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37b0f756628794a84110eb215fa74601c618a7d0 | wikidoc | Metolachlor | Metolachlor
# Overview
Metolachlor is a pre-emergent herbicide used to control certain broadleaf plants such as corn, soybean, peanuts, grain sorghum and cotton. Products containing metolachlor have trade names such as Dual, Pimagram, Bicep, CGA-24705, and Pennant. Metolachlor is a member of the chemical family known as chloroacetanilides. It is also sometimes used in combination more often with other herbicides used to control certain broad leaved weeds.
# Agricultural use
Metolachlor is the second most popular herbicide used in the United States. Its wide use has led to the contamination of both ground and surface waters and concentrations ranging from 0.08 to 4.5 parts per billion (ppb) have been detected from normal agricultrual use in Iowa, Pennsylvania and Wisconsin. Out of 1,997 surface water sampled from 312 locations in 14 states, metolachlor was found in 1,644 of them at the maximum concentration of 138 ppb.
# Safety
Exposure of metolachlor in humans commonly occurs through contact with the skin which can cause slight skin irritation or through contact with the eyes. Symptoms of metolachlor intoxication in humans include shortnness of breath, dark urine, diarrhea, dizziness, sweating, nausea, anemia abdominal cramps, and jaundice.
Metolachlor is classified as a Category C pesticide by the United States Environmental Protection Agency (USEPA) which indicates limited evidence of carcinogenicity. Evidence of the bioaccumulation of metolachlor in edible species of fish as well as its adverse effect on the growth and development raise concerns on its effects on human health. There is no set maximum concentration (maximum concentration level, MCL) for metolachlor that is allowed in drinking water, the USEPA does have a health advisory level (HAL) of 0.525 mg/L for this chemical.
Studies have shown that metolachlor induces cytotoxic and genotoxic effects in human lymphocytes. Genotoxic effects have also been observed in tadpoles exposed to metolachlor. Evidence also reveals that metolachlor affects cell growth. Cell division in yeast was reduced, and chicken embryos exposed to metolchlor showed a significant decrease in the average body mass compared to the control.
# Ecological effects
Some animals have been shown to be moderately tolerant of metolachlor. Among them is wildfowl which can tolerate moderate exposure to metolachlor. Metolachlor is also moderately toxic to both cold and warm water fish including the bluegill sunfish, rainbow trout and carp. Exposure of metolachlor to some fish and algae in water show very little accumulation of the chemical and any if even accumulated is rapidly excreted upon placing the organisms in clean water.
# Fate in the environment
Metabolites of metolachlor have been found in varying levels treated plants. Plants however, retain their metolachlor metabolites although animals that consume such plants are able to break down and eliminate the chemical rapidly. Some parts of plants, such as the leaves of cotton can retain much higher levels of metolachlor residues compared to other parts of the plants such as the seeds that can contain little.
The breakdown of metolachlor in the soil is affected by a number of factors such as moisture, temperature, microbial activity, soil type , concentration of oxygen and nitrification and is mobile and easily leached through soil. The effect of changes in moisture content and temperature related to microbial activity also affects metolachlor breakdown. | Metolachlor
Template:Chembox new
# Overview
Metolachlor is a pre-emergent herbicide used to control certain broadleaf plants such as corn, soybean, peanuts, grain sorghum and cotton. Products containing metolachlor have trade names such as Dual, Pimagram, Bicep, CGA-24705, and Pennant. Metolachlor is a member of the chemical family known as chloroacetanilides. It is also sometimes used in combination more often with other herbicides used to control certain broad leaved weeds.
# Agricultural use
Metolachlor is the second most popular herbicide used in the United States.[1] Its wide use has led to the contamination of both ground and surface waters and concentrations ranging from 0.08 to 4.5 parts per billion (ppb) have been detected from normal agricultrual use in Iowa, Pennsylvania and Wisconsin.[2] Out of 1,997 surface water sampled from 312 locations in 14 states, metolachlor was found in 1,644 of them at the maximum concentration of 138 ppb.
# Safety
Exposure of metolachlor in humans commonly occurs through contact with the skin which can cause slight skin irritation or through contact with the eyes. Symptoms of metolachlor intoxication in humans include shortnness of breath, dark urine, diarrhea, dizziness, sweating, nausea, anemia abdominal cramps, and jaundice.
Metolachlor is classified as a Category C pesticide by the United States Environmental Protection Agency (USEPA) which indicates limited evidence of carcinogenicity.[3] Evidence of the bioaccumulation of metolachlor in edible species of fish as well as its adverse effect on the growth and development raise concerns on its effects on human health. There is no set maximum concentration (maximum concentration level, MCL) for metolachlor that is allowed in drinking water, the USEPA does have a health advisory level (HAL) of 0.525 mg/L for this chemical.
Studies have shown that metolachlor induces cytotoxic and genotoxic effects in human lymphocytes.[4] Genotoxic effects have also been observed in tadpoles exposed to metolachlor.[5] Evidence also reveals that metolachlor affects cell growth. Cell division in yeast was reduced,[6] and chicken embryos exposed to metolchlor showed a significant decrease in the average body mass compared to the control.[7]
# Ecological effects
Some animals have been shown to be moderately tolerant of metolachlor. Among them is wildfowl which can tolerate moderate exposure to metolachlor. Metolachlor is also moderately toxic to both cold and warm water fish including the bluegill sunfish, rainbow trout and carp. Exposure of metolachlor to some fish and algae in water show very little accumulation of the chemical and any if even accumulated is rapidly excreted upon placing the organisms in clean water.
# Fate in the environment
Metabolites of metolachlor have been found in varying levels treated plants. Plants however, retain their metolachlor metabolites although animals that consume such plants are able to break down and eliminate the chemical rapidly. Some parts of plants, such as the leaves of cotton can retain much higher levels of metolachlor residues compared to other parts of the plants such as the seeds that can contain little.
The breakdown of metolachlor in the soil is affected by a number of factors such as moisture, temperature, microbial activity, soil type , concentration of oxygen and nitrification and is mobile and easily leached through soil. The effect of changes in moisture content and temperature related to microbial activity also affects metolachlor breakdown. | https://www.wikidoc.org/index.php/Metoalachlor | |
a1d01abeba3d2bd10eb9c302bcb180630f0e6e92 | wikidoc | Metreleptin | Metreleptin
# 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
Metreleptin is a endocrine agent that is FDA approved for the treatment of the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Patients with Generalized Lipodystrophy
- Metreleptin for injection is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.
- The safety and effectiveness of Metreleptin for the treatment of complications of partial lipodystrophy have not been established.
- The safety and effectiveness of Metreleptin for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH), have not been established.
- Metreleptin is not indicated for use in patients with HIV-related lipodystrophy.
- Metreleptin is not indicated for use in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of congenital or acquired generalized lipodystrophy.
- See Table 1 for the recommended daily dose and maximum recommended daily dose in adults and pediatric patients.
- Based on clinical response (e.g., inadequate metabolic control) or other considerations (e.g., tolerability issues, excessive weight loss ), Metreleptin dosage may be decreased or increased to the maximum dosage listed in Table 1.
- Metreleptin should be administered once daily at the same time every day. Metreleptin can be administered any time of day without regard to the timing of meals.
- Instruct patients that if a dose is missed, administer the dose as soon as noticed, and resume the normal dosing schedule the next day.
- Healthcare practitioners should provide proper training to patients and caregivers regarding how to prepare and administer the correct dose of Metreleptin prior to self-use. The patients and caregivers should prepare and administer the first dose of Metreleptin under the supervision of a qualified healthcare professional.
- Instruct patients to store the vials of lyophilized powder in their carton in the refrigerator as soon as received .
- Metreleptin can be reconstituted aseptically with 2.2 mL of sterile Bacteriostatic Water for Injection (BWFI), USP (0.9% benzyl alcohol), or with 2.2 mL of sterile Water for Injection (WFI).
- When reconstituted in BWFI, Metreleptin solution can be used within 3 days when stored in the refrigerator between 36°F and 46°F (2°C and 8°C) and protected from light . Discard unused reconstituted solution after 3 days. Attach the supplied sticker to the vial and enter the discard date.
- For use in neonates and infants, reconstitute with preservative-free sterile WFI . When reconstituted in sterile WFI, Metreleptin should be administered immediately. Unused reconstituted solution cannot be saved for later use and should be discarded.
- Reconstitution of the Lyophilized Powder
- Instruct patients to follow the directions below for reconstitution of the lyophilized powder:
- Remove the vial containing the Metreleptin lyophilized powder from the refrigerator and allow the vial to warm to room temperature prior to use.
- Visually inspect the vial containing Metreleptin. The cake of lyophilized powder should be intact and white in color.
- Using a 3-mL syringe with a 22-gauge or smaller diameter needle withdraw 2.2 mL of sterile Bacteriostatic Water for Injection (BWFI) or preservative-free sterile Water for Injection (WFI). Do not reconstitute Metreleptin with other diluents.
- Inject the BWFI or WFI into the vial containing the lyophilized powder of Metreleptin, slowly injecting down the side of the vial. It is normal for some bubbles to form.
- Remove the needle and syringe from the vial and gently swirl the contents to reconstitute. Do not shake or vigorously agitate. When properly mixed, the Metreleptin reconstituted solution should be clear and free of clumps or dry powder, bubbles or foam. Do not use the solution if discolored or cloudy, or if particulate matter remains.
- Regarding the compatibility of Metreleptin reconstituted solution with other solutions:
- Do not mix with, or transfer into, the contents of another vial of Metreleptin.
- Do not add other medications, including insulin. Use a separate syringe for insulin injections.
- Healthcare practitioners should instruct patients and caregivers on the proper subcutaneous injection technique with care to avoid intramuscular injection in patients with minimal subcutaneous adipose tissue. Never administer Metreleptin intravenously or intramuscularly.
- Instruct patients to follow the recommended injection technique:
- Using a 1-mL syringe with a needle appropriate for subcutaneous injection, withdraw the prescribed dose of Metreleptin reconstituted solution.
- Remove any large air pockets or large bubbles from the filled syringe prior to administration. Some small bubbles may remain in the syringe.
- Administer Metreleptin into the subcutaneous tissue of the abdomen, thigh or upper arm. Advise patients to use a different injection site each day when injecting in the same region. After choosing an injection site, pinch the skin and at a 45-degree angle, inject the Metreleptin reconstituted solution subcutaneously. Avoid intramuscular injection, especially in patients with minimal subcutaneous adipose tissue.
- Doses exceeding 1 mL can be administered as two injections (the total daily dose divided equally) to minimize potential injection-site discomfort due to injection volume. When dividing doses due to volume, doses can be administered one after the other.
- Do not mix Metreleptin with insulin. Use a separate syringe for each medication. If Metreleptin and insulin are administered at the same time of day, they may be injected in the same body area using two different injection sites.
- See the Metreleptin Instructions for Use for complete administration instructions.
- Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue (e.g., sulfonylurea) may be necessary in some patients to minimize the risk of hypoglycemia . Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogue (e.g., sulfonylurea) when treating with Metreleptin.
- When discontinuing Metreleptin therapy in patients with risk factors for pancreatitis (e.g., history of pancreatitis, severe hypertriglyceridemia), tapering of the dose over a one-week period is recommended. During tapering, monitor triglyceride levels and consider initiating or adjusting the dose of lipid-lowering medications as needed. Signs and/or symptoms consistent with pancreatitis should prompt an appropriate clinical evaluation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metreleptin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metreleptin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Metreleptin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metreleptin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metreleptin in pediatric patients.
# Contraindications
- Metreleptin is contraindicated in patients with general obesity not associated with congenital leptin deficiency. Metreleptin has not been shown to be effective in treating general obesity, and the development of anti-metreleptin antibodies with neutralizing activity has been reported in obese patients treated with Metreleptin .
- Metreleptin is contraindicated in patients with prior severe hypersensitivity reactions to metreleptin or to any of the product components. Known hypersensitivity reactions have included urticaria and generalized rash
# Warnings
- Anti-metreleptin antibodies with in vitro neutralizing activity to leptin associated with adverse events consistent with loss of endogenous leptin activity and/or loss of efficacy have been identified in two patients with generalized lipodystrophy treated with Metreleptin (severe infections, increases in HbA1cand triglycerides), and in three patients without lipodystrophy who received Metreleptin in clinical studies (excessive weight gain, development of glucose intolerance or diabetes mellitus). The clinical implications associated with development of anti-metreleptin antibodies with neutralizing activity are not well characterized at this time due to the small number of reports. Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of Metreleptin efficacy during treatment.
- Three cases of T-cell lymphoma have been reported in the Metreleptin lipodystrophy program; all three patients had acquired generalized lipodystrophy. Two of these patients were diagnosed with peripheral T-cell lymphoma while receiving Metreleptin. Both had immunodeficiency and significant hematologic abnormalities including severe bone marrow abnormalities before the start of Metreleptin treatment. A separate case of anaplastic large cell lymphoma was reported in a patient receiving Metreleptin who did not have hematological abnormalities before treatment.
- Lymphoproliferative disorders, including lymphomas, have been reported in patients with acquired generalized lipodystrophy not treated with Metreleptin. A causal relationship between Metreleptin treatment and the development and/or progression of lymphoma has not been established. Acquired lipodystrophies are associated with autoimmune disorders, and autoimmune disorders are associated with an increased risk of malignancies including lymphomas.
- The benefits and risks of Metreleptin treatment should be carefully considered in patients with acquired generalized lipodystrophy and/or those with significant hematologic abnormalities (including leukopenia, neutropenia, bone marrow abnormalities, lymphoma, and/or lymphadenopathy).
- Metreleptin is available only through a restricted distribution program under a REMS, called the Metreleptin REMS Program, because of the risks associated with the development of anti-metreleptin antibodies that neutralize endogenous leptin and/or Metreleptin and the risk for lymphoma .
- Notable requirements of the Metreleptin REMS Program include the following:
- Prescribers must be certified with the program by enrolling and completing training.
- Pharmacies must be certified with the program and only dispense Metreleptin after receipt of the Metreleptin REMS Prescription Authorization Form for each new prescription.
- Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue (e.g., sulfonylurea) may be necessary in some patients to minimize the risk of hypoglycemia . Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogue (e.g., sulfonylurea), when treating with Metreleptin.
- Leptin plays a role in immune system homeostasis. Acquired lipodystrophies are associated with autoimmune disorders including autoimmune hepatitis and membranoproliferative glomerulonephritis. Cases of progression of autoimmune hepatitis and membranoproliferative glomerulonephritis (associated with massive proteinuria and renal failure) were observed in some patients with acquired generalized lipodystrophy treated with Metreleptin. A causal relationship between Metreleptin treatment and the development and/or progression of autoimmune disease has not been established. The potential benefits and risks of Metreleptin treatment should be carefully considered in patients with autoimmune disease.
- There have been reports of generalized hypersensitivity (e.g., urticaria or generalized rash) in patients taking Metreleptin. If a hypersensitivity reaction occurs, instruct the patient to promptly seek medical advice regarding discontinuation of Metreleptin.
- Metreleptin contains benzyl alcohol when reconstituted with BWFI. Metreleptin contains no preservative when reconstituted with sterile Water for Injection (WFI). Preservative-free WFI is recommended for use in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients, particularly in neonates and premature infants
# 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 Metreleptin was evaluated in 48 patients with generalized lipodystrophy in a single-arm, open-label study . The median duration of exposure in this trial was 2.7 years with a range of 3.6 months to 10.9 years. The most frequent adverse reactions are summarized in Table 2.
- In patients with generalized lipodystrophy receiving Metreleptin in this study, less common adverse reactions included injection-site erythema and urticaria (N=2 ).
- Six patients (13%) had 7 adverse reactions of hypoglycemia, 6 of which occurred in the setting of concomitant insulin use, with or without oral antihyperglycemic agents.
- Two patients (4%) had events of pancreatitis, both of whom had a medical history of pancreatitis.
- As with all therapeutic proteins, there is potential for immunogenicity. Anti-metreleptin antibodies were detected in 84% (36/43) of generalized lipodystrophy patients studied in the Metreleptin trials. Total anti-metreleptin antibody titers ranged between 1:5 and 1:1,953,125. The incompleteness of the current immunogenicity database precludes understanding of the magnitude and persistence of the observed anti-drug antibody responses. Anti-metreleptin antibodies with neutralizing activity associated with adverse events consistent with loss of endogenous leptin activity and/or loss of Metreleptin efficacy were observed in 6% (2/33) of the patients with generalized lipodystrophy tested. Adverse events reported in these two patients included severe infections and worsening of metabolic control (increases in HbA1c and/or triglycerides). Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of Metreleptin efficacy during treatment. Contact AstraZeneca at 1-866-216-1526 for testing of clinical samples.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. The immunogenicity assays utilized in clinical trials lacked sensitivity, resulting in potential underestimation of the number of samples positive for anti-metreleptin antibodies with neutralizing activity. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to metreleptin with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Metreleptin in the drug label.
# Drug Interactions
- No formal drug interaction studies were performed.
- Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. This should be taken into account when prescribing concomitant drugs metabolized by CYP450 (e.g., oral contraceptives and drugs with a narrow therapeutic index). The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Metreleptin, in patients being treated with these types of agents, therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the agent adjusted as needed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There is a program that monitors outcomes in women exposed to Metreleptin during pregnancy. Women who become pregnant during Metreleptin treatment are encouraged to enroll. Patients or their physicians should call 1-855-6Metreleptin to enroll.
- There are no adequate and well-controlled studies of Metreleptin in pregnant women. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations and 15% to 20% for pregnancy loss. In a pre- and postnatal development study in mice, administration of metreleptin caused prolonged gestation and dystocia resulting in maternal death during parturition and lower survival of offspring in the immediate postnatal period at doses starting approximately at the maximum recommended clinical dose. Because animal reproduction studies are not always predictive of human response, Metreleptin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
### Clinical Considerations
- The contribution of Metreleptin to obstetrical risks and complications is unknown compared with those already documented in the lipodystrophy patient population (e.g., gestational diabetes, macrosomia, eclampsia, intrauterine growth retardation, intrauterine death, and miscarriage).
- The effects of Metreleptin on labor and delivery in pregnant women are unknown. In an in vitro study of human myometrial tissue exposed to a recombinant leptin, human uterine contractility was inhibited. Furthermore, prolonged gestation and dystocia were observed in animal studies with metreleptin (see below).
- Metreleptin administered to pregnant mice during the period of organogenesis was not teratogenic at doses ranging between 7- and 15-fold the maximum recommended clinical dose, based on body surface area of a 20- and 60-kg patient, respectively.
- In a pre- and postnatal development study in mice, metreleptin administered at doses of 3, 10, and 30 mg/kg (approximately 1-, 5-, and 15-fold the clinical dose for a 60-kg subject, based on body surface area) from gestation day 6 to lactation day 21 caused prolonged gestation and dystocia at all doses, starting at approximately the maximum recommended clinical dose. Prolonged gestation resulted in the death of some females during parturition and lower survival of offspring within the immediate postnatal period. Consistent with metreleptin pharmacology, decreased maternal body weight was observed from gestation throughout lactation at all doses and resulted in reduced weight of offspring at birth, which persisted into adulthood. However, no developmental abnormalities were observed and reproductive performance of the first or second generations was not affected at any dose.
- Placental transfer of metreleptin into the fetus was low (approximately 1%) following subcutaneous dosing.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metreleptin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Metreleptin during labor and delivery.
### Nursing Mothers
- It is not known if MYALEPT is present in human milk. Endogenous leptin is present in human milk. Because of the potential for serious adverse reactions (including possible adverse reactions related to passage of anti-metreleptin antibodies) in nursing infants from MYALEPT a decision should be made whether to discontinue nursing or discontinue the drug, taking into account importance of drug to the mother [
### Pediatric Use
- The MYALEPT study included a total of 35 pediatric patients (73%) with an age range from 1 to 17 years . No clinically meaningful differences were observed in the efficacy and safety of MYALEPT between pediatric and adult patients.
- MYALEPT contains benzyl alcohol when reconstituted with BWFI. MYALEPT contains no preservative when reconstituted with WFI. Preservative-free WFI is recommended for use in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome" (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.
- Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome," the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. When reconstituted with 2.2 mL of BWFI, MYALEPT contains 1.76 mg of benzyl alcohol per mg of metreleptin or 9 mg of benzyl alcohol per mL of reconstituted product.
