of tesamorelin® after subcutaneous administration of a 2 mg dose was determined to be less than 4% in healthy adult subjects. Single and multiple dose pharmacokinetics of tesamorelin® have been characterized in healthy subjects and HIV-infected patients without lipodystrophy following 2 mg subcutaneous administration.
- The mean values [coefficient of variation (CV)] of the extent of absorption (AUC) for tesamorelin were 634.6 (72.4) and 852.8 (91.9) pg.h/mL in healthy subjects and HIV-infected patients, respectively, after a single subcutaneous administration of a 2 mg tesamorelin® dose. The mean (CV) peak tesamorelin concentration (Cmax) values were 2874.6 (43.9) pg/mL in healthy subjects and 2822.3 (48.9) pg/mL in HIV-infected patients. The median peak plasma tesamorelin concentration (Tmax) was 0.15 h in both populations.
Distribution
- The mean volume of distribution (±SD) of tesamorelin following a single subcutaneous administration was 9.4±3.1 L/kg in healthy subjects and 10.5±6.1 L/kg in HIV-infected patients.
Metabolism
- No formal metabolism studies have been performed in humans.
Elimination
- Mean elimination half-life (T1/2) of tesamorelin was 26 and 38 minutes in healthy subjects and HIV-infected patients, respectively, after subcutaneous administration for 14 consecutive days.
Drug Interactions
Simvastatin
- The effect of multiple dose administration of tesamorelin® (2 mg) on the pharmacokinetics of simvastatin and simvastatin acid was evaluated in healthy subjects. Co-administration of tesamorelin® and simvastatin (a sensitive CYP3A substrate) resulted in 8% decrease in extent of absorption (AUCinf) and 5% increase in rate of absorption (Cmax) of simvastatin. For simvastatin acid there was a 15% decrease in AUCinf and 1% decrease in Cmax.
Ritonavir
- The effect of multiple dose administration of tesamorelin® (2 mg) on the pharmacokinetics of ritonavir was evaluated in healthy subjects. Co-administration of tesamorelin® with ritonavir resulted in 9% decrease in AUCinf and 11% decrease in Cmax of ritonavir.
Specific Populations
- Pharmacokinetics of tesamorelin in patients with renal or hepatic impairment, in pediatric patients, or in elderly patients has not been established.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
- Life-time carcinogenicity studies in rodents have not been conducted with tesamorelin acetate. No potential mutagenicity of tesamorelin acetate was revealed in a battery of tests including induction of gene mutations in bacteria (the Ames test), gene mutations in mammalian cells grown in vitro (hamster CHOK1 cells), and chromosomal damage in intact animals (bone marrow cells in mice). There was no effect on fertility in male or female rats following administration of tesamorelin acetate at doses up to 0.6 mg/kg (approximately equal to clinical exposure) for 28 days in males or 14 days in females. In the 26-week toxicity study in rats, females given approximately 16 and 25 times the clinical dose were more likely to be in diestrus.
# Clinical Studies
- Two multicenter, randomized, double-blind, placebo-controlled studies were conducted in HIV-infected patients with lipodystrophy and excess abdominal fat (abdominal lipohypertrophy). Both studies (Study 1 and 2) consisted of a 26-week Main Phase and a 26-week Extension Phase. Main inclusion criteria were age 18-65 years, a waist circumference ≥95 cm (37.4 inches) and a waist-to-hip ratio ≥0.94 for men and ≥94 cm (37.0 inches) and ≥0.88 for women, respectively, and fasting blood glucose (FBG) <150 mg/dL (8.33 mmol/L). Main exclusion criteria included BMI ≤ 20 kg/m2, type 1 diabetes, type 2 diabetes, if previously treated with insulin or with oral hypoglycemic or insulin-sensitizing agents, history of malignancy, and hypopituitarism. Patients were on a stable anti-retroviral regimen for at least 8 weeks prior to randomization. Patients meeting the inclusion/exclusion criteria were randomized in a 2:1 ratio to receive 2 mg tesamorelin® or placebo subcutaneously daily for 26 weeks. The primary efficacy assessment for each of these studies was the percent change from baseline to Week 26 (Main Phase) in visceral adipose tissue (VAT), as assessed by computed tomography (CT) scan at L4-L5 vertebral level. Secondary endpoints included changes from baseline in patient-reported outcomes related to body image, triglycerides, ratio of total cholesterol to HDL cholesterol, IGF-1 levels, and safety parameters. Other endpoints included changes from baseline in waist circumference, abdominal subcutaneous tissue (SAT), trunk fat, and lean body mass. In both studies, tesamorelin®-treated patients completing the 26-week treatment period were re-randomized to blinded therapy with either daily placebo or 2 mg tesamorelin® for an additional 26-week treatment period (Extension Phase) in order to assess maintenance of VAT reduction and to gather long-term safety data. For inclusion in the Extension Phase studies, subjects must have completed the Main Phase with FBG ≤ 150 mg/dL.
Main Phase (Baseline to Week 26):
Study 1
- This study randomized 412 HIV-infected patients with lipodystrophy and excess abdominal fat to receive either tesamorelin® (N=273) or placebo (N=137). At baseline for the two groups combined, mean age was 48 years; 86% were male; 75% were white, 14% were Black/African American, and 8% were Hispanic; mean weight was 90 kg; mean BMI was 29 kg/m2; mean waist circumference was 104 cm; mean hip circumference was 100 cm; mean VAT was 176 cm2; mean CD4 cell count was 606 cells/mm3; 69% had undetectable viral load (<50 copies/mL); and 33.7% randomized to tesamorelin® and 36.6% randomized to placebo had impaired glucose tolerance, while 5.6% randomized to tesamorelin® and 6.7% randomized to placebo had diet-controlled diabetes mellitus. The twenty-six week completion rate in Study 1 was 80%.
Study 2
- This study randomized 404 HIV-infected patients with lipodystrophy and excess abdominal fat to receive either tesamorelin® (N=270) or placebo (N=126). At baseline for the two groups combined, mean age was 48 years; 84% were male; 77% were white, 12% were Black/African American, and 9% were Hispanic; mean weight was 88 kg; mean BMI was 29 kg/m2; mean waist circumference was 105 cm; mean hip circumference was 100 cm; mean VAT was 189 cm2; mean CD4 cell count was 592 cells/mm3; 83% had undetectable viral load (<50 copies/mL); and 44.1% randomized to tesamorelin® and 39.7% randomized to placebo had impaired glucose tolerance, while 9.3% randomized to tesamorelin® and 9.5% randomized to placebo had diet-controlled diabetes mellitus. The twenty-six week completion rate in Study 2 was 74%.
- Results for the Main Phases of Studies 1 and 2 are presented in Tables 3 and 4.
- A subgroup analysis by gender showed that there were no statistical differences in the percent change from baseline in visceral adipose tissue (VAT) and IGF-1 responses, respectively, between males and females.
- At Week 26, treatment with tesamorelin® resulted in a reduction from baseline in mean trunk fat of 1.0 kg in Study 1 and 0.8 kg in Study 2, respectively (compared with an increase of 0.4 kg in Study 1 and of 0.2 kg in Study 2, respectively, in patients receiving placebo). Treatment with tesamorelin® resulted in an increase from baseline in mean lean body mass of 1.3 kg in Study 1 and of 1.2 kg in Study 2, respectively (compared with a decrease of 0.2 kg in Study 1 and of 0.03 kg in Study 2, respectively, in patients receiving placebo).
- On average, there were no adverse effects of tesamorelin® on lipids or subcutaneous adipose tissue (SAT). tesamorelin® did not adversely alter antiretroviral effectiveness, such as mean circulating levels of CD4 counts or HIV-1 RNA (viral load).
Patient Reported Outcomes
- Patients rated the degree of distress associated with their belly appearance on a 9-point rating scale that was then transformed to a score from 0 (extremely upsetting and distressing) to 100 (extremely encouraging). A score of 50 indicated neutral (no feeling either way). A positive change from baseline score indicated improvement, i.e., less distress.
- The cumulative distribution of response (change from baseline to 26 weeks) is shown in Figure 1 for both treatment groups. A curve shifted to the right on this scale indicates a greater percentage of patients reporting improvement.
Extension Phase (Weeks 26-52):
- In the double-blind Extension Phase, patients on tesamorelin® completing the 26-week Main Phase were re-randomized to receive 2 mg tesamorelin® or placebo.
Study 1
- This study re-randomized 207 HIV-infected patients with lipodystrophy who completed tesamorelin® treatment in the Main Phase to receive either tesamorelin® (N=154) or placebo (N=50) for an additional 26-week duration (3:1 randomization ratio). At baseline (Week 26) for the two groups combined, mean age was 48 years; 88% were male; 78% were white, 12% were Black/African American, and 8% were Hispanic; mean weight was 90 kg; mean BMI was 29 kg/m2; mean waist circumference was 102 cm; mean hip circumference was 100 cm; mean VAT was 145 cm2; mean CD4 cell count was 639 cells/mm3; 68% had undetectable viral load (<50 copies/mL); and for those tesamorelin®-treated patients completing the 26-week treatment period that were re-randomized to tesamorelin® (T-T group) or re-randomized to placebo, 36.6% and 32.0%, respectively, had impaired glucose tolerance, while 2.0% re-randomized to tesamorelin® and 6.0% re-randomized to placebo had diet-controlled diabetes mellitus. The completion rate for patients randomized into the extension phase of Study 1 was 83%.
Study 2
- This study re-randomized 177 HIV-infected patients with lipodystrophy who completed tesamorelin® treatment in the Main Phase to receive either tesamorelin® (N=92) or placebo (N=85) for an additional 26-week duration (1:1 randomization ratio). At baseline (Week 26) for the two groups combined, mean age was 48 years; 90% were male; 84% were white, 9% were Black/African American, and 7% were Hispanic; mean weight was 89 kg; mean BMI was 28 kg/m2; mean waist circumference was 105 cm; mean hip circumference was 100 cm; mean VAT was 172 cm2; mean CD4 cell count was 579 cells/mm3; 82% had undetectable viral load (<50 copies/mL); and for those tesamorelin®-treated patients completing the 26-week treatment period that were re-randomized to tesamorelin® (T-T group) or re-randomized to placebo, 48.9% and 50.6%, respectively, had impaired glucose tolerance, while 4.3% re-randomized to tesamorelin® and 12.9% re-randomized to placebo had diet-controlled diabetes mellitus. The completion rate for patients randomized into the extension phase of Study 2 was 81%.
- Results for the Extension Phases of Studies 1 and 2 are presented in Tables 5 and 6.
- Figure 2. shows the percent change in VAT from baseline (Week 0) over time until 52 weeks in completer patients.
- Data in Figure 2 are expressed as mean values. T-T (tesamorelin to tesamorelin) refers to the group of patients who received tesamorelin for Weeks 0-26 and were re-randomized to tesamorelin for Weeks 26-52. T-P (tesamorelin to placebo) refers to the group of patients who received tesamorelin for Weeks 0-26 and were re-randomized to placebo for Weeks 26-52. P-T (placebo to tesamorelin) refers to the group of patients who received placebo for Weeks 0-26 and were switched to tesamorelin (treated open label) for Weeks 26-52.
- Patients treated with tesamorelin® for 52 weeks (T-T group) showed no change between Weeks 26 and 52 in mean trunk fat (increase of 0.1 kg in Study 1 and decrease of 0.5 kg in Study 2, respectively, compared with an increase of 1.4 kg in patients in the T-P group in Study 1 and an increase of 1.09 kg in Study 2, respectively) nor was there a change from Week 26 baseline in mean lean body mass (decrease of 0.1 kg in Study 1 and increase of 0.1 kg in Study 2, respectively, compared with a decrease of 1.8 kg in patients in the T-P group in Study 1 and a decrease of 1.7 kg in Study 2, respectively).
- There was no adverse effect of tesamorelin® on lipids or subcutaneous adipose tissue (SAT). tesamorelin® did not adversely alter antiretroviral effectiveness, such as mean circulating levels of CD4 counts or HIV-1 RNA (viral load).
# How Supplied
- Tesamorelin (tesamorelin for injection) is supplied as a sterile, white to off-white lyophilized powder. Each single-use vial of tesamorelin® contains 2 mg of tesamorelin as the free base (2.2 mg tesamorelin acetate, anhydrous) and the following inactive ingredient: 100 mg mannitol, USP.
- tesamorelin® is available in a package comprised of two boxes. One box contains 30 vials of tesamorelin® and a second box contains 30 single-use 10 mL bottles of reconstitution diluent (Sterile Water for Injection, USP), disposable syringes, and needles sufficient for a 30 day supply.
- After reconstitution with Sterile Water for Injection, USP the reconstituted solution concentration is 1 mg/mL and should be injected immediately.
## Storage
- Tesamorelin vials should be protected from light and be kept in the original box until time of use. Non-reconstituted tesamorelin® must be stored at refrigerated temperature, between 2°C and 8°C (36°F and 46°F) until dispensed. Upon dispensing, the patient may store non-reconstituted tesamorelin® at refrigerated temperature until the expiration date, or at or below 25°C (77°F) for 3 months or until the expiration date, whichever occurs first. The reconstitution diluent (Sterile Water for Injection, USP), syringes and needles should be stored at controlled room temperature of 20ºC to 25ºC (68°F to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Fluid retention – Advise patients that treatment with tesamorelin may cause symptoms consistent with fluid retention, including edema, arthralgia, and carpal tunnel syndrome. These reactions are either transient or resolve with discontinuation of treatment.
- Hypersensitivity Reactions – Advise patients that hypersensitivity reactions (e.g., rash, urticaria) may occur during treatment with tesamorelin®. Advise patients to seek prompt medical attention and to immediately discontinue treatment with tesamorelin®.
Injection Site Reactions – Advise patients of possible injection site reactions, including injection site erythema, pruritus, pain, irritation, and bruising. To reduce the incidence of injection site reactions, advise patients to rotate the site of injection.
- Counsel patients that they should never share an tesamorelin® syringe with another person, even if the needle is changed. Sharing of syringes or needles between patients may pose a risk of transmission of infection.
Pregnancy
- Advise women to discontinue tesamorelin® if pregnancy occurs, as the drug offers no known benefit to pregnant women and could result in fetal harm.
Nursing Mothers
- Because of both the potential for HIV-1 infection transmission and serious adverse reactions in nursing infants, mothers receiving tesamorelin® should be instructed not to human milk-feed
# Precautions with Alcohol
- Alcohol-Tesamorelin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tesamorelin
# Look-Alike Drug Names
-
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tesamorelin | |
f6fb80503216ab11f8e75da06b06316f4ad5d8b3 | wikidoc | Th-fronting | Th-fronting
# Background
Th-fronting is a merger that occurs (historically independently) in Cockney, Newfoundland English, African American Vernacular English, and Liberian English (though the details differ among those accents), by which Early Modern English Template:IPA merge with Template:IPA.
Apparently, no accents with the merger completely merge the phonemes, because virtually all speakers of such accents know which words "should" have which sound; moreover, in many accents the two sounds appear in free variation. Where th-fronting is applied, pairs such as three/free, slither/sliver, and oath/oaf are homophonous. Th-fronting of the voiced consonant Template:IPA does not occur at the beginning of a word, but only intervocalically and at the end of a word.
The use of the labiodental fricatives Template:IPA and Template:IPA for the dental fricatives Template:IPA and Template:IPA is a well known feature of the proverbial Cockney. It has recently been noted as spreading through non-standard accents in England (cf. Trudgill 1988, 43).
Although th-fronting 'pops up' occasionally in the middle and upper (middle) class English accents as well, there is still a marked social difference between working and middle class speakers. Th-fronting is regarded as a 'boundary marker' between Cockney and Estuary English, as depicted in the first descriptions of the latter form of English and confirmed by a phonetic study conducted by researcher Ulrike Altendorf. Nevertheless, Altendorf points out that th-fronting "pops up" occasionally in middle class (Estuary) speech as well and concludes that "it is currently making its way into the middle class English accent and thus into Estuary English".
Here's a sample of a speaker of the Cockney accent that has th-fronting:
My dad came from Wapping and me mum came from Poplar. Me dad was one of eleven kids… and Wapping in them days really was one of the poorest parts of London. I mean they really didn't have shoes on their feet. I'm talking about seventy years ago now. Erm… and Poplar was… sli… just slightly a cut above Wapping; erm… you was either East End respectable or you was sort of East End villain, you know, and my family was respectable on both sides. But me father had a very tough time because his father died when he was nineteen, leaving him the only one working to bring up eleven brothers… ten brothers and sisters and on a Thursday night he'd sometimes go home and the youngest two would be crying in the corner and he'd say “What's the matter with them, ma?” “Oh, well, Harry, you know it's Thursday night, and you don't get paid till tomorrow.” and they literally didn't have any food in the house.
In that recording father and brother are pronounced Template:IPA and Template:IPA; Thursday is pronounced Template:IPA.
Th-fronting has been spreading in Southern England at a slower rate than t-glottalization.
Th-fronting in the speech of working-class adolescents in Glasgow was reported in 1998 and when it was reported, it provoked interest which was both academic interest and general interest.
The finding of th-fronting in Glaswegian creates a difficulty for models of language change which hinge on dialect contact associated with geographical mobility since the Glaswegian
speakers who used most in the 1997 sample are also those with the lowest geographical mobility.
See also
- List of th-fronting homophones
- Speech_sound_disorder | Th-fronting
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Th-fronting is a merger that occurs (historically independently) in Cockney, Newfoundland English, African American Vernacular English, and Liberian English (though the details differ among those accents), by which Early Modern English Template:IPA merge with Template:IPA. [1]
Apparently, no accents with the merger completely merge the phonemes, because virtually all speakers of such accents know which words "should" have which sound; moreover, in many accents the two sounds appear in free variation. Where th-fronting is applied, pairs such as three/free, slither/sliver, and oath/oaf are homophonous. Th-fronting of the voiced consonant Template:IPA does not occur at the beginning of a word, but only intervocalically and at the end of a word.
The use of the labiodental fricatives Template:IPA and Template:IPA for the dental fricatives Template:IPA and Template:IPA is a well known feature of the proverbial Cockney. It has recently been noted as spreading through non-standard accents in England (cf. Trudgill 1988, 43)[2].
Although th-fronting 'pops up' occasionally in the middle and upper (middle) class English accents as well, there is still a marked social difference between working and middle class speakers. Th-fronting is regarded as a 'boundary marker' between Cockney and Estuary English, as depicted in the first descriptions of the latter form of English [3] [4] and confirmed by a phonetic study conducted by researcher Ulrike Altendorf. Nevertheless, Altendorf points out that th-fronting "pops up" occasionally in middle class (Estuary) speech as well and concludes that "it is currently making its way into the middle class English accent and thus into Estuary English".
[5]
Here's a sample of a speaker of the Cockney accent that has th-fronting:
- http://www.gazzaro.it/accents/sound/Cockney.mp3
My dad came from Wapping and me mum came from Poplar. Me dad was one of eleven kids… and Wapping in them days really was one of the poorest parts of London. I mean they really didn't have shoes on their feet. I'm talking about seventy years ago now. Erm… and Poplar was… sli… just slightly a cut above Wapping; erm… you was either East End respectable or you was sort of East End villain, you know, and my family was respectable on both sides. But me father had a very tough time because his father died when he was nineteen, leaving him the only one working to bring up eleven brothers… ten brothers and sisters and on a Thursday night he'd sometimes go home and the youngest two would be crying in the corner and he'd say “What's the matter with them, ma?” “Oh, well, Harry, you know it's Thursday night, and you don't get paid till tomorrow.” and they literally didn't have any food in the house.
In that recording father and brother are pronounced Template:IPA and Template:IPA; Thursday is pronounced Template:IPA.
Th-fronting has been spreading in Southern England at a slower rate than t-glottalization.
Th-fronting in the speech of working-class adolescents in Glasgow was reported in 1998 and when it was reported, it provoked interest which was both academic interest and general interest.
The finding of th-fronting in Glaswegian creates a difficulty for models of language change which hinge on dialect contact associated with geographical mobility since the Glaswegian
speakers who used [f] most in the 1997 sample are also those with the lowest geographical mobility.
See also
- List of th-fronting homophones
- Speech_sound_disorder | https://www.wikidoc.org/index.php/Th-fronting | |
86532e8e4bac95582e9ddfc5f0c69a05e03b8ae4 | wikidoc | Th-stopping | Th-stopping
# Background
Th-stopping is the realization of the dental fricatives Template:IPA as stops, which occurs in several dialects of English. In some accents, such as Hiberno-English, some varieties of Newfoundland English, some varieties of New York-New Jersey English, and Indian English, they are realized as the dental stops Template:IPA and as such do not merge with the alveolar stops Template:IPA. Thus pairs like tin/thin and den/then are not homophonous (Wells 1982: 428–29, 498, 500, 515). In other accents, such as Caribbean English and Liberian English, such pairs are merged (Wells 1982: 565–66, 635).
For some New Yorkers, the fricatives Template:IPA and Template:IPA are pronounced as affricatives or stops, rather than as fricatives. Usually they remain dental, so that the oppositions Template:IPA and Template:IPA are not lost. Thus thanks may be pronounced Template:IPA, Template:IPA or Template:IPA in decreasing order of statusfulness, all are distinct from tanks. The Template:IPA variant has a weakish articulation. the Template:IPA opposition may be lost, exceptionally in the environment of a following Template:IPA (making three homophonous with tree), and in the case of the word with, (so that with a may rhyme with the nonrhotic pronunciation of "bitter-bidder"; with you may be Template:IPA, following the same yod-coalescence rule as hit you. These pronunciation are all stigmatized.
The Template:IPA opposition seems to be lost more readily, though not as readily as the Brooklynese stereotype might lead one to believe. As in many other places, initial Template:IPA is subject to assimilation or deletion in a range of environments in relatively informal and/or popular speech, e.g. who's there Template:IPA; as in many other places, it is also subject to stopping there Template:IPA. This option extends to one or two words in which the Template:IPA is not initial, e.g. other, which can thus become a homonym of utter-udder. But it would not be usual for southern to be pronounced identically with sudden or breathe with breed.
In African American Vernacular English, in the words with and nothing, Template:IPA may occur corresponding to standard Template:IPA, thus Template:IPA for with and Template:IPA for nothing. (Wolfram 1969:83) Th-stopping is also reported for some other non-initial Template:IPAs, apparently particularly when preceded by a nasal and followed by a plosive, as keep your mout closed (Wolfram 1969:90). In initial position, Template:IPA occurs in AAVE just as in standard accents: thin is Template:IPA, without the stopping of West Indian accents. (Wolfram 1969:130, does however mention the use of 'a lenis Template:IPA' as a rare variant.) Stopping of initial Template:IPA, however, is frequent making then homophonous with den.
See also
- List of Th-stopping homophones
- Speech sound disorder | Th-stopping
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Background
Th-stopping is the realization of the dental fricatives Template:IPA as stops, which occurs in several dialects of English. In some accents, such as Hiberno-English, some varieties of Newfoundland English, some varieties of New York-New Jersey English, and Indian English, they are realized as the dental stops Template:IPA and as such do not merge with the alveolar stops Template:IPA. Thus pairs like tin/thin and den/then are not homophonous (Wells 1982: 428–29, 498, 500, 515).[1] In other accents, such as Caribbean English and Liberian English, such pairs are merged (Wells 1982: 565–66, 635).[1]
For some New Yorkers, the fricatives Template:IPA and Template:IPA are pronounced as affricatives or stops, rather than as fricatives. Usually they remain dental, so that the oppositions Template:IPA and Template:IPA are not lost. Thus thanks may be pronounced Template:IPA, Template:IPA or Template:IPA in decreasing order of statusfulness, all are distinct from tanks. The Template:IPA variant has a weakish articulation. the Template:IPA opposition may be lost, exceptionally in the environment of a following Template:IPA (making three homophonous with tree), and in the case of the word with, (so that with a may rhyme with the nonrhotic pronunciation of "bitter-bidder"; with you may be Template:IPA, following the same yod-coalescence rule as hit you. These pronunciation are all stigmatized.
The Template:IPA opposition seems to be lost more readily, though not as readily as the Brooklynese stereotype might lead one to believe. As in many other places, initial Template:IPA is subject to assimilation or deletion in a range of environments in relatively informal and/or popular speech, e.g. who's there Template:IPA; as in many other places, it is also subject to stopping there Template:IPA. This option extends to one or two words in which the Template:IPA is not initial, e.g. other, which can thus become a homonym of utter-udder. But it would not be usual for southern to be pronounced identically with sudden or breathe with breed.
In African American Vernacular English, in the words with and nothing, Template:IPA may occur corresponding to standard Template:IPA, thus Template:IPA for with and Template:IPA for nothing. (Wolfram 1969:83) Th-stopping is also reported for some other non-initial Template:IPAs, apparently particularly when preceded by a nasal and followed by a plosive, as keep your mout closed (Wolfram 1969:90). In initial position, Template:IPA occurs in AAVE just as in standard accents: thin is Template:IPA, without the stopping of West Indian accents. (Wolfram 1969:130, does however mention the use of 'a lenis Template:IPA' as a rare variant.) Stopping of initial Template:IPA, however, is frequent making then homophonous with den.
See also
- List of Th-stopping homophones
- Speech sound disorder | https://www.wikidoc.org/index.php/Th-stopping | |
e4e0bc0e330be379d46007e439761bd017b866fd | wikidoc | Theil index | Theil index
The Theil index, derived by econometrician Henri Theil, is a statistic used to measure economic inequality.
# Mathematics
The formula is
T=\frac{1}{N}\sum_{i=1}^N \left( \frac{x_i}{\overline{x}} \cdot \ln{\frac{x_i}{\overline{x}}} \right)
where x_i is the income of the ith person, \overline{x}= \frac{1}{N} \sum_{i=1}^N x_i is the mean income, and N is the number of people. The first term inside the sum can be considered the individual's share of aggregate income, and the second term is that person's income relative to the mean. If everyone has the same (i.e., mean) income, then the index is 0. If one person has all the income, then the index is ln N.
The Theil index is derived from Shannon's measure of information entropy. Letting T be the Theil index and S be Shannon's information entropy measure,
Shannon derived his entropy measure in terms of the probability of an event occurring. This can be interpreted in the Theil index as the probability a dollar drawn at random from the population came from a specific individual. This is the same as the first term, the individual's share of aggregate income.
With reference to information theory, Theil's measure is a redundancy rather than an entropy. The redundancy of a system at a given time is the difference between its maximum entropy and its present entropy at that time.
# Decomposability
One of the advantages of the Theil index is that it is a weighted average of inequality within subgroups, plus inequality among those subgroups. For example, inequality within the United States is the average inequality within each state, weighted by state income, plus the inequality among states.
If the population is divided into m certain subgroups and s_k is the income share of group k, T_k is the Theil index for that subgroup, and \overline{x}_k is the average income in group k, then the Theil index is
T = \sum_{k=1}^m s_k T_k + \sum_{k=1}^m s_k \ln{\frac{\overline{x}_k}{\overline{x}}}.
Another, more popular, measure of inequality is the Gini coefficient. The Gini coefficient is more intuitive to many people since it is based on the Lorenz curve. However, it is not easily decomposable like the Theil.
# Application of the Theil index
Theil's index takes an equal distribution for reference which is similar to distributions in statistical physics. An index for an actual system is an actual redundancy, that is, the difference between maximum entropy and actual entropy of that system.
Theil's measure can be converted into one of the indexes of Anthony Barnes Atkinson. The result of the conversion also is called normalized Theil index. James E. Foster used such a measure to replace the Gini coefficient in Amartya Sen's welfare function W=f(income,inequality). The income e.g. is the average income for individuals in a group of income earners. Thus, Foster's welfare function can be computed directly from the Theil index T, if the conversion is included into the computation of the average per capita welfare function:
Note: This image is not the Theil Index in each area of the United States, but of contributions to the US Theil Index by each area (the Theil Index is always positive, individual contributions to the Theil Index may be negative or positive).
# Pareto principle
For resource distributions described by only two quantiles, the Theil index is 0 for 50:50 distributions and reaches 1 at 82:18, which is very close to a distribution often referred to as "Pareto Principle". Higher inequities yield Theil indices above 1.
# Theil index and Hoover index
A comparison of the Hoover index (also called Robin Hood index) and the Theil index shows the meaning of both indices:
- For the Hoover index, the relative deviations in each quantile are summed up. Each deviation is weighted by its own sign (+1 or −1). Thus, the Hoover index is the most simple inequality measure. It has no normative foundations and does not refer to any models from physics or information theory.
- For the symmetrized Theil index, the relative deviations in each quantile are summed up as well. But each deviation is weighted by its relative information weight. Thus, the Theil index is an indicator not only for the plain relative inequality, it also attempts to indicate how much attention inequality can get.
The following formulas illustrate that difference in the categories symmetry and percevability. For the formulas, a notation is used, where the amount N of quantiles only appears as upper border of summations. Thus, inequities can be computed for quantiles with different widths A_i. For example, E_i could be the income in the quantile #i and A_i could be the amount (absolute or relative) of earners in the quantile #i. E_\text{total} then would be the sum of incomes of all N quantiles and A_\text{total} would be the sum of the income earners in all N quantiles.
Computation of the (asymmetric) Theil index T :
T = \ln{\frac{{A}_\text{total}}{{E}_\text{total}}} - \frac{\sum_{i=1}^N {{E}_i} \ln{\frac{{A}_i}{{E}_i}}}{{E}_\text{total}}.
With normalized data, {{E}'_i}=E_i/E_\text{total} and {{A}'_i}=A_i/A_\text{total} would apply. This would simplify the formula:
\color{Gray} T = 0 - \frac{\sum_{i=1}^N {{E}'_i} \ln{\frac{{A}'_i}{{E}'_i}}}{1} = \sum_{i=1}^N {{E}'_i} \ln{\frac{{E}'_i}{{A}'_i}}
Computation of the symmetrized Theil index T_s:
T_s = \frac{1}{2} \left( \ln{\frac{{A}_\text{total}}{{E}_\text{total}}} - \frac{\sum_{i=1}^N {{E}_i} \ln{\frac{{A}_i}{{E}_i}}}{{E}_\text{total}} + \ln{\frac{{E}_\text{total}}{{A}_\text{total}}} - \frac{\sum_{i=1}^N {{A}_i} \ln{\frac{{E}_i}{{A}_i}}}{{A}_\text{total}} \right).
This leads to:
T_s = {\frac{1}{2}} \sum_{i=1}^N \color{OliveGreen} \ln{\frac{{E}_i}{{A}_i}} \color{Black} \left( {\frac{{E}_i}{{E}_\text{total}}} - {\frac{{A}_i}{{A}_\text{total}}} \right).
For comparison, the Hoover index H:
H = {\frac{1}{2}} \sum_{i=1}^N \color{Blue} \color{Black} \left| {\frac{{E}_i}{{E}_\text{total}}} - {\frac{{A}_i}{{A}_\text{total}}} \right|. | Theil index
The Theil index[1], derived by econometrician Henri Theil, is a statistic used to measure economic inequality.
# Mathematics
The formula is
T=\frac{1}{N}\sum_{i=1}^N \left( \frac{x_i}{\overline{x}} \cdot \ln{\frac{x_i}{\overline{x}}} \right)
</math>
where <math>x_i</math> is the income of the <math>i</math>th person, <math>\overline{x}= \frac{1}{N} \sum_{i=1}^N x_i </math> is the mean income, and <math>N</math> is the number of people. The first term inside the sum can be considered the individual's share of aggregate income, and the second term is that person's income relative to the mean. If everyone has the same (i.e., mean) income, then the index is 0. If one person has all the income, then the index is ln N.
The Theil index is derived from Shannon's measure of information entropy. Letting T be the Theil index and S be Shannon's information entropy measure,
Shannon derived his entropy measure in terms of the probability of an event occurring. This can be interpreted in the Theil index as the probability a dollar drawn at random from the population came from a specific individual. This is the same as the first term, the individual's share of aggregate income.
With reference to information theory[2], Theil's measure is a redundancy rather than an entropy. The redundancy of a system at a given time is the difference between its maximum entropy and its present entropy at that time.[3]
# Decomposability
One of the advantages of the Theil index is that it is a weighted average of inequality within subgroups, plus inequality among those subgroups. For example, inequality within the United States is the average inequality within each state, weighted by state income, plus the inequality among states.
If the population is divided into <math>m</math> certain subgroups and <math>s_k</math> is the income share of group <math>k</math>, <math>T_k</math> is the Theil index for that subgroup, and <math>\overline{x}_k</math> is the average income in group <math>k</math>, then the Theil index is
T = \sum_{k=1}^m s_k T_k + \sum_{k=1}^m s_k \ln{\frac{\overline{x}_k}{\overline{x}}}.
</math>
Another, more popular, measure of inequality is the Gini coefficient. The Gini coefficient is more intuitive to many people since it is based on the Lorenz curve. However, it is not easily decomposable like the Theil.
# Application of the Theil index
Theil's index takes an equal distribution for reference which is similar to distributions in statistical physics. An index for an actual system is an actual redundancy, that is, the difference between maximum entropy and actual entropy of that system.
Theil's measure can be converted[3] into one of the indexes of Anthony Barnes Atkinson. The result of the conversion also is called normalized Theil index[4]. James E. Foster[5] used such a measure to replace the Gini coefficient in Amartya Sen's welfare function W=f(income,inequality). The income e.g. is the average income for individuals in a group of income earners. Thus, Foster's welfare function can be computed directly from the Theil index T, if the conversion is included into the computation of the average per capita welfare function:
Note: This image is not the Theil Index in each area of the United States, but of contributions to the US Theil Index by each area (the Theil Index is always positive, individual contributions to the Theil Index may be negative or positive).
# Pareto principle
For resource distributions described by only two quantiles, the Theil index is 0 for 50:50 distributions and reaches 1 at 82:18[6], which is very close to a distribution often referred to as "Pareto Principle". Higher inequities yield Theil indices above 1.
# Theil index and Hoover index
A comparison of the Hoover index (also called Robin Hood index) and the Theil index shows the meaning of both indices:
- For the Hoover index, the relative deviations in each quantile are summed up. Each deviation is weighted by its own sign (+1 or −1). Thus, the Hoover index is the most simple inequality measure. It has no normative foundations and does not refer to any models from physics or information theory.
- For the symmetrized Theil index, the relative deviations in each quantile are summed up as well. But each deviation is weighted by its relative information weight. Thus, the Theil index is an indicator not only for the plain relative inequality, it also attempts to indicate how much attention inequality can get.
The following formulas illustrate that difference in the categories symmetry and percevability. For the formulas, a notation[8] is used, where the amount <math>N</math> of quantiles only appears as upper border of summations. Thus, inequities can be computed for quantiles with different widths <math>A_i</math>. For example, <math>E_i</math> could be the income in the quantile #i and <math>A_i</math> could be the amount (absolute or relative) of earners in the quantile #i. <math>E_\text{total}</math> then would be the sum of incomes of all <math>N</math> quantiles and <math>A_\text{total}</math> would be the sum of the income earners in all <math>N</math> quantiles.
Computation of the (asymmetric) Theil index T [9]:
T = \ln{\frac{{A}_\text{total}}{{E}_\text{total}}} - \frac{\sum_{i=1}^N {{E}_i} \ln{\frac{{A}_i}{{E}_i}}}{{E}_\text{total}}.
</math>
With normalized data, <math>{{E}'_i}=E_i/E_\text{total}</math> and <math>{{A}'_i}=A_i/A_\text{total}</math> would apply. This would simplify the formula:
<math>
\color{Gray} T = 0 - \frac{\sum_{i=1}^N {{E}'_i} \ln{\frac{{A}'_i}{{E}'_i}}}{1} = \sum_{i=1}^N {{E}'_i} \ln{\frac{{E}'_i}{{A}'_i}}
</math>
Computation of the symmetrized Theil index <math>T_s</math>:
T_s = \frac{1}{2} \left( \ln{\frac{{A}_\text{total}}{{E}_\text{total}}} - \frac{\sum_{i=1}^N {{E}_i} \ln{\frac{{A}_i}{{E}_i}}}{{E}_\text{total}} + \ln{\frac{{E}_\text{total}}{{A}_\text{total}}} - \frac{\sum_{i=1}^N {{A}_i} \ln{\frac{{E}_i}{{A}_i}}}{{A}_\text{total}} \right).
</math>
This leads to:
T_s = {\frac{1}{2}} \sum_{i=1}^N \color{OliveGreen} \ln{\frac{{E}_i}{{A}_i}} \color{Black} \left( {\frac{{E}_i}{{E}_\text{total}}} - {\frac{{A}_i}{{A}_\text{total}}} \right).
</math>
For comparison, the Hoover index <math>H</math>:
H = {\frac{1}{2}} \sum_{i=1}^N \color{Blue} \color{Black} \left| {\frac{{E}_i}{{E}_\text{total}}} - {\frac{{A}_i}{{A}_\text{total}}} \right|.
</math> | https://www.wikidoc.org/index.php/Theil_index | |
fe7689840ff30691f476de897d5f837de1f86a10 | wikidoc | Theobromine | Theobromine
# Overview
Theobromine, also known as xantheose, is a bitter alkaloid of the cacao plant, and is therefore found in chocolate. It is in the methylxanthine class of chemical compounds, which also includes the similar compounds theophylline and caffeine. Despite its name, the compound contains no bromine — theobromine is derived from Theobroma, the name of the genus of the cacao tree, (which itself is made up of the Greek roots theo ("God") and broma ("food"), meaning "food of the gods") with the suffix -ine given to alkaloids and other basic nitrogen-containing compounds.
Theobromine is a water insoluble, crystalline, bitter powder; the colour has been listed as either white or colourless. It has a similar, but lesser, effect to caffeine, making it a lesser homologue. Theobromine is an isomer of theophylline as well as paraxanthine. Theobromine is categorized as a dimethyl xanthine, which means it is a xanthine with two methyl groups.
Theobromine was first isolated from the seeds of the cacao tree in 1878 and then shortly afterwards was synthesized from xanthine by Hermann Emil Fischer.
# Sources
Theobromine is the primary alkaloid found in cocoa and chocolate; chocolate contains 0.5-2.7% theobromine. Theobromine can also be found in small amounts in the kola nut (1.0-2.5%), the guarana berry, and the tea plant.
Cocoa powder such as Hershey's cocoa contains 108mg of (or 2.16%) theobromine per tablespoon (5g) of powder. However, cocoa powder with more concentrated amounts of theobromine up to at least 10% also exists. Chocolate contains 0.5-2.7% theobromine, although white chocolate contains only trace amounts. Theobromine can also be found in small amounts in the kola nut (1.0-2.5%), the guarana berry, and the tea plant.
In the human liver, caffeine is metabolised by enzymes into 10% theobromine, 4% theophylline, and 80% paraxanthine.
The plant species with the largest amounts of theobromine are:
- Theobroma cacao
- Theobroma bicolor
- Yerba mate
- Camellia sinensis
- Cola acuminata
- Theobroma angustifolium
- Guarana
- Coffea arabica
The mean theobromine concentrations in cocoa and carob products are:
# Therapeutic uses
Following its discovery in the late 1800s, theobromine was put to use by 1916, where it was recommended by the publication Principles of Medical Treatment as a treatment for edema (excessive liquid in parts of the body), syphilitic angina attacks, and degenerative angina. The American Journal of Clinical Nutrition notes that theobromine was once used as a treatment for other circulatory problems including arteriosclerosis, certain vascular diseases, angina pectoris, and hypertension.
In modern medicine, theobromine is used as a vasodilator (a blood vessel widener), an aid in urinating, and heart stimulant. In addition, the future use of theobromine in such fields as cancer prevention has been patented.
Theobromine has also been used in birth defect experiments involving mice and rabbits. A decreased fetal weight was noted in rabbits following forced feeding, but not after other administration of theobromine. Birth defects were not seen in rats.
# Pharmacology
In the human liver, theobromine is metabolized into methylxanthine and subsequently into methyluric acid.
As a methylated xanthine, theobromine is a potent Cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor; this means that it helps prevent the enzyme phosphodiesterase from converting the active cAMP to an inactive form. Cyclic Adenosine Monophosphate works as a second messenger in many hormone- and neurotransmitter-controlled metabolic systems, such as the breakdown of glycogen. When the inactivation of cAMP is inhibited by a compound such as theobromine, the effects of the neurotransmitter or hormone which stimulated the production of cAMP are much longer lived. The net result is generally a stimulatory effect.
# Effects
## Humans
While theobromine and caffeine are similar in that they are related alkaloids, theobromine has a lesser impact on the human central nervous system and it stimulates the heart to a greater degree. While theobromine is not as addictive, it has been cited as possibly causing addiction to chocolate. A Sexual Odyssey: From Forbidden Fruit to Cybersex discusses how chocolate's alleged aphrodisiac effects may be caused by a number of factors. These include the stimulative effects of theobromine, pleasure induced by the hypothalamus as an effect of chocolate's sweet and fatty nature, or how chocolate affects the levels of serotonin. While serotonin has a pleasurable effect, in high concentrations it can be converted to melatonin which in large amounts reduces sexual drive.
As it is a myocardial stimulant as well as a vasodilator, it increases heartbeat, yet it also dilates blood vessels, causing a reduced blood pressure. However, a recent paper published suggested that the decrease in blood pressure may be caused by flavanols. Furthermore, its draining effect allows it to be used to treat cardiac failure, which can be caused by an excessive accumulation of fluid.
A 2005 study published by Imperial College London concluded that theobromine has an antitussive (cough-reducing) effect superior to codeine by suppressing vagus nerve activity. Additionally, theobromine is helpful in treating asthma since it relaxes the smooth muscles, including the ones found in the bronchi.
There is a possible association between theobromine and an increased risk of suffering from prostate cancer.
Theobromine can cause sleeplessness, tremors, restlessness, anxiety, as well as contribute to increased production of urine. Additional side effects include loss of appetite, nausea, and vomiting.
## Animals
The amount of theobromine found in chocolate is small enough that it can be safely consumed by humans, but animals that metabolize theobromine more slowly, such as dogs, can succumb to theobromine poisoning from as little as 50 grams of chocolate for a smaller dog and 400 grams for an average-sized dog. Complications include digestive issues, dehydration, excitability, and a slow heart rate. Later stages of theobromine poisoning include epileptic-like seizures and death. If caught early on, theobromine poisoning is treatable.
## Other
Theobromine is known to induce gene mutations in lower eukaryotes and bacteria. At the time of a 1997 report by the IARC, genetic mutations had not been found in higher eukaryotes, such as humans. | Theobromine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Theobromine, also known as xantheose,[2] is a bitter alkaloid of the cacao plant, and is therefore found in chocolate. It is in the methylxanthine class of chemical compounds,[3] which also includes the similar compounds theophylline and caffeine.[2] Despite its name, the compound contains no bromine — theobromine is derived from Theobroma, the name of the genus of the cacao tree, (which itself is made up of the Greek roots theo ("God") and broma ("food"), meaning "food of the gods")[4] with the suffix -ine given to alkaloids and other basic nitrogen-containing compounds.[5]
Theobromine is a water insoluble, crystalline, bitter powder; the colour has been listed as either white or colourless.[6] It has a similar, but lesser, effect to caffeine, making it a lesser homologue. Theobromine is an isomer of theophylline as well as paraxanthine. Theobromine is categorized as a dimethyl xanthine,[7] which means it is a xanthine[8] with two methyl groups.[9]
Theobromine was first isolated from the seeds of the cacao tree in 1878[10] and then shortly afterwards was synthesized from xanthine by Hermann Emil Fischer.[11]
# Sources
Theobromine is the primary alkaloid found in cocoa and chocolate; chocolate contains 0.5-2.7% theobromine. Theobromine can also be found in small amounts in the kola nut (1.0-2.5%), the guarana berry, and the tea plant.[12]
Cocoa powder such as Hershey's cocoa contains 108mg of (or 2.16%) theobromine per tablespoon (5g) of powder.[13] However, cocoa powder with more concentrated amounts of theobromine up to at least 10% also exists.[14] Chocolate contains 0.5-2.7% theobromine, although white chocolate contains only trace amounts.[15] Theobromine can also be found in small amounts in the kola nut (1.0-2.5%), the guarana berry, and the tea plant.[12]
In the human liver, caffeine is metabolised by enzymes into 10% theobromine, 4% theophylline, and 80% paraxanthine.[16]
The plant species with the largest amounts of theobromine are:[17]
- Theobroma cacao
- Theobroma bicolor
- Yerba mate
- Camellia sinensis
- Cola acuminata
- Theobroma angustifolium
- Guarana
- Coffea arabica
The mean theobromine concentrations in cocoa and carob products are:[18]
# Therapeutic uses
Following its discovery in the late 1800s, theobromine was put to use by 1916, where it was recommended by the publication Principles of Medical Treatment as a treatment for edema (excessive liquid in parts of the body), syphilitic angina attacks, and degenerative angina.[19] The American Journal of Clinical Nutrition notes that theobromine was once used as a treatment for other circulatory problems including arteriosclerosis, certain vascular diseases, angina pectoris, and hypertension.[20]
In modern medicine, theobromine is used as a vasodilator (a blood vessel widener), an aid in urinating, and heart stimulant.[2] In addition, the future use of theobromine in such fields as cancer prevention has been patented.[21]
Theobromine has also been used in birth defect experiments involving mice and rabbits. A decreased fetal weight was noted in rabbits following forced feeding, but not after other administration of theobromine. Birth defects were not seen in rats.[22]
# Pharmacology
In the human liver, theobromine is metabolized into methylxanthine and subsequently into methyluric acid.[23]
As a methylated xanthine, theobromine is a potent Cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitor;[8] this means that it helps prevent the enzyme phosphodiesterase from converting the active cAMP to an inactive form.[24] Cyclic Adenosine Monophosphate works as a second messenger in many hormone- and neurotransmitter-controlled metabolic systems, such as the breakdown of glycogen. When the inactivation of cAMP is inhibited by a compound such as theobromine, the effects of the neurotransmitter or hormone which stimulated the production of cAMP are much longer lived. The net result is generally a stimulatory effect.[25]
# Effects
## Humans
While theobromine and caffeine are similar in that they are related alkaloids, theobromine has a lesser impact on the human central nervous system and it stimulates the heart to a greater degree.[26] While theobromine is not as addictive, it has been cited as possibly causing addiction to chocolate.[27] A Sexual Odyssey: From Forbidden Fruit to Cybersex discusses how chocolate's alleged aphrodisiac effects may be caused by a number of factors. These include the stimulative effects of theobromine, pleasure induced by the hypothalamus as an effect of chocolate's sweet and fatty nature, or how chocolate affects the levels of serotonin. While serotonin has a pleasurable effect, in high concentrations it can be converted to melatonin which in large amounts reduces sexual drive.[26]
As it is a myocardial stimulant as well as a vasodilator, it increases heartbeat, yet it also dilates blood vessels, causing a reduced blood pressure.[28] However, a recent paper published suggested that the decrease in blood pressure may be caused by flavanols.[20] Furthermore, its draining effect allows it to be used to treat cardiac failure, which can be caused by an excessive accumulation of fluid.[28]
A 2005 study published by Imperial College London concluded that theobromine has an antitussive (cough-reducing) effect superior to codeine by suppressing vagus nerve activity.[29] Additionally, theobromine is helpful in treating asthma since it relaxes the smooth muscles, including the ones found in the bronchi.[30]
There is a possible association between theobromine and an increased risk of suffering from prostate cancer.[31]
Theobromine can cause sleeplessness, tremors, restlessness, anxiety, as well as contribute to increased production of urine.[30] Additional side effects include loss of appetite, nausea, and vomiting.[32]
## Animals
The amount of theobromine found in chocolate is small enough that it can be safely consumed by humans, but animals that metabolize theobromine more slowly, such as dogs, can succumb to theobromine poisoning from as little as 50 grams of chocolate for a smaller dog and 400 grams for an average-sized dog. Complications include digestive issues, dehydration, excitability, and a slow heart rate. Later stages of theobromine poisoning include epileptic-like seizures and death. If caught early on, theobromine poisoning is treatable.[33]
## Other
Theobromine is known to induce gene mutations in lower eukaryotes and bacteria. At the time of a 1997 report by the IARC, genetic mutations had not been found in higher eukaryotes, such as humans.[34] | https://www.wikidoc.org/index.php/Theobromine | |
e2c5b3cb12d3b744f6ec6308a256ad714817b323 | wikidoc | TheraSphere | TheraSphere
# Overview
TheraSphere is a hepatocellular carcinoma (HCC) treatment therapy that consists of millions of microscopic, radioactive glass microspheres (20-30 micrometres in diameter) being infused into the arteries that feed liver tumors, bathing the malignancy in high levels of 90Y radiation. It is currently approved for patients as a neoadjuvant to surgery or transplantation by the US FDA and is being used at a number of clinical centers in the United States.
# Description
TheraSphere consists of insoluble glass microspheres where Yttrium-90 is an integral constituent of the glass. Each milligram contains between 22,000 and 73,000 microspheres. Yttrium-90 is a pure beta emitter and decays to stable zirconium-90 with a physical half-life of 64.2 hours (2.67 days). The average energy of the beta emissions from yttrium-90 is 0.9367 MeV.
Following embolization of the yttrium-90 glass microspheres in tumorous liver tissue, the beta radiation emitted provides a therapeutic effect. The microspheres are delivered into the liver tumor through a catheter placed into the hepatic artery that supplies blood to the tumor(This is usually performed in a hospital's radiology suite and patients remain conscious throughout the procedure). The microspheres are unable to pass through the vasculature of the liver due to arteriolar capillary blockade and are trapped in the tumor. There they exert a local radiotherapeutic effect with some damage to surrounding normal liver tissue.
# Efficacy
Low-risk patients with unresectable liver cancer appear to gain control over their malignancies for at least 2 years when treated with TheraSphere. They survived a median of 800 days compared with a median of 258 days for high risk patients (P <.0001) in a study of 140 patients (106 male). The patients underwent 238 administrations of the particles. Approximately 34% of patients responded to the treatment according to evaluation by Response Evaluation Criteria in Solid Tumors (RECIST), meaning their overall tumor burden decreased by 50% or more.
In a separate study based on follow-up data from 43 treated patients, 20 patients (47%) had an objective tumor response based on percent reduction in tumor size and 34 patients (79%) had a tumor response when percent reduction and/or tumor necrosis were used as a composite measure of tumor response. | TheraSphere
# Overview
TheraSphere is a hepatocellular carcinoma (HCC) treatment therapy that consists of millions of microscopic, radioactive glass microspheres (20-30 micrometres in diameter) being infused into the arteries that feed liver tumors, bathing the malignancy in high levels of 90Y radiation. It is currently approved for patients as a neoadjuvant to surgery or transplantation by the US FDA and is being used at a number of clinical centers in the United States.
# Description
TheraSphere consists of insoluble glass microspheres where Yttrium-90 is an integral constituent of the glass. Each milligram contains between 22,000 and 73,000 microspheres. Yttrium-90 is a pure beta emitter and decays to stable zirconium-90 with a physical half-life of 64.2 hours (2.67 days). The average energy of the beta emissions from yttrium-90 is 0.9367 MeV.
Following embolization of the yttrium-90 glass microspheres in tumorous liver tissue, the beta radiation emitted provides a therapeutic effect. The microspheres are delivered into the liver tumor through a catheter placed into the hepatic artery that supplies blood to the tumor(This is usually performed in a hospital's radiology suite and patients remain conscious throughout the procedure). The microspheres are unable to pass through the vasculature of the liver due to arteriolar capillary blockade and are trapped in the tumor. There they exert a local radiotherapeutic effect with some damage to surrounding normal liver tissue.[1][2]
# Efficacy
Low-risk patients with unresectable liver cancer appear to gain control over their malignancies for at least 2 years when treated with TheraSphere. They survived a median of 800 days compared with a median of 258 days for high risk patients (P <.0001) in a study of 140 patients (106 male). The patients underwent 238 administrations of the particles. Approximately 34% of patients responded to the treatment according to evaluation by Response Evaluation Criteria in Solid Tumors (RECIST), meaning their overall tumor burden decreased by 50% or more.[3]
In a separate study based on follow-up data from 43 treated patients, 20 patients (47%) had an objective tumor response based on percent reduction in tumor size and 34 patients (79%) had a tumor response when percent reduction and/or tumor necrosis were used as a composite measure of tumor response.[4] | https://www.wikidoc.org/index.php/TheraSphere | |
f93d4a89b6d0d552a6556a2e0e038a938df86d6c | wikidoc | Thermogenin | Thermogenin
Thermogenin (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or UCP1) is an uncoupling protein found in the mitochondria of brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis, and makes a quantitatively important contribution to countering heat loss in babies which would otherwise occur due to their high surface area-volume ratio.
# Mechanism
UCPs are transmembrane proteins that decrease the proton gradient generated in oxidative phosphorylation. They do this by increasing the permeability of the inner mitochondrial membrane, allowing protons that have been pumped into the intermembrane space to return to the mitochondrial matrix. UCP1-mediated heat generation in brown fat uncouples the respiratory chain, allowing for fast substrate oxidation with a low rate of ATP production. UCP1 is related to other mitochondrial metabolite transporters such as the adenine nucleotide translocator, a proton channel in the mitochondrial inner membrane that permits the translocation of protons from the mitochondrial intermembrane space to the mitochondrial matrix. UCP1 is restricted to brown adipose tissue, where it provides a mechanism for the enormous heat-generating capacity of the tissue.
UCP1 is activated in the brown fat cell by fatty acids and inhibited by nucleotides. Fatty acids cause the following signaling cascade: Sympathetic nervous system terminals release Norepinephrine onto a Beta-3 adrenergic receptor on the plasma membrane. This activates adenylyl cyclase, which catalyses the conversion of ATP to cyclic AMP (cAMP). cAMP activates protein kinase A, causing its active C subunits to be freed from its regulatory R subunits. Active protein kinase A, in turn, phosphorylates triacylglycerol lipase, thereby activating it. The lipase converts triacylglycerols into free fatty acids, which activate UCP1, overriding the inhibition caused by purine nucleotides (GDP and ADP). During the termination of thermogenesis, thermogenin is inactivated and residual fatty acids are disposed of through oxidation, allowing the cell to resume its normal energy-conserving state.
# History
Uncoupling protein 1 was discovered in 1978 and was first cloned in 1988.
Uncoupling protein two (UCP2), a homolog of UCP1, was identified in 1997. UCP2 localizes to a wide variety of tissues, and is thought to be involved in regulating reactive oxygen species (ROS). In the past decade, three additional homologs of UCP1 have been identified, including UCP3, UCP4, and BMCP1 (also known as UCP5).
# Clinical relevance
Methods of delivering UCP1 to cells by gene transfer therapy or methods of its upregulation have been an important line of enquiry in research into the treatment of obesity, due to their ability to dissipate excess metabolic stores. | Thermogenin
Thermogenin (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or UCP1)[1] is an uncoupling protein found in the mitochondria of brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis, and makes a quantitatively important contribution to countering heat loss in babies which would otherwise occur due to their high surface area-volume ratio.
# Mechanism
UCPs are transmembrane proteins that decrease the proton gradient generated in oxidative phosphorylation. They do this by increasing the permeability of the inner mitochondrial membrane, allowing protons that have been pumped into the intermembrane space to return to the mitochondrial matrix. UCP1-mediated heat generation in brown fat uncouples the respiratory chain, allowing for fast substrate oxidation with a low rate of ATP production. UCP1 is related to other mitochondrial metabolite transporters such as the adenine nucleotide translocator, a proton channel in the mitochondrial inner membrane that permits the translocation of protons from the mitochondrial intermembrane space to the mitochondrial matrix. UCP1 is restricted to brown adipose tissue, where it provides a mechanism for the enormous heat-generating capacity of the tissue.
UCP1 is activated in the brown fat cell by fatty acids and inhibited by nucleotides. Fatty acids cause the following signaling cascade: Sympathetic nervous system terminals release Norepinephrine onto a Beta-3 adrenergic receptor on the plasma membrane. This activates adenylyl cyclase, which catalyses the conversion of ATP to cyclic AMP (cAMP). cAMP activates protein kinase A, causing its active C subunits to be freed from its regulatory R subunits. Active protein kinase A, in turn, phosphorylates triacylglycerol lipase, thereby activating it. The lipase converts triacylglycerols into free fatty acids, which activate UCP1, overriding the inhibition caused by purine nucleotides (GDP and ADP). During the termination of thermogenesis, thermogenin is inactivated and residual fatty acids are disposed of through oxidation, allowing the cell to resume its normal energy-conserving state.
# History
Uncoupling protein 1 was discovered in 1978[2] and was first cloned in 1988.[3][4]
Uncoupling protein two (UCP2), a homolog of UCP1, was identified in 1997. UCP2 localizes to a wide variety of tissues, and is thought to be involved in regulating reactive oxygen species (ROS). In the past decade, three additional homologs of UCP1 have been identified, including UCP3, UCP4, and BMCP1 (also known as UCP5).
# Clinical relevance
Methods of delivering UCP1 to cells by gene transfer therapy or methods of its upregulation have been an important line of enquiry in research into the treatment of obesity, due to their ability to dissipate excess metabolic stores.[5] | https://www.wikidoc.org/index.php/Thermogenin | |
266ba2a6bf0c90df9ddb50b2badae48a4bcf5617 | wikidoc | Thiambutene | Thiambutene
The Thiambutenes are a family of opioid analgesic drugs. The parent compound thiambutene has no analgesic effects, but several compounds from this group are analgesics with around the same potency as morphine.
Notable compounds include dimethylthiambutene, diethylthiambutene, ethylmethylthiambutene, pyrrolidinylthiambutene and piperidylthiambutene. Of these, ethylmethylthiambutene is the most potent, with 1.3x the potency of morphine, pyrrolidinylthiambutene is the least potent at 0.7x, and the rest are all around the same potency as morphine. Diethylthiambutene has been the most widely used, mainly in veterinary medicine.
All of these compounds produced anticholinergic and antihistamine side effects, except for two of the weaker compounds diallylthiambutene and morpholinylthiambutene. They also all have a chiral centre around the alpha carbon (where the R1 group is attached) and so have two stereoisomers, with the dextro isomer being the more potent in all cases, although both isomers are active.
Three of these compounds are explicitly listed as illegal drugs under UN convention, diethylthiambutene, dimethylthiambutene and ethylmethylthiambutene, and so are illegal throughout the world, but the rest will only be illegal in countries such as the USA, Australia and New Zealand that have laws equivalent to the Federal Analog Act.
File:Thiambutene general.png | Thiambutene
The Thiambutenes are a family of opioid analgesic drugs. The parent compound thiambutene has no analgesic effects, but several compounds from this group are analgesics with around the same potency as morphine.
Notable compounds include dimethylthiambutene, diethylthiambutene, ethylmethylthiambutene, pyrrolidinylthiambutene and piperidylthiambutene. Of these, ethylmethylthiambutene is the most potent, with 1.3x the potency of morphine, pyrrolidinylthiambutene is the least potent at 0.7x, and the rest are all around the same potency as morphine.[1][2] Diethylthiambutene has been the most widely used, mainly in veterinary medicine.