### Geriatic Use
- Clinical trials of MYALEPT did not include sufficient numbers of subjects aged 65 and over (n=1) to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Metreleptin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metreleptin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metreleptin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metreleptin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metreleptin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metreleptin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Metreleptin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Metreleptin in the drug label.
# Overdosage
- There were no reports of overdose in the lipodystrophy clinical trial program of MYALEPT. In the event of an overdose, patients should be monitored and appropriate supportive treatment be initiated as dictated by the patient’s clinical status.
# Pharmacology
## Mechanism of Action
- Adipocytes store lipids to meet the fuel requirements of non-adipose tissues during fasting. In patients with generalized lipodystrophy, the deficiency of adipose tissue leads to hypertriglyceridemia and ectopic deposition of fat in non-adipose tissues such as liver and muscle, contributing to metabolic abnormalities including insulin resistance. Native leptin is a hormone predominantly secreted by adipose tissue that informs the central nervous system of the status of energy stores in the body. In patients with generalized lipodystrophy, leptin deficiency, resulting from the loss of adipose tissue, contributes to excess caloric intake, which exacerbates the metabolic abnormalities.
- MYALEPT (metreleptin) for injection exerts its function by binding to and activating the human leptin receptor (ObR), which belongs to the Class I cytokine family of receptors that signals through the JAK/STAT transduction pathway.
## Structure
- MYALEPT (metreleptin) for injection is a recombinant human leptin analog for injection that binds to and activates the leptin receptor. Metreleptin (recombinant methionyl-human leptin) is produced in E. coli and differs from native human leptin by the addition of a methionine residue at its amino terminus. Metreleptin is a 147-amino acid, nonglycosylated, polypeptide with one disulfide bond between Cys-97 and Cys-147 and a molecular weight of approximately 16.15 kDa.
- MYALEPT is supplied as a sterile, white, solid, lyophilized cake containing 11.3 mg that is reconstituted with 2.2 mL of BWFI or WFI to a final formulation of 5 mg/mL metreleptin for subcutaneous injection. Inactive ingredients are: glutamic acid (1.47 mg/mL), glycine (20 mg/mL), polysorbate 20 (0.1 mg/mL), and sucrose (10 mg/mL), pH 4.25.
## Pharmacodynamics
- Clinical studies in patients with generalized lipodystrophy suggest that MYALEPT increases insulin sensitivity and reduces food intake. Improvements in insulin sensitivity and reductions in food intake are consistent with lower HbA1c, fasting glucose, and fasting triglyceride values that were seen in the MYALEPT clinical trial
## Pharmacokinetics
- There are limited data on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy, and therefore, no formal exposure-response analysis has been performed. It should be noted that the leptin assay measures both endogenous leptin as well as exogenously administered metreleptin.
- Peak serum leptin concentration (Cmax) occurred approximately 4.0 to 4.3 hours after subcutaneous administration of single doses ranging from 0.1 to 0.3 mg/kg in healthy subjects. In a supportive trial in lipodystrophy patients, the median Tmax of metreleptin was 4 hours (range: 2 to 8 hours; N=5) following single-dose administration of metreleptin.
- In studies of healthy adult subjects, following intravenous administration of metreleptin, leptin volume of distribution was approximately 4 to 5 times plasma volume; volumes (Vz) (mean ± SD) were 370 ± 184 mL/kg, 398 ± 92 mL/kg, and 463 ± 116 mL/kg for 0.3, 1.0, and 3.0 mg/kg/day doses, respectively.
- No formal metabolism studies have been conducted with metreleptin. Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Following single subcutaneous doses of 0.01 to 0.3 mg/mL metreleptin in healthy subjects, the half-life was 3.8 to 4.7 hours. The clearance of metreleptin is expected to be delayed in the presence of leptin antibodies .
- No drug interaction studies have been conducted in lipodystrophy patients .
- No formal pharmacokinetic studies were conducted in patients with renal impairment. Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Hence, the pharmacokinetics of metreleptin may be altered in subjects with renal impairment.
- No formal pharmacokinetic studies were conducted in patients with hepatic impairment.
- Specific clinical studies have not been conducted to assess the effect of age, gender, race, or body mass index on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy.
## Nonclinical Toxicology
- Two-year carcinogenicity studies in rodents have not been conducted with metreleptin. No proliferative or preneoplastic lesions were observed in mice or dogs following treatment up to six months. However, leptin is reported in the literature to promote cell proliferation in vitro and tumor progression in some mouse models of cancer.
- Metreleptin was not mutagenic in the Ames bacterial mutagenicity assay or clastogenic in an in vitrochromosomal aberration assay in Chinese hamster ovary cells and human peripheral blood lymphocytes. Metreleptin was not mutagenic or clastogenic in an in vivo mouse micronucleus assay.
- In a fertility study in mice, metreleptin had no adverse effects on mating, fertility, or early embryonic development at doses ranging between 7 and 15 times the maximum recommended clinical dose based on body surface area of a 20- and 60-kg patient, respectively.
# Clinical Studies
- An open-label, single-arm study evaluated MYALEPT treatment in patients with congenital or acquired generalized lipodystrophy and diabetes mellitus, hypertriglyceridemia, and/or increased fasting insulin.
- Baseline Disease Characteristics and Demographics
- Of the 48 patients enrolled, 32 (67%) had congenital generalized lipodystrophy and 16 (33%) had acquired generalized lipodystrophy. Overall, 36 (75%) patients were female, 22 (46%) were Caucasian, 10 (21%) Hispanic, and 9 (19%) Black. The median age at baseline was 15 years (range: 1 - 68 years), with 35 (73%) patients being less than 18 years of age. The median fasting leptin concentration at baseline was 0.7 ng/mL in males (range: 0.3 - 3.3 ng/mL) and 1.0 ng/mL in females (range: 0.3 - 3.3 ng/mL).
- The median duration of MYALEPT treatment was 2.7 years (range: 3.6 months - 10.9 years). MYALEPT was administered subcutaneously either once daily or twice daily (in two equal doses). The weighted average daily dose (i.e., the average dose taking into account duration of treatment at different doses) for the 36 patients with baseline body weight greater than 40 kg was 2.6 mg for males and 4.6 mg for females during the first year of treatment, and 3.2 mg for males and 6.3 mg for females over the entire study period. For the 12 patients with baseline body weight less than 40 kg, the weighted average daily dose was 0.06 to 0.11 mg/kg (0.8-4.3 mg) over the entire study period.
- At baseline, 37 (77%) patients had HbA1c values of 7% or greater, 19 (40%) had HbA1c values of 9% or greater, 33 (69%) had fasting plasma glucose values of 126 mg/dL or greater, 17 (35%) had fasting triglyceride values of 500 mg/dL or greater, and 11 (23%) had fasting triglyceride values of 1000 mg/dL or greater.
- Patients treated with MYALEPT had mean/median reductions in HbA1c, fasting glucose, and triglycerides at 1 year (Table 3). The changes in HbA1c, fasting glucose, and triglycerides observed at Month 4 were similar to those at 1 year. Concomitant antihyperglycemic and lipid-altering medication dosage regimens were not held constant during the study; for example, some patients treated with insulin had their dosage increased and others had large reductions or discontinuation of insulin.
# How Supplied
- MYALEPT (metreleptin) for injection for subcutaneous administration is supplied in a single carton containing one vial for reconstitution (NDC 66780-310-01).
- Each vial contains 11.3 mg metreleptin (as a sterile, white, solid, lyophilized cake) to deliver 5 mg per mL of metreleptin when reconstituted with 2.2 mL of BWFI or
- MYALEPT should be stored in the refrigerator at 36°F to 46°F (2°C to 8°C) and protected from light until preparing for use. Keep MYALEPT vials in the carton when not in use.
- MYALEPT should not be used past the expiration date.
- Do not freeze MYALEPT.
- Do not use if the white lyophilized cake is discolored.
- Use with BWFI: when MYALEPT is reconstituted with BWFI, the vial can be used for multiple doses within 3 days when stored in the refrigerator at 36°F to 46°F (2°C to 8°C) and protected from light.
- Use with WFI: when MYALEPT is reconstituted with WFI, the vial can be used for a single dose should be administered immediately. Unused reconstituted solution cannot be saved for later *use and should be discarded.
- After reconstitution, the vials should not be frozen (below 0°C) or shaken vigorously. If the reconstituted product is inadvertently frozen, it should be thrown away.
- After reconstitution, the mixture should be clear and colorless. Do not use if visible particulates are present in the solution.
- Keep out of the reach of children.
## Storage
There is limited information regarding Metreleptin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients that neutralizing antibodies may result in loss in activity of endogenous leptin or loss of efficacy of MYALEPT. Advise patients on symptoms or signs that would warrant antibody testing.
- Advise patients that lymphoma has been reported in patients both treated and not treated with MYALEPT. Advise patients on symptoms or signs that indicate changes in hematologic status and the importance of routine laboratory assessments and physician monitoring .
- Advise patients that the risk of hypoglycemia is increased when MYALEPT is used in combination with insulin or an insulin secretagogue (e.g., sulfonylurea). Explain the symptoms, treatment, and conditions that predispose to development of hypoglycemia to the patient. Advise patients who are taking concomitant insulin, especially those on high doses, or an insulin secretagogue, to closely monitor blood glucose. Hypoglycemia management should be reviewed and reinforced when initiating MYALEPT therapy, particularly when concomitantly administered with insulin or an insulin secretagogue .
- Advise patients that worsening of autoimmune disease has been reported during the clinical study of MYALEPT. Advise patients with a history of autoimmune disease on symptoms or signs that indicate exacerbation of underlying autoimmune disease and the importance of routine laboratory assessments and physician monitoring .
- Inform patients that hypersensitivity reactions have been reported during use of MYALEPT. If symptoms of hypersensitivity reactions occur, patients should seek medical advice
Advise nursing mothers that breastfeeding is not recommended with MYALEPT use .
- Inform patients that each vial of MYALEPT requires reconstitution with BWFI or preservative-free WFI, and administration as subcutaneous injection using a syringe and needle. Injections can be given at any time of the day, with or without meals.
- Patients and caregivers should receive proper training in how to prepare and administer the correct dose of MYALEPT prior to self-administration. The first dose of MYALEPT should be administered by the patient or caregiver under the supervision of a qualified healthcare professional.
- Advise patients on injection technique, dosing regimen, and the importance of proper storage of MYALEPT. Care should be taken to avoid intramuscular injection, especially in patients with minimal subcutaneous adipose tissue.
- Advise patients to read the Instructions for Use for complete administration instructions. The MYALEPT Medication Guide and Instructions for Use should be reviewed before starting therapy and each time the prescription is refilled.
- When discontinuing MYALEPT in patients with a history of pancreatitis and/or severe hypertriglyceridemia, instruct patients to taper their dose over a one-week period. Advise patients that additional monitoring of triglyceride levels and possible initiation or dose adjustment of lipid-lowering medications may be considered
# Precautions with Alcohol
- Alcohol-Metreleptin 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 Metreleptin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Metreleptin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Black Box Warning
# Overview
Metreleptin is a endocrine agent that is FDA approved for the treatment of the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Patients with Generalized Lipodystrophy
- Metreleptin for injection is indicated as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy.
- The safety and effectiveness of Metreleptin for the treatment of complications of partial lipodystrophy have not been established.
- The safety and effectiveness of Metreleptin for the treatment of liver disease, including nonalcoholic steatohepatitis (NASH), have not been established.
- Metreleptin is not indicated for use in patients with HIV-related lipodystrophy.
- Metreleptin is not indicated for use in patients with metabolic disease, including diabetes mellitus and hypertriglyceridemia, without concurrent evidence of congenital or acquired generalized lipodystrophy.
- See Table 1 for the recommended daily dose and maximum recommended daily dose in adults and pediatric patients.
- Based on clinical response (e.g., inadequate metabolic control) or other considerations (e.g., tolerability issues, excessive weight loss [especially in pediatric patients]), Metreleptin dosage may be decreased or increased to the maximum dosage listed in Table 1.
- Metreleptin should be administered once daily at the same time every day. Metreleptin can be administered any time of day without regard to the timing of meals.
- Instruct patients that if a dose is missed, administer the dose as soon as noticed, and resume the normal dosing schedule the next day.
- Healthcare practitioners should provide proper training to patients and caregivers regarding how to prepare and administer the correct dose of Metreleptin prior to self-use. The patients and caregivers should prepare and administer the first dose of Metreleptin under the supervision of a qualified healthcare professional.
- Instruct patients to store the vials of lyophilized powder in their carton in the refrigerator as soon as received .
- Metreleptin can be reconstituted aseptically with 2.2 mL of sterile Bacteriostatic Water for Injection (BWFI), USP (0.9% benzyl alcohol), or with 2.2 mL of sterile Water for Injection (WFI).
- When reconstituted in BWFI, Metreleptin solution can be used within 3 days when stored in the refrigerator between 36°F and 46°F (2°C and 8°C) and protected from light . Discard unused reconstituted solution after 3 days. Attach the supplied sticker to the vial and enter the discard date.
- For use in neonates and infants, reconstitute with preservative-free sterile WFI . When reconstituted in sterile WFI, Metreleptin should be administered immediately. Unused reconstituted solution cannot be saved for later use and should be discarded.
- Reconstitution of the Lyophilized Powder
- Instruct patients to follow the directions below for reconstitution of the lyophilized powder:
- Remove the vial containing the Metreleptin lyophilized powder from the refrigerator and allow the vial to warm to room temperature prior to use.
- Visually inspect the vial containing Metreleptin. The cake of lyophilized powder should be intact and white in color.
- Using a 3-mL syringe with a 22-gauge or smaller diameter needle withdraw 2.2 mL of sterile Bacteriostatic Water for Injection (BWFI) or preservative-free sterile Water for Injection (WFI). Do not reconstitute Metreleptin with other diluents.
- Inject the BWFI or WFI into the vial containing the lyophilized powder of Metreleptin, slowly injecting down the side of the vial. It is normal for some bubbles to form.
- Remove the needle and syringe from the vial and gently swirl the contents to reconstitute. Do not shake or vigorously agitate. When properly mixed, the Metreleptin reconstituted solution should be clear and free of clumps or dry powder, bubbles or foam. Do not use the solution if discolored or cloudy, or if particulate matter remains.
- Regarding the compatibility of Metreleptin reconstituted solution with other solutions:
- Do not mix with, or transfer into, the contents of another vial of Metreleptin.
- Do not add other medications, including insulin. Use a separate syringe for insulin injections.
- Healthcare practitioners should instruct patients and caregivers on the proper subcutaneous injection technique with care to avoid intramuscular injection in patients with minimal subcutaneous adipose tissue. Never administer Metreleptin intravenously or intramuscularly.
- Instruct patients to follow the recommended injection technique:
- Using a 1-mL syringe with a needle appropriate for subcutaneous injection, withdraw the prescribed dose of Metreleptin reconstituted solution.
- Remove any large air pockets or large bubbles from the filled syringe prior to administration. Some small bubbles may remain in the syringe.
- Administer Metreleptin into the subcutaneous tissue of the abdomen, thigh or upper arm. Advise patients to use a different injection site each day when injecting in the same region. After choosing an injection site, pinch the skin and at a 45-degree angle, inject the Metreleptin reconstituted solution subcutaneously. Avoid intramuscular injection, especially in patients with minimal subcutaneous adipose tissue.
- Doses exceeding 1 mL can be administered as two injections (the total daily dose divided equally) to minimize potential injection-site discomfort due to injection volume. When dividing doses due to volume, doses can be administered one after the other.
- Do not mix Metreleptin with insulin. Use a separate syringe for each medication. If Metreleptin and insulin are administered at the same time of day, they may be injected in the same body area using two different injection sites.
- See the Metreleptin Instructions for Use for complete administration instructions.
- Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue (e.g., sulfonylurea) may be necessary in some patients to minimize the risk of hypoglycemia . Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogue (e.g., sulfonylurea) when treating with Metreleptin.
- When discontinuing Metreleptin therapy in patients with risk factors for pancreatitis (e.g., history of pancreatitis, severe hypertriglyceridemia), tapering of the dose over a one-week period is recommended. During tapering, monitor triglyceride levels and consider initiating or adjusting the dose of lipid-lowering medications as needed. Signs and/or symptoms consistent with pancreatitis should prompt an appropriate clinical evaluation.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metreleptin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metreleptin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Metreleptin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Metreleptin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Metreleptin in pediatric patients.
# Contraindications
- Metreleptin is contraindicated in patients with general obesity not associated with congenital leptin deficiency. Metreleptin has not been shown to be effective in treating general obesity, and the development of anti-metreleptin antibodies with neutralizing activity has been reported in obese patients treated with Metreleptin .
- Metreleptin is contraindicated in patients with prior severe hypersensitivity reactions to metreleptin or to any of the product components. Known hypersensitivity reactions have included urticaria and generalized rash
# Warnings
- Anti-metreleptin antibodies with in vitro neutralizing activity to leptin associated with adverse events consistent with loss of endogenous leptin activity and/or loss of efficacy have been identified in two patients with generalized lipodystrophy treated with Metreleptin (severe infections, increases in HbA1cand triglycerides), and in three patients without lipodystrophy who received Metreleptin in clinical studies (excessive weight gain, development of glucose intolerance or diabetes mellitus). The clinical implications associated with development of anti-metreleptin antibodies with neutralizing activity are not well characterized at this time due to the small number of reports. Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of Metreleptin efficacy during treatment.
- Three cases of T-cell lymphoma have been reported in the Metreleptin lipodystrophy program; all three patients had acquired generalized lipodystrophy. Two of these patients were diagnosed with peripheral T-cell lymphoma while receiving Metreleptin. Both had immunodeficiency and significant hematologic abnormalities including severe bone marrow abnormalities before the start of Metreleptin treatment. A separate case of anaplastic large cell lymphoma was reported in a patient receiving Metreleptin who did not have hematological abnormalities before treatment.
- Lymphoproliferative disorders, including lymphomas, have been reported in patients with acquired generalized lipodystrophy not treated with Metreleptin. A causal relationship between Metreleptin treatment and the development and/or progression of lymphoma has not been established. Acquired lipodystrophies are associated with autoimmune disorders, and autoimmune disorders are associated with an increased risk of malignancies including lymphomas.
- The benefits and risks of Metreleptin treatment should be carefully considered in patients with acquired generalized lipodystrophy and/or those with significant hematologic abnormalities (including leukopenia, neutropenia, bone marrow abnormalities, lymphoma, and/or lymphadenopathy).
- Metreleptin is available only through a restricted distribution program under a REMS, called the Metreleptin REMS Program, because of the risks associated with the development of anti-metreleptin antibodies that neutralize endogenous leptin and/or Metreleptin and the risk for lymphoma .
- Notable requirements of the Metreleptin REMS Program include the following:
- Prescribers must be certified with the program by enrolling and completing training.
- Pharmacies must be certified with the program and only dispense Metreleptin after receipt of the Metreleptin REMS Prescription Authorization Form for each new prescription.
- Dosage adjustments, including possible large reductions, of insulin or insulin secretagogue (e.g., sulfonylurea) may be necessary in some patients to minimize the risk of hypoglycemia . Closely monitor blood glucose in patients on concomitant insulin therapy, especially those on high doses, or insulin secretagogue (e.g., sulfonylurea), when treating with Metreleptin.
- Leptin plays a role in immune system homeostasis. Acquired lipodystrophies are associated with autoimmune disorders including autoimmune hepatitis and membranoproliferative glomerulonephritis. Cases of progression of autoimmune hepatitis and membranoproliferative glomerulonephritis (associated with massive proteinuria and renal failure) were observed in some patients with acquired generalized lipodystrophy treated with Metreleptin. A causal relationship between Metreleptin treatment and the development and/or progression of autoimmune disease has not been established. The potential benefits and risks of Metreleptin treatment should be carefully considered in patients with autoimmune disease.
- There have been reports of generalized hypersensitivity (e.g., urticaria or generalized rash) in patients taking Metreleptin. If a hypersensitivity reaction occurs, instruct the patient to promptly seek medical advice regarding discontinuation of Metreleptin.
- Metreleptin contains benzyl alcohol when reconstituted with BWFI. Metreleptin contains no preservative when reconstituted with sterile Water for Injection (WFI). Preservative-free WFI is recommended for use in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death in pediatric patients, particularly in neonates and premature infants
# 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 Metreleptin was evaluated in 48 patients with generalized lipodystrophy in a single-arm, open-label study . The median duration of exposure in this trial was 2.7 years with a range of 3.6 months to 10.9 years. The most frequent adverse reactions are summarized in Table 2.
- In patients with generalized lipodystrophy receiving Metreleptin in this study, less common adverse reactions included injection-site erythema and urticaria (N=2 [4%]).
- Six patients (13%) had 7 adverse reactions of hypoglycemia, 6 of which occurred in the setting of concomitant insulin use, with or without oral antihyperglycemic agents.
- Two patients (4%) had events of pancreatitis, both of whom had a medical history of pancreatitis.
- As with all therapeutic proteins, there is potential for immunogenicity. Anti-metreleptin antibodies were detected in 84% (36/43) of generalized lipodystrophy patients studied in the Metreleptin trials. Total anti-metreleptin antibody titers ranged between 1:5 and 1:1,953,125. The incompleteness of the current immunogenicity database precludes understanding of the magnitude and persistence of the observed anti-drug antibody responses. Anti-metreleptin antibodies with neutralizing activity associated with adverse events consistent with loss of endogenous leptin activity and/or loss of Metreleptin efficacy were observed in 6% (2/33) of the patients with generalized lipodystrophy tested. Adverse events reported in these two patients included severe infections and worsening of metabolic control (increases in HbA1c and/or triglycerides). Test for anti-metreleptin antibodies with neutralizing activity in patients who develop severe infections or show signs suspicious for loss of Metreleptin efficacy during treatment. Contact AstraZeneca at 1-866-216-1526 for testing of clinical samples.
- The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. The immunogenicity assays utilized in clinical trials lacked sensitivity, resulting in potential underestimation of the number of samples positive for anti-metreleptin antibodies with neutralizing activity. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to metreleptin with the incidence of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Metreleptin in the drug label.
# Drug Interactions
- No formal drug interaction studies were performed.
- Leptin is a cytokine and may have the potential to alter the formation of cytochrome P450 (CYP450) enzymes. This should be taken into account when prescribing concomitant drugs metabolized by CYP450 (e.g., oral contraceptives and drugs with a narrow therapeutic index). The effect of metreleptin on CYP450 enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Metreleptin, in patients being treated with these types of agents, therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) should be performed and the individual dose of the agent adjusted as needed.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- There is a program that monitors outcomes in women exposed to Metreleptin during pregnancy. Women who become pregnant during Metreleptin treatment are encouraged to enroll. Patients or their physicians should call 1-855-6Metreleptin to enroll.
- There are no adequate and well-controlled studies of Metreleptin in pregnant women. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations and 15% to 20% for pregnancy loss. In a pre- and postnatal development study in mice, administration of metreleptin caused prolonged gestation and dystocia resulting in maternal death during parturition and lower survival of offspring in the immediate postnatal period at doses starting approximately at the maximum recommended clinical dose. Because animal reproduction studies are not always predictive of human response, Metreleptin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
### Clinical Considerations
- The contribution of Metreleptin to obstetrical risks and complications is unknown compared with those already documented in the lipodystrophy patient population (e.g., gestational diabetes, macrosomia, eclampsia, intrauterine growth retardation, intrauterine death, and miscarriage).
- The effects of Metreleptin on labor and delivery in pregnant women are unknown. In an in vitro study of human myometrial tissue exposed to a recombinant leptin, human uterine contractility was inhibited. Furthermore, prolonged gestation and dystocia were observed in animal studies with metreleptin (see below).
- Metreleptin administered to pregnant mice during the period of organogenesis was not teratogenic at doses ranging between 7- and 15-fold the maximum recommended clinical dose, based on body surface area of a 20- and 60-kg patient, respectively.
- In a pre- and postnatal development study in mice, metreleptin administered at doses of 3, 10, and 30 mg/kg (approximately 1-, 5-, and 15-fold the clinical dose for a 60-kg subject, based on body surface area) from gestation day 6 to lactation day 21 caused prolonged gestation and dystocia at all doses, starting at approximately the maximum recommended clinical dose. Prolonged gestation resulted in the death of some females during parturition and lower survival of offspring within the immediate postnatal period. Consistent with metreleptin pharmacology, decreased maternal body weight was observed from gestation throughout lactation at all doses and resulted in reduced weight of offspring at birth, which persisted into adulthood. However, no developmental abnormalities were observed and reproductive performance of the first or second generations was not affected at any dose.
- Placental transfer of metreleptin into the fetus was low (approximately 1%) following subcutaneous dosing.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metreleptin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Metreleptin during labor and delivery.
### Nursing Mothers
- It is not known if MYALEPT is present in human milk. Endogenous leptin is present in human milk. Because of the potential for serious adverse reactions (including possible adverse reactions related to passage of anti-metreleptin antibodies) in nursing infants from MYALEPT a decision should be made whether to discontinue nursing or discontinue the drug, taking into account importance of drug to the mother [
### Pediatric Use
- The MYALEPT study included a total of 35 pediatric patients (73%) with an age range from 1 to 17 years . No clinically meaningful differences were observed in the efficacy and safety of MYALEPT between pediatric and adult patients.
- MYALEPT contains benzyl alcohol when reconstituted with BWFI. MYALEPT contains no preservative when reconstituted with WFI. Preservative-free WFI is recommended for use in neonates and infants. The preservative benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome" (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages >99 mg/kg/day in neonates and low-birth weight infants. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.
- Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome," the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birth-weight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources. When reconstituted with 2.2 mL of BWFI, MYALEPT contains 1.76 mg of benzyl alcohol per mg of metreleptin or 9 mg of benzyl alcohol per mL of reconstituted product.
### Geriatic Use
- Clinical trials of MYALEPT did not include sufficient numbers of subjects aged 65 and over (n=1) to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Metreleptin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Metreleptin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Metreleptin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Metreleptin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metreleptin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Metreleptin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Metreleptin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Metreleptin in the drug label.
# Overdosage
- There were no reports of overdose in the lipodystrophy clinical trial program of MYALEPT. In the event of an overdose, patients should be monitored and appropriate supportive treatment be initiated as dictated by the patient’s clinical status.
# Pharmacology
## Mechanism of Action
- Adipocytes store lipids to meet the fuel requirements of non-adipose tissues during fasting. In patients with generalized lipodystrophy, the deficiency of adipose tissue leads to hypertriglyceridemia and ectopic deposition of fat in non-adipose tissues such as liver and muscle, contributing to metabolic abnormalities including insulin resistance. Native leptin is a hormone predominantly secreted by adipose tissue that informs the central nervous system of the status of energy stores in the body. In patients with generalized lipodystrophy, leptin deficiency, resulting from the loss of adipose tissue, contributes to excess caloric intake, which exacerbates the metabolic abnormalities.
- MYALEPT (metreleptin) for injection exerts its function by binding to and activating the human leptin receptor (ObR), which belongs to the Class I cytokine family of receptors that signals through the JAK/STAT transduction pathway.
## Structure
- MYALEPT (metreleptin) for injection is a recombinant human leptin analog for injection that binds to and activates the leptin receptor. Metreleptin (recombinant methionyl-human leptin) is produced in E. coli and differs from native human leptin by the addition of a methionine residue at its amino terminus. Metreleptin is a 147-amino acid, nonglycosylated, polypeptide with one disulfide bond between Cys-97 and Cys-147 and a molecular weight of approximately 16.15 kDa.
- MYALEPT is supplied as a sterile, white, solid, lyophilized cake containing 11.3 mg that is reconstituted with 2.2 mL of BWFI or WFI to a final formulation of 5 mg/mL metreleptin for subcutaneous injection. Inactive ingredients are: glutamic acid (1.47 mg/mL), glycine (20 mg/mL), polysorbate 20 (0.1 mg/mL), and sucrose (10 mg/mL), pH 4.25.
## Pharmacodynamics
- Clinical studies in patients with generalized lipodystrophy suggest that MYALEPT increases insulin sensitivity and reduces food intake. Improvements in insulin sensitivity and reductions in food intake are consistent with lower HbA1c, fasting glucose, and fasting triglyceride values that were seen in the MYALEPT clinical trial
## Pharmacokinetics
- There are limited data on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy, and therefore, no formal exposure-response analysis has been performed. It should be noted that the leptin assay measures both endogenous leptin as well as exogenously administered metreleptin.
- Peak serum leptin concentration (Cmax) occurred approximately 4.0 to 4.3 hours after subcutaneous administration of single doses ranging from 0.1 to 0.3 mg/kg in healthy subjects. In a supportive trial in lipodystrophy patients, the median Tmax of metreleptin was 4 hours (range: 2 to 8 hours; N=5) following single-dose administration of metreleptin.
- In studies of healthy adult subjects, following intravenous administration of metreleptin, leptin volume of distribution was approximately 4 to 5 times plasma volume; volumes (Vz) (mean ± SD) were 370 ± 184 mL/kg, 398 ± 92 mL/kg, and 463 ± 116 mL/kg for 0.3, 1.0, and 3.0 mg/kg/day doses, respectively.
- No formal metabolism studies have been conducted with metreleptin. Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Following single subcutaneous doses of 0.01 to 0.3 mg/mL metreleptin in healthy subjects, the half-life was 3.8 to 4.7 hours. The clearance of metreleptin is expected to be delayed in the presence of leptin antibodies [see ADVERSE REACTIONS (6.2)].
- No drug interaction studies have been conducted in lipodystrophy patients [see DRUG INTERACTIONS (7)].
- No formal pharmacokinetic studies were conducted in patients with renal impairment. Nonclinical data indicate renal clearance is the major route of metreleptin elimination, with no apparent contribution of systemic metabolism or degradation. Hence, the pharmacokinetics of metreleptin may be altered in subjects with renal impairment.
- No formal pharmacokinetic studies were conducted in patients with hepatic impairment.
- Specific clinical studies have not been conducted to assess the effect of age, gender, race, or body mass index on the pharmacokinetics of metreleptin in patients with generalized lipodystrophy.
## Nonclinical Toxicology
- Two-year carcinogenicity studies in rodents have not been conducted with metreleptin. No proliferative or preneoplastic lesions were observed in mice or dogs following treatment up to six months. However, leptin is reported in the literature to promote cell proliferation in vitro and tumor progression in some mouse models of cancer.
- Metreleptin was not mutagenic in the Ames bacterial mutagenicity assay or clastogenic in an in vitrochromosomal aberration assay in Chinese hamster ovary cells and human peripheral blood lymphocytes. Metreleptin was not mutagenic or clastogenic in an in vivo mouse micronucleus assay.
- In a fertility study in mice, metreleptin had no adverse effects on mating, fertility, or early embryonic development at doses ranging between 7 and 15 times the maximum recommended clinical dose based on body surface area of a 20- and 60-kg patient, respectively.
# Clinical Studies
- An open-label, single-arm study evaluated MYALEPT treatment in patients with congenital or acquired generalized lipodystrophy and diabetes mellitus, hypertriglyceridemia, and/or increased fasting insulin.
- Baseline Disease Characteristics and Demographics
- Of the 48 patients enrolled, 32 (67%) had congenital generalized lipodystrophy and 16 (33%) had acquired generalized lipodystrophy. Overall, 36 (75%) patients were female, 22 (46%) were Caucasian, 10 (21%) Hispanic, and 9 (19%) Black. The median age at baseline was 15 years (range: 1 - 68 years), with 35 (73%) patients being less than 18 years of age. The median fasting leptin concentration at baseline was 0.7 ng/mL in males (range: 0.3 - 3.3 ng/mL) and 1.0 ng/mL in females (range: 0.3 - 3.3 ng/mL).
- The median duration of MYALEPT treatment was 2.7 years (range: 3.6 months - 10.9 years). MYALEPT was administered subcutaneously either once daily or twice daily (in two equal doses). The weighted average daily dose (i.e., the average dose taking into account duration of treatment at different doses) for the 36 patients with baseline body weight greater than 40 kg was 2.6 mg for males and 4.6 mg for females during the first year of treatment, and 3.2 mg for males and 6.3 mg for females over the entire study period. For the 12 patients with baseline body weight less than 40 kg, the weighted average daily dose was 0.06 to 0.11 mg/kg (0.8-4.3 mg) over the entire study period.
- At baseline, 37 (77%) patients had HbA1c values of 7% or greater, 19 (40%) had HbA1c values of 9% or greater, 33 (69%) had fasting plasma glucose values of 126 mg/dL or greater, 17 (35%) had fasting triglyceride values of 500 mg/dL or greater, and 11 (23%) had fasting triglyceride values of 1000 mg/dL or greater.
- Patients treated with MYALEPT had mean/median reductions in HbA1c, fasting glucose, and triglycerides at 1 year (Table 3). The changes in HbA1c, fasting glucose, and triglycerides observed at Month 4 were similar to those at 1 year. Concomitant antihyperglycemic and lipid-altering medication dosage regimens were not held constant during the study; for example, some patients treated with insulin had their dosage increased and others had large reductions or discontinuation of insulin.
# How Supplied
- MYALEPT (metreleptin) for injection for subcutaneous administration is supplied in a single carton containing one vial for reconstitution (NDC 66780-310-01).
- Each vial contains 11.3 mg metreleptin (as a sterile, white, solid, lyophilized cake) to deliver 5 mg per mL of metreleptin when reconstituted with 2.2 mL of BWFI or
- MYALEPT should be stored in the refrigerator at 36°F to 46°F (2°C to 8°C) and protected from light until preparing for use. Keep MYALEPT vials in the carton when not in use.
- MYALEPT should not be used past the expiration date.
- Do not freeze MYALEPT.
- Do not use if the white lyophilized cake is discolored.
- Use with BWFI: when MYALEPT is reconstituted with BWFI, the vial can be used for multiple doses within 3 days when stored in the refrigerator at 36°F to 46°F (2°C to 8°C) and protected from light.
- Use with WFI: when MYALEPT is reconstituted with WFI, the vial can be used for a single dose should be administered immediately. Unused reconstituted solution cannot be saved for later *use and should be discarded.
- After reconstitution, the vials should not be frozen (below 0°C) or shaken vigorously. If the reconstituted product is inadvertently frozen, it should be thrown away.
- After reconstitution, the mixture should be clear and colorless. Do not use if visible particulates are present in the solution.
- Keep out of the reach of children.
## Storage
There is limited information regarding Metreleptin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise patients that neutralizing antibodies may result in loss in activity of endogenous leptin or loss of efficacy of MYALEPT. Advise patients on symptoms or signs that would warrant antibody testing.
- Advise patients that lymphoma has been reported in patients both treated and not treated with MYALEPT. Advise patients on symptoms or signs that indicate changes in hematologic status and the importance of routine laboratory assessments and physician monitoring .
- Advise patients that the risk of hypoglycemia is increased when MYALEPT is used in combination with insulin or an insulin secretagogue (e.g., sulfonylurea). Explain the symptoms, treatment, and conditions that predispose to development of hypoglycemia to the patient. Advise patients who are taking concomitant insulin, especially those on high doses, or an insulin secretagogue, to closely monitor blood glucose. Hypoglycemia management should be reviewed and reinforced when initiating MYALEPT therapy, particularly when concomitantly administered with insulin or an insulin secretagogue .
- Advise patients that worsening of autoimmune disease has been reported during the clinical study of MYALEPT. Advise patients with a history of autoimmune disease on symptoms or signs that indicate exacerbation of underlying autoimmune disease and the importance of routine laboratory assessments and physician monitoring .
- Inform patients that hypersensitivity reactions have been reported during use of MYALEPT. If symptoms of hypersensitivity reactions occur, patients should seek medical advice
Advise nursing mothers that breastfeeding is not recommended with MYALEPT use .
- Inform patients that each vial of MYALEPT requires reconstitution with BWFI or preservative-free WFI, and administration as subcutaneous injection using a syringe and needle. Injections can be given at any time of the day, with or without meals.
- Patients and caregivers should receive proper training in how to prepare and administer the correct dose of MYALEPT prior to self-administration. The first dose of MYALEPT should be administered by the patient or caregiver under the supervision of a qualified healthcare professional.
- Advise patients on injection technique, dosing regimen, and the importance of proper storage of MYALEPT. Care should be taken to avoid intramuscular injection, especially in patients with minimal subcutaneous adipose tissue.
- Advise patients to read the Instructions for Use for complete administration instructions. The MYALEPT Medication Guide and Instructions for Use should be reviewed before starting therapy and each time the prescription is refilled.
- When discontinuing MYALEPT in patients with a history of pancreatitis and/or severe hypertriglyceridemia, instruct patients to taper their dose over a one-week period. Advise patients that additional monitoring of triglyceride levels and possible initiation or dose adjustment of lipid-lowering medications may be considered
# Precautions with Alcohol
- Alcohol-Metreleptin 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 Metreleptin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Metreleptin | |
ae8a448379d1e9a37d07961c9102c840b27779f1 | wikidoc | Trichlorfon | Trichlorfon
# Overview
Metrifonate (INN) or trichlorfon (USAN) is an irreversible organophosphate acetylcholinesterase inhibitor. It is a prodrug which is activated non-enzymatically into 2,2-dichlorovinyl dimethyl phosphate (DDVP).
It is used as an insecticide.
It can be used to treat schistosomiasis caused by Schistoma haematobium but is no longer commercially available.
It has been proposed for use in treatment of Alzheimer's disease, but use for that purpose is not currently recommended. | Trichlorfon
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Metrifonate (INN) or trichlorfon (USAN) is an irreversible organophosphate acetylcholinesterase inhibitor.[1] It is a prodrug which is activated non-enzymatically into 2,2-dichlorovinyl dimethyl phosphate (DDVP).
It is used as an insecticide.
It can be used to treat schistosomiasis caused by Schistoma haematobium but is no longer commercially available.[2]
It has been proposed for use in treatment of Alzheimer's disease, but use for that purpose is not currently recommended.[3] | https://www.wikidoc.org/index.php/Metrifonate | |
60f0702ffe03fef814599946e2c49d0fd90a6f17 | wikidoc | Telmisartan | Telmisartan
- When pregnancy is detected, discontinue telmisartan as soon as possible .
- Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus .
## Hypertension
- Dosing information
- Dosage must be individualized.
- Usual starting dosage: 40 mg PO qd‘’‘.
- Dosage range of 20 to 80 mg .
- Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks.
- When additional blood pressure reduction beyond that achieved with 80 mg telmisartan tablets is required, a diuretic may be added.
- No initial dosage adjustment is necessary for elderly patients or patients with renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored.
- Telmisartan tablets may be administered with other antihypertensive agents.
- Telmisartan tablets may be administered with or without food.
## Atrial fibrillation, Recurrence; Prophylaxis - Hypertension
- Dosing information
- 80-160 mg PO qd
## Kidney disease
- Dosing information
- 80 mg/day
## Left ventricular hypertrophy
- Dosing information
- 80 mg/day
Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Do not co-administer aliskiren with Telmisartan HCT in patients with diabetes.
# Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Telmisartan as soon as possible.
# Hypotension
In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with Telmisartan. Either correct this condition prior to administration of Telmisartan, or start treatment under close medical supervision with a reduced dose.
If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
# Hyperkalemia
Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk.
# Impaired Hepatic Function
As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan at low doses and titrate slowly in these patients.
# Impaired Renal Function
As a consequence of inhibiting the renin-angiotensin-aldosterone system, anticipate changes in renal function in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results have been reported with Telmisartan.
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of Telmisartan in patients with unilateral or bilateral renal artery stenosis, but anticipate an effect similar to that seen with ACE inhibitors.
# Dual Blockade of the renin-angiotensin-aldosterone system
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function.
The ONTARGET trial enrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomizing them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of Telmisartan and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of Telmisartan and ramipril is not recommended.
Renal dysfunction upon use with ramipril.
# Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
## Hypertension
Telmisartan has been evaluated for safety in more than 3700 patients, including 1900 treated for over 6 months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have infrequently required discontinuation of therapy.
In placebo-controlled trials involving 1041 patients treated with various doses of Telmisartan (20 to 160 mg) monotherapy for up to 12 weeks, the overall incidence of adverse events was similar to that in patients treated with placebo.
Adverse events occurring at an incidence of ≥1% in patients treated with Telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 1.
In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing,hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy because of adverse events was required in 2.8% of 1455 patients treated with Telmisartan tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials.
The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients.
The incidence of cough occurring with telmisartan in 6 placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%).
In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with Telmisartan monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to Telmisartan tablets:
- Autonomic Nervous System: impotence, increased sweating, flushing;
- Body as a Whole: allergy, fever, leg pain, malaise.
- Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG.
- CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoesthesia.
- Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders.
- Metabolic: gout, hypercholesterolemia, diabetes mellitus.
- Musculoskeletal: arthritis, arthralgia, leg cramps.