All of these compounds produced anticholinergic and antihistamine side effects, except for two of the weaker compounds diallylthiambutene and morpholinylthiambutene. They also all have a chiral centre around the alpha carbon (where the R1 group is attached) and so have two stereoisomers, with the dextro isomer being the more potent in all cases, although both isomers are active.[3]
Three of these compounds are explicitly listed as illegal drugs under UN convention, diethylthiambutene, dimethylthiambutene and ethylmethylthiambutene, and so are illegal throughout the world, but the rest will only be illegal in countries such as the USA, Australia and New Zealand that have laws equivalent to the Federal Analog Act.
File:Thiambutene general.png | https://www.wikidoc.org/index.php/Thiambutene | |
4e7b5d644cb713206e4c443e075d0b7eafd76702 | wikidoc | Thienamycin | Thienamycin
Thienamycin, one of the most potent naturally-produced antibiotics known thus far, was discovered in Streptomyces cattleya in 1976. Thienamycin has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes.
# History
In 1976, fermentation broths obtained from the soil bacteria Streptomyces cattleya were found to be active in screens for inhibitors of peptidoglycan biosynthesis. Initial attempts to isolate the active species proved difficult due to the chemical instability of that component. After many attempts and extensive purification, the material was finally isolated in >90% purity, allowing for the structural elucidation of thienamycin in 1979 (Figure 1).
Thienamycin was the first among the naturally-occurring class of carbapenem antibiotics to be discovered and isolated. Carbapenems are similar in structure to their antibiotic “cousins” the penicillins. Like penicillins, carbapenems contain a β-lactam ring (cyclic amide) fused to a five-membered ring. Carbapenems differ in structure from penicillins in that within the five-membered ring a sulfur is replaced by a carbon atom (C1) and an unsaturation is present between C2 and C3 in the five-membered ring.
# Mechanism of Action
In vitro, thienamycin employs a similar mode of action as penicillins through disrupting the cell wall synthesis (peptidoglycan biosynthesis) of various Gram-positive and Gram-negative bacteria (Staphylococcus aureus,Staphylococcus epidermidis, Pseudomonas aeruginosa to name a few). In a study carried out by Spratt et al., they found that, although thienamycin binds to all of the penicillin-binding proteins (PBP) in Escherichia coli, it preferentially binds to PBP-1 and PBP-2, which are both associated with the elongation of the cell wall.
Unlike pencillins, which are rendered ineffective through rapid hydrolysis by the β-lactamase enzyme present in some strains of bacteria, thienamycin remains antimicrobially active. Neu et al. found that thienamycin displayed high activity against bacteria that were resistant to other β-lactamase stable compounds (cephalosporins), highlighting the superiority of thienamycin as an antibiotic among β-lactams.
# Biosynthesis
The formation of thienamycin is thought to occur through a different pathway from classic β-lactams (penicillins, cephalosporins). Production of classic β-lactams in both fungi and bacteria occur through two steps: First, the condensation of L-cysteine, L-Valine, and L-α-amino adipic acid by ACV synthetase (ACVS, a nonribsomal peptide synthetase) and then cyclization of this formed tripeptide by isopenicillin N synthetase (IPNS).
The gene cluster (thn) for the biosynthesis of thienamycin by S. cattleya was identified and sequenced, finally, in 2003, lending insight into the biosynthetic mechanism for thienamycin formation. Based on previous work and on this significant breakthrough, a tentative biosynthetic pathway has been proposed (Figure 2).
The biosynthesis of thienamycin begins with the condensation of acetyl-S-CoA with γ-glutamyl phosphate to form the pyrroline ring. The hydroxyethyl side chain of thienamycin is thought to be a result of two separate methyl transfers from S-adenosyl methionine. According to the proposed biosynthesis, one methylation step occurs immediately after formation of the pyrroline ring, and the other methylation step occurs after formation of the bicyclic ring. According to the proposed gene functions (Table 1), ThnK, ThnL, and ThnP could catalyze these methyl-transfer steps. After the first methylation step occurs, β-lactam synthetase (ThnM) is thought to catalyze the formation of the β-lactam ring fused to the five-membered ring. Incorporation of the cysteaminyl side chain is then assisted by ThnV and/or ThnT. Oxidations occur between C6 and C8, followed by the second methylation step (mentioned above), then reduction at C6 and C8, and subsequently oxidation between C2 and C3. Hydroxylation by ThnG gives thienamycin as the final product (Note: see Figure 2 for a potential alternative pathway).
# Total Synthesis
Due to low titre and to difficulties in isolating and purifying thienamycin produced via fermentation, total synthesis is the preferred method for commercial production. Numerous methods are available in the literature for the total synthesis of thienamycin. One synthetic route is given in Figure 3.
The starting β-lactam for the pathway given above can be synthesized via the following method (Figure 4):
# Clinical Use
Thienamycin itself is extremely unstable and decomposes in aqueous solution. Consequently, thienamycin is impractical for clinical treatment of bacterial infections. For this reason, stable derivatives of thienamycin were created for medicinal consumption. One such derivative, imipenem, was formulated in 1985. Imipenem, an N-formimidoyl derivative of thienamycin, is rapidly metabolized by the renal dihydropeptidase enzyme found in the human body. To prevent its rapid degradation, imipenem is normally co-administered with cilastatin, an inhibitor of this enzyme. | Thienamycin
Template:Chembox new
Thienamycin, one of the most potent naturally-produced antibiotics known thus far, was discovered in Streptomyces cattleya in 1976. Thienamycin has excellent activity against both Gram-positive and Gram-negative bacteria and is resistant to bacterial β-lactamase enzymes.
# History
In 1976, fermentation broths obtained from the soil bacteria Streptomyces cattleya were found to be active in screens for inhibitors of peptidoglycan biosynthesis[1]. Initial attempts to isolate the active species proved difficult due to the chemical instability of that component. After many attempts and extensive purification, the material was finally isolated in >90% purity, allowing for the structural elucidation of thienamycin in 1979 (Figure 1)[2].
Thienamycin was the first among the naturally-occurring class of carbapenem antibiotics to be discovered and isolated. Carbapenems are similar in structure to their antibiotic “cousins” the penicillins. Like penicillins, carbapenems contain a β-lactam ring (cyclic amide) fused to a five-membered ring. Carbapenems differ in structure from penicillins in that within the five-membered ring a sulfur is replaced by a carbon atom (C1) and an unsaturation is present between C2 and C3 in the five-membered ring.
# Mechanism of Action
In vitro, thienamycin employs a similar mode of action as penicillins through disrupting the cell wall synthesis (peptidoglycan biosynthesis) of various Gram-positive and Gram-negative bacteria (Staphylococcus aureus,Staphylococcus epidermidis, Pseudomonas aeruginosa to name a few)[3]. In a study carried out by Spratt et al., they found that, although thienamycin binds to all of the penicillin-binding proteins (PBP) in Escherichia coli, it preferentially binds to PBP-1 and PBP-2, which are both associated with the elongation of the cell wall[4].
Unlike pencillins, which are rendered ineffective through rapid hydrolysis by the β-lactamase enzyme present in some strains of bacteria, thienamycin remains antimicrobially active. Neu et al. found that thienamycin displayed high activity against bacteria that were resistant to other β-lactamase stable compounds (cephalosporins), highlighting the superiority of thienamycin as an antibiotic among β-lactams[5].
# Biosynthesis
The formation of thienamycin is thought to occur through a different pathway from classic β-lactams (penicillins, cephalosporins). Production of classic β-lactams in both fungi and bacteria occur through two steps: First, the condensation of L-cysteine, L-Valine, and L-α-amino adipic acid by ACV synthetase (ACVS, a nonribsomal peptide synthetase) and then cyclization of this formed tripeptide by isopenicillin N synthetase (IPNS).
The gene cluster (thn) for the biosynthesis of thienamycin by S. cattleya was identified and sequenced, finally, in 2003, lending insight into the biosynthetic mechanism for thienamycin formation[6]. Based on previous work[7] and on this significant breakthrough, a tentative biosynthetic pathway has been proposed (Figure 2).
The biosynthesis of thienamycin begins with the condensation of acetyl-S-CoA with γ-glutamyl phosphate to form the pyrroline ring. The hydroxyethyl side chain of thienamycin is thought to be a result of two separate methyl transfers from S-adenosyl methionine[8]. According to the proposed biosynthesis, one methylation step occurs immediately after formation of the pyrroline ring, and the other methylation step occurs after formation of the bicyclic ring. According to the proposed gene functions (Table 1), ThnK, ThnL, and ThnP could catalyze these methyl-transfer steps. After the first methylation step occurs, β-lactam synthetase (ThnM) is thought to catalyze the formation of the β-lactam ring fused to the five-membered ring. Incorporation of the cysteaminyl side chain is then assisted by ThnV and/or ThnT. Oxidations occur between C6 and C8, followed by the second methylation step (mentioned above), then reduction at C6 and C8, and subsequently oxidation between C2 and C3. Hydroxylation by ThnG gives thienamycin as the final product (Note: see Figure 2 for a potential alternative pathway).
# Total Synthesis
Due to low titre and to difficulties in isolating and purifying thienamycin produced via fermentation, total synthesis is the preferred method for commercial production. Numerous methods are available in the literature for the total synthesis of thienamycin. One synthetic route[9] is given in Figure 3.
The starting β-lactam for the pathway given above can be synthesized via the following method (Figure 4):[10]
# Clinical Use
Thienamycin itself is extremely unstable and decomposes in aqueous solution. Consequently, thienamycin is impractical for clinical treatment of bacterial infections. For this reason, stable derivatives of thienamycin were created for medicinal consumption. One such derivative, imipenem, was formulated in 1985. Imipenem, an N-formimidoyl derivative of thienamycin, is rapidly metabolized by the renal dihydropeptidase enzyme found in the human body. To prevent its rapid degradation, imipenem is normally co-administered with cilastatin, an inhibitor of this enzyme. | https://www.wikidoc.org/index.php/Thienamycin | |
0ce00769425b5933a4e51cf2b61d625e9d03bcf5 | wikidoc | Thioguanine | Thioguanine
# 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
Thioguanine is an antimetabolite that is FDA approved for the treatment of acute nonlymphocytic leukemias and chronic phase of chronic myelogenous leukemia. Common adverse reactions include loss of appetite, nausea, stomatitis, vomiting and myelosuppression.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Thioguanine is indicated for remission induction and remission consolidation treatment of acute nonlymphocytic leukemias.
- However, it is not recommended for use during maintenance therapy or similar long-term continuous treatments due to the high risk of liver toxicity.
- Dosage:
- 2 mg/kg of body weight per day.
- If, after 4 weeks on this dosage, there is no clinical improvement and no leukocyte or platelet depression, the dosage may be cautiously increased to 3 mg/kg/day.
- More objective responses are observed with busulfan, and therefore busulfan is usually regarded as the preferred drug.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thioguanine in adult patients.
### Non–Guideline-Supported Use
- Intracranial tumor
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Thioguanine is indicated for remission induction and remission consolidation treatment of acute nonlymphocytic leukemias.
- However, it is not recommended for use during maintenance therapy or similar long-term continuous treatments due to the high risk of liver toxicity.
- Dosage:
- 2 mg/kg of body weight per day
- If, after 4 weeks on this dosage, there is no clinical improvement and no leukocyte or platelet depression, the dosage may be cautiously increased to 3 mg/kg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thioguanine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Thioguanine in pediatric patients.
# Contraindications
Thioguanine should not be used in patients whose disease has demonstrated prior resistance to this drug. In animals and humans, there is usually complete cross-resistance between mercaptopurine and thioguanine.
# Warnings
- This liver toxicity has been observed in a high proportion of children receiving thioguanine as part of maintenance therapy for acute lymphoblastic leukemia and in other conditions associated with continuous use of thioguanine. This liver toxicity is particularly prevalent in males. Liver toxicity usually presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or with signs of portal hypertension (splenomegaly, thrombocytopenia, and oesophageal varices). Histopathological features associated with this toxicity include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis.
- Thioguanine therapy should be discontinued in patients with evidence of liver toxicity as reversal of signs and symptoms of liver toxicity have been reported upon withdrawal.
- Patients must be carefully monitored. Early indications of liver toxicity are signs associated with portal hypertension such as thrombocytopenia out of proportion with neutropenia and splenomegaly. Elevations of liver enzymes have also been reported in association with liver toxicity but do not always occur.
- The most consistent, dose-related toxicity is bone marrow suppression. This may be manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Any one of these findings may also reflect progression of the underlying disease. Since thioguanine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an abnormally large fall in any of the formed elements of the blood.
- There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effects of thioguanine and prone to developing rapid bone marrow suppression following the initiation of treatment. Substantial dosage reductions may be required to avoid the development of life-threatening bone marrow suppression in these patients. Prescribers should be aware that some laboratories offer testing for TPMT deficiency. Since bone marrow suppression may be associated with factors other than TPMT deficiency, TPMT testing may not identify all patients at risk for severe toxicity. Therefore, close monitoring of clinical and hematologic parameters is important. Bone marrow suppression could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or sulphasalazine.
- It is recommended that evaluation of the hemoglobin concentration or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained frequently while the patient is on thioguanine therapy. In cases where the cause of fluctuations in the formed elements in the peripheral blood is obscure, bone marrow examination may be useful for the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a given dosage of thioguanine must be based not only on the absolute hematologic values, but also upon the rapidity with which changes are occurring. In many instances, particularly during the induction phase of acute leukemia, complete blood counts will need to be done more frequently in order to evaluate the effect of the therapy. The dosage of thioguanine may need to be reduced when this agent is combined with other drugs whose primary toxicity is myelosuppression.
- Myelosuppression is often unavoidable during the induction phase of adult acute nonlymphocytic leukemias if remission induction is to be successful. Whether or not this demands modification or cessation of dosage depends both upon the response of the underlying disease and a careful consideration of supportive facilities (granulocyte and platelet transfusions) which may be available. Life-threatening infections and bleeding have been observed as consequences of thioguanine-induced granulocytopenia and thrombocytopenia.
- The effect of thioguanine on the immunocompetence of patients is unknown.
# Adverse Reactions
## Clinical Trials Experience
- The most frequent adverse reaction to thioguanine is myelosuppression. The induction of complete remission of acute myelogenous leukemia usually requires combination chemotherapy in dosages which produce marrow hypoplasia. Since consolidation and maintenance of remission are also effected by multiple-drug regimens whose component agents cause myelosuppression, pancytopenia is observed in nearly all patients. Dosages and schedules must be adjusted to prevent life-threatening cytopenias whenever these adverse reactions are observed.
- Hyperuricemia frequently occurs in patients receiving thioguanine as a consequence of rapid cell lysis accompanying the antineoplastic effect. Adverse effects can be minimized by increased hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor such as allopurinol. Unlike mercaptopurine and azathioprine, thioguanine may be continued in the usual dosage when allopurinol is used conjointly to inhibit uric acid formation.
- Less frequent adverse reactions include nausea, vomiting, anorexia, and stomatitis. Intestinal necrosis and perforation have been reported in patients who received multiple-drug chemotherapy including thioguanine.
- Liver toxicity associated with vascular endothelial damage has been reported when thioguanine is used in maintenance or similar long-term continuous therapy which is not recommended. This usually presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or signs and symptoms of portal hypertension (splenomegaly, thrombocytopenia, and esophageal varices). Elevation of liver transaminases, alkaline phosphatase, and gamma glutamyl transferase and jaundice may also occur. Histopathological features associated with this toxicity include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis.
- Liver toxicity during short-term cyclical therapy presents as veno-occlusive disease. Reversal of signs and symptoms of this liver toxicity has been reported upon withdrawal of short-term or long-term continuous therapy.
- Centrilobular hepatic necrosis has been reported in a few cases; however, the reports are confounded by the use of high doses of thioguanine, other chemotherapeutic agents, and oral contraceptives and chronic alcohol abuse.
## Postmarketing Experience
There is limited information regarding Thioguanine Postmarketing Experience in the drug label.
# Drug Interactions
There is usually complete cross-resistance between mercaptopurine and thioguanine.
- As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Drugs such as thioguanine are potential mutagens and teratogens. Thioguanine may cause fetal harm when administered to a pregnant woman. Thioguanine has been shown to be teratogenic in rats when given in doses 5 times the human dose. When given to the rat on the 4th and 5th days of gestation, 13% of surviving placentas did not contain fetuses, and 19% of offspring were malformed or stunted. The malformations noted included generalized edema, cranial defects, and general skeletal hypoplasia, hydrocephalus, ventral hernia, situs inversus, and incomplete development of the limbs. 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 the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Thioguanine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Thioguanine during labor and delivery.
### Nursing Mothers
It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for thioguanine, 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
There is no FDA guidance on the use of Thioguanine in pediatric settings.
### Geriatic Use
Clinical studies of thioguanine 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. 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 Thioguanine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Thioguanine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Thioguanine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Thioguanine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Thioguanine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Thioguanine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
It is advisable to monitor liver function tests (serum transaminases, alkaline phosphatase, bilirubin) at weekly intervals when first beginning therapy and at monthly intervals thereafter. It may be advisable to perform liver function tests more frequently in patients with known pre-existing liver disease or in patients who are receiving thioguanine and other hepatotoxic drugs. Patients should be instructed to discontinue thioguanine immediately if clinical jaundice is detected.
# IV Compatibility
There is limited information regarding the compatibility of Thioguanine and IV administrations.
# Overdosage
Signs and symptoms of overdosage may be immediate, such as nausea, vomiting, malaise, hypotension, and diaphoresis; or delayed, such as myelosuppression and azotemia. It is not known whether thioguanine is dialyzable. Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of thioguanine into active metabolites with long persistence. The oral LD50 of thioguanine was determined to be 823 mg/kg ± 50.73 mg/kg and 740 mg/kg ± 45.24 mg/kg for male and female rats, respectively. Symptoms of overdosage may occur after a single dose of as little as 2.0 to 3.0 mg/kg thioguanine. As much as 35 mg/kg has been given in a single oral dose with reversible myelosuppression observed. There is no known pharmacologic antagonist of thioguanine. The drug should be discontinued immediately if unintended toxicity occurs during treatment. Severe hematologic toxicity may require supportive therapy with platelet transfusions for bleeding, and granulocyte transfusions and antibiotics if sepsis is documented. If a patient is seen immediately following an accidental overdosage of the drug, it may be useful to induce emesis.
# Pharmacology
## Mechanism of Action
- Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanylic acid (TGMP). This nucleotide reaches high intracellular concentrations at therapeutic doses. TPMT interferes at several points with the synthesis of guanine nucleotides. It inhibits de novo purine biosynthesis by pseudo-feedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase—the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. At one time TGMP was felt to be a significant inhibitor of ATP:GMP phosphotransferase (guanylate kinase), but recent results have shown this not to be so.
- Thioguanylic acid is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) (as well as their 2′-deoxyribosyl analogues) by the same enzymes which metabolize guanine nucleotides. Thioguanine nucleotides are incorporated into both the RNA and the DNA by phosphodiester linkages and it has been argued that incorporation of such fraudulent bases contributes to the cytotoxicity of thioguanine.
- Thus, thioguanine has multiple metabolic effects and at present it is not possible to designate one major site of action. Its tumor inhibitory properties may be due to one or more of its effects on (a) feedback inhibition of de novo purine synthesis; (b) inhibition of purine nucleotide interconversions; or (c) incorporation into the DNA and the RNA. The net consequence of its actions is a sequential blockade of the synthesis and utilization of the purine nucleotides.
## Structure
Thioguanine, known chemically as 2-amino-1,7-dihydro-6H-purine-6-thione. Its structural formula is:
## Pharmacodynamics
There is limited information regarding Thioguanine Pharmacodynamics in the drug label.
## Pharmacokinetics
- Clinical studies have shown that the absorption of an oral dose of thioguanine in humans is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%). Following oral administration of 35S-6-thioguanine, total plasma radioactivity reached a maximum at 8 hours and declined slowly thereafter. Parent drug represented only a very small fraction of the total plasma radioactivity at any time, being virtually undetectable throughout the period of measurements.
- The oral administration of radiolabeled thioguanine revealed only trace quantities of parent drug in the urine. However, a methylated metabolite, 2-amino-6-methylthiopurine (MTG), appeared very early, rose to a maximum 6 to 8 hours after drug administration, and was still being excreted after 12 to 22 hours. Radiolabeled sulfate appeared somewhat later than MTG but was the principal metabolite after 8 hours. Thiouric acid and some unidentified products were found in the urine in small amounts. Intravenous administration of 35S-6-thioguanine disclosed a median plasma half-disappearance time of 80 minutes (range: 25 to 240 minutes) when the compound was given in single doses of 65 to 300 mg/m2. Although initial plasma levels of thioguanine did correlate with the dose level, there was no correlation between the plasma half-disappearance time and the dose.
Thioguanine is incorporated into the DNA and the RNA of human bone marrow cells. Studies with intravenous 35S-6-thioguanine have shown that the amount of thioguanine incorporated into nucleic acids is more than 100 times higher after 5 daily doses than after a single dose. With the 5-dose schedule, from one-half to virtually all of the guanine in the residual DNA was replaced by thioguanine. Tissue distribution studies of 35S-6-thioguanine in mice showed only traces of radioactivity in brain after oral administration. No measurements have been made of thioguanine concentrations in human cerebrospinal fluid (CSF), but observations on tissue distribution in animals, together with the lack of CNS penetration by the closely related compound, mercaptopurine, suggest that thioguanine does not reach therapeutic concentrations in the CSF.
Monitoring of plasma levels of thioguanine during therapy is of questionable value. There is technical difficulty in determining plasma concentrations, which are seldom greater than 1 to 2 mcg/mL after a therapeutic oral dose. More significantly, thioguanine enters rapidly into the anabolic and catabolic pathways for purines, and the active intracellular metabolites have appreciably longer half-lives than the parent drug. The biochemical effects of a single dose of thioguanine are evident long after the parent drug has disappeared from plasma. Because of this rapid metabolism of thioguanine to active intracellular derivatives, hemodialysis would not be expected to appreciably reduce toxicity of the drug.
The catabolism of thioguanine and its metabolites is complex and shows significant differences between humans and the mouse. In both humans and mice, after oral administration of 35S-6-thioguanine, urine contains virtually no detectable intact thioguanine. While deamination and subsequent oxidation to thiouric acid occurs only to a small extent in humans, it is the main pathway in mice. The product of deamination by guanase, 6-thioxanthine is inactive, having negligible antitumor activity. This pathway of thioguanine inactivation is not dependent on the action of xanthine oxidase, and an inhibitor of that enzyme (such as allopurinol) will not block the detoxification of thioguanine even though the inactive 6-thioxanthine is normally further oxidized by xanthine oxidase to thiouric acid before it is eliminated. In humans, methylation of thioguanine is much more extensive than in the mouse. The product of methylation, 2-amino-6-methylthiopurine, is also substantially less active and less toxic than thioguanine and its formation is likewise unaffected by the presence of allopurinol. Appreciable amounts of inorganic sulfate are also found in both murine and human urine, presumably arising from further metabolism of the methylated derivatives.
## Nonclinical Toxicology
In some animal tumors, resistance to the effect of thioguanine correlates with the loss of HGPRTase activity and the resulting inability to convert thioguanine to thioguanylic acid. However, other resistance mechanisms, such as increased catabolism of TGMP by a nonspecific phosphatase, may be operative. Although not invariable, it is usual to find cross-resistance between thioguanine and its close analogue, mercaptopurine.
# Clinical Studies
FDA package insert for Thioguanine contains no information regarding Clinical Studies.
# How Supplied
- Thioguanine 40 mg tablets
- Bottles of 25 tablets (NDC 76388-880-25)
## Storage
Store at 15° to 25°C (59° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be informed that the major toxicities of thioguanine are related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. sore throat Patients should never be allowed to take the drug without medical supervision and should be advised to consult their physician if they experience fever, , jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia. Women of childbearing potential should be advised to avoid becoming pregnant.
# Precautions with Alcohol
Alcohol-Thioguanine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tabloid
# Look-Alike Drug Names
There is limited information regarding Thioguanine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Thioguanine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2];Aparna Vuppala, M.B.B.S. [3]
# 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
Thioguanine is an antimetabolite that is FDA approved for the treatment of acute nonlymphocytic leukemias and chronic phase of chronic myelogenous leukemia. Common adverse reactions include loss of appetite, nausea, stomatitis, vomiting and myelosuppression.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Thioguanine is indicated for remission induction and remission consolidation treatment of acute nonlymphocytic leukemias.
- However, it is not recommended for use during maintenance therapy or similar long-term continuous treatments due to the high risk of liver toxicity.
- Dosage:
- 2 mg/kg of body weight per day.
- If, after 4 weeks on this dosage, there is no clinical improvement and no leukocyte or platelet depression, the dosage may be cautiously increased to 3 mg/kg/day.
- More objective responses are observed with busulfan, and therefore busulfan is usually regarded as the preferred drug.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thioguanine in adult patients.
### Non–Guideline-Supported Use
- Intracranial tumor
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Thioguanine is indicated for remission induction and remission consolidation treatment of acute nonlymphocytic leukemias.
- However, it is not recommended for use during maintenance therapy or similar long-term continuous treatments due to the high risk of liver toxicity.
- Dosage:
- 2 mg/kg of body weight per day
- If, after 4 weeks on this dosage, there is no clinical improvement and no leukocyte or platelet depression, the dosage may be cautiously increased to 3 mg/kg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thioguanine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Thioguanine in pediatric patients.
# Contraindications
Thioguanine should not be used in patients whose disease has demonstrated prior resistance to this drug. In animals and humans, there is usually complete cross-resistance between mercaptopurine and thioguanine.
# Warnings
- This liver toxicity has been observed in a high proportion of children receiving thioguanine as part of maintenance therapy for acute lymphoblastic leukemia and in other conditions associated with continuous use of thioguanine. This liver toxicity is particularly prevalent in males. Liver toxicity usually presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or with signs of portal hypertension (splenomegaly, thrombocytopenia, and oesophageal varices). Histopathological features associated with this toxicity include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis.
- Thioguanine therapy should be discontinued in patients with evidence of liver toxicity as reversal of signs and symptoms of liver toxicity have been reported upon withdrawal.
- Patients must be carefully monitored. Early indications of liver toxicity are signs associated with portal hypertension such as thrombocytopenia out of proportion with neutropenia and splenomegaly. Elevations of liver enzymes have also been reported in association with liver toxicity but do not always occur.
- The most consistent, dose-related toxicity is bone marrow suppression. This may be manifested by anemia, leukopenia, thrombocytopenia, or any combination of these. Any one of these findings may also reflect progression of the underlying disease. Since thioguanine may have a delayed effect, it is important to withdraw the medication temporarily at the first sign of an abnormally large fall in any of the formed elements of the blood.
- There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effects of thioguanine and prone to developing rapid bone marrow suppression following the initiation of treatment. Substantial dosage reductions may be required to avoid the development of life-threatening bone marrow suppression in these patients. Prescribers should be aware that some laboratories offer testing for TPMT deficiency. Since bone marrow suppression may be associated with factors other than TPMT deficiency, TPMT testing may not identify all patients at risk for severe toxicity. Therefore, close monitoring of clinical and hematologic parameters is important. Bone marrow suppression could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or sulphasalazine.
- It is recommended that evaluation of the hemoglobin concentration or hematocrit, total white blood cell count and differential count, and quantitative platelet count be obtained frequently while the patient is on thioguanine therapy. In cases where the cause of fluctuations in the formed elements in the peripheral blood is obscure, bone marrow examination may be useful for the evaluation of marrow status. The decision to increase, decrease, continue, or discontinue a given dosage of thioguanine must be based not only on the absolute hematologic values, but also upon the rapidity with which changes are occurring. In many instances, particularly during the induction phase of acute leukemia, complete blood counts will need to be done more frequently in order to evaluate the effect of the therapy. The dosage of thioguanine may need to be reduced when this agent is combined with other drugs whose primary toxicity is myelosuppression.
- Myelosuppression is often unavoidable during the induction phase of adult acute nonlymphocytic leukemias if remission induction is to be successful. Whether or not this demands modification or cessation of dosage depends both upon the response of the underlying disease and a careful consideration of supportive facilities (granulocyte and platelet transfusions) which may be available. Life-threatening infections and bleeding have been observed as consequences of thioguanine-induced granulocytopenia and thrombocytopenia.
- The effect of thioguanine on the immunocompetence of patients is unknown.
# Adverse Reactions
## Clinical Trials Experience
- The most frequent adverse reaction to thioguanine is myelosuppression. The induction of complete remission of acute myelogenous leukemia usually requires combination chemotherapy in dosages which produce marrow hypoplasia. Since consolidation and maintenance of remission are also effected by multiple-drug regimens whose component agents cause myelosuppression, pancytopenia is observed in nearly all patients. Dosages and schedules must be adjusted to prevent life-threatening cytopenias whenever these adverse reactions are observed.
- Hyperuricemia frequently occurs in patients receiving thioguanine as a consequence of rapid cell lysis accompanying the antineoplastic effect. Adverse effects can be minimized by increased hydration, urine alkalinization, and the prophylactic administration of a xanthine oxidase inhibitor such as allopurinol. Unlike mercaptopurine and azathioprine, thioguanine may be continued in the usual dosage when allopurinol is used conjointly to inhibit uric acid formation.
- Less frequent adverse reactions include nausea, vomiting, anorexia, and stomatitis. Intestinal necrosis and perforation have been reported in patients who received multiple-drug chemotherapy including thioguanine.
- Liver toxicity associated with vascular endothelial damage has been reported when thioguanine is used in maintenance or similar long-term continuous therapy which is not recommended. This usually presents as the clinical syndrome of hepatic veno-occlusive disease (hyperbilirubinemia, tender hepatomegaly, weight gain due to fluid retention, and ascites) or signs and symptoms of portal hypertension (splenomegaly, thrombocytopenia, and esophageal varices). Elevation of liver transaminases, alkaline phosphatase, and gamma glutamyl transferase and jaundice may also occur. Histopathological features associated with this toxicity include hepatoportal sclerosis, nodular regenerative hyperplasia, peliosis hepatitis, and periportal fibrosis.
- Liver toxicity during short-term cyclical therapy presents as veno-occlusive disease. Reversal of signs and symptoms of this liver toxicity has been reported upon withdrawal of short-term or long-term continuous therapy.
- Centrilobular hepatic necrosis has been reported in a few cases; however, the reports are confounded by the use of high doses of thioguanine, other chemotherapeutic agents, and oral contraceptives and chronic alcohol abuse.
## Postmarketing Experience
There is limited information regarding Thioguanine Postmarketing Experience in the drug label.
# Drug Interactions
There is usually complete cross-resistance between mercaptopurine and thioguanine.
- As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Drugs such as thioguanine are potential mutagens and teratogens. Thioguanine may cause fetal harm when administered to a pregnant woman. Thioguanine has been shown to be teratogenic in rats when given in doses 5 times the human dose. When given to the rat on the 4th and 5th days of gestation, 13% of surviving placentas did not contain fetuses, and 19% of offspring were malformed or stunted. The malformations noted included generalized edema, cranial defects, and general skeletal hypoplasia, hydrocephalus, ventral hernia, situs inversus, and incomplete development of the limbs. 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 the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Thioguanine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Thioguanine during labor and delivery.
### Nursing Mothers
It is not known whether this drug is excreted in human milk. Because of the potential for tumorigenicity shown for thioguanine, 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
There is no FDA guidance on the use of Thioguanine in pediatric settings.
### Geriatic Use
Clinical studies of thioguanine 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. 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 Thioguanine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Thioguanine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Thioguanine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Thioguanine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Thioguanine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Thioguanine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
It is advisable to monitor liver function tests (serum transaminases, alkaline phosphatase, bilirubin) at weekly intervals when first beginning therapy and at monthly intervals thereafter. It may be advisable to perform liver function tests more frequently in patients with known pre-existing liver disease or in patients who are receiving thioguanine and other hepatotoxic drugs. Patients should be instructed to discontinue thioguanine immediately if clinical jaundice is detected.
# IV Compatibility
There is limited information regarding the compatibility of Thioguanine and IV administrations.
# Overdosage
Signs and symptoms of overdosage may be immediate, such as nausea, vomiting, malaise, hypotension, and diaphoresis; or delayed, such as myelosuppression and azotemia. It is not known whether thioguanine is dialyzable. Hemodialysis is thought to be of marginal use due to the rapid intracellular incorporation of thioguanine into active metabolites with long persistence. The oral LD50 of thioguanine was determined to be 823 mg/kg ± 50.73 mg/kg and 740 mg/kg ± 45.24 mg/kg for male and female rats, respectively. Symptoms of overdosage may occur after a single dose of as little as 2.0 to 3.0 mg/kg thioguanine. As much as 35 mg/kg has been given in a single oral dose with reversible myelosuppression observed. There is no known pharmacologic antagonist of thioguanine. The drug should be discontinued immediately if unintended toxicity occurs during treatment. Severe hematologic toxicity may require supportive therapy with platelet transfusions for bleeding, and granulocyte transfusions and antibiotics if sepsis is documented. If a patient is seen immediately following an accidental overdosage of the drug, it may be useful to induce emesis.
# Pharmacology
## Mechanism of Action
- Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanylic acid (TGMP). This nucleotide reaches high intracellular concentrations at therapeutic doses. TPMT interferes at several points with the synthesis of guanine nucleotides. It inhibits de novo purine biosynthesis by pseudo-feedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase—the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. At one time TGMP was felt to be a significant inhibitor of ATP:GMP phosphotransferase (guanylate kinase), but recent results have shown this not to be so.
- Thioguanylic acid is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) (as well as their 2′-deoxyribosyl analogues) by the same enzymes which metabolize guanine nucleotides. Thioguanine nucleotides are incorporated into both the RNA and the DNA by phosphodiester linkages and it has been argued that incorporation of such fraudulent bases contributes to the cytotoxicity of thioguanine.
- Thus, thioguanine has multiple metabolic effects and at present it is not possible to designate one major site of action. Its tumor inhibitory properties may be due to one or more of its effects on (a) feedback inhibition of de novo purine synthesis; (b) inhibition of purine nucleotide interconversions; or (c) incorporation into the DNA and the RNA. The net consequence of its actions is a sequential blockade of the synthesis and utilization of the purine nucleotides.
## Structure
Thioguanine, known chemically as 2-amino-1,7-dihydro-6H-purine-6-thione. Its structural formula is:
## Pharmacodynamics
There is limited information regarding Thioguanine Pharmacodynamics in the drug label.
## Pharmacokinetics
- Clinical studies have shown that the absorption of an oral dose of thioguanine in humans is incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%). Following oral administration of 35S-6-thioguanine, total plasma radioactivity reached a maximum at 8 hours and declined slowly thereafter. Parent drug represented only a very small fraction of the total plasma radioactivity at any time, being virtually undetectable throughout the period of measurements.
- The oral administration of radiolabeled thioguanine revealed only trace quantities of parent drug in the urine. However, a methylated metabolite, 2-amino-6-methylthiopurine (MTG), appeared very early, rose to a maximum 6 to 8 hours after drug administration, and was still being excreted after 12 to 22 hours. Radiolabeled sulfate appeared somewhat later than MTG but was the principal metabolite after 8 hours. Thiouric acid and some unidentified products were found in the urine in small amounts. Intravenous administration of 35S-6-thioguanine disclosed a median plasma half-disappearance time of 80 minutes (range: 25 to 240 minutes) when the compound was given in single doses of 65 to 300 mg/m2. Although initial plasma levels of thioguanine did correlate with the dose level, there was no correlation between the plasma half-disappearance time and the dose.
Thioguanine is incorporated into the DNA and the RNA of human bone marrow cells. Studies with intravenous 35S-6-thioguanine have shown that the amount of thioguanine incorporated into nucleic acids is more than 100 times higher after 5 daily doses than after a single dose. With the 5-dose schedule, from one-half to virtually all of the guanine in the residual DNA was replaced by thioguanine. Tissue distribution studies of 35S-6-thioguanine in mice showed only traces of radioactivity in brain after oral administration. No measurements have been made of thioguanine concentrations in human cerebrospinal fluid (CSF), but observations on tissue distribution in animals, together with the lack of CNS penetration by the closely related compound, mercaptopurine, suggest that thioguanine does not reach therapeutic concentrations in the CSF.
Monitoring of plasma levels of thioguanine during therapy is of questionable value. There is technical difficulty in determining plasma concentrations, which are seldom greater than 1 to 2 mcg/mL after a therapeutic oral dose. More significantly, thioguanine enters rapidly into the anabolic and catabolic pathways for purines, and the active intracellular metabolites have appreciably longer half-lives than the parent drug. The biochemical effects of a single dose of thioguanine are evident long after the parent drug has disappeared from plasma. Because of this rapid metabolism of thioguanine to active intracellular derivatives, hemodialysis would not be expected to appreciably reduce toxicity of the drug.
The catabolism of thioguanine and its metabolites is complex and shows significant differences between humans and the mouse. In both humans and mice, after oral administration of 35S-6-thioguanine, urine contains virtually no detectable intact thioguanine. While deamination and subsequent oxidation to thiouric acid occurs only to a small extent in humans, it is the main pathway in mice. The product of deamination by guanase, 6-thioxanthine is inactive, having negligible antitumor activity. This pathway of thioguanine inactivation is not dependent on the action of xanthine oxidase, and an inhibitor of that enzyme (such as allopurinol) will not block the detoxification of thioguanine even though the inactive 6-thioxanthine is normally further oxidized by xanthine oxidase to thiouric acid before it is eliminated. In humans, methylation of thioguanine is much more extensive than in the mouse. The product of methylation, 2-amino-6-methylthiopurine, is also substantially less active and less toxic than thioguanine and its formation is likewise unaffected by the presence of allopurinol. Appreciable amounts of inorganic sulfate are also found in both murine and human urine, presumably arising from further metabolism of the methylated derivatives.
## Nonclinical Toxicology
In some animal tumors, resistance to the effect of thioguanine correlates with the loss of HGPRTase activity and the resulting inability to convert thioguanine to thioguanylic acid. However, other resistance mechanisms, such as increased catabolism of TGMP by a nonspecific phosphatase, may be operative. Although not invariable, it is usual to find cross-resistance between thioguanine and its close analogue, mercaptopurine.
# Clinical Studies
FDA package insert for Thioguanine contains no information regarding Clinical Studies.
# How Supplied
- Thioguanine 40 mg tablets
- Bottles of 25 tablets (NDC 76388-880-25)
## Storage
Store at 15° to 25°C (59° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be informed that the major toxicities of thioguanine are related to myelosuppression, hepatotoxicity, and gastrointestinal toxicity. sore throat Patients should never be allowed to take the drug without medical supervision and should be advised to consult their physician if they experience fever, , jaundice, nausea, vomiting, signs of local infection, bleeding from any site, or symptoms suggestive of anemia. Women of childbearing potential should be advised to avoid becoming pregnant.
# Precautions with Alcohol
Alcohol-Thioguanine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tabloid [1]
# Look-Alike Drug Names
There is limited information regarding Thioguanine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Thioguanine | |
dcd15b62da6ad7d9008daf538c9fd8a4a8748517 | wikidoc | Thioredoxin | Thioredoxin
Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes, including redox signaling. In humans, thioredoxins are encoded by TXN and TXN2 genes. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the developing embryo. Although not entirely understood, thioredoxin plays a central role in humans and is increasingly linked to medicine through their response to reactive oxygen species (ROS). In plants, thioredoxins regulate a spectrum of critical functions, ranging from photosynthesis to growth, flowering and the development and germination of seeds. They have also recently been found to play a role in cell-to-cell communication.
# Function
Thioredoxins are proteins that act as antioxidants by facilitating the reduction of other proteins by cysteine thiol-disulfide exchange. Thioredoxins are found in nearly all known organisms and are essential for life in mammals.
Thioredoxin is a 12-kD oxidoreductase enzyme containing a dithiol-disulfide active site. It is ubiquitous and found in many organisms from plants and bacteria to mammals. Multiple in vitro substrates for thioredoxin have been identified, including ribonuclease, choriogonadotropins, coagulation factors, glucocorticoid receptor, and insulin. Reduction of insulin is classically used as an activity test.
Thioredoxins are characterized at the level of their amino acid sequence by the presence of two vicinal cysteines in a CXXC motif. These two cysteines are the key to the ability of thioredoxin to reduce other proteins. Thioredoxin proteins also have a characteristic tertiary structure termed the thioredoxin fold.
The thioredoxins are kept in the reduced state by the flavoenzyme thioredoxin reductase, in a NADPH-dependent reaction. Thioredoxins act as electron donors to peroxidases and ribonucleotide reductase. The related glutaredoxins share many of the functions of thioredoxins, but are reduced by glutathione rather than a specific reductase.
The benefit of thioredoxins to reduce oxidative stress is shown by transgenic mice that overexpress thioredoxin, are more resistant to inflammation, and live 35% longer — supporting the free radical theory of aging. However, the controls of this study were short lived, which may have contributed to the apparent increase in longevity.
Plants have an unusually complex complement of Trxs composed of six well-defined types (Trxs f, m, x, y, h, and o) that reside in different cell compartments and function in an array of processes. In 2010 it was discovered for the first time that thioredoxin proteins are able to move from cell to cell, representing a novel form of cellular communication in plants.
# Mechanism of action
The primary function of Thioredoxin (Trx) is the reduction of oxidized cysteine residues and the cleavage of disulfide bonds. For Trx1, this process begins by attack of Cys32, one of the residues conserved in the thioredoxin CXXC motif, onto the oxidized group of the substrate. Almost immediately after this event Cys35, the other conserved Cys residue in Trx1, forms a disulfide bond with Cys32, thereby transferring 2 electrons to the substrate which is now in its reduced form. Oxidized Trx1 is then reduced by thioredoxin reductase, which in turn is reduced by NADPH as described above.
# Interactions
Thioredoxin has been shown to interact with:
- ASK1,
- Collagen, type I, alpha 1,
- Glucocorticoid receptor,
- SENP1,
- TXNIP.
- NF-κB – by reducing a disulfide bond in NF-κB, Trx1 promotes binding of this transcription factor to DNA.
- AP1 via Ref1 – Trx1 indirectly increases the DNA-binding activity of activator protein 1 (AP1) by reducing the DNA repair enzyme redox factor 1 (Ref-1), which in turn reduces AP1 in an example of a redox regulation cascade.
- AMPK – AMPK function in cardiomyocytes is preserved during oxidative stress due to an interaction between AMPK and Trx1. By forming a disulfide bridge between the two proteins, Trx1 prevents the formation and aggregation of oxidized AMPK, thereby allowing AMPK to function normally and participate in signaling cascades.
# Effect on cardiac hypertrophy
Trx1 has been shown to downregulate cardiac hypertrophy, the thickening of the walls of the lower heart chambers, by interactions with several different targets. Trx1 upregulates the transcriptional activity of nuclear respiratory factors 1 and 2 (NRF1 and NRF2) and stimulates the expression of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α). Furthermore, Trx1 reduces two cysteine residues in histone deacetylase 4 (HDAC4), which allows HDAC4 to be imported from the cytosol, where the oxidized form resides, into the nucleus. Once in the nucleus, reduced HDAC4 downregulates the activity of transcription factors such as NFAT that mediate cardiac hypertrophy. Trx 1 also controls microRNA levels in the heart and has been found to inhibit cardiac hypertrophy by upregulating miR-98/let-7. | Thioredoxin
Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes, including redox signaling. In humans, thioredoxins are encoded by TXN and TXN2 genes.[1][2] Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the developing embryo. Although not entirely understood, thioredoxin plays a central role in humans and is increasingly linked to medicine through their response to reactive oxygen species (ROS). In plants, thioredoxins regulate a spectrum of critical functions, ranging from photosynthesis to growth, flowering and the development and germination of seeds. They have also recently been found to play a role in cell-to-cell communication.[3]
# Function
Thioredoxins are proteins that act as antioxidants by facilitating the reduction of other proteins by cysteine thiol-disulfide exchange. Thioredoxins are found in nearly all known organisms and are essential for life in mammals.[4][5]
Thioredoxin is a 12-kD oxidoreductase enzyme containing a dithiol-disulfide active site. It is ubiquitous and found in many organisms from plants and bacteria to mammals. Multiple in vitro substrates for thioredoxin have been identified, including ribonuclease, choriogonadotropins, coagulation factors, glucocorticoid receptor, and insulin. Reduction of insulin is classically used as an activity test.[6]
Thioredoxins are characterized at the level of their amino acid sequence by the presence of two vicinal cysteines in a CXXC motif. These two cysteines are the key to the ability of thioredoxin to reduce other proteins. Thioredoxin proteins also have a characteristic tertiary structure termed the thioredoxin fold.
The thioredoxins are kept in the reduced state by the flavoenzyme thioredoxin reductase, in a NADPH-dependent reaction.[7] Thioredoxins act as electron donors to peroxidases and ribonucleotide reductase.[8] The related glutaredoxins share many of the functions of thioredoxins, but are reduced by glutathione rather than a specific reductase.
The benefit of thioredoxins to reduce oxidative stress is shown by transgenic mice that overexpress thioredoxin, are more resistant to inflammation, and live 35% longer[9] — supporting the free radical theory of aging. However, the controls of this study were short lived, which may have contributed to the apparent increase in longevity.[10]
Plants have an unusually complex complement of Trxs composed of six well-defined types (Trxs f, m, x, y, h, and o) that reside in different cell compartments and function in an array of processes. In 2010 it was discovered for the first time that thioredoxin proteins are able to move from cell to cell, representing a novel form of cellular communication in plants.[3]
# Mechanism of action
The primary function of Thioredoxin (Trx) is the reduction of oxidized cysteine residues and the cleavage of disulfide bonds.[11] For Trx1, this process begins by attack of Cys32, one of the residues conserved in the thioredoxin CXXC motif, onto the oxidized group of the substrate.[12] Almost immediately after this event Cys35, the other conserved Cys residue in Trx1, forms a disulfide bond with Cys32, thereby transferring 2 electrons to the substrate which is now in its reduced form. Oxidized Trx1 is then reduced by thioredoxin reductase, which in turn is reduced by NADPH as described above.[12]
# Interactions
Thioredoxin has been shown to interact with:
- ASK1,[13][14][15]
- Collagen, type I, alpha 1,[16]
- Glucocorticoid receptor,[17]
- SENP1,[18]
- TXNIP.[19]
- NF-κB – by reducing a disulfide bond in NF-κB, Trx1 promotes binding of this transcription factor to DNA.[20]
- AP1 via Ref1 – Trx1 indirectly increases the DNA-binding activity of activator protein 1 (AP1) by reducing the DNA repair enzyme redox factor 1 (Ref-1), which in turn reduces AP1 in an example of a redox regulation cascade.[21]
- AMPK – AMPK function in cardiomyocytes is preserved during oxidative stress due to an interaction between AMPK and Trx1. By forming a disulfide bridge between the two proteins, Trx1 prevents the formation and aggregation of oxidized AMPK, thereby allowing AMPK to function normally and participate in signaling cascades.[22]
# Effect on cardiac hypertrophy
Trx1 has been shown to downregulate cardiac hypertrophy, the thickening of the walls of the lower heart chambers, by interactions with several different targets. Trx1 upregulates the transcriptional activity of nuclear respiratory factors 1 and 2 (NRF1 and NRF2) and stimulates the expression of peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α).[23][24] Furthermore, Trx1 reduces two cysteine residues in histone deacetylase 4 (HDAC4), which allows HDAC4 to be imported from the cytosol, where the oxidized form resides,[25] into the nucleus.[26] Once in the nucleus, reduced HDAC4 downregulates the activity of transcription factors such as NFAT that mediate cardiac hypertrophy.[12] Trx 1 also controls microRNA levels in the heart and has been found to inhibit cardiac hypertrophy by upregulating miR-98/let-7.[27] | https://www.wikidoc.org/index.php/Thioredoxin | |
19b5f48001281ff7c0f8e9e7bc978f497c434f02 | wikidoc | Thiosulfate | Thiosulfate
# 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
Thiosulfate is a antidote that is FDA approved for the treatment of for sequential use with sodium nitrite for the treatment of acute cyanide poisoning that is judged to be life-threatening. Common adverse reactions include hypotension, prolonged bleeding time.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Sodium Thiosulfate Injection is indicated for sequential use with sodium nitrite for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potential risks associated with Sodium Thiosulfate Injection should be carefully weighed against the potential benefits, especially if the patient is not critical.
- Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to sodium nitroprusside.
- The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Sodium Thiosulfate Injection and Sodium Nitrite Injection should be administered without delay.
- In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.
- The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.
- Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Sodium Thiosulfate Injection smoke-inhalation victims should be assessed for the following:
- Exposure to fire or smoke in an enclosed area
Presence of soot around the mouth, nose, or oropharynx
- Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.
- Caution should be exercised when administering cyanide antidotes, other than sodium nitrite, simultaneously with Sodium Thiosulfate Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than sodium nitrite, with Sodium Thiosulfate Injection, these drugs should not be administered concurrently in the same IV line.
- Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of sodium nitrite and sodium thiosulfate should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer sodium nitrite and sodium thiosulfate.
- Sodium nitrite injection and sodium thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Sodium nitrite should be administered first, followed immediately by sodium thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.
- If signs of poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and sodium thiosulfate.
- In adult and pediatric patients with known anemia, it is recommended that the dosage of sodium nitrite should be reduced proportionately to the hemoglobin concentration.
- All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Patients should be monitored for at least 24-48 hours after Sodium Thiosulfate Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.
- Chemical incompatibility has been reported between Sodium Thiosulfate Injection and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thiosulfate in adult patients.
### Non–Guideline-Supported Use
- Antineoplastic adverse reaction - Injection site extravasation
- Calciphylaxis
- Carboplatin adverse reaction - Ototoxicity
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Thiosulfate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thiosulfate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Thiosulfate in pediatric patients.
# Contraindications
There is limited information regarding Thiosulfate Contraindications in the drug label.
# Warnings
- Sodium thiosulfate drug product may contain trace impurities of sodium sulfite. The presence of a trace amount of sulfites in this product should not deter administration of the drug for treatment of emergency situations, even if the patient is sulfite-sensitive.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Thiosulfate in the drug label.
## Postmarketing Experience
- There have been no controlled clinical trials conducted to systematically assess the adverse events profile of sodium thiosulfate.
- The medical literature has reported the following adverse events in association with sodium thiosulfate administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.
- Cardiovascular system
- Hypotension
- Central nervous system
- Headache, disorientation
- Gastrointestinal system
- Nausea, vomiting
- Hematological
- Prolonged bleeding time
- Body as a Whole
- Salty taste in mouth, warm sensation over body
- In humans, rapid administration of concentrated solutions or solutions not freshly prepared, and administration of large doses of sodium thiosulfate have been associated with a higher incidence of nausea and vomiting. However, administration of 0.1 g sodium thiosulfate per pound up to a maximum of 15 g in a 10-15% solution over 10-15 minutes was associated with nausea and vomiting in 7 of 26 patients without concomitant cyanide intoxication.
- In a series of 11 human subjects, a single intravenous infusion of 50 mL of 50% sodium thiosulfate was associated with increases in clotting time 1-3 days after administration. However, no significant changes were observed in other hematological parameters.
# Drug Interactions
- Formal drug interaction studies have not been conducted with Sodium Thiosulfate Injection.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women. Sodium Thiosulfate Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
There are no reported epidemiological studies of congenital anomalies in infants born to women treated with sodium thiosulfate during pregnancy. In animal studies, there are no teratogenic effects in offspring of hamsters treated during pregnancy with sodium thiosulfate in doses similar to those given intravenously to treat cyanide poisoning in humans. Other studies suggest that treatment with sodium thiosulfate ameliorates the teratogenic effects of maternal cyanide poisoning in hamsters. In other studies, sodium thiosulfate was not embryotoxic or teratogenic in mice, rats, hamsters, or rabbits at maternal doses of up to 550, 400, 400 and 580 mg/kg/day, respectively.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Thiosulfate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Thiosulfate during labor and delivery.
### Nursing Mothers
- It is not known whether sodium thiosulfate is excreted in human milk. Because Sodium Thiosulfate Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Sodium Thiosulfate Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of sodium thiosulfate.
### Pediatric Use
- There are case reports in the medical literature of sodium nitrite in conjunction with sodium thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of sodium thiosulfate in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
### Geriatic Use
- Sodium thiosulfate is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Thiosulfate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Thiosulfate with respect to specific racial populations.
### Renal Impairment
- Sodium thiosulfate is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Hepatic Impairment
There is no FDA guidance on the use of Thiosulfate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Thiosulfate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Thiosulfate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.
- Blood pressure must be monitored during treatment.
- Patients should be monitored for at least 24-48 hours after Sodium Thiosulfate Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated.
- Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.
# IV Compatibility
There is limited information regarding IV Compatibility of Thiosulfate in the drug label.
# Overdosage
- There is limited information about the effects of large doses of sodium thiosulfate in humans. Oral administration of 3 g sodium thiosulfate per day for 1-2 weeks in humans resulted in reductions in room air arterial oxygen saturation to as low as 75%, which was due to a rightward shift in the oxygen hemoglobin dissociation curve. The subjects returned to baseline oxygen saturations 1 week after discontinuation of sodium thiosulfate. A single intravenous administration of 20 mL of 10% sodium thiosulfate reportedly did not change oxygen saturations.
# Pharmacology
## Mechanism of Action
- Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration.
- Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.
- The synergy resulting from treatment of cyanide poisoning with the combination of sodium nitrite and sodium thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
- Sodium nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:
- NaNO2 + Hemoglobin → Methemoglobin
- HCN + Methemoglobin → Cyanomethemoglobin
- Vasodilation has also been cited to account for at least part of the therapeutic effect of sodium nitrite. It has been suggested that sodium nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, sodium nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
- The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine.
## Structure
- Sodium thiosulfate has the chemical name thiosulfuric acid, disodium salt, pentahydrate. The chemical formula is Na2S2O3- 5H2O and the molecular weight is 248.17.
- The structural formula is:
- Structure of Sodium Thiosulfate Pentahydrate
- Sodium Thiosulfate Injection is a cyanide antidote which contains one 50 mL glass vial containing a 25% solution of sodium thiosulfate injection.
- Sodium thiosulfate injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 12.5 grams of sodium thiosulfate in 50 mL solution (250 mg/mL). Each mL also contains 2.8 mg boric acid and 4.4 mg of potassium chloride. The pH of the solution is adjusted with boric acid and/or sodium hydroxide. Sodium thiosulfate injection is a clear solution with a pH between 7.5 and 9.5.
## Pharmacodynamics
- In dogs, pretreatment with sodium thiosulfate to achieve a steady state level of 2 µmol/mL increased the rate of conversion of cyanide to thiocyanate over 30-fold.
## Pharmacokinetics
- Thiosulfate taken orally is not systemically absorbed. Most of the thiosulfate is oxidized to sulfate or is incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys. Approximately 20-50% of exogenously administered thiosulfate is eliminated unchanged via the kidneys. After an intravenous injection of 1 g sodium thiosulfate in patients, the reported serum thiosulfate half-life was approximately 20 minutes. However, after an intravenous injection of a substantially higher dose of sodium thiosulfate (150 mg/kg, that is, 9 g for 60 kg body weight) in normal healthy men, the reported elimination half-life was 182 minutes.
- The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with sodium nitrite and sodium thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.
- After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.
## Nonclinical Toxicology
- Long-term studies in animals have not been performed to evaluate the potential carcinogenicity of sodium thiosulfate.
- The mutagenic potential of sodium thiosulfate has been examined in the in vitro Bacterial Reverse Mutation Assay (Ames Assay). Sodium thiosulfate was not mutagenic in the absence of metabolic activation in S. typhimurium strains TA98, TA100, TA1535, TA537, or TA1538. Sodium thiosulfate was not mutagenic in the presence of metabolic activation in strains TA 98, TA1535, TA1537, TA1538 or E. coli strain WP2.
- Clinical studies to evaluate the potential effects of sodium thiosulfate intake on fertility of either males or females have not been reported.
- There are no preclinical studies examining the effects of sodium thiosulfate on fertility.
- Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of sodium thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of sodium nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of sodium nitrite and sodium thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) sodium nitrite or 1 g/kg sodium thiosulfate alone or in sequence immediately after subcutaneous injection of sodium cyanide into dogs over a range of doses.
- Subsequent doses of 10 mg/kg sodium nitrite and/or 0.5 g/kg sodium thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of sodium cyanide required to cause death, and when administered together, sodium nitrite and sodium thiosulfate resulted in a synergistic effect in raising the lethal dose of sodium cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.
- Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous sodium nitrite and sodium thiosulfate in the treatment of cyanide poisoning.
- While intravenous injection of sodium nitrite and sodium thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of sodium nitrite, with or without sodium thiosulfate, was found not to be effective in the same setting.
# Clinical Studies
The human data supporting the use of sodium nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of sodium thiosulfate report its use in conjunction with sodium nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
- There have been no human studies to prospectively and systematically evaluate the safety of sodium thiosulfate or sodium nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
# How Supplied
- Each Sodium Thiosulfate carton (NDC 60267-705-50) consists of the following:
- One 50 mL glass vial of sodium thiosulfate injection 250 mg/mL (containing 12.5 grams of sodium thiosulfate).
## Storage
- Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F).
- Protect from direct light. Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Sodium Thiosulfate Injection is indicated for cyanide poisoning and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.
- When feasible, patients should be informed of the possibility of hypotension.
- Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.
# Precautions with Alcohol
- Alcohol-Thiosulfate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SODIUM THIOSULFATE®
# Look-Alike Drug Names
- A® — B®
# Drug Shortage Status
# Price | Thiosulfate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [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
Thiosulfate is a antidote that is FDA approved for the treatment of for sequential use with sodium nitrite for the treatment of acute cyanide poisoning that is judged to be life-threatening. Common adverse reactions include hypotension, prolonged bleeding time.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Sodium Thiosulfate Injection is indicated for sequential use with sodium nitrite for the treatment of acute cyanide poisoning that is judged to be life-threatening. When the diagnosis of cyanide poisoning is uncertain, the potential risks associated with Sodium Thiosulfate Injection should be carefully weighed against the potential benefits, especially if the patient is not critical.
- Cyanide poisoning may result from inhalation, ingestion, or dermal exposure to various cyanide-containing compounds, including smoke from closed-space fires. Sources of cyanide poisoning include hydrogen cyanide and its salts, cyanogenic plants, aliphatic nitriles, and prolonged exposure to sodium nitroprusside.
- The presence and extent of cyanide poisoning are often initially unknown. There is no widely available, rapid, confirmatory cyanide blood test. Treatment decisions must be made on the basis of clinical history and signs and symptoms of cyanide intoxication. If clinical suspicion of cyanide poisoning is high, Sodium Thiosulfate Injection and Sodium Nitrite Injection should be administered without delay.
- In some settings, panic symptoms including tachypnea and vomiting may mimic early cyanide poisoning signs. The presence of altered mental status (e.g., confusion and disorientation) and/or mydriasis is suggestive of true cyanide poisoning although these signs can occur with other toxic exposures as well.