- Psychiatric: anxiety, depression, nervousness.
- Resistance Mechanism: infection, fungal infection, abscess, otitis media.
- Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis.
- Skin: dermatitis, rash, eczema, pruritus.
- Urinary: micturition frequency, cystitis.
- Vascular: cerebrovascular disorder.
- Special Senses: abnormal vision, conjunctivitis, tinnitus, earache.
During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated).
## Clinical Laboratory Findings
In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of Telmisartan tablets.
Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy because of anemia.
Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy because of increases in creatinine and blood urea nitrogen.
Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy because of abnormal hepatic function.
## Cardiovascular Risk Reduction
Because common adverse reactions were well characterized in studies of telmisartan in hypertension, only adverse events leading to discontinuation and serious adverse events were recorded in subsequent studies of telmisartan for cardiovascular risk reduction. In TRANSCEND (N=5926, 4 years and 8 months of follow-up), discontinuations for adverse events were 8.4% on telmisartan and 7.6% on placebo. The only serious adverse events at least 1% more common on telmisartan than placebo were intermittent claudication (7% vs 6%) and skin ulcer (3% vs 2%).
The most frequent spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, increased CPK, anaphylactic reaction, tendon pain (including tendonitis, tenosynovitis), drug eruption (toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), hypoglycemia (in diabetic patients), and angioedema (with fatal outcome).
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including Telmisartan.
Digoxin: When Telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Therefore, monitor digoxin levels when initiating, adjusting, and discontinuing telmisartan for the purpose of keeping the digoxin level within the therapeutic range.
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including Telmisartan. Therefore, monitor serum lithium levels during concomitant use.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including telmisartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving telmisartan and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including telmisartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmaxand AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Concomitant use of Telmisartan and ramipril is not recommended.
Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Telmisartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Telmisartan for hypotension, oliguria, and hyperkalemia.
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Safety and effectiveness in pediatric patients have not been established.
Of the total number of patients receiving Telmisartan in the cardiovascular risk reduction study (ONTARGET), the percentage of patients ≥65 to <75 years of age was 42%; 15% of patients were ≥75 years old. No overall differences in effectiveness and safety were observed in these patients compared to 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.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.
Telmisartan is chemically described as 4'--1'-yl)methyl]--2-carboxylic acid. Its empirical formula is C33H30N4O2, its molecular weight is 514.63, and its structural formula is:
Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base.
Telmisartan is available as tablets for oral administration, containing 20 mg, 40 mg or 80 mg of telmisartan. The tablets contain the following inactive ingredients: sodium hydroxide, meglumine, povidone, sorbitol, and magnesium stearate. Telmisartan tablets are hygroscopic and require protection from moisture.
Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α1 - acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters indicating additional tissue binding.
## Metabolism and Elimination
Following either intravenous or oral administration of 14C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively).
Telmisartan is metabolized by conjugation to form a pharmacologically inactive acyl glucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.
Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.
## Specific Populations
No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration .
In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% .
Plasma concentrations of telmisartan are generally 2 to 3 times higher in females than in males. In clinical trials, however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary.
The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years .
Telmisartan pharmacokinetics have not been investigated in patients <18 years of age.
There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day).
Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.
No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day).
# Developmental Toxicity
There is no clinical experience with the use of Telmisartan tablets in pregnant women. No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day . In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m2 basis, the maximum recommended human dose of telmisartan (80 mg/day).
The antihypertensive effects of Telmisartan have been demonstrated in six principal placebo-controlled clinical trials, studying a range of 20 to 160 mg; one of these examined the antihypertensive effects of telmisartan and Hydrochlorothiazidein combination. The studies involved a total of 1773 patients with mild to moderate , 1031 of whom were treated with telmisartan. Following once daily administration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure.
Upon initiation of antihypertensive treatment with telmisartan, blood pressure was reduced after the first dose, with a maximal reduction by about 4 weeks. With cessation of treatment with Telmisartan tablets, blood pressure gradually returned to baseline values over a period of several days to one week. During long term studies (without placebo control) the effect of telmisartan appeared to be maintained for up to at least one year. The antihypertensive effect of telmisartan is not influenced by patient age, gender, weight, or body mass index. Blood pressure response in black patients (usually a low-renin population) is noticeably less than that in Caucasian patients. This has been true for most, but not all, angiotensin II antagonists and ACE inhibitors.
In a controlled study, the addition of telmisartan to Hydrochlorothiazideproduced an additional dose-related reduction in blood pressure that was similar in magnitude to the reduction achieved with telmisartan monotherapy. Hydrochlorothiazidealso had an added blood pressure effect when added to telmisartan.
The onset of antihypertensive activity occurs within 3 hours after administration of a single oral dose. At doses of 20, 40, and 80 mg, the antihypertensive effect of once daily administration of telmisartan is maintained for the full 24-hour dose interval. With automated ambulatory blood pressure monitoring and conventional blood pressure measurements, the 24-hour trough-to-peak ratio for 40 to 80 mg doses of telmisartan was 70 to 100% for both systolic and diastolic blood pressure. The incidence of symptomatic orthostasis after the first dose in all controlled trials was low (0.04%).
There were no changes in the heart rate of patients treated with telmisartan in controlled trials.
There are no trials of Telmisartan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.
Telmisartan tablets USP 20 mg: white to off-white circular shaped flat beveled edge tablets with ‘G’ engraved on one side and ‘199’ engraved on the other side.
Bottles of 100 (NDC 68462-199-01)
Carton of 30 Tablets (3 x 10 Unit-Dose) NDC 68462-199-13
Telmisartan tablets USP 40 mg: white to off-white capsule shaped tablets with ‘G’ engraved on one side and ‘200’ engraved on other side.
Bottles of 100 (NDC 68462-200-01)
Carton of 30 Tablets (3 x 10 Unit-Dose) NDC 68462-200-13
Telmisartan tablets USP 80 mg: white to off-white capsule shaped tablets with ‘G’ engraved on one side and ‘201’ engraved on other side.
Bottles of 100 (NDC 68462-201-01)
Carton of 30 Tablets (3 x 10 Unit-Dose) NDC 68462-201-13
Read this Patient Information before you start taking telmisartan tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.
## What is the most important information I should know about telmisartan tablets?
Telmisartan tablets can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking telmisartan tablets, tell your doctor right away.
What are telmisartan tablets?
## Telmisartan tablets are a prescription medicine used:
- to treat high blood pressure (hypertension)
It is not known if telmisartan tablets are safe and effective in children.
## Who should not take telmisartan tablets?
You should not take telmisartan tablets if you are allergic (hypersensitive) to the active ingredient (telmisartan) or any of the other ingredients listed at the end of this leaflet.
For patients with diabetes, if you are taking telmisartan you should not take aliskiren.
## What should I tell my doctor before taking telmisartan tablets?
Before you take telmisartan tablets, tell your doctor if you:
- have liver problems
- have kidney problems
- have heart problems
- have any other medical conditions
- are pregnant or are planning to become pregnant. See “What is the most important information I should know about telmisartan tablets?”
- are breast-feeding or plan to breast-feed. It is not known if telmisartan passes into your breast milk. You and your doctor should decide if you will take telmisartan tablets or breast-feed. You should not do both. Talk with your doctor about the best way to feed your baby if you take telmisartan tablets.
## Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
For patients with diabetes, if you are taking telmisartan you should not take aliskiren.
Telmisartan tablets may affect the way other medicines work, and other medicines may affect how telmisartan tablets work. Especially tell your doctor if you take:
- aliskiren
- digoxin (Lanoxin®, Lanoxicaps®)
- lithium (Eskalith®, Lithobid®)
- medicines used to treat pain and arthritis, called non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors
- ramipril (Altace®) or other medicines used to treat your high blood pressure or heart problem
- water pills (diuretic)
Know the medicines you take. Keep a list of them and show it to your doctor or pharmacist when you get a new medicine.
## How should I take telmisartan tablets?
- Take telmisartan tablets exactly as your doctor tells you to take it.
- Your doctor will tell you how much telmisartan to take and when to take it.
- Do not change your dose unless your doctor tells you to.
- Take telmisartan tablets one time each day at the same time.
- Take telmisartan tablets with or without food.
- If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Take the next dose at your regular time.
- If you take too much telmisartan, call your doctor, or go to the nearest hospital emergency room right away.
- Read the “How to Open the Blister” at the end of this leaflet before you use telmisartan tablets. Talk with your doctor if you do not understand the instructions.
## What are the possible side effects of telmisartan tablets?
Telmisartan tablets may cause serious side effects, including:
- Injury or death to your unborn baby. See “What is the most important information I should know about telmisartan tablets?”
- Low blood pressure (hypotension) is most likely to happen if you also:
- take water pills (diuretics)
- are on a low-salt diet
- get dialysis treatments
- have heart problems
- get sick with vomiting or diarrhea
If you feel faint or dizzy, lie down and call your doctor right away.
- Kidney problems, which may get worse if you already have kidney disease. You may have changes in your kidney test results, and you may need a lower dose of telmisartan tablets. Call your doctor if you get:
- swelling in your feet, ankles, or hands
- unexplained weight gain
Call your doctor right away if you get any of the symptoms listed above.
- High potassium in the blood (hyperkalemia). Your doctor may check your potassium levels as needed.
Rare, serious allergic reactions may happen. Tell your doctor right away if you get any of these symptoms:
- swelling of the face, tongue, throat
- difficulty breathing
- skin rash
The most common side effects of telmisartan tablets include:
- sinus pain and congestion (sinusitis)
- back pain
- diarrhea
These are not all the possible side effects with telmisartan tablets. Tell your doctor if you have any side effect that bothers you or that does not go away. 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 telmisartan tablets?
- Store telmisartan tablets between 59°F to 86°F (15°C to 30°C).
- Do not remove telmisartan tablets from blisters until right before you take them.
Keep telmisartan tablets and all medicines out of the reach of children.
## General information about telmisartan tablets
- Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use telmisartan tablets for a condition for which it was not prescribed. Do not give telmisartan tablets to other people, even if they have the same condition you have. It may harm them.
- This Patient Information leaflet summarizes the most important information about telmisartan tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about telmisartan tablets that is written for health professionals.
- For more information, call Glenmark Generics Inc., USA at 1 (888)721-7115 or visit www.glenmarkgenerics.com.
## What are the ingredients in telmisartan tablets USP?
Active Ingredient: telmisartan USP
Inactive Ingredients: crospovidone, lactose monohydrate, magnesium stearate, meglumine, povidone and sodium hydroxide pellets
## What is High Blood Pressure (Hypertension)?
Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. Telmisartan tablets can help your blood vessels relax so your blood pressure is lower. Medicines that lower your blood pressure lower your chance of having a stroke or heart attack.
High blood pressure makes the heart work harder to pump blood throughout the body and causes damage to the blood vessels. If high blood pressure is not treated, it can lead to stroke, heart attack, heart failure, kidney failure, and vision problems.
## How to open the blister:
1. Tear (You may also use scissors to tear the blister apart)
2. Peel (Peel off the paper layer from the aluminum foil)
3. Push (Push the tablet through the foil)
- ↑ Du H, Fan J, Ling Z, Woo K, Su L, Chen S; et al. (2013). "Effect of nifedipine versus telmisartan on prevention of atrial fibrillation recurrence in hypertensive patients". Hypertension. 61 (4): 786–92. doi:10.1161/HYPERTENSIONAHA.111.202309. PMID 23438932.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J; et al. (2008). "Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial". Lancet. 372 (9638): 547–53. doi:10.1016/S0140-6736(08)61236-2. PMID 18707986.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) Review in: ACP J Club. 2008 Dec 16;149(6):7 Review in: Evid Based Med. 2009 Feb;14(1):11
- ↑ Galzerano D, Tammaro P, Cerciello A, Breglio R, Mallardo M, Lama D; et al. (2004). "Freehand three-dimensional echocardiographic evaluation of the effect of telmisartan compared with hydrochlorothiazide on left ventricular mass in hypertensive patients with mild-to-moderate hypertension: a multicentre study". J Hum Hypertens. 18 (1): 53–9. doi:10.1038/sj.jhh.1001637. PMID 14688811.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | Telmisartan
- When pregnancy is detected, discontinue telmisartan as soon as possible [see Warnings and Precautions (5.1)].
- Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1)].
### Hypertension
- Dosing information
- Dosage must be individualized.
- Usual starting dosage: 40 mg PO qd‘’‘.
- Dosage range of 20 to 80 mg [see Clinical Studies (14.1)].
- Most of the antihypertensive effect is apparent within 2 weeks and maximal reduction is generally attained after 4 weeks.
- When additional blood pressure reduction beyond that achieved with 80 mg telmisartan tablets is required, a diuretic may be added.
- No initial dosage adjustment is necessary for elderly patients or patients with renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored.
- Telmisartan tablets may be administered with other antihypertensive agents.
- Telmisartan tablets may be administered with or without food.
### Atrial fibrillation, Recurrence; Prophylaxis - Hypertension
- Dosing information
- 80-160 mg PO qd [1]
### Kidney disease
- Dosing information
- 80 mg/day[2]
### Left ventricular hypertrophy
- Dosing information
- 80 mg/day[3]
Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Do not co-administer aliskiren with Telmisartan HCT in patients with diabetes.
## Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Telmisartan as soon as possible.
## Hypotension
In patients with an activated renin-angiotensin system, such as volume- or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with Telmisartan. Either correct this condition prior to administration of Telmisartan, or start treatment under close medical supervision with a reduced dose.
If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
## Hyperkalemia
Hyperkalemia may occur in patients on ARBs, particularly in patients with advanced renal impairment, heart failure, on renal replacement therapy, or on potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes or other drugs that increase potassium levels. Consider periodic determinations of serum electrolytes to detect possible electrolyte imbalances, particularly in patients at risk.
## Impaired Hepatic Function
As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. Initiate telmisartan at low doses and titrate slowly in these patients.
## Impaired Renal Function
As a consequence of inhibiting the renin-angiotensin-aldosterone system, anticipate changes in renal function in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure or renal dysfunction), treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results have been reported with Telmisartan.
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of Telmisartan in patients with unilateral or bilateral renal artery stenosis, but anticipate an effect similar to that seen with ACE inhibitors.
## Dual Blockade of the renin-angiotensin-aldosterone system
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function (including acute renal failure) have been reported. Dual blockade of the renin-angiotensin-aldosterone system (e.g., by adding an ACE-inhibitor to an angiotensin II receptor antagonist) should include close monitoring of renal function.
The ONTARGET trial enrolled 25,620 patients ≥55 years old with atherosclerotic disease or diabetes with end-organ damage, randomizing them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of Telmisartan and ramipril did not obtain any additional benefit compared to monotherapy, but experienced an increased incidence of renal dysfunction (e.g., acute renal failure) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of Telmisartan and ramipril is not recommended.
Renal dysfunction upon use with ramipril.
## Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reactions rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
### Hypertension
Telmisartan has been evaluated for safety in more than 3700 patients, including 1900 treated for over 6 months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have infrequently required discontinuation of therapy.
In placebo-controlled trials involving 1041 patients treated with various doses of Telmisartan (20 to 160 mg) monotherapy for up to 12 weeks, the overall incidence of adverse events was similar to that in patients treated with placebo.
Adverse events occurring at an incidence of ≥1% in patients treated with Telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented in Table 1.
In addition to the adverse events in the table, the following events occurred at a rate of ≥1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing,hypertension, chest pain, nausea, and peripheral edema. Discontinuation of therapy because of adverse events was required in 2.8% of 1455 patients treated with Telmisartan tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials.
The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients.
The incidence of cough occurring with telmisartan in 6 placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%).
In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with Telmisartan monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to Telmisartan tablets:
- Autonomic Nervous System: impotence, increased sweating, flushing;
- Body as a Whole: allergy, fever, leg pain, malaise.
- Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG.
- CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoesthesia.
- Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders.
- Metabolic: gout, hypercholesterolemia, diabetes mellitus.
- Musculoskeletal: arthritis, arthralgia, leg cramps.
- Psychiatric: anxiety, depression, nervousness.
- Resistance Mechanism: infection, fungal infection, abscess, otitis media.
- Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis.
- Skin: dermatitis, rash, eczema, pruritus.
- Urinary: micturition frequency, cystitis.
- Vascular: cerebrovascular disorder.
- Special Senses: abnormal vision, conjunctivitis, tinnitus, earache.
During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated).
### Clinical Laboratory Findings
In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of Telmisartan tablets.
Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy because of anemia.
Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy because of increases in creatinine and blood urea nitrogen.
Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy because of abnormal hepatic function.
### Cardiovascular Risk Reduction
Because common adverse reactions were well characterized in studies of telmisartan in hypertension, only adverse events leading to discontinuation and serious adverse events were recorded in subsequent studies of telmisartan for cardiovascular risk reduction. In TRANSCEND (N=5926, 4 years and 8 months of follow-up), discontinuations for adverse events were 8.4% on telmisartan and 7.6% on placebo. The only serious adverse events at least 1% more common on telmisartan than placebo were intermittent claudication (7% vs 6%) and skin ulcer (3% vs 2%).
The most frequent spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, increased CPK, anaphylactic reaction, tendon pain (including tendonitis, tenosynovitis), drug eruption (toxic skin eruption mostly reported as toxicoderma, rash, and urticaria), hypoglycemia (in diabetic patients), and angioedema (with fatal outcome).
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including Telmisartan.
Digoxin: When Telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. Therefore, monitor digoxin levels when initiating, adjusting, and discontinuing telmisartan for the purpose of keeping the digoxin level within the therapeutic range.
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists including Telmisartan. Therefore, monitor serum lithium levels during concomitant use.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including telmisartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving telmisartan and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including telmisartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
Ramipril and Ramiprilat: Co-administration of telmisartan 80 mg once daily and ramipril 10 mg once daily to healthy subjects increases steady-state Cmax and AUC of ramipril 2.3- and 2.1-fold, respectively, and Cmax and AUC of ramiprilat 2.4- and 1.5-fold, respectively. In contrast, Cmaxand AUC of telmisartan decrease by 31% and 16%, respectively. When co-administering telmisartan and ramipril, the response may be greater because of the possibly additive pharmacodynamic effects of the combined drugs, and also because of the increased exposure to ramipril and ramiprilat in the presence of telmisartan. Concomitant use of Telmisartan and ramipril is not recommended.
Other Drugs: Co-administration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glyburide, simvastatin, hydrochlorothiazide, warfarin, or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Telmisartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Telmisartan for hypotension, oliguria, and hyperkalemia.
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Safety and effectiveness in pediatric patients have not been established.
Of the total number of patients receiving Telmisartan in the cardiovascular risk reduction study (ONTARGET), the percentage of patients ≥65 to <75 years of age was 42%; 15% of patients were ≥75 years old. No overall differences in effectiveness and safety were observed in these patients compared to 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.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Telmisartan has much greater affinity (>3,000 fold) for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because telmisartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Telmisartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of telmisartan on blood pressure.
Telmisartan is chemically described as 4'-[(1,4'-dimethyl-2'-propyl [2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid. Its empirical formula is C33H30N4O2, its molecular weight is 514.63, and its structural formula is:
Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base.
Telmisartan is available as tablets for oral administration, containing 20 mg, 40 mg or 80 mg of telmisartan. The tablets contain the following inactive ingredients: sodium hydroxide, meglumine, povidone, sorbitol, and magnesium stearate. Telmisartan tablets are hygroscopic and require protection from moisture.
Telmisartan is highly bound to plasma proteins (>99.5%), mainly albumin and α1 - acid glycoprotein. Plasma protein binding is constant over the concentration range achieved with recommended doses. The volume of distribution for telmisartan is approximately 500 liters indicating additional tissue binding.
### Metabolism and Elimination
Following either intravenous or oral administration of 14C-labeled telmisartan, most of the administered dose (>97%) was eliminated unchanged in feces via biliary excretion; only minute amounts were found in the urine (0.91% and 0.49% of total radioactivity, respectively).
Telmisartan is metabolized by conjugation to form a pharmacologically inactive acyl glucuronide; the glucuronide of the parent compound is the only metabolite that has been identified in human plasma and urine. After a single dose, the glucuronide represents approximately 11% of the measured radioactivity in plasma. The cytochrome P450 isoenzymes are not involved in the metabolism of telmisartan.
Total plasma clearance of telmisartan is >800 mL/min. Terminal half-life and total clearance appear to be independent of dose.
### Specific Populations
No dosage adjustment is necessary in patients with decreased renal function. Telmisartan is not removed from blood by hemofiltration [see Warnings and Precautions (5.5) and Dosage and Administration (2.1)].