- The expert advice of a regional poison control center may be obtained by calling 1-800-222-1222.
- Not all smoke inhalation victims will have cyanide poisoning and may present with burns, trauma, and exposure to other toxic substances making a diagnosis of cyanide poisoning particularly difficult. Prior to administration of Sodium Thiosulfate Injection smoke-inhalation victims should be assessed for the following:
- Exposure to fire or smoke in an enclosed area
Presence of soot around the mouth, nose, or oropharynx
- Although hypotension is highly suggestive of cyanide poisoning, it is only present in a small percentage of cyanide-poisoned smoke inhalation victims. Also indicative of cyanide poisoning is a plasma lactate concentration greater than or equal to 10 mmol/L (a value higher than that typically listed in the table of signs and symptoms of isolated cyanide poisoning because carbon monoxide associated with smoke inhalation also contributes to lactic acidemia). If cyanide poisoning is suspected, treatment should not be delayed to obtain a plasma lactate concentration.
- Caution should be exercised when administering cyanide antidotes, other than sodium nitrite, simultaneously with Sodium Thiosulfate Injection, as the safety of co-administration has not been established. If a decision is made to administer another cyanide antidote, other than sodium nitrite, with Sodium Thiosulfate Injection, these drugs should not be administered concurrently in the same IV line.
- Comprehensive treatment of acute cyanide intoxication requires support of vital functions. Administration of sodium nitrite and sodium thiosulfate should be considered adjunctive to appropriate supportive therapies. Airway, ventilatory and circulatory support, and oxygen administration should not be delayed to administer sodium nitrite and sodium thiosulfate.
- Sodium nitrite injection and sodium thiosulfate injection are administered by slow intravenous injection. They should be given as early as possible after a diagnosis of acute life-threatening cyanide poisoning has been established. Sodium nitrite should be administered first, followed immediately by sodium thiosulfate. Blood pressure must be monitored during infusion in both adults and children. The rate of infusion should be decreased if significant hypotension is noted.
- If signs of poisoning reappear, repeat treatment using one-half the original dose of both sodium nitrite and sodium thiosulfate.
- In adult and pediatric patients with known anemia, it is recommended that the dosage of sodium nitrite should be reduced proportionately to the hemoglobin concentration.
- All parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
- Patients should be monitored for at least 24-48 hours after Sodium Thiosulfate Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated. Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.
- Chemical incompatibility has been reported between Sodium Thiosulfate Injection and hydroxocobalamin and these drugs should not be administered simultaneously through the same IV line.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thiosulfate in adult patients.
### Non–Guideline-Supported Use
- Antineoplastic adverse reaction - Injection site extravasation [1]
- Calciphylaxis [2]
- Carboplatin adverse reaction - Ototoxicity [3]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Thiosulfate in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thiosulfate in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Thiosulfate in pediatric patients.
# Contraindications
There is limited information regarding Thiosulfate Contraindications in the drug label.
# Warnings
- Sodium thiosulfate drug product may contain trace impurities of sodium sulfite. The presence of a trace amount of sulfites in this product should not deter administration of the drug for treatment of emergency situations, even if the patient is sulfite-sensitive.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Thiosulfate in the drug label.
## Postmarketing Experience
- There have been no controlled clinical trials conducted to systematically assess the adverse events profile of sodium thiosulfate.
- The medical literature has reported the following adverse events in association with sodium thiosulfate administration. These adverse events were not reported in the context of controlled trials or with consistent monitoring and reporting methodologies for adverse events. Therefore, frequency of occurrence of these adverse events cannot be assessed.
- Cardiovascular system
- Hypotension
- Central nervous system
- Headache, disorientation
- Gastrointestinal system
- Nausea, vomiting
- Hematological
- Prolonged bleeding time
- Body as a Whole
- Salty taste in mouth, warm sensation over body
- In humans, rapid administration of concentrated solutions or solutions not freshly prepared, and administration of large doses of sodium thiosulfate have been associated with a higher incidence of nausea and vomiting. However, administration of 0.1 g sodium thiosulfate per pound up to a maximum of 15 g in a 10-15% solution over 10-15 minutes was associated with nausea and vomiting in 7 of 26 patients without concomitant cyanide intoxication.
- In a series of 11 human subjects, a single intravenous infusion of 50 mL of 50% sodium thiosulfate was associated with increases in clotting time 1-3 days after administration. However, no significant changes were observed in other hematological parameters.
# Drug Interactions
- Formal drug interaction studies have not been conducted with Sodium Thiosulfate Injection.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women. Sodium Thiosulfate Injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
There are no reported epidemiological studies of congenital anomalies in infants born to women treated with sodium thiosulfate during pregnancy. In animal studies, there are no teratogenic effects in offspring of hamsters treated during pregnancy with sodium thiosulfate in doses similar to those given intravenously to treat cyanide poisoning in humans. Other studies suggest that treatment with sodium thiosulfate ameliorates the teratogenic effects of maternal cyanide poisoning in hamsters. In other studies, sodium thiosulfate was not embryotoxic or teratogenic in mice, rats, hamsters, or rabbits at maternal doses of up to 550, 400, 400 and 580 mg/kg/day, respectively.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Thiosulfate in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Thiosulfate during labor and delivery.
### Nursing Mothers
- It is not known whether sodium thiosulfate is excreted in human milk. Because Sodium Thiosulfate Injection may be administered in life-threatening situations, breast-feeding is not a contraindication to its use. Because many drugs are excreted in human milk, caution should be exercised following Sodium Thiosulfate Injection administration to a nursing woman. There are no data to determine when breastfeeding may be safely restarted following administration of sodium thiosulfate.
### Pediatric Use
- There are case reports in the medical literature of sodium nitrite in conjunction with sodium thiosulfate being administered to pediatric patients with cyanide poisoning; however, there have been no clinical studies to evaluate the safety or efficacy of sodium thiosulfate in the pediatric population. As for adult patients, dosing recommendations for pediatric patients have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
### Geriatic Use
- Sodium thiosulfate is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Gender
There is no FDA guidance on the use of Thiosulfate with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Thiosulfate with respect to specific racial populations.
### Renal Impairment
- Sodium thiosulfate is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
### Hepatic Impairment
There is no FDA guidance on the use of Thiosulfate in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Thiosulfate in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Thiosulfate in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
- Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
- Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.
- Blood pressure must be monitored during treatment.
- Patients should be monitored for at least 24-48 hours after Sodium Thiosulfate Injection administration for adequacy of oxygenation and perfusion and for recurrent signs and symptoms of cyanide toxicity. When possible, hemoglobin/hematocrit should be obtained when treatment is initiated.
- Measurements of oxygen saturation using standard pulse oximetry and calculated oxygen saturation values based on measured PO2 are unreliable in the presence of methemoglobinemia.
# IV Compatibility
There is limited information regarding IV Compatibility of Thiosulfate in the drug label.
# Overdosage
- There is limited information about the effects of large doses of sodium thiosulfate in humans. Oral administration of 3 g sodium thiosulfate per day for 1-2 weeks in humans resulted in reductions in room air arterial oxygen saturation to as low as 75%, which was due to a rightward shift in the oxygen hemoglobin dissociation curve. The subjects returned to baseline oxygen saturations 1 week after discontinuation of sodium thiosulfate. A single intravenous administration of 20 mL of 10% sodium thiosulfate reportedly did not change oxygen saturations.
# Pharmacology
## Mechanism of Action
- Exposure to a high dose of cyanide can result in death within minutes due to the inhibition of cytochrome oxidase resulting in arrest of cellular respiration.
- Specifically, cyanide binds rapidly with cytochrome a3, a component of the cytochrome c oxidase complex in mitochondria. Inhibition of cytochrome a3 prevents the cell from using oxygen and forces anaerobic metabolism, resulting in lactate production, cellular hypoxia and metabolic acidosis. In massive acute cyanide poisoning, the mechanism of toxicity may involve other enzyme systems as well.
- The synergy resulting from treatment of cyanide poisoning with the combination of sodium nitrite and sodium thiosulfate is the result of differences in their primary mechanisms of action as antidotes for cyanide poisoning.
- Sodium nitrite is thought to exert its therapeutic effect by reacting with hemoglobin to form methemoglobin, an oxidized form of hemoglobin incapable of oxygen transport but with high affinity for cyanide. Cyanide preferentially binds to methemoglobin over cytochrome a3, forming the nontoxic cyanomethemoglobin. Methemoglobin displaces cyanide from cytochrome oxidase, allowing resumption of aerobic metabolism. The chemical reaction is as follows:
- NaNO2 + Hemoglobin → Methemoglobin
- HCN + Methemoglobin → Cyanomethemoglobin
- Vasodilation has also been cited to account for at least part of the therapeutic effect of sodium nitrite. It has been suggested that sodium nitrite-induced methemoglobinemia may be more efficacious against cyanide poisoning than comparable levels of methemoglobinemia induced by other oxidants. Also, sodium nitrite appears to retain some efficacy even when the formation of methemoglobin is inhibited by methylene blue.
- The primary route of endogenous cyanide detoxification is by enzymatic transulfuration to thiocyanate (SCN-), which is relatively nontoxic and readily excreted in the urine.
## Structure
- Sodium thiosulfate has the chemical name thiosulfuric acid, disodium salt, pentahydrate. The chemical formula is Na2S2O3• 5H2O and the molecular weight is 248.17.
- The structural formula is:
- Structure of Sodium Thiosulfate Pentahydrate
- Sodium Thiosulfate Injection is a cyanide antidote which contains one 50 mL glass vial containing a 25% solution of sodium thiosulfate injection.
- Sodium thiosulfate injection is a sterile aqueous solution and is intended for intravenous injection. Each vial contains 12.5 grams of sodium thiosulfate in 50 mL solution (250 mg/mL). Each mL also contains 2.8 mg boric acid and 4.4 mg of potassium chloride. The pH of the solution is adjusted with boric acid and/or sodium hydroxide. Sodium thiosulfate injection is a clear solution with a pH between 7.5 and 9.5.
## Pharmacodynamics
- In dogs, pretreatment with sodium thiosulfate to achieve a steady state level of 2 µmol/mL increased the rate of conversion of cyanide to thiocyanate over 30-fold.
## Pharmacokinetics
- Thiosulfate taken orally is not systemically absorbed. Most of the thiosulfate is oxidized to sulfate or is incorporated into endogenous sulphur compounds; a small proportion is excreted through the kidneys. Approximately 20-50% of exogenously administered thiosulfate is eliminated unchanged via the kidneys. After an intravenous injection of 1 g sodium thiosulfate in patients, the reported serum thiosulfate half-life was approximately 20 minutes. However, after an intravenous injection of a substantially higher dose of sodium thiosulfate (150 mg/kg, that is, 9 g for 60 kg body weight) in normal healthy men, the reported elimination half-life was 182 minutes.
- The apparent terminal elimination half life and volume of distribution of cyanide, in a patient treated for an acute cyanide poisoning with sodium nitrite and sodium thiosulfate administration, have been reported to be 19 hours and 0.41 L/kg, respectively. Additionally, an initial elimination half life of cyanide has been reported to be approximately 1-3 hours.
- After detoxification, in healthy subjects, thiocyanate is excreted mainly in the urine at a rate inversely proportional to creatinine clearance. In healthy subjects, the elimination half-life and volume of distribution of thiocyanate have been reported to be 2.7 days and 0.25 L/kg, respectively. However, in subjects with renal insufficiency the reported elimination half life is approximately 9 days.
## Nonclinical Toxicology
- Long-term studies in animals have not been performed to evaluate the potential carcinogenicity of sodium thiosulfate.
- The mutagenic potential of sodium thiosulfate has been examined in the in vitro Bacterial Reverse Mutation Assay (Ames Assay). Sodium thiosulfate was not mutagenic in the absence of metabolic activation in S. typhimurium strains TA98, TA100, TA1535, TA537, or TA1538. Sodium thiosulfate was not mutagenic in the presence of metabolic activation in strains TA 98, TA1535, TA1537, TA1538 or E. coli strain WP2.
- Clinical studies to evaluate the potential effects of sodium thiosulfate intake on fertility of either males or females have not been reported.
- There are no preclinical studies examining the effects of sodium thiosulfate on fertility.
- Due to the extreme toxicity of cyanide, experimental evaluation of treatment efficacy has predominantly been completed in animal models. The efficacy of sodium thiosulfate treatment alone to counteract the toxicity of cyanide was initially reported in 1895 by Lang. The efficacy of amyl nitrite treatment in cyanide poisoning of the dog model was first reported in 1888 by Pedigo. Further studies in the dog model, which demonstrated the utility of sodium nitrite as a therapeutic intervention, were reported in 1929 by Mladoveanu and Gheorghiu. However, Hugs and Chen et al. independently reported upon the superior efficacy of the combination of sodium nitrite and sodium thiosulfate in 1932-1933. Treatment consisted of intravenously administered 22.5 mg/kg (half the lethal dose) sodium nitrite or 1 g/kg sodium thiosulfate alone or in sequence immediately after subcutaneous injection of sodium cyanide into dogs over a range of doses.
- Subsequent doses of 10 mg/kg sodium nitrite and/or 0.5 g/kg sodium thiosulfate were administered when clinical signs or symptoms of poisoning persisted or reappeared. Either therapy administered alone increased the dose of sodium cyanide required to cause death, and when administered together, sodium nitrite and sodium thiosulfate resulted in a synergistic effect in raising the lethal dose of sodium cyanide. The combined therapy appeared to have reduced efficacy when therapy was delayed until signs of poisoning (e.g. convulsions) appeared; however, other investigators have reported survival in dogs that were administered antidotal treatment after respiratory arrest had occurred.
- Animal studies conducted in other species (e.g., rat, guinea pig, sheep, pigeon and cat) have also supported a synergistic effect of intravenous sodium nitrite and sodium thiosulfate in the treatment of cyanide poisoning.
- While intravenous injection of sodium nitrite and sodium thiosulfate was effective in reversing the effects of lethal doses of cyanide in dogs, intramuscular injection of sodium nitrite, with or without sodium thiosulfate, was found not to be effective in the same setting.
# Clinical Studies
The human data supporting the use of sodium nitrite for cyanide poisoning consists primarily of published case reports. There are no randomized controlled clinical trials. Nearly all the human data describing the use of sodium thiosulfate report its use in conjunction with sodium nitrite. Dosing recommendations for humans have been based on theoretical calculations of antidote detoxifying potential, extrapolation from animal experiments, and a small number of human case reports.
- There have been no human studies to prospectively and systematically evaluate the safety of sodium thiosulfate or sodium nitrite in humans. Available human safety information is based largely on anecdotal case reports and case series of limited scope.
# How Supplied
- Each Sodium Thiosulfate carton (NDC 60267-705-50) consists of the following:
- One 50 mL glass vial of sodium thiosulfate injection 250 mg/mL (containing 12.5 grams of sodium thiosulfate).
## Storage
- Store at controlled room temperature between 20°C and 25°C (68°F to 77°F); excursions permitted from 15 to 30°C (59 to 86°F).
- Protect from direct light. Do not freeze.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Sodium Thiosulfate Injection is indicated for cyanide poisoning and in this setting, patients will likely be unresponsive or may have difficulty in comprehending counseling information.
- When feasible, patients should be informed of the possibility of hypotension.
- Where feasible, patients should be informed of the need for close monitoring of blood pressure and oxygenation.
# Precautions with Alcohol
- Alcohol-Thiosulfate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SODIUM THIOSULFATE®[5]
# Look-Alike Drug Names
- A® — B®[6]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Thiosulfate | |
5a95e2dd6827bdcaecc644041259599a6b345baf | wikidoc | Thoracotomy | Thoracotomy
Thoracotomy is an incision into the chest. It is performed by a surgeon, and, rarely, by emergency physicians and paramedics, to gain access to the thoracic organs, most commonly the heart, the lungs, the esophagus or thoracic aorta, or for access to the anterior spine such as is necessary for access to tumors in the spine.
Thoracotomy is a major surgical maneuver—the first step in cardiothoracic surgery, which involves major procedures such as coronary artery bypass surgery and lobectomy or pneumonectomy for lung cancer—and as such requires general anesthesia with endotracheal tube insertion and mechanical ventilation.
# Approaches
There probably are many different approaches to thoracotomy. The most common modalities of thoracotomy follow.
Median sternotomy provides wide access to the mediastinum and is the incision of choice for most open-heart surgery and access to the anterior mediastinum.
Posterolateral thoracotomy is a very common approach for operations on the lung or posterior mediastinum, including the esophagus. When performed over the 5th intercostal space, it allows optimal access to the pulmonary hilum (pulmonary artery and pulmonary vein) and therefore is considered the approach of choice for pulmonary resection (pneumonectomy and lobectomy).
Anterolateral thoracotomy is performed upon the anterior chest wall; left anterolateral thoracotomy is the incision of choice for open chest massage, a critical maneuver in the management of traumatic cardiac arrest. Anterolateral thoracotomy, like most surgical incisions, requires the use of tissue retractors—in this case, a "rib spreader" such as the Tuffier retractor.
Bilateral anterolateral thoracotomy combined with transverse sternotomy results in the "clamshell" incision, the largest incision commonly used in thoracic surgery.
Upon completion of the surgical procedure, the chest is closed. One or more chest tubes—with one end inside the opened pleural cavity and the other submerged under saline solution inside a sealed container, forming an airtight drainage system—are necessary to remove air and fluid from the pleural cavity, preventing the development of pneumothorax or hemothorax.
# Complications
In addition to pneumothorax, complications from thoracotomy include air leaks, infection, bleeding and respiratory failure. Postoperative pain is universal and intense, generally requiring opioids, and does interfere with the recovery of respiratory function.
# VATS
Video-assisted thoracic surgery (VATS) is a less invasive alternative to thoracotomy in selected cases, much like laparoscopic surgery. Like laparoscopic surgery, its applications are rapidly expanding. Robotic surgery is a new but rarely used innovation with questionable advantages.
de:Thorakotomie
no:Thoracotomi | Thoracotomy
Thoracotomy is an incision into the chest. It is performed by a surgeon, and, rarely, by emergency physicians and paramedics, to gain access to the thoracic organs, most commonly the heart, the lungs, the esophagus or thoracic aorta, or for access to the anterior spine such as is necessary for access to tumors in the spine.
Thoracotomy is a major surgical maneuver—the first step in cardiothoracic surgery, which involves major procedures such as coronary artery bypass surgery and lobectomy or pneumonectomy for lung cancer—and as such requires general anesthesia with endotracheal tube insertion and mechanical ventilation.
# Approaches
There probably are many different approaches to thoracotomy. The most common modalities of thoracotomy follow.
Median sternotomy provides wide access to the mediastinum and is the incision of choice for most open-heart surgery and access to the anterior mediastinum.
Posterolateral thoracotomy is a very common approach for operations on the lung or posterior mediastinum, including the esophagus. When performed over the 5th intercostal space, it allows optimal access to the pulmonary hilum (pulmonary artery and pulmonary vein) and therefore is considered the approach of choice for pulmonary resection (pneumonectomy and lobectomy).
Anterolateral thoracotomy is performed upon the anterior chest wall; left anterolateral thoracotomy is the incision of choice for open chest massage, a critical maneuver in the management of traumatic cardiac arrest. Anterolateral thoracotomy, like most surgical incisions, requires the use of tissue retractors—in this case, a "rib spreader" such as the Tuffier retractor.
Bilateral anterolateral thoracotomy combined with transverse sternotomy results in the "clamshell" incision, the largest incision commonly used in thoracic surgery.
Upon completion of the surgical procedure, the chest is closed. One or more chest tubes—with one end inside the opened pleural cavity and the other submerged under saline solution inside a sealed container, forming an airtight drainage system—are necessary to remove air and fluid from the pleural cavity, preventing the development of pneumothorax or hemothorax.
# Complications
In addition to pneumothorax, complications from thoracotomy include air leaks, infection, bleeding and respiratory failure. Postoperative pain is universal and intense, generally requiring opioids, and does interfere with the recovery of respiratory function.
# VATS
Video-assisted thoracic surgery (VATS) is a less invasive alternative to thoracotomy in selected cases, much like laparoscopic surgery. Like laparoscopic surgery, its applications are rapidly expanding. Robotic surgery is a new but rarely used innovation with questionable advantages.
Template:Respiratory system surgeries and other procedures
de:Thorakotomie
no:Thoracotomi
Template:Jb1
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Thoracotomy | |
b4b81e71ded63a7ffe22fa948491c3a918c126f1 | wikidoc | Thromboxane | Thromboxane
# Overview
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2.
Thromboxane is named for its role in clot formation (thrombosis).
# Production
It is produced in platelets by thromboxane-A synthase from the endoperoxides produced by the cyclooxygenase (COX) enzyme from arachidonic acid.
# Mechanism
Thromboxane acts by binding to any of the thromboxane receptors, G-protein coupled receptors coupled to the G protein Gq.
# Functions
Thromboxane is a vasoconstrictor and a potent hypertensive agent, and it facilitates platelet aggregation.
It is in homeostatic balance in the circulatory system with prostacyclin, a related compound.
The mechanism of secretion of thromboxanes from platelets is still unclear.
# Role of A2 in platelet aggregation
Thromboxane A2 (TXA2), produced by activated platelets, has prothrombotic properties, stimulating activation of new platelets as well as increasing platelet aggregation.
Platelet aggregation is achieved by mediating expression of the glycoprotein complex GP IIb/IIIa in the cell membrane of platelets. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot.
# Pathology
It is believed that the vasoconstriction caused by thromboxanes plays a role in Prinzmetal's angina.
# Suppression
The widely used drug aspirin acts by inhibiting the ability of the COX enzyme to synthesize the precursors of thromboxane within platelets.
It inhibits the COX enzyme both non-competitively and irreversibly.
The side effect of this is that people who regularly take aspirin will suffer from excessive bleeding whenever the skin is perforated. | Thromboxane
# Overview
Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2.
Thromboxane is named for its role in clot formation (thrombosis).
# Production
It is produced in platelets by thromboxane-A synthase from the endoperoxides produced by the cyclooxygenase (COX) enzyme from arachidonic acid.
# Mechanism
Thromboxane acts by binding to any of the thromboxane receptors, G-protein coupled receptors coupled to the G protein Gq[1].
# Functions
Thromboxane is a vasoconstrictor and a potent hypertensive agent, and it facilitates platelet aggregation.
It is in homeostatic balance in the circulatory system with prostacyclin, a related compound.
The mechanism of secretion of thromboxanes from platelets is still unclear.
# Role of A2 in platelet aggregation
Thromboxane A2 (TXA2), produced by activated platelets, has prothrombotic properties, stimulating activation of new platelets as well as increasing platelet aggregation.
Platelet aggregation is achieved by mediating expression of the glycoprotein complex GP IIb/IIIa in the cell membrane of platelets. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot.
# Pathology
It is believed that the vasoconstriction caused by thromboxanes plays a role in Prinzmetal's angina.
# Suppression
The widely used drug aspirin acts by inhibiting the ability of the COX enzyme to synthesize the precursors of thromboxane within platelets.
It inhibits the COX enzyme both non-competitively and irreversibly.
The side effect of this is that people who regularly take aspirin will suffer from excessive bleeding whenever the skin is perforated.
# External links
- Thromboxanes at the US National Library of Medicine Medical Subject Headings (MeSH)
Template:Eicosanoids
de:Thromboxan
Template:Jb1
Template:WH
Template:WikiDoc Sources
- ↑ Rat kidney thromboxane receptor: molecular cloning, signal ... | https://www.wikidoc.org/index.php/Thromboxane | |
1a27afe3514a6599e0f5e9fb2c09235d1b891942 | wikidoc | Thymosin α1 | Thymosin α1
Thymosin α1 is a peptide fragment derived from prothymosin alpha, a protein that in humans is encoded by the PTMA gene.
It was the first of the peptides from Thymosin Fraction 5 to be completely sequenced and synthesized. Unlike β thymosins, to which it is genetically and chemically unrelated, thymosin α1 is produced as a 28-amino acid fragment, from a longer, 113-amino acid precursor, prothymosin α.
# Function
Thymosin α1 is believed to be a major component of Thymosin Fraction 5 responsible for the activity of that preparation in restoring immune function in animals lacking thymus glands. It has been found to enhance cell-mediated immunity in humans as well as experimental animals.
# Therapeutic application
As of 2009 Thymosin α1 is approved in 35 under-developed or developing countries for the treatment of Hepatitis B and C, and it is also used to boost the immune response in the treatment of other diseases.
## Clinical studies
Clinical trials suggest it may be useful in septic shock, acute respiratory distress syndrome, peritonitis, acute cytomegalovirus infection, TB, severe acute respiratory syndrome, and lung infections in critically ill patients., and for chronic hepatitis B.
It has been studied for possible use in treating cancer (eg with chemotherapy). | Thymosin α1
Thymosin α1 is a peptide fragment derived from prothymosin alpha, a protein that in humans is encoded by the PTMA gene.[1]
It was the first of the peptides from Thymosin Fraction 5 to be completely sequenced and synthesized. Unlike β thymosins, to which it is genetically and chemically unrelated, thymosin α1 is produced as a 28-amino acid fragment, from a longer, 113-amino acid precursor, prothymosin α.[2]
# Function
Thymosin α1 is believed to be a major component of Thymosin Fraction 5 responsible for the activity of that preparation in restoring immune function in animals lacking thymus glands. It has been found to enhance cell-mediated immunity in humans as well as experimental animals.[3]
# Therapeutic application
As of 2009[update] Thymosin α1 is approved in 35 under-developed or developing countries for the treatment of Hepatitis B and C, and it is also used to boost the immune response in the treatment of other diseases.[4][5]
## Clinical studies
Clinical trials suggest it may be useful in septic shock, acute respiratory distress syndrome, peritonitis, acute cytomegalovirus infection, TB, severe acute respiratory syndrome, and lung infections in critically ill patients.,[5] and for chronic hepatitis B.[6]
It has been studied for possible use in treating cancer (eg with chemotherapy).[7] | https://www.wikidoc.org/index.php/Thymosin_%CE%B11 | |
68d505ef363cfe0a99c534d254db48163284b592 | wikidoc | Ticarcillin | Ticarcillin
# Overview
Ticarcillin is a carboxypenicillin. It is almost invariably sold and used in combination with clavulanate as Timentin®. Because it is a penicillin, it also falls within the larger class of beta-lactam antibiotics. Its main clinical use is as an injectable antibiotic for the treatment of gram negative bacteria, in particular, Pseudomonas aeruginosa.
Chemically, ticarcillin is C15H16N2O6S2 (CAS number 34787-01-4). It is provided as a white or pale yellow powder. It is highly soluble in water, but should only be dissolved immediately before use to prevent degradation.
# Mechanism of Action
Ticarcillin's antibiotic properties arise from its ability to prevent cross-linking of peptidoglycan during cell wall synthesis when the bacteria tries to divide, causing death.
Ticarcillin is similar to penicilin in that it contains a β-lactam ring. This can lead to resistance in bacteria containing β-lactamase, which cleaves the ring and inactivates it. It is often paired with a β-lactamase inhibitor such as clavulanic acid. Because of ticarcillins similarties to penicillin, including the β-lactam ring, it can cause similar allergic reactions in patients sensitive to penicillin.
# Other Uses
In molecular biology, ticarcillin is used to as an alternative to ampicillin to test the uptake of marker genes into bacteria. It prevents the appearance of satellite colonies that occur when ampicillin breaks down in the media. It is also used in plant molecular biology to kill agrobacterium, which is used to deliver genes to plant cells.
# Dosing and Posology
Ticarcillin is not absorbed orally, and therefore must be given by intravenous or intramuscular injection. The usual adult dose of Timentin is 3.5g four times a day.
# Trade Names and Preparations
- Ticarcillin: Ticar® (Formerly marketed by Beecham, then SmithKline Beecham until 1999, when it merged with Glaxo to form GlaxoSmithKline; no longer available in the UK. US distribution ceased in 2004. Ticar was replaced by Timentin.)
- Ticarcillin/clavulanate: Timentin® (UK and US, marketed by Beecham, then GlaxoSmithKline). | Ticarcillin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Ticarcillin is a carboxypenicillin. It is almost invariably sold and used in combination with clavulanate as Timentin®. Because it is a penicillin, it also falls within the larger class of beta-lactam antibiotics. Its main clinical use is as an injectable antibiotic for the treatment of gram negative bacteria, in particular, Pseudomonas aeruginosa.
Chemically, ticarcillin is C15H16N2O6S2 (CAS number 34787-01-4). It is provided as a white or pale yellow powder. It is highly soluble in water, but should only be dissolved immediately before use to prevent degradation.
# Mechanism of Action
Ticarcillin's antibiotic properties arise from its ability to prevent cross-linking of peptidoglycan during cell wall synthesis when the bacteria tries to divide, causing death.
Ticarcillin is similar to penicilin in that it contains a β-lactam ring. This can lead to resistance in bacteria containing β-lactamase, which cleaves the ring and inactivates it. It is often paired with a β-lactamase inhibitor such as clavulanic acid. Because of ticarcillins similarties to penicillin, including the β-lactam ring, it can cause similar allergic reactions in patients sensitive to penicillin.
# Other Uses
In molecular biology, ticarcillin is used to as an alternative to ampicillin to test the uptake of marker genes into bacteria. It prevents the appearance of satellite colonies that occur when ampicillin breaks down in the media. It is also used in plant molecular biology to kill agrobacterium, which is used to deliver genes to plant cells.
# Dosing and Posology
Ticarcillin is not absorbed orally, and therefore must be given by intravenous or intramuscular injection. The usual adult dose of Timentin is 3.5g four times a day.
# Trade Names and Preparations
- Ticarcillin: Ticar® (Formerly marketed by Beecham, then SmithKline Beecham until 1999, when it merged with Glaxo to form GlaxoSmithKline; no longer available in the UK. US distribution ceased in 2004. Ticar was replaced by Timentin.)
- Ticarcillin/clavulanate: Timentin® (UK and US, marketed by Beecham, then GlaxoSmithKline).
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Ticarcillin | |
eb2b855bc35973b4ae8c573eabcfe5b94267b391 | wikidoc | Ticlopidine | Ticlopidine
# 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
Ticlopidine is a platelet aggregation inhibitor that is FDA approved for the prophylaxis of thromboembolic stroke, and subacute stent thrombosis in patients undergoing successful coronary stent implantation.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, abdominal pain, diarrhea, indigestion, loss of appetite, nausea, hemorrhage, leukopenia, dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Stroke
- Dosing Information
- Recommended dose: 250 mg bid taken with food.
### Coronary Artery Stenting
- Dosing Information
- Recommended dose: 250 mg bid taken with food together with antiplatelet doses of aspirin for up to 30 days of therapy following successful stent implantation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ticlopidine in adult patients.
### Non–Guideline-Supported Use
### Coronary artery bypass graft
- Dosing Information
- Recommended dose: 250 mg q12h
### Hemodialysis
- Dosing Information
- Recommended dose: 250 mg daily
### Acute Ischemic Heart Disease
- Dosing Information
- Recommended dose: 250 mg q12h
### Myocardial Infarction
- Dosing Information
- Recommended dose: 250 mg q12h
### Prophylaxis for Postoperative Thrombosis
- Dosing Information
- Recommended dose: 250 mg q12h 2 days before surgery until the seventh postoperative day
### Rheumatoid arthritis
- Dosing Information
- Recommended dose: 250mg/day
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ticlopidine 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 Ticlopidine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ticlopidine in pediatric patients.
# Contraindications
- Hypersensitivity to the drug
- Presence of hematopoietic disorders such as neutropenia and thrombocytopenia or a past history of either TTP or aplastic anemia.
- Presence of a hemostatic disorder or active pathological bleeding (such as bleeding peptic ulcer or intracranial bleeding)
- Patients with severe liver impairment
# Warnings
### General
- Ticlopidine should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or pathological conditions.
- If it is desired to eliminate the antiplatelet effects of ticlopidine prior to elective surgery, the drug should be discontinued 10 to 14 days prior to surgery.
- Several controlled clinical studies have found increased surgical blood loss in patients undergoing surgery during treatment with ticlopidine.
- In TASS and CATS it was recommended that patients have ticlopidine discontinued prior to elective surgery.
- Several hundred patients underwent surgery during the trials, and no excessive surgical bleeding was reported.
- Prolonged bleeding time is normalized within 2 hours after administration of 20 mg methylprednisolone IV.
- Platelet transfusions may also be used to reverse the effect of ticlopidine on bleeding.
- Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.
### GI Bleeding
- Ticlopidine prolongs template bleeding time.
- The drug should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers).
- Drugs that might induce such lesions should be used with caution in patients on ticlopidine
- Ticlopidine therapy causes increased serum cholesterol and triglycerides.
- Serum total cholesterol levels are increased 8% to 10% within 1 month of therapy and persist at that level.
- The ratios of the lipoprotein subfractions are unchanged.
- The tolerance and long-term safety of coadministration of ticlopidine with heparin, oral anticoagulants or fibrinolytic agents have not been established.
- In trials for cardiac stenting, patients received heparin and ticlopidine concomitantly for approximately 12 hours.
- If a patient is switched from an anticoagulant or fibrinolytic drug to ticlopidine, the former drug should be discontinued prior to ticlopidine administration.
- Ticlopidine therapy has been associated with elevations of alkaline phosphatase, bilirubin, and transaminases, which generally occurred within 1 to 4 months of therapy initiation.
- In controlled clinical trials in stroke patients, the incidence of elevated alkaline phosphatase (greater than two times upper limit of normal) was 7.6% in ticlopidine patients, 6% in placebo patients and 2.5% in aspirin patients.
- The incidence of elevated AST (SGOT) (greater than two times upper limit of normal) was 3.1% in ticlopidine patients, 4% in placebo patients and 2.1% in aspirin patients. No progressive increases were observed in closely monitored clinical trials (eg, no transaminase greater than 10 times the upper limit of normal was seen), but most patients with these abnormalities had therapy discontinued.
- Occasionally patients had developed minor elevations in bilirubin.
- Postmarketing experience includes rare individuals with elevations in their transaminases and bilirubin to >10X above the upper limits of normal.
- Based on postmarketing and clinical trial experience, liver function testing, including ALT, AST, and GGT, should be considered whenever liver dysfunction is suspected, particularly during the first 4 months of treatment.
# Adverse Reactions
## Clinical Trials Experience
Adverse reactions in stroke patients were relatively frequent with over 50% of patients reporting at least one. Most (30% to 40%) involved the gastrointestinal tract. Most adverse effects are mild, but 21% of patients discontinued therapy because of an adverse event, principally diarrhea, rash, nausea, vomiting, GI pain and neutropenia. Most adverse effects occur early in the course of treatment, but a new onset of adverse effects can occur after several months.
The incidence rates of adverse events listed in the following table were derived from multicenter, controlled clinical trials in stroke patients described above comparing ticlopidine, placebo and aspirin over study periods of up to 5.8 years. Adverse events considered by the investigator to be probably drug-related that occurred in at least 1% of patients treated with ticlopidine are shown in the following table:
### Hematological
Neutropenia may occur suddenly. Bone marrow examination typically shows a reduction in white blood cell precursors. After withdrawal of ticlopidine, the neutrophil count usually rises to >1200/mm3 within 1 to 3 weeks.
Rarely, thrombocytopenia may occur in isolation or together with neutropenia.
TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes seen on peripheral smear), neurological findings, renal dysfunction, and fever. The signs and symptoms can occur in any order, in particular, clinical symptoms may precede laboratory findings by hours or days. With prompt treatment (often including plasmapheresis), 70% to 80% of patients will survive with minimal or no sequelae. Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.
Aplastic anemia is characterized by anemia, thrombocytopenia and neutropenia together with a bone marrow examination that shows decreases in the precursor cells for red blood cells, white blood cells, and platelets. Patients may present with signs or symptoms suggestive of infection, in association with low white blood cell and platelet counts. Prompt treatment, which may include the use of drugs to stimulate the bone marrow, can minimize the mortality associated with aplastic anemia.
Rare cases of agranulocytosis, pancytopenia, or leukemia have been reported in postmarketing experience, some of which have been fatal. All forms of hematological adverse reactions are potentially fatal.
### Gastrointestinal
Ticlopidine therapy has been associated with a variety of gastrointestinal complaints including diarrhea and nausea. The majority of cases are mild, but about 13% of patients discontinued therapy because of these. They usually occur within 3 months of initiation of therapy and typically are resolved within 1 to 2 weeks without discontinuation of therapy. If the effect is severe or persistent, therapy should be discontinued. In some cases of severe or bloody diarrhea, colitis was later diagnosed.
### Hemorrhagic
Ticlopidine has been associated with increased bleeding, spontaneous posttraumatic bleeding and perioperative bleeding including, but not limited to, gastrointestinal bleeding. It has also been associated with a number of bleeding complications such as ecchymosis, epistaxis, hematuria and conjunctival hemorrhage.
Intracerebral bleeding was rare in clinical trials in stroke patients with ticlopidine, with an incidence no greater than that seen with comparator agents (ticlopidine 0.5%, aspirin 0.6%, placebo 0.75%). It has also been reported postmarketing.
### Rash
Ticlopidine has been associated with a maculopapular or urticarial rash (often with pruritus). Rash usually occurs within 3 months of initiation of therapy with a mean onset time of 11 days. If drug is discontinued, recovery occurs within several days. Many rashes do not recur on drug rechallenge. There have been rare reports of severe rashes, including Stevens-Johnson syndrome, erythema multiforme and exfoliative dermatitis.
### Less Frequent Adverse Reactions (Probably Related)
Clinical adverse experiences occurring in 0.5% to 1.0% of stroke patients in controlled trials include:
- Digestive System: GI fullness
- Skin and Appendages: urticaria
- Nervous System: headache
- Body as a Whole: asthenia, pain
- Hemostatic System: epistaxis
- Special Senses: tinnitus
## Postmarketing Experience
In addition, rarer, relatively serious and potentially fatal events associated with the use of ticlopidine have also been reported from postmarketing experience:
- Hemolytic anemia with reticulocytosis
- Immune thrombocytopenia
- Hepatitis
- Hepatocellular jaundice
- Cholestatic jaundice
- Hepatic necrosis
- Hepatic failure
- Peptic ulcer
- Renal failure
- Nephrotic syndrome
- Hyponatremia
- Vasculitis
- Sepsis
- Allergic reactions (including angioedema, allergic pneumonitis, and anaphylaxis)
- Systemic lupus (positive ANA)
- Peripheral neuropathy
- Serum sickness
- Arthropathy
- Myositis
# Drug Interactions
Therapeutic doses of ticlopidine caused a 30% increase in the plasma half-life of antipyrine and may cause analogous effects on similarly metabolized drugs. Therefore, the dose of drugs metabolized by hepatic microsomal enzymes with low therapeutic ratios or being given to patients with hepatic impairment may require adjustment to maintain optimal therapeutic blood levels when starting or stopping concomitant therapy with ticlopidine. Studies of specific drug interactions yielded the following results:
### Aspirin and other NSAIDs
Ticlopidine potentiates the effect of aspirin or other NSAIDs on platelet aggregation. The safety of concomitant use of ticlopidine and NSAIDs has not been established. The safety of concomitant use of ticlopidine and aspirin beyond 30 days has not been established. Aspirin did not modify the ticlopidine-mediated inhibition of ADP-induced platelet aggregation, but ticlopidine potentiated the effect of aspirin on collagen-induced platelet aggregation. Caution should be exercised in patients who have lesions with a propensity to bleed, such as ulcers. Long-term concomitant use of aspirin and ticlopidine is not recommended.
### Antacids
Administration of ticlopidine after antacids resulted in an 18% decrease in plasma levels of ticlopidine.
### Cimetidine
Chronic administration of cimetidine reduced the clearance of a single dose of ticlopidine by 50%.
### Digoxin
Coadministration of ticlopidine with digoxin resulted in a slight decrease (approximately 15%) in digoxin plasma levels. Little or no change in therapeutic efficacy of digoxin would be expected.
### Theophylline
In normal volunteers, concomitant administration of ticlopidine resulted in a significant increase in the theophylline elimination half-life from 8.6 to 12.2 hours and a comparable reduction in total plasma clearance of theophylline.
### Phenobarbital
In 6 normal volunteers, the inhibitory effects of ticlopidine on platelet aggregation were not altered by chronic administration of phenobarbital.
### Phenytoin
In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of phenytoin. However, the protein binding interactions of ticlopidine and its metabolites have not been studied in vivo. Several cases of elevated phenytoin plasma levels with associated somnolence and lethargy have been reported following coadministration with ticlopidine. Caution should be exercised in coadministering this drug with ticlopidine, and it may be useful to remeasure phenytoin blood concentrations.
### Propranolol
In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of propranolol. However, the protein binding interactions of ticlopidine and its metabolites have not been studied in vivo. Caution should be exercised in coadministering this drug with ticlopidine.
### Other Concomitant Therapy
Although specific interaction studies were not performed, in clinical studies ticlopidine was used concomitantly with beta blockers, calcium channel blockers and diuretics without evidence of clinically significant adverse interactions.
### Food Interaction
The oral bioavailability of ticlopidine is increased by 20% when taken after a meal. Administration of ticlopidine with food is recommended to maximize gastrointestinal tolerance. In controlled trials in stroke patients, ticlopidine was taken with meals.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Teratology studies have been conducted in mice (doses up to 200 mg/kg/day), rats (doses up to 400 mg/kg/day) and rabbits (doses up to 200 mg/kg/day). Doses of 400 mg/kg in rats, 200 mg/kg/day in mice and 100 mg/kg in rabbits produced maternal toxicity, as well as fetal toxicity, but there was no evidence of a teratogenic potential of ticlopidine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS): B1
Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
### Labor and Delivery
There is no FDA guidance on use of Ticlopidine during labor and delivery.
### Nursing Mothers
Studies in rats have shown ticlopidine is excreted in the milk. 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 ticlopidine, 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 in pediatric patients have not been established.
### Geriatic Use
Clearance of ticlopidine is somewhat lower in elderly patients and trough levels are increased. The major clinical trials with ticlopidine in stroke patients were conducted in an elderly population with an average age of 64 years. Of the total number of patients in the therapeutic trials, 45% of patients were over 65 years old and 12% were over 75 years old. No overall differences in effectiveness or safety were observed between these patients and younger patients, 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.
### Gender
There is no FDA guidance on the use of Ticlopidine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ticlopidine with respect to specific racial populations.
### Renal Impairment
Patients with mildly (Ccr 50 to 80 mL/min) or moderately (Ccr 20 to 50 mL/min) impaired renal function were compared to normal subjects (Ccr 80 to 150 mL/min) in a study of the pharmacokinetic and platelet pharmacodynamic effects of ticlopidine (250 mg bid) for 11 days. Concentrations of unchanged ticlopidine were measured after a single 250-mg dose and after the final 250-mg dose on Day 11.
AUC values of ticlopidine increased by 28% and 60% in mild and moderately impaired patients, respectively, and plasma clearance decreased by 37% and 52%, respectively, but there were no statistically significant differences in ADP-induced platelet aggregation. In this small study (26 patients), bleeding times showed significant prolongation only in the moderately impaired patients.
### Hepatic Impairment
Since ticlopidine is metabolized by the liver, dosing of ticlopidine or other drugs metabolized in the liver may require adjustment upon starting or stopping concomitant therapy. Because of limited experience in patients with severe hepatic disease, who may have bleeding diatheses, the use of ticlopidine is not recommended in this population
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ticlopidine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ticlopidine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Starting just before initiating treatment and continuing through the third month of therapy, patients receiving ticlopidine must be monitored every 2 weeks. Because of ticlopidine’s long plasma half-life, patients who discontinue ticlopidine during this 3-month period should continue to be monitored for 2 weeks after discontinuation. More frequent monitoring, and monitoring after the first 3 months of therapy, is necessary only in patients with clinical signs (eg, signs or symptoms suggestive of infection) or laboratory signs (eg, neutrophil count less than 70% of the baseline count, decrease in hematocrit or platelet count) that suggest incipient hematological adverse reactions.
Clinically, fever might suggest neutropenia, TTP, or aplastic anemia; TTP might also be suggested by weakness, pallor, petechiae or purpura, dark urine (due to blood, bile pigments, or hemoglobin) or jaundice, or neurological changes. Patients should be told to discontinue ticlopidine and to contact the physician immediately upon the occurrence of any of these findings.
Laboratory monitoring should include a complete blood count, with special attention to the absolute neutrophil count (WBC x % neutrophils), platelet count, and the appearance of the peripheral smear. Ticlopidine is occasionally associated with thrombocytopenia unrelated to TTP or aplastic anemia. Any acute, unexplained reduction in hemoglobin or platelet count should prompt further investigation for a diagnosis of TTP, and the appearance of schistocytes (fragmented RBCs) on the smear should be treated as presumptive evidence of TTP. A simultaneous decrease in platelet count and WBC count should prompt further investigation for a diagnosis of aplastic anemia. If there are laboratory signs of TTP or aplastic anemia, or if the neutrophil count is confirmed to be <1200/mm3, then ticlopidine should be discontinued immediately.
# IV Compatibility
There is limited information regarding the compatibility of Ticlopidine and IV administrations.
# Overdosage
One case of deliberate overdosage with ticlopidine has been reported by a foreign postmarketing surveillance program. A 38-year-old male took a single 6000-mg dose of ticlopidine hydrochloride (equivalent to 24 standard 250-mg tablets). The only abnormalities reported were increased bleeding time and increased SGPT. No special therapy was instituted and the patient recovered without sequelae.
Single oral doses of ticlopidine at 1600 mg/kg and 500 mg/kg were lethal to rats and mice, respectively. Symptoms of acute toxicity were GI hemorrhage, convulsions, hypothermia, dyspnea, loss of equilibrium and abnormal gait.
# Pharmacology
## Mechanism of Action
When taken orally, ticlopidine hydrochloride causes a time- and dose-dependent inhibition of both platelet aggregation and release of platelet granule constituents, as well as a prolongation of bleeding time. The intact drug has no significant in vitro activity at the concentrations attained in vivo; and, although analysis of urine and plasma indicates at least 20 metabolites, no metabolite which accounts for the activity of ticlopidine has been isolated.
Ticlopidine hydrochloride, after oral ingestion, interferes with platelet membrane function by inhibiting ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet interactions. The effect on platelet function is irreversible for the life of the platelet, as shown both by persistent inhibition of fibrinogen binding after washing platelets ex vivo and by inhibition of platelet aggregation after resuspension of platelets in buffered medium.
## Structure
Ticlopidine hydrochloride is a platelet aggregation inhibitor. Chemically it is 5--4,5,6,7-tetrahydrothieno pyridine hydrochloride. The structural formula is:
Ticlopidine hydrochloride is a white crystalline solid. It is freely soluble in water and self-buffers to a pH of 3.6. It also dissolves freely in methanol, is sparingly soluble in methylene chloride and ethanol, slightly soluble in acetone and insoluble in a buffer solution of pH 6.3.
## Pharmacodynamics
In healthy volunteers over the age of 50, substantial inhibition (over 50%) of ADP-induced platelet aggregation is detected within 4 days after administration of ticlopidine hydrochloride 250 mg bid, and maximum platelet aggregation inhibition (60% to 70%) is achieved after 8 to 11 days. Lower doses cause less, and more delayed, platelet aggregation inhibition, while doses above 250 mg bid give little additional effect on platelet aggregation but an increased rate of adverse effects. The dose of 250 mg bid is the only dose that has been evaluated in controlled clinical trials.
After discontinuation of ticlopidine hydrochloride, bleeding time and other platelet function tests return to normal within 2 weeks, in the majority of patients.
At the recommended therapeutic dose (250 mg bid), ticlopidine hydrochloride has no known significant pharmacological actions in man other than inhibition of platelet function and prolongation of the bleeding time.
## Pharmacokinetics
After oral administration of a single 250-mg dose, ticlopidine hydrochloride is rapidly absorbed with peak plasma levels occurring at approximately 2 hours after dosing and is extensively metabolized. Absorption is greater than 80%. Administration after meals results in a 20% increase in the AUC of ticlopidine.
Ticlopidine hydrochloride displays nonlinear pharmacokinetics and clearance decreases markedly on repeated dosing. In older volunteers the apparent half-life of ticlopidine after a single 250-mg dose is about 12.6 hours; with repeat dosing at 250 mg bid, the terminal elimination half-life rises to 4 to 5 days and steady-state levels of ticlopidine hydrochloride in plasma are obtained after approximately 14 to 21 days.
Ticlopidine hydrochloride binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein. At concentrations attained with the recommended dose, only 15% or less ticlopidine in plasma is bound to this protein.
Ticlopidine hydrochloride is metabolized extensively by the liver; only trace amounts of intact drug are detected in the urine. Following an oral dose of radioactive ticlopidine hydrochloride administered in solution, 60% of the radioactivity is recovered in the urine and 23% in the feces. Approximately 1/3 of the dose excreted in the feces is intact ticlopidine hydrochloride, possibly excreted in the bile. Ticlopidine hydrochloride is a minor component in plasma (5%) after a single dose, but at steady-state is the major component (15%). Approximately 40% to 50% of the radioactive metabolites circulating in plasma are covalently bound to plasma proteins, probably by acylation.
Clearance of ticlopidine decreases with age. Steady-state trough values in elderly patients (mean age 70 years) are about twice those in younger volunteer populations.
## Nonclinical Toxicology
In a 2-year oral carcinogenicity study in rats, ticlopidine at daily doses of up to 100 mg/kg (610 mg/m2) was not tumorigenic. For a 70-kg person (1.73 m2 body surface area) the dose represents 14 times the recommended clinical dose on a mg/kg basis and two times the clinical dose on body surface area basis. In a 78-week oral carcinogenicity study in mice, ticlopidine at daily doses up to 275 mg/kg (1180 mg/m2) was not tumorigenic. The dose represents 40 times the recommended clinical dose on a mg/kg basis and four times the clinical dose on body surface area basis.
Ticlopidine was not mutagenic in vitro in the Ames test, the rat hepatocyte DNA-repair assay, or the Chinese-hamster fibroblast chromosomal aberration test; or in vivo in the mouse spermatozoid morphology test, the Chinese-hamster micronucleus test, or the Chinese-hamster bone-marrow-cell sister-chromatid exchange test. Ticlopidine was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg/day.
# Clinical Studies
### Stroke Patients
The effect of ticlopidine on the risk of stroke and cardiovascular events was studied in two multicenter, randomized, double-blind trials.
In a trial comparing ticlopidine and aspirin (The Ticlopidine Aspirin Stroke Study or TASS), 3069 patients (1987 men, 1082 women) who had experienced such stroke precursors as transient ischemic attack (TIA), transient monocular blindness (amaurosis fugax), reversible ischemic neurological deficit or minor stroke, were randomized to ticlopidine 250 mg bid or aspirin 650 mg bid. The study was designed to follow patients for at least 2 years and up to 5 years.
Over the duration of the study, ticlopidine significantly reduced the risk of fatal and nonfatal stroke by 24% (p =.011) from 18.1 to 13.8 per 100 patients followed for 5 years, compared to aspirin. During the first year, when the risk of stroke is greatest, the reduction in risk of stroke (fatal and nonfatal) compared to aspirin was 48%; the reduction was similar in men and women.
In a trial comparing ticlopidine with placebo (The Canadian American Ticlopidine Study or CATS) 1073 patients who had experienced a previous atherothrombotic stroke were treated with ticlopidine 250 mg bid or placebo for up to 3 years.
Ticlopidine significantly reduced the overall risk of stroke by 24% (p=.017) from 24.6 to 18.6 per 100 patients followed for 3 years, compared to placebo. During the first year the reduction in risk of fatal and nonfatal stroke over placebo was 33%.
### Stent Patients
The ability of ticlopidine to reduce the rate of thrombotic events after the placement of coronary artery stents has been studied in five randomized trials, one of substantial size (Stent Anticoagulation Restenosis Study or STARS) described below, and four smaller studies. In these trials, ticlopidine 250 mg bid with ASA (dose range from 100 mg bid to 325 mg qd) was compared to aspirin alone or to anticoagulant therapy plus aspirin. The trials enrolled patients undergoing both planned (elective) and unplanned coronary stent placement. The types of stents used, the use of intravascular ultrasound, and the use of high-pressure stent deployment varied among the trials, although all patients in STARS received a Palmaz-Schatz stent. The primary efficacy endpoints of the trials were similar, and included death, myocardial infarction and the need for repeat coronary angioplasty or CABG. All trials followed patients for at least 30 days.
In STARS, patients were randomized to receive one of three regimens for 4 weeks: aspirin alone, aspirin plus coumadin, or aspirin plus ticlopidine. Therapy was initiated following successful coronary stent placement. The primary endpoint was the incidence of stent thrombosis, defined as death, Q-Wave MI, or angiographic thrombus within the stented vessel demonstrated at the time of documented ischemia requiring emergent revascularization. The incidence rates for the primary endpoint and its components at 30 days are shown in the table below.
The use of ticlopidine plus aspirin did not affect the rate of non-Q-wave MIs when compared with aspirin alone or aspirin plus anticoagulants in STARS.
The use of ticlopidine plus aspirin was associated with a lower rate of recurrent cardiovascular events when compared with aspirin alone or aspirin plus anticoagulants in the other four randomized trials.
The rate of serious bleeding complications and neutropenia in STARS are shown in the table below. There were no cases of thrombotic thrombocytopenic purpura (TTP) or aplastic anemia reported in 1346 patients who received ticlopidine plus aspirin in the five randomized trials.
# How Supplied
Ticlopidine tablets are available as white to off-white, oval, film-coated, unscored, 250 mg tablets, debossed with “93” on one side and “154”on the other. They are packaged in bottles of 100 (NDC 42291-803-01)
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
## Storage
Store at controlled room temperature, between 20° and 25°C (68° and 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be told that a decrease in the number of white blood cells (neutropenia) or platelets (thrombocytopenia) can occur with ticlopidine, especially during the first 3 months of treatment and that neutropenia, if it is severe, can result in an increased risk of infection. They should be told it is critically important to obtain the scheduled blood tests to detect neutropenia or thrombocytopenia. Patients should also be reminded to contact their physicians if they experience any indication of infection such as fever, chills, or sore throat, any of which might be a consequence of neutropenia. Thrombocytopenia may be part of a syndrome called TTP. Symptoms and signs of TTP, such as fever, weakness, difficulty speaking, seizures, yellowing of skin or eyes, dark or bloody urine, pallor or petechiae (pinpoint hemorrhagic spots on the skin), should be reported immediately.
All patients should be told that it may take them longer than usual to stop bleeding when they take ticlopidine and that they should report any unusual bleeding to their physician. Patients should tell physicians and dentists that they are taking ticlopidine before any surgery is scheduled and before any new drug is prescribed.
Patients should be told to promptly report side effects of ticlopidine such as severe or persistent diarrhea, skin rashes or subcutaneous bleeding or any signs of cholestasis, such as yellow skin or sclera, dark urine, or light-colored stools.
Patients should be told to take ticlopidine with food or just after eating in order to minimize gastrointestinal discomfort.
# Precautions with Alcohol
Alcohol-Ticlopidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ticlid
- Ticlopidine
# Look-Alike Drug Names
- Ticlid - Tequin
# Drug Shortage Status
Drug Shortage
# Price | Ticlopidine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [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
Ticlopidine is a platelet aggregation inhibitor that is FDA approved for the prophylaxis of thromboembolic stroke, and subacute stent thrombosis in patients undergoing successful coronary stent implantation.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash, abdominal pain, diarrhea, indigestion, loss of appetite, nausea, hemorrhage, leukopenia, dizziness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Stroke
- Dosing Information
- Recommended dose: 250 mg bid taken with food.
### Coronary Artery Stenting
- Dosing Information
- Recommended dose: 250 mg bid taken with food together with antiplatelet doses of aspirin for up to 30 days of therapy following successful stent implantation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ticlopidine in adult patients.
### Non–Guideline-Supported Use
### Coronary artery bypass graft
- Dosing Information
- Recommended dose: 250 mg q12h[1][2]
### Hemodialysis
- Dosing Information
- Recommended dose: 250 mg daily[3]
### Acute Ischemic Heart Disease
- Dosing Information
- Recommended dose: 250 mg q12h[4]
### Myocardial Infarction
- Dosing Information
- Recommended dose: 250 mg q12h[5]
### Prophylaxis for Postoperative Thrombosis
- Dosing Information
- Recommended dose: 250 mg q12h 2 days before surgery until the seventh postoperative day[6]
### Rheumatoid arthritis
- Dosing Information
- Recommended dose: 250mg/day[7][8]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ticlopidine 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 Ticlopidine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ticlopidine in pediatric patients.
# Contraindications
- Hypersensitivity to the drug
- Presence of hematopoietic disorders such as neutropenia and thrombocytopenia or a past history of either TTP or aplastic anemia.
- Presence of a hemostatic disorder or active pathological bleeding (such as bleeding peptic ulcer or intracranial bleeding)
- Patients with severe liver impairment
# Warnings
### General
- Ticlopidine should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or pathological conditions.
- If it is desired to eliminate the antiplatelet effects of ticlopidine prior to elective surgery, the drug should be discontinued 10 to 14 days prior to surgery.
- Several controlled clinical studies have found increased surgical blood loss in patients undergoing surgery during treatment with ticlopidine.
- In TASS and CATS it was recommended that patients have ticlopidine discontinued prior to elective surgery.
- Several hundred patients underwent surgery during the trials, and no excessive surgical bleeding was reported.
- Prolonged bleeding time is normalized within 2 hours after administration of 20 mg methylprednisolone IV.
- Platelet transfusions may also be used to reverse the effect of ticlopidine on bleeding.
- Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.
### GI Bleeding
- Ticlopidine prolongs template bleeding time.
- The drug should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers).
- Drugs that might induce such lesions should be used with caution in patients on ticlopidine
- Ticlopidine therapy causes increased serum cholesterol and triglycerides.
- Serum total cholesterol levels are increased 8% to 10% within 1 month of therapy and persist at that level.
- The ratios of the lipoprotein subfractions are unchanged.
- The tolerance and long-term safety of coadministration of ticlopidine with heparin, oral anticoagulants or fibrinolytic agents have not been established.
- In trials for cardiac stenting, patients received heparin and ticlopidine concomitantly for approximately 12 hours.
- If a patient is switched from an anticoagulant or fibrinolytic drug to ticlopidine, the former drug should be discontinued prior to ticlopidine administration.
- Ticlopidine therapy has been associated with elevations of alkaline phosphatase, bilirubin, and transaminases, which generally occurred within 1 to 4 months of therapy initiation.
- In controlled clinical trials in stroke patients, the incidence of elevated alkaline phosphatase (greater than two times upper limit of normal) was 7.6% in ticlopidine patients, 6% in placebo patients and 2.5% in aspirin patients.
- The incidence of elevated AST (SGOT) (greater than two times upper limit of normal) was 3.1% in ticlopidine patients, 4% in placebo patients and 2.1% in aspirin patients. No progressive increases were observed in closely monitored clinical trials (eg, no transaminase greater than 10 times the upper limit of normal was seen), but most patients with these abnormalities had therapy discontinued.