In patients with hepatic insufficiency, plasma concentrations of telmisartan are increased, and absolute bioavailability approaches 100% [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)].
Plasma concentrations of telmisartan are generally 2 to 3 times higher in females than in males. In clinical trials, however, no significant increases in blood pressure response or in the incidence of orthostatic hypotension were found in women. No dosage adjustment is necessary.
The pharmacokinetics of telmisartan do not differ between the elderly and those younger than 65 years [see Dosage and Administration (2.1)].
Telmisartan pharmacokinetics have not been investigated in patients <18 years of age.
There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day).
Genotoxicity assays did not reveal any telmisartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test.
No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day).
## Developmental Toxicity
There is no clinical experience with the use of Telmisartan tablets in pregnant women. No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m2 basis, the maximum recommended human dose of telmisartan (80 mg/day).
The antihypertensive effects of Telmisartan have been demonstrated in six principal placebo-controlled clinical trials, studying a range of 20 to 160 mg; one of these examined the antihypertensive effects of telmisartan and Hydrochlorothiazidein combination. The studies involved a total of 1773 patients with mild to moderate [[hypertension ]](diastolic blood pressure of 95 to 114 mmHg), 1031 of whom were treated with telmisartan. Following once daily administration of telmisartan, the magnitude of blood pressure reduction from baseline after placebo subtraction was approximately (SBP/DBP) 6-8/6 mmHg for 20 mg, 9-13/6-8 mmHg for 40 mg, and 12-13/7-8 mmHg for 80 mg. Larger doses (up to 160 mg) did not appear to cause a further decrease in blood pressure.
Upon initiation of antihypertensive treatment with telmisartan, blood pressure was reduced after the first dose, with a maximal reduction by about 4 weeks. With cessation of treatment with Telmisartan tablets, blood pressure gradually returned to baseline values over a period of several days to one week. During long term studies (without placebo control) the effect of telmisartan appeared to be maintained for up to at least one year. The antihypertensive effect of telmisartan is not influenced by patient age, gender, weight, or body mass index. Blood pressure response in black patients (usually a low-renin population) is noticeably less than that in Caucasian patients. This has been true for most, but not all, angiotensin II antagonists and ACE inhibitors.
In a controlled study, the addition of telmisartan to Hydrochlorothiazideproduced an additional dose-related reduction in blood pressure that was similar in magnitude to the reduction achieved with telmisartan monotherapy. Hydrochlorothiazidealso had an added blood pressure effect when added to telmisartan.
The onset of antihypertensive activity occurs within 3 hours after administration of a single oral dose. At doses of 20, 40, and 80 mg, the antihypertensive effect of once daily administration of telmisartan is maintained for the full 24-hour dose interval. With automated ambulatory blood pressure monitoring and conventional blood pressure measurements, the 24-hour trough-to-peak ratio for 40 to 80 mg doses of telmisartan was 70 to 100% for both systolic and diastolic blood pressure. The incidence of symptomatic orthostasis after the first dose in all controlled trials was low (0.04%).
There were no changes in the heart rate of patients treated with telmisartan in controlled trials.
There are no trials of Telmisartan demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.
Telmisartan tablets USP 20 mg: white to off-white circular shaped flat beveled edge tablets with ‘G’ engraved on one side and ‘199’ engraved on the other side.
Bottles of 100 (NDC 68462-199-01)
Carton of 30 Tablets (3 x 10 Unit-Dose) NDC 68462-199-13
Telmisartan tablets USP 40 mg: white to off-white capsule shaped tablets with ‘G’ engraved on one side and ‘200’ engraved on other side.
Bottles of 100 (NDC 68462-200-01)
Carton of 30 Tablets (3 x 10 Unit-Dose) NDC 68462-200-13
Telmisartan tablets USP 80 mg: white to off-white capsule shaped tablets with ‘G’ engraved on one side and ‘201’ engraved on other side.
Bottles of 100 (NDC 68462-201-01)
Carton of 30 Tablets (3 x 10 Unit-Dose) NDC 68462-201-13
Read this Patient Information before you start taking telmisartan tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment.
### What is the most important information I should know about telmisartan tablets?
Telmisartan tablets can cause harm or death to an unborn baby. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant. If you get pregnant while taking telmisartan tablets, tell your doctor right away.
What are telmisartan tablets?
### Telmisartan tablets are a prescription medicine used:
- to treat high blood pressure (hypertension)
It is not known if telmisartan tablets are safe and effective in children.
### Who should not take telmisartan tablets?
You should not take telmisartan tablets if you are allergic (hypersensitive) to the active ingredient (telmisartan) or any of the other ingredients listed at the end of this leaflet.
For patients with diabetes, if you are taking telmisartan you should not take aliskiren.
### What should I tell my doctor before taking telmisartan tablets?
Before you take telmisartan tablets, tell your doctor if you:
- have liver problems
- have kidney problems
- have heart problems
- have any other medical conditions
- are pregnant or are planning to become pregnant. See “What is the most important information I should know about telmisartan tablets?”
- are breast-feeding or plan to breast-feed. It is not known if telmisartan passes into your breast milk. You and your doctor should decide if you will take telmisartan tablets or breast-feed. You should not do both. Talk with your doctor about the best way to feed your baby if you take telmisartan tablets.
### Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.
For patients with diabetes, if you are taking telmisartan you should not take aliskiren.
Telmisartan tablets may affect the way other medicines work, and other medicines may affect how telmisartan tablets work. Especially tell your doctor if you take:
- aliskiren
- digoxin (Lanoxin®, Lanoxicaps®)
- lithium (Eskalith®, Lithobid®)
- medicines used to treat pain and arthritis, called non-steroidal anti-inflammatory drugs (NSAIDs), including COX-2 inhibitors
- ramipril (Altace®) or other medicines used to treat your high blood pressure or heart problem
- water pills (diuretic)
Know the medicines you take. Keep a list of them and show it to your doctor or pharmacist when you get a new medicine.
### How should I take telmisartan tablets?
- Take telmisartan tablets exactly as your doctor tells you to take it.
- Your doctor will tell you how much telmisartan to take and when to take it.
- Do not change your dose unless your doctor tells you to.
- Take telmisartan tablets one time each day at the same time.
- Take telmisartan tablets with or without food.
- If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Take the next dose at your regular time.
- If you take too much telmisartan, call your doctor, or go to the nearest hospital emergency room right away.
- Read the “How to Open the Blister” at the end of this leaflet before you use telmisartan tablets. Talk with your doctor if you do not understand the instructions.
### What are the possible side effects of telmisartan tablets?
Telmisartan tablets may cause serious side effects, including:
- Injury or death to your unborn baby. See “What is the most important information I should know about telmisartan tablets?”
- Low blood pressure (hypotension) is most likely to happen if you also:
- take water pills (diuretics)
- are on a low-salt diet
- get dialysis treatments
- have heart problems
- get sick with vomiting or diarrhea
If you feel faint or dizzy, lie down and call your doctor right away.
- Kidney problems, which may get worse if you already have kidney disease. You may have changes in your kidney test results, and you may need a lower dose of telmisartan tablets. Call your doctor if you get:
- swelling in your feet, ankles, or hands
- unexplained weight gain
Call your doctor right away if you get any of the symptoms listed above.
- High potassium in the blood (hyperkalemia). Your doctor may check your potassium levels as needed.
Rare, serious allergic reactions may happen. Tell your doctor right away if you get any of these symptoms:
- swelling of the face, tongue, throat
- difficulty breathing
- skin rash
The most common side effects of telmisartan tablets include:
- sinus pain and congestion (sinusitis)
- back pain
- diarrhea
These are not all the possible side effects with telmisartan tablets. Tell your doctor if you have any side effect that bothers you or that does not go away. 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 telmisartan tablets?
- Store telmisartan tablets between 59°F to 86°F (15°C to 30°C).
- Do not remove telmisartan tablets from blisters until right before you take them.
Keep telmisartan tablets and all medicines out of the reach of children.
### General information about telmisartan tablets
- Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use telmisartan tablets for a condition for which it was not prescribed. Do not give telmisartan tablets to other people, even if they have the same condition you have. It may harm them.
- This Patient Information leaflet summarizes the most important information about telmisartan tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about telmisartan tablets that is written for health professionals.
- For more information, call Glenmark Generics Inc., USA at 1 (888)721-7115 or visit www.glenmarkgenerics.com.
### What are the ingredients in telmisartan tablets USP?
Active Ingredient: telmisartan USP
Inactive Ingredients: crospovidone, lactose monohydrate, magnesium stearate, meglumine, povidone and sodium hydroxide pellets
### What is High Blood Pressure (Hypertension)?
Blood pressure is the force in your blood vessels when your heart beats and when your heart rests. You have high blood pressure when the force is too much. Telmisartan tablets can help your blood vessels relax so your blood pressure is lower. Medicines that lower your blood pressure lower your chance of having a stroke or heart attack.
High blood pressure makes the heart work harder to pump blood throughout the body and causes damage to the blood vessels. If high blood pressure is not treated, it can lead to stroke, heart attack, heart failure, kidney failure, and vision problems.
### How to open the blister:
1. Tear (You may also use scissors to tear the blister apart)
2. Peel (Peel off the paper layer from the aluminum foil)
3. Push (Push the tablet through the foil)
- ↑ Du H, Fan J, Ling Z, Woo K, Su L, Chen S; et al. (2013). "Effect of nifedipine versus telmisartan on prevention of atrial fibrillation recurrence in hypertensive patients". Hypertension. 61 (4): 786–92. doi:10.1161/HYPERTENSIONAHA.111.202309. PMID 23438932.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- ↑ Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J; et al. (2008). "Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial". Lancet. 372 (9638): 547–53. doi:10.1016/S0140-6736(08)61236-2. PMID 18707986.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) Review in: ACP J Club. 2008 Dec 16;149(6):7 Review in: Evid Based Med. 2009 Feb;14(1):11
- ↑ Galzerano D, Tammaro P, Cerciello A, Breglio R, Mallardo M, Lama D; et al. (2004). "Freehand three-dimensional echocardiographic evaluation of the effect of telmisartan compared with hydrochlorothiazide on left ventricular mass in hypertensive patients with mild-to-moderate hypertension: a multicentre study". J Hum Hypertens. 18 (1): 53–9. doi:10.1038/sj.jhh.1001637. PMID 14688811.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link) | https://www.wikidoc.org/index.php/Micardis | |
2c07b44d70cb418fabef36c5333aabed1159c1d3 | wikidoc | Micrococcus | Micrococcus
Micrococcus (mi’ krō kŏk’ Əs) is a genus of bacteria in the Micrococcaceae family. Micrococcus occurs in a wide range of environments, including human skin, water, dust, and soil. Micrococci have Gram-positive spherical cells ranging from about 0.5 to 3 micrometers in diameter and are typically appear in tetrads. Micrococcus has a substantial cell wall, which may comprise as much as 50% of the cell mass. The genome of Micrococcus is rich in guanine and cytosine (GC), typically exhibiting 65 to 75% GC-content. Micrococci often carry plasmids (ranging from 1 to 100MDa in size) that provide the organism with useful traits.
# Species
Some species of Micrococcus, such as M. luteus (yellow) and M. roseus (red) produce yellow or pink colonies when grown on solid media. Isolates of M. luteus have been found to overproduce riboflavin when grown on toxic organic pollutants like pyridine. Hybridization studies indicate that species within the genus Micrococcus are not closely related, showing as little as %50 sequence homology. This suggests that some Micrococcus species may, on the basis of ribosomal RNA analysis, eventually be re-classified into other microbial genera. These are neat!
# Environmental
Micrococci have been isolated from human skin, animal and dairy products, and beer. They are found in many other places in the environment, including water, dust, and soil. M. luteus on human skin transforms compounds in sweat into compounds with an unpleasant odor. Micrococci can grow well in environments with little water or high salt concentrations. Most are mesophiles; some, like Micrococcus antarcticus (found in Antarctica) are psychrophiles.
Though not a spore former, Micrococcus cells can survive for an extended period of time: unprotected cultures of soil micrococci have been revived after storage in a refrigerator for 10 years. Recent work by Greenblat et al. demonstrate that Micrococcus luteus has survived for at least 34,000 to 170,000 years on the basis of 16S rRNA analysis, and possibly much longer.
# Pathogenesis
Micrococcus is generally thought to be a saprophytic or commensal organism, though it can be an opportunistic pathogen, particularly in hosts with compromised immune systems, such as HIV patients. It can be difficult to identify Micrococcus as the cause of an infection, since the organism is a normally present in skin microflora, and the genus is seldom linked to disease. In rare cases, death of immunocompromised patients has occurred from pulmonary infections caused by Micrococcus. Micrococci may be involved in other infections, including recurrent bacteremia, septic shock, septic arthritis, endocarditis, meningitis, and cavitating pneumonia (immunosuppressed patients).
# Industrial uses
Micrococci, like many other representatives of the Actinobacteria, can be catabolically versatile, with the ability to utilize a wide range of unusual substrates, such as pyridine, herbicides, chlorinated biphenyls, and oil. They are likely involved in detoxification or biodegradation of many other environmental pollutants. Other Micrococcus isolates produce various useful products, such as long-chain (C21-C34) aliphatic hydrocarbons for lubricating oils. | Micrococcus
Micrococcus (mi’ krō kŏk’ Əs) is a genus of bacteria in the Micrococcaceae family. Micrococcus occurs in a wide range of environments, including human skin, water, dust, and soil. Micrococci have Gram-positive spherical cells ranging from about 0.5 to 3 micrometers in diameter and are typically appear in tetrads. Micrococcus has a substantial cell wall, which may comprise as much as 50% of the cell mass. The genome of Micrococcus is rich in guanine and cytosine (GC), typically exhibiting 65 to 75% GC-content. Micrococci often carry plasmids (ranging from 1 to 100MDa in size) that provide the organism with useful traits.
# Species
Some species of Micrococcus, such as M. luteus (yellow) and M. roseus (red) produce yellow or pink colonies when grown on solid media. Isolates of M. luteus have been found to overproduce riboflavin when grown on toxic organic pollutants like pyridine.[1] Hybridization studies indicate that species within the genus Micrococcus are not closely related, showing as little as %50 sequence homology. This suggests that some Micrococcus species may, on the basis of ribosomal RNA analysis, eventually be re-classified into other microbial genera. These are neat!
# Environmental
Micrococci have been isolated from human skin, animal and dairy products, and beer. They are found in many other places in the environment, including water, dust, and soil. M. luteus on human skin transforms compounds in sweat into compounds with an unpleasant odor. Micrococci can grow well in environments with little water or high salt concentrations. Most are mesophiles; some, like Micrococcus antarcticus (found in Antarctica) are psychrophiles.
Though not a spore former, Micrococcus cells can survive for an extended period of time: unprotected cultures of soil micrococci have been revived after storage in a refrigerator for 10 years.[citation needed] Recent work by Greenblat et al. demonstrate that Micrococcus luteus has survived for at least 34,000 to 170,000 years on the basis of 16S rRNA analysis, and possibly much longer. [2]
# Pathogenesis
Micrococcus is generally thought to be a saprophytic or commensal organism, though it can be an opportunistic pathogen, particularly in hosts with compromised immune systems, such as HIV patients.[3] It can be difficult to identify Micrococcus as the cause of an infection, since the organism is a normally present in skin microflora, and the genus is seldom linked to disease. In rare cases, death of immunocompromised patients has occurred from pulmonary infections caused by Micrococcus. Micrococci may be involved in other infections, including recurrent bacteremia, septic shock, septic arthritis, endocarditis, meningitis, and cavitating pneumonia (immunosuppressed patients).
# Industrial uses
Micrococci, like many other representatives of the Actinobacteria, can be catabolically versatile, with the ability to utilize a wide range of unusual substrates, such as pyridine, herbicides, chlorinated biphenyls, and oil.[4][5] They are likely involved in detoxification or biodegradation of many other environmental pollutants.[6] Other Micrococcus isolates produce various useful products, such as long-chain (C21-C34) aliphatic hydrocarbons for lubricating oils. | https://www.wikidoc.org/index.php/Micrococcus | |
ba15bb909f24e8b806a5a7f08b26d03d030e51b4 | wikidoc | Microdontia | Microdontia
# Overview
Microdontia is a condition in which teeth appear smaller than normal. In the generalized form, all teeth are involved. In the localized form, only a few teeth are involved. The most common teeth affected are the upper lateral incisors and third molars. The affected teeth may be of normal or abnormal morphology.
# Classification
There are 3 types of microdontia:
- True generalized microdontia
- Relative generalized microdontia
- Microdontia involving a single tooth
# True Generalized Microdontia
All the teeth are smaller in size, mainly reported in the case of pituitary dwarfism. All the teeth are well formed and small.
# Relative Generalized Microdontia
There is an illusion of true microdontia.
# Microdontia involving a single tooth
Commonly affects the maxilla, mainly lateral incisors and third molar. the lateral incisors become peg shaped.
# Causes
- Faciogenital dysplasia
- Focal dermal hypoplasia
- Incontinentia pigmenti
- Johanson-Blizzard syndrome
- Down syndrome
- Microcephaly, macrotia and mental retardation syndrome
- Microcephalic osteodysplastic primordial dwarfism with tooth abnormality
- Williams-Beuren syndrome
- Cranioectodermal dysplasia
- Ectodermal dysplasia, Margarita Island type
- Ellis-van Creveld syndrome
- Gorlin-Chaudhry-Moss syndrome
- Immunoosseous dysplasia, Schimke type
- Larsen syndrome
- Microcephalic osteodysplastic dwarfism, type II
- Odontotrichomelic syndrome
- Polydactyly, postaxial with dental and vertebral anomalies
- Rothmund-Thomson syndrome
- Spondyloepimetaphyseal dysplasia with abnormal dentition
- Coffin-Lowry syndrome
- Ectodermal dysplasia type I
- Ectodermal dysplasia, hypohidrotic with hypothyroidism and agenesis of the corpus callosum
- Cleft lip/palate ectodermal dysplasia
- Cartilage hair hypoplasia
- Witkop syndrome
- Uncombable hair, retinal pigmentary dystrophy, dental anomalies, brachydactyly
- Otodental dysplasia
- Symphalangism, Kantaputra type
- Oculodento-digital dysplasia
- Niikawa-Kuroki syndrome
- Hair-nail-skin-tooth dysplasia
- Ehlers-Danlos type VI
- Ectodermal dysplasia
- Axenfeld-Rieger syndrome
- Ankyloblepharon-ectodermal defects-cleft lip/palate | Microdontia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Microdontia is a condition in which teeth appear smaller than normal. In the generalized form, all teeth are involved. In the localized form, only a few teeth are involved. The most common teeth affected are the upper lateral incisors and third molars. The affected teeth may be of normal or abnormal morphology.
# Classification
There are 3 types of microdontia:
- True generalized microdontia
- Relative generalized microdontia
- Microdontia involving a single tooth[1]
# True Generalized Microdontia
All the teeth are smaller in size, mainly reported in the case of pituitary dwarfism. All the teeth are well formed and small.
# Relative Generalized Microdontia
There is an illusion of true microdontia.
# Microdontia involving a single tooth
Commonly affects the maxilla, mainly lateral incisors and third molar. the lateral incisors become peg shaped.
# Causes
- Faciogenital dysplasia
- Focal dermal hypoplasia
- Incontinentia pigmenti
- Johanson-Blizzard syndrome
- Down syndrome
- Microcephaly, macrotia and mental retardation syndrome
- Microcephalic osteodysplastic primordial dwarfism with tooth abnormality
- Williams-Beuren syndrome
- Cranioectodermal dysplasia
- Ectodermal dysplasia, Margarita Island type
- Ellis-van Creveld syndrome
- Gorlin-Chaudhry-Moss syndrome
- Immunoosseous dysplasia, Schimke type
- Larsen syndrome
- Microcephalic osteodysplastic dwarfism, type II
- Odontotrichomelic syndrome
- Polydactyly, postaxial with dental and vertebral anomalies
- Rothmund-Thomson syndrome
- Spondyloepimetaphyseal dysplasia with abnormal dentition
- Coffin-Lowry syndrome
- Ectodermal dysplasia type I
- Ectodermal dysplasia, hypohidrotic with hypothyroidism and agenesis of the corpus callosum
- Cleft lip/palate ectodermal dysplasia
- Cartilage hair hypoplasia
- Witkop syndrome
- Uncombable hair, retinal pigmentary dystrophy, dental anomalies, brachydactyly
- Otodental dysplasia
- Symphalangism, Kantaputra type
- Oculodento-digital dysplasia
- Niikawa-Kuroki syndrome
- Hair-nail-skin-tooth dysplasia
- Ehlers-Danlos type VI
- Ectodermal dysplasia
- Axenfeld-Rieger syndrome
- Ankyloblepharon-ectodermal defects-cleft lip/palate | https://www.wikidoc.org/index.php/Microdontia | |
9d02ae4d618306cf53ae483ad3e0caa8a3b5d278 | wikidoc | Microsphere | Microsphere
This article largely refers to micropheres or protein protocells as small spherical units postulated by some scientists as a key stage in the origin of life. The term microsphere is otherwise widely being used in various areas, such as, materials and pharmaceutical sciences, for spherical particles composed of various natural and synthetic materials with diameters in the micrometer range.