- Occasionally patients had developed minor elevations in bilirubin.
- Postmarketing experience includes rare individuals with elevations in their transaminases and bilirubin to >10X above the upper limits of normal.
- Based on postmarketing and clinical trial experience, liver function testing, including ALT, AST, and GGT, should be considered whenever liver dysfunction is suspected, particularly during the first 4 months of treatment.
# Adverse Reactions
## Clinical Trials Experience
Adverse reactions in stroke patients were relatively frequent with over 50% of patients reporting at least one. Most (30% to 40%) involved the gastrointestinal tract. Most adverse effects are mild, but 21% of patients discontinued therapy because of an adverse event, principally diarrhea, rash, nausea, vomiting, GI pain and neutropenia. Most adverse effects occur early in the course of treatment, but a new onset of adverse effects can occur after several months.
The incidence rates of adverse events listed in the following table were derived from multicenter, controlled clinical trials in stroke patients described above comparing ticlopidine, placebo and aspirin over study periods of up to 5.8 years. Adverse events considered by the investigator to be probably drug-related that occurred in at least 1% of patients treated with ticlopidine are shown in the following table:
### Hematological
Neutropenia may occur suddenly. Bone marrow examination typically shows a reduction in white blood cell precursors. After withdrawal of ticlopidine, the neutrophil count usually rises to >1200/mm3 within 1 to 3 weeks.
Rarely, thrombocytopenia may occur in isolation or together with neutropenia.
TTP is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever. The signs and symptoms can occur in any order, in particular, clinical symptoms may precede laboratory findings by hours or days. With prompt treatment (often including plasmapheresis), 70% to 80% of patients will survive with minimal or no sequelae. Because platelet transfusions may accelerate thrombosis in patients with TTP on ticlopidine, they should, if possible, be avoided.
Aplastic anemia is characterized by anemia, thrombocytopenia and neutropenia together with a bone marrow examination that shows decreases in the precursor cells for red blood cells, white blood cells, and platelets. Patients may present with signs or symptoms suggestive of infection, in association with low white blood cell and platelet counts. Prompt treatment, which may include the use of drugs to stimulate the bone marrow, can minimize the mortality associated with aplastic anemia.
Rare cases of agranulocytosis, pancytopenia, or leukemia have been reported in postmarketing experience, some of which have been fatal. All forms of hematological adverse reactions are potentially fatal.
### Gastrointestinal
Ticlopidine therapy has been associated with a variety of gastrointestinal complaints including diarrhea and nausea. The majority of cases are mild, but about 13% of patients discontinued therapy because of these. They usually occur within 3 months of initiation of therapy and typically are resolved within 1 to 2 weeks without discontinuation of therapy. If the effect is severe or persistent, therapy should be discontinued. In some cases of severe or bloody diarrhea, colitis was later diagnosed.
### Hemorrhagic
Ticlopidine has been associated with increased bleeding, spontaneous posttraumatic bleeding and perioperative bleeding including, but not limited to, gastrointestinal bleeding. It has also been associated with a number of bleeding complications such as ecchymosis, epistaxis, hematuria and conjunctival hemorrhage.
Intracerebral bleeding was rare in clinical trials in stroke patients with ticlopidine, with an incidence no greater than that seen with comparator agents (ticlopidine 0.5%, aspirin 0.6%, placebo 0.75%). It has also been reported postmarketing.
### Rash
Ticlopidine has been associated with a maculopapular or urticarial rash (often with pruritus). Rash usually occurs within 3 months of initiation of therapy with a mean onset time of 11 days. If drug is discontinued, recovery occurs within several days. Many rashes do not recur on drug rechallenge. There have been rare reports of severe rashes, including Stevens-Johnson syndrome, erythema multiforme and exfoliative dermatitis.
### Less Frequent Adverse Reactions (Probably Related)
Clinical adverse experiences occurring in 0.5% to 1.0% of stroke patients in controlled trials include:
- Digestive System: GI fullness
- Skin and Appendages: urticaria
- Nervous System: headache
- Body as a Whole: asthenia, pain
- Hemostatic System: epistaxis
- Special Senses: tinnitus
## Postmarketing Experience
In addition, rarer, relatively serious and potentially fatal events associated with the use of ticlopidine have also been reported from postmarketing experience:
- Hemolytic anemia with reticulocytosis
- Immune thrombocytopenia
- Hepatitis
- Hepatocellular jaundice
- Cholestatic jaundice
- Hepatic necrosis
- Hepatic failure
- Peptic ulcer
- Renal failure
- Nephrotic syndrome
- Hyponatremia
- Vasculitis
- Sepsis
- Allergic reactions (including angioedema, allergic pneumonitis, and anaphylaxis)
- Systemic lupus (positive ANA)
- Peripheral neuropathy
- Serum sickness
- Arthropathy
- Myositis
# Drug Interactions
Therapeutic doses of ticlopidine caused a 30% increase in the plasma half-life of antipyrine and may cause analogous effects on similarly metabolized drugs. Therefore, the dose of drugs metabolized by hepatic microsomal enzymes with low therapeutic ratios or being given to patients with hepatic impairment may require adjustment to maintain optimal therapeutic blood levels when starting or stopping concomitant therapy with ticlopidine. Studies of specific drug interactions yielded the following results:
### Aspirin and other NSAIDs
Ticlopidine potentiates the effect of aspirin or other NSAIDs on platelet aggregation. The safety of concomitant use of ticlopidine and NSAIDs has not been established. The safety of concomitant use of ticlopidine and aspirin beyond 30 days has not been established. Aspirin did not modify the ticlopidine-mediated inhibition of ADP-induced platelet aggregation, but ticlopidine potentiated the effect of aspirin on collagen-induced platelet aggregation. Caution should be exercised in patients who have lesions with a propensity to bleed, such as ulcers. Long-term concomitant use of aspirin and ticlopidine is not recommended.
### Antacids
Administration of ticlopidine after antacids resulted in an 18% decrease in plasma levels of ticlopidine.
### Cimetidine
Chronic administration of cimetidine reduced the clearance of a single dose of ticlopidine by 50%.
### Digoxin
Coadministration of ticlopidine with digoxin resulted in a slight decrease (approximately 15%) in digoxin plasma levels. Little or no change in therapeutic efficacy of digoxin would be expected.
### Theophylline
In normal volunteers, concomitant administration of ticlopidine resulted in a significant increase in the theophylline elimination half-life from 8.6 to 12.2 hours and a comparable reduction in total plasma clearance of theophylline.
### Phenobarbital
In 6 normal volunteers, the inhibitory effects of ticlopidine on platelet aggregation were not altered by chronic administration of phenobarbital.
### Phenytoin
In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of phenytoin. However, the protein binding interactions of ticlopidine and its metabolites have not been studied in vivo. Several cases of elevated phenytoin plasma levels with associated somnolence and lethargy have been reported following coadministration with ticlopidine. Caution should be exercised in coadministering this drug with ticlopidine, and it may be useful to remeasure phenytoin blood concentrations.
### Propranolol
In vitro studies demonstrated that ticlopidine does not alter the plasma protein binding of propranolol. However, the protein binding interactions of ticlopidine and its metabolites have not been studied in vivo. Caution should be exercised in coadministering this drug with ticlopidine.
### Other Concomitant Therapy
Although specific interaction studies were not performed, in clinical studies ticlopidine was used concomitantly with beta blockers, calcium channel blockers and diuretics without evidence of clinically significant adverse interactions.
### Food Interaction
The oral bioavailability of ticlopidine is increased by 20% when taken after a meal. Administration of ticlopidine with food is recommended to maximize gastrointestinal tolerance. In controlled trials in stroke patients, ticlopidine was taken with meals.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
Teratology studies have been conducted in mice (doses up to 200 mg/kg/day), rats (doses up to 400 mg/kg/day) and rabbits (doses up to 200 mg/kg/day). Doses of 400 mg/kg in rats, 200 mg/kg/day in mice and 100 mg/kg in rabbits produced maternal toxicity, as well as fetal toxicity, but there was no evidence of a teratogenic potential of ticlopidine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, this drug should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS): B1
Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage.
### Labor and Delivery
There is no FDA guidance on use of Ticlopidine during labor and delivery.
### Nursing Mothers
Studies in rats have shown ticlopidine is excreted in the milk. 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 ticlopidine, 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 in pediatric patients have not been established.
### Geriatic Use
Clearance of ticlopidine is somewhat lower in elderly patients and trough levels are increased. The major clinical trials with ticlopidine in stroke patients were conducted in an elderly population with an average age of 64 years. Of the total number of patients in the therapeutic trials, 45% of patients were over 65 years old and 12% were over 75 years old. No overall differences in effectiveness or safety were observed between these patients and younger patients, 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.
### Gender
There is no FDA guidance on the use of Ticlopidine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ticlopidine with respect to specific racial populations.
### Renal Impairment
Patients with mildly (Ccr 50 to 80 mL/min) or moderately (Ccr 20 to 50 mL/min) impaired renal function were compared to normal subjects (Ccr 80 to 150 mL/min) in a study of the pharmacokinetic and platelet pharmacodynamic effects of ticlopidine (250 mg bid) for 11 days. Concentrations of unchanged ticlopidine were measured after a single 250-mg dose and after the final 250-mg dose on Day 11.
AUC values of ticlopidine increased by 28% and 60% in mild and moderately impaired patients, respectively, and plasma clearance decreased by 37% and 52%, respectively, but there were no statistically significant differences in ADP-induced platelet aggregation. In this small study (26 patients), bleeding times showed significant prolongation only in the moderately impaired patients.
### Hepatic Impairment
Since ticlopidine is metabolized by the liver, dosing of ticlopidine or other drugs metabolized in the liver may require adjustment upon starting or stopping concomitant therapy. Because of limited experience in patients with severe hepatic disease, who may have bleeding diatheses, the use of ticlopidine is not recommended in this population
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ticlopidine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ticlopidine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
Starting just before initiating treatment and continuing through the third month of therapy, patients receiving ticlopidine must be monitored every 2 weeks. Because of ticlopidine’s long plasma half-life, patients who discontinue ticlopidine during this 3-month period should continue to be monitored for 2 weeks after discontinuation. More frequent monitoring, and monitoring after the first 3 months of therapy, is necessary only in patients with clinical signs (eg, signs or symptoms suggestive of infection) or laboratory signs (eg, neutrophil count less than 70% of the baseline count, decrease in hematocrit or platelet count) that suggest incipient hematological adverse reactions.
Clinically, fever might suggest neutropenia, TTP, or aplastic anemia; TTP might also be suggested by weakness, pallor, petechiae or purpura, dark urine (due to blood, bile pigments, or hemoglobin) or jaundice, or neurological changes. Patients should be told to discontinue ticlopidine and to contact the physician immediately upon the occurrence of any of these findings.
Laboratory monitoring should include a complete blood count, with special attention to the absolute neutrophil count (WBC x % neutrophils), platelet count, and the appearance of the peripheral smear. Ticlopidine is occasionally associated with thrombocytopenia unrelated to TTP or aplastic anemia. Any acute, unexplained reduction in hemoglobin or platelet count should prompt further investigation for a diagnosis of TTP, and the appearance of schistocytes (fragmented RBCs) on the smear should be treated as presumptive evidence of TTP. A simultaneous decrease in platelet count and WBC count should prompt further investigation for a diagnosis of aplastic anemia. If there are laboratory signs of TTP or aplastic anemia, or if the neutrophil count is confirmed to be <1200/mm3, then ticlopidine should be discontinued immediately.
# IV Compatibility
There is limited information regarding the compatibility of Ticlopidine and IV administrations.
# Overdosage
One case of deliberate overdosage with ticlopidine has been reported by a foreign postmarketing surveillance program. A 38-year-old male took a single 6000-mg dose of ticlopidine hydrochloride (equivalent to 24 standard 250-mg tablets). The only abnormalities reported were increased bleeding time and increased SGPT. No special therapy was instituted and the patient recovered without sequelae.
Single oral doses of ticlopidine at 1600 mg/kg and 500 mg/kg were lethal to rats and mice, respectively. Symptoms of acute toxicity were GI hemorrhage, convulsions, hypothermia, dyspnea, loss of equilibrium and abnormal gait.
# Pharmacology
## Mechanism of Action
When taken orally, ticlopidine hydrochloride causes a time- and dose-dependent inhibition of both platelet aggregation and release of platelet granule constituents, as well as a prolongation of bleeding time. The intact drug has no significant in vitro activity at the concentrations attained in vivo; and, although analysis of urine and plasma indicates at least 20 metabolites, no metabolite which accounts for the activity of ticlopidine has been isolated.
Ticlopidine hydrochloride, after oral ingestion, interferes with platelet membrane function by inhibiting ADP-induced platelet-fibrinogen binding and subsequent platelet-platelet interactions. The effect on platelet function is irreversible for the life of the platelet, as shown both by persistent inhibition of fibrinogen binding after washing platelets ex vivo and by inhibition of platelet aggregation after resuspension of platelets in buffered medium.
## Structure
Ticlopidine hydrochloride is a platelet aggregation inhibitor. Chemically it is 5-[(2-chlorophenyl)methyl]-4,5,6,7-tetrahydrothieno [3,2-c] pyridine hydrochloride. The structural formula is:
Ticlopidine hydrochloride is a white crystalline solid. It is freely soluble in water and self-buffers to a pH of 3.6. It also dissolves freely in methanol, is sparingly soluble in methylene chloride and ethanol, slightly soluble in acetone and insoluble in a buffer solution of pH 6.3.
## Pharmacodynamics
In healthy volunteers over the age of 50, substantial inhibition (over 50%) of ADP-induced platelet aggregation is detected within 4 days after administration of ticlopidine hydrochloride 250 mg bid, and maximum platelet aggregation inhibition (60% to 70%) is achieved after 8 to 11 days. Lower doses cause less, and more delayed, platelet aggregation inhibition, while doses above 250 mg bid give little additional effect on platelet aggregation but an increased rate of adverse effects. The dose of 250 mg bid is the only dose that has been evaluated in controlled clinical trials.
After discontinuation of ticlopidine hydrochloride, bleeding time and other platelet function tests return to normal within 2 weeks, in the majority of patients.
At the recommended therapeutic dose (250 mg bid), ticlopidine hydrochloride has no known significant pharmacological actions in man other than inhibition of platelet function and prolongation of the bleeding time.
## Pharmacokinetics
After oral administration of a single 250-mg dose, ticlopidine hydrochloride is rapidly absorbed with peak plasma levels occurring at approximately 2 hours after dosing and is extensively metabolized. Absorption is greater than 80%. Administration after meals results in a 20% increase in the AUC of ticlopidine.
Ticlopidine hydrochloride displays nonlinear pharmacokinetics and clearance decreases markedly on repeated dosing. In older volunteers the apparent half-life of ticlopidine after a single 250-mg dose is about 12.6 hours; with repeat dosing at 250 mg bid, the terminal elimination half-life rises to 4 to 5 days and steady-state levels of ticlopidine hydrochloride in plasma are obtained after approximately 14 to 21 days.
Ticlopidine hydrochloride binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein. At concentrations attained with the recommended dose, only 15% or less ticlopidine in plasma is bound to this protein.
Ticlopidine hydrochloride is metabolized extensively by the liver; only trace amounts of intact drug are detected in the urine. Following an oral dose of radioactive ticlopidine hydrochloride administered in solution, 60% of the radioactivity is recovered in the urine and 23% in the feces. Approximately 1/3 of the dose excreted in the feces is intact ticlopidine hydrochloride, possibly excreted in the bile. Ticlopidine hydrochloride is a minor component in plasma (5%) after a single dose, but at steady-state is the major component (15%). Approximately 40% to 50% of the radioactive metabolites circulating in plasma are covalently bound to plasma proteins, probably by acylation.
Clearance of ticlopidine decreases with age. Steady-state trough values in elderly patients (mean age 70 years) are about twice those in younger volunteer populations.
## Nonclinical Toxicology
In a 2-year oral carcinogenicity study in rats, ticlopidine at daily doses of up to 100 mg/kg (610 mg/m2) was not tumorigenic. For a 70-kg person (1.73 m2 body surface area) the dose represents 14 times the recommended clinical dose on a mg/kg basis and two times the clinical dose on body surface area basis. In a 78-week oral carcinogenicity study in mice, ticlopidine at daily doses up to 275 mg/kg (1180 mg/m2) was not tumorigenic. The dose represents 40 times the recommended clinical dose on a mg/kg basis and four times the clinical dose on body surface area basis.
Ticlopidine was not mutagenic in vitro in the Ames test, the rat hepatocyte DNA-repair assay, or the Chinese-hamster fibroblast chromosomal aberration test; or in vivo in the mouse spermatozoid morphology test, the Chinese-hamster micronucleus test, or the Chinese-hamster bone-marrow-cell sister-chromatid exchange test. Ticlopidine was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg/day.
# Clinical Studies
### Stroke Patients
The effect of ticlopidine on the risk of stroke and cardiovascular events was studied in two multicenter, randomized, double-blind trials.
In a trial comparing ticlopidine and aspirin (The Ticlopidine Aspirin Stroke Study or TASS), 3069 patients (1987 men, 1082 women) who had experienced such stroke precursors as transient ischemic attack (TIA), transient monocular blindness (amaurosis fugax), reversible ischemic neurological deficit or minor stroke, were randomized to ticlopidine 250 mg bid or aspirin 650 mg bid. The study was designed to follow patients for at least 2 years and up to 5 years.
Over the duration of the study, ticlopidine significantly reduced the risk of fatal and nonfatal stroke by 24% (p =.011) from 18.1 to 13.8 per 100 patients followed for 5 years, compared to aspirin. During the first year, when the risk of stroke is greatest, the reduction in risk of stroke (fatal and nonfatal) compared to aspirin was 48%; the reduction was similar in men and women.
In a trial comparing ticlopidine with placebo (The Canadian American Ticlopidine Study or CATS) 1073 patients who had experienced a previous atherothrombotic stroke were treated with ticlopidine 250 mg bid or placebo for up to 3 years.
Ticlopidine significantly reduced the overall risk of stroke by 24% (p=.017) from 24.6 to 18.6 per 100 patients followed for 3 years, compared to placebo. During the first year the reduction in risk of fatal and nonfatal stroke over placebo was 33%.
### Stent Patients
The ability of ticlopidine to reduce the rate of thrombotic events after the placement of coronary artery stents has been studied in five randomized trials, one of substantial size (Stent Anticoagulation Restenosis Study or STARS) described below, and four smaller studies. In these trials, ticlopidine 250 mg bid with ASA (dose range from 100 mg bid to 325 mg qd) was compared to aspirin alone or to anticoagulant therapy plus aspirin. The trials enrolled patients undergoing both planned (elective) and unplanned coronary stent placement. The types of stents used, the use of intravascular ultrasound, and the use of high-pressure stent deployment varied among the trials, although all patients in STARS received a Palmaz-Schatz stent. The primary efficacy endpoints of the trials were similar, and included death, myocardial infarction and the need for repeat coronary angioplasty or CABG. All trials followed patients for at least 30 days.
In STARS, patients were randomized to receive one of three regimens for 4 weeks: aspirin alone, aspirin plus coumadin, or aspirin plus ticlopidine. Therapy was initiated following successful coronary stent placement. The primary endpoint was the incidence of stent thrombosis, defined as death, Q-Wave MI, or angiographic thrombus within the stented vessel demonstrated at the time of documented ischemia requiring emergent revascularization. The incidence rates for the primary endpoint and its components at 30 days are shown in the table below.
The use of ticlopidine plus aspirin did not affect the rate of non-Q-wave MIs when compared with aspirin alone or aspirin plus anticoagulants in STARS.
The use of ticlopidine plus aspirin was associated with a lower rate of recurrent cardiovascular events when compared with aspirin alone or aspirin plus anticoagulants in the other four randomized trials.
The rate of serious bleeding complications and neutropenia in STARS are shown in the table below. There were no cases of thrombotic thrombocytopenic purpura (TTP) or aplastic anemia reported in 1346 patients who received ticlopidine plus aspirin in the five randomized trials.
# How Supplied
Ticlopidine tablets are available as white to off-white, oval, film-coated, unscored, 250 mg tablets, debossed with “93” on one side and “154”on the other. They are packaged in bottles of 100 (NDC 42291-803-01)
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
## Storage
Store at controlled room temperature, between 20° and 25°C (68° and 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be told that a decrease in the number of white blood cells (neutropenia) or platelets (thrombocytopenia) can occur with ticlopidine, especially during the first 3 months of treatment and that neutropenia, if it is severe, can result in an increased risk of infection. They should be told it is critically important to obtain the scheduled blood tests to detect neutropenia or thrombocytopenia. Patients should also be reminded to contact their physicians if they experience any indication of infection such as fever, chills, or sore throat, any of which might be a consequence of neutropenia. Thrombocytopenia may be part of a syndrome called TTP. Symptoms and signs of TTP, such as fever, weakness, difficulty speaking, seizures, yellowing of skin or eyes, dark or bloody urine, pallor or petechiae (pinpoint hemorrhagic spots on the skin), should be reported immediately.
All patients should be told that it may take them longer than usual to stop bleeding when they take ticlopidine and that they should report any unusual bleeding to their physician. Patients should tell physicians and dentists that they are taking ticlopidine before any surgery is scheduled and before any new drug is prescribed.
Patients should be told to promptly report side effects of ticlopidine such as severe or persistent diarrhea, skin rashes or subcutaneous bleeding or any signs of cholestasis, such as yellow skin or sclera, dark urine, or light-colored stools.
Patients should be told to take ticlopidine with food or just after eating in order to minimize gastrointestinal discomfort.
# Precautions with Alcohol
Alcohol-Ticlopidine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Ticlid
- Ticlopidine
# Look-Alike Drug Names
- Ticlid - Tequin
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Ticlid | |
6bc4da3c4b9491c654dd40049c8458e9be261cf1 | wikidoc | Tigecycline | Tigecycline
# 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
Tigecycline is an antibiotic that is FDA approved for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections and community-acquired pneumonia. Common adverse reactions include nausea, vomiting, diarrhea, abdominal pain, headache and increased SGPT.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Complicated Skin and Skin Structure Infections
Caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.
- Dosage:
- Initial dose of 100 mg
- Followed by 50 mg every 12 hours
- Intravenous infusions of tigecycline should be administered over approximately 30 to 60 minutes every 12 hours.
- Duration of treatment is 5 to 14 days.
### Complicated Intra-abdominal Infections
Caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.
- Dosage:
- Initial dose of 100 mg
- Followed by 50 mg every 12 hours
- Intravenous infusions of tigecycline should be administered over approximately 30 to 60 minutes every 12 hours.
- Duration of treatment is 5 to 14 days.
### Community-acquired pneumonia
Caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila.
- Dosage:
- Initial dose of 100 mg
- Followed by 50 mg every 12 hours
- Intravenous infusions of tigecycline should be administered over approximately 30 to 60 minutes every 12 hours.
- Duration of treatment is 7 to 14 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tigecycline in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tigecycline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy of the proposed pediatric dosing regimens have not been evaluated due to the observed increase in mortality associated with tigecycline in adult patients. Tigecycline should not be used in pediatric patients unless no alternative antibacterial drugs are available. Under these circumstances, the following doses are suggested:
- Pediatric patients aged 8 to 11 years should receive 1.2 mg/kg of tigecycline every 12 hours intravenously to a maximum dose of 50 mg of tigecycline every 12 hours.
- Pediatric patients aged 12 to 17 years should receive 50 mg of tigecycline every 12 hours,
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tigecycline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tigecycline in pediatric patients.
# Contraindications
- Tigecycline is contraindicated for use in patients who have known hypersensitivity to tigecycline.
# Warnings
### All-Cause Mortality
- An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in tigecycline-treated patients versus comparator-treated patients. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving tigecycline and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, the adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline and comparator-treated patients. An analysis of mortality in all trials conducted for approved indications (cSSSI, cIAI, and CABP), including post-market trials showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).
- The cause of this mortality difference has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. tigecycline should be reserved for use in situations when alternative treatments are not suitable.
### Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia
- A trial of patients with hospital acquired, including ventilator-associated, pneumonia failed to demonstrate the efficacy of tigecycline. In this trial, patients were randomized to receive tigecycline (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received tigecycline had lower cure rates (47.9% versus 70.1% for the clinically evaluable population).
- In this trial, greater mortality was seen in patients with ventilator-associated pneumonia who received tigecycline (25/131 versus 15/122 in comparator-treated patients). Particularly high mortality was seen among tigecycline-treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 versus 1/13 in comparator-treated patients).
### Anaphylaxis/Anaphylactoid Reactions
- Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening. tigecycline is structurally similar to tetracycline-class antibiotics and should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics.
### Hepatic Effects
- Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Adverse events may occur after the drug has been discontinued.
### Pancreatitis
- Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis.
### Use During Pregnancy
- Tigecycline may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline.
### Tooth Development
- The use of tigecycline during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of studies in rats with tigecycline have shown bone discoloration. tigecycline should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.
### Clostridium difficile Associated Diarrhea
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including tigecycline, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to 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 antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
### Patients With Intestinal Perforation
- Caution should be exercised when considering tigecycline monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with tigecycline and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with tigecycline had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.
### Tetracycline-Class Effects
- tigecycline is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACI.
### Superinfection
- As with other antibacterial drugs, use of tigecycline may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.
### Development of Drug-Resistant Bacteria
- Prescribing tigecycline 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 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 clinical trials, 2514 patients were treated with tigecycline. tigecycline was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of treatment-emergent adverse reactions through test of cure reported in ≥2% of patients in these trials.
In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving tigecycline and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline and comparator-treated patients. The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities.
An analysis of mortality in all trials conducted for approved indications - cSSSI, cIAI, and CABP, including post-market trials (315, 400, 900) - showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).
In comparative clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with tigecycline (7%) versus comparators (6%). Serious adverse events of sepsis/septic shock were more frequently reported for subjects treated with tigecycline (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established.
The most common treatment-emergent adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy. The majority of cases of nausea and vomiting associated with tigecycline and comparators were either mild or moderate in severity. In patients treated with tigecycline, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).
In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for tigecycline and 9% for vancomycin/aztreonam; vomiting incidence was 20% for tigecycline and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for tigecycline and 21% for imipenem/cilastatin; vomiting incidence was 20% for tigecycline and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for tigecycline and 8% for levofloxacin; vomiting incidence was 16% for tigecycline and 6% for levofloxacin.
Discontinuation from tigecycline was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%).
The following adverse reactions were reported infrequently (<2%) in patients receiving tigecycline in clinical studies:
- Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis
- Cardiovascular System: thrombophlebitis
- Digestive System: anorexia, jaundice, abnormal stools
- Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia
- Special Senses: taste perversion
- Hemic and Lymphatic System: partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia
- Skin and Appendages: pruritus
- Urogenital System: vaginal moniliasis, vaginitis, leukorrhea
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of tigecycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.
- anaphylaxis/anaphylactoid reactions
- acute pancreatitis
- hepatic cholestasis, and jaundice
- severe skin reactions, including Stevens-Johnson Syndrome
- symptomatic hypoglycemia in patients with and without diabetes mellitus
# Drug Interactions
### Warfarin
- Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.
### Oral Contraceptives
- Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with reductions in fetal weights and an increased incidence of skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg∙hr/mL and 6 mcg∙hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose.
There are no adequate and well-controlled studies of tigecycline in pregnant women. tigecycline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tigecycline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tigecycline during labor and delivery.
### Nursing Mothers
Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.
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 tigecycline is administered to a nursing woman.
### Pediatric Use
Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of the increased mortality observed in tigecycline-treated adult patients in clinical trials, pediatric trials of tigecycline to evaluate the safety and efficacy of tigecycline were not conducted.
In situations where there are no other alternative antibacterial drugs, pediatric dosing has been proposed based on data from pediatric pharmacokinetic studies.
Because of effects on tooth development, use in patients under 8 years of age is not recommended.
### Geriatic Use
Of the total number of subjects who received tigecycline in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. No unexpected overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out.
No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline.
### Gender
In a pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance between women (20.7±6.5 L/h) and men (22.8±8.7 L/h). Therefore, no dosage adjustment is necessary based on gender.
### Race
In a pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and 3 subjects classified as "other" participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance among the Asian subjects (28.8±8.8 L/h), Black subjects (23.0±7.8 L/h), Hispanic subjects (24.3±6.5 L/h), White subjects (22.1±8.9 L/h), and "other" subjects (25.0±4.8 L/h). Therefore, no dosage adjustment is necessary based on race.
### Renal Impairment
A single dose study compared 6 subjects with severe renal impairment (creatinine clearance <30 mL/min), 4 end stage renal disease (ESRD) patients receiving tigecycline 2 hours before hemodialysis, 4 ESRD patients receiving tigecycline 1 hour after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not significantly altered in any of the renally impaired patient groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of tigecycline is necessary in patients with renal impairment or in patients undergoing hemodialysis.
### Hepatic Impairment
No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response.
### Females of Reproductive Potential and Males
Tigecycline did not affect mating or fertility in rats at exposures up to 5 times the human daily dose based on AUC (28 mcg∙hr/mL at 12 mg/kg/day). In female rats, there were no compound-related effects on ovaries or estrous cycles at exposures up to 5 times the human daily dose based on AUC.
### Immunocompromised Patients
There is no FDA guidance one the use of Tigecycline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Tigecycline Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tigecycline and IV administrations.
# Overdosage
No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of tigecycline at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. In single-dose intravenous toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD50) was 124 mg/kg in males and 98 mg/kg in females. In rats, the estimated LD50 was 106 mg/kg for both sexes. Tigecycline is not removed in significant quantities by hemodialysis.
# Pharmacology
There is limited information regarding Tigecycline Pharmacology in the drug label.
## Mechanism of Action
Tigecycline, a glycylcycline, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. Tigecycline carries a glycylamido moiety attached to the 9-position of minocycline. The substitution pattern is not present in any naturally occurring or semisynthetic tetracycline and imparts certain microbiologic properties to tigecycline. In general, tigecycline is considered bacteriostatic; however, tigecycline has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.
## Structure
- The empirical formula is C29H39N5O8 and the molecular weight is 585.65.
- The following represents the chemical structure of tigecycline:
## Pharmacodynamics
No significant effect of a single intravenous dose of tigecycline 50 mg or 200 mg on QTc interval was detected in a randomized, placebo- and active-controlled four-arm crossover thorough QTc study of 46 healthy subjects.
## Pharmacokinetics
The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 3. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.
The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues.
Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC0–12h (134 mcg∙h/mL) in alveolar cells was approximately 78-fold higher than the AUC0–12h in the serum, and the AUC0–12h (2.28 mcg∙h/mL) in epithelial lining fluid was approximately 32% higher than the AUC0–12h in serum. The AUC0–12h (1.61 mcg∙h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0–12h in the serum of 10 healthy subjects.
In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at 4 hours after tigecycline administration were higher in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6), and lower in synovial fluid (0.58-fold, n=5), and bone (0.35-fold, n=6) relative to serum. The concentration of tigecycline in these tissues after multiple doses has not been studied.
Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and feces, but a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.
The recovery of total radioactivity in feces and urine following administration of 14C-tigecycline indicates that 59% of the dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Approximately 22% of the total dose is excreted as unchanged tigecycline in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline and its metabolites. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.
## Nonclinical Toxicology
### Carcinogenesis and Mutagenesis
Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline. No mutagenic or clastogenic potential was found in a battery of tests, including in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, in vitro forward mutation assay in CHO cells (HGRPT locus), in vitro forward mutation assays in mouse lymphoma cells, and in vivo mouse micronucleus assay.
### Animal Toxicology and/or Pharmacology
In two week studies, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8 times and 10 times the human daily dose based on AUC in rats and dogs, (AUC of approximately 50 and 60 mcg∙hr/mL at doses of 30 and 12 mg/kg/day) respectively. These alterations were shown to be reversible after two weeks of dosing.
# Clinical Studies
### Complicated Skin and Skin Structure Infections
Tigecycline was evaluated in adults for the treatment of complicated skin and skin structure infections (cSSSI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 300 and 305). These studies compared tigecycline (100 mg intravenous initial dose followed by 50 mg every 12 hours) with vancomycin (1 g intravenous every 12 hours)/aztreonam (2 g intravenous every 12 hours) for 5 to 14 days. Patients with complicated deep soft tissue infections including wound infections and cellulitis (≥10 cm, requiring surgery/drainage or with complicated underlying disease), major abscesses, infected ulcers, and burns were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See TABLE 6. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7.
### Complicated Intra-abdominal Infections
Tigecycline was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 301 and 306). These studies compared tigecycline (100 mg intravenous initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg intravenous every 6 hours) for 5 to 14 days. Patients with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis were enrolled in the studies. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the microbiologically evaluable (ME) and the microbiologic modified intent-to-treat (m-mITT) patients. See TABLE 8. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 9.
### Community-Acquired Bacterial Pneumonia
Tigecycline was evaluated in adults for the treatment of community-acquired bacterial pneumonia (CABP) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 308 and 313). These studies compared tigecycline (100 mg intravenous initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg intravenous every 12 or 24 hours). In one study (Study 308), after at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was 7 to 14 days. Patients with community-acquired bacterial pneumonia who required hospitalization and intravenous therapy were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See TABLE 10. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 11.
To further evaluate the treatment effect of tigecycline, a post-hoc analysis was conducted in CABP patients with a higher risk of mortality, for whom the treatment effect of antibiotics is supported by historical evidence. The higher-risk group included CABP patients from the two studies with any of the following factors:
- Age ≥50 years
- PSI score ≥3
- Streptococcus pneumoniae bacteremia
The results of this analysis are shown in Table 12. Age ≥50 was the most common risk factor in the higher-risk group.
# How Supplied
Tigecycline for injection is supplied in:
- Single-dose 5 mL glass vial
- Single-dose 10 mL glass vial
Each containing 50 mg tigecycline lyophilized powder for reconstitution.
## Storage
Stored at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including tigecycline should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When tigecycline is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by tigecycline or other antibacterial drugs in the future.
- Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
# Precautions with Alcohol
Alcohol-Tigecycline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tygacil
# Look-Alike Drug Names
There is limited information regarding Tigecycline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tigecycline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [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
Tigecycline is an antibiotic that is FDA approved for the treatment of complicated skin and skin structure infections, complicated intra-abdominal infections and community-acquired pneumonia. Common adverse reactions include nausea, vomiting, diarrhea, abdominal pain, headache and increased SGPT.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Complicated Skin and Skin Structure Infections
Caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.
- Dosage:
- Initial dose of 100 mg
- Followed by 50 mg every 12 hours
- Intravenous infusions of tigecycline should be administered over approximately 30 to 60 minutes every 12 hours.
- Duration of treatment is 5 to 14 days.
### Complicated Intra-abdominal Infections
Caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.
- Dosage:
- Initial dose of 100 mg
- Followed by 50 mg every 12 hours
- Intravenous infusions of tigecycline should be administered over approximately 30 to 60 minutes every 12 hours.
- Duration of treatment is 5 to 14 days.
### Community-acquired pneumonia
Caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila.
- Dosage:
- Initial dose of 100 mg
- Followed by 50 mg every 12 hours
- Intravenous infusions of tigecycline should be administered over approximately 30 to 60 minutes every 12 hours.
- Duration of treatment is 7 to 14 days.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tigecycline in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tigecycline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and efficacy of the proposed pediatric dosing regimens have not been evaluated due to the observed increase in mortality associated with tigecycline in adult patients. Tigecycline should not be used in pediatric patients unless no alternative antibacterial drugs are available. Under these circumstances, the following doses are suggested:
- Pediatric patients aged 8 to 11 years should receive 1.2 mg/kg of tigecycline every 12 hours intravenously to a maximum dose of 50 mg of tigecycline every 12 hours.
- Pediatric patients aged 12 to 17 years should receive 50 mg of tigecycline every 12 hours,
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tigecycline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tigecycline in pediatric patients.
# Contraindications
- Tigecycline is contraindicated for use in patients who have known hypersensitivity to tigecycline.
# Warnings
### All-Cause Mortality
- An increase in all-cause mortality has been observed in a meta-analysis of Phase 3 and 4 clinical trials in tigecycline-treated patients versus comparator-treated patients. In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving tigecycline and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, the adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline and comparator-treated patients. An analysis of mortality in all trials conducted for approved indications (cSSSI, cIAI, and CABP), including post-market trials showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).
- The cause of this mortality difference has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities. tigecycline should be reserved for use in situations when alternative treatments are not suitable.
### Mortality Imbalance and Lower Cure Rates in Hospital-Acquired Pneumonia
- A trial of patients with hospital acquired, including ventilator-associated, pneumonia failed to demonstrate the efficacy of tigecycline. In this trial, patients were randomized to receive tigecycline (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received tigecycline had lower cure rates (47.9% versus 70.1% for the clinically evaluable population).
- In this trial, greater mortality was seen in patients with ventilator-associated pneumonia who received tigecycline (25/131 [19.1%] versus 15/122 [12.3%] in comparator-treated patients). Particularly high mortality was seen among tigecycline-treated patients with ventilator-associated pneumonia and bacteremia at baseline (9/18 [50.0%] versus 1/13 [7.7%] in comparator-treated patients).
### Anaphylaxis/Anaphylactoid Reactions
- Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including tigecycline, and may be life-threatening. tigecycline is structurally similar to tetracycline-class antibiotics and should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics.
### Hepatic Effects
- Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Adverse events may occur after the drug has been discontinued.
### Pancreatitis
- Acute pancreatitis, including fatal cases, has occurred in association with tigecycline treatment. The diagnosis of acute pancreatitis should be considered in patients taking tigecycline who develop clinical symptoms, signs, or laboratory abnormalities suggestive of acute pancreatitis. Cases have been reported in patients without known risk factors for pancreatitis. Patients usually improve after tigecycline discontinuation. Consideration should be given to the cessation of the treatment with tigecycline in cases suspected of having developed pancreatitis.
### Use During Pregnancy
- Tigecycline may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline.
### Tooth Development
- The use of tigecycline during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of studies in rats with tigecycline have shown bone discoloration. tigecycline should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.
### Clostridium difficile Associated Diarrhea
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including tigecycline, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to 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 antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
- If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
### Patients With Intestinal Perforation
- Caution should be exercised when considering tigecycline monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with tigecycline and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with tigecycline had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.
### Tetracycline-Class Effects
- tigecycline is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACI.
### Superinfection
- As with other antibacterial drugs, use of tigecycline may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken.
### Development of Drug-Resistant Bacteria
- Prescribing tigecycline 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 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 clinical trials, 2514 patients were treated with tigecycline. tigecycline was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of treatment-emergent adverse reactions through test of cure reported in ≥2% of patients in these trials.
In all 13 Phase 3 and 4 trials that included a comparator, death occurred in 4.0% (150/3788) of patients receiving tigecycline and 3.0% (110/3646) of patients receiving comparator drugs. In a pooled analysis of these trials, based on a random effects model by trial weight, an adjusted risk difference of all-cause mortality was 0.6% (95% CI 0.1, 1.2) between tigecycline and comparator-treated patients. The cause of the imbalance has not been established. Generally, deaths were the result of worsening infection, complications of infection or underlying co-morbidities.
An analysis of mortality in all trials conducted for approved indications - cSSSI, cIAI, and CABP, including post-market trials (315, 400, 900) - showed an adjusted mortality rate of 2.5% (66/2640) for tigecycline and 1.8% (48/2628) for comparator, respectively. The adjusted risk difference for mortality stratified by trial weight was 0.6% (95% CI 0.0, 1.2).
In comparative clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with tigecycline (7%) versus comparators (6%). Serious adverse events of sepsis/septic shock were more frequently reported for subjects treated with tigecycline (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established.
The most common treatment-emergent adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy. The majority of cases of nausea and vomiting associated with tigecycline and comparators were either mild or moderate in severity. In patients treated with tigecycline, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).
In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for tigecycline and 9% for vancomycin/aztreonam; vomiting incidence was 20% for tigecycline and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for tigecycline and 21% for imipenem/cilastatin; vomiting incidence was 20% for tigecycline and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for tigecycline and 8% for levofloxacin; vomiting incidence was 16% for tigecycline and 6% for levofloxacin.
Discontinuation from tigecycline was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%).
The following adverse reactions were reported infrequently (<2%) in patients receiving tigecycline in clinical studies:
- Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis
- Cardiovascular System: thrombophlebitis
- Digestive System: anorexia, jaundice, abnormal stools
- Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia
- Special Senses: taste perversion
- Hemic and Lymphatic System: partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia
- Skin and Appendages: pruritus
- Urogenital System: vaginal moniliasis, vaginitis, leukorrhea
## Postmarketing Experience
The following adverse reactions have been identified during post-approval use of tigecycline. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.
- anaphylaxis/anaphylactoid reactions
- acute pancreatitis
- hepatic cholestasis, and jaundice
- severe skin reactions, including Stevens-Johnson Syndrome
- symptomatic hypoglycemia in patients with and without diabetes mellitus
# Drug Interactions
### Warfarin
- Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin.
### Oral Contraceptives
- Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with reductions in fetal weights and an increased incidence of skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg∙hr/mL and 6 mcg∙hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose.
There are no adequate and well-controlled studies of tigecycline in pregnant women. tigecycline should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): D
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tigecycline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tigecycline during labor and delivery.
### Nursing Mothers
Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk.
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 tigecycline is administered to a nursing woman.
### Pediatric Use
Use in patients under 18 years of age is not recommended. Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of the increased mortality observed in tigecycline-treated adult patients in clinical trials, pediatric trials of tigecycline to evaluate the safety and efficacy of tigecycline were not conducted.
In situations where there are no other alternative antibacterial drugs, pediatric dosing has been proposed based on data from pediatric pharmacokinetic studies.
Because of effects on tooth development, use in patients under 8 years of age is not recommended.
### Geriatic Use
Of the total number of subjects who received tigecycline in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. No unexpected overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out.
No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline.
### Gender
In a pooled analysis of 38 women and 298 men participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance between women (20.7±6.5 L/h) and men (22.8±8.7 L/h). Therefore, no dosage adjustment is necessary based on gender.
### Race
In a pooled analysis of 73 Asian subjects, 53 Black subjects, 15 Hispanic subjects, 190 White subjects, and 3 subjects classified as "other" participating in clinical pharmacology studies, there was no significant difference in the mean (±SD) tigecycline clearance among the Asian subjects (28.8±8.8 L/h), Black subjects (23.0±7.8 L/h), Hispanic subjects (24.3±6.5 L/h), White subjects (22.1±8.9 L/h), and "other" subjects (25.0±4.8 L/h). Therefore, no dosage adjustment is necessary based on race.
### Renal Impairment
A single dose study compared 6 subjects with severe renal impairment (creatinine clearance <30 mL/min), 4 end stage renal disease (ESRD) patients receiving tigecycline 2 hours before hemodialysis, 4 ESRD patients receiving tigecycline 1 hour after hemodialysis, and 6 healthy control subjects. The pharmacokinetic profile of tigecycline was not significantly altered in any of the renally impaired patient groups, nor was tigecycline removed by hemodialysis. No dosage adjustment of tigecycline is necessary in patients with renal impairment or in patients undergoing hemodialysis.
### Hepatic Impairment
No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response.
### Females of Reproductive Potential and Males
Tigecycline did not affect mating or fertility in rats at exposures up to 5 times the human daily dose based on AUC (28 mcg∙hr/mL at 12 mg/kg/day). In female rats, there were no compound-related effects on ovaries or estrous cycles at exposures up to 5 times the human daily dose based on AUC.
### Immunocompromised Patients
There is no FDA guidance one the use of Tigecycline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Tigecycline Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tigecycline and IV administrations.
# Overdosage
No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of tigecycline at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. In single-dose intravenous toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD50) was 124 mg/kg in males and 98 mg/kg in females. In rats, the estimated LD50 was 106 mg/kg for both sexes. Tigecycline is not removed in significant quantities by hemodialysis.
# Pharmacology
There is limited information regarding Tigecycline Pharmacology in the drug label.
## Mechanism of Action
Tigecycline, a glycylcycline, inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. This prevents incorporation of amino acid residues into elongating peptide chains. Tigecycline carries a glycylamido moiety attached to the 9-position of minocycline. The substitution pattern is not present in any naturally occurring or semisynthetic tetracycline and imparts certain microbiologic properties to tigecycline. In general, tigecycline is considered bacteriostatic; however, tigecycline has demonstrated bactericidal activity against isolates of S. pneumoniae and L. pneumophila.
## Structure
- The empirical formula is C29H39N5O8 and the molecular weight is 585.65.
- The following represents the chemical structure of tigecycline:
## Pharmacodynamics
No significant effect of a single intravenous dose of tigecycline 50 mg or 200 mg on QTc interval was detected in a randomized, placebo- and active-controlled four-arm crossover thorough QTc study of 46 healthy subjects.
## Pharmacokinetics
The mean pharmacokinetic parameters of tigecycline after single and multiple intravenous doses based on pooled data from clinical pharmacology studies are summarized in Table 3. Intravenous infusions of tigecycline were administered over approximately 30 to 60 minutes.
The in vitro plasma protein binding of tigecycline ranges from approximately 71% to 89% at concentrations observed in clinical studies (0.1 to 1.0 mcg/mL). The steady-state volume of distribution of tigecycline averaged 500 to 700 L (7 to 9 L/kg), indicating tigecycline is extensively distributed beyond the plasma volume and into the tissues.
Following the administration of tigecycline 100 mg followed by 50 mg every 12 hours to 33 healthy volunteers, the tigecycline AUC0–12h (134 mcg∙h/mL) in alveolar cells was approximately 78-fold higher than the AUC0–12h in the serum, and the AUC0–12h (2.28 mcg∙h/mL) in epithelial lining fluid was approximately 32% higher than the AUC0–12h in serum. The AUC0–12h (1.61 mcg∙h/mL) of tigecycline in skin blister fluid was approximately 26% lower than the AUC0–12h in the serum of 10 healthy subjects.
In a single-dose study, tigecycline 100 mg was administered to subjects prior to undergoing elective surgery or medical procedure for tissue extraction. Concentrations at 4 hours after tigecycline administration were higher in gallbladder (38-fold, n=6), lung (3.7-fold, n=5), and colon (2.3-fold, n=6), and lower in synovial fluid (0.58-fold, n=5), and bone (0.35-fold, n=6) relative to serum. The concentration of tigecycline in these tissues after multiple doses has not been studied.
Tigecycline is not extensively metabolized. In vitro studies with tigecycline using human liver microsomes, liver slices, and hepatocytes led to the formation of only trace amounts of metabolites. In healthy male volunteers receiving 14C-tigecycline, tigecycline was the primary 14C-labeled material recovered in urine and feces, but a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) were also present.
The recovery of total radioactivity in feces and urine following administration of 14C-tigecycline indicates that 59% of the dose is eliminated by biliary/fecal excretion, and 33% is excreted in urine. Approximately 22% of the total dose is excreted as unchanged tigecycline in urine. Overall, the primary route of elimination for tigecycline is biliary excretion of unchanged tigecycline and its metabolites. Glucuronidation and renal excretion of unchanged tigecycline are secondary routes.
## Nonclinical Toxicology
### Carcinogenesis and Mutagenesis
Lifetime studies in animals have not been performed to evaluate the carcinogenic potential of tigecycline. No mutagenic or clastogenic potential was found in a battery of tests, including in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, in vitro forward mutation assay in CHO cells (HGRPT locus), in vitro forward mutation assays in mouse lymphoma cells, and in vivo mouse micronucleus assay.
### Animal Toxicology and/or Pharmacology
In two week studies, decreased erythrocytes, reticulocytes, leukocytes, and platelets, in association with bone marrow hypocellularity, have been seen with tigecycline at exposures of 8 times and 10 times the human daily dose based on AUC in rats and dogs, (AUC of approximately 50 and 60 mcg∙hr/mL at doses of 30 and 12 mg/kg/day) respectively. These alterations were shown to be reversible after two weeks of dosing.
# Clinical Studies
### Complicated Skin and Skin Structure Infections
Tigecycline was evaluated in adults for the treatment of complicated skin and skin structure infections (cSSSI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 300 and 305). These studies compared tigecycline (100 mg intravenous initial dose followed by 50 mg every 12 hours) with vancomycin (1 g intravenous every 12 hours)/aztreonam (2 g intravenous every 12 hours) for 5 to 14 days. Patients with complicated deep soft tissue infections including wound infections and cellulitis (≥10 cm, requiring surgery/drainage or with complicated underlying disease), major abscesses, infected ulcers, and burns were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See TABLE 6. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 7.
### Complicated Intra-abdominal Infections
Tigecycline was evaluated in adults for the treatment of complicated intra-abdominal infections (cIAI) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 301 and 306). These studies compared tigecycline (100 mg intravenous initial dose followed by 50 mg every 12 hours) with imipenem/cilastatin (500 mg intravenous every 6 hours) for 5 to 14 days. Patients with complicated diagnoses including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, intra-abdominal abscess, perforation of intestine, and peritonitis were enrolled in the studies. The primary efficacy endpoint was the clinical response at the TOC visit for the co-primary populations of the microbiologically evaluable (ME) and the microbiologic modified intent-to-treat (m-mITT) patients. See TABLE 8. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 9.
### Community-Acquired Bacterial Pneumonia
Tigecycline was evaluated in adults for the treatment of community-acquired bacterial pneumonia (CABP) in two randomized, double-blind, active-controlled, multinational, multicenter studies (Studies 308 and 313). These studies compared tigecycline (100 mg intravenous initial dose followed by 50 mg every 12 hours) with levofloxacin (500 mg intravenous every 12 or 24 hours). In one study (Study 308), after at least 3 days of intravenous therapy, a switch to oral levofloxacin (500 mg daily) was permitted for both treatment arms. Total therapy was 7 to 14 days. Patients with community-acquired bacterial pneumonia who required hospitalization and intravenous therapy were enrolled in the studies. The primary efficacy endpoint was the clinical response at the test of cure (TOC) visit in the co-primary populations of the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) patients. See TABLE 10. Clinical cure rates at TOC by pathogen in the microbiologically evaluable patients are presented in Table 11.
To further evaluate the treatment effect of tigecycline, a post-hoc analysis was conducted in CABP patients with a higher risk of mortality, for whom the treatment effect of antibiotics is supported by historical evidence. The higher-risk group included CABP patients from the two studies with any of the following factors:
- Age ≥50 years
- PSI score ≥3
- Streptococcus pneumoniae bacteremia
The results of this analysis are shown in Table 12. Age ≥50 was the most common risk factor in the higher-risk group.
# How Supplied
Tigecycline for injection is supplied in:
- Single-dose 5 mL glass vial
- Single-dose 10 mL glass vial
Each containing 50 mg tigecycline lyophilized powder for reconstitution.
## Storage
Stored at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be counseled that antibacterial drugs including tigecycline should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When tigecycline is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by tigecycline or other antibacterial drugs in the future.
- Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.
# Precautions with Alcohol
Alcohol-Tigecycline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tygacil [1]
# Look-Alike Drug Names
There is limited information regarding Tigecycline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tigecycline | |
e3b80a255dc284555e228d42c4768fe05f842751 | wikidoc | Tiludronate | Tiludronate
# Overview
Tiludronic acid (INN; also known as tiludronate) is a bisphosphonate used for treatment of Paget's disease of bone (osteitis deformans) in human medicine. It has the tradename Skelid. In veterinary medicine, tiludronic acid is used to treat navicular disease and bone spavin in horses. Its tradenames are Tildren and Equidronate. It is approved for treatment of navicular disease and distal tarsal osteoarthritis in Europe, and was approved for treatment of navicular disease in the United States in 2014.
# Mechanism of action
Tiludronate is a non-nitrogenous bisphosphonate that inhibits osteoclasts, the primary cell responsible for the breakdown of bone required for bone remodeling. Non-nitrogenous bisphosphonates are metabolized by osteoclasts to compounds that then replace a portion of the adenosine triphosphate (ATP) molecule, making it non-functional. These non-functional molecules then competitively inhibit ATP in the cell, reducing cell energy and leading to apoptosis. Decreased levels of osteoclasts subsequently reduce the degree of breakdown of bone and bone turnover. Non-nitrogenous bisphosphonates are less potent relative to nitrogenous bisphosphonates.
# Use in equine medicine
Tiludronate has been used primarily for the treatment of diseases in horses that are associated with inappropriate osteolysis, such as navicular disease and osteoarthritis. It has specifically been shown to improve lameness in horses with osteoarthritis of the distal hock joints (bone spavin) and vertebral column.
## Method of administration
Tildren is administered intravenously. It is labeled for 0.1mg/kg dosing, once daily for 10 days by slow intravenous injection, which for a 500kg horse works out to be 1 vial per day. However, one study giving all 10 doses at once (1 mg/kg IV as a single CRI) was found to have the same pharmacological effects, and is used clinically. It may be given systemically or locally, by regional limb perfusion. Although RLP is thought to have certain benefits, including decreased cost and reduced risk of adverse effects, some diseases must be treated systemically, such as osteoarthritis of the vertebral column. Systemic administration is often given by adding a 1 mg/kg dose into a 1 liter fluid bag, which is slowly given over 60-90 minutes. Its effects are reported to last 4 months or longer, with a peak effect 6-8 weeks post treatment. The effects of regional limb perfusion has come into question due to in vitro studies showing that high doses given by RLP or intraarticular injection may damage articular cartilage by chondrocyte apoptosis. Further studies are needed to evaluate the safety of Tildren administration via RLP.
## Adverse reactions and contraindications
Tildren has been shown to have several adverse effects.
- Signs of colic, which is usually self-limiting, occurs in 30-45% of horses.
- Tachycardia
- Electrolyte disturbances: primarily calcium, magnesium, and potassium, which can last for several hours. Caution should be used in horses with disease processes that could be affected by electrolyte disturbances, such as hyperkalemic periodic paralysis or cardiac disease.
- Kidney damage: it is eliminated by the kidney and is not recommended for use in animals with impaired renal function.
- Less serious reactions include stiffness of the neck, decreased appetite, fever, and increased urination.
It is not recommended for under four years of age due to lack of studies evaluating its safety in growing animals, or pregnant or lactating animals since its affect on fetal one has not been studied. | Tiludronate
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tiludronic acid (INN; also known as tiludronate) is a bisphosphonate used for treatment of Paget's disease of bone (osteitis deformans) in human medicine. It has the tradename Skelid. In veterinary medicine, tiludronic acid is used to treat navicular disease and bone spavin in horses. Its tradenames are Tildren and Equidronate. It is approved for treatment of navicular disease and distal tarsal osteoarthritis in Europe,[1] and was approved for treatment of navicular disease in the United States in 2014.
# Mechanism of action
Tiludronate is a non-nitrogenous bisphosphonate that inhibits osteoclasts, the primary cell responsible for the breakdown of bone required for bone remodeling. Non-nitrogenous bisphosphonates are metabolized by osteoclasts to compounds that then replace a portion of the adenosine triphosphate (ATP) molecule, making it non-functional. These non-functional molecules then competitively inhibit ATP in the cell, reducing cell energy and leading to apoptosis.[2] Decreased levels of osteoclasts subsequently reduce the degree of breakdown of bone and bone turnover. Non-nitrogenous bisphosphonates are less potent relative to nitrogenous bisphosphonates.
# Use in equine medicine
Tiludronate has been used primarily for the treatment of diseases in horses that are associated with inappropriate osteolysis, such as navicular disease[3] and osteoarthritis. It has specifically been shown to improve lameness in horses with osteoarthritis of the distal hock joints (bone spavin)[4] and vertebral column.[5]
## Method of administration
Tildren is administered intravenously. It is labeled for 0.1mg/kg dosing, once daily for 10 days by slow intravenous injection, which for a 500kg horse works out to be 1 vial per day. However, one study giving all 10 doses at once (1 mg/kg IV as a single CRI) was found to have the same pharmacological effects, and is used clinically.[6] It may be given systemically or locally, by regional limb perfusion. Although RLP is thought to have certain benefits, including decreased cost and reduced risk of adverse effects, some diseases must be treated systemically, such as osteoarthritis of the vertebral column. Systemic administration is often given by adding a 1 mg/kg dose into a 1 liter fluid bag, which is slowly given over 60-90 minutes. Its effects are reported to last 4 months or longer, with a peak effect 6-8 weeks post treatment.[7] The effects of regional limb perfusion has come into question due to in vitro studies showing that high doses given by RLP or intraarticular injection may damage articular cartilage by chondrocyte apoptosis.[8] Further studies are needed to evaluate the safety of Tildren administration via RLP.
## Adverse reactions and contraindications
Tildren has been shown to have several adverse effects.[9]
- Signs of colic, which is usually self-limiting, occurs in 30-45% of horses.
- Tachycardia
- Electrolyte disturbances: primarily calcium, magnesium, and potassium, which can last for several hours. Caution should be used in horses with disease processes that could be affected by electrolyte disturbances, such as hyperkalemic periodic paralysis or cardiac disease.
- Kidney damage: it is eliminated by the kidney and is not recommended for use in animals with impaired renal function.
- Less serious reactions include stiffness of the neck, decreased appetite, fever, and increased urination.
It is not recommended for under four years of age due to lack of studies evaluating its safety in growing animals, or pregnant or lactating animals since its affect on fetal one has not been studied. | https://www.wikidoc.org/index.php/Tiludronate | |
e4b884e0ac2c270ea42e4d7c43f06987ce9081f7 | wikidoc | Time series | Time series
In statistics, signal processing, and many other fields, a time series is a sequence of data points, measured typically at successive times, spaced at (often uniform) time intervals. Time series analysis comprises methods that attempt to understand such time series, often either to understand the underlying context of the data points (where did they come from? what generated them?), or to make forecasts (predictions). Time series forecasting is the use of a model to forecast future events based on known past events: to forecast future data points before they are measured. A standard example in econometrics is the opening price of a share of stock based on its past performance.
The term time series analysis is used to distinguish a problem, firstly from more ordinary data analysis problems (where there is no natural ordering of the context of individual observations), and secondly from spatial data analysis where there is a context that observations (often) relate to geographical locations. There are additional possibilities in the form of space-time models (often called spatial-temporal analysis). A time series model will generally reflect the fact that observations close together in time will be more closely related than observations further apart. In addition, time series models will often make use of the natural one-way ordering of time so that values in a series for a given time will be expressed as deriving in some way from past values, rather than from future values (see time-reversibility.)
Methods for time series analyses are often divided into two classes: frequency-domain methods and time-domain methods. The former centre around spectral analysis and recently wavelet analysis, and can be regarded as model-free analyses well-suited to exploratory investigations. Time-domain methods have a model-free subset consisting of the examination of auto-correlation and cross-correlation analysis, but it is here that partly and fully-specified time series models make their appearance.
# Time Series Analyses
There are several types of data analysis available for time series which are appropriate for different purposes.
## General Exploration
- Graphical examination of data series
- Autocorrelation analysis to examine serial dependence
- Spectral analysis to examine cyclic behaviour which need not be related to seasonality
## Description
- Separation into components representing trend, seasonality, slow and fast variation, Cyclical irregular
- Simple properties of marginal distributions
## Prediction and Forecasting
- Fully-formed statistical models for stochastic simulation purposes, so as to generate alternative versions of the time series, representing what might happen over non-specfic time-periods in the future (prediction).
- Simple or fully-formed statistical models to describe the likely outcome of the time series in the immediate future, given knowledge of the most recent outcomes (forecasting).
# Time Series Models
As shown by Box and Jenkins in their 1976 book, Time Series Analysis: Forecasting and Control, models for time series data can have many forms and represent different stochastic processes. When modeling variations in the level of a process, three broad classes of practical importance are the autoregressive (AR) models, the integrated (I) models, and the moving average (MA) models (the MA process is related but not to be confused with the concept of moving average ). These three classes depend linearly on previous data points and are treated in more detail in the articles autoregressive moving average models (ARMA) and autoregressive integrated moving average (ARIMA). The autoregressive fractionally integrated moving average (ARFIMA) model generalizes the former three. Extensions of these classes to deal with vector-valued data are available under the heading of multivariate time-series models and sometimes the preceding acronyms are extended by including an initial "V" for "vector". An additional set of extensions of these models is available for use where the observed time-series is driven by some "forcing" time-series (which may not have a causal effect on the observed series): the distinction from the multivariate case is that the forcing series may be deterministic or under the experimenter's control. For these models, the acronyms are extended with a final "X" for "exogenous".
Non-linear dependence of the level of a series on previous data points is of interest, partly because of the possibility of producing a chaotic time series. However, more importantly, empirical investigations can indicate the advantage of using predictions derived from non-linear models, over those from linear models.
Among other types of non-linear time series models, there are models to represent the changes of variance along time (heteroskedasticity). These models are called autoregressive conditional heteroskedasticity (ARCH) and the collection comprises a wide variety of representation (GARCH, TARCH, EGARCH, FIGARCH, CGARCH, etc). Here changes in variability are related to, or predicted by, recent past values of the observed series. This is in contrast to other possible representations of locally-varying variability, where the variability might be modelled as being driven by a separate time-varying process, as in a doubly stochastic model.
In recent work on model-free analyses, wavelet transform based methods (for example locally stationary wavelets and wavelet decomposed neural networks) have gained favor. Multiscale (often referred to as multiresolution) techniques decompose a given time series, attempting to illustrate time dependence at multiple scales.
## Notation
A number of different notations are in use for time-series analysis:
is a common notation which specifies a time series X which is indexed by the natural numbers. Another common notation is:
## Conditions
There are two sets of conditions under which much of the theory is built:
- Stationary process
- Ergodicity
However, ideas of stationarity must be expanded to consider two important ideas: strict stationarity and second-order stationarity. Both models and applications can be developed under each of these conditions, although the models in the latter case might be considered as only partly specified.
In addition, time-series analysis can be applied where the series are seasonally stationary and non-stationary.
## Models
The general representation of an autoregressive model, well-known as AR(p), is
where the term εt is the source of randomness and is called white noise. It is assumed to have the following characteristics:
1. E=0 \,
2. E=\sigma^2 \,
3. E=0 \quad\forall t\not=s \,
With these assumptions, the process is specified up to second-order moments and, subject to conditions on the coefficients, may be second-order stationary.
If the noise also has a normal distribution, it is called normal white noise:
In this case the AR process may be strictly stationary, again subject to conditions on the coefficients.
# Related tools
Tools for investigating time-series data include:
- Consideration of the autocorrelation function and the spectral density function (also cross-correlation functions and cross-spectral density functions)
- Performing a Fourier transform to investigate the series in the frequency domain.
- Use of a filter to remove unwanted noise.
- Principal components analysis (or empirical orthogonal function analysis)
- Singular spectrum analysis
- Artificial neural networks
- time-frequency analysis techniques:
Continuous wavelet transform
Short-time Fourier transform
Chirplet transform
Fractional Fourier transform
- Continuous wavelet transform
- Short-time Fourier transform
- Chirplet transform
- Fractional Fourier transform
- Chaotic analysis
Correlation dimension
Recurrence plots
Recurrence quantification analysis
Lyapunov exponents
- Correlation dimension
- Recurrence plots
- Recurrence quantification analysis
- Lyapunov exponents | Time series
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
In statistics, signal processing, and many other fields, a time series is a sequence of data points, measured typically at successive times, spaced at (often uniform) time intervals. Time series analysis comprises methods that attempt to understand such time series, often either to understand the underlying context of the data points (where did they come from? what generated them?), or to make forecasts (predictions). Time series forecasting is the use of a model to forecast future events based on known past events: to forecast future data points before they are measured. A standard example in econometrics is the opening price of a share of stock based on its past performance.
The term time series analysis is used to distinguish a problem, firstly from more ordinary data analysis problems (where there is no natural ordering of the context of individual observations), and secondly from spatial data analysis where there is a context that observations (often) relate to geographical locations. There are additional possibilities in the form of space-time models (often called spatial-temporal analysis). A time series model will generally reflect the fact that observations close together in time will be more closely related than observations further apart. In addition, time series models will often make use of the natural one-way ordering of time so that values in a series for a given time will be expressed as deriving in some way from past values, rather than from future values (see time-reversibility.)
Methods for time series analyses are often divided into two classes: frequency-domain methods and time-domain methods. The former centre around spectral analysis and recently wavelet analysis, and can be regarded as model-free analyses well-suited to exploratory investigations. Time-domain methods have a model-free subset consisting of the examination of auto-correlation and cross-correlation analysis, but it is here that partly and fully-specified time series models make their appearance.
# Time Series Analyses
There are several types of data analysis available for time series which are appropriate for different purposes.
## General Exploration
- Graphical examination of data series
- Autocorrelation analysis to examine serial dependence
- Spectral analysis to examine cyclic behaviour which need not be related to seasonality
## Description
- Separation into components representing trend, seasonality, slow and fast variation, Cyclical irregular
- Simple properties of marginal distributions
## Prediction and Forecasting
- Fully-formed statistical models for stochastic simulation purposes, so as to generate alternative versions of the time series, representing what might happen over non-specfic time-periods in the future (prediction).
- Simple or fully-formed statistical models to describe the likely outcome of the time series in the immediate future, given knowledge of the most recent outcomes (forecasting).
# Time Series Models
As shown by Box and Jenkins in their 1976 book, Time Series Analysis: Forecasting and Control, models for time series data can have many forms and represent different stochastic processes. When modeling variations in the level of a process, three broad classes of practical importance are the autoregressive (AR) models, the integrated (I) models, and the moving average (MA) models (the MA process is related but not to be confused with the concept of moving average ). These three classes depend linearly on previous data points and are treated in more detail in the articles autoregressive moving average models (ARMA) and autoregressive integrated moving average (ARIMA). The autoregressive fractionally integrated moving average (ARFIMA) model generalizes the former three. Extensions of these classes to deal with vector-valued data are available under the heading of multivariate time-series models and sometimes the preceding acronyms are extended by including an initial "V" for "vector". An additional set of extensions of these models is available for use where the observed time-series is driven by some "forcing" time-series (which may not have a causal effect on the observed series): the distinction from the multivariate case is that the forcing series may be deterministic or under the experimenter's control. For these models, the acronyms are extended with a final "X" for "exogenous".
Non-linear dependence of the level of a series on previous data points is of interest, partly because of the possibility of producing a chaotic time series. However, more importantly, empirical investigations can indicate the advantage of using predictions derived from non-linear models, over those from linear models.
Among other types of non-linear time series models, there are models to represent the changes of variance along time (heteroskedasticity). These models are called autoregressive conditional heteroskedasticity (ARCH) and the collection comprises a wide variety of representation (GARCH, TARCH, EGARCH, FIGARCH, CGARCH, etc). Here changes in variability are related to, or predicted by, recent past values of the observed series. This is in contrast to other possible representations of locally-varying variability, where the variability might be modelled as being driven by a separate time-varying process, as in a doubly stochastic model.
In recent work on model-free analyses, wavelet transform based methods (for example locally stationary wavelets and wavelet decomposed neural networks) have gained favor. Multiscale (often referred to as multiresolution) techniques decompose a given time series, attempting to illustrate time dependence at multiple scales.
## Notation
A number of different notations are in use for time-series analysis:
is a common notation which specifies a time series X which is indexed by the natural numbers. Another common notation is:
## Conditions
There are two sets of conditions under which much of the theory is built:
- Stationary process
- Ergodicity
However, ideas of stationarity must be expanded to consider two important ideas: strict stationarity and second-order stationarity. Both models and applications can be developed under each of these conditions, although the models in the latter case might be considered as only partly specified.
In addition, time-series analysis can be applied where the series are seasonally stationary and non-stationary.
## Models
The general representation of an autoregressive model, well-known as AR(p), is
where the term εt is the source of randomness and is called white noise. It is assumed to have the following characteristics:
1. <math> E[\varepsilon_t]=0 \,</math>
2. <math> E[\varepsilon^2_t]=\sigma^2 \, </math>
3. <math> E[\varepsilon_t\varepsilon_s]=0 \quad\forall t\not=s \, </math>
With these assumptions, the process is specified up to second-order moments and, subject to conditions on the coefficients, may be second-order stationary.
If the noise also has a normal distribution, it is called normal white noise:
In this case the AR process may be strictly stationary, again subject to conditions on the coefficients.
# Related tools
Tools for investigating time-series data include:
- Consideration of the autocorrelation function and the spectral density function (also cross-correlation functions and cross-spectral density functions)
- Performing a Fourier transform to investigate the series in the frequency domain.
- Use of a filter to remove unwanted noise.
- Principal components analysis (or empirical orthogonal function analysis)
- Singular spectrum analysis
- Artificial neural networks
- time-frequency analysis techniques:
Continuous wavelet transform
Short-time Fourier transform
Chirplet transform
Fractional Fourier transform
- Continuous wavelet transform
- Short-time Fourier transform
- Chirplet transform
- Fractional Fourier transform
- Chaotic analysis
Correlation dimension
Recurrence plots
Recurrence quantification analysis
Lyapunov exponents
- Correlation dimension
- Recurrence plots
- Recurrence quantification analysis
- Lyapunov exponents | https://www.wikidoc.org/index.php/Time-series | |
3d1dd2aa05263ca02b78a726827005079a28825d | wikidoc | Tinea nigra | Tinea nigra
# Overview
Tinea nigra (also known as "superficial phaeohyphomycosis," and "Tinea nigra palmaris et plantaris") is a superficial fungal infection that causes dark brown to black painless patches on the palms of the hands and the soles of the feet.:311
# Causes
This infection is caused by the fungus formerly classified as Exophiala werneckii but more recently classified as Hortaea werneckii.
The causative organism has also been described as Phaeoannellomyces werneckii.
# Diagnosis
Diagnosis of tinea nigra causing fungus is made on microscopic examination of skin scrapings, mixed with potassium hydroxide (KOH). The KOH lyses the nonfungal debris.
## Physical Examination
### Skin
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
- Tinea nigra. Adapted from Dermatology Atlas.
# Differential diagnosis
Tinea nigra must be differentiated from other diseases presenting with an erythmatous, scaly, annular and pruritic rash. The differentials include the following:
# Treatment
Treatment consists of topical application of dandruff shampoo, which contains selenium sulfide, over the skin. Topical antifungal imidazoles may also be used, such as Ketoconazole. This is the same treatment plan for tinea or pityriasis versicolor. | Tinea nigra
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
# Overview
Tinea nigra (also known as "superficial phaeohyphomycosis,"[1] and "Tinea nigra palmaris et plantaris"[1]) is a superficial fungal infection that causes dark brown to black painless patches on the palms of the hands and the soles of the feet.[2]:311
# Causes
This infection is caused by the fungus formerly classified as Exophiala werneckii but more recently classified as Hortaea werneckii.[3]
The causative organism has also been described as Phaeoannellomyces werneckii.[4]
# Diagnosis
Diagnosis of tinea nigra causing fungus is made on microscopic examination of skin scrapings, mixed with potassium hydroxide (KOH).[5] The KOH lyses the nonfungal debris.[5]
## Physical Examination
### Skin
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
- Tinea nigra. Adapted from Dermatology Atlas.[6]
# Differential diagnosis
Tinea nigra must be differentiated from other diseases presenting with an erythmatous, scaly, annular and pruritic rash. The differentials include the following:
# Treatment
Treatment consists of topical application of dandruff shampoo, which contains selenium sulfide, over the skin. Topical antifungal imidazoles may also be used, such as Ketoconazole. This is the same treatment plan for tinea or pityriasis versicolor. | https://www.wikidoc.org/index.php/Tinea_nigra | |
6c947e76ed525d9cc530b7cda75c12dab4085f81 | wikidoc | Tioconazole | Tioconazole
# 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.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Tioconazole is a antifungal , anti-Infective agent and imidazole that is FDA approved for the treatment of Vaginal antifungal. Common adverse reactions include mild increase in vaginal burning, itching or irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Treats vaginal yeast infections
### DIRECTIONS
- before using this product read the enclosed brochure and instructions on foil packet for complete directions and information
- adults and children 12 years and over:
- open the foil packet just before use and remove purple cap
- insert entire contents of applicator into the vagina at bedtime. Throw applicator away after use.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tioconazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tioconazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Children under 12 years of age: ask a doctor
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tioconazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tioconazole in pediatric patients.
# Contraindications
There is limited information regarding Contraindications of Tioconazole in pediatric patients.
# Warnings
- For vaginal use only
- if you have never had a vaginal yeast infection diagnosed by a doctor
- do not use tampons, douches, spermicides, or other vaginal products. Condoms and diaphragms may be damaged and fail to prevent pregnancy or sexually transmitted disease (STDs).
- do not have vaginal intercourse
- mild increase in vaginal burning, itching or irritation may occur
- symptoms do not get better after 3 days
- symptoms last more than 7 days
- you get a rash or hives, abdominal pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge
- If swallowed, get medical help or contact a Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Tioconazole in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tioconazole in the drug label.
# Drug Interactions
There is limited information regarding Drug Interactions of Tioconazole in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- ask a health professional before use.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tioconazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tioconazole during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Tioconazole with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Tioconazole with respect to pediatric patients.
### Geriatic Use
- If swallowed, get medical help or contact a Poison Control Center right away.
### Gender
There is no FDA guidance on the use of Tioconazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tioconazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tioconazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tioconazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tioconazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tioconazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Tioconazole in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Tioconazole in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Tioconazole in the drug label.
# Pharmacology
## Mechanism of Action
## Structure
- butylated hydroxyanisole, magnesium aluminum silicate, white petrolatum
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Tioconazole in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Tioconazole in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Tioconazole in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Tioconazole in the drug label.
# How Supplied
There is limited information regarding Tioconazole How Supplied in the drug label.
## Storage
- Store at 20° - 25°C (68° - 77°F)
# Images
## Drug Images
## Package and Label Display Panel
Compare to 1-Day active ingredient
tioconazole 1
tioconozole ointment 6.5% - vaginal antifungal
1 dose vaginal treatment
ready-to-use prefilled applicator
cures most vaginal yeast infections
1 dose treatment
NET WT 4.6g (0.16 OZ) filled applicator
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Tioconazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
# Look-Alike Drug Names
There is limited information regarding Tioconazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tioconazole
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [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.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Tioconazole is a antifungal , anti-Infective agent and imidazole that is FDA approved for the treatment of Vaginal antifungal. Common adverse reactions include mild increase in vaginal burning, itching or irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Treats vaginal yeast infections
### DIRECTIONS
- before using this product read the enclosed brochure and instructions on foil packet for complete directions and information
- adults and children 12 years and over:
- open the foil packet just before use and remove purple cap
- insert entire contents of applicator into the vagina at bedtime. Throw applicator away after use.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tioconazole in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tioconazole in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Children under 12 years of age: ask a doctor
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tioconazole in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tioconazole in pediatric patients.
# Contraindications
There is limited information regarding Contraindications of Tioconazole in pediatric patients.
# Warnings
- For vaginal use only
- if you have never had a vaginal yeast infection diagnosed by a doctor
- do not use tampons, douches, spermicides, or other vaginal products. Condoms and diaphragms may be damaged and fail to prevent pregnancy or sexually transmitted disease (STDs).
- do not have vaginal intercourse
- mild increase in vaginal burning, itching or irritation may occur
- symptoms do not get better after 3 days
- symptoms last more than 7 days
- you get a rash or hives, abdominal pain, fever, chills, nausea, vomiting, or foul-smelling vaginal discharge
- If swallowed, get medical help or contact a Poison Control Center right away.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Tioconazole in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Tioconazole in the drug label.
# Drug Interactions
There is limited information regarding Drug Interactions of Tioconazole in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- ask a health professional before use.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tioconazole in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tioconazole during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Tioconazole with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Tioconazole with respect to pediatric patients.
### Geriatic Use
- If swallowed, get medical help or contact a Poison Control Center right away.
### Gender
There is no FDA guidance on the use of Tioconazole with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tioconazole with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tioconazole in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tioconazole in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tioconazole in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tioconazole in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Tioconazole in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Tioconazole in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Tioconazole in the drug label.
# Pharmacology
## Mechanism of Action
-
## Structure
- butylated hydroxyanisole, magnesium aluminum silicate, white petrolatum
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Tioconazole in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Tioconazole in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Tioconazole in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Tioconazole in the drug label.
# How Supplied
There is limited information regarding Tioconazole How Supplied in the drug label.
## Storage
- Store at 20° - 25°C (68° - 77°F)
# Images
## Drug Images
## Package and Label Display Panel
Compare to 1-Day active ingredient
tioconazole 1
tioconozole ointment 6.5% - vaginal antifungal
1 dose vaginal treatment
ready-to-use prefilled applicator
cures most vaginal yeast infections
1 dose treatment
NET WT 4.6g (0.16 OZ) filled applicator
# Patient Counseling Information
# Precautions with Alcohol
- Alcohol-Tioconazole interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- ®
# Look-Alike Drug Names
There is limited information regarding Tioconazole Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tioconazole | |
28a07340e0ac145d304e53f2c5641f7feaf1a7e5 | wikidoc | Tissue bank | Tissue bank
# Overview
A Tissue Bank, as used in this article, is a term most commonly used to describe an establishment that collects and harvests human cadaver tissue for the purposes of medical research and education.
A Tissue bank may also refer to a location where biomedical tissue is stored under cryogenic conditions, and is generally used in a more clinical sense. See Biomedical Tissue for more on this.
# Willed Body Donation
Most U.S. Tissue bank companies get their supply of cadaver tissue through Willed Body Donation programs run by the Tissue bank itself. They then charge their customers (mainly medical instrument companies) for services associated with preparation of the cadaver tissue (i.e. - tranportation, refrigeration, harvesting, etc.) rather than charging money for the donated tissue itself, which is illegal.
The American Association of Tissue Banks (AATB) is the most recognized accrediting body for American Tissue Banks.
- Many universities across the U.S. also offer tissue to surgical training facilities meant for medical research and education on cadaveric specimens. Most universities obtain this tissue through their own whole body donation programs. | Tissue bank
# Overview
A Tissue Bank, as used in this article, is a term most commonly used to describe an establishment that collects and harvests human cadaver tissue for the purposes of medical research and education.
A Tissue bank may also refer to a location where biomedical tissue is stored under cryogenic conditions, and is generally used in a more clinical sense. See Biomedical Tissue for more on this.
# Willed Body Donation
Most U.S. Tissue bank companies get their supply of cadaver tissue through Willed Body Donation programs run by the Tissue bank itself. They then charge their customers (mainly medical instrument companies) for services associated with preparation of the cadaver tissue (i.e. - tranportation, refrigeration, harvesting, etc.) rather than charging money for the donated tissue itself, which is illegal.
The American Association of Tissue Banks (AATB) is the most recognized accrediting body for American Tissue Banks.
- Many universities across the U.S. also offer tissue to surgical training facilities meant for medical research and education on cadaveric specimens. Most universities obtain this tissue through their own whole body donation programs.
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Tissue_bank | |
a6dd9a97eb2d24b87a27b3adbb5400fcfe08a06a | wikidoc | Tobacconist | Tobacconist
a tobacconist is an expert dealer in tobacco and the related accouterments.
Tobacco accouterments include pipes, pipe holders, pipe lighters, pipe reamers, pipe cleaners, pipe tampers, pipe pokers, pipe ashtrays, cigar bits, cigar cutters, cigar lighters, cigar holders, cigar cases, cigar ashtrays, cigar savors, humidification/humidifiers, humidors, hygrometers, cigarette holders, cigarette snuffers, matches, air ventilation and filtration, and more.
A tobacconist is someone licensed to sell tobacco in various forms as well as smoking supplies. A tobacconist may sell pipes, pipe-cleaning kits, cigars, etc.
# Uses in art
The Tobacconist, Victorian Walk is a featured exhibit at the Museum of London. It showcases shops in an effort to recreate the late 19th century.
mk:Тутунџија | Tobacconist
a tobacconist is an expert dealer in tobacco and the related accouterments.
Tobacco accouterments include pipes, pipe holders, pipe lighters, pipe reamers, pipe cleaners, pipe tampers, pipe pokers, pipe ashtrays, cigar bits, cigar cutters, cigar lighters, cigar holders, cigar cases, cigar ashtrays, cigar savors, humidification/humidifiers, humidors, hygrometers, cigarette holders, cigarette snuffers, matches, air ventilation and filtration, and more.
A tobacconist is someone licensed to sell tobacco in various forms as well as smoking supplies. A tobacconist may sell pipes, pipe-cleaning kits, cigars, etc.
# Uses in art
The Tobacconist, Victorian Walk is a featured exhibit at the Museum of London. It showcases shops in an effort to recreate the late 19th century.
Template:Job-stub
mk:Тутунџија
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Tobacconist | |
c9539aff3d16f6b133e6e56efeed7161cf921db7 | wikidoc | Tocilizumab | Tocilizumab
# 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
Tocilizumab is an interleukin-6 (IL-6) receptor antagonist that is FDA approved for the treatment of rheumatoid arthritis (RA), polyarticular juvenile idiopathic arthritis (PJIA), systemic juvenile idiopathic arthritis (SJIA). There is a Black Box Warning for this drug as shown here. Common adverse reactions include upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, injection site reactions.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tocilizumab may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection.
- Recommended Intravenous (IV) Dosage Regimen:
- The recommended dosage of Tocilizumab for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.
- Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Recommended Subcutaneous (SC) Dosage Regimen:
- Patients less than 100 kg weight - 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response
- Patients at or above 100 kg weight - 162 mg administered subcutaneously every week
- When transitioning from Tocilizumab intravenous therapy to subcutaneous administration administer the first subcutaneous dose instead of the next scheduled intravenous dose.
- Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Tocilizumab may be used alone or in combination with methotrexate. The recommended dosage of Tocilizumab for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:
- Recommended Intravenous PJIA Dosage Every 4 Weeks
- Patients less than 30 kg weight - 10 mg per kg
- Patients at or above 30 kg weight - 8 mg per kg
- Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.
- Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Subcutaneous administration is not approved for PJIA.
- Tocilizumab may be used alone or in combination with methotrexate. The recommended dose of Tocilizumab for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is:
- Recommended Intravenous SJIA Dosage Every 2 Weeks
- Patients less than 30 kg weight - 12 mg per kg
- Patients at or above 30 kg weight - 8 mg per kg
- Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.
- Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Subcutaneous administration is not approved for SJIA.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tocilizumab in adult patients.
### Non–Guideline-Supported Use
- Tocilizumab 8 mg/kg IV every 4 weeks.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Tocilizumab may be used alone or in combination with methotrexate. The recommended dosage of Tocilizumab for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:
- Recommended Intravenous PJIA Dosage Every 4 Weeks
- Patients less than 30 kg weight - 10 mg per kg
- Patients at or above 30 kg weight - 8 mg per kg
- Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.
- Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Subcutaneous administration is not approved for PJIA.
- Tocilizumab may be used alone or in combination with methotrexate. The recommended dose of Tocilizumab for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is:
- Recommended Intravenous SJIA Dosage Every 2 Weeks
- Patients less than 30 kg weight - 12 mg per kg
- Patients at or above 30 kg weight - 8 mg per kg
- Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.
- Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Subcutaneous administration is not approved for SJIA
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tocilizumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tocilizumab in pediatric patients.
# Contraindications
- Tocilizumab is contraindicated in patients with known hypersensitivity to Tocilizumab.
# Warnings
### Precautions
- Serious Infections
- Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including Tocilizumab for rheumatoid arthritis. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with Tocilizumab. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections.
- Do not administer Tocilizumab in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating Tocilizumab in patients:
with chronic or recurrent infection;
who have been exposed to tuberculosis;
with a history of serious or an opportunistic infection;
who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
with underlying conditions that may predispose them to infection.
- with chronic or recurrent infection;
- who have been exposed to tuberculosis;
- with a history of serious or an opportunistic infection;
- who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
- with underlying conditions that may predispose them to infection.
- Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Tocilizumab, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants.
- Hold Tocilizumab if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with Tocilizumab should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient.
- Tuberculosis
- Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating Tocilizumab.
- Consider anti-tuberculosis therapy prior to initiation of Tocilizumab in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
- Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
- It is recommended that patients be screened for latent tuberculosis infection prior to starting Tocilizumab. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating Tocilizumab.
- Viral Reactivation
- Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with Tocilizumab. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded.
- Gastrointestinal Perforations
- Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in RA patients. Use Tocilizumab with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation.
- Laboratory Parameters
- Rheumatoid Arthritis
- Neutropenia
- Treatment with Tocilizumab was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience.
- It is not recommended to initiate Tocilizumab treatment in patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm 3. In patients who develop an absolute neutrophil count less than 500 per mm 3 treatment is not recommended.
- Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on ANC results.
- Thrombocytopenia
- Treatment with Tocilizumab was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials.
- It is not recommended to initiate Tocilizumab treatment in patients with a platelet count below 100,000 per mm 3. In patients who develop a platelet count less than 50,000 per mm 3 treatment is not recommended.
- Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts.
- Elevated Liver Enzymes
- Treatment with Tocilizumab was associated with a higher incidence of transaminase elevations. These elevations did not result in apparent permanent or clinically evident hepatic injury in clinical trials. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with Tocilizumab.
- In one case, a patient who had received Tocilizumab 8 mg per kg monotherapy without elevations in transaminases experienced elevation in AST to above 10× ULN and elevation in ALT to above 16× ULN when MTX was initiated in combination with Tocilizumab. Transaminases normalized when both treatments were held, but elevations recurred when MTX and Tocilizumab were restarted at lower doses. Elevations resolved when MTX and Tocilizumab were discontinued.
- It is not recommended to initiate Tocilizumab treatment in patients with elevated transaminases ALT or AST greater than 1.5× ULN. In patients who develop elevated ALT or AST greater than 5× ULN treatment is not recommended.
- Monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, other liver function tests such as bilirubin should be considered. For recommended modifications based on transaminases.
- Lipid Abnormalities
- Treatment with Tocilizumab was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol.
- Assess lipid parameters approximately 4 to 8 weeks following initiation of Tocilizumab therapy, then at approximately 24 week intervals.
- Manage patients according to clinical guidelines for the management of hyperlipidemia.
- Polyarticular and Systemic Juvenile Idiopathic Arthritis
- A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with Tocilizumab treatment in the PJIA and SJIA populations. Monitor neutrophils, platelets, ALT and AST at the time of the second infusion and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Monitor lipids as above for RA.
- Immunosuppression
- The impact of treatment with Tocilizumab on the development of malignancies is not known but malignancies were observed in clinical studies. Tocilizumab is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.
- Hypersensitivity Reactions, Including Anaphylaxis
- Hypersensitivity reactions, including anaphylaxis, have been reported in association with Tocilizumab and anaphylactic events with a fatal outcome have been reported with intravenous infusion of Tocilizumab. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous Tocilizumab, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the subcutaneous all-exposure population. In the SJIA controlled trial with intravenous Tocilizumab, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous Tocilizumab, 0 out of 188 patients (0%) in the Tocilizumab all-exposure population experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria. Injection site reactions were categorized separately.
- In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous Tocilizumab, with or without concomitant arthritis therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of Tocilizumab. Tocilizumab for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. For Tocilizumab subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of Tocilizumab immediately and discontinue Tocilizumab permanently. Do not administer Tocilizumab to patients with known hypersensitivity to Tocilizumab.
- Demyelinating Disorders
- The impact of treatment with Tocilizumab on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of Tocilizumab in patients with preexisting or recent onset demyelinating disorders.
- Active Hepatic Disease and Hepatic Impairment
- Treatment with Tocilizumab is not recommended in patients with active hepatic disease or hepatic impairment.
- Vaccinations
- Avoid use of live vaccines concurrently with Tocilizumab as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Tocilizumab.
- No data are available on the effectiveness of vaccination in patients receiving Tocilizumab. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly PJIA and SJIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Tocilizumab therapy. The interval between live vaccinations and initiation of Tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
# 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 predict the rates observed in a broader patient population in clinical practice.
- The Tocilizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of Tocilizumab-IV 8 mg per kg monotherapy (288 patients), Tocilizumab-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or Tocilizumab-IV 4 mg per kg in combination with methotrexate (774 patients).
- The all exposure population includes all patients in registration studies who received at least one dose of Tocilizumab-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years.
- All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian.
- The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with Tocilizumab-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.
- The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking Tocilizumab-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of Tocilizumab-IV were increased hepatic transaminase values (per protocol requirement) and serious infections.
- Overall Infections
- In the 24 week, controlled clinical studies, the rate of infections in the Tocilizumab-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis.
- The overall rate of infections with Tocilizumab-IV in the all exposure population remained consistent with rates in the controlled periods of the studies.
- Serious Infections
- In the 24 week, controlled clinical studies, the rate of serious infections in the Tocilizumab-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.
- In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported.
- Gastrointestinal Perforations
- During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with Tocilizumab-IV therapy.
- In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate. The relative contribution of these concomitant medications versus Tocilizumab-IV to the development of GI perforations is not known.
- Infusion Reactions
- In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting.
- Anaphylaxis
- Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with Tocilizumab-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of Tocilizumab-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction.
- Laboratory Abnormalities
- Neutropenia
- In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm3 occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm3 and the occurrence of serious infections.
- In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies.
- Thrombocytopenia
- In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events.
- In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies.
- Elevated Liver Enzymes
- Liver enzyme abnormalities are summarized in TABLE 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of Tocilizumab-IV, or reduction in Tocilizumab-IV dose, resulted in decrease or normalization of liver enzymes. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency.
- Lipids
- Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of Tocilizumab-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below:
Mean LDL increased by 13 mg per dL in the Tocilizumab 4 mg per kg+DMARD arm, 20 mg per dL in the Tocilizumab 8 mg per kg+DMARD, and 25 mg per dL in Tocilizumab 8 mg per kg monotherapy.
Mean HDL increased by 3 mg per dL in the Tocilizumab 4 mg per kg+DMARD arm, 5 mg per dL in the Tocilizumab 8 mg per kg+DMARD, and 4 mg per dL in Tocilizumab 8 mg per kg monotherapy.
Mean LDL/HDL ratio increased by an average of 0.14 in the Tocilizumab 4 mg per kg+DMARD arm, 0.15 in the Tocilizumab 8 mg per kg+DMARD, and 0.26 in Tocilizumab 8 mg per kg monotherapy.
ApoB/ApoA1 ratios were essentially unchanged in Tocilizumab-treated patients.
Elevated lipids responded to lipid lowering agents.
- Mean LDL increased by 13 mg per dL in the Tocilizumab 4 mg per kg+DMARD arm, 20 mg per dL in the Tocilizumab 8 mg per kg+DMARD, and 25 mg per dL in Tocilizumab 8 mg per kg monotherapy.
- Mean HDL increased by 3 mg per dL in the Tocilizumab 4 mg per kg+DMARD arm, 5 mg per dL in the Tocilizumab 8 mg per kg+DMARD, and 4 mg per dL in Tocilizumab 8 mg per kg monotherapy.
- Mean LDL/HDL ratio increased by an average of 0.14 in the Tocilizumab 4 mg per kg+DMARD arm, 0.15 in the Tocilizumab 8 mg per kg+DMARD, and 0.26 in Tocilizumab 8 mg per kg monotherapy.
- ApoB/ApoA1 ratios were essentially unchanged in Tocilizumab-treated patients.
- Elevated lipids responded to lipid lowering agents.
- In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials.
- Immunogenicity
- In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies.
- The data reflect the percentage of patients whose test results were positive for antibodies to tocilizumab in specific assays. The observed incidence of 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 medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to tocilizumab with the incidence of antibodies to other products may be misleading.
- Malignancies
- During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving Tocilizumab-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the Tocilizumab-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years).
- In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period.
- Other Adverse Reactions
- Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg Tocilizumab-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in TABLE 2.
- Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with Tocilizumab-IV in controlled trials were:
Oral herpes simplex
Stomatitis, gastric ulcer
Weight increased, total bilirubin increased
Leukopenia
Peripheral edema
Dyspnea, cough
Conjunctivitis
Nephrolithiasis
Hypothyroidism
- The Tocilizumab-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously (SC) and 8 mg/kg intravenously (IV) every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week SC or placebo in 656 patients. All patients in both studies received background non-biologic DMARDs.
- The safety observed for Tocilizumab administered subcutaneously was consistent with the known safety profile of intravenous Tocilizumab, with the exception of injection site reactions, which were more common with Tocilizumab-SC compared with placebo SC injections (IV arm).
- Injection Site Reactions
- In the 6-month control period, in SC-I, the frequency of injection site reactions was 10.1% (64/631) and 2.4% (15/631) for the weekly Tocilizumab-SC and placebo SC (IV-arm) groups, respectively. In SC-II, the frequency of injection site reactions was 7.1% (31/437) and 4.1% (9/218) for the every other week SC Tocilizumab and placebo groups, respectively. These injection site reactions (including erythema, pruritus, pain and hematoma) were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation.
- Immunogenicity
- In the 6-month control period in SC-I, 0.8% (5/625) in the Tocilizumab-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed neutralizing antibodies. In SC-II, 1.6% (7/434) in the Tocilizumab-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti- tocilizumab antibodies; of these, 1.4% (6/434) in the Tocilizumab-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies.
- A total of 1454 (>99%) patients who received Tocilizumab-SC in the all exposure group have been tested for anti-tocilizumab antibodies. Thirteen patients (0.9%) developed anti-tocilizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies.
- The rate is consistent with previous intravenous experience. No correlation of antibody development to adverse events or loss of clinical response was observed.
- Laboratory Abnormalities
- Neutropenia
- During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% and 3.7% of patients receiving Tocilizumab-SC weekly and every other week, respectively.
- There was no clear relationship between decreases in neutrophils below 1 × 109/L and the occurrence of serious infections.
- Thrombocytopenia
- During routine laboratory monitoring in the Tocilizumab-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤50 × 103/mcL.
- Elevated Liver Enzymes
- During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥3 × ULN occurred in 6.5% and 1.4% of patients, respectively, receiving Tocilizumab-SC weekly and 3.4% and 0.7% receiving Tocilizumab SC every other week.
- Lipids
- During routine laboratory monitoring in the Tocilizumab-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving Tocilizumab-SC weekly, every other week and placebo, respectively.
- The safety of Tocilizumab-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the Tocilizumab-IV all exposure population (defined as patients who received at least one dose of Tocilizumab-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients.
- Infections
- The rate of infections in the Tocilizumab-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%).
- Infusion Reactions
- In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the Tocilizumab-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients.
- No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported.
- Immunogenicity
- One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.
- Laboratory Abnormalities
- Neutropenia
- During routine laboratory monitoring in the Tocilizumab-IV all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 3.7% of patients.
- There was no clear relationship between decreases in neutrophils below 1 × 109 per L and the occurrence of serious infections.
- Thrombocytopenia
- During routine laboratory monitoring in the Tocilizumab-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50 × 103 per mcL without associated bleeding events.
- Elevated Liver Enzymes
- During routine laboratory monitoring in the Tocilizumab-IV all exposure population, elevation in ALT or AST at or greater than 3 × ULN occurred in 4% and less than 1% of patients, respectively.
- Lipids
- During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 × ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 × ULN occurred in one patient (0.5%).
- The data described below reflect exposure to Tocilizumab-IV in one randomized, double-blind, placebo-controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy. At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with Tocilizumab-IV (8 or 12 mg per kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated with Tocilizumab-IV in the open-label extension phase.
- The most common adverse events (at least 5%) seen in Tocilizumab-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea.
- Infections
- In the 12 week controlled phase, the rate of all infections in the Tocilizumab-IV group was 345 per 100 patient-years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years.
- In the 12 week controlled phase, the rate of serious infections in the Tocilizumab-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media.
- Macrophage Activation Syndrome
- In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with Tocilizumab-IV. One patient in the placebo group escaped to Tocilizumab-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had Tocilizumab-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the Tocilizumab-IV SJIA clinical development experience; however no definitive conclusions can be made.
- Infusion Reactions
- Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of Tocilizumab-IV and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.
- Within 24 hours after infusion, 16% of patients in the Tocilizumab-IV treatment group and 5% of patients in the placebo group experienced an event. In the Tocilizumab-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.
- Anaphylaxis
- Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with Tocilizumab-IV during the controlled and open label extension study.
- Immunogenicity
- All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study.
- Laboratory Abnormalities
- Neutropenia
- During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 × 109 per L occurred in 7% of patients in the Tocilizumab-IV group, and in no patients in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the Tocilizumab-IV group. There was no clear relationship between decrease in neutrophils below 1 × 109 per L and the occurrence of serious infections.
- Thrombocytopenia
- During routine monitoring in the 12 week controlled phase, 1% of patients in the Tocilizumab-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100 × 103 per mcL.
- In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the Tocilizumab-IV group, with no associated bleeding.
- Elevated Liver Enzymes
- During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3× ULN occurred in 5% and 3% of patients, respectively in the Tocilizumab-IV group and in 0% of placebo patients.
- In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3× ULN occurred in 13% and 5% of Tocilizumab-IV treated patients, respectively.
- Lipids
- During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5× ULN – 2x ULN occurred in 1.5% of the Tocilizumab-IV group and in 0% of placebo patients. Elevation in LDL greater than 1.5× ULN – 2x ULN occurred in 1.9% of patients in the Tocilizumab-IV group and 0% of the placebo group.
- In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of intravenous Tocilizumab. 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.
- Fatal anaphylaxis
- Stevens-Johnson Syndrome
# Drug Interactions
- Other Drugs for Treatment of Rheumatoid Arthritis
- Population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance.
- Concomitant administration of a single intravenous dose of 10 mg per kg Tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.
- Tocilizumab has not been studied in combination with biological DMARDs such as TNF antagonists.
- Interactions with CYP450 Substrates
- Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effects on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of Tocilizumab, respectively. The effect of tocilizumab on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Tocilizumab, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering Tocilizumab with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.
- Live Vaccines
- Avoid use of live vaccines concurrently with Tocilizumab
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Pregnancy Exposure Registry
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Tocilizumab during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.
- Risk Summary
- Adequate and well-controlled studies with Tocilizumab have not been conducted in pregnant women. In animal reproduction studies, administration of tocilizumab to cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at dose exposures 1.25 times the human dose exposure of 8 mg per kg every 2 to 4 weeks. The incidence of malformations and pregnancy loss in human pregnancies has not been established for Tocilizumab. However, all pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. Tocilizumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Clinical Considerations
- In general, monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
- Animal Data
- An embryo-fetal developmental toxicity study was performed in which pregnant cynomolgus monkeys were treated intravenously with tocilizumab (daily doses of 2, 10, or 50 mg per kg from gestation day 20-50) during organogenesis. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at 10 mg per kg and 50 mg per kg doses (1.25 and 6.25 times the human dose of 8 mg per kg every 2 to 4 weeks based on a mg per kg comparison). Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg per kg intravenously with treatment every three days from implantation until day 21 after delivery (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tocilizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tocilizumab during labor and delivery.
### Nursing Mothers
- It is not known whether tocilizumab is present in human milk or if it would be absorbed systemically in a breastfed infant after ingestion. IgG is excreted in human milk and therefore it is expected that tocilizumab could be present in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Tocilizumab, 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
- Tocilizumab by intravenous use is indicated for the treatment of pediatric patients with:
- Active systemic juvenile idiopathic arthritis in patients 2 years of age and older
- Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older
- Safety and effectiveness of Tocilizumab in pediatric patients with conditions other than PJIA or SJIA have not been established. Children under the age of two have not been studied. SC administration has not been studied in pediatric patients. Testing of a murine analogue of tocilizumab did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.
### Geriatic Use
- Of the 2644 patients who received Tocilizumab in Studies I to V, a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. Of the 1069 patients who received Tocilizumab-SC in studies SC-I and SC-II there were 295 patients 65 years of age and older, including 41 patients 75 years and older. The frequency of serious infection among Tocilizumab treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
### Gender
There is no FDA guidance on the use of Tocilizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tocilizumab with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is required in patients with mild renal impairment. Tocilizumab has not been studied in patients with moderate to severe renal impairment.
### Hepatic Impairment
- The safety and efficacy of Tocilizumab have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tocilizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tocilizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Tocilizumab in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tocilizumab in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There are limited data available on overdoses with Tocilizumab. One case of accidental overdose was reported with intravenous Tocilizumab in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia.
### Management
- In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Tocilizumab in the drug label.
# Pharmacology
There is limited information regarding Tocilizumab Pharmacology in the drug label.
## Mechanism of Action
- Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis.
## Structure
- Tocilizumab (tocilizumab) is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. Tocilizumab has a molecular weight of approximately 148 kDa.
- Tocilizumab is supplied as a sterile, preservative-free solution for intravenous (IV) infusion at a concentration of 20 mg per mL. Tocilizumab is a colorless to pale yellow liquid, with a pH of about 6.5. Single-use vials are available for intravenous administration containing 80 mg per 4 mL, 200 mg per 10 mL, or 400 mg per 20 mL of Tocilizumab. Injectable solutions of Tocilizumab are formulated in an aqueous solution containing disodium phosphate dodecahydrate and sodium dihydrogen phosphate dehydrate (as a 15 mmol per L phosphate buffer), polysorbate 80 (0.5 mg per mL), and sucrose (50 mg per mL).
- Tocilizumab solution for subcutaneous administration is supplied as a sterile, colorless to yellowish, preservative-free liquid solution of approximately pH 6.0. It is supplied in a 1 mL ready-to-use, single-use prefilled syringe (PFS) with a needle safety device. Each device delivers 0.9 mL (162 mg) of Tocilizumab, in a histidine buffered solution composed of Tocilizumab (180 mg/mL), polysorbate 80, L-histidine and L-histidine monohydrochloride, L-arginine and L-arginine hydrochloride, L-methionine, and water for injection.
## Pharmacodynamics
- In clinical studies with the 4 mg per kg and 8 mg per kg IV doses or the 162 mg weekly and every other weekly SC doses of Tocilizumab, decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg Tocilizumab. Pharmacodynamic changes were also observed to occur after Tocilizumab administration in PJIA and SJIA patients (decreases in CRP, ESR, and increases in hemoglobin). The relationship between these pharmacodynamic findings and clinical efficacy is not known.
- In healthy subjects administered Tocilizumab in doses from 2 to 28 mg per kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to the nadir 3 to 5 days following Tocilizumab administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following Tocilizumab administration.
## Pharmacokinetics
- The pharmacokinetics characterized in healthy subjects and RA patients suggested that PK is similar between the two populations. The clearance (CL) of tocilizumab decreased with increased doses. At the 10 mg per kg single dose in RA patients, mean CL was 0.29 ± 0.10 mL per hr per kg and mean apparent terminal t1/2 was 151 ± 59 hours (6.3 days).
- The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis of 1793 rheumatoid arthritis patients treated with Tocilizumab 4 and 8 mg per kg every 4 weeks for 24 weeks.
- The pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional increase in area under the curve (AUC) and trough concentration (Cmin) was observed for doses of 4 and 8 mg per kg every 4 weeks. Maximum concentration (Cmax) increased dose-proportionally. At steady-state, estimated AUC and Cmin were 2.7 and 6.5-fold higher at 8 mg per kg as compared to 4 mg per kg, respectively. In a long-term study with dosing for 104 weeks, observed Cmin was sustained over time.
- For doses of Tocilizumab 4 mg per kg given every 4 weeks, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 13000 ± 5800 mcg∙h per mL, 1.49 ± 2.13 mcg per mL, and 88.3 ± 41.4 mcg per mL, respectively. The accumulation ratios for AUC and Cmax were 1.11 and 1.02, respectively. The accumulation ratio was higher for Cmin (1.96). Steady-state was reached following the first administration for Cmax and AUC, respectively, and after 16 weeks Cmin. For doses of Tocilizumab 8 mg per kg given every 4 weeks, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 35000 ± 15500 mcg∙h per mL, 9.74 ± 10.5 mcg per mL, and 183 ± 85.6 mcg per mL, respectively. The accumulation ratios for AUC and Cmax were 1.22 and 1.06, respectively. The accumulation ratio was higher for Cmin (2.35). Steady-state was reached following the first administration and after 8 and 20 weeks for Cmax, AUC, and Cmin, respectively. Tocilizumab AUC, Cmin and Cmax increased with increase of body weight. At body weight at or above 100 kg, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 55500 ± 14100 mcg∙h per mL, 19.0 ± 12.0 mcg per mL, and 269 ± 57 mcg per mL, respectively, which are higher than mean exposure values for the patient population. Therefore, Tocilizumab doses exceeding 800 mg per infusion are not recommended.
- The pharmacokinetics of tocilizumab was characterized using a population pharmacokinetic analysis using a database composed of 1759 rheumatoid arthritis patients treated with 162 mg SC every week, 162 mg SC every other week, and 8 mg/kg every 4 weeks for 24 weeks.
- The pharmacokinetic parameters of tocilizumab did not change with time. For the 162 mg every week dose, the estimated mean (±SD) steady-state AUC1week, Cmin and Cmax of tocilizumab were 8200 ± 3600 mcg∙h/mL, 44.6 ± 20.6 mcg/mL, and 50.9 ± 21.8 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 6.83, 6.37, and 5.47, respectively. Steady state was reached after 12 weeks for AUC, Cmin, and Cmax.
- For the 162 mg every other week dose, the estimated mean (±SD) steady-state AUC2week, Cmin, and Cmax of tocilizumab were 3200 ± 2700 mcg∙h/mL, 5.6 ± 7.0 mcg/mL, and 12.3 ± 8.7 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 2.67, 5.6, and 2.12, respectively. Steady state was reached after 12 weeks for AUC and Cmin, and after 10 weeks for Cmax.
- The pharmacokinetics of tocilizumab was determined using a population pharmacokinetic analysis on a database composed of 188 patients with polyarticular juvenile idiopathic arthritis.
- For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks, the estimated mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 29500 ± 8660 mcg∙hr/mL, 182 ± 37 mcg/mL and 7.49 ± 8.2 mcg/mL, respectively.
- For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks, the estimated mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 23200 ± 6100 mcg∙hr/mL, 175 ± 32 mcg/mL and 2.35 ± 3.59 mcg/mL, respectively.
- The accumulation ratios were 1.05 and 1.16 for AUC4weeks, and 1.43 and 2.22 for Cmin for 10 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) doses, respectively. No accumulation for Cmax was observed.
- The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 75 patients with SJIA treated with 8 mg per kg (patients with a body weight at or above 30 kg) or 12 mg per kg (patients with a body weight less than 30 kg), given every 2 weeks. The estimated mean (± SD) AUC2 weeks, Cmax and Cmin of tocilizumab were 32200 ± 9960 mcg∙hr per mL, 245 ± 57.2 mcg per mL and 57.5 ± 23.3 mcg per mL, respectively. The accumulation ratio for Cmin (week 12 over week 2) was 3.2 ± 1.3. Steady state was reached on or after week 12. Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight.
- Absorption
- Following SC dosing in rheumatoid arthritis patients, the absorption half-life was around 4 days. The bioavailability for the SC formulation was 0.8.
- Distribution
- Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.
- In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L.
- In pediatric patients with SJIA, the central volume of distribution was 0.94 L, the peripheral volume of distribution was 1.60 L resulting in a volume of distribution at steady state of 2.54 L.
- Elimination
- The total clearance of tocilizumab is concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA, 5.8 mL per h in pediatric patients with PJIA, and 7.1 mL per h in pediatric patients with SJIA. The concentration-dependent nonlinear clearance plays a major role at low tocilizumab concentrations. Once the nonlinear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.
- The t1/2 of tocilizumab is concentration-dependent. For IV administration, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For SC administration, the concentration-dependent apparent t1/2 is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state.
- The t1/2 of tocilizumab in children with PJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg or 10 mg/kg for body weight less than 30 kg) during a dosing interval at steady state.
- The t1/2 of tocilizumab in pediatric patients with SJIA is up to 23 days for the two body weight categories at week 12.
- Pharmacokinetics in Special Populations
- Population pharmacokinetic analyses in adult rheumatoid arthritis patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. The body weight-based dose (8 mg per kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg. There was an inverse relationship between tocilizumab exposure and body weight for flat dose SC regimens.
- Hepatic Impairment
- No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted.
- Renal Impairment
- No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted.
- Most of the RA patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (creatinine clearance less than 80 mL per min and at or above 50 mL per min based on Cockcroft-Gault) did not impact the pharmacokinetics of tocilizumab. No dose adjustment is required in patients with mild renal impairment.
- Drug Interactions
- In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of Tocilizumab, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when Tocilizumab is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates).
- Simvastatin
- Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with Tocilizumab, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of Tocilizumab (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of Tocilizumab in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of Tocilizumab (due to normalization of CYP3A4) or higher exposures after discontinuation of Tocilizumab.
- Omeprazole
- Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after Tocilizumab infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects.
- Dextromethorphan
- Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of Tocilizumab (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after Tocilizumab infusion.
## Nonclinical Toxicology
- Carcinogenesis
- No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab.
- Impairment of Fertility
- Fertility studies conducted in male and female mice using a murine analogue of tocilizumab administered by the intravenous route at a dose of 50 mg/kg every three days showed no impairment of fertility.
# Clinical Studies
- The efficacy and safety of intravenously administered Tocilizumab was assessed in five randomized, double-blind, multicenter studies in patients greater than 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. Tocilizumab was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V).
- Study I evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 24 weeks prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response. In this study, 67% of patients were MTX-naïve, and over 40% of patients had rheumatoid arthritis less than 2 years. Patients received Tocilizumab 8 mg per kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of Tocilizumab patients who achieved an ACR 20 response at Week 24.
- Study II was a 104-week study with an ongoing optional 156-week extension phase that evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received Tocilizumab 8 mg per kg, Tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). Upon completion of 52-weeks, patients received open-label treatment with Tocilizumab 8 mg per kg through 104 weeks or they had the option to continue their double-blind treatment if they maintained a greater than 70% improvement in swollen/tender joint count. Two pre-specified interim analyses at week 24 and week 52 were conducted. The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At weeks 52 and 104, the primary endpoints were change from baseline in modified total Sharp-Genant score and the area under the curve (AUC) of the change from baseline in HAQ-DI score.
- Study III evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received Tocilizumab 8 mg per kg, Tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24.
- Study IV evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received Tocilizumab 8 mg per kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24.
- Study V evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization. Patients received Tocilizumab 8 mg per kg, Tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20response at week 24.
- Clinical Response
- The percentages of intravenous Tocilizumab-treated patients achieving ACR 20, 50 and 70 responses are shown in TABLE 3. In all intravenous studies, patients treated with 8 mg per kg Tocilizumab had higher ACR 20, ACR 50, and ACR 70 response rates versus MTX- or placebo-treated patients at week 24.
- During the 24 week controlled portions of Studies I to V, patients treated with Tocilizumab at a dose of 4 mg per kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with Tocilizumab 8 mg per kg.
- In study II, a greater proportion of patients treated with 4 mg per kg and 8 mg per kg Tocilizumab + MTX achieved a low level of disease activity as measured by a DAS 28-ESR less than 2.6 compared with placebo +MTX treated patients at week 52. The proportion of Tocilizumab-treated patients achieving DAS 28-ESR less than 2.6, and the number of residual active joints in these responders in Study II are shown in TABLE 4.
- The results of the components of the ACR response criteria for Studies III and V are shown in TABLE 5. Similar results to Study III were observed in Studies I, II and IV.
- The percent of ACR 20 responders by visit for Study III is shown in FIGURE 1. Similar response curves were observed in studies I, II, IV, and V.
- Radiographic Response
- In Study II, structural joint damage was assessed radiographically and expressed as change in total Sharp-Genant score and its components, the erosion score and joint space narrowing score. Radiographs of hands/wrists and forefeet were obtained at baseline, 24 weeks, 52 weeks, and 104 weeks and scored by readers unaware of treatments group and visit number. The results from baseline to week 52 are shown in TABLE 6. Tocilizumab 4 mg per kg slowed (less than 75% inhibition compared to the control group) and Tocilizumab 8 mg per kg inhibited (at least 75% inhibition compared to the control group) the progression of structural damage compared to placebo plus MTX at week 52.
- The mean change from baseline to week 104 in Total Sharp-Genant Score for the Tocilizumab 4 mg per kg groups was 0.47 (SD = 1.47) and for the 8 mg per kg groups was 0.34 (SD = 1.24). By the week 104, most patients in the control (placebo + MTX) group had crossed over to active treatment, and results are therefore not included for comparison. Patients in the active groups may have crossed over to the alternate active dose group, and results are reported per original randomized dose group.
- In the placebo group, 66% of patients experienced no radiographic progression (Total Sharp-Genant Score change ≤ 0) at week 52 compared to 78% and 83% in the Tocilizumab 4 mg per kg and 8 mg per kg, respectively. Following 104 weeks of treatment, 75% and 83% of patients initially randomized to Tocilizumab 4 mg per kg and 8 mg per kg, respectively, experienced no progression of structural damage compared to 66% of placebo treated patients.
- Health Related Outcomes
- In Study II, physical function and disability were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI). Both dosing groups of Tocilizumab demonstrated a greater improvement compared to the placebo group in the AUC of change from baseline in the HAQ-DI through week 52. The mean change from baseline to week 52 in HAQ-DI was 0.6, 0.5, and 0.4 for Tocilizumab 8 mg per kg, Tocilizumab 4 mg per kg, and placebo treatment groups, respectively. Sixty-three percent (63%) and sixty percent (60%) of patients in the Tocilizumab 8 mg per kg and Tocilizumab 4 mg per kg treatment groups, respectively, achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) at week 52 compared to 53% in the placebo treatment group.
- The efficacy and safety of subcutaneously administered Tocilizumab was assessed in two double-blind, controlled, multicenter studies in patients with active RA. One study (SC-I) was a non-inferiority study that compared the efficacy and safety of Tocilizumab 162 mg administered every week subcutaneously (SC) to 8 mg per kg intravenously every four weeks. The second study (SC-II) was a placebo controlled superiority study that evaluated the safety and efficacy of Tocilizumab 162 mg administered every other week SC to placebo. Both SC-I and SC-II required patients to be >18 years of age with moderate to severe active rheumatoid arthritis diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline (SC-I) or at least 8 tender and 6 swollen joints at baseline (SC-II), and an inadequate response to their existing DMARD therapy, where approximately 20% also had a history of inadequate response to at least one TNF inhibitor. All patients in both SC studies received background non-biologic DMARD(s).
- In SC-I, 1262 patients were randomized 1:1 to receive Tocilizumab SC 162 mg every week or Tocilizumab intravenous 8 mg/kg every four weeks in combination with DMARD(s). In SC-II, 656 patients were randomized 2:1 to Tocilizumab SC 162 mg every other week or placebo, in combination with DMARD(s). The primary endpoint in both studies was the proportion of patients who achieved an ACR20 response at Week 24.
- The clinical response to 24 weeks of Tocilizumab SC therapy is shown in TABLE 7. In SC-I, the primary outcome measure was ACR20 at Week 24. The pre-specified non-inferiority margin was a treatment difference of 12%. The study demonstrated non-inferiority of Tocilizumab with respect to ACR20 at Week 24; ACR50, ACR70, and DAS28 responses are also shown in TABLE 7. In SC-II, a greater portion of patients treated with Tocilizumab 162 mg SC every other week achieved ACR20, ACR50, and ACR70 responses compared to placebo-treated patients (TABLE 7). Further, a greater proportion of patients treated with Tocilizumab 162 mg SC every other week achieved a low level of disease activity as measured by a DAS28-ESR less than 2.6 at Week 24 compared to those treated with placebo (TABLE 7).
- The results of the components of the ACR response criteria and the percent of ACR20 responders by visit for Tocilizumab-SC in Studies SC-I and SC-II were consistent with those observed for Tocilizumab-IV.
- Radiographic Response
- In study SC-II, the progression of structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde modified total Sharp score (mTSS). At week 24, significantly less radiographic progression was observed in patients receiving Tocilizumab SC every other week plus DMARD(s) compared to placebo plus DMARD(s); mean change from baseline in mTSS of 0.62 vs. 1.23, respectively, with an adjusted mean difference of -0.60 (-1.1, -0.1). These results are consistent with those observed in patients treated with intravenous Tocilizumab.
- Health Related Outcomes
- In studies SC-I and SC-II, the mean decrease from baseline to week 24 in HAQ-DI was 0.6, 0.6, 0.4 and 0.3, and the proportion of patients who achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) was 65%, 67%, 58% and 47%, for the SC every week, IV 8 mg/kg, SC every other week, and placebo treatment groups, respectively.
- The efficacy of Tocilizumab was assessed in a three-part study including an open-label extension in children 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis (PJIA), who had an inadequate response to methotrexate or inability to tolerate methotrexate. Patients had at least 6 months of active disease (mean disease duration of 4.2 ± 3.7 years), with at least five joints with active arthritis (swollen or limitation of movement accompanied by pain and/or tenderness) and/or at least 3 active joints having limitation of motion (mean, 20 ± 14 active joints). The patients treated had subtypes of JIA that at disease onset included Rheumatoid Factor Positive or Negative Polyarticular JIA, or Extended Oligoarticular JIA. Treatment with a stable dose of methotrexate was permitted but was not required during the study. Concurrent use of disease modifying antirheumatic drugs (DMARDs), other than methotrexate, or other biologics (e.g., TNF antagonists or T cell costimulation modulator) were not permitted in the study.
- Part I consisted of a 16-week active Tocilizumab treatment lead-in period (n=188) followed by Part II, a 24-week randomized double-blind placebo-controlled withdrawal period, followed by Part III, a 64-week open-label period. Eligible patients weighing at or above 30 kg received Tocilizumab at 8 mg/kg IV once every four weeks. Patients weighing less than 30 kg were randomized 1:1 to receive either Tocilizumab 8 mg/kg or 10 mg/kg IV every four weeks. At the conclusion of the open-label Part I, 91% of patients taking background MTX in addition to tocilizumab and 83% of patients on tocilizumab monotherapy achieved an ACR 30 response at week 16 compared to baseline and entered the blinded withdrawal period (Part II) of the study. The proportions of patients with JIA ACR 50/70 responses in Part I were 84.0%, and 64%, respectively for patients taking background MTX in addition to tocilizumab and 80% and 55% respectively for patients on tocilizumab monotherapy.