In 1953, Stanley Miller and Harold Urey demonstrated that many simple biomolecules could be formed spontaneously from inorganic precursor compounds under laboratory conditions designed to mimic those found on Earth before the evolution of life. Of particular interest was the substantial yield of amino acids obtained, since amino acids are the building blocks for proteins.
In 1957, Sidney Fox demonstrated that amino acids could be encouraged to polymerize upon exposure to moderate heat. These polypeptides formed spherical shells—microspheres. Under appropriate conditions, microspheres will bud new spheres at their surfaces.
Although roughly cellular in appearance, microspheres in and of themselves are not alive. They do not reproduce or pass on any type of genetic material. However they may have been important in the development of life, providing a membrane-enclosed volume which is similar to that of a cell.
One useful discovery made from the research of microspheres is a way to fight cancer on a molecular level.
According to Wake Oncologists,
"SIR-Spheres micropheres are radioactive polymer spheres that emit beta radiation. Physicians insert a catheter through the groin into the hepatic artery and deliver millions of micropheres directly to the tumor site. The SIR-Spheres microspheres target the liver tumors sparing healthy liver tissue. Approximately 55 physicians in the United States use Sirtex’s SIR-Spheres micropheres in more than 60 medical centers." | Microsphere
This article largely refers to micropheres or protein protocells as small spherical units postulated by some scientists as a key stage in the origin of life. The term microsphere is otherwise widely being used in various areas, such as, materials and pharmaceutical sciences, for spherical particles composed of various natural and synthetic materials with diameters in the micrometer range.
In 1953, Stanley Miller and Harold Urey demonstrated that many simple biomolecules could be formed spontaneously from inorganic precursor compounds under laboratory conditions designed to mimic those found on Earth before the evolution of life. Of particular interest was the substantial yield of amino acids obtained, since amino acids are the building blocks for proteins.
In 1957, Sidney Fox demonstrated that amino acids could be encouraged to polymerize upon exposure to moderate heat. These polypeptides formed spherical shells—microspheres. Under appropriate conditions, microspheres will bud new spheres at their surfaces.
Although roughly cellular in appearance, microspheres in and of themselves are not alive. They do not reproduce or pass on any type of genetic material. However they may have been important in the development of life, providing a membrane-enclosed volume which is similar to that of a cell.
One useful discovery made from the research of microspheres is a way to fight cancer on a molecular level.
According to Wake Oncologists,
"SIR-Spheres micropheres are radioactive polymer spheres that emit beta radiation. Physicians insert a catheter through the groin into the hepatic artery and deliver millions of micropheres directly to the tumor site. The SIR-Spheres microspheres target the liver tumors sparing healthy liver tissue. Approximately 55 physicians in the United States use Sirtex’s SIR-Spheres micropheres in more than 60 medical centers." | https://www.wikidoc.org/index.php/Microsphere | |
1e7a7ce2e24e94600cddd8d54df6869ec27a80a3 | wikidoc | Microtrauma | Microtrauma
Microtrauma is the general term given to small injuries to the body.
Microtrauma can include the microtearing of muscle fibres, the sheath around the muscle and the connective tissue. It can also include stress to the tendons, and to the bones (see Wolf's Law). It is unknown whether or not the ligaments adapt like this. Increased lubrication in response to microtrauma to the bowels is a key factor to the beneficial effects of dietary fibre in increasing bowel robustness, though this is dissimilar to muscular hypertrophy. Some believe microtrauma to the skin (compression, impact, abrasion) can also cause increases in a skin's thickness, as seen in running barefoot. If it does occur, it might be increased skin cell replication at sites under stress where cells rapidly slough off or undergo compression or abrasion.
Most microtrauma cause a low level of inflammation that cannot be seen or felt. These injuries can arise in muscle, ligament, vertebrae, and discs, either singly or in combination. Repetitive microtrauma which are not allowed time to heal can result in the development of more serious conditions.
Back pain can develop gradually as a result of microtrauma brought about by repetitive activity over time. Because of the slow and progressive onset of this internal injury, the condition is often ignored until the symptoms become acute, often resulting in disabling injury. Acute back injuries can arise from stressful lifting techniques done without adequate recovery, especially when experimenting with more ballistic work, or work where the extensor spinae are stressed during spinal flexion when much of the load is commonly taken up by the slower to heal ligaments which may not adapt progressively to the stress. While the acute injury may seem to be caused by a single well-defined incident, it may have been preventable or lessened if not for the years of injury to the musculoskeletal support mechanism by repetitive microtrauma.
One possible example of beneficial microtrauma is in the form of microtears to the muscle fibres as a result of intensive exercise. This is done deliberately in weight training in order to stimulate the building of stronger muscles, ligaments, and tendons during the repair process. However, it is not known if this practice is as beneficial as originally thought. Sufficient time must be allowed for healing, to avoid overtraining. | Microtrauma
Microtrauma is the general term given to small injuries to the body.
Microtrauma can include the microtearing of muscle fibres, the sheath around the muscle and the connective tissue. It can also include stress to the tendons, and to the bones (see Wolf's Law). It is unknown whether or not the ligaments adapt like this. Increased lubrication in response to microtrauma to the bowels is a key factor to the beneficial effects of dietary fibre in increasing bowel robustness, though this is dissimilar to muscular hypertrophy. Some believe microtrauma to the skin (compression, impact, abrasion) can also cause increases in a skin's thickness, as seen in running barefoot. If it does occur, it might be increased skin cell replication at sites under stress where cells rapidly slough off or undergo compression or abrasion.
Most microtrauma cause a low level of inflammation that cannot be seen or felt. These injuries can arise in muscle, ligament, vertebrae, and discs, either singly or in combination. Repetitive microtrauma which are not allowed time to heal can result in the development of more serious conditions.
Back pain can develop gradually as a result of microtrauma brought about by repetitive activity over time. Because of the slow and progressive onset of this internal injury, the condition is often ignored until the symptoms become acute, often resulting in disabling injury. Acute back injuries can arise from stressful lifting techniques done without adequate recovery, especially when experimenting with more ballistic work, or work where the extensor spinae are stressed during spinal flexion when much of the load is commonly taken up by the slower to heal ligaments which may not adapt progressively to the stress. While the acute injury may seem to be caused by a single well-defined incident, it may have been preventable or lessened if not for the years of injury to the musculoskeletal support mechanism by repetitive microtrauma.
One possible example of beneficial microtrauma is in the form of microtears to the muscle fibres as a result of intensive exercise. This is done deliberately in weight training in order to stimulate the building of stronger muscles, ligaments, and tendons during the repair process. However, it is not known if this practice is as beneficial as originally thought. Sufficient time must be allowed for healing, to avoid overtraining. | https://www.wikidoc.org/index.php/Microtrauma | |
d487f063ac7c2b1b93801f3bdf95ae5a52bf7314 | wikidoc | Midostaurin | Midostaurin
# 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
Midostaurin is a kinase inhibitor that is FDA approved for the treatment of newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation, aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL). Common adverse reactions include (AML) ebrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infection, or (ASM, SM-AHN, or MCL) nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Midostaurin is indicated, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by a FDA approved test.
Limitations of Use
- Midostaurin is not indicated as a single-agent induction therapy for the treatment of patients with AML.
- Midostaurin is indicated for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).
- Select patients for the treatment of AML with midostaurin based on the presence of FLT3 mutation positivity. Information on FDA-approved tests for the detection of FLT3 mutation in AML is available at: .
- The recommended dose of midostaurin for patients with acute myeloid leukemia is 50 mg orally twice daily with food on Days 8 to 21 of each cycle of induction with cytarabine and daunorubicin and on Days 8 to 21 of each cycle of consolidation with high-dose cytarabine. For a description of the experience with single-agent treatment with midostaurin beyond induction and consolidation.
- The recommended dose of midostaurin for patients with ASM, SM-AHN, and MCL is 100 mg orally twice daily with food. Continue treatment until disease progression or unacceptable toxicity occurs. Table 1 provides recommendations for dose modifications of midostaurin in patients with ASM, SM-AHN, and MCL. Monitor patients for toxicity at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter while on treatment.
- Administer prophylactic anti-emetics before treatment with midostaurin to reduce the risk of nausea and vomiting.
- Administer midostaurin orally with food, twice daily at approximately 12 hour intervals. Do not open or crush midostaurin capsules.
- If a dose of midostaurin is missed or vomited, do not make up the dose; take the next dose at the usual scheduled time.
- Consider interval assessments of QT by EKG if midostaurin is taken concurrently with medications that can prolong the QT interval.
- 25 mg capsules: pale orange oblong soft capsule with red ink imprint ‘PKC NVR’.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding midostaurin Off-Label NGuideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding midostaurin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Midostaurin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding midostaurin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding midostaurin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Midostaurin is contraindicated in patients with hypersensitivity to midostaurin or to any of the excipients. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment).
# Warnings
- Based on its mechanism of action and findings from animal reproduction studies, midostaurin may cause fetal harm when administered to pregnant women. In animal studies, midostaurin caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose. Advise pregnant women of the potential risk to the fetus. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating midostaurin therapy. Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose. Advise males with female partners to use effective contraception during treatment with midostaurin and for 4 months after the last dose.
- Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with midostaurin as monotherapy or with chemotherapy. Monitor patients for pulmonary symptoms. Discontinue midostaurin in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology.
# 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 evaluation of midostaurin (50 mg twice daily with food) in patients with newly diagnosed FLT3 mutated AML is based on a randomized, double-blind, trial of midostaurin (n = 345) or placebo (n = 335) with chemotherapy. The overall median duration of exposure was 42 days (range 2 to 576 days) for patients in the midostaurin plus chemotherapy arm versus 34 days (range 1 to 465 days) for patients in the placebo plus chemotherapy arm. On the midostaurin plus chemotherapy arm, 35% of patients completed induction and consolidation therapy, compared to 25% of patients on the placebo plus chemotherapy arm.
- The most frequent (incidence greater than or equal to 20%) adverse drug reactions (ADRs) in the midostaurin plus chemotherapy arm were febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infections. The most frequent Grade 3/4 adverse reactions (incidence greater than or equal to 10%) were febrile neutropenia, device-related infection and mucositis.
- The most frequent serious adverse reaction (≥ 10%) in patients in the midostaurin plus chemotherapy arm was febrile neutropenia (16%), which occurred at a similar rate in the placebo arm (16%).
- Discontinuation due to any adverse reaction occurred in 9% of patients in the midostaurin arm versus 6% in the placebo arm. The most frequent (> 1%) Grade 3/4 adverse reactions leading to discontinuation in the midostaurin arm was renal insufficiency (1%).
- Excluding deaths due to disease progression, no fatal adverse reactions occurred in the study. Overall, the most frequent non-treatment related cause of death in the midostaurin plus chemotherapy arm was sepsis (2%) and occurred at a similar rate in the placebo arm (2%).
- Table 2 presents the frequency category of adverse reactions reported in the randomized trial in patients with newly diagnosed FLT3 mutated AML. Adverse reactions are listed according to body system. Within each body system, the adverse reactions are ranked by frequency, with the most frequent reactions first. Table 3 presents the key laboratory abnormalities from the same randomized trial in patients with newly diagnosed FLT3 mutated AML.
- Other notable adverse reactions occurring in less than 10% of patients treated with midostaurin but at least 2% more frequently than in the placebo group included:
- Infections and infestations: Cellulitisa (7%), fungal infectiona (7%)
- Metabolism and nutrition disorders: Hyperuricemia (8%)
- Nervous system disorders: Tremor (4%)
- Eye disorders: Eyelid edema (3%)
- Cardiac disorders: Hypertensiona (8%), pericardial effusion (4%)
- Respiratory, thoracic and mediastinal disorders: pleural effusion (6%)
- Skin and subcutaneous tissue disorders: Dry skin (7%)
- General disorders and administration site conditions: Thrombosisa (5%)
- Investigations: Weight increased (7%), hypercalcemia (3%)
- abased on grouping of individual PTs:
- Thrombosis: e.g., thrombosis in device, thrombosis
- Cellulitis: e.g., cellulitis, erysipelas
- Fungal infection: e.g., Bronchopulmonary aspergillosis, pneumonia fungal, splenic infection fungal, hepatic candidiasis
- In Study 1, 205 patients (120 in midostaurin arm and 85 in placebo arm) who remained in remission following completion of consolidation continued to receive either single agent midostaurin or placebo for a median of 11 months (range 0.5 to 17 months) with 69 in the midostaurin arm and 51 in the placebo completing 12 treatment cycles. Common adverse reactions (greater than or equal to 5% difference between the midostaurin and placebo arms) reported for these patients included nausea (47% vs. 18%), hyperglycemia (20% vs. 13%) and vomiting (19% vs. 5%).
- Two single-arm, open-label multicenter trials (Study 2 and Study 3) evaluated the safety of midostaurin (100 mg twice daily with food) as a single agent in 142 adult patients total with ASM, SM-AHN, or MCL. The median age was 63 (range: 24 to 82), 63% had an ECOG performance status of 0 or 1, and 75% had no hepatic impairment (bilirubin and AST ≤ ULN) at baseline. The median duration of exposure to midostaurin was 11.4 months (range: 0 to 81 months), with 34% treated for ≥ 24 months.
- The most frequent adverse reactions (≥ 20%), excluding laboratory terms, were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea (Table 4). Grade ≥ 3 adverse reactions reported in ≥ 5%, excluding laboratory terms, were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency (Table 4).
- Adverse reactions led to dose modifications (interruption or reduction) in 56% of patients. Among these, the most frequent adverse reactions (> 5%) were gastrointestinal symptoms, QT prolongation, neutropenia, pyrexia, thrombocytopenia, gastrointestinal hemorrhage, lipase increase, and fatigue. The median time to first dose modification for toxicity was 1.6 months, with 75% of dose modifications first occurring within 5 months of starting treatment.
- Treatment discontinuation due to adverse reactions occurred in 21% of patients. The most frequent adverse reactions causing treatment discontinuation included infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
- Serious adverse reactions were reported in 68% of patients, most commonly (≥ 20%) due to infections and gastrointestinal disorders.
- On-treatment deaths unrelated to the underlying malignancy occurred in 16 patients (11%), most commonly from infection (sepsis or pneumonia), followed by cardiac events. Of the on-treatment deaths from disease progression, 4 were also attributable to infection.
- Table 4 summarizes the adverse reactions reported in ≥ 10% of the patients with advanced SM.
- Gastrointestinal Toxicities Leading to Treatment Modification:
- In patients with advanced SM, the median time to onset of nausea was 9 days, with 75% of cases beginning within the first 3 months. The median time to onset of vomiting was 1 month.
- Other clinically significant adverse reactions occurring in ≤ 10% of patients included:
- Infections and infestations: Sepsis (9%)a, bronchitis (6%), cellulitis or erysipelas (5%)
- Blood and lymphatic system disorders: Febrile neutropenia (8%)
- Cardiac disorders: Cardiac failure (6%), myocardial infarction or ischemia (4%)a
- Immune system disorders: Hypersensitivity (4%)a
- Nervous system disorders: Disturbance in attention (7%), tremor (6%), mental status changes (4%)
- Ear and labyrinth disorders: Vertigo (5%)
- Vascular disorders: Hypotension (9%), hematoma (6%)
- Respiratory, thoracic and mediastinal disorders: Oropharyngeal pain (4%), interstitial lung disease or pneumonitis (2%), pulmonary edema (3%)a
- Gastrointestinal disorders: Dyspepsia (6%), gastritis (3%)a
- General disorders and administration site conditions: Chills (5%)
- Investigations: Weight increased (6%)
- Injury, poisoning and procedural complications: Contusion (6%)
- aGrouped terms
- Sepsis: e.g., sepsis, staphylococcal/Enterobacter/Escherichia sepsis
- Hypersensitivity: includes one report of anaphylactic shock
- Myocardial infarction or ischemia: e.g., myocardial infarction and acute myocardial infarction, angina pectoris
- Gastritis: gastritis, gastritis erosive, gastritis hemorrhagic
- Pulmonary edema: pulmonary edema, pulmonary congestion
- Table 5 summarizes new or worsening laboratory abnormalities. Common (≥ 10%) Grade 3 or higher non-hematologic laboratory abnormalities were hyperglycemia (non-fasting), lipase increase, and hyperuricemia. The most common (≥ 20%) Grade 3 or higher hematologic laboratory abnormalities were lymphopenia, anemia, thrombocytopenia, and neutropenia. Grade 4 hematologic abnormalities occurring in ≥ 5% were thrombocytopenia (13%), neutropenia (8%), anemia (6%), and lymphopenia (6%).
## Postmarketing Experience
There is limited information regarding Midostaurin Postmarketing Experience in the drug label.
# Drug Interactions
- Effect of Strong Cytochrome P450 (CYP) 3A Inhibitors and Inducers
- Table 6 lists the potential effects of the coadministration of strong CYP3A modulators on midostaurin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midostaurin during pregnancy. Females who may have been exposed to midostaurin during pregnancy directly or through a male partner receiving midostaurin therapy should contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at /.
- Based on mechanism of action and findings in animal reproduction studies, midostaurin may cause fetal harm when administered to a pregnant woman . There are no available data on midostaurin use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, oral administration of midostaurin to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus.
- The background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
- When midostaurin was administered to female rats prior to mating and through the first week of pregnancy at a dose of 60 mg/kg/day (approximately 0.1 times the human exposure at the recommended dose based on AUC), there were increases in pre- and post-implantation loss, including total litter loss, resulting in a reduction in the number of live embryos.
- During organogenesis, midostaurin administered at oral doses greater than or equal to 3 mg/kg/day (approximately 0.004 times the human exposure at the recommended dose by AUC) to pregnant female rats caused late embryo-fetal death. Dilated lateral brain ventricles were observed in offspring of rats given doses greater than or equal to 3 mg/kg/day. Extra rib and reduced fetal birth weight with effects on fetal growth (severe renal pelvic cavitation and widened anterior fontanelle) were observed in the absence of maternal toxicity at the highest dose of 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). Midostaurin administered orally to pregnant rabbits during organogenesis led to maternal toxicity with spontaneous abortions and some delay in fetal growth (reduced fetal birth weight) at doses greater than or equal to 10 mg/kg/day (approximately 0.01 times the human exposure at the recommended dose by AUC).
- In an oral pre- and postnatal development study in the rat, adverse effects upon maternal performance included dams with signs of dystocia and a lower live litter size at 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). For the F1 offspring, lower body weights, accelerated complete eye opening and delayed auricular startle ontogeny were noted at 30 mg/kg/day.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Midostaurin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Midostaurin during labor and delivery.
### Nursing Mothers
- There are no data on the presence of midostaurin or its active metabolites in human milk, the effect on the breastfed infant, or the effect on milk production. Orally administered midostaurin and its active metabolites pass into the milk of lactating rats within 1 hour of a 30 mg/kg/day dose, with approximately 5 times more in the milk of lactating rats compared to plasma. Because of the potential for serious adverse reactions in breastfed infants from midostaurin advise women not to breastfeed during treatment with midostaurin and for at least 4 months after the last dose.
### Pediatric Use
- Safety and effectiveness of midostaurin have not been established in pediatric patients.
### Geriatic Use
- Of the 142 patients with advanced SM in clinical studies of midostaurin, 64 (45%) were aged 65 and over, and 16 (11%) were aged 75 years and over. No overall differences in safety or response rate were observed between the subjects aged 65 and over compared with younger subjects. Greater sensitivity of older individuals cannot be ruled out.
- Clinical studies in AML with midostaurin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
- In general, administration for elderly patients should be cautious, based on patient’s eligibility for concomitant chemotherapy and reflecting the greater frequency of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Midostaurin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Midostaurin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Midostaurin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Midostaurin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating midostaurin.