- In Part II, patients (ITT, n=163) were randomized to Tocilizumab (same dose received in Part I) or placebo in a 1:1 ratio that was stratified by concurrent methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR 30 flare criteria (relative to Week 16) and qualified for escape.
- The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative to week 16. JIA ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to Week 16.
- Tocilizumab treated patients experienced significantly fewer disease flares compared to placebo-treated patients (26% versus 48% ; adjusted difference in proportions -21%, 95% CI: -35%, -8%).
- During the withdrawal phase (Part II), more patients treated with Tocilizumab showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo.
- The efficacy of Tocilizumab for the treatment of active SJIA was assessed in a 12-week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (Tocilizumab:placebo = 2:1) to one of two treatment groups: 75 patients received Tocilizumab infusions every two weeks at either 8 mg per kg for patients at or above 30 kg or 12 mg per kg for patients less than 30 kg and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR 70 response. After 12 weeks or at the time of escape, due to disease worsening, patients were treated with Tocilizumab in the open-label extension phase at weight appropriate dosing.
- The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR 30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding 7 days). JIA ACR (American College of Rheumatology) responses are defined as the percentage improvement (e.g., 30%, 50%, 70%) in 3 of any 6 core outcome variables compared to baseline, with worsening in no more than 1 of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (childhood health assessment questionnaire-CHAQ).
- Primary endpoint result and JIA ACR response rates at Week 12 are shown in TABLE 8.
- The treatment effect of Tocilizumab was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks).
- Systemic Features
- Of patients with fever or rash at baseline, those treated with Tocilizumab had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated patients. Responses were consistent in the open label extension (data available through 44 weeks).
- Corticosteroid Tapering
- Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), Tocilizumab patients achieved a JIA ACR 70 response at week 6 or 8 enabling corticosteroid dose reduction. Seventeen (24%) Tocilizumab patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) Tocilizumab patients off oral corticosteroids. Of these 44 patients 50% were off corticosteroids 18 weeks or more.
- Health Related Outcomes
- Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of patients in the Tocilizumab treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of ≥ 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group.
# How Supplied
- For Intravenous Infusion
- Tocilizumab (tocilizumab) is supplied in single-use vials as a preservative-free, sterile concentrate (20 mg per mL) solution for intravenous infusion. The following packaging configurations are available:
- Individually packaged, single-use vials:
- NDC 50242-135-01 providing 80 mg per 4 mL
- NDC 50242-136-01 providing 200 mg per 10 mL
- NDC 50242-137-01 providing 400 mg per 20 mL
- For Subcutaneous Injection
- Tocilizumab (tocilizumab) for subcutaneous administration is supplied as a sterile preservative-free liquid solution in a single-use prefilled syringe. The following packaging configurations are available:
- NDC 50242-138-01 prefilled syringe providing 162 mg per 0.9mL
- Storage and Stability: Do not use beyond expiration date on the container, package or prefilled syringe. Tocilizumab must be refrigerated at 2ºC to 8ºC (36°F to 46°F). Do not freeze. Protect the vials and syringes from light by storage in the original package until time of use, and keep syringes dry. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particles are observed, the solution should not be used.
## Storage
There is limited information regarding Tocilizumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients and parents or guardians of minors with PJIA or SJIA of the potential benefits and risks of Tocilizumab. Physicians should instruct their patients to read the Medication Guide before starting Tocilizumab therapy.
- Infections:
- Inform patients that Tocilizumab may lower their resistance to infections. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment.
- Gastrointestinal Perforation:
- Inform patients that some patients who have been treated with Tocilizumab have had serious side effects in the stomach and intestines. Instruct the patient of the importance of contacting their doctor immediately when symptoms of severe, persistent abdominal pain appear to assure rapid evaluation and appropriate treatment.
- Hypersensitivity and Serious Allergic Reactions
- Assess patient suitability for home use for SC injection. Inform patients that some patients who have been treated with Tocilizumab have developed serious allergic reactions, including anaphylaxis. Advise patients to seek immediate medical attention if they experience any symptom of serious allergic reactions.
- Instruction on Injection Technique
- Perform the first injection under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer subcutaneous Tocilizumab, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous Tocilizumab and the suitability for home use .
- Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes, out of the reach of children. Do not warm Tocilizumab in any other way.
- Advise patients to consult their healthcare provider if the full dose is not received.
- A puncture-resistant container for disposal of needles and syringes should be used and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper syringe and needle disposal, and caution against reuse of these items.
# Precautions with Alcohol
- Alcohol-Tocilizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tocilizumab®
# Look-Alike Drug Names
There is limited information regarding Tocilizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tocilizumab
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.
# Black Box Warning
# Overview
Tocilizumab is an interleukin-6 (IL-6) receptor antagonist that is FDA approved for the treatment of rheumatoid arthritis (RA), polyarticular juvenile idiopathic arthritis (PJIA), systemic juvenile idiopathic arthritis (SJIA). There is a Black Box Warning for this drug as shown here. Common adverse reactions include upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, injection site reactions.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tocilizumab may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection.
- Recommended Intravenous (IV) Dosage Regimen:
- The recommended dosage of Tocilizumab for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.
- Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Recommended Subcutaneous (SC) Dosage Regimen:
- Patients less than 100 kg weight - 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response
- Patients at or above 100 kg weight - 162 mg administered subcutaneously every week
- When transitioning from Tocilizumab intravenous therapy to subcutaneous administration administer the first subcutaneous dose instead of the next scheduled intravenous dose.
- Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Tocilizumab may be used alone or in combination with methotrexate. The recommended dosage of Tocilizumab for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:
- Recommended Intravenous PJIA Dosage Every 4 Weeks
- Patients less than 30 kg weight - 10 mg per kg
- Patients at or above 30 kg weight - 8 mg per kg
- Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.
- Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Subcutaneous administration is not approved for PJIA.
- Tocilizumab may be used alone or in combination with methotrexate. The recommended dose of Tocilizumab for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is:
- Recommended Intravenous SJIA Dosage Every 2 Weeks
- Patients less than 30 kg weight - 12 mg per kg
- Patients at or above 30 kg weight - 8 mg per kg
- Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.
- Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Subcutaneous administration is not approved for SJIA.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tocilizumab in adult patients.
### Non–Guideline-Supported Use
- Tocilizumab 8 mg/kg IV every 4 weeks.[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Tocilizumab may be used alone or in combination with methotrexate. The recommended dosage of Tocilizumab for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:
- Recommended Intravenous PJIA Dosage Every 4 Weeks
- Patients less than 30 kg weight - 10 mg per kg
- Patients at or above 30 kg weight - 8 mg per kg
- Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.
- Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Subcutaneous administration is not approved for PJIA.
- Tocilizumab may be used alone or in combination with methotrexate. The recommended dose of Tocilizumab for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is:
- Recommended Intravenous SJIA Dosage Every 2 Weeks
- Patients less than 30 kg weight - 12 mg per kg
- Patients at or above 30 kg weight - 8 mg per kg
- Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.
- Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
- Subcutaneous administration is not approved for SJIA
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tocilizumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tocilizumab in pediatric patients.
# Contraindications
- Tocilizumab is contraindicated in patients with known hypersensitivity to Tocilizumab.
# Warnings
### Precautions
- Serious Infections
- Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including Tocilizumab for rheumatoid arthritis. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with Tocilizumab. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections.
- Do not administer Tocilizumab in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating Tocilizumab in patients:
with chronic or recurrent infection;
who have been exposed to tuberculosis;
with a history of serious or an opportunistic infection;
who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
with underlying conditions that may predispose them to infection.
- with chronic or recurrent infection;
- who have been exposed to tuberculosis;
- with a history of serious or an opportunistic infection;
- who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
- with underlying conditions that may predispose them to infection.
- Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Tocilizumab, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants.
- Hold Tocilizumab if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with Tocilizumab should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient.
- Tuberculosis
- Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating Tocilizumab.
- Consider anti-tuberculosis therapy prior to initiation of Tocilizumab in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
- Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
- It is recommended that patients be screened for latent tuberculosis infection prior to starting Tocilizumab. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating Tocilizumab.
- Viral Reactivation
- Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with Tocilizumab. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded.
- Gastrointestinal Perforations
- Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in RA patients. Use Tocilizumab with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation.
- Laboratory Parameters
- Rheumatoid Arthritis
- Neutropenia
- Treatment with Tocilizumab was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience.
- It is not recommended to initiate Tocilizumab treatment in patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm 3. In patients who develop an absolute neutrophil count less than 500 per mm 3 treatment is not recommended.
- Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on ANC results.
- Thrombocytopenia
- Treatment with Tocilizumab was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials.
- It is not recommended to initiate Tocilizumab treatment in patients with a platelet count below 100,000 per mm 3. In patients who develop a platelet count less than 50,000 per mm 3 treatment is not recommended.
- Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts.
- Elevated Liver Enzymes
- Treatment with Tocilizumab was associated with a higher incidence of transaminase elevations. These elevations did not result in apparent permanent or clinically evident hepatic injury in clinical trials. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with Tocilizumab.
- In one case, a patient who had received Tocilizumab 8 mg per kg monotherapy without elevations in transaminases experienced elevation in AST to above 10× ULN and elevation in ALT to above 16× ULN when MTX was initiated in combination with Tocilizumab. Transaminases normalized when both treatments were held, but elevations recurred when MTX and Tocilizumab were restarted at lower doses. Elevations resolved when MTX and Tocilizumab were discontinued.
- It is not recommended to initiate Tocilizumab treatment in patients with elevated transaminases ALT or AST greater than 1.5× ULN. In patients who develop elevated ALT or AST greater than 5× ULN treatment is not recommended.
- Monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, other liver function tests such as bilirubin should be considered. For recommended modifications based on transaminases.
- Lipid Abnormalities
- Treatment with Tocilizumab was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol.
- Assess lipid parameters approximately 4 to 8 weeks following initiation of Tocilizumab therapy, then at approximately 24 week intervals.
- Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.
- Polyarticular and Systemic Juvenile Idiopathic Arthritis
- A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with Tocilizumab treatment in the PJIA and SJIA populations. Monitor neutrophils, platelets, ALT and AST at the time of the second infusion and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Monitor lipids as above for RA.
- Immunosuppression
- The impact of treatment with Tocilizumab on the development of malignancies is not known but malignancies were observed in clinical studies. Tocilizumab is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.
- Hypersensitivity Reactions, Including Anaphylaxis
- Hypersensitivity reactions, including anaphylaxis, have been reported in association with Tocilizumab and anaphylactic events with a fatal outcome have been reported with intravenous infusion of Tocilizumab. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous Tocilizumab, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the subcutaneous all-exposure population. In the SJIA controlled trial with intravenous Tocilizumab, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous Tocilizumab, 0 out of 188 patients (0%) in the Tocilizumab all-exposure population experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria. Injection site reactions were categorized separately.
- In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous Tocilizumab, with or without concomitant arthritis therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of Tocilizumab. Tocilizumab for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. For Tocilizumab subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of Tocilizumab immediately and discontinue Tocilizumab permanently. Do not administer Tocilizumab to patients with known hypersensitivity to Tocilizumab.
- Demyelinating Disorders
- The impact of treatment with Tocilizumab on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of Tocilizumab in patients with preexisting or recent onset demyelinating disorders.
- Active Hepatic Disease and Hepatic Impairment
- Treatment with Tocilizumab is not recommended in patients with active hepatic disease or hepatic impairment.
- Vaccinations
- Avoid use of live vaccines concurrently with Tocilizumab as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Tocilizumab.
- No data are available on the effectiveness of vaccination in patients receiving Tocilizumab. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly PJIA and SJIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Tocilizumab therapy. The interval between live vaccinations and initiation of Tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
# 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 predict the rates observed in a broader patient population in clinical practice.
- The Tocilizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of Tocilizumab-IV 8 mg per kg monotherapy (288 patients), Tocilizumab-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or Tocilizumab-IV 4 mg per kg in combination with methotrexate (774 patients).
- The all exposure population includes all patients in registration studies who received at least one dose of Tocilizumab-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years.
- All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian.
- The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with Tocilizumab-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.
- The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking Tocilizumab-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of Tocilizumab-IV were increased hepatic transaminase values (per protocol requirement) and serious infections.
- Overall Infections
- In the 24 week, controlled clinical studies, the rate of infections in the Tocilizumab-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis.
- The overall rate of infections with Tocilizumab-IV in the all exposure population remained consistent with rates in the controlled periods of the studies.
- Serious Infections
- In the 24 week, controlled clinical studies, the rate of serious infections in the Tocilizumab-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.
- In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported.
- Gastrointestinal Perforations
- During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with Tocilizumab-IV therapy.
- In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate. The relative contribution of these concomitant medications versus Tocilizumab-IV to the development of GI perforations is not known.
- Infusion Reactions
- In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting.
- Anaphylaxis
- Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with Tocilizumab-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of Tocilizumab-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction.
- Laboratory Abnormalities
- Neutropenia
- In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm3 occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm3 and the occurrence of serious infections.
- In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies.
- Thrombocytopenia
- In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg Tocilizumab-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events.
- In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies.
- Elevated Liver Enzymes
- Liver enzyme abnormalities are summarized in TABLE 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of Tocilizumab-IV, or reduction in Tocilizumab-IV dose, resulted in decrease or normalization of liver enzymes. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency.
- Lipids
- Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of Tocilizumab-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below:
Mean LDL increased by 13 mg per dL in the Tocilizumab 4 mg per kg+DMARD arm, 20 mg per dL in the Tocilizumab 8 mg per kg+DMARD, and 25 mg per dL in Tocilizumab 8 mg per kg monotherapy.
Mean HDL increased by 3 mg per dL in the Tocilizumab 4 mg per kg+DMARD arm, 5 mg per dL in the Tocilizumab 8 mg per kg+DMARD, and 4 mg per dL in Tocilizumab 8 mg per kg monotherapy.
Mean LDL/HDL ratio increased by an average of 0.14 in the Tocilizumab 4 mg per kg+DMARD arm, 0.15 in the Tocilizumab 8 mg per kg+DMARD, and 0.26 in Tocilizumab 8 mg per kg monotherapy.
ApoB/ApoA1 ratios were essentially unchanged in Tocilizumab-treated patients.
Elevated lipids responded to lipid lowering agents.
- Mean LDL increased by 13 mg per dL in the Tocilizumab 4 mg per kg+DMARD arm, 20 mg per dL in the Tocilizumab 8 mg per kg+DMARD, and 25 mg per dL in Tocilizumab 8 mg per kg monotherapy.
- Mean HDL increased by 3 mg per dL in the Tocilizumab 4 mg per kg+DMARD arm, 5 mg per dL in the Tocilizumab 8 mg per kg+DMARD, and 4 mg per dL in Tocilizumab 8 mg per kg monotherapy.
- Mean LDL/HDL ratio increased by an average of 0.14 in the Tocilizumab 4 mg per kg+DMARD arm, 0.15 in the Tocilizumab 8 mg per kg+DMARD, and 0.26 in Tocilizumab 8 mg per kg monotherapy.
- ApoB/ApoA1 ratios were essentially unchanged in Tocilizumab-treated patients.
- Elevated lipids responded to lipid lowering agents.
- In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials.
- Immunogenicity
- In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies.
- The data reflect the percentage of patients whose test results were positive for antibodies to tocilizumab in specific assays. The observed incidence of 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 medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to tocilizumab with the incidence of antibodies to other products may be misleading.
- Malignancies
- During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving Tocilizumab-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the Tocilizumab-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years).
- In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period.
- Other Adverse Reactions
- Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg Tocilizumab-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in TABLE 2.
- Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with Tocilizumab-IV in controlled trials were:
Oral herpes simplex
Stomatitis, gastric ulcer
Weight increased, total bilirubin increased
Leukopenia
Peripheral edema
Dyspnea, cough
Conjunctivitis
Nephrolithiasis
Hypothyroidism
- The Tocilizumab-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously (SC) and 8 mg/kg intravenously (IV) every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week SC or placebo in 656 patients. All patients in both studies received background non-biologic DMARDs.
- The safety observed for Tocilizumab administered subcutaneously was consistent with the known safety profile of intravenous Tocilizumab, with the exception of injection site reactions, which were more common with Tocilizumab-SC compared with placebo SC injections (IV arm).
- Injection Site Reactions
- In the 6-month control period, in SC-I, the frequency of injection site reactions was 10.1% (64/631) and 2.4% (15/631) for the weekly Tocilizumab-SC and placebo SC (IV-arm) groups, respectively. In SC-II, the frequency of injection site reactions was 7.1% (31/437) and 4.1% (9/218) for the every other week SC Tocilizumab and placebo groups, respectively. These injection site reactions (including erythema, pruritus, pain and hematoma) were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation.
- Immunogenicity
- In the 6-month control period in SC-I, 0.8% (5/625) in the Tocilizumab-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed neutralizing antibodies. In SC-II, 1.6% (7/434) in the Tocilizumab-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti- tocilizumab antibodies; of these, 1.4% (6/434) in the Tocilizumab-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies.
- A total of 1454 (>99%) patients who received Tocilizumab-SC in the all exposure group have been tested for anti-tocilizumab antibodies. Thirteen patients (0.9%) developed anti-tocilizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies.
- The rate is consistent with previous intravenous experience. No correlation of antibody development to adverse events or loss of clinical response was observed.
- Laboratory Abnormalities
- Neutropenia
- During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% and 3.7% of patients receiving Tocilizumab-SC weekly and every other week, respectively.
- There was no clear relationship between decreases in neutrophils below 1 × 109/L and the occurrence of serious infections.
- Thrombocytopenia
- During routine laboratory monitoring in the Tocilizumab-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤50 × 103/mcL.
- Elevated Liver Enzymes
- During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥3 × ULN occurred in 6.5% and 1.4% of patients, respectively, receiving Tocilizumab-SC weekly and 3.4% and 0.7% receiving Tocilizumab SC every other week.
- Lipids
- During routine laboratory monitoring in the Tocilizumab-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving Tocilizumab-SC weekly, every other week and placebo, respectively.
- The safety of Tocilizumab-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the Tocilizumab-IV all exposure population (defined as patients who received at least one dose of Tocilizumab-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients.
- Infections
- The rate of infections in the Tocilizumab-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%).
- Infusion Reactions
- In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the Tocilizumab-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients.
- No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported.
- Immunogenicity
- One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.
- Laboratory Abnormalities
- Neutropenia
- During routine laboratory monitoring in the Tocilizumab-IV all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 3.7% of patients.
- There was no clear relationship between decreases in neutrophils below 1 × 109 per L and the occurrence of serious infections.
- Thrombocytopenia
- During routine laboratory monitoring in the Tocilizumab-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50 × 103 per mcL without associated bleeding events.
- Elevated Liver Enzymes
- During routine laboratory monitoring in the Tocilizumab-IV all exposure population, elevation in ALT or AST at or greater than 3 × ULN occurred in 4% and less than 1% of patients, respectively.
- Lipids
- During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 × ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 × ULN occurred in one patient (0.5%).
- The data described below reflect exposure to Tocilizumab-IV in one randomized, double-blind, placebo-controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy. At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with Tocilizumab-IV (8 or 12 mg per kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated with Tocilizumab-IV in the open-label extension phase.
- The most common adverse events (at least 5%) seen in Tocilizumab-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea.
- Infections
- In the 12 week controlled phase, the rate of all infections in the Tocilizumab-IV group was 345 per 100 patient-years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years.
- In the 12 week controlled phase, the rate of serious infections in the Tocilizumab-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media.
- Macrophage Activation Syndrome
- In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with Tocilizumab-IV. One patient in the placebo group escaped to Tocilizumab-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had Tocilizumab-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the Tocilizumab-IV SJIA clinical development experience; however no definitive conclusions can be made.
- Infusion Reactions
- Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of Tocilizumab-IV and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.
- Within 24 hours after infusion, 16% of patients in the Tocilizumab-IV treatment group and 5% of patients in the placebo group experienced an event. In the Tocilizumab-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.
- Anaphylaxis
- Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with Tocilizumab-IV during the controlled and open label extension study.
- Immunogenicity
- All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study.
- Laboratory Abnormalities
- Neutropenia
- During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 × 109 per L occurred in 7% of patients in the Tocilizumab-IV group, and in no patients in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the Tocilizumab-IV group. There was no clear relationship between decrease in neutrophils below 1 × 109 per L and the occurrence of serious infections.
- Thrombocytopenia
- During routine monitoring in the 12 week controlled phase, 1% of patients in the Tocilizumab-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100 × 103 per mcL.
- In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the Tocilizumab-IV group, with no associated bleeding.
- Elevated Liver Enzymes
- During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3× ULN occurred in 5% and 3% of patients, respectively in the Tocilizumab-IV group and in 0% of placebo patients.
- In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3× ULN occurred in 13% and 5% of Tocilizumab-IV treated patients, respectively.
- Lipids
- During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5× ULN – 2x ULN occurred in 1.5% of the Tocilizumab-IV group and in 0% of placebo patients. Elevation in LDL greater than 1.5× ULN – 2x ULN occurred in 1.9% of patients in the Tocilizumab-IV group and 0% of the placebo group.
- In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data.
## Postmarketing Experience
- The following adverse reactions have been identified during postapproval use of intravenous Tocilizumab. 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.
- Fatal anaphylaxis
- Stevens-Johnson Syndrome
# Drug Interactions
- Other Drugs for Treatment of Rheumatoid Arthritis
- Population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance.
- Concomitant administration of a single intravenous dose of 10 mg per kg Tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.
- Tocilizumab has not been studied in combination with biological DMARDs such as TNF antagonists.
- Interactions with CYP450 Substrates
- Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effects on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of Tocilizumab, respectively. The effect of tocilizumab on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Tocilizumab, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering Tocilizumab with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.
- Live Vaccines
- Avoid use of live vaccines concurrently with Tocilizumab
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- Pregnancy Exposure Registry
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Tocilizumab during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.
- Risk Summary
- Adequate and well-controlled studies with Tocilizumab have not been conducted in pregnant women. In animal reproduction studies, administration of tocilizumab to cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at dose exposures 1.25 times the human dose exposure of 8 mg per kg every 2 to 4 weeks. The incidence of malformations and pregnancy loss in human pregnancies has not been established for Tocilizumab. However, all pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. Tocilizumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Clinical Considerations
- In general, monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester.
- Animal Data
- An embryo-fetal developmental toxicity study was performed in which pregnant cynomolgus monkeys were treated intravenously with tocilizumab (daily doses of 2, 10, or 50 mg per kg from gestation day 20-50) during organogenesis. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at 10 mg per kg and 50 mg per kg doses (1.25 and 6.25 times the human dose of 8 mg per kg every 2 to 4 weeks based on a mg per kg comparison). Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg per kg intravenously with treatment every three days from implantation until day 21 after delivery (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tocilizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tocilizumab during labor and delivery.
### Nursing Mothers
- It is not known whether tocilizumab is present in human milk or if it would be absorbed systemically in a breastfed infant after ingestion. IgG is excreted in human milk and therefore it is expected that tocilizumab could be present in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Tocilizumab, 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
- Tocilizumab by intravenous use is indicated for the treatment of pediatric patients with:
- Active systemic juvenile idiopathic arthritis in patients 2 years of age and older
- Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older
- Safety and effectiveness of Tocilizumab in pediatric patients with conditions other than PJIA or SJIA have not been established. Children under the age of two have not been studied. SC administration has not been studied in pediatric patients. Testing of a murine analogue of tocilizumab did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.
### Geriatic Use
- Of the 2644 patients who received Tocilizumab in Studies I to V, a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. Of the 1069 patients who received Tocilizumab-SC in studies SC-I and SC-II there were 295 patients 65 years of age and older, including 41 patients 75 years and older. The frequency of serious infection among Tocilizumab treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
### Gender
There is no FDA guidance on the use of Tocilizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tocilizumab with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is required in patients with mild renal impairment. Tocilizumab has not been studied in patients with moderate to severe renal impairment.
### Hepatic Impairment
- The safety and efficacy of Tocilizumab have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tocilizumab in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tocilizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Tocilizumab in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Tocilizumab in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- There are limited data available on overdoses with Tocilizumab. One case of accidental overdose was reported with intravenous Tocilizumab in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia.
### Management
- In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Tocilizumab in the drug label.
# Pharmacology
There is limited information regarding Tocilizumab Pharmacology in the drug label.
## Mechanism of Action
- Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, lymphocytes, monocytes and fibroblasts. IL-6 has been shown to be involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, initiation of hepatic acute phase protein synthesis, and stimulation of hematopoietic precursor cell proliferation and differentiation. IL-6 is also produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis.
## Structure
- Tocilizumab (tocilizumab) is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. Tocilizumab has a molecular weight of approximately 148 kDa.
- Tocilizumab is supplied as a sterile, preservative-free solution for intravenous (IV) infusion at a concentration of 20 mg per mL. Tocilizumab is a colorless to pale yellow liquid, with a pH of about 6.5. Single-use vials are available for intravenous administration containing 80 mg per 4 mL, 200 mg per 10 mL, or 400 mg per 20 mL of Tocilizumab. Injectable solutions of Tocilizumab are formulated in an aqueous solution containing disodium phosphate dodecahydrate and sodium dihydrogen phosphate dehydrate (as a 15 mmol per L phosphate buffer), polysorbate 80 (0.5 mg per mL), and sucrose (50 mg per mL).
- Tocilizumab solution for subcutaneous administration is supplied as a sterile, colorless to yellowish, preservative-free liquid solution of approximately pH 6.0. It is supplied in a 1 mL ready-to-use, single-use prefilled syringe (PFS) with a needle safety device. Each device delivers 0.9 mL (162 mg) of Tocilizumab, in a histidine buffered solution composed of Tocilizumab (180 mg/mL), polysorbate 80, L-histidine and L-histidine monohydrochloride, L-arginine and L-arginine hydrochloride, L-methionine, and water for injection.
## Pharmacodynamics
- In clinical studies with the 4 mg per kg and 8 mg per kg IV doses or the 162 mg weekly and every other weekly SC doses of Tocilizumab, decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg Tocilizumab. Pharmacodynamic changes were also observed to occur after Tocilizumab administration in PJIA and SJIA patients (decreases in CRP, ESR, and increases in hemoglobin). The relationship between these pharmacodynamic findings and clinical efficacy is not known.
- In healthy subjects administered Tocilizumab in doses from 2 to 28 mg per kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to the nadir 3 to 5 days following Tocilizumab administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following Tocilizumab administration.
## Pharmacokinetics
- The pharmacokinetics characterized in healthy subjects and RA patients suggested that PK is similar between the two populations. The clearance (CL) of tocilizumab decreased with increased doses. At the 10 mg per kg single dose in RA patients, mean CL was 0.29 ± 0.10 mL per hr per kg and mean apparent terminal t1/2 was 151 ± 59 hours (6.3 days).
- The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis of 1793 rheumatoid arthritis patients treated with Tocilizumab 4 and 8 mg per kg every 4 weeks for 24 weeks.
- The pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional increase in area under the curve (AUC) and trough concentration (Cmin) was observed for doses of 4 and 8 mg per kg every 4 weeks. Maximum concentration (Cmax) increased dose-proportionally. At steady-state, estimated AUC and Cmin were 2.7 and 6.5-fold higher at 8 mg per kg as compared to 4 mg per kg, respectively. In a long-term study with dosing for 104 weeks, observed Cmin was sustained over time.
- For doses of Tocilizumab 4 mg per kg given every 4 weeks, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 13000 ± 5800 mcg∙h per mL, 1.49 ± 2.13 mcg per mL, and 88.3 ± 41.4 mcg per mL, respectively. The accumulation ratios for AUC and Cmax were 1.11 and 1.02, respectively. The accumulation ratio was higher for Cmin (1.96). Steady-state was reached following the first administration for Cmax and AUC, respectively, and after 16 weeks Cmin. For doses of Tocilizumab 8 mg per kg given every 4 weeks, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 35000 ± 15500 mcg∙h per mL, 9.74 ± 10.5 mcg per mL, and 183 ± 85.6 mcg per mL, respectively. The accumulation ratios for AUC and Cmax were 1.22 and 1.06, respectively. The accumulation ratio was higher for Cmin (2.35). Steady-state was reached following the first administration and after 8 and 20 weeks for Cmax, AUC, and Cmin, respectively. Tocilizumab AUC, Cmin and Cmax increased with increase of body weight. At body weight at or above 100 kg, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 55500 ± 14100 mcg∙h per mL, 19.0 ± 12.0 mcg per mL, and 269 ± 57 mcg per mL, respectively, which are higher than mean exposure values for the patient population. Therefore, Tocilizumab doses exceeding 800 mg per infusion are not recommended.
- The pharmacokinetics of tocilizumab was characterized using a population pharmacokinetic analysis using a database composed of 1759 rheumatoid arthritis patients treated with 162 mg SC every week, 162 mg SC every other week, and 8 mg/kg every 4 weeks for 24 weeks.
- The pharmacokinetic parameters of tocilizumab did not change with time. For the 162 mg every week dose, the estimated mean (±SD) steady-state AUC1week, Cmin and Cmax of tocilizumab were 8200 ± 3600 mcg∙h/mL, 44.6 ± 20.6 mcg/mL, and 50.9 ± 21.8 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 6.83, 6.37, and 5.47, respectively. Steady state was reached after 12 weeks for AUC, Cmin, and Cmax.
- For the 162 mg every other week dose, the estimated mean (±SD) steady-state AUC2week, Cmin, and Cmax of tocilizumab were 3200 ± 2700 mcg∙h/mL, 5.6 ± 7.0 mcg/mL, and 12.3 ± 8.7 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 2.67, 5.6, and 2.12, respectively. Steady state was reached after 12 weeks for AUC and Cmin, and after 10 weeks for Cmax.
- The pharmacokinetics of tocilizumab was determined using a population pharmacokinetic analysis on a database composed of 188 patients with polyarticular juvenile idiopathic arthritis.
- For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks, the estimated mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 29500 ± 8660 mcg∙hr/mL, 182 ± 37 mcg/mL and 7.49 ± 8.2 mcg/mL, respectively.
- For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks, the estimated mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 23200 ± 6100 mcg∙hr/mL, 175 ± 32 mcg/mL and 2.35 ± 3.59 mcg/mL, respectively.
- The accumulation ratios were 1.05 and 1.16 for AUC4weeks, and 1.43 and 2.22 for Cmin for 10 mg/kg (BW less than 30 kg) and 8 mg/kg (BW at or above 30 kg) doses, respectively. No accumulation for Cmax was observed.
- The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 75 patients with SJIA treated with 8 mg per kg (patients with a body weight at or above 30 kg) or 12 mg per kg (patients with a body weight less than 30 kg), given every 2 weeks. The estimated mean (± SD) AUC2 weeks, Cmax and Cmin of tocilizumab were 32200 ± 9960 mcg∙hr per mL, 245 ± 57.2 mcg per mL and 57.5 ± 23.3 mcg per mL, respectively. The accumulation ratio for Cmin (week 12 over week 2) was 3.2 ± 1.3. Steady state was reached on or after week 12. Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight.
- Absorption
- Following SC dosing in rheumatoid arthritis patients, the absorption half-life was around 4 days. The bioavailability for the SC formulation was 0.8.
- Distribution
- Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.
- In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L.
- In pediatric patients with SJIA, the central volume of distribution was 0.94 L, the peripheral volume of distribution was 1.60 L resulting in a volume of distribution at steady state of 2.54 L.
- Elimination
- The total clearance of tocilizumab is concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA, 5.8 mL per h in pediatric patients with PJIA, and 7.1 mL per h in pediatric patients with SJIA. The concentration-dependent nonlinear clearance plays a major role at low tocilizumab concentrations. Once the nonlinear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.
- The t1/2 of tocilizumab is concentration-dependent. For IV administration, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For SC administration, the concentration-dependent apparent t1/2 is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state.
- The t1/2 of tocilizumab in children with PJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight at or above 30 kg or 10 mg/kg for body weight less than 30 kg) during a dosing interval at steady state.
- The t1/2 of tocilizumab in pediatric patients with SJIA is up to 23 days for the two body weight categories at week 12.
- Pharmacokinetics in Special Populations
- Population pharmacokinetic analyses in adult rheumatoid arthritis patients showed that age, gender and race did not affect the pharmacokinetics of tocilizumab. Linear clearance was found to increase with body size. The body weight-based dose (8 mg per kg) resulted in approximately 86% higher exposure in patients who are greater than 100 kg in comparison to patients who are less than 60 kg. There was an inverse relationship between tocilizumab exposure and body weight for flat dose SC regimens.
- Hepatic Impairment
- No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted.
- Renal Impairment
- No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted.
- Most of the RA patients in the population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (creatinine clearance less than 80 mL per min and at or above 50 mL per min based on Cockcroft-Gault) did not impact the pharmacokinetics of tocilizumab. No dose adjustment is required in patients with mild renal impairment.
- Drug Interactions
- In vitro data suggested that IL-6 reduced mRNA expression for several CYP450 isoenzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, and this reduced expression was reversed by co-incubation with tocilizumab at clinically relevant concentrations. Accordingly, inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Its effect on CYP2C8 or transporters (e.g., P-gp) is unknown. This is clinically relevant for CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted. Upon initiation of Tocilizumab, in patients being treated with these types of medicinal products, therapeutic monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the medicinal product adjusted as needed. Caution should be exercised when Tocilizumab is coadministered with drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives (CYP3A4 substrates).
- Simvastatin
- Simvastatin is a CYP3A4 and OATP1B1 substrate. In 12 RA patients not treated with Tocilizumab, receiving 40 mg simvastatin, exposures of simvastatin and its metabolite, simvastatin acid, was 4- to 10-fold and 2-fold higher, respectively, than the exposures observed in healthy subjects. One week following administration of a single infusion of Tocilizumab (10 mg per kg), exposure of simvastatin and simvastatin acid decreased by 57% and 39%, respectively, to exposures that were similar or slightly higher than those observed in healthy subjects. Exposures of simvastatin and simvastatin acid increased upon withdrawal of Tocilizumab in RA patients. Selection of a particular dose of simvastatin in RA patients should take into account the potentially lower exposures that may result after initiation of Tocilizumab (due to normalization of CYP3A4) or higher exposures after discontinuation of Tocilizumab.
- Omeprazole
- Omeprazole is a CYP2C19 and CYP3A4 substrate. In RA patients receiving 10 mg omeprazole, exposure to omeprazole was approximately 2 fold higher than that observed in healthy subjects. In RA patients receiving 10 mg omeprazole, before and one week after Tocilizumab infusion (8 mg per kg), the omeprazole AUCinf decreased by 12% for poor (N=5) and intermediate metabolizers (N=5) and by 28% for extensive metabolizers (N=8) and were slightly higher than those observed in healthy subjects.
- Dextromethorphan
- Dextromethorphan is a CYP2D6 and CYP3A4 substrate. In 13 RA patients receiving 30 mg dextromethorphan, exposure to dextromethorphan was comparable to that in healthy subjects. However, exposure to its metabolite, dextrorphan (a CYP3A4 substrate), was a fraction of that observed in healthy subjects. One week following administration of a single infusion of Tocilizumab (8 mg per kg), dextromethorphan exposure was decreased by approximately 5%. However, a larger decrease (29%) in dextrorphan levels was noted after Tocilizumab infusion.
## Nonclinical Toxicology
- Carcinogenesis
- No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab.
- Impairment of Fertility
- Fertility studies conducted in male and female mice using a murine analogue of tocilizumab administered by the intravenous route at a dose of 50 mg/kg every three days showed no impairment of fertility.
# Clinical Studies
- The efficacy and safety of intravenously administered Tocilizumab was assessed in five randomized, double-blind, multicenter studies in patients greater than 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. Tocilizumab was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V).
- Study I evaluated patients with moderate to severe active rheumatoid arthritis who had not been treated with MTX within 24 weeks prior to randomization, or who had not discontinued previous methotrexate treatment as a result of clinically important toxic effects or lack of response. In this study, 67% of patients were MTX-naïve, and over 40% of patients had rheumatoid arthritis less than 2 years. Patients received Tocilizumab 8 mg per kg monotherapy or MTX alone (dose titrated over 8 weeks from 7.5 mg to a maximum of 20 mg weekly). The primary endpoint was the proportion of Tocilizumab patients who achieved an ACR 20 response at Week 24.
- Study II was a 104-week study with an ongoing optional 156-week extension phase that evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received Tocilizumab 8 mg per kg, Tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). Upon completion of 52-weeks, patients received open-label treatment with Tocilizumab 8 mg per kg through 104 weeks or they had the option to continue their double-blind treatment if they maintained a greater than 70% improvement in swollen/tender joint count. Two pre-specified interim analyses at week 24 and week 52 were conducted. The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At weeks 52 and 104, the primary endpoints were change from baseline in modified total Sharp-Genant score and the area under the curve (AUC) of the change from baseline in HAQ-DI score.
- Study III evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to MTX. Patients received Tocilizumab 8 mg per kg, Tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24.
- Study IV evaluated patients who had an inadequate response to their existing therapy, including one or more DMARDs. Patients received Tocilizumab 8 mg per kg or placebo every four weeks, in combination with the stable DMARDs. The primary endpoint was the proportion of patients who achieved an ACR 20 response at week 24.
- Study V evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomization. Patients received Tocilizumab 8 mg per kg, Tocilizumab 4 mg per kg, or placebo every four weeks, in combination with MTX (10 to 25 mg weekly). The primary endpoint was the proportion of patients who achieved an ACR 20response at week 24.
- Clinical Response
- The percentages of intravenous Tocilizumab-treated patients achieving ACR 20, 50 and 70 responses are shown in TABLE 3. In all intravenous studies, patients treated with 8 mg per kg Tocilizumab had higher ACR 20, ACR 50, and ACR 70 response rates versus MTX- or placebo-treated patients at week 24.
- During the 24 week controlled portions of Studies I to V, patients treated with Tocilizumab at a dose of 4 mg per kg in patients with inadequate response to DMARDs or TNF antagonist therapy had lower response rates compared to patients treated with Tocilizumab 8 mg per kg.
- In study II, a greater proportion of patients treated with 4 mg per kg and 8 mg per kg Tocilizumab + MTX achieved a low level of disease activity as measured by a DAS 28-ESR less than 2.6 compared with placebo +MTX treated patients at week 52. The proportion of Tocilizumab-treated patients achieving DAS 28-ESR less than 2.6, and the number of residual active joints in these responders in Study II are shown in TABLE 4.
- The results of the components of the ACR response criteria for Studies III and V are shown in TABLE 5. Similar results to Study III were observed in Studies I, II and IV.
- The percent of ACR 20 responders by visit for Study III is shown in FIGURE 1. Similar response curves were observed in studies I, II, IV, and V.
- Radiographic Response
- In Study II, structural joint damage was assessed radiographically and expressed as change in total Sharp-Genant score and its components, the erosion score and joint space narrowing score. Radiographs of hands/wrists and forefeet were obtained at baseline, 24 weeks, 52 weeks, and 104 weeks and scored by readers unaware of treatments group and visit number. The results from baseline to week 52 are shown in TABLE 6. Tocilizumab 4 mg per kg slowed (less than 75% inhibition compared to the control group) and Tocilizumab 8 mg per kg inhibited (at least 75% inhibition compared to the control group) the progression of structural damage compared to placebo plus MTX at week 52.
- The mean change from baseline to week 104 in Total Sharp-Genant Score for the Tocilizumab 4 mg per kg groups was 0.47 (SD = 1.47) and for the 8 mg per kg groups was 0.34 (SD = 1.24). By the week 104, most patients in the control (placebo + MTX) group had crossed over to active treatment, and results are therefore not included for comparison. Patients in the active groups may have crossed over to the alternate active dose group, and results are reported per original randomized dose group.
- In the placebo group, 66% of patients experienced no radiographic progression (Total Sharp-Genant Score change ≤ 0) at week 52 compared to 78% and 83% in the Tocilizumab 4 mg per kg and 8 mg per kg, respectively. Following 104 weeks of treatment, 75% and 83% of patients initially randomized to Tocilizumab 4 mg per kg and 8 mg per kg, respectively, experienced no progression of structural damage compared to 66% of placebo treated patients.
- Health Related Outcomes
- In Study II, physical function and disability were assessed using the Health Assessment Questionnaire Disability Index (HAQ-DI). Both dosing groups of Tocilizumab demonstrated a greater improvement compared to the placebo group in the AUC of change from baseline in the HAQ-DI through week 52. The mean change from baseline to week 52 in HAQ-DI was 0.6, 0.5, and 0.4 for Tocilizumab 8 mg per kg, Tocilizumab 4 mg per kg, and placebo treatment groups, respectively. Sixty-three percent (63%) and sixty percent (60%) of patients in the Tocilizumab 8 mg per kg and Tocilizumab 4 mg per kg treatment groups, respectively, achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) at week 52 compared to 53% in the placebo treatment group.
- The efficacy and safety of subcutaneously administered Tocilizumab was assessed in two double-blind, controlled, multicenter studies in patients with active RA. One study (SC-I) was a non-inferiority study that compared the efficacy and safety of Tocilizumab 162 mg administered every week subcutaneously (SC) to 8 mg per kg intravenously every four weeks. The second study (SC-II) was a placebo controlled superiority study that evaluated the safety and efficacy of Tocilizumab 162 mg administered every other week SC to placebo. Both SC-I and SC-II required patients to be >18 years of age with moderate to severe active rheumatoid arthritis diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline (SC-I) or at least 8 tender and 6 swollen joints at baseline (SC-II), and an inadequate response to their existing DMARD therapy, where approximately 20% also had a history of inadequate response to at least one TNF inhibitor. All patients in both SC studies received background non-biologic DMARD(s).
- In SC-I, 1262 patients were randomized 1:1 to receive Tocilizumab SC 162 mg every week or Tocilizumab intravenous 8 mg/kg every four weeks in combination with DMARD(s). In SC-II, 656 patients were randomized 2:1 to Tocilizumab SC 162 mg every other week or placebo, in combination with DMARD(s). The primary endpoint in both studies was the proportion of patients who achieved an ACR20 response at Week 24.
- The clinical response to 24 weeks of Tocilizumab SC therapy is shown in TABLE 7. In SC-I, the primary outcome measure was ACR20 at Week 24. The pre-specified non-inferiority margin was a treatment difference of 12%. The study demonstrated non-inferiority of Tocilizumab with respect to ACR20 at Week 24; ACR50, ACR70, and DAS28 responses are also shown in TABLE 7. In SC-II, a greater portion of patients treated with Tocilizumab 162 mg SC every other week achieved ACR20, ACR50, and ACR70 responses compared to placebo-treated patients (TABLE 7). Further, a greater proportion of patients treated with Tocilizumab 162 mg SC every other week achieved a low level of disease activity as measured by a DAS28-ESR less than 2.6 at Week 24 compared to those treated with placebo (TABLE 7).
- The results of the components of the ACR response criteria and the percent of ACR20 responders by visit for Tocilizumab-SC in Studies SC-I and SC-II were consistent with those observed for Tocilizumab-IV.
- Radiographic Response
- In study SC-II, the progression of structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde modified total Sharp score (mTSS). At week 24, significantly less radiographic progression was observed in patients receiving Tocilizumab SC every other week plus DMARD(s) compared to placebo plus DMARD(s); mean change from baseline in mTSS of 0.62 vs. 1.23, respectively, with an adjusted mean difference of -0.60 (-1.1, -0.1). These results are consistent with those observed in patients treated with intravenous Tocilizumab.
- Health Related Outcomes
- In studies SC-I and SC-II, the mean decrease from baseline to week 24 in HAQ-DI was 0.6, 0.6, 0.4 and 0.3, and the proportion of patients who achieved a clinically relevant improvement in HAQ-DI (change from baseline of ≥ 0.3 units) was 65%, 67%, 58% and 47%, for the SC every week, IV 8 mg/kg, SC every other week, and placebo treatment groups, respectively.
- The efficacy of Tocilizumab was assessed in a three-part study including an open-label extension in children 2 to 17 years of age with active polyarticular juvenile idiopathic arthritis (PJIA), who had an inadequate response to methotrexate or inability to tolerate methotrexate. Patients had at least 6 months of active disease (mean disease duration of 4.2 ± 3.7 years), with at least five joints with active arthritis (swollen or limitation of movement accompanied by pain and/or tenderness) and/or at least 3 active joints having limitation of motion (mean, 20 ± 14 active joints). The patients treated had subtypes of JIA that at disease onset included Rheumatoid Factor Positive or Negative Polyarticular JIA, or Extended Oligoarticular JIA. Treatment with a stable dose of methotrexate was permitted but was not required during the study. Concurrent use of disease modifying antirheumatic drugs (DMARDs), other than methotrexate, or other biologics (e.g., TNF antagonists or T cell costimulation modulator) were not permitted in the study.
- Part I consisted of a 16-week active Tocilizumab treatment lead-in period (n=188) followed by Part II, a 24-week randomized double-blind placebo-controlled withdrawal period, followed by Part III, a 64-week open-label period. Eligible patients weighing at or above 30 kg received Tocilizumab at 8 mg/kg IV once every four weeks. Patients weighing less than 30 kg were randomized 1:1 to receive either Tocilizumab 8 mg/kg or 10 mg/kg IV every four weeks. At the conclusion of the open-label Part I, 91% of patients taking background MTX in addition to tocilizumab and 83% of patients on tocilizumab monotherapy achieved an ACR 30 response at week 16 compared to baseline and entered the blinded withdrawal period (Part II) of the study. The proportions of patients with JIA ACR 50/70 responses in Part I were 84.0%, and 64%, respectively for patients taking background MTX in addition to tocilizumab and 80% and 55% respectively for patients on tocilizumab monotherapy.
- In Part II, patients (ITT, n=163) were randomized to Tocilizumab (same dose received in Part I) or placebo in a 1:1 ratio that was stratified by concurrent methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR 30 flare criteria (relative to Week 16) and qualified for escape.
- The primary endpoint was the proportion of patients with a JIA ACR 30 flare at week 40 relative to week 16. JIA ACR 30 flare was defined as 3 or more of the 6 core outcome variables worsening by at least 30% with no more than 1 of the remaining variables improving by more than 30% relative to Week 16.
- Tocilizumab treated patients experienced significantly fewer disease flares compared to placebo-treated patients (26% [21/82] versus 48% [39/81]; adjusted difference in proportions -21%, 95% CI: -35%, -8%).
- During the withdrawal phase (Part II), more patients treated with Tocilizumab showed JIA ACR 30/50/70 responses at Week 40 compared to patients withdrawn to placebo.
- The efficacy of Tocilizumab for the treatment of active SJIA was assessed in a 12-week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (Tocilizumab:placebo = 2:1) to one of two treatment groups: 75 patients received Tocilizumab infusions every two weeks at either 8 mg per kg for patients at or above 30 kg or 12 mg per kg for patients less than 30 kg and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR 70 response. After 12 weeks or at the time of escape, due to disease worsening, patients were treated with Tocilizumab in the open-label extension phase at weight appropriate dosing.
- The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR 30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding 7 days). JIA ACR (American College of Rheumatology) responses are defined as the percentage improvement (e.g., 30%, 50%, 70%) in 3 of any 6 core outcome variables compared to baseline, with worsening in no more than 1 of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (childhood health assessment questionnaire-CHAQ).
- Primary endpoint result and JIA ACR response rates at Week 12 are shown in TABLE 8.
- The treatment effect of Tocilizumab was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks).
- Systemic Features
- Of patients with fever or rash at baseline, those treated with Tocilizumab had fewer systemic features; 35 out of 41 (85%) became fever free (no temperature recording at or above 37.5°C in the preceding 14 days) compared to 5 out of 24 (21%) of placebo-treated patients, and 14 out of 22 (64%) became free of rash compared to 2 out of 18 (11%) of placebo-treated patients. Responses were consistent in the open label extension (data available through 44 weeks).
- Corticosteroid Tapering
- Of the patients receiving oral corticosteroids at baseline, 8 out of 31 (26%) placebo and 48 out of 70 (69%), Tocilizumab patients achieved a JIA ACR 70 response at week 6 or 8 enabling corticosteroid dose reduction. Seventeen (24%) Tocilizumab patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR 30 flare or occurrence of systemic symptoms to week 12. In the open label portion of the study, by week 44, there were 44 out of 103 (43%) Tocilizumab patients off oral corticosteroids. Of these 44 patients 50% were off corticosteroids 18 weeks or more.
- Health Related Outcomes
- Physical function and disability were assessed using the Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). Seventy-seven percent (58 out of 75) of patients in the Tocilizumab treatment group achieved a minimal clinically important improvement in CHAQ-DI (change from baseline of ≥ 0.13 units) at week 12 compared to 19% (7 out of 37) in the placebo treatment group.
# How Supplied
- For Intravenous Infusion
- Tocilizumab (tocilizumab) is supplied in single-use vials as a preservative-free, sterile concentrate (20 mg per mL) solution for intravenous infusion. The following packaging configurations are available:
- Individually packaged, single-use vials:
- NDC 50242-135-01 providing 80 mg per 4 mL
- NDC 50242-136-01 providing 200 mg per 10 mL
- NDC 50242-137-01 providing 400 mg per 20 mL
- For Subcutaneous Injection
- Tocilizumab (tocilizumab) for subcutaneous administration is supplied as a sterile preservative-free liquid solution in a single-use prefilled syringe. The following packaging configurations are available:
- NDC 50242-138-01 prefilled syringe providing 162 mg per 0.9mL
- Storage and Stability: Do not use beyond expiration date on the container, package or prefilled syringe. Tocilizumab must be refrigerated at 2ºC to 8ºC (36°F to 46°F). Do not freeze. Protect the vials and syringes from light by storage in the original package until time of use, and keep syringes dry. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particles are observed, the solution should not be used.
## Storage
There is limited information regarding Tocilizumab Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients and parents or guardians of minors with PJIA or SJIA of the potential benefits and risks of Tocilizumab. Physicians should instruct their patients to read the Medication Guide before starting Tocilizumab therapy.
- Infections:
- Inform patients that Tocilizumab may lower their resistance to infections. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment.
- Gastrointestinal Perforation:
- Inform patients that some patients who have been treated with Tocilizumab have had serious side effects in the stomach and intestines. Instruct the patient of the importance of contacting their doctor immediately when symptoms of severe, persistent abdominal pain appear to assure rapid evaluation and appropriate treatment.
- Hypersensitivity and Serious Allergic Reactions
- Assess patient suitability for home use for SC injection. Inform patients that some patients who have been treated with Tocilizumab have developed serious allergic reactions, including anaphylaxis. Advise patients to seek immediate medical attention if they experience any symptom of serious allergic reactions.
- Instruction on Injection Technique
- Perform the first injection under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer subcutaneous Tocilizumab, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous Tocilizumab and the suitability for home use [See Patient Instructions for Use].
- Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes, out of the reach of children. Do not warm Tocilizumab in any other way.
- Advise patients to consult their healthcare provider if the full dose is not received.
- A puncture-resistant container for disposal of needles and syringes should be used and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper syringe and needle disposal, and caution against reuse of these items.
# Precautions with Alcohol
- Alcohol-Tocilizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Tocilizumab®[2]
# Look-Alike Drug Names
There is limited information regarding Tocilizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tocilizumab | |
183c9354bd75f47ba89dc98a11ce97d581f302d5 | wikidoc | Tofacitinib | Tofacitinib
# 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
Tofacitinib is an anti rheumatic that is FDA approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, hepatic steatosis, pruritis, tendonitis, pyrexia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tofacitinib is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
- Tofacitinib should not be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine.
- The recommended dose of tofacitinib is 5 mg twice daily.
- Tofacitinib dosage should be reduced to 5 mg once daily in patients:
- With moderate or severe renal insufficiency
- With moderate hepatic impairment
- Receiving potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g., ketoconazole)
- Receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).
- Tofacitinib should not be used in patients with severe hepatic impairment.
- It is recommended that tofacitinib not be initiated in patients with a lymphocyte count less than 500 cells/mm3, an absolute neutrophil count (ANC) less than 1000 cells/mm3, or who have hemoglobin levels less than 9 g/dL.
- Coadministration of tofacitinib with potent inducers of CYP3A4 (e.g., rifampin) may result in loss of or reduced clinical response to tofacitinib.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tofacitinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tofacitinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tofacitinib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tofacitinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tofacitinib in pediatric patients.
# Contraindications
There is limited information regarding Tofacitinib Contraindications in the drug label.
# Warnings
- Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving tofacitinib. The most common serious infections reported with tofacitinib included pneumonia, cellulitis, herpes zoster and urinary tract infection.
- Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus were reported with tofacitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.
- Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis, coccidioidomycosis, and listeriosis).
- Tofacitinib should not be initiated in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients:
- with chronic or recurrent infection
- who have been exposed to tuberculosis
- with a history of a serious or an opportunistic infection
- who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
- with underlying conditions that may predispose them to infection.
- Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib. Tofacitinib should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.
- A patient who develops a new infection during treatment with tofacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
- Patients should be evaluated and tested for latent or active infection prior to administration of tofacitinib.
- Anti-tuberculosis therapy should also be considered prior to administration of tofacitinib in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
- Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
- Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering tofacitinib.
- Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with tofacitinib. The impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials.
- Consider the risks and benefits of tofacitinib treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing tofacitinib in patients who develop a malignancy. Malignancies were observed in clinical studies of tofacitinib.
- In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving tofacitinib with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure.
- Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with tofacitinib.
- In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high dose corticosteroids, and mycophenolic acid products, ]-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with tofacitinib (2.3%) compared to 0 out of 111 patients treated with cyclosporine.
- Events of gastrointestinal perforation have been reported in clinical studies with tofacitinib in rheumatoid arthritis patients, although the role of JAK inhibition in these events is not known.
- Tofacitinib should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
- Treatment with tofacitinib was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.
- Avoid initiation of tofacitinib treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3 treatment with tofacitinib is not recommended.
- Monitor lymphocyte counts at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts
- Treatment with tofacitinib was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.
- Avoid initiation of tofacitinib treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500–1000 cells/mm3, interrupt tofacitinib dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with tofacitinib is not recommended.
- Monitor neutrophil counts at baseline and after 4–8 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC results
- Avoid initiation of tofacitinib treatment in patients with a low hemoglobin level (i.e. less than 9 g/dL). Treatment with tofacitinib should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.
- Monitor hemoglobin at baseline and after 4–8 weeks of treatment and every 3 months thereafter. For recommended modifications based on hemoglobin results.
- Treatment with tofacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.
- Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of tofacitinib should be interrupted until this diagnosis has been excluded.
- Treatment with tofacitinib was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
- Assessment of lipid parameters should be performed approximately 4–8 weeks following initiation of tofacitinib therapy.
- Manage patients according to clinical guidelines for the management of hyperlipidemia.
- No data are available on the response to vaccination or on the secondary transmission of infection by live vaccines to patients receiving tofacitinib. Live vaccines should not be given concurrently with tofacitinib.
- Update immunizations in agreement with current immunization guidelines prior to initiating tofacitinib therapy.
# 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 predict the rates observed in a broader patient population in clinical practice.
- The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of tofacitinib 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, tofacitinib 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with tofacitinib at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore some analyses that follow include patients who changed treatment by design or by patient response from placebo to tofacitinib in both the placebo and tofacitinib group of a given interval. Comparisons between placebo and tofacitinib were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and tofacitinib 10 mg twice daily were based on the first 12 months of exposure.
- The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of tofacitinib doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.
- The most common serious adverse reactions were serious infections.
- The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking tofacitinib and 3% for placebo-treated patients.
- In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.
- The most commonly reported infections with tofacitinib were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).
- In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received tofacitinib 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily tofacitinib group minus placebo.
- In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of tofacitinib and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
- The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection.
- In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of tofacitinib, or 10 mg twice daily of tofacitinib.
- In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of tofacitinib and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
- Cases of disseminated tuberculosis were also reported. The median tofacitinib exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days)
- In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of tofacitinib, or 10 mg twice daily of tofacitinib.
- In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of tofacitinib and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
- The median tofacitinib exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).
- In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either tofacitinib 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily tofacitinib group minus placebo.
- In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of tofacitinib and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with tofacitinib 10 mg twice daily.
- The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.
- In the controlled clinical trials, confirmed decreases in lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily tofacitinib groups combined during the first 3 months of exposure.
- Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.
- In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily tofacitinib groups combined during the first 3 months of exposure.
- There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.
- There was no clear relationship between neutropenia and the occurrence of serious infections.
- In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials.
- Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3× ULN) were observed in patients treated with tofacitinib. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tofacitinib, or reduction in tofacitinib dose, resulted in decrease or normalization of liver enzymes.
- In the controlled monotherapy trials (0–3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and tofacitinib 5 mg, and 10 mg twice daily groups.
- In the controlled background DMARD trials (0–3 months), ALT elevations greater than 3× ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3× ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.
- One case of drug-induced liver injury was reported in a patient treated with tofacitinib 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3× ULN and bilirubin elevations greater than 2× ULN, which required hospitalizations and a liver biopsy.
- In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below:
- Mean LDL cholesterol increased by 15% in the tofacitinib 5 mg twice daily arm and 19% in the tofacitinib 10 mg twice daily arm.
- Mean HDL cholesterol increased by 10% in the tofacitinib 5 mg twice daily arm and 12% in the tofacitinib 10 mg twice daily arm.
- Mean LDL/HDL ratios were essentially unchanged in tofacitinib-treated patients.
- In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.
- In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials.
- In the controlled clinical trials, dose-related elevations in serum creatinine were observed with tofacitinib treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from tofacitinib treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.
- Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily tofacitinib and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in Table 4.
## Postmarketing Experience
- Blood and lymphatic system disorders
- Anemia
- Metabolism and nutrition disorders
- Dehydration
- Psychiatric disorders
- Insomnia
- Nervous system disorders
- Paresthesia
- Respiratory, thoracic and mediastinal disorders
- Dyspnea, cough, sinus congestion
- Gastrointestinal disorders
- Abdominal pain, dyspepsia, vomiting, gastritis, nausea
- Hepatobiliary disorders
- Hepatic steatosis
- Skin and subcutaneous tissue disorders
- Rash, erythema, pruritus
- Musculoskeletal, connective tissue and bone disorders
- Musculoskeletal pain, arthralgia, tendonitis, joint swelling
- General disorders and administration site conditions
- Pyrexia, fatigue, peripheral edema
# Drug Interactions
- Tofacitinib exposure is increased when tofacitinib is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole).
- Tofacitinib exposure is increased when tofacitinib is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).
- Tofacitinib exposure is decreased when tofacitinib is coadministered with potent CYP3A4 inducers (e.g., rifampin) .
- There is a risk of added immunosuppression when tofacitinib is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in rheumatoid arthritis.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women. Tofacitinib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).
- In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum).
- In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity.
- Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).
- In a peri- and postnatal rat study, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the MRHD (on an AUC basis at oral doses of 50 mg/kg/day). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).
- Pregnancy registry has been established to monitor the outcomes of pregnant women exposed to XELJAN
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tofacitinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tofacitinib during labor and delivery.
### Nursing Mothers
- Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib 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 tofacitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug for the mother.
### Pediatric Use
- The safety and effectiveness of tofacitinib in pediatric patients have not been established.
### Geriatic Use
- Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among tofacitinib-treated subjects 65 years of age and older was higher than among those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
### Gender
There is no FDA guidance on the use of Tofacitinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tofacitinib with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is required in patients with mild renal impairment. Tofacitinib dose should be reduced to 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, tofacitinib was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min.
### Hepatic Impairment
- Treatment with tofacitinib is not recommended in patients with severe hepatic impairment. No dose adjustment is required in patients with mild hepatic impairment. tofacitinib dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment. The safety and efficacy of tofacitinib have not been studied in patients with severe hepatic impairment or in patients with positive hepatitis B virus or hepatitis C virus serology
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tofacitinib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tofacitinib in patients who are immunocompromised.
### Nonteratogenic effects:
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Laboratory monitoring –Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids.
- Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib. Tofacitinib should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.
- Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
- Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.
# IV Compatibility
There is limited information regarding IV Compatibility of Tofacitinib in the drug label.
# Overdosage
- Signs, Symptoms, and Laboratory Findings of Acute Overdosage in Humans
- There is no experience with overdose of tofacitinib.
- Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.
- There is no specific antidote for overdose with tofacitinib. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.
# Pharmacology
## Mechanism of Action
- Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.
## Structure
## Pharmacodynamics
- Treatment with XELJANZ was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8–10 weeks after initiation of therapy. These changes generally resolved within 2–6 weeks after discontinuation of treatment. Treatment with XELJANZ was associated with dose-dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.
Total serum IgG, IgM, and IgA levels after 6-month dosing in patients with rheumatoid arthritis were lower than placebo; however, changes were small and not dose-dependent.
After treatment with XELJANZ in patients with rheumatoid arthritis, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with XELJANZ treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life.
## Pharmacokinetics
Following oral administration of XELJANZ, peak plasma concentrations are reached within 0.5–1 hour, elimination half-life is ~3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 24–48 hours with negligible accumulation after twice daily administration.
Absorption
The absolute oral bioavailability of tofacitinib is 74%. Coadministration of XELJANZ with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, XELJANZ was administered without regard to meals.
Distribution
After intravenous administration, the volume of distribution is 87 L. The protein binding of tofacitinib is ~40%. Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.
Metabolism and Elimination
Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.
Pharmacokinetics in Rheumatoid Arthritis Patients
Population PK analysis in rheumatoid arthritis patients indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, gender and race (Figure 1). An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this difference is not considered to be clinically relevant. The between-subject variability (% coefficient of variation) in AUC of tofacitinib is estimated to be approximately 27%.
Specific Populations
The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of tofacitinib is shown in Figure 1.
Reference values for weight, age, gender, and race comparisons are 70 kg, 55 years, male, and White, respectively; Reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function.
Drug Interactions
Potential for XELJANZ to Influence the PK of Other Drugs
In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 185 times the steady state Cmax of a 5 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when coadministered with XELJANZ.
In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, coadministration with XELJANZ is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.
In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.
Dosing recommendations for coadministered drugs following administration with XELJANZ are shown in Figure 2.
## Nonclinical Toxicology
- In a 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately 6 times the MRHD (on an AUC basis at oral doses of 5 mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels 1 times the MRHD (on an AUC basis at oral doses of 1 mg/kg twice daily).
- The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the MRHD (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.
- In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the MRHD on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.
- Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.
- In rats, tofacitinib at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the MRHD (on an AUC basis at oral doses of 1 mg/kg/day). Tofacitinib exposure levels at approximately 133 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.
# Clinical Studies
- The XELJANZ clinical development program included two dose-ranging trials and five confirmatory trials.
- Dose selection for XELJANZ was based on two pivotal dose-ranging trials.
- Dose-Ranging Study 1 was a 6-month monotherapy trial in 384 patients with active rheumatoid arthritis who had an inadequate response to a DMARD. Patients who previously received adalimumab therapy were excluded. Patients were randomized to 1 of 7 monotherapy treatments: XELJANZ 1, 3, 5, 10 or 15 mg twice daily, adalimumab 40 mg subcutaneously every other week for 10 weeks followed by XELJANZ 5 mg twice daily for 3 months, or placebo.
- Dose-Ranging Study 2 was a 6-month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to MTX alone received one of 6 dose regimens of XELJANZ (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX.
- The results of XELJANZ-treated patients achieving ACR20 responses in Studies 1 and 2 are shown in Figure 4. Although a dose-response relationship was observed in Study 1, the proportion of patients with an ACR20 response did not clearly differ between the 10 mg and 15 mg doses. Furthermore, there was a smaller proportion of patients who responded to adalimumab monotherapy compared to those treated with XELJANZ doses 3 mg twice daily and greater. In Study 2, a smaller proportion of patients achieved an ACR20 response in the placebo and XELJANZ 1 mg groups compared to patients treated with the other XELJANZ doses. However, there was no difference in the proportion of responders among patients treated with XELJANZ 3, 5, 10, 15 mg twice daily or 20 mg once daily doses.
CONFIRMATORY TRIALS
Study I was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received XELJANZ 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.
Study II was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received XELJANZ 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.
Study III was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received XELJANZ 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX.
Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study IV is an ongoing 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study V was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF-inhibiting biologic agent received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.
Clinical Response
The percentages of XELJANZ-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies I, IV, and V are shown in Table 5. Similar results were observed with Studies II and III. In all trials, patients treated with either 5 or 10 mg twice daily XELJANZ had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in XELJANZ-treated patients were consistent at 6 and 12 months.
# How Supplied
- XELJANZ is provided as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) tablets: White, round, immediate-release film-coated tablets, debossed with "Pfizer" on one side, and "JKI 5" on the other side, and available in:
## Storage
- Store at 20°C to 25°C (68°F to 77°F).
- Do not repackage.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking XELJANZ. Instruct patients to take XELJANZ only as prescribed.
# Precautions with Alcohol
- Alcohol-Tofacitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- XELJANZ ®
# Look-Alike Drug Names
There is limited information regarding Tofacitinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tofacitinib
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [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
Tofacitinib is an anti rheumatic that is FDA approved for the treatment of adult patients with moderately to severely active rheumatoid arthritis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anemia, hepatic steatosis, pruritis, tendonitis, pyrexia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Tofacitinib is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
- Tofacitinib should not be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine.
- The recommended dose of tofacitinib is 5 mg twice daily.
- Tofacitinib dosage should be reduced to 5 mg once daily in patients:
- With moderate or severe renal insufficiency
- With moderate hepatic impairment
- Receiving potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g., ketoconazole)
- Receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).
- Tofacitinib should not be used in patients with severe hepatic impairment.
- It is recommended that tofacitinib not be initiated in patients with a lymphocyte count less than 500 cells/mm3, an absolute neutrophil count (ANC) less than 1000 cells/mm3, or who have hemoglobin levels less than 9 g/dL.
- Coadministration of tofacitinib with potent inducers of CYP3A4 (e.g., rifampin) may result in loss of or reduced clinical response to tofacitinib.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tofacitinib in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tofacitinib in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Tofacitinib in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tofacitinib in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tofacitinib in pediatric patients.
# Contraindications
There is limited information regarding Tofacitinib Contraindications in the drug label.
# Warnings
- Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in rheumatoid arthritis patients receiving tofacitinib. The most common serious infections reported with tofacitinib included pneumonia, cellulitis, herpes zoster and urinary tract infection.
- Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcus, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus, and BK virus were reported with tofacitinib. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.
- Other serious infections that were not reported in clinical studies may also occur (e.g., histoplasmosis, coccidioidomycosis, and listeriosis).
- Tofacitinib should not be initiated in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients:
- with chronic or recurrent infection
- who have been exposed to tuberculosis
- with a history of a serious or an opportunistic infection
- who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
- with underlying conditions that may predispose them to infection.
- Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib. Tofacitinib should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.
- A patient who develops a new infection during treatment with tofacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
- Patients should be evaluated and tested for latent or active infection prior to administration of tofacitinib.
- Anti-tuberculosis therapy should also be considered prior to administration of tofacitinib in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
- Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
- Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering tofacitinib.
- Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with tofacitinib. The impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials.
- Consider the risks and benefits of tofacitinib treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing tofacitinib in patients who develop a malignancy. Malignancies were observed in clinical studies of tofacitinib.
- In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving tofacitinib with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure.
- Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with tofacitinib.
- In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high dose corticosteroids, and mycophenolic acid products, [Epstein Barr Virus]]-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with tofacitinib (2.3%) compared to 0 out of 111 patients treated with cyclosporine.
- Events of gastrointestinal perforation have been reported in clinical studies with tofacitinib in rheumatoid arthritis patients, although the role of JAK inhibition in these events is not known.
- Tofacitinib should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
- Treatment with tofacitinib was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.
- Avoid initiation of tofacitinib treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3 treatment with tofacitinib is not recommended.
- Monitor lymphocyte counts at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts
- Treatment with tofacitinib was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.
- Avoid initiation of tofacitinib treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500–1000 cells/mm3, interrupt tofacitinib dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with tofacitinib is not recommended.
- Monitor neutrophil counts at baseline and after 4–8 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC results
- Avoid initiation of tofacitinib treatment in patients with a low hemoglobin level (i.e. less than 9 g/dL). Treatment with tofacitinib should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.
- Monitor hemoglobin at baseline and after 4–8 weeks of treatment and every 3 months thereafter. For recommended modifications based on hemoglobin results.
- Treatment with tofacitinib was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.
- Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of tofacitinib should be interrupted until this diagnosis has been excluded.
- Treatment with tofacitinib was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
- Assessment of lipid parameters should be performed approximately 4–8 weeks following initiation of tofacitinib therapy.
- Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.
- No data are available on the response to vaccination or on the secondary transmission of infection by live vaccines to patients receiving tofacitinib. Live vaccines should not be given concurrently with tofacitinib.
- Update immunizations in agreement with current immunization guidelines prior to initiating tofacitinib therapy.
# 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 predict the rates observed in a broader patient population in clinical practice.
- The following data includes two Phase 2 and five Phase 3 double-blind, controlled, multicenter trials. In these trials, patients were randomized to doses of tofacitinib 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, tofacitinib 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven protocols included provisions for patients taking placebo to receive treatment with tofacitinib at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore some analyses that follow include patients who changed treatment by design or by patient response from placebo to tofacitinib in both the placebo and tofacitinib group of a given interval. Comparisons between placebo and tofacitinib were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and tofacitinib 10 mg twice daily were based on the first 12 months of exposure.
- The long-term safety population includes all patients who participated in a double-blind, controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies. The design of the long-term safety studies allowed for modification of tofacitinib doses according to clinical judgment. This limits the interpretation of the long-term safety data with respect to dose.
- The most common serious adverse reactions were serious infections.
- The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking tofacitinib and 3% for placebo-treated patients.
- In the seven controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.
- The most commonly reported infections with tofacitinib were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).
- In the seven controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received tofacitinib 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily tofacitinib group minus placebo.
- In the seven controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of tofacitinib and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
- The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection.
- In the seven controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of tofacitinib, or 10 mg twice daily of tofacitinib.
- In the seven controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of tofacitinib and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
- Cases of disseminated tuberculosis were also reported. The median tofacitinib exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days)
- In the seven controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of tofacitinib, or 10 mg twice daily of tofacitinib.
- In the seven controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of tofacitinib and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib.
- The median tofacitinib exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).
- In the seven controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either tofacitinib 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily tofacitinib group minus placebo.
- In the seven controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of tofacitinib and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of tofacitinib. The rate difference between tofacitinib doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily tofacitinib minus 5 mg twice daily tofacitinib. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with tofacitinib 10 mg twice daily.
- The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.
- In the controlled clinical trials, confirmed decreases in lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily tofacitinib groups combined during the first 3 months of exposure.
- Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.
- In the controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily tofacitinib groups combined during the first 3 months of exposure.
- There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.
- There was no clear relationship between neutropenia and the occurrence of serious infections.
- In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the controlled clinical trials.
- Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3× ULN) were observed in patients treated with tofacitinib. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tofacitinib, or reduction in tofacitinib dose, resulted in decrease or normalization of liver enzymes.
- In the controlled monotherapy trials (0–3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and tofacitinib 5 mg, and 10 mg twice daily groups.
- In the controlled background DMARD trials (0–3 months), ALT elevations greater than 3× ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3× ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.
- One case of drug-induced liver injury was reported in a patient treated with tofacitinib 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3× ULN and bilirubin elevations greater than 2× ULN, which required hospitalizations and a liver biopsy.
- In the controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the controlled clinical trials are summarized below:
- Mean LDL cholesterol increased by 15% in the tofacitinib 5 mg twice daily arm and 19% in the tofacitinib 10 mg twice daily arm.
- Mean HDL cholesterol increased by 10% in the tofacitinib 5 mg twice daily arm and 12% in the tofacitinib 10 mg twice daily arm.
- Mean LDL/HDL ratios were essentially unchanged in tofacitinib-treated patients.
- In a controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.
- In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the controlled clinical trials.
- In the controlled clinical trials, dose-related elevations in serum creatinine were observed with tofacitinib treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from tofacitinib treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.
- Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily tofacitinib and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in Table 4.
## Postmarketing Experience
- Blood and lymphatic system disorders
- Anemia
- Metabolism and nutrition disorders
- Dehydration
- Psychiatric disorders
- Insomnia
- Nervous system disorders
- Paresthesia
- Respiratory, thoracic and mediastinal disorders
- Dyspnea, cough, sinus congestion
- Gastrointestinal disorders
- Abdominal pain, dyspepsia, vomiting, gastritis, nausea
- Hepatobiliary disorders
- Hepatic steatosis
- Skin and subcutaneous tissue disorders
- Rash, erythema, pruritus
- Musculoskeletal, connective tissue and bone disorders
- Musculoskeletal pain, arthralgia, tendonitis, joint swelling
- General disorders and administration site conditions
- Pyrexia, fatigue, peripheral edema
# Drug Interactions
- Tofacitinib exposure is increased when tofacitinib is coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole).
- Tofacitinib exposure is increased when tofacitinib is coadministered with medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).
- Tofacitinib exposure is decreased when tofacitinib is coadministered with potent CYP3A4 inducers (e.g., rifampin) .
- There is a risk of added immunosuppression when tofacitinib is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in rheumatoid arthritis.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There are no adequate and well-controlled studies in pregnant women. Tofacitinib should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Tofacitinib has been shown to be fetocidal and teratogenic in rats and rabbits when given at exposures 146 times and 13 times, respectively, the maximum recommended human dose (MRHD).
- In a rat embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 146 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively, and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum).
- In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day). In the rabbit embryofetal developmental study, tofacitinib was teratogenic at exposure levels approximately 13 times the MRHD (on an AUC basis at oral doses of 30 mg/kg/day) in the absence of signs of maternal toxicity.
- Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).
- In a peri- and postnatal rat study, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the MRHD (on an AUC basis at oral doses of 50 mg/kg/day). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day).
- Pregnancy registry has been established to monitor the outcomes of pregnant women exposed to XELJAN
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tofacitinib in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tofacitinib during labor and delivery.
### Nursing Mothers
- Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib 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 tofacitinib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug for the mother.
### Pediatric Use
- The safety and effectiveness of tofacitinib in pediatric patients have not been established.
### Geriatic Use
- Of the 3315 patients who enrolled in Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among tofacitinib-treated subjects 65 years of age and older was higher than among those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
### Gender
There is no FDA guidance on the use of Tofacitinib with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tofacitinib with respect to specific racial populations.
### Renal Impairment
- No dose adjustment is required in patients with mild renal impairment. Tofacitinib dose should be reduced to 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, tofacitinib was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/min.
### Hepatic Impairment
- Treatment with tofacitinib is not recommended in patients with severe hepatic impairment. No dose adjustment is required in patients with mild hepatic impairment. tofacitinib dose should be reduced to 5 mg once daily in patients with moderate hepatic impairment. The safety and efficacy of tofacitinib have not been studied in patients with severe hepatic impairment or in patients with positive hepatitis B virus or hepatitis C virus serology
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tofacitinib in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tofacitinib in patients who are immunocompromised.
### Nonteratogenic effects:
# Administration and Monitoring
### Administration
- Oral
### Monitoring
- Laboratory monitoring –Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids.
- Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib. Tofacitinib should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis.
- Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
- Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.
# IV Compatibility
There is limited information regarding IV Compatibility of Tofacitinib in the drug label.
# Overdosage
- Signs, Symptoms, and Laboratory Findings of Acute Overdosage in Humans
- There is no experience with overdose of tofacitinib.
- Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.
- There is no specific antidote for overdose with tofacitinib. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate treatment.
# Pharmacology
## Mechanism of Action
- Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.
## Structure
-
## Pharmacodynamics
- Treatment with XELJANZ was associated with dose-dependent reductions of circulating CD16/56+ natural killer cells, with estimated maximum reductions occurring at approximately 8–10 weeks after initiation of therapy. These changes generally resolved within 2–6 weeks after discontinuation of treatment. Treatment with XELJANZ was associated with dose-dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+ and CD8+) were small and inconsistent. The clinical significance of these changes is unknown.
Total serum IgG, IgM, and IgA levels after 6-month dosing in patients with rheumatoid arthritis were lower than placebo; however, changes were small and not dose-dependent.
After treatment with XELJANZ in patients with rheumatoid arthritis, rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout dosing. Changes in CRP observed with XELJANZ treatment do not reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic activity compared to the pharmacokinetic half-life.
## Pharmacokinetics
Following oral administration of XELJANZ, peak plasma concentrations are reached within 0.5–1 hour, elimination half-life is ~3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 24–48 hours with negligible accumulation after twice daily administration.
Absorption
The absolute oral bioavailability of tofacitinib is 74%. Coadministration of XELJANZ with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, XELJANZ was administered without regard to meals.
Distribution
After intravenous administration, the volume of distribution is 87 L. The protein binding of tofacitinib is ~40%. Tofacitinib binds predominantly to albumin and does not appear to bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.
Metabolism and Elimination
Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.
Pharmacokinetics in Rheumatoid Arthritis Patients
Population PK analysis in rheumatoid arthritis patients indicated no clinically relevant change in tofacitinib exposure, after accounting for differences in renal function (i.e., creatinine clearance) between patients, based on age, weight, gender and race (Figure 1). An approximately linear relationship between body weight and volume of distribution was observed, resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this difference is not considered to be clinically relevant. The between-subject variability (% coefficient of variation) in AUC of tofacitinib is estimated to be approximately 27%.
Specific Populations
The effect of renal and hepatic impairment and other intrinsic factors on the pharmacokinetics of tofacitinib is shown in Figure 1.
Reference values for weight, age, gender, and race comparisons are 70 kg, 55 years, male, and White, respectively; Reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function.
Drug Interactions
Potential for XELJANZ to Influence the PK of Other Drugs
In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 185 times the steady state Cmax of a 5 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when coadministered with XELJANZ.
In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, coadministration with XELJANZ is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.
In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.
Dosing recommendations for coadministered drugs following administration with XELJANZ are shown in Figure 2.
## Nonclinical Toxicology
- In a 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately 6 times the MRHD (on an AUC basis at oral doses of 5 mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels 1 times the MRHD (on an AUC basis at oral doses of 1 mg/kg twice daily).
- The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the MRHD (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.
- In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the MRHD on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.
- Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.
- In rats, tofacitinib at exposure levels approximately 17 times the MRHD (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the MRHD (on an AUC basis at oral doses of 1 mg/kg/day). Tofacitinib exposure levels at approximately 133 times the MRHD (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.
# Clinical Studies
- The XELJANZ clinical development program included two dose-ranging trials and five confirmatory trials.
- Dose selection for XELJANZ was based on two pivotal dose-ranging trials.
- Dose-Ranging Study 1 was a 6-month monotherapy trial in 384 patients with active rheumatoid arthritis who had an inadequate response to a DMARD. Patients who previously received adalimumab therapy were excluded. Patients were randomized to 1 of 7 monotherapy treatments: XELJANZ 1, 3, 5, 10 or 15 mg twice daily, adalimumab 40 mg subcutaneously every other week for 10 weeks followed by XELJANZ 5 mg twice daily for 3 months, or placebo.
- Dose-Ranging Study 2 was a 6-month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to MTX alone received one of 6 dose regimens of XELJANZ (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX.
- The results of XELJANZ-treated patients achieving ACR20 responses in Studies 1 and 2 are shown in Figure 4. Although a dose-response relationship was observed in Study 1, the proportion of patients with an ACR20 response did not clearly differ between the 10 mg and 15 mg doses. Furthermore, there was a smaller proportion of patients who responded to adalimumab monotherapy compared to those treated with XELJANZ doses 3 mg twice daily and greater. In Study 2, a smaller proportion of patients achieved an ACR20 response in the placebo and XELJANZ 1 mg groups compared to patients treated with the other XELJANZ doses. However, there was no difference in the proportion of responders among patients treated with XELJANZ 3, 5, 10, 15 mg twice daily or 20 mg once daily doses.
CONFIRMATORY TRIALS
Study I was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received XELJANZ 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.
Study II was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received XELJANZ 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.
Study III was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received XELJANZ 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX.
Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study IV is an ongoing 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study V was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF-inhibiting biologic agent received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.
Clinical Response
The percentages of XELJANZ-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies I, IV, and V are shown in Table 5. Similar results were observed with Studies II and III. In all trials, patients treated with either 5 or 10 mg twice daily XELJANZ had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in XELJANZ-treated patients were consistent at 6 and 12 months.
# How Supplied
- XELJANZ is provided as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) tablets: White, round, immediate-release film-coated tablets, debossed with "Pfizer" on one side, and "JKI 5" on the other side, and available in:
## Storage
- Store at 20°C to 25°C (68°F to 77°F).
- Do not repackage.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking XELJANZ. Instruct patients to take XELJANZ only as prescribed.
# Precautions with Alcohol
- Alcohol-Tofacitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- XELJANZ ®[1]
# Look-Alike Drug Names
There is limited information regarding Tofacitinib Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Tofacitinib | |
e88430a2bba740672e2c8bccb5f82d2c7c84fe88 | wikidoc | Toll (gene) | Toll (gene)
The Toll genes encode members of the Toll-like receptor class of proteins. ("Toll" is German for "amazing" or "mad".) Toll genes were originally identified in the fruit fly Drosophila melanogaster in 1985,
, and cloned in 1988. Since then, eleven known mammalian Toll genes have been identified.
In flies, Toll was first identified as a gene important in embryogenesis in establishing the dorsal-ventral axis. In 1996, Toll was found to have a role in the fly's immunity to fungal infections. Both mammalian and invertebrate Toll genes are required for innate immunity.
Toll-like receptors in mammals were identified in 1997 at Yale University by Ruslan Medzhitov and Charles Janeway.
Their name derives from Christiane Nüsslein-Volhard's 1985 exclamation, "Das war ja toll!" | Toll (gene)
The Toll genes encode members of the Toll-like receptor class of proteins. ("Toll" is German for "amazing" or "mad".)[1] Toll genes were originally identified in the fruit fly Drosophila melanogaster in 1985, [2]
, and cloned in 1988.[3] Since then, eleven known mammalian Toll genes have been identified.
In flies, Toll was first identified as a gene important in embryogenesis in establishing the dorsal-ventral axis. In 1996, Toll was found to have a role in the fly's immunity to fungal infections. Both mammalian and invertebrate Toll genes are required for innate immunity.
Toll-like receptors in mammals were identified in 1997 at Yale University by Ruslan Medzhitov and Charles Janeway.[4]
Their name derives from Christiane Nüsslein-Volhard's 1985 exclamation, "Das war ja toll!"[2] | https://www.wikidoc.org/index.php/Toll_(gene) | |
9beb527666a2b72de5c0f36da85216d40f3bc5f0 | wikidoc | Tolperisone | Tolperisone
# Overview
Tolperisone, a piperidine derivative, is a centrally acting muscle relaxant. Trade names include Biocalm, Muscodol, Mydeton, Mydocalm, Myolax, Myoxan and Viveo.
# Clinical use
In Tolperisone is indicated for use in the treatment of pathologically increased tone of the cross-striated muscle caused by neurological diseases (damage of the pyramidal tract, multiple sclerosis, myelopathy, encephalomyelitis) and of spastic paralysis and other encephalopathies manifested with muscular dystonia.
Other possible uses include:
- Spondylosis
- Spondylarthrosis
- Cervical and lumbar syndromes
- Arthrosis of the large joints
- Obliterating atherosclerosis of the extremity vessels
- Diabetic angiopathy
- Thromboangiitis obliterans
- Raynaud's syndrome
# Contraindications and cautions
Manufacturers report that tolperisone should not be used in patients with myasthenia gravis. Only limited data are available regarding the safety in children, youths, during pregnancy and breastfeeding. It is not known whether tolperisone is excreted into mother's milk.
# Side effects
Adverse effects occur in fewer than 1% of patients and include muscle weakness, headache, arterial hypotension, nausea, vomiting, dyspepsia, and dry mouth. All effects are reversible.
Allergic reactions occur in fewer than 0.1% of patient and include skin rash, hives, Quincke's edema, and in some cases anaphylactic shock.
# Overdose
Excitability has been noted after ingestion of high doses by children.
In suicide studies of three isolated cases, it is believed that ingestion of tolperisone was the cause of death.
# Interactions
Tolperisone does not have a significant potential for interactions with other pharmaceutical drugs. It cannot be excluded that combination with other centrally acting muscle relaxants, benzodiazepines or non-steroidal anti-inflammatory drugs (NSAIDs) may make a dose reduction necessary in some patients.
# Mechanism of action
Tolperisone is a centrally acting muscle relaxant that acts at the reticular formation in the brain stem by blocking voltage-gated sodium and calcium channels.
# Pharmacokinetics
Tolperisone is absorbed nearly completely from the gut and reaches its peak blood plasma concentration after 1.5 hours. It is extensively metabolised in the liver and kidneys. The substance is excreted via the kidneys in two phases; the first with a half-life of two hours, and the second with a half-life of 12 hours. | Tolperisone
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Tolperisone, a piperidine derivative, is a centrally acting muscle relaxant. Trade names include Biocalm, Muscodol, Mydeton, Mydocalm, Myolax, Myoxan and Viveo.
# Clinical use
In Tolperisone is indicated for use in the treatment of pathologically increased tone of the cross-striated muscle caused by neurological diseases (damage of the pyramidal tract, multiple sclerosis, myelopathy, encephalomyelitis) and of spastic paralysis and other encephalopathies manifested with muscular dystonia.[1][2]
Other possible uses include:[citation needed]
- Spondylosis
- Spondylarthrosis
- Cervical and lumbar syndromes
- Arthrosis of the large joints
- Obliterating atherosclerosis of the extremity vessels
- Diabetic angiopathy
- Thromboangiitis obliterans
- Raynaud's syndrome
# Contraindications and cautions
Manufacturers report that tolperisone should not be used in patients with myasthenia gravis. Only limited data are available regarding the safety in children, youths, during pregnancy and breastfeeding. It is not known whether tolperisone is excreted into mother's milk.[1][2]
# Side effects
Adverse effects occur in fewer than 1% of patients and include muscle weakness, headache, arterial hypotension, nausea, vomiting, dyspepsia, and dry mouth. All effects are reversible.[1][2]
Allergic reactions occur in fewer than 0.1% of patient and include skin rash, hives, Quincke's edema, and in some cases anaphylactic shock.[1][3][4][5]
# Overdose
Excitability has been noted after ingestion of high doses by children.[1]
In suicide studies of three isolated cases, it is believed that ingestion of tolperisone was the cause of death.[6]
# Interactions
Tolperisone does not have a significant potential for interactions with other pharmaceutical drugs. It cannot be excluded that combination with other centrally acting muscle relaxants, benzodiazepines or non-steroidal anti-inflammatory drugs (NSAIDs) may make a dose reduction necessary in some patients.[1][2]
# Mechanism of action
Tolperisone is a centrally acting muscle relaxant that acts at the reticular formation in the brain stem[1] by blocking voltage-gated sodium and calcium channels.[7][8]
# Pharmacokinetics
Tolperisone is absorbed nearly completely from the gut and reaches its peak blood plasma concentration after 1.5 hours. It is extensively metabolised in the liver and kidneys. The substance is excreted via the kidneys in two phases; the first with a half-life of two hours, and the second with a half-life of 12 hours.[1] | https://www.wikidoc.org/index.php/Tolperisone | |
a3cf08e8062cf99e261518de98d79e6ccbbd378b | wikidoc | Tonic water | Tonic water
Tonic water (or Indian tonic water) is a carbonated soft drink flavored with quinine.
The drink gains its name from the medicinal effects of this slightly bitter flavoring. The quinine was added to the drink as a prophylactic against malaria, since it was originally intended for consumption in tropical areas of India and Africa where that disease is endemic.
Tonic water originally contained only carbonated water and a large amount of quinine. However, most tonic water today contains a medically insignificant amount of quinine, and is thus used for its flavor only. It is consequently less bitter, and is also usually sweetened. Some manufacturers also produce diet tonic water. In the United States, the Food and Drug Administration limits the quinine content in tonic water to 83 ppm (83 mg per liter if calculated by mass), which is one-half to one-quarter the concentration used in therapeutic tonic.
Tonic water is often used as a drink mixer for cocktails, especially those made with gin (for example, a gin and tonic). Tonic water with lemon or lime flavor added is known as bitter lemon or bitter lime, respectively. Such soft drinks are more popular in Europe than in the United States.
Tonic water will fluoresce under ultraviolet light, due to the presence of quinine. In fact, the sensitivity of quinine to ultraviolet light (UV) is such that it will fluoresce in direct sunlight. | Tonic water
Tonic water (or Indian tonic water) is a carbonated soft drink flavored with quinine.
The drink gains its name from the medicinal effects of this slightly bitter flavoring. The quinine was added to the drink as a prophylactic against malaria, since it was originally intended for consumption in tropical areas of India and Africa where that disease is endemic.
Tonic water originally contained only carbonated water and a large amount of quinine. However, most tonic water today contains a medically insignificant amount of quinine, and is thus used for its flavor only. It is consequently less bitter, and is also usually sweetened. Some manufacturers also produce diet tonic water. In the United States, the Food and Drug Administration limits the quinine content in tonic water to 83 ppm (83 mg per liter if calculated by mass), which is one-half to one-quarter the concentration used in therapeutic tonic.
Tonic water is often used as a drink mixer for cocktails, especially those made with gin (for example, a gin and tonic). Tonic water with lemon or lime flavor added is known as bitter lemon or bitter lime, respectively. Such soft drinks are more popular in Europe than in the United States.
Tonic water will fluoresce under ultraviolet light, due to the presence of quinine. In fact, the sensitivity of quinine to ultraviolet light (UV) is such that it will fluoresce in direct sunlight. | https://www.wikidoc.org/index.php/Tonic_water | |
28b6c80b68471606621c46a54f3d7ec96a969bb4 | wikidoc | Torticollis | Torticollis
# Overview
Torticollis, or wry neck, is a condition in which the head is tilted toward one side, and the chin is elevated and turned toward the opposite side.
# In children
Torticollis can be congenital or acquired.
## Congenital muscular torticollis
The etiology of congenital muscular torticollis is unclear. Birth trauma or intrauterine malposition is considered to cause damage to the sternocleidomastoid muscle in the neck. This results in a shortening or excessive contraction of the sternocleidomastoid muscle, often with limited range of motion in both rotation and lateral bending. The head is typically tilted in lateral bending toward the affected muscle and rotated toward the opposite side.
The reported incidence of congenital torticollis is 0.3-2.0 %. Sometimes a mass (a sternomastiod tumor) in the affected muscle may be noted, this appears at the age of two to four weeks, it disappears gradually, but sometimes the muscle becomes fibrotic. It is likely to disappear within the first five to eight months of life.
The condition is treated initially with physical therapy, with stretching to correct the tightness, strengthening exercises to achieve muscular balance, handling to stimulate symmetry. A TOT Collar is sometimes used. About 5–10% require surgery, "surgical release" of the muscle if stretching fails.
Infants with torticollis have a higher risk for plagiocephaly. Altering the head position and using a pillow when supine helps as does giving a lot of tummy time when awake.
Other less common causes such as tumors, infections, ophthalmologic problems and other abnormalities should be ruled out. For example, ocular torticollis due to cranial nerve IV palsy should not be treated with physical therapy. In this situation, the torticollis is a neurologic adaptation designed to maintain binocularity. Treatment should be targeted at the extraocular muscle imbalance.
In general, if torticollis is not corrected facial asymmetry can develop. Head position should corrected before adulthood (to about the age of 18 there can be improvement). Younger children show the best results.
Congenital torticollis develops in the infant but can be diagnosed at older ages, even in adults who were missed as infants/children.
The word torticollis means wry neck: Acquired torticollis is not the same as congenital torticollis. All ages can suffer from acquired torticollis.
A common, but effective, treatment involves a multi-phase process:
1) Low-impact exercise to increase strong form neck stability
2) Chiropractic manipulation of the neck.
3) Extended heat application.
4) Repetitive shiatsu massage.
## Acquired torticollis
Acquired torticollis occurs because of another problem and usually presents in previously normal children.
- Trauma to the neck can cause atlantoaxial rotatory subluxation, in which the two vertebrae closest to the skull slide with respect to each other, tearing stabilizing ligaments; this condition is treated with traction to reduce the subluxation, followed by bracing or casting until the ligamentous injury heals.
- Tumors of the skull base (posterior fossa tumors) can compress the nerve supply to the neck and cause torticollis, and these problems must be treated surgically.
- Infections in the posterior pharynx can irritate the nerves supplying the neck muscles and cause torticollis, and these infections may be treated with antibiotics if they are not too severe, but could require surgical debridement in intractable cases.
- Ear infections and surgical removal of the adenoids can cause an entity known as Grisel's syndrome, a subluxation of the upper cervical joints, mostly the atlantoaxial joint, due to inflammatory laxity of the ligaments caused by an infection. This bridge must either be broken through manipulation of the neck, or surgically resected.
- The use of certain drugs, such as antipsychotics, can cause torticollis. and Pergolide
- There are many other rare causes of torticollis.
## Evaluation
Evaluation of a child with torticollis begins with history taking to determine circumstances surrounding birth and any possibility of trauma or associated symptoms. Physical examination reveals decreased rotation and bending to the side opposite from the affected muscle. Some say that congenital cases more often involve the right side, but there is not complete agreement about this in published studies. Evaluation should include a thorough neurologic examination, and the possibility of associated conditions such as developmental dysplasia of the hip and clubfoot should be examined. Radiographs of the cervical spine should be obtained to rule out obvious bony abnormality, and MRI should be considered if there is concern about structural problems or other conditions.
Evaluation by an ophthalmologist should be considered in children to ensure that the torticollis is not caused by vision problems (IV cranial nerve palsy, nystagmus-associated "null position," etc.). Most cases in infants respond well to physical therapy. Other causes should be treated as noted above.
# In adults
Wry Neck can also occur in adults for various reasons, such as an injury to the neck or simply sleeping in an awkward position. One may find that upon awakening it is extremely difficult to lift one's head or is extremely painful to move it.
# In animals
The condition can also occur in animals, usually as a result of an inner ear infection but sometimes as a result of an injury. It is seen largely in domestic rodents and rabbits, but may also appear in dogs and other animals. | Torticollis
For patient information click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Torticollis, or wry neck, is a condition in which the head is tilted toward one side, and the chin is elevated and turned toward the opposite side.
# In children
Torticollis can be congenital or acquired.
## Congenital muscular torticollis
The etiology of congenital muscular torticollis is unclear. Birth trauma or intrauterine malposition is considered to cause damage to the sternocleidomastoid muscle in the neck. This results in a shortening or excessive contraction of the sternocleidomastoid muscle, often with limited range of motion in both rotation and lateral bending. The head is typically tilted in lateral bending toward the affected muscle and rotated toward the opposite side.
The reported incidence of congenital torticollis is 0.3-2.0 %.[1] Sometimes a mass (a sternomastiod tumor) in the affected muscle may be noted, this appears at the age of two to four weeks, it disappears gradually, but sometimes the muscle becomes fibrotic. It is likely to disappear within the first five to eight months of life.
The condition is treated initially with physical therapy, with stretching to correct the tightness, strengthening exercises to achieve muscular balance, handling to stimulate symmetry. A TOT Collar is sometimes used. About 5–10% require surgery,[2][3] "surgical release" of the muscle if stretching fails.
Infants with torticollis have a higher risk for plagiocephaly. Altering the head position and using a pillow when supine helps as does giving a lot of tummy time when awake.
Other less common causes such as tumors, infections, ophthalmologic problems and other abnormalities should be ruled out. For example, ocular torticollis due to cranial nerve IV palsy should not be treated with physical therapy. In this situation, the torticollis is a neurologic adaptation designed to maintain binocularity. Treatment should be targeted at the extraocular muscle imbalance.
In general, if torticollis is not corrected facial asymmetry can develop. Head position should corrected before adulthood (to about the age of 18 there can be improvement). Younger children show the best results.
Congenital torticollis develops in the infant but can be diagnosed at older ages, even in adults who were missed as infants/children.
The word torticollis means wry neck: Acquired torticollis is not the same as congenital torticollis. All ages can suffer from acquired torticollis.
A common, but effective, treatment involves a multi-phase process:
1) Low-impact exercise to increase strong form neck stability
2) Chiropractic manipulation of the neck.
3) Extended heat application.
4) Repetitive shiatsu massage.
## Acquired torticollis
Acquired torticollis occurs because of another problem and usually presents in previously normal children.
- Trauma to the neck can cause atlantoaxial rotatory subluxation, in which the two vertebrae closest to the skull slide with respect to each other, tearing stabilizing ligaments; this condition is treated with traction to reduce the subluxation, followed by bracing or casting until the ligamentous injury heals.
- Tumors of the skull base (posterior fossa tumors) can compress the nerve supply to the neck and cause torticollis, and these problems must be treated surgically.
- Infections in the posterior pharynx can irritate the nerves supplying the neck muscles and cause torticollis, and these infections may be treated with antibiotics if they are not too severe, but could require surgical debridement in intractable cases.
- Ear infections and surgical removal of the adenoids can cause an entity known as Grisel's syndrome, a subluxation of the upper cervical joints, mostly the atlantoaxial joint, due to inflammatory laxity of the ligaments caused by an infection. This bridge must either be broken through manipulation of the neck, or surgically resected.
- The use of certain drugs, such as antipsychotics, can cause torticollis.[4] and Pergolide
- There are many other rare causes of torticollis.
## Evaluation
Evaluation of a child with torticollis begins with history taking to determine circumstances surrounding birth and any possibility of trauma or associated symptoms. Physical examination reveals decreased rotation and bending to the side opposite from the affected muscle. Some say that congenital cases more often involve the right side, but there is not complete agreement about this in published studies. Evaluation should include a thorough neurologic examination, and the possibility of associated conditions such as developmental dysplasia of the hip and clubfoot should be examined. Radiographs of the cervical spine should be obtained to rule out obvious bony abnormality, and MRI should be considered if there is concern about structural problems or other conditions.
Evaluation by an ophthalmologist should be considered in children to ensure that the torticollis is not caused by vision problems (IV cranial nerve palsy, nystagmus-associated "null position," etc.). Most cases in infants respond well to physical therapy. Other causes should be treated as noted above.
# In adults
Wry Neck can also occur in adults for various reasons, such as an injury to the neck or simply sleeping in an awkward position. One may find that upon awakening it is extremely difficult to lift one's head or is extremely painful to move it.
# In animals
The condition can also occur in animals, usually as a result of an inner ear infection but sometimes as a result of an injury. It is seen largely in domestic rodents and rabbits, but may also appear in dogs and other animals. | https://www.wikidoc.org/index.php/Torticollis | |
61f926b0428596a12fcfa26c45f0dbf0a386fea5 | wikidoc | Toxic metal | Toxic metal
# Overview
Toxic metals are metals that form poisonous soluble compounds and have no biological role, i.e. are not essential minerals, or are in the wrong form. Often heavy metals are thought as synonymous, but lighter metals also have toxicity, as exemplified by beryllium, and not all heavy metals are particularly toxic and some are even essential (such as iron). The definition may also include trace elements when considered in abnormally high, toxic doses. A difference is that there is no beneficial dose for a toxic metal with no biological role.
Toxic metals imitate the action of an essential element in the body, distorting the metabolic process to cause illness. Many metals, particularly heavy metals are toxic, but some heavy metals are essential, have a low toxicity, and bismuth is even non-toxic. Most often the definition includes at least cadmium, lead, mercury and the radioactive metals. Metalloids (arsenic, polonium) may be included in the definition. Radioactive metals have both radiation toxicity and chemical toxicity. Metals in an oxidation state abnormal to the body may also become toxic: chromium(III) is an essential trace element, but chromium(VI) is a carcinogen.
The toxicity is a function of solubility, so that as insoluble salts or even in the metallic form, toxic metals may have negligible toxicity. On the other hand, organometallic forms, such as dimethyl mercury and tetraethyl lead, are extremely toxic.
Toxic metals bioaccumulate in the body and in the food chain. The exceptions are barium and aluminum. Therefore, a common characteristic of toxic metals is the chronic nature of their toxicity.
Toxic metals:
- Barium
- Beryllium
- Aluminum
- Cadmium
- Lead - lead poisoning
- Mercury - mercury poisoning
- Thallium
- Antimony
- Radioactive metals:
Thorium
Uranium
The transuraniums, such as plutonium, americium, etc.
Polonium (a metalloid)
Radioactive isotopes of lighter elements, e.g. cobalt-60.
- Thorium
- Uranium
- The transuraniums, such as plutonium, americium, etc.
- Polonium (a metalloid)
- Radioactive isotopes of lighter elements, e.g. cobalt-60.
- Arsenic (see arsenic poisoning) is a metalloid.
Trace elements with toxicity:
- Chromium as hexavalent Cr(VI)
- Nickel
- Copper
- Iron | Toxic metal
# Overview
Toxic metals are metals that form poisonous soluble compounds and have no biological role, i.e. are not essential minerals, or are in the wrong form[1]. Often heavy metals are thought as synonymous, but lighter metals also have toxicity, as exemplified by beryllium, and not all heavy metals are particularly toxic and some are even essential (such as iron). The definition may also include trace elements when considered in abnormally high, toxic doses. A difference is that there is no beneficial dose for a toxic metal with no biological role.
Toxic metals imitate the action of an essential element in the body, distorting the metabolic process to cause illness. Many metals, particularly heavy metals are toxic, but some heavy metals are essential, have a low toxicity, and bismuth is even non-toxic. Most often the definition includes at least cadmium, lead, mercury and the radioactive metals. Metalloids (arsenic, polonium) may be included in the definition. Radioactive metals have both radiation toxicity and chemical toxicity. Metals in an oxidation state abnormal to the body may also become toxic: chromium(III) is an essential trace element, but chromium(VI) is a carcinogen.
The toxicity is a function of solubility, so that as insoluble salts or even in the metallic form, toxic metals may have negligible toxicity. On the other hand, organometallic forms, such as dimethyl mercury and tetraethyl lead, are extremely toxic.
Toxic metals bioaccumulate in the body and in the food chain. The exceptions are barium and aluminum. Therefore, a common characteristic of toxic metals is the chronic nature of their toxicity.
Toxic metals:
- Barium
- Beryllium
- Aluminum
- Cadmium
- Lead - lead poisoning
- Mercury - mercury poisoning
- Thallium
- Antimony
- Radioactive metals:
Thorium
Uranium
The transuraniums, such as plutonium, americium, etc.
Polonium (a metalloid)
Radioactive isotopes of lighter elements, e.g. cobalt-60.
- Thorium
- Uranium
- The transuraniums, such as plutonium, americium, etc.
- Polonium (a metalloid)
- Radioactive isotopes of lighter elements, e.g. cobalt-60.
- Arsenic (see arsenic poisoning) is a metalloid.
Trace elements with toxicity:
- Chromium as hexavalent Cr(VI)
- Nickel
- Copper
- Iron | https://www.wikidoc.org/index.php/Toxic_metal | |
63961cf3066af8bc717ba19d08ded7baaec80673 | wikidoc | Trabectedin | Trabectedin
# 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
Trabectedin is an alkylating drug that is FDA approved for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Common adverse reactions include nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache (≥20%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Trabectedin is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen
- Recommended Dose and Schedule
- The recommended dose is 1.5 mg/m2 administered as an intravenous infusion over 24 hours through a central venous line every 21 days (3 weeks), until disease progression or unacceptable toxicity, in patients with normal bilirubin and AST or ALT less than or equal to 2.5 times the upper limit of normal.
- Hepatic Impairment: The recommended dose is 0.9 mg/m2 in patients with moderate hepatic impairment (bilirubin levels 1.5 times to 3 times the upper limit of normal, and AST and ALT less than 8 times the upper limit of normal). Do not administer Trabectedin to patients with severe hepatic impairment (bilirubin levels above 3 times to 10 times the upper limit of normal, and any AST and ALT).
- Premedication
- Administer dexamethasone 20 mg intravenously 30 minutes prior to each dose of Trabectedin.
- Dose Modifications
- Permanently discontinue Trabectedin for:
- The recommended dose modifications for adverse reactions are listed in Table 1. Once reduced, the dose of Trabectedin should not be increased in subsequent treatment cycles.
- Table 1: Recommended Dose Modification
YONDELIS: Trabectedin's Brand name
The recommended starting doses and dose reductions for Trabectedin are listed in Table 2:
- Table 2: Recommended Starting Doses and Dose Reductions
YONDELIS: Trabectedin's Brand name
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trabectedin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trabectedin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness 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 Trabectedin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trabectedin in pediatric patients.
# Contraindications
Trabectedin is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin.
# Warnings
Neutropenic sepsis, including fatal cases, can occur with Trabectedin. In Trial 1, the incidence of Grade 3 or 4 neutropenia, based on laboratory values, in patients receiving Trabectedin was 43% (161/378). The median time to the first occurrence of Grade 3 or 4 neutropenia was 16 days (range: 8 days to 9.7 months); the median time to complete resolution of neutropenia was 13 days (range: 3 days to 2.3 months). Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 18 patients (5%) treated with Trabectedin. Ten patients (2.6%) experienced neutropenic sepsis, 5 of whom had febrile neutropenia, which was fatal in 4 patients (1.1%).
Assess neutrophil count prior to administration of each dose of Trabectedin and periodically throughout the treatment cycle. Withhold Trabectedin for neutrophil counts of less than 1,500 cells/microliter on the day of dosing. Permanently reduce the dose of Trabectedin for life-threatening or prolonged, severe neutropenia in the preceding cycle.
Trabectedin can cause rhabdomyolysis and musculoskeletal toxicity. In Trial 1, rhabdomyolysis leading to death occurred in 3 (0.8%) of the 378 patients receiving Trabectedin. Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378 patients receiving Trabectedin, including Grade 3 or 4 CPK elevation in 24 patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine with any CPK elevation, including 1 patient (0.6%) with Grade 3 CPK elevation. Among the 24 patients receiving Trabectedin with Grade 3 or 4 CPK elevation, renal failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of renal failure occurred in 4 of these 11 patients (1.1%). The median time to first occurrence of Grade 3 or 4 CPK elevations was 2 months (range: 1 to 11.5 months). The median time to complete resolution was 14 days (range: 5 days to 1 month).
Assess CPK levels prior to each administration of Trabectedin. Withhold Trabectedin for serum CPK levels more than 2.5 times the upper limit of normal. Permanently discontinue Trabectedin for rhabdomyolysis.
Hepatotoxicity, including hepatic failure, can occur with Trabectedin. Patients with serum bilirubin levels above the upper limit of normal or AST or ALT levels >2.5 × upper limit of normal were not enrolled in Trial 1. In Trial 1, the incidence of Grade 3–4 elevated liver function tests (LFTs; defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) was 35% (134/378) in patients receiving Trabectedin. The median time to development of Grade 3–4 elevation in ALT or AST was 29 days (range: 3 days to 11.5 months). Of the 134 patients with Grade 3–4 elevations in LFTs, 114 (85%) experienced complete resolution with the median time to complete resolution of 13 days (range: 4 days to 4.4 months).
In Trial 1, the incidence of drug-induced liver injury (defined as concurrent elevation in ALT or AST of more than three times the upper limit of normal, alkaline phosphatase less than two times the upper limit of normal, and total bilirubin at least two times the upper limit of normal) was 1.3% (5/378) in patients receiving Trabectedin. ALT or AST elevation greater than eight times the upper limit of normal occurred in 18% (67/378) of patients receiving Trabectedin.
Assess LFTs prior to each administration of Trabectedin and as clinically indicated based on underlying severity of pre-existing hepatic impairment. Manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation based on severity and duration of LFT abnormality.
Cardiomyopathy including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur with Trabectedin. In Trial 1, patients with a history of New York Heart Association Class II to IV heart failure or abnormal left ventricular ejection fraction (LVEF) at baseline were ineligible. In Trial 1, cardiomyopathy occurred in 23 patients (6%) receiving Trabectedin and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving Trabectedin and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving Trabectedin and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving Trabectedin was 5.3 months (range: 26 days to 15.3 months).
Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of Trabectedin and at 2- to 3-month intervals thereafter until Trabectedin is discontinued. Withhold Trabectedin for LVEF below lower limit of normal. Permanently discontinue Trabectedin for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks.
Extravasation of Trabectedin, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than 1 week after the extravasation. There is no specific antidote for extravasation of Trabectedin. Administer Trabectedin through a central venous line.
Based on its mechanism of action, Trabectedin can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose of Trabectedin. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of Trabectedin.
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are discussed in more detail in other sections of the labeling:
- Anaphylaxis
- Neutropenic Sepsis
- Rhabdomyolysis
- Hepatotoxicity
- Cardiomyopathy
- Extravasation Resulting in Tissue Necrosis
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 described below reflect exposure to Trabectedin in 755 patients with soft tissue sarcoma including 197 (26%) patients exposed to Trabectedin for greater than or equal to 6 months and 57 (8%) patients exposed to Trabectedin for greater than or equal to 1 year. The safety of Trabectedin was evaluated in six open-label, single-arm trials, in which 377 patients received Trabectedin and one open-label, randomized, active-controlled clinical trial in which 378 patients received Trabectedin (Trial 1). All patients received Trabectedin at the recommended dosing regimen of 1.5 mg/m2 administered as an intravenous infusion over 24 hours once every 3 weeks (q3wk, 24-h). The median age was 54 years (range: 18 to 81 years), 63% were female, and all patients had metastatic soft tissue sarcoma.
Tables 3 and 4 present selected adverse reactions and laboratory abnormalities, respectively, observed in Trial 1, an open-label, randomized (2:1), active-controlled trial in which 550 patients with previously treated leiomyosarcoma or liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) received Trabectedin 1.5 mg/m2 intravenous infusion over 24 hours once every 3 weeks (n=378) or dacarbazine 1000 mg/m2 intravenous infusion over 20 to 120 minutes once every 3 weeks (n=172). All patients treated with Trabectedin were required to receive dexamethasone 20 mg intravenous injection 30 minutes prior to start of the Trabectedin infusion.
In Trial 1, patients had been previously treated with an anthracycline- and ifosfamide-containing regimen or with an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen. The trial excluded patients with known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, such as cirrhosis or active hepatitis, and history of myocardial infarction within 6 months, history of New York Heart Association Class II to IV heart failure, or abnormal left ventricular ejection fraction at baseline. The median age of patients in Trial 1 was 57 years (range: 17 to 81 years), with 69% female, 77% White, 12% Black or African American, 4% Asian, and <1% American Indian or Alaska Native. The median duration of exposure to trabectedin was 13 weeks (range: 1 to 127 weeks) with 30% of patients exposed to Trabectedin for greater than 6 months and 7% of patients exposed to Trabectedin for greater than 1 year.
In Trial 1, adverse reactions resulting in permanent discontinuation of Trabectedin occurred in 26% (98/378) of patients; the most common were increased liver tests (defined as ALT, AST, alkaline phosphatase, bilirubin) (5.6%), thrombocytopenia (3.4%), fatigue (1.6%), increased creatine phosphokinase (1.1%), and decreased ejection fraction (1.1%). Adverse reactions that led to dose reductions occurred in 42% (158/378) of patients treated with Trabectedin; the most common were increased liver tests (24%), neutropenia (including febrile neutropenia) (8%), thrombocytopenia (4.2%), fatigue (3.7%), increased creatine phosphokinase (2.4%), nausea (1.1%), and vomiting (1.1%). Adverse reactions led to dose interruptions in 52% (198/378) of patients treated with Trabectedin; the most common were neutropenia (31%), thrombocytopenia (15%), increased liver tests (6%), fatigue (2.9%), anemia (2.6%), increased creatinine (1.1%), and nausea (1.1%).
The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. The most common laboratory abnormalities (≥20%) were increases in AST or ALT, increased alkaline phosphatase, hypoalbuminemia, increased creatinine, increased creatine phosphokinase, anemia, neutropenia, and thrombocytopenia.
- Table 3: Selected Adverse Reactions- Occurring in ≥10% of Patients Receiving Trabectedin and at a Higher Incidence than in the Control Arm - Trial 1
YONDELIS: Trabectedin's Brand name
Other clinically important adverse reactions observed in <10% of patients (N=755) with soft tissue sarcoma receiving Trabectedin were:
- Nervous system disorders: peripheral neuropathy, paresthesia, hypoesthesia.
- Respiratory, thoracic, and mediastinal disorders: pulmonary embolism.
- Table 4: Incidence of Selected Treatment-Emergent Laboratory Abnormalities- - Trial 1
YONDELIS: Trabectedin's Brand name
## Postmarketing Experience
There is limited information regarding Trabectedin Postmarketing Experience in the drug label.
# Drug Interactions
Coadministration of Trabectedin with ketoconazole, a strong CYP3A inhibitor, increased systemic exposure of trabectedin by 66%. Avoid using strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir,lopinavir, ritonavir, boceprevir, nelfinavir,saquinavir, telaprevir, nefazodone, conivaptan) in patients taking Trabectedin. Avoid taking grapefruit or grapefruit juice during Trabectedin treatment. If a strong CYP3A inhibitor for short-term use (i.e., less than 14 days) must be used, administer the strong CYP3A inhibitor 1 week after the Trabectedin infusion, and discontinue it the day prior to the next Trabectedin infusion.
Coadministration of Trabectedin with rifampin, a strong CYP3A inducer, decreased systemic exposure of trabectedin by 31%. Avoid using strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John's wort) in patients taking Trabectedin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
. Based on its mechanism of action, trabectedin can cause fetal harm when administered during pregnancy. There are no available data with the use of Trabectedin during pregnancy. Animal reproductive and developmental studies at relevant doses have not been conducted with trabectedin; however, placental transfer of trabectedin was demonstrated in pregnant rats. Advise pregnant woman of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population are unknown; however, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trabectedin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trabectedin during labor and delivery.
### Nursing Mothers
There are no data on the presence of trabectedin in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions from Trabectedin in breastfed infants, advise a nursing woman to discontinue nursing during treatment with Trabectedin.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Clinical studies of Trabectedin 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 Trabectedin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trabectedin with respect to specific racial populations.
### Renal Impairment
No dose adjustment is recommended in patients with mild (creatinine clearance (CLcr) 60–89 mL/min) or moderate (CLcr of 30–59 mL/min) renal impairment.
The pharmacokinetics of trabectedin has not been evaluated in patients with severe renal impairment (CLcr <30 mL/min) or end stage renal disease.
### Hepatic Impairment
The mean trabectedin exposure was (97%) higher in patients with moderate (bilirubin levels 1.5 to 3.0 times the upper limit of normal, and AST and ALT less than 8 times the upper limit of normal) hepatic impairment compared to patients with normal (total bilirubin ≤ the upper limit of normal, and AST and ALT ≤ the upper limit of normal) liver function. Reduce Trabectedin dose in patients with moderate hepatic impairment.
Do not administer Trabectedin to patients with severe hepatic impairment (bilirubin levels above 3 times to 10 times the upper limit of normal, and any AST and ALT).
### Females of Reproductive Potential and Males
- Contraception
- Females: Advise female patients of reproductive potential to use effective contraception during and for 2 months after the last dose of Trabectedin.
- Males: Trabectedin may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for 5 months after the last dose of Trabectedin.
- Infertility: Trabectedin may result in decreased fertility in males and females.
### Immunocompromised Patients
There is no FDA guidance one the use of Trabectedin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Preparation
- Trabectedin is a cytotoxic drug. Follow applicable special handling and disposal procedures.
- Using aseptic technique, inject 20 mL of Sterile Water for Injection, USP into the vial. Shake the vial until complete dissolution. The reconstituted solution is clear, colorless to pale brownish-yellow, and contains 0.05 mg/mL of trabectedin.
- Inspect for particulate matter and discoloration prior to further dilution. Discard vial if particles or discoloration are observed.
- Immediately following reconstitution, withdraw the calculated volume of trabectedin and further dilute in 500 mL of 0.9% Sodium Chloride, USP or 5% Dextrose Injection, USP.
- Do not mix Trabectedin with other drugs.
- Discard any remaining solution within 30 hours of reconstituting the lyophilized powder.
- Trabectedin diluted solution is compatible with Type I colorless glass vials, polyvinylchloride (PVC) and polyethylene (PE) bags and tubing, PE and polypropylene (PP) mixture bags, polyethersulfone (PES) in-line filters, titanium, platinum or plastic ports, silicone and polyurethane catheters, and pumps having contact surfaces made of PVC, PE, or PE/PP.
- Administration
- Infuse the reconstituted, diluted solution over 24 hours through a central venous line using an infusion set with a 0.2 micron polyethersulfone (PES) in-line filter to reduce the risk of exposure to adventitious pathogens that may be introduced during solution preparation.
- Complete infusion within 30 hours of initial reconstitution. Discard any unused portion of the reconstituted product or of the infusion solution.
### Monitoring
There is limited information regarding Trabectedin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Trabectedin and IV administrations.
# Overdosage
There is no specific antidote for Trabectedin. Hemodialysis is not expected to enhance the elimination of Trabectedin because trabectedin is highly bound to plasma proteins (97%) and not significantly renally excreted.
# Pharmacology
## Mechanism of Action
Trabectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove. Adduct formation triggers a cascade of events that can affect the subsequent activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death.
## Structure
Trabectedin is an alkylating agent with the chemical name (1'R,6R,6aR,7R,13S,14S,16R)-5-(acetyloxy)-3',4',6,6a,7,13,14,16-octahydro-6',8,14-trihydroxy-7',9-dimethoxy-4,10,23-trimethyl-spiroisoquinobenzazocine-20,1'(2'H)-isoquinolin]-19-one. The molecular formula is C39H43N3O11S. The molecular weight is 761.84 daltons. The chemical structure is shown below:
Trabectedin is hydrophobic and has a low solubility in water.