Females
- Midostaurin may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for 4 months after the last dose.
Males
- Males with female sexual partners of reproductive potential should use effective contraception during midostaurin treatment and for at least 4 months after stopping treatment with midostaurin.
- Based on findings in animals, midostaurin may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.
### Immunocompromised Patients
There is no FDA guidance one the use of Midostaurin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer prophylactic anti-emetics before treatment with midostaurin to reduce the risk of nausea and vomiting.
- Administer midostaurin orally with food, twice daily at approximately 12 hour intervals. Do not open or crush midostaurin capsules.
- If a dose of midostaurin is missed or vomited, do not make up the dose; take the next dose at the usual scheduled time.
- Consider interval assessments of QT by EKG if midostaurin is taken concurrently with medications that can prolong the QT interval.
### Monitoring
- Disease response or stabilization may indicate efficacy.
- FLT3 mutation: Prior to initiation, with an FDA-approved companion diagnostic test available at .
- Pregnancy status (women of reproductive potential): Within 7 days prior to initiation of therapy.
- CBC: At least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter during therapy; include a differential.
- Toxicities, including nausea, vomiting, and other non-hematologic toxicities: At least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter during therapy.
- Pulmonary symptoms of interstitial lung disease or pneumonitis.
# IV Compatibility
There is limited information regarding the compatibility of Midostaurin and IV administrations.
# Overdosage
There is limited information regarding Midostaurin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFRα/β, VEGFR2, as well as members of the serine/threonine kinase PKC (protein kinase C) family.
- Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells.
## Structure
## Pharmacodynamics
Cardiac Electrophysiology
- The effect of midostaurin (75 mg twice daily for 3 days) on the QTc interval was evaluated in a randomized, placebo and moxifloxacin controlled, multiple-dose, blinded, parallel study. There was no clinically significant prolongation of QTc interval or relationship between changes in QTc and concentrations for midostaurin and its active metabolites (CGP62221 and CGP52421). The study duration was not long enough to estimate the effects of the metabolite CGP52421 on the QT/QTc interval.
- In pooled clinical studies in patients with advanced SM, 4.7% patients had a post-baseline QTcF > 480 ms, no patients had a QTcF > 500 ms, and 6.3% patients had a QTcF > 60 ms compared to baseline.
- In a randomized placebo-controlled study in patients with AML, the proportion of patients with QTc prolongation was higher in patients randomized to midostaurin as compared to placebo (QTcF > 480 ms: 10.1% vs 5.7%; QTcF > 500 ms: 6.2% vs 2.6%; QTcF > 60 ms: 18.4% vs 10.7%).
## Pharmacokinetics
- Midostaurin exhibits time-dependent pharmacokinetics with an initial increase in minimum concentrations (Cmin) that reach the highest Cmin concentrations during the first week followed by a decline to a steady-state after approximately 28 days. The pharmacokinetics of the CGP62221 showed a similar trend. The plasma concentrations of CGP52421 continued to increase after one month of treatment.
- The highest Cmin and steady-state of midostaurin, CGP62221, and CGP52421 were similar when midostaurin was administered with food at a dose of 50 mg twice daily or 100 mg twice daily.
Absorption
- The time to maximal concentrations (Tmax) occurred between 1 to 3 hours post dose in the fasted state.
- Midostaurin exposure, represented by area under the curve over time to infinity (AUCinf), increased 1.2-fold when midostaurin was coadministered with a standard meal (457 calories, 50 g fat, 21 g proteins, and 18 g carbohydrates) and 1.6-fold when coadministered with a high-fat meal (1007 calories, 66 g fat, 32 g proteins, and 64 g carbohydrates) compared to when midostaurin was administered in a fasted state. Midostaurin maximum concentrations (Cmax) were reduced by 20% with a standard meal and by 27% with a high-fat meal compared to a fasted state. Tmax was delayed when midostaurin was administered with a standard meal or a high-fat meal (median Tmax = 2.5 hrs to 3 hrs).
Distribution
- Midostaurin has an estimated geometric mean volume of distribution (% coefficient of variation) of 95.2 L (31%). Midostaurin and its metabolites are distributed mainly in plasma in vitro. Midostaurin, CGP62221, and CGP52421 are greater than 99.8% bound to plasma protein in vitro. Midostaurin is mainly bound to α1-acid glycoprotein in vitro.
Elimination
- The geometric mean terminal half-life (% coefficient of variation) is 19 hours (39%) for midostaurin, 32 hours (31%) for CGP62221 and 482 hours (25%) for CGP52421.
Metabolism
- Midostaurin is primarily metabolized by CYP3A4. CGP62221 and CGP52421 (mean ± standard deviation) account for 28 ± 2.7% and 38 ± 6.6% respectively of the total circulating radioactivity.
Excretion
- Fecal excretion accounted for 95% of the recovered dose with 91% of the recovered dose excreted as metabolites and 4% of the recovered dose as unchanged midostaurin. Only 5% of the recovered dose was found in urine.
- Age (20-94 years), sex, race, and mild (total bilirubin greater than 1.0 to 1.5 times the upper limit of normal (ULN) or aspartate aminotransferase (AST) greater than the ULN) or moderate (total bilirubin 1.5 to 3.0 times the ULN and any value for AST) hepatic impairment or renal impairment (creatinine clearance (CLCr) ≥ 30 mL/min) did not have clinically meaningful effects on the pharmacokinetics of midostaurin, CGP62221, or CGP52421. The pharmacokinetics of midostaurin in patients with baseline severe hepatic impairment (total bilirubin greater than 3.0 times the ULN and any value for AST) or severe renal impairment (CLCr 15 to 29 mL/min) is unknown.
Drug Interaction Studies
- Coadministration of ketoconazole (400 mg daily for 10 days) with a single dose of midostaurin (50 mg) on Day 6 increased AUCinf of midostaurin by 10.4-fold and CGP62221 by 3.5-fold and area under the curve over time to last measurable concentrations (AUC0-t) of CGP52421 by 1.2-fold compared to a single midostaurin dose coadministered with placebo.
- Coadministration of itraconazole (100 mg twice daily on Days 22-28 for 13 doses) with multiple doses of midostaurin (100 mg twice daily on Days 1 to 2 and 50 mg twice daily on Days 3 to 28) increased Day 28 Cmin concentrations of midostaurin by 2.1-fold, CGP62221 by 1.2-fold, and CGP52421 by 1.3-fold compared to the respective Day 21 Cmin concentrations with midostaurin alone.
- Coadministration of rifampicin (600 mg daily on Days 1 to 14) with a single dose of midostaurin (50 mg) on Day 9 decreased AUCinf of midostaurin by 96% and CGP62221 by 92% and AUC0-t of CGP52421 by 59%.
- Midazolam (sensitive CYP3A substrate) AUCinf was not affected following 4 days of midostaurin administration. The clinical relevance of this interaction is unknown as the midostaurin was administered for only 4 days.
- Midostaurin inhibits CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A; CGP62221 inhibits CYP1A2, CYP2C8, CYP2C9, and CYP3A; and CGP52421 inhibits CYP2D6 and CYP3A in vitro. Midostaurin, CGP52421, and CGP62221 induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A in vitro.
- Midostaurin inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); CGP52421 and CGP62221 inhibit organic anion transporter polypeptide (OATP) 1B1 in vitro.
## Nonclinical Toxicology
- Carcinogenicity studies have not been performed with midostaurin.
- Midostaurin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or in Chinese hamster V97 cells. Midostaurin increased the frequency of polyploidy cells in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells, but was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 200 mg/kg (1200 mg/m2). This dose was approximately 20-fold the recommended human dose, based on body surface area.
- Reproductive toxicity was observed in a fertility study, in male and females rats given oral doses of midostaurin at 10, 30 and 60 mg/kg/day (approximately 0.01, 0.05, and 0.1 times, respectively, the AUC at the recommended human dose). In males, testicular degeneration and atrophy was observed at doses greater than or equal to 10 mg/kg/day and reduced sperm count and motility, and a decrease in reproductive organ weights were observed at 60 mg/kg/day. In females, increased resorptions, decreased pregnancy rate, and decreased number of implants and live embryos were observed at 60 mg/kg/day. In a 3-month toxicology study in dogs, there was inhibition of spermatogenesis at doses greater than or equal to 3 mg/kg/day (approximately 0.01 times the exposure at the recommended human dose).
# Clinical Studies
Study 1
- Midostaurin in combination with chemotherapy was investigated in a randomized, double-blind placebo-controlled trial of 717 patients with newly-diagnosed FLT3-mutated AML. In this study, FLT3 mutation status was determined prospectively with a clinical trial assay and verified retrospectively using the companion diagnostic LeukoStrat® CDx FLT3 Mutation Assay, which is an FDA-approved test for selection of patients with AML for midostaurin treatment. Patients were stratified by FLT3 mutation status: TKD, ITD with allelic ratio less than 0.7, and ITD with allelic ratio greater than or equal to 0.7. Patients with acute promyelocytic leukemia or therapy-related AML were not eligible. Patients were randomized (1:1) to receive midostaurin 50 mg twice daily (n = 360) or placebo (n = 357) with food on Days 8-21 in combination with daunorubicin (60 mg/m2 daily on Days 1 to 3) /cytarabine (200 mg/m2 daily on Days 1 to 7) for up to two cycles of induction and high dose cytarabine (3 g/m2 every 12 hours on Days 1, 3 and 5) for up to four cycles of consolidation, followed by continuous midostaurin or placebo treatment according to initial assignment for up to 12 additional 28-day cycles. There was no re-randomization at the start of post consolidation therapy. Patients who proceeded to hematopoietic stem cell transplantation (SCT) stopped receiving study treatment.
- The randomized patients had a median age of 47 years (range, 18-60 years), 44% were male, and 88% had a performance status of 0-1. AML was de novo onset in 95%. The percentage of patients with FLT3-ITD allelic ratio < 0.7, FLT3-ITD allelic ratio ≥ 0.7, and FLT3-TKD mutations were identical (per randomized FLT3 stratum) on both arms (48%, 30%, and 23%, respectively). Of the 563 patients with NPM1 testing, 58% had an NPM1 mutation. The two treatment groups were generally balanced with respect to the baseline demographics and disease characteristics, except that the placebo arm had a higher percentage of females (59%) than in the midostaurin arm (52%). NPM1 mutations were identified in 55% of patients tested on the midostaurin arm and 60% of patients tested on the placebo arm.
- A second course of induction was administered to 25% of the patients, 62% initiated at least one cycle of consolidation, 29% initiated maintenance, and 17% completed all 12 planned cycles of maintenance; 21% of the patients underwent SCT in first CR. The overall rate of SCT (induction failure, first CR or salvage after relapse) was 59% (214/360) of patients in the midostaurin plus standard chemotherapy arm vs. 55% (197/357) in the placebo plus standard chemotherapy arm. All patients were followed for survival.
- Efficacy was established on the basis of overall survival (OS), measured from the date of randomization until death by any cause. The primary analysis was conducted after a minimum follow-up of approximately 3.5 years after the randomization of the last patient. Midostaurin plus standard chemotherapy was superior to placebo plus standard chemotherapy in OS (HR 0.77; 95% CI 0.63, 0.95; 2 sided p = 0.016) (Figure 1). Because survival curves plateaued before reaching the median, median survival could not be reliably estimated.
- The analysis of event-free survival (EFS), defined as a failure to obtain a complete remission (CR) within 60 days of initiation of protocol therapy, or relapse, or death from any cause, showed a statistically significant improvement with a median of 8.2 months for midostaurin plus standard chemotherapy versus 3.0 months for placebo plus standard chemotherapy with HR 0.78 (95% CI 0.66, 0.93) and 2 sided p = 0.005. In an exploratory analysis of EFS defined as a failure to obtain a CR any time during induction, or relapse, or death from any cause with failures assigned as an event on study day 1, the median EFS was 10.6 months for midostaurin plus standard chemotherapy versus 5.6 months for placebo plus standard chemotherapy with HR 0.72 (95% CI 0.61, 0.86).
Study 2
- A single-arm, open-label, multicenter trial evaluated the efficacy of midostaurin as a single agent in ASM, SM-AHN, and MCL, collectively referred to as advanced SM. The study enrolled 116 adult patients with relapse or progression to 0, 1, or 2 prior regimens for SM. The study excluded patients with serum creatinine > 2.0 mg/dL, hepatic transaminases > 2.5 x upper limit of normal (ULN) or > 5 x ULN if disease-related, total bilirubin > 1.5 x ULN or > 3 x ULN if disease-related, QTc > 450 msec, cardiovascular disease including left-ventricular ejection fraction < 50%, or any pulmonary infiltrates. In addition, the study excluded patients with acute-stage or life-threatening AHN. Patients received midostaurin 100 mg orally twice daily in 28-day cycles until disease progression or intolerable toxicity.
- Of the 116 patients treated, a study steering committee identified 89 patients who had measurable C-findings and were evaluable for response. The median age in this group was 64 years (range: 25 to 82), 64% of patients were male, and nearly all patients (97%) were Caucasian. Among these patients, 36% had prior therapy for SM, and 82% had the KIT D816V mutation detected at baseline. Their median duration of treatment was 11 months (range: < 1 to 68 months), with treatment ongoing in 17%.
- Efficacy was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles of midostaurin by modified Valent criteria for ASM and SM-AHN (Table 7). Table 7 shows responses to midostaurin according to modified Valent criteria. Confirmed major or partial responses occurred in 46 of 73 patients with a documented KIT D816V mutation, 7 of 16 with wild-type or unknown status with respect to KIT D816V mutation, and 21 of 32 having prior therapy for SM.
- As a post-hoc exploratory analysis, efficacy was also assessed using modified 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Response after 6 cycles of midostaurin was determined using a computational algorithm. The efficacy of midostaurin for MCL was based on the CR results by these criteria. There were 115 patients evaluable for response assessment, of whom 47 (41%) had prior therapy for SM, and 93 (81%) had a documented D816V mutation at baseline. Table 8 provides the results of this analysis. Overall response by modified IWG-MRT-ECNM criteria was reported for 16 (17%) of 93 patients with a documented D816V mutation, and in 8 (17%) of 47 patients having prior therapy for SM.
Study 3
- Study 3 was a single-arm, multicenter, open-label trial of 26 patients with advanced SM. Midostaurin was administered orally at 100 mg twice daily with food. The median age in this group was 64 years, 58% of patients were male and most were Caucasian (81%). Eligibility criteria were similar to Study 2. By Valent criteria per investigator assessment, of 17 patients with SM-AHN, 10 achieved a response (1 partial, 9 major) by 2 cycles that was sustained for at least 8 weeks. Patients who received concomitant corticosteroids were included. Of the 6 patients with MCL, 1 achieved partial response and 1 achieved major response. Median DOR for either group had not been reached, with DOR ranging from 3.4+ to 79.2+ months in patients with SM-AHN and 28.6+ to 32.1+ months in patients with MCL. The subtype of SM in the remaining 3 patients was unconfirmed.
# How Supplied
- Midostaurin 25 mg capsules
- Pale orange oblong soft capsule with red ink imprint ‘PKC NVR’; available in:
- 56 soft capsules………………………………………………………………………………………NDC 0078-0698-99
- Contents: Each carton contains two inner packs, each with 28 capsules (7 blister cards with 4 capsules each)
- 112 soft capsules……………………………………………………………………………………..NDC 0078-0698-19
- Contents: Each carton contains four inner packs, each with 28 capsules (7 blister cards with 4 capsules each)
## Storage
- Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store in the original package to protect from moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Pulmonary Adverse Reactions: Inform patients to seek medical attention for new cough, chest discomfort, or shortness of breath.
- Gastrointestinal Adverse Reactions: Inform patients that midostaurin can cause nausea, vomiting, and diarrhea. Advise patients to contact their healthcare provider if these symptoms occur or are persisting despite supportive medications.
- Embryo-Fetal Toxicity
- Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy.
- Advise male patients with female partners of reproductive potential to use effective contraception during treatment with midostaurin and for 4 months after the last dose.
- Advise females who may have been exposed to midostaurin during pregnancy directly or through male partner receiving midostaurin therapy to contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and /or at /.
- Lactation
- Advise women not to breastfeed during treatment with midostaurin and for at least 4 months after the final dose.
- Infertility
- Advise females and males of reproductive potential that midostaurin may impair fertility.
# Precautions with Alcohol
Alcohol-Midostaurin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Rydapt
# Look-Alike Drug Names
There is limited information regarding Midostaurin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Midostaurin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand
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# Overview
Midostaurin is a kinase inhibitor that is FDA approved for the treatment of newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation, aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL). Common adverse reactions include (AML) ebrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infection, or (ASM, SM-AHN, or MCL) nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Midostaurin is indicated, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive, as detected by a FDA approved test.
Limitations of Use
- Midostaurin is not indicated as a single-agent induction therapy for the treatment of patients with AML.
- Midostaurin is indicated for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).
- Select patients for the treatment of AML with midostaurin based on the presence of FLT3 mutation positivity. Information on FDA-approved tests for the detection of FLT3 mutation in AML is available at: http://www.fda.gov/CompanionDiagnostics.
- The recommended dose of midostaurin for patients with acute myeloid leukemia is 50 mg orally twice daily with food on Days 8 to 21 of each cycle of induction with cytarabine and daunorubicin and on Days 8 to 21 of each cycle of consolidation with high-dose cytarabine. For a description of the experience with single-agent treatment with midostaurin beyond induction and consolidation.
- The recommended dose of midostaurin for patients with ASM, SM-AHN, and MCL is 100 mg orally twice daily with food. Continue treatment until disease progression or unacceptable toxicity occurs. Table 1 provides recommendations for dose modifications of midostaurin in patients with ASM, SM-AHN, and MCL. Monitor patients for toxicity at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter while on treatment.
- Administer prophylactic anti-emetics before treatment with midostaurin to reduce the risk of nausea and vomiting.
- Administer midostaurin orally with food, twice daily at approximately 12 hour intervals. Do not open or crush midostaurin capsules.
- If a dose of midostaurin is missed or vomited, do not make up the dose; take the next dose at the usual scheduled time.
- Consider interval assessments of QT by EKG if midostaurin is taken concurrently with medications that can prolong the QT interval.
- 25 mg capsules: pale orange oblong soft capsule with red ink imprint ‘PKC NVR’.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding midostaurin Off-Label NGuideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding midostaurin Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Midostaurin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding midostaurin Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding midostaurin Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Midostaurin is contraindicated in patients with hypersensitivity to midostaurin or to any of the excipients. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment).
# Warnings
- Based on its mechanism of action and findings from animal reproduction studies, midostaurin may cause fetal harm when administered to pregnant women. In animal studies, midostaurin caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose. Advise pregnant women of the potential risk to the fetus. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating midostaurin therapy. Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose. Advise males with female partners to use effective contraception during treatment with midostaurin and for 4 months after the last dose.
- Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with midostaurin as monotherapy or with chemotherapy. Monitor patients for pulmonary symptoms. Discontinue midostaurin in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology.
# 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 evaluation of midostaurin (50 mg twice daily with food) in patients with newly diagnosed FLT3 mutated AML is based on a randomized, double-blind, trial of midostaurin (n = 345) or placebo (n = 335) with chemotherapy. The overall median duration of exposure was 42 days (range 2 to 576 days) for patients in the midostaurin plus chemotherapy arm versus 34 days (range 1 to 465 days) for patients in the placebo plus chemotherapy arm. On the midostaurin plus chemotherapy arm, 35% of patients completed induction and consolidation therapy, compared to 25% of patients on the placebo plus chemotherapy arm.
- The most frequent (incidence greater than or equal to 20%) adverse drug reactions (ADRs) in the midostaurin plus chemotherapy arm were febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infections. The most frequent Grade 3/4 adverse reactions (incidence greater than or equal to 10%) were febrile neutropenia, device-related infection and mucositis.
- The most frequent serious adverse reaction (≥ 10%) in patients in the midostaurin plus chemotherapy arm was febrile neutropenia (16%), which occurred at a similar rate in the placebo arm (16%).
- Discontinuation due to any adverse reaction occurred in 9% of patients in the midostaurin arm versus 6% in the placebo arm. The most frequent (> 1%) Grade 3/4 adverse reactions leading to discontinuation in the midostaurin arm was renal insufficiency (1%).