Trabectedin for injection is supplied as a sterile lyophilized white to off-white powder/cake in a single-dose vial. Each single-dose vial contains 1 mg of trabectedin, 27.2 mg potassium dihydrogen phosphate, 400 mg sucrose, and phosphoric acid and potassium hydroxide (for pH adjustment to 3.6 – 4.2).
## Pharmacodynamics
- Cardiac Electrophysiology
- The effect of trabectedin on the QT/QTc interval was evaluated in 75 patients who received placebo on day 1 and trabectedin (1.3 mg/m2) as a 3-hour intravenous infusion on day 2. No patients in the study showed a QTc interval exceeding 500 msec or more than 60 msec increase from baseline, and no large changes in the mean QTc interval (i.e., >20 msec) were observed.
## Pharmacokinetics
The pharmacokinetics of trabectedin is characterized by a rapid decline phase at the end of the infusion and slower exponential phases. Population pharmacokinetic analyses suggest that the pharmacokinetics of trabectedin is dose-proportional (over the dose range of 0.024 to 1.8 mg/m2) and exposure is time-independent. No accumulation of trabectedin in plasma is observed upon repeated administrations every 3 weeks.
- Distribution
- Binding of trabectedin to human plasma proteins was approximately 97%, independent of trabectedin concentrations ranging from 10 ng/mL to 100 ng/mL. Steady state volume of distribution of trabectedin exceeds 5000 L.
- Elimination
- The estimated mean (% coefficient of variation) clearance of trabectedin is 31.5 L/hr (50%) and the terminal elimination half-life is approximately 175 hours.
- Metabolism
- CYP3A is the predominant CYP enzyme responsible for the hepatic metabolism of trabectedin.
- Trabectedin was extensively metabolized with negligible unchanged drug in urine and feces following administration of trabectedin to humans.
- Excretion
- In patients with solid tumors, following a 3-hour or a 24-hour intravenous infusion of 14C-labeled trabectedin, 64% of the total administered radioactive dose was recovered in 24 days, with 58% in feces and 6% in urine.
- Specific Populations
- The following population characteristics are not associated with a clinically significant effect on the pharmacokinetics of trabectedin: sex, age (19 to 83 years), body weight (36 to 148 kg), body surface area (0.9 to 2.8 m2), mild hepatic impairment, or mild to moderate renal impairment. The effects of severe hepatic impairment, severe renal impairment or end stage renal disease on trabectedin exposure are unknown.
- Hepatic Impairment
- The geometric mean dose normalized trabectedin exposure (AUC) increased by 97% (90% CI: 20%, 222%) in patients with moderate hepatic impairment following administration of a single Trabectedin dose of 0.58 mg/m2 or 0.9 mg/m2 compared to patients with normal liver function following administration of a single Trabectedin dose of 1.3 mg/m2.
- Drug Interactions
- Effect of Strong CYP3A Inhibitors on Trabectedin
- Coadministration of multiple doses of ketoconazole (200 mg twice daily for 7.5 days) with a single dose of Trabectedin (0.58 mg/m2) on day 1 increased trabectedin dose-normalized AUC by 66% and Cmax by 22% compared to a single Trabectedin dose (1.3 mg/m2) given alone.
- Effect of Strong CYP3A Inducers on Trabectedin
- Coadministration of multiple doses of rifampin (600 mg daily for 6 days) with a single Trabectedin dose (1.3 mg/m2) on day 6 decreased trabectedin AUC by 31% and Cmax by 21% compared to a single Trabectedin dose (1.3 mg/m2) given alone.
- Effect of Trabectedin on CYP Enzymes
- In vitro, trabectedin has limited inhibition or induction potential of major CYP enzymes (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4).
## Nonclinical Toxicology
Trabectedin is genotoxic in both in vitro and in vivo studies. Long-term carcinogenicity studies have not been performed.
Fertility studies with trabectedin were not performed. In male rats there were limited histopathological signs of hemorrhage and degeneration in the testes following repeated administration of trabectedin at doses approximately 0.2 times the 1.5 mg/m2 human dose based on body surface area.
# Clinical Studies
The clinical efficacy and safety of Trabectedin in patients with metastatic or recurrent leiomyosarcoma or liposarcoma were demonstrated in Trial 1, a randomized (2:1), open-label, active-controlled trial comparing treatment with Trabectedin 1.5 mg/m2 as a 24-hour continuous intravenous infusion once every 3 weeks to dacarbazine 1000 mg/m2 intravenous infusion (20 to 120 minutes) once every 3 weeks. Treatment continued in both arms until disease progression or unacceptable toxicity; all patients in the Trabectedin arm were required to receive dexamethasone 20 mg intravenous injection prior to each Trabectedin infusion. Patients were required to have unresectable, locally advanced or metastatic leiomyosarcoma or liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) and previous treatment with an anthracycline- and ifosfamide-containing regimen or an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen. Randomization was stratified by subtype of soft tissue sarcoma (leiomyosarcoma vs. liposarcoma), ECOG performance status (0 vs. 1), and number of prior chemotherapy regimens (1 vs. ≥2). The efficacy outcome measures were investigator-assessed progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), overall survival (OS), objective response rate (ORR), and duration of response (DOR). Patients in the dacarbazine arm were not offered Trabectedin at the time of disease progression.
A total of 518 patients were randomized, 345 to the Trabectedin arm and 173 patients to the dacarbazine arm. The median patient age was 56 years (range: 17 to 81); 30% were male; 76% White, 12% Black, and 4% Asian; 73% had leiomyosarcomas and 27% liposarcomas; 49% had an ECOG PS of 0; and 89% received ≥2 prior chemotherapy regimens. The most common (≥20%) pre-study chemotherapeutic agents administered were doxorubicin (90%), gemcitabine (81%), docetaxel (74%), and ifosfamide (59%). Approximately 10% of patients had received pazopanib.
Trial 1 demonstrated a statistically significant improvement in PFS. An exploratory analysis of independent radiology committee-determined PFS, in a subgroup consisting of approximately 60% of the total population, provided similar results to the investigator-determined PFS. Efficacy results from Trial 1 are presented in the table below.
- Table 5: Efficacy Results for Trial 1
YONDELIS: Trabectedin's Brand name
- Figure 1: Kaplan-Meier Curves of Progression-Free Survival in Trial 1
YONDELIS: Trabectedin's Brand name
# How Supplied
Trabectedin is supplied in a glass vial containing 1 mg trabectedin. Each carton contains one vial (NDC: 59676-610-01).
## Storage
Store Trabectedin vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF).
Trabectedin is a cytotoxic drug. Follow applicable special handling and disposal procedures.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Myelosuppression: Inform patients of the risks of myelosuppression. Instruct patients to immediately contact their healthcare provider for fever or unusual bruising, bleeding, tiredness, or paleness.
- Rhabdomyolysis: Advise patients to contact their healthcare provider if they experience severe muscle pain or weakness.
- Hepatotoxicity: Advise patients to contact their healthcare provider immediately for yellowing of skin and eyes (jaundice), pain in the upper right quadrant, severe nausea or vomiting, difficulty in concentrating, disorientation, or confusion.
- Cardiomyopathy: Advise patients to contact their healthcare provider for new onset chest pain, shortness of breath, fatigue, lower extremity edema, or heart palpitations.
- Hypersensitivity: Advise patients to seek immediate medical attention for symptoms of allergic reactions including difficulty breathing, chest tightness, wheezing, severe dizziness or light-headedness, swelling of the lips or skin rash.
- Extravasation: Inform patients of the risks of extravasation and to notify their healthcare provider for redness, swelling, itchiness and discomfort or leakage at the injection site.
- Embryofetal toxicity: Advise pregnant women of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Trabectedin.
- Females and males of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with Trabectedin and for at least 2 months after last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Trabectedin and for at least 5 months after the last dose.
- Lactation: Advise females not to breastfeed during treatment with Trabectedin.
# Precautions with Alcohol
Alcohol-Trabectedin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
YONDELIS®
# Look-Alike Drug Names
There is limited information regarding Trabectedin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Trabectedin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [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
Trabectedin is an alkylating drug that is FDA approved for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen. Common adverse reactions include nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache (≥20%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Trabectedin is indicated for the treatment of patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-containing regimen
- Recommended Dose and Schedule
- The recommended dose is 1.5 mg/m2 administered as an intravenous infusion over 24 hours through a central venous line every 21 days (3 weeks), until disease progression or unacceptable toxicity, in patients with normal bilirubin and AST or ALT less than or equal to 2.5 times the upper limit of normal.
- Hepatic Impairment: The recommended dose is 0.9 mg/m2 in patients with moderate hepatic impairment (bilirubin levels 1.5 times to 3 times the upper limit of normal, and AST and ALT less than 8 times the upper limit of normal). Do not administer Trabectedin to patients with severe hepatic impairment (bilirubin levels above 3 times to 10 times the upper limit of normal, and any AST and ALT).
- Premedication
- Administer dexamethasone 20 mg intravenously 30 minutes prior to each dose of Trabectedin.
- Dose Modifications
- Permanently discontinue Trabectedin for:
- The recommended dose modifications for adverse reactions are listed in Table 1. Once reduced, the dose of Trabectedin should not be increased in subsequent treatment cycles.
- Table 1: Recommended Dose Modification
YONDELIS: Trabectedin's Brand name
The recommended starting doses and dose reductions for Trabectedin are listed in Table 2:
- Table 2: Recommended Starting Doses and Dose Reductions
YONDELIS: Trabectedin's Brand name
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Trabectedin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trabectedin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness 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 Trabectedin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Trabectedin in pediatric patients.
# Contraindications
Trabectedin is contraindicated in patients with known severe hypersensitivity, including anaphylaxis, to trabectedin.
# Warnings
Neutropenic sepsis, including fatal cases, can occur with Trabectedin. In Trial 1, the incidence of Grade 3 or 4 neutropenia, based on laboratory values, in patients receiving Trabectedin was 43% (161/378). The median time to the first occurrence of Grade 3 or 4 neutropenia was 16 days (range: 8 days to 9.7 months); the median time to complete resolution of neutropenia was 13 days (range: 3 days to 2.3 months). Febrile neutropenia (fever ≥38.5°C with Grade 3 or 4 neutropenia) occurred in 18 patients (5%) treated with Trabectedin. Ten patients (2.6%) experienced neutropenic sepsis, 5 of whom had febrile neutropenia, which was fatal in 4 patients (1.1%).
Assess neutrophil count prior to administration of each dose of Trabectedin and periodically throughout the treatment cycle. Withhold Trabectedin for neutrophil counts of less than 1,500 cells/microliter on the day of dosing. Permanently reduce the dose of Trabectedin for life-threatening or prolonged, severe neutropenia in the preceding cycle.
Trabectedin can cause rhabdomyolysis and musculoskeletal toxicity. In Trial 1, rhabdomyolysis leading to death occurred in 3 (0.8%) of the 378 patients receiving Trabectedin. Elevations in creatine phosphokinase (CPK) occurred in 122 (32%) of the 378 patients receiving Trabectedin, including Grade 3 or 4 CPK elevation in 24 patients (6%), compared to 15 (9%) of the 172 patients receiving dacarbazine with any CPK elevation, including 1 patient (0.6%) with Grade 3 CPK elevation. Among the 24 patients receiving Trabectedin with Grade 3 or 4 CPK elevation, renal failure occurred in 11 patients (2.9%); rhabdomyolysis with the complication of renal failure occurred in 4 of these 11 patients (1.1%). The median time to first occurrence of Grade 3 or 4 CPK elevations was 2 months (range: 1 to 11.5 months). The median time to complete resolution was 14 days (range: 5 days to 1 month).
Assess CPK levels prior to each administration of Trabectedin. Withhold Trabectedin for serum CPK levels more than 2.5 times the upper limit of normal. Permanently discontinue Trabectedin for rhabdomyolysis.
Hepatotoxicity, including hepatic failure, can occur with Trabectedin. Patients with serum bilirubin levels above the upper limit of normal or AST or ALT levels >2.5 × upper limit of normal were not enrolled in Trial 1. In Trial 1, the incidence of Grade 3–4 elevated liver function tests (LFTs; defined as elevations in ALT, AST, total bilirubin, or alkaline phosphatase) was 35% (134/378) in patients receiving Trabectedin. The median time to development of Grade 3–4 elevation in ALT or AST was 29 days (range: 3 days to 11.5 months). Of the 134 patients with Grade 3–4 elevations in LFTs, 114 (85%) experienced complete resolution with the median time to complete resolution of 13 days (range: 4 days to 4.4 months).
In Trial 1, the incidence of drug-induced liver injury (defined as concurrent elevation in ALT or AST of more than three times the upper limit of normal, alkaline phosphatase less than two times the upper limit of normal, and total bilirubin at least two times the upper limit of normal) was 1.3% (5/378) in patients receiving Trabectedin. ALT or AST elevation greater than eight times the upper limit of normal occurred in 18% (67/378) of patients receiving Trabectedin.
Assess LFTs prior to each administration of Trabectedin and as clinically indicated based on underlying severity of pre-existing hepatic impairment. Manage elevated LFTs with treatment interruption, dose reduction, or permanent discontinuation based on severity and duration of LFT abnormality.
Cardiomyopathy including cardiac failure, congestive heart failure, ejection fraction decreased, diastolic dysfunction, or right ventricular dysfunction can occur with Trabectedin. In Trial 1, patients with a history of New York Heart Association Class II to IV heart failure or abnormal left ventricular ejection fraction (LVEF) at baseline were ineligible. In Trial 1, cardiomyopathy occurred in 23 patients (6%) receiving Trabectedin and in four patients (2.3%) receiving dacarbazine. Grade 3 or 4 cardiomyopathy occurred in 15 patients (4%) receiving Trabectedin and 2 patients (1.2%) receiving dacarbazine; cardiomyopathy leading to death occurred in 1 patient (0.3%) receiving Trabectedin and in none of the patients receiving dacarbazine. The median time to development of Grade 3 or 4 cardiomyopathy in patients receiving Trabectedin was 5.3 months (range: 26 days to 15.3 months).
Assess LVEF by echocardiogram or multigated acquisition (MUGA) scan before initiation of Trabectedin and at 2- to 3-month intervals thereafter until Trabectedin is discontinued. Withhold Trabectedin for LVEF below lower limit of normal. Permanently discontinue Trabectedin for symptomatic cardiomyopathy or persistent left ventricular dysfunction that does not recover to lower limit of normal within 3 weeks.
Extravasation of Trabectedin, resulting in tissue necrosis requiring debridement, can occur. Evidence of tissue necrosis can occur more than 1 week after the extravasation. There is no specific antidote for extravasation of Trabectedin. Administer Trabectedin through a central venous line.
Based on its mechanism of action, Trabectedin can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during therapy and for at least 2 months after the last dose of Trabectedin. Advise males with female partners of reproductive potential to use effective contraception during therapy and for at least 5 months after the last dose of Trabectedin.
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are discussed in more detail in other sections of the labeling:
- Anaphylaxis
- Neutropenic Sepsis
- Rhabdomyolysis
- Hepatotoxicity
- Cardiomyopathy
- Extravasation Resulting in Tissue Necrosis
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 described below reflect exposure to Trabectedin in 755 patients with soft tissue sarcoma including 197 (26%) patients exposed to Trabectedin for greater than or equal to 6 months and 57 (8%) patients exposed to Trabectedin for greater than or equal to 1 year. The safety of Trabectedin was evaluated in six open-label, single-arm trials, in which 377 patients received Trabectedin and one open-label, randomized, active-controlled clinical trial in which 378 patients received Trabectedin (Trial 1). All patients received Trabectedin at the recommended dosing regimen of 1.5 mg/m2 administered as an intravenous infusion over 24 hours once every 3 weeks (q3wk, 24-h). The median age was 54 years (range: 18 to 81 years), 63% were female, and all patients had metastatic soft tissue sarcoma.
Tables 3 and 4 present selected adverse reactions and laboratory abnormalities, respectively, observed in Trial 1, an open-label, randomized (2:1), active-controlled trial in which 550 patients with previously treated leiomyosarcoma or liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) received Trabectedin 1.5 mg/m2 intravenous infusion over 24 hours once every 3 weeks (n=378) or dacarbazine 1000 mg/m2 intravenous infusion over 20 to 120 minutes once every 3 weeks (n=172). All patients treated with Trabectedin were required to receive dexamethasone 20 mg intravenous injection 30 minutes prior to start of the Trabectedin infusion.
In Trial 1, patients had been previously treated with an anthracycline- and ifosfamide-containing regimen or with an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen. The trial excluded patients with known central nervous system metastasis, elevated serum bilirubin or significant chronic liver disease, such as cirrhosis or active hepatitis, and history of myocardial infarction within 6 months, history of New York Heart Association Class II to IV heart failure, or abnormal left ventricular ejection fraction at baseline. The median age of patients in Trial 1 was 57 years (range: 17 to 81 years), with 69% female, 77% White, 12% Black or African American, 4% Asian, and <1% American Indian or Alaska Native. The median duration of exposure to trabectedin was 13 weeks (range: 1 to 127 weeks) with 30% of patients exposed to Trabectedin for greater than 6 months and 7% of patients exposed to Trabectedin for greater than 1 year.
In Trial 1, adverse reactions resulting in permanent discontinuation of Trabectedin occurred in 26% (98/378) of patients; the most common were increased liver tests (defined as ALT, AST, alkaline phosphatase, bilirubin) (5.6%), thrombocytopenia (3.4%), fatigue (1.6%), increased creatine phosphokinase (1.1%), and decreased ejection fraction (1.1%). Adverse reactions that led to dose reductions occurred in 42% (158/378) of patients treated with Trabectedin; the most common were increased liver tests (24%), neutropenia (including febrile neutropenia) (8%), thrombocytopenia (4.2%), fatigue (3.7%), increased creatine phosphokinase (2.4%), nausea (1.1%), and vomiting (1.1%). Adverse reactions led to dose interruptions in 52% (198/378) of patients treated with Trabectedin; the most common were neutropenia (31%), thrombocytopenia (15%), increased liver tests (6%), fatigue (2.9%), anemia (2.6%), increased creatinine (1.1%), and nausea (1.1%).
The most common adverse reactions (≥20%) were nausea, fatigue, vomiting, constipation, decreased appetite, diarrhea, peripheral edema, dyspnea, and headache. The most common laboratory abnormalities (≥20%) were increases in AST or ALT, increased alkaline phosphatase, hypoalbuminemia, increased creatinine, increased creatine phosphokinase, anemia, neutropenia, and thrombocytopenia.
- Table 3: Selected Adverse Reactions* Occurring in ≥10% of Patients Receiving Trabectedin and at a Higher Incidence than in the Control Arm - Trial 1
YONDELIS: Trabectedin's Brand name
Other clinically important adverse reactions observed in <10% of patients (N=755) with soft tissue sarcoma receiving Trabectedin were:
- Nervous system disorders: peripheral neuropathy, paresthesia, hypoesthesia.
- Respiratory, thoracic, and mediastinal disorders: pulmonary embolism.
- Table 4: Incidence of Selected Treatment-Emergent Laboratory Abnormalities* - Trial 1
YONDELIS: Trabectedin's Brand name
## Postmarketing Experience
There is limited information regarding Trabectedin Postmarketing Experience in the drug label.
# Drug Interactions
Coadministration of Trabectedin with ketoconazole, a strong CYP3A inhibitor, increased systemic exposure of trabectedin by 66%. Avoid using strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir,lopinavir, ritonavir, boceprevir, nelfinavir,saquinavir, telaprevir, nefazodone, conivaptan) in patients taking Trabectedin. Avoid taking grapefruit or grapefruit juice during Trabectedin treatment. If a strong CYP3A inhibitor for short-term use (i.e., less than 14 days) must be used, administer the strong CYP3A inhibitor 1 week after the Trabectedin infusion, and discontinue it the day prior to the next Trabectedin infusion.
Coadministration of Trabectedin with rifampin, a strong CYP3A inducer, decreased systemic exposure of trabectedin by 31%. Avoid using strong CYP3A inducers (e.g., rifampin, phenobarbital, St. John's wort) in patients taking Trabectedin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
. Based on its mechanism of action, trabectedin can cause fetal harm when administered during pregnancy. There are no available data with the use of Trabectedin during pregnancy. Animal reproductive and developmental studies at relevant doses have not been conducted with trabectedin; however, placental transfer of trabectedin was demonstrated in pregnant rats. Advise pregnant woman of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population are unknown; however, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Trabectedin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Trabectedin during labor and delivery.
### Nursing Mothers
There are no data on the presence of trabectedin in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions from Trabectedin in breastfed infants, advise a nursing woman to discontinue nursing during treatment with Trabectedin.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Clinical studies of Trabectedin 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 Trabectedin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Trabectedin with respect to specific racial populations.
### Renal Impairment
No dose adjustment is recommended in patients with mild (creatinine clearance (CLcr) 60–89 mL/min) or moderate (CLcr of 30–59 mL/min) renal impairment.
The pharmacokinetics of trabectedin has not been evaluated in patients with severe renal impairment (CLcr <30 mL/min) or end stage renal disease.
### Hepatic Impairment
The mean trabectedin exposure was (97%) higher in patients with moderate (bilirubin levels 1.5 to 3.0 times the upper limit of normal, and AST and ALT less than 8 times the upper limit of normal) hepatic impairment compared to patients with normal (total bilirubin ≤ the upper limit of normal, and AST and ALT ≤ the upper limit of normal) liver function. Reduce Trabectedin dose in patients with moderate hepatic impairment.
Do not administer Trabectedin to patients with severe hepatic impairment (bilirubin levels above 3 times to 10 times the upper limit of normal, and any AST and ALT).
### Females of Reproductive Potential and Males
- Contraception
- Females: Advise female patients of reproductive potential to use effective contraception during and for 2 months after the last dose of Trabectedin.
- Males: Trabectedin may damage spermatozoa, resulting in possible genetic and fetal abnormalities. Advise males with a female sexual partner of reproductive potential to use effective contraception during and for 5 months after the last dose of Trabectedin.
- Infertility: Trabectedin may result in decreased fertility in males and females.
### Immunocompromised Patients
There is no FDA guidance one the use of Trabectedin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Preparation
- Trabectedin is a cytotoxic drug. Follow applicable special handling and disposal procedures.
- Using aseptic technique, inject 20 mL of Sterile Water for Injection, USP into the vial. Shake the vial until complete dissolution. The reconstituted solution is clear, colorless to pale brownish-yellow, and contains 0.05 mg/mL of trabectedin.
- Inspect for particulate matter and discoloration prior to further dilution. Discard vial if particles or discoloration are observed.
- Immediately following reconstitution, withdraw the calculated volume of trabectedin and further dilute in 500 mL of 0.9% Sodium Chloride, USP or 5% Dextrose Injection, USP.
- Do not mix Trabectedin with other drugs.
- Discard any remaining solution within 30 hours of reconstituting the lyophilized powder.
- Trabectedin diluted solution is compatible with Type I colorless glass vials, polyvinylchloride (PVC) and polyethylene (PE) bags and tubing, PE and polypropylene (PP) mixture bags, polyethersulfone (PES) in-line filters, titanium, platinum or plastic ports, silicone and polyurethane catheters, and pumps having contact surfaces made of PVC, PE, or PE/PP.
- Administration
- Infuse the reconstituted, diluted solution over 24 hours through a central venous line using an infusion set with a 0.2 micron polyethersulfone (PES) in-line filter to reduce the risk of exposure to adventitious pathogens that may be introduced during solution preparation.
- Complete infusion within 30 hours of initial reconstitution. Discard any unused portion of the reconstituted product or of the infusion solution.
### Monitoring
There is limited information regarding Trabectedin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Trabectedin and IV administrations.
# Overdosage
There is no specific antidote for Trabectedin. Hemodialysis is not expected to enhance the elimination of Trabectedin because trabectedin is highly bound to plasma proteins (97%) and not significantly renally excreted.
# Pharmacology
## Mechanism of Action
Trabectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove. Adduct formation triggers a cascade of events that can affect the subsequent activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death.
## Structure
Trabectedin is an alkylating agent with the chemical name (1'R,6R,6aR,7R,13S,14S,16R)-5-(acetyloxy)-3',4',6,6a,7,13,14,16-octahydro-6',8,14-trihydroxy-7',9-dimethoxy-4,10,23-trimethyl-spiro[6,16-(epithiopropanoxymethano)-7,13-imino-12H-1,3-dioxolo[7,8]isoquino[3,2-b][3]benzazocine-20,1'(2'H)-isoquinolin]-19-one. The molecular formula is C39H43N3O11S. The molecular weight is 761.84 daltons. The chemical structure is shown below:
Trabectedin is hydrophobic and has a low solubility in water.
Trabectedin for injection is supplied as a sterile lyophilized white to off-white powder/cake in a single-dose vial. Each single-dose vial contains 1 mg of trabectedin, 27.2 mg potassium dihydrogen phosphate, 400 mg sucrose, and phosphoric acid and potassium hydroxide (for pH adjustment to 3.6 – 4.2).
## Pharmacodynamics
- Cardiac Electrophysiology
- The effect of trabectedin on the QT/QTc interval was evaluated in 75 patients who received placebo on day 1 and trabectedin (1.3 mg/m2) as a 3-hour intravenous infusion on day 2. No patients in the study showed a QTc interval exceeding 500 msec or more than 60 msec increase from baseline, and no large changes in the mean QTc interval (i.e., >20 msec) were observed.
## Pharmacokinetics
The pharmacokinetics of trabectedin is characterized by a rapid decline phase at the end of the infusion and slower exponential phases. Population pharmacokinetic analyses suggest that the pharmacokinetics of trabectedin is dose-proportional (over the dose range of 0.024 to 1.8 mg/m2) and exposure is time-independent. No accumulation of trabectedin in plasma is observed upon repeated administrations every 3 weeks.
- Distribution
- Binding of trabectedin to human plasma proteins was approximately 97%, independent of trabectedin concentrations ranging from 10 ng/mL to 100 ng/mL. Steady state volume of distribution of trabectedin exceeds 5000 L.
- Elimination
- The estimated mean (% coefficient of variation) clearance of trabectedin is 31.5 L/hr (50%) and the terminal elimination half-life is approximately 175 hours.
- Metabolism
- CYP3A is the predominant CYP enzyme responsible for the hepatic metabolism of trabectedin.
- Trabectedin was extensively metabolized with negligible unchanged drug in urine and feces following administration of trabectedin to humans.
- Excretion
- In patients with solid tumors, following a 3-hour or a 24-hour intravenous infusion of 14C-labeled trabectedin, 64% of the total administered radioactive dose was recovered in 24 days, with 58% in feces and 6% in urine.
- Specific Populations
- The following population characteristics are not associated with a clinically significant effect on the pharmacokinetics of trabectedin: sex, age (19 to 83 years), body weight (36 to 148 kg), body surface area (0.9 to 2.8 m2), mild hepatic impairment, or mild to moderate renal impairment. The effects of severe hepatic impairment, severe renal impairment or end stage renal disease on trabectedin exposure are unknown.
- Hepatic Impairment
- The geometric mean dose normalized trabectedin exposure (AUC) increased by 97% (90% CI: 20%, 222%) in patients with moderate hepatic impairment following administration of a single Trabectedin dose of 0.58 mg/m2 or 0.9 mg/m2 compared to patients with normal liver function following administration of a single Trabectedin dose of 1.3 mg/m2.
- Drug Interactions
- Effect of Strong CYP3A Inhibitors on Trabectedin
- Coadministration of multiple doses of ketoconazole (200 mg twice daily for 7.5 days) with a single dose of Trabectedin (0.58 mg/m2) on day 1 increased trabectedin dose-normalized AUC by 66% and Cmax by 22% compared to a single Trabectedin dose (1.3 mg/m2) given alone.
- Effect of Strong CYP3A Inducers on Trabectedin
- Coadministration of multiple doses of rifampin (600 mg daily for 6 days) with a single Trabectedin dose (1.3 mg/m2) on day 6 decreased trabectedin AUC by 31% and Cmax by 21% compared to a single Trabectedin dose (1.3 mg/m2) given alone.
- Effect of Trabectedin on CYP Enzymes
- In vitro, trabectedin has limited inhibition or induction potential of major CYP enzymes (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4).
## Nonclinical Toxicology
Trabectedin is genotoxic in both in vitro and in vivo studies. Long-term carcinogenicity studies have not been performed.
Fertility studies with trabectedin were not performed. In male rats there were limited histopathological signs of hemorrhage and degeneration in the testes following repeated administration of trabectedin at doses approximately 0.2 times the 1.5 mg/m2 human dose based on body surface area.
# Clinical Studies
The clinical efficacy and safety of Trabectedin in patients with metastatic or recurrent leiomyosarcoma or liposarcoma were demonstrated in Trial 1, a randomized (2:1), open-label, active-controlled trial comparing treatment with Trabectedin 1.5 mg/m2 as a 24-hour continuous intravenous infusion once every 3 weeks to dacarbazine 1000 mg/m2 intravenous infusion (20 to 120 minutes) once every 3 weeks. Treatment continued in both arms until disease progression or unacceptable toxicity; all patients in the Trabectedin arm were required to receive dexamethasone 20 mg intravenous injection prior to each Trabectedin infusion. Patients were required to have unresectable, locally advanced or metastatic leiomyosarcoma or liposarcoma (dedifferentiated, myxoid round cell, or pleomorphic) and previous treatment with an anthracycline- and ifosfamide-containing regimen or an anthracycline-containing regimen and one additional cytotoxic chemotherapy regimen. Randomization was stratified by subtype of soft tissue sarcoma (leiomyosarcoma vs. liposarcoma), ECOG performance status (0 vs. 1), and number of prior chemotherapy regimens (1 vs. ≥2). The efficacy outcome measures were investigator-assessed progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1), overall survival (OS), objective response rate (ORR), and duration of response (DOR). Patients in the dacarbazine arm were not offered Trabectedin at the time of disease progression.
A total of 518 patients were randomized, 345 to the Trabectedin arm and 173 patients to the dacarbazine arm. The median patient age was 56 years (range: 17 to 81); 30% were male; 76% White, 12% Black, and 4% Asian; 73% had leiomyosarcomas and 27% liposarcomas; 49% had an ECOG PS of 0; and 89% received ≥2 prior chemotherapy regimens. The most common (≥20%) pre-study chemotherapeutic agents administered were doxorubicin (90%), gemcitabine (81%), docetaxel (74%), and ifosfamide (59%). Approximately 10% of patients had received pazopanib.
Trial 1 demonstrated a statistically significant improvement in PFS. An exploratory analysis of independent radiology committee-determined PFS, in a subgroup consisting of approximately 60% of the total population, provided similar results to the investigator-determined PFS. Efficacy results from Trial 1 are presented in the table below.
- Table 5: Efficacy Results for Trial 1
YONDELIS: Trabectedin's Brand name
- Figure 1: Kaplan-Meier Curves of Progression-Free Survival in Trial 1
YONDELIS: Trabectedin's Brand name
# How Supplied
Trabectedin is supplied in a glass vial containing 1 mg trabectedin. Each carton contains one vial (NDC: 59676-610-01).
## Storage
Store Trabectedin vials in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF).
Trabectedin is a cytotoxic drug. Follow applicable special handling and disposal procedures.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Myelosuppression: Inform patients of the risks of myelosuppression. Instruct patients to immediately contact their healthcare provider for fever or unusual bruising, bleeding, tiredness, or paleness.
- Rhabdomyolysis: Advise patients to contact their healthcare provider if they experience severe muscle pain or weakness.
- Hepatotoxicity: Advise patients to contact their healthcare provider immediately for yellowing of skin and eyes (jaundice), pain in the upper right quadrant, severe nausea or vomiting, difficulty in concentrating, disorientation, or confusion.
- Cardiomyopathy: Advise patients to contact their healthcare provider for new onset chest pain, shortness of breath, fatigue, lower extremity edema, or heart palpitations.
- Hypersensitivity: Advise patients to seek immediate medical attention for symptoms of allergic reactions including difficulty breathing, chest tightness, wheezing, severe dizziness or light-headedness, swelling of the lips or skin rash.
- Extravasation: Inform patients of the risks of extravasation and to notify their healthcare provider for redness, swelling, itchiness and discomfort or leakage at the injection site.
- Embryofetal toxicity: Advise pregnant women of the potential risk to a fetus. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Trabectedin.
- Females and males of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with Trabectedin and for at least 2 months after last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with Trabectedin and for at least 5 months after the last dose.
- Lactation: Advise females not to breastfeed during treatment with Trabectedin.
# Precautions with Alcohol
Alcohol-Trabectedin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
YONDELIS®
# Look-Alike Drug Names
There is limited information regarding Trabectedin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Trabectedin | |
06324347eab62f06a53d654f23cf10c2bd833960 | wikidoc | Trace amine | Trace amine
Trace amines are endogenous compounds structurally related to classical biogenic amines, such as catecholamines, serotonin and histamine. Trace amines include p-tyramine, β-phenylethylamine, tryptamine, octopamine, and 3-iodothyronamine, and are found in the nervous systems of animals from insects to mammals. Also the entheogenic DMT is created in small amounts by the human body during normal metabolism by the enzyme tryptamine-N-methyltransferase.
Trace amines overlap substantially with classical biogenic amines neurotransmitters regarding to chemical properties, synthesis, and breakdown; trace amines commonly colocalize in neurons with these neurotransmitters.
Psychiatric disorders such as depression and schizophrenia have been linked to irregular levels of trace amines. | Trace amine
Trace amines are endogenous compounds structurally related to classical biogenic amines, such as catecholamines, serotonin and histamine. Trace amines include p-tyramine, β-phenylethylamine, tryptamine, octopamine, and 3-iodothyronamine, and are found in the nervous systems of animals from insects to mammals. Also the entheogenic DMT is created in small amounts by the human body during normal metabolism[1] by the enzyme tryptamine-N-methyltransferase.
Trace amines overlap substantially with classical biogenic amines neurotransmitters regarding to chemical properties, synthesis, and breakdown; trace amines commonly colocalize in neurons with these neurotransmitters.
Psychiatric disorders such as depression and schizophrenia have been linked to irregular levels of trace amines. | https://www.wikidoc.org/index.php/Trace_amine | |
e99bc3e8f5420c7be7d8f46651b5e9b93278900d | wikidoc | Transferrin | Transferrin
Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron (Fe) in biological fluids. Human transferrin is encoded by the TF gene.
Transferrin glycoproteins bind iron tightly, but reversibly. Although iron bound to transferrin is less than 0.1% (4 mg) of total body iron, it forms the most vital iron pool with the highest rate of turnover (25 mg/24 h). Transferrin has a molecular weight of around 80 kDa and contains two specific high-affinity Fe(III) binding sites. The affinity of transferrin for Fe(III) is extremely high (association constant is 1020 M−1 at pH 7.4) but decreases progressively with decreasing pH below neutrality.
When not bound to iron, transferrin is known as "apotransferrin" (see also apoprotein).
# Transport mechanism
When a transferrin protein loaded with iron encounters a transferrin receptor on the surface of a cell, e.g., erythroid precursors in the bone marrow, it binds to it and is transported into the cell in a vesicle by receptor-mediated endocytosis. The pH of the vesicle is reduced by hydrogen ion pumps (H+ ATPases) to about 5.5, causing transferrin to release its iron ions. The receptor with its ligand bound transferrin is then transported through the endocytic cycle back to the cell surface, ready for another round of iron uptake.
Each transferrin molecule has the ability to carry two iron ions in the ferric form (Fe3+).
The gene coding for transferrin in humans is located in chromosome band 3q21.
Medical professionals may check serum transferrin level in iron deficiency and in iron overload disorders such as hemochromatosis.
# Structure
In humans, transferrin consists of a polypeptide chain containing 679 amino acids and two carbohydrate chains. The protein is composed of alpha helices and beta sheets that form two domains. The N- and C- terminal sequences are represented by globular lobes and between the two lobes is an iron-binding site.
The amino acids which bind the iron ion to the transferrin are identical for both lobes; two tyrosines, one histidine, and one aspartic acid. For the iron ion to bind, an anion is required, preferably carbonate (CO2−3).
Transferrin also has a transferrin iron-bound receptor; it is a disulfide-linked homodimer. In humans, each monomer consists of 760 amino acids. It enables ligand bonding to the transferrin, as each monomer can bind to one or two atoms of iron. Each monomer consists of three domains: the protease, the helical, and the apical domains. The shape of a transferrin receptor resembles a butterfly based on the intersection of three clearly shaped domains.
- Transferrin bound to its receptor.
Transferrin bound to its receptor.
- Transferrin receptor complex.
Transferrin receptor complex.
# Tissue distribution
The liver is the main site of transferrin synthesis but other tissues and organs, including the brain, also produce transferrin. A major source of transferrin secretion in the brain is the choroid plexus in the ventricular system. The main role of transferrin is to deliver iron from absorption centers in the duodenum and white blood cell macrophages to all tissues. Transferrin plays a key role in areas where erythropoiesis and active cell division occur. The receptor helps maintain iron homeostasis in the cells by controlling iron concentrations.
# Immune system
Transferrin is also associated with the innate immune system. It is found in the mucosa and binds iron, thus creating an environment low in free iron that impedes bacterial survival in a process called iron withholding. The level of transferrin decreases in inflammation.
# Role in disease
An increased plasma transferrin level is often seen in patients suffering from iron deficiency anemia, during pregnancy, and with the use of oral contraceptives, reflecting an increase in transferrin protein expression. When plasma transferrin levels rise, there is a reciprocal decrease in percent transferrin iron saturation, and a corresponding increase in total iron binding capacity in iron deficient states A decreased plasma transferrin can occur in iron overload diseases and protein malnutrition. An absence of transferrin results from a rare genetic disorder known as atransferrinemia, a condition characterized by anemia and hemosiderosis in the heart and liver that leads to heart failure and many other complications.
Transferrin and its receptor have been shown to diminish tumour cells when the receptor is used to attract antibodies.
# Other effects
Carbohydrate deficient transferrin increases in the blood with heavy ethanol consumption and can be monitored through laboratory testing.
Transferrin is an acute phase protein and is therefore seen to decrease in inflammation, cancers, and certain diseases.
# Pathology
Atransferrinemia is associated with a deficiency in transferrin.
In nephrotic syndrome, urinary loss of transferrin, along with other serum proteins such as thyroxine-binding globulin, gammaglobulin, and anti-thrombin III, can manifest as iron-resistant microcytic anemia.
# Reference ranges
An example reference range for transferrin is 204–360 mg/dL. Laboratory test results should always be interpreted using the reference range provided by the laboratory that performed the test.
A high transferrin level may indicate an iron deficiency anemia. Levels of serum iron and total iron binding capacity (TIBC) are used in conjunction with transferrin to specify any abnormality. See interpretation of TIBC. Low transferrin likely indicates malnutrition.
# Interactions
Transferrin has been shown to interact with insulin-like growth factor 2 and IGFBP3. Transcriptional regulation of transferrin is upregulated by retinoic acid.
# Related proteins
Members of the family include blood serotransferrin (or siderophilin, usually simply called transferrin); lactotransferrin (lactoferrin); milk transferrin; egg white ovotransferrin (conalbumin); and membrane-associated melanotransferrin. | Transferrin
Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron (Fe) in biological fluids.[1] Human transferrin is encoded by the TF gene.[2]
Transferrin glycoproteins bind iron tightly, but reversibly. Although iron bound to transferrin is less than 0.1% (4 mg) of total body iron, it forms the most vital iron pool with the highest rate of turnover (25 mg/24 h). Transferrin has a molecular weight of around 80 kDa and contains two specific high-affinity Fe(III) binding sites. The affinity of transferrin for Fe(III) is extremely high (association constant is 1020 M−1 at pH 7.4)[3] but decreases progressively with decreasing pH below neutrality.
When not bound to iron, transferrin is known as "apotransferrin" (see also apoprotein).
# Transport mechanism
When a transferrin protein loaded with iron encounters a transferrin receptor on the surface of a cell, e.g., erythroid precursors in the bone marrow, it binds to it and is transported into the cell in a vesicle by receptor-mediated endocytosis. The pH of the vesicle is reduced by hydrogen ion pumps (H+ ATPases) to about 5.5, causing transferrin to release its iron ions. The receptor with its ligand bound transferrin is then transported through the endocytic cycle back to the cell surface, ready for another round of iron uptake.
Each transferrin molecule has the ability to carry two iron ions in the ferric form (Fe3+).
The gene coding for transferrin in humans is located in chromosome band 3q21.[2]
Medical professionals may check serum transferrin level in iron deficiency and in iron overload disorders such as hemochromatosis.
# Structure
In humans, transferrin consists of a polypeptide chain containing 679 amino acids and two carbohydrate chains. The protein is composed of alpha helices and beta sheets that form two domains.[4] The N- and C- terminal sequences are represented by globular lobes and between the two lobes is an iron-binding site.
The amino acids which bind the iron ion to the transferrin are identical for both lobes; two tyrosines, one histidine, and one aspartic acid. For the iron ion to bind, an anion is required, preferably carbonate (CO2−3).[4]
Transferrin also has a transferrin iron-bound receptor; it is a disulfide-linked homodimer.[5] In humans, each monomer consists of 760 amino acids. It enables ligand bonding to the transferrin, as each monomer can bind to one or two atoms of iron. Each monomer consists of three domains: the protease, the helical, and the apical domains. The shape of a transferrin receptor resembles a butterfly based on the intersection of three clearly shaped domains.[4]
- Transferrin bound to its receptor.[6]
Transferrin bound to its receptor.[6]
- Transferrin receptor complex.[7]
Transferrin receptor complex.[7]
# Tissue distribution
The liver is the main site of transferrin synthesis but other tissues and organs, including the brain, also produce transferrin. A major source of transferrin secretion in the brain is the choroid plexus in the ventricular system.[8] The main role of transferrin is to deliver iron from absorption centers in the duodenum and white blood cell macrophages to all tissues. Transferrin plays a key role in areas where erythropoiesis and active cell division occur.[5] The receptor helps maintain iron homeostasis in the cells by controlling iron concentrations.[5]
# Immune system
Transferrin is also associated with the innate immune system. It is found in the mucosa and binds iron, thus creating an environment low in free iron that impedes bacterial survival in a process called iron withholding. The level of transferrin decreases in inflammation.[9]
# Role in disease
An increased plasma transferrin level is often seen in patients suffering from iron deficiency anemia, during pregnancy, and with the use of oral contraceptives, reflecting an increase in transferrin protein expression. When plasma transferrin levels rise, there is a reciprocal decrease in percent transferrin iron saturation, and a corresponding increase in total iron binding capacity in iron deficient states[10] A decreased plasma transferrin can occur in iron overload diseases and protein malnutrition. An absence of transferrin results from a rare genetic disorder known as atransferrinemia, a condition characterized by anemia and hemosiderosis in the heart and liver that leads to heart failure and many other complications.
Transferrin and its receptor have been shown to diminish tumour cells when the receptor is used to attract antibodies.[5]
# Other effects
Carbohydrate deficient transferrin increases in the blood with heavy ethanol consumption and can be monitored through laboratory testing.[11]
Transferrin is an acute phase protein and is therefore seen to decrease in inflammation, cancers, and certain diseases.[12]
# Pathology
Atransferrinemia is associated with a deficiency in transferrin.
In nephrotic syndrome, urinary loss of transferrin, along with other serum proteins such as thyroxine-binding globulin, gammaglobulin, and anti-thrombin III, can manifest as iron-resistant microcytic anemia.
# Reference ranges
An example reference range for transferrin is 204–360 mg/dL.[13] Laboratory test results should always be interpreted using the reference range provided by the laboratory that performed the test.
A high transferrin level may indicate an iron deficiency anemia. Levels of serum iron and total iron binding capacity (TIBC) are used in conjunction with transferrin to specify any abnormality. See interpretation of TIBC. Low transferrin likely indicates malnutrition.
# Interactions
Transferrin has been shown to interact with insulin-like growth factor 2[14] and IGFBP3.[15] Transcriptional regulation of transferrin is upregulated by retinoic acid.[16]
# Related proteins
Members of the family include blood serotransferrin (or siderophilin, usually simply called transferrin); lactotransferrin (lactoferrin); milk transferrin; egg white ovotransferrin (conalbumin); and membrane-associated melanotransferrin.[17] | https://www.wikidoc.org/index.php/Transferrin | |
6c0978708877830147a53a683f8267ff5f37bd2d | wikidoc | Trauma team | Trauma team
# Overview
A Trauma team is a group of healthcare workers who attend to seriously ill or injured casualties who arrive at a hospital emergency department. The team is composed of a number of specific roles, with a typical team consisting of:
- Team Leader - Trauma Surgeon, Orthopaedic Surgeon, Emergency Medicine Physician, or Anesthesiologist doctor who takes command
- Additionally: An Emergency Medicine Physician (optional)
- Additionally: Anesthesiologist
- Respiratory Therapist (Canada/USA)
- Three nurses
- Radiographer
- Scribe - a nurse or doctor who deals with administration
Other specialities can be added depending on the nature of the injury, for example a neurological surgeon will attend if there is a serious head injury. All staff should be trained in Advanced Trauma Life Support techniques. Each hospital will have a list of criteria that require the activation of the trauma team, such as a fall of over 6 meters or a fracture of 2 or more bones. | Trauma team
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A Trauma team is a group of healthcare workers who attend to seriously ill or injured casualties who arrive at a hospital emergency department. The team is composed of a number of specific roles, with a typical team consisting of:
- Team Leader - Trauma Surgeon, Orthopaedic Surgeon, Emergency Medicine Physician, or Anesthesiologist doctor who takes command
- Additionally: An Emergency Medicine Physician (optional)
- Additionally: Anesthesiologist
- Respiratory Therapist (Canada/USA)
- Three nurses
- Radiographer
- Scribe - a nurse or doctor who deals with administration
Other specialities can be added depending on the nature of the injury, for example a neurological surgeon will attend if there is a serious head injury. All staff should be trained in Advanced Trauma Life Support techniques. Each hospital will have a list of criteria that require the activation of the trauma team, such as a fall of over 6 meters or a fracture of 2 or more bones. | https://www.wikidoc.org/index.php/Trauma_team | |
33229e1e50e17bcf6347e8d8c5e16209042e8cdd | wikidoc | Tree in bud | Tree in bud
# Overview
The "tree-in-bud" pattern at thin-section computed tomography is characterized by small centrilobular nodules of soft-tissue attenuation connected to multiple branching linear structures of similar caliber originating from a single stalk. This pattern also resembles the small objects used in the childhood game of jacks.
# Causes
- Initially described in cases of endobronchial spread of Mycobacterium tuberculosis.
- The "tree-in-bud" pattern has subsequently been reported as a manifestation of a variety of entities, including:
Peripheral airway diseases such as infection (bacterial, fungal, viral, or parasitic)
Congenital disorders
Idiopathic disorders (obliterative bronchiolitis, panbronchiolitis)
Aspiration
Inhalation
Immunologic disorders
Connective tissue disorders
Peripheral pulmonary vascular diseases (i.e. neoplastic pulmonary emboli).
- Peripheral airway diseases such as infection (bacterial, fungal, viral, or parasitic)
- Congenital disorders
- Idiopathic disorders (obliterative bronchiolitis, panbronchiolitis)
- Aspiration
- Inhalation
- Immunologic disorders
- Connective tissue disorders
- Peripheral pulmonary vascular diseases (i.e. neoplastic pulmonary emboli). | Tree in bud
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The "tree-in-bud" pattern at thin-section computed tomography is characterized by small centrilobular nodules of soft-tissue attenuation connected to multiple branching linear structures of similar caliber originating from a single stalk. This pattern also resembles the small objects used in the childhood game of jacks.
# Causes
- Initially described in cases of endobronchial spread of Mycobacterium tuberculosis.
- The "tree-in-bud" pattern has subsequently been reported as a manifestation of a variety of entities, including:
Peripheral airway diseases such as infection (bacterial, fungal, viral, or parasitic)
Congenital disorders
Idiopathic disorders (obliterative bronchiolitis, panbronchiolitis)
Aspiration
Inhalation
Immunologic disorders
Connective tissue disorders
Peripheral pulmonary vascular diseases (i.e. neoplastic pulmonary emboli).
- Peripheral airway diseases such as infection (bacterial, fungal, viral, or parasitic)
- Congenital disorders
- Idiopathic disorders (obliterative bronchiolitis, panbronchiolitis)
- Aspiration
- Inhalation
- Immunologic disorders
- Connective tissue disorders
- Peripheral pulmonary vascular diseases (i.e. neoplastic pulmonary emboli).
-
- | https://www.wikidoc.org/index.php/Tree_in_bud | |
b3f81b1784958a7090728c9d61b01df4204bc57e | wikidoc | Trefentanil | Trefentanil
Trefentanil (A-3665) is an opioid analgesic that is an analogue of fentanyl and was developed in the early 1990s.
Trefentanil is most similar to short-acting fentanyl analogues such as alfentanil. In comparative studies, trefentanil was slightly more potent and shorter acting than alfentanil as an analgesic, but induced significantly more severe respiratory depression. For this reason trefentanil has not been adopted for clinical use, although it is still used in research.
Trefentanil has very similar effects to alfentanil, much like those of fentanyl itself but more potent and shorter lasting. Side effects of fentanyl analogues are similar to those of fentanyl, and include itching, nausea and potentially serious respiratory depression which can be life-threatening. The risk of respiratory depression is especially high with potent fentanyl analogues such as alfentanil and trefentanil, and these drugs pose a significant risk of death if used outside of a hospital setting with appropriate artificial breathing apparatus available. | Trefentanil
Trefentanil (A-3665) is an opioid analgesic that is an analogue of fentanyl and was developed in the early 1990s.
Trefentanil is most similar to short-acting fentanyl analogues such as alfentanil. In comparative studies, trefentanil was slightly more potent and shorter acting than alfentanil as an analgesic,[1] but induced significantly more severe respiratory depression.[2] For this reason trefentanil has not been adopted for clinical use, although it is still used in research.
Trefentanil has very similar effects to alfentanil, much like those of fentanyl itself but more potent and shorter lasting. Side effects of fentanyl analogues are similar to those of fentanyl, and include itching, nausea and potentially serious respiratory depression which can be life-threatening. The risk of respiratory depression is especially high with potent fentanyl analogues such as alfentanil and trefentanil, and these drugs pose a significant risk of death if used outside of a hospital setting with appropriate artificial breathing apparatus available. | https://www.wikidoc.org/index.php/Trefentanil | |
814957a8d19da114afb099311c51d4fb6fade1e8 | wikidoc | Trichinella | Trichinella
Trichinella is the genus of parasitic roundworms of the phylum Nematoda that cause trichinosis. Members of this genus are often called trichinella or trichina worms. A characteristic of nematoda are one-way digestive tract, and a pseudoceolom (body cavity made up of only an ectoderm and endoderm).
Varieties of trichinella included the species:
# Differential diagnosis
Trichinella infection must be differentiated from other causes of viral, bacterial, and parasitic gastroentritis.
8Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field
Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field
† It could be as high as 1000 based on patient's immunity system.
The table below summarizes the findings that differentiate inflammatory causes of chronic diarrhea
de:Trichinen
no:Trikiner
sv:Trikiner
- ↑ Konvolinka CW (1994). "Acute diverticulitis under age forty". Am J Surg. 167 (6): 562–5. PMID 8209928..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}
- ↑ Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR; et al. (2005). "Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology". Can J Gastroenterol. 19 Suppl A: 5A–36A. PMID 16151544.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Satsangi J, Silverberg MS, Vermeire S, Colombel JF (2006). "The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications". Gut. 55 (6): 749–53. doi:10.1136/gut.2005.082909. PMC 1856208. PMID 16698746.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 4.0 4.1 Haque R, Huston CD, Hughes M, Houpt E, Petri WA (2003). "Amebiasis". N Engl J Med. 348 (16): 1565–73. doi:10.1056/NEJMra022710. PMID 12700377.CS1 maint: Multiple names: authors list (link) | Trichinella
Trichinella is the genus of parasitic roundworms of the phylum Nematoda that cause trichinosis. Members of this genus are often called trichinella or trichina worms. A characteristic of nematoda are one-way digestive tract, and a pseudoceolom (body cavity made up of only an ectoderm and endoderm).
Varieties of trichinella included the species:
# Differential diagnosis
Trichinella infection must be differentiated from other causes of viral, bacterial, and parasitic gastroentritis.
8Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field
Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field
† It could be as high as 1000 based on patient's immunity system.
The table below summarizes the findings that differentiate inflammatory causes of chronic diarrhea[1][2][3][4][4]
Template:Invertebrate-stub
de:Trichinen
no:Trikiner
sv:Trikiner
- ↑ Konvolinka CW (1994). "Acute diverticulitis under age forty". Am J Surg. 167 (6): 562–5. PMID 8209928..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}
- ↑ Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR; et al. (2005). "Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology". Can J Gastroenterol. 19 Suppl A: 5A–36A. PMID 16151544.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
- ↑ Satsangi J, Silverberg MS, Vermeire S, Colombel JF (2006). "The Montreal classification of inflammatory bowel disease: controversies, consensus, and implications". Gut. 55 (6): 749–53. doi:10.1136/gut.2005.082909. PMC 1856208. PMID 16698746.CS1 maint: Multiple names: authors list (link)
- ↑ Jump up to: 4.0 4.1 Haque R, Huston CD, Hughes M, Houpt E, Petri WA (2003). "Amebiasis". N Engl J Med. 348 (16): 1565–73. doi:10.1056/NEJMra022710. PMID 12700377.CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Trichinella | |
38dfc4ca7f4684f31e0d8e089e9d190ca30c194d | wikidoc | Trichromacy | Trichromacy
# Overview
Trichromacy is the condition of possessing three independent channels for conveying color information, derived from the three different cone types. Organisms with trichromacy are called trichromats.
The normal explanation of trichromacy is that the organism's retina contains three types of color receptors (called cone cells in vertebrates) with different absorption spectra. In practice the number of such receptor types may be greater than three, since different types may be active at different light intensities. In vertebrates with three types of cone cells, at low light intensities the rod cells may contribute to color vision, giving a small region of tetrachromacy in the color space.
Humans and other closely related primates are usually trichromats, as are female New World monkeys of most species, and both male and female howler monkeys. Recent research suggests that trichromacy may also be quite general among marsupials. Most other mammals are currently thought to be dichromats, with only two types of cone (though the possibility of limited trichromacy at low light levels where the rods and cones are both active). Some species of insects (such as honeybees) are also trichromats, being sensitive to ultraviolet, blue and green instead of blue, green and red.
# Trichromatic color vision
Trichromatic color vision is the ability of humans and some other animals to see different colors, mediated by interactions among three types of color-sensing cone cells. The trichromatic color theory began in the 18th century, when Thomas Young proposed that color vision was a result of three different photoreceptors. Hermann von Helmholtz later expanding on Young's ideas using color-matching experiments which showed that people with normal vision needed three wavelengths to create the normal range of colors. Each of the three types of cones in the retina of the eye contains a different type of photosensitive pigment, which is composed of a transmembrane protein called opsin and a light-sensitive molecule called 11-cis retinal. Each different pigment is especially sensitive to a certain wavelength of light (that is, the pigment is most likely to produce a cellular response when it is hit by a photon with the specific wavelength to which that pigment is most sensitive). The three types of cones are L, M, and S, which have pigments that respond best to light of long (especially 560 nm), medium (530 nm), and short (420 nm) wavelengths respectively.
Since the likelihood of response of a given cone varies not only with the wavelength of the light that hits it but also with its intensity, the brain would not be able to discriminate different colors if it had input from only one type of cone. Thus, interactions between at least two types of cone is necessary to produce the ability to perceive color. With at least two types of cones, the brain can compare the signals from each type and determine both the intensity and color of the light. For example, moderate stimulation of a medium-wavelength cone cell could mean that it is being stimulated by very bright red (long-wavelength) light, or by not very intense yellowish-green light. But very bright red light would produce a stronger response from L cones than from M cones, while not very intense yellowish light would produce a stronger response from M cones than from other cones (counterintuitively, a "strong response" here refers to a large hyperpolarization, since rods and cones communicate that they are being stimulated by not firing). Thus trichromatic color vision is accomplished by using combinations of cell responses. | Trichromacy
# Overview
Trichromacy is the condition of possessing three independent channels for conveying color information, derived from the three different cone types.[1] Organisms with trichromacy are called trichromats.
The normal explanation of trichromacy is that the organism's retina contains three types of color receptors (called cone cells in vertebrates) with different absorption spectra. In practice the number of such receptor types may be greater than three, since different types may be active at different light intensities. In vertebrates with three types of cone cells, at low light intensities the rod cells may contribute to color vision, giving a small region of tetrachromacy in the color space.
Humans and other closely related primates are usually trichromats, as are female New World monkeys of most species, and both male and female howler monkeys. Recent research suggests that trichromacy may also be quite general among marsupials. Most other mammals are currently thought to be dichromats, with only two types of cone (though the possibility of limited trichromacy at low light levels where the rods and cones are both active). Some species of insects (such as honeybees) are also trichromats, being sensitive to ultraviolet, blue and green instead of blue, green and red.
# Trichromatic color vision
Trichromatic color vision is the ability of humans and some other animals to see different colors, mediated by interactions among three types of color-sensing cone cells. The trichromatic color theory began in the 18th century, when Thomas Young proposed that color vision was a result of three different photoreceptors. Hermann von Helmholtz later expanding on Young's ideas using color-matching experiments which showed that people with normal vision needed three wavelengths to create the normal range of colors. Each of the three types of cones in the retina of the eye contains a different type of photosensitive pigment, which is composed of a transmembrane protein called opsin and a light-sensitive molecule called 11-cis retinal. Each different pigment is especially sensitive to a certain wavelength of light (that is, the pigment is most likely to produce a cellular response when it is hit by a photon with the specific wavelength to which that pigment is most sensitive). The three types of cones are L, M, and S, which have pigments that respond best to light of long (especially 560 nm), medium (530 nm), and short (420 nm) wavelengths respectively.[2]
Since the likelihood of response of a given cone varies not only with the wavelength of the light that hits it but also with its intensity, the brain would not be able to discriminate different colors if it had input from only one type of cone. Thus, interactions between at least two types of cone is necessary to produce the ability to perceive color. With at least two types of cones, the brain can compare the signals from each type and determine both the intensity and color of the light. For example, moderate stimulation of a medium-wavelength cone cell could mean that it is being stimulated by very bright red (long-wavelength) light, or by not very intense yellowish-green light. But very bright red light would produce a stronger response from L cones than from M cones, while not very intense yellowish light would produce a stronger response from M cones than from other cones (counterintuitively, a "strong response" here refers to a large hyperpolarization, since rods and cones communicate that they are being stimulated by not firing). Thus trichromatic color vision is accomplished by using combinations of cell responses. | https://www.wikidoc.org/index.php/Trichromacy |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.