- Excluding deaths due to disease progression, no fatal adverse reactions occurred in the study. Overall, the most frequent non-treatment related cause of death in the midostaurin plus chemotherapy arm was sepsis (2%) and occurred at a similar rate in the placebo arm (2%).
- Table 2 presents the frequency category of adverse reactions reported in the randomized trial in patients with newly diagnosed FLT3 mutated AML. Adverse reactions are listed according to body system. Within each body system, the adverse reactions are ranked by frequency, with the most frequent reactions first. Table 3 presents the key laboratory abnormalities from the same randomized trial in patients with newly diagnosed FLT3 mutated AML.
- Other notable adverse reactions occurring in less than 10% of patients treated with midostaurin but at least 2% more frequently than in the placebo group included:
- Infections and infestations: Cellulitisa (7%), fungal infectiona (7%)
- Metabolism and nutrition disorders: Hyperuricemia (8%)
- Nervous system disorders: Tremor (4%)
- Eye disorders: Eyelid edema (3%)
- Cardiac disorders: Hypertensiona (8%), pericardial effusion (4%)
- Respiratory, thoracic and mediastinal disorders: pleural effusion (6%)
- Skin and subcutaneous tissue disorders: Dry skin (7%)
- General disorders and administration site conditions: Thrombosisa (5%)
- Investigations: Weight increased (7%), hypercalcemia (3%)
- abased on grouping of individual PTs:
- Thrombosis: e.g., thrombosis in device, thrombosis
- Cellulitis: e.g., cellulitis, erysipelas
- Fungal infection: e.g., Bronchopulmonary aspergillosis, pneumonia fungal, splenic infection fungal, hepatic candidiasis
- In Study 1, 205 patients (120 in midostaurin arm and 85 in placebo arm) who remained in remission following completion of consolidation continued to receive either single agent midostaurin or placebo for a median of 11 months (range 0.5 to 17 months) with 69 in the midostaurin arm and 51 in the placebo completing 12 treatment cycles. Common adverse reactions (greater than or equal to 5% difference between the midostaurin and placebo arms) reported for these patients included nausea (47% vs. 18%), hyperglycemia (20% vs. 13%) and vomiting (19% vs. 5%).
- Two single-arm, open-label multicenter trials (Study 2 and Study 3) evaluated the safety of midostaurin (100 mg twice daily with food) as a single agent in 142 adult patients total with ASM, SM-AHN, or MCL. The median age was 63 (range: 24 to 82), 63% had an ECOG performance status of 0 or 1, and 75% had no hepatic impairment (bilirubin and AST ≤ ULN) at baseline. The median duration of exposure to midostaurin was 11.4 months (range: 0 to 81 months), with 34% treated for ≥ 24 months.
- The most frequent adverse reactions (≥ 20%), excluding laboratory terms, were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea (Table 4). Grade ≥ 3 adverse reactions reported in ≥ 5%, excluding laboratory terms, were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency (Table 4).
- Adverse reactions led to dose modifications (interruption or reduction) in 56% of patients. Among these, the most frequent adverse reactions (> 5%) were gastrointestinal symptoms, QT prolongation, neutropenia, pyrexia, thrombocytopenia, gastrointestinal hemorrhage, lipase increase, and fatigue. The median time to first dose modification for toxicity was 1.6 months, with 75% of dose modifications first occurring within 5 months of starting treatment.
- Treatment discontinuation due to adverse reactions occurred in 21% of patients. The most frequent adverse reactions causing treatment discontinuation included infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
- Serious adverse reactions were reported in 68% of patients, most commonly (≥ 20%) due to infections and gastrointestinal disorders.
- On-treatment deaths unrelated to the underlying malignancy occurred in 16 patients (11%), most commonly from infection (sepsis or pneumonia), followed by cardiac events. Of the on-treatment deaths from disease progression, 4 were also attributable to infection.
- Table 4 summarizes the adverse reactions reported in ≥ 10% of the patients with advanced SM.
- Gastrointestinal Toxicities Leading to Treatment Modification:
- In patients with advanced SM, the median time to onset of nausea was 9 days, with 75% of cases beginning within the first 3 months. The median time to onset of vomiting was 1 month.
- Other clinically significant adverse reactions occurring in ≤ 10% of patients included:
- Infections and infestations: Sepsis (9%)a, bronchitis (6%), cellulitis or erysipelas (5%)
- Blood and lymphatic system disorders: Febrile neutropenia (8%)
- Cardiac disorders: Cardiac failure (6%), myocardial infarction or ischemia (4%)a
- Immune system disorders: Hypersensitivity (4%)a
- Nervous system disorders: Disturbance in attention (7%), tremor (6%), mental status changes (4%)
- Ear and labyrinth disorders: Vertigo (5%)
- Vascular disorders: Hypotension (9%), hematoma (6%)
- Respiratory, thoracic and mediastinal disorders: Oropharyngeal pain (4%), interstitial lung disease or pneumonitis (2%), pulmonary edema (3%)a
- Gastrointestinal disorders: Dyspepsia (6%), gastritis (3%)a
- General disorders and administration site conditions: Chills (5%)
- Investigations: Weight increased (6%)
- Injury, poisoning and procedural complications: Contusion (6%)
- aGrouped terms
- Sepsis: e.g., sepsis, staphylococcal/Enterobacter/Escherichia sepsis
- Hypersensitivity: includes one report of anaphylactic shock
- Myocardial infarction or ischemia: e.g., myocardial infarction and acute myocardial infarction, angina pectoris
- Gastritis: gastritis, gastritis erosive, gastritis hemorrhagic
- Pulmonary edema: pulmonary edema, pulmonary congestion
- Table 5 summarizes new or worsening laboratory abnormalities. Common (≥ 10%) Grade 3 or higher non-hematologic laboratory abnormalities were hyperglycemia (non-fasting), lipase increase, and hyperuricemia. The most common (≥ 20%) Grade 3 or higher hematologic laboratory abnormalities were lymphopenia, anemia, thrombocytopenia, and neutropenia. Grade 4 hematologic abnormalities occurring in ≥ 5% were thrombocytopenia (13%), neutropenia (8%), anemia (6%), and lymphopenia (6%).
## Postmarketing Experience
There is limited information regarding Midostaurin Postmarketing Experience in the drug label.
# Drug Interactions
- Effect of Strong Cytochrome P450 (CYP) 3A Inhibitors and Inducers
- Table 6 lists the potential effects of the coadministration of strong CYP3A modulators on midostaurin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midostaurin during pregnancy. Females who may have been exposed to midostaurin during pregnancy directly or through a male partner receiving midostaurin therapy should contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://psi.novartis.com/.
- Based on mechanism of action and findings in animal reproduction studies, midostaurin may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on midostaurin use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, oral administration of midostaurin to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose (see Data). Advise pregnant women of the potential risk to a fetus.
- The background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
- When midostaurin was administered to female rats prior to mating and through the first week of pregnancy at a dose of 60 mg/kg/day (approximately 0.1 times the human exposure at the recommended dose based on AUC), there were increases in pre- and post-implantation loss, including total litter loss, resulting in a reduction in the number of live embryos.
- During organogenesis, midostaurin administered at oral doses greater than or equal to 3 mg/kg/day (approximately 0.004 times the human exposure at the recommended dose by AUC) to pregnant female rats caused late embryo-fetal death. Dilated lateral brain ventricles were observed in offspring of rats given doses greater than or equal to 3 mg/kg/day. Extra rib and reduced fetal birth weight with effects on fetal growth (severe renal pelvic cavitation and widened anterior fontanelle) were observed in the absence of maternal toxicity at the highest dose of 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). Midostaurin administered orally to pregnant rabbits during organogenesis led to maternal toxicity with spontaneous abortions and some delay in fetal growth (reduced fetal birth weight) at doses greater than or equal to 10 mg/kg/day (approximately 0.01 times the human exposure at the recommended dose by AUC).
- In an oral pre- and postnatal development study in the rat, adverse effects upon maternal performance included dams with signs of dystocia and a lower live litter size at 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). For the F1 offspring, lower body weights, accelerated complete eye opening and delayed auricular startle ontogeny were noted at 30 mg/kg/day.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Midostaurin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Midostaurin during labor and delivery.
### Nursing Mothers
- There are no data on the presence of midostaurin or its active metabolites in human milk, the effect on the breastfed infant, or the effect on milk production. Orally administered midostaurin and its active metabolites pass into the milk of lactating rats within 1 hour of a 30 mg/kg/day dose, with approximately 5 times more in the milk of lactating rats compared to plasma. Because of the potential for serious adverse reactions in breastfed infants from midostaurin advise women not to breastfeed during treatment with midostaurin and for at least 4 months after the last dose.
### Pediatric Use
- Safety and effectiveness of midostaurin have not been established in pediatric patients.
### Geriatic Use
- Of the 142 patients with advanced SM in clinical studies of midostaurin, 64 (45%) were aged 65 and over, and 16 (11%) were aged 75 years and over. No overall differences in safety or response rate were observed between the subjects aged 65 and over compared with younger subjects. Greater sensitivity of older individuals cannot be ruled out.
- Clinical studies in AML with midostaurin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
- In general, administration for elderly patients should be cautious, based on patient’s eligibility for concomitant chemotherapy and reflecting the greater frequency of concomitant disease or other drug therapy.
### Gender
There is no FDA guidance on the use of Midostaurin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Midostaurin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Midostaurin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Midostaurin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
- Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating midostaurin.
Females
- Midostaurin may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for 4 months after the last dose.
Males
- Males with female sexual partners of reproductive potential should use effective contraception during midostaurin treatment and for at least 4 months after stopping treatment with midostaurin.
- Based on findings in animals, midostaurin may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.
### Immunocompromised Patients
There is no FDA guidance one the use of Midostaurin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Administer prophylactic anti-emetics before treatment with midostaurin to reduce the risk of nausea and vomiting.
- Administer midostaurin orally with food, twice daily at approximately 12 hour intervals. Do not open or crush midostaurin capsules.
- If a dose of midostaurin is missed or vomited, do not make up the dose; take the next dose at the usual scheduled time.
- Consider interval assessments of QT by EKG if midostaurin is taken concurrently with medications that can prolong the QT interval.
### Monitoring
- Disease response or stabilization may indicate efficacy.
- FLT3 mutation: Prior to initiation, with an FDA-approved companion diagnostic test available at http://www.fda/gov/CompanionDiagnostics.
- Pregnancy status (women of reproductive potential): Within 7 days prior to initiation of therapy.
- CBC: At least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter during therapy; include a differential.
- Toxicities, including nausea, vomiting, and other non-hematologic toxicities: At least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter during therapy.
- Pulmonary symptoms of interstitial lung disease or pneumonitis.
# IV Compatibility
There is limited information regarding the compatibility of Midostaurin and IV administrations.
# Overdosage
There is limited information regarding Midostaurin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFRα/β, VEGFR2, as well as members of the serine/threonine kinase PKC (protein kinase C) family.
- Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells.
## Structure
## Pharmacodynamics
Cardiac Electrophysiology
- The effect of midostaurin (75 mg twice daily for 3 days) on the QTc interval was evaluated in a randomized, placebo and moxifloxacin controlled, multiple-dose, blinded, parallel study. There was no clinically significant prolongation of QTc interval or relationship between changes in QTc and concentrations for midostaurin and its active metabolites (CGP62221 and CGP52421). The study duration was not long enough to estimate the effects of the metabolite CGP52421 on the QT/QTc interval.
- In pooled clinical studies in patients with advanced SM, 4.7% patients had a post-baseline QTcF > 480 ms, no patients had a QTcF > 500 ms, and 6.3% patients had a QTcF > 60 ms compared to baseline.
- In a randomized placebo-controlled study in patients with AML, the proportion of patients with QTc prolongation was higher in patients randomized to midostaurin as compared to placebo (QTcF > 480 ms: 10.1% vs 5.7%; QTcF > 500 ms: 6.2% vs 2.6%; QTcF > 60 ms: 18.4% vs 10.7%).
## Pharmacokinetics
- Midostaurin exhibits time-dependent pharmacokinetics with an initial increase in minimum concentrations (Cmin) that reach the highest Cmin concentrations during the first week followed by a decline to a steady-state after approximately 28 days. The pharmacokinetics of the CGP62221 showed a similar trend. The plasma concentrations of CGP52421 continued to increase after one month of treatment.
- The highest Cmin and steady-state of midostaurin, CGP62221, and CGP52421 were similar when midostaurin was administered with food at a dose of 50 mg twice daily or 100 mg twice daily.
Absorption
- The time to maximal concentrations (Tmax) occurred between 1 to 3 hours post dose in the fasted state.
- Midostaurin exposure, represented by area under the curve over time to infinity (AUCinf), increased 1.2-fold when midostaurin was coadministered with a standard meal (457 calories, 50 g fat, 21 g proteins, and 18 g carbohydrates) and 1.6-fold when coadministered with a high-fat meal (1007 calories, 66 g fat, 32 g proteins, and 64 g carbohydrates) compared to when midostaurin was administered in a fasted state. Midostaurin maximum concentrations (Cmax) were reduced by 20% with a standard meal and by 27% with a high-fat meal compared to a fasted state. Tmax was delayed when midostaurin was administered with a standard meal or a high-fat meal (median Tmax = 2.5 hrs to 3 hrs).
Distribution
- Midostaurin has an estimated geometric mean volume of distribution (% coefficient of variation) of 95.2 L (31%). Midostaurin and its metabolites are distributed mainly in plasma in vitro. Midostaurin, CGP62221, and CGP52421 are greater than 99.8% bound to plasma protein in vitro. Midostaurin is mainly bound to α1-acid glycoprotein in vitro.
Elimination
- The geometric mean terminal half-life (% coefficient of variation) is 19 hours (39%) for midostaurin, 32 hours (31%) for CGP62221 and 482 hours (25%) for CGP52421.
Metabolism
- Midostaurin is primarily metabolized by CYP3A4. CGP62221 and CGP52421 (mean ± standard deviation) account for 28 ± 2.7% and 38 ± 6.6% respectively of the total circulating radioactivity.
Excretion
- Fecal excretion accounted for 95% of the recovered dose with 91% of the recovered dose excreted as metabolites and 4% of the recovered dose as unchanged midostaurin. Only 5% of the recovered dose was found in urine.
- Age (20-94 years), sex, race, and mild (total bilirubin greater than 1.0 to 1.5 times the upper limit of normal (ULN) or aspartate aminotransferase (AST) greater than the ULN) or moderate (total bilirubin 1.5 to 3.0 times the ULN and any value for AST) hepatic impairment or renal impairment (creatinine clearance (CLCr) ≥ 30 mL/min) did not have clinically meaningful effects on the pharmacokinetics of midostaurin, CGP62221, or CGP52421. The pharmacokinetics of midostaurin in patients with baseline severe hepatic impairment (total bilirubin greater than 3.0 times the ULN and any value for AST) or severe renal impairment (CLCr 15 to 29 mL/min) is unknown.
Drug Interaction Studies
- Coadministration of ketoconazole (400 mg daily for 10 days) with a single dose of midostaurin (50 mg) on Day 6 increased AUCinf of midostaurin by 10.4-fold and CGP62221 by 3.5-fold and area under the curve over time to last measurable concentrations (AUC0-t) of CGP52421 by 1.2-fold compared to a single midostaurin dose coadministered with placebo.
- Coadministration of itraconazole (100 mg twice daily on Days 22-28 for 13 doses) with multiple doses of midostaurin (100 mg twice daily on Days 1 to 2 and 50 mg twice daily on Days 3 to 28) increased Day 28 Cmin concentrations of midostaurin by 2.1-fold, CGP62221 by 1.2-fold, and CGP52421 by 1.3-fold compared to the respective Day 21 Cmin concentrations with midostaurin alone.
- Coadministration of rifampicin (600 mg daily on Days 1 to 14) with a single dose of midostaurin (50 mg) on Day 9 decreased AUCinf of midostaurin by 96% and CGP62221 by 92% and AUC0-t of CGP52421 by 59%.
- Midazolam (sensitive CYP3A substrate) AUCinf was not affected following 4 days of midostaurin administration. The clinical relevance of this interaction is unknown as the midostaurin was administered for only 4 days.
- Midostaurin inhibits CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A; CGP62221 inhibits CYP1A2, CYP2C8, CYP2C9, and CYP3A; and CGP52421 inhibits CYP2D6 and CYP3A in vitro. Midostaurin, CGP52421, and CGP62221 induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A in vitro.
- Midostaurin inhibits P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); CGP52421 and CGP62221 inhibit organic anion transporter polypeptide (OATP) 1B1 in vitro.
## Nonclinical Toxicology
- Carcinogenicity studies have not been performed with midostaurin.
- Midostaurin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or in Chinese hamster V97 cells. Midostaurin increased the frequency of polyploidy cells in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells, but was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 200 mg/kg (1200 mg/m2). This dose was approximately 20-fold the recommended human dose, based on body surface area.
- Reproductive toxicity was observed in a fertility study, in male and females rats given oral doses of midostaurin at 10, 30 and 60 mg/kg/day (approximately 0.01, 0.05, and 0.1 times, respectively, the AUC at the recommended human dose). In males, testicular degeneration and atrophy was observed at doses greater than or equal to 10 mg/kg/day and reduced sperm count and motility, and a decrease in reproductive organ weights were observed at 60 mg/kg/day. In females, increased resorptions, decreased pregnancy rate, and decreased number of implants and live embryos were observed at 60 mg/kg/day. In a 3-month toxicology study in dogs, there was inhibition of spermatogenesis at doses greater than or equal to 3 mg/kg/day (approximately 0.01 times the exposure at the recommended human dose).
# Clinical Studies
Study 1
- Midostaurin in combination with chemotherapy was investigated in a randomized, double-blind placebo-controlled trial of 717 patients with newly-diagnosed FLT3-mutated AML. In this study, FLT3 mutation status was determined prospectively with a clinical trial assay and verified retrospectively using the companion diagnostic LeukoStrat® CDx FLT3 Mutation Assay, which is an FDA-approved test for selection of patients with AML for midostaurin treatment. Patients were stratified by FLT3 mutation status: TKD, ITD with allelic ratio less than 0.7, and ITD with allelic ratio greater than or equal to 0.7. Patients with acute promyelocytic leukemia or therapy-related AML were not eligible. Patients were randomized (1:1) to receive midostaurin 50 mg twice daily (n = 360) or placebo (n = 357) with food on Days 8-21 in combination with daunorubicin (60 mg/m2 daily on Days 1 to 3) /cytarabine (200 mg/m2 daily on Days 1 to 7) for up to two cycles of induction and high dose cytarabine (3 g/m2 every 12 hours on Days 1, 3 and 5) for up to four cycles of consolidation, followed by continuous midostaurin or placebo treatment according to initial assignment for up to 12 additional 28-day cycles. There was no re-randomization at the start of post consolidation therapy. Patients who proceeded to hematopoietic stem cell transplantation (SCT) stopped receiving study treatment.
- The randomized patients had a median age of 47 years (range, 18-60 years), 44% were male, and 88% had a performance status of 0-1. AML was de novo onset in 95%. The percentage of patients with FLT3-ITD allelic ratio < 0.7, FLT3-ITD allelic ratio ≥ 0.7, and FLT3-TKD mutations were identical (per randomized FLT3 stratum) on both arms (48%, 30%, and 23%, respectively). Of the 563 patients with NPM1 testing, 58% had an NPM1 mutation. The two treatment groups were generally balanced with respect to the baseline demographics and disease characteristics, except that the placebo arm had a higher percentage of females (59%) than in the midostaurin arm (52%). NPM1 mutations were identified in 55% of patients tested on the midostaurin arm and 60% of patients tested on the placebo arm.
- A second course of induction was administered to 25% of the patients, 62% initiated at least one cycle of consolidation, 29% initiated maintenance, and 17% completed all 12 planned cycles of maintenance; 21% of the patients underwent SCT in first CR. The overall rate of SCT (induction failure, first CR or salvage after relapse) was 59% (214/360) of patients in the midostaurin plus standard chemotherapy arm vs. 55% (197/357) in the placebo plus standard chemotherapy arm. All patients were followed for survival.
- Efficacy was established on the basis of overall survival (OS), measured from the date of randomization until death by any cause. The primary analysis was conducted after a minimum follow-up of approximately 3.5 years after the randomization of the last patient. Midostaurin plus standard chemotherapy was superior to placebo plus standard chemotherapy in OS (HR 0.77; 95% CI 0.63, 0.95; 2 sided p = 0.016) (Figure 1). Because survival curves plateaued before reaching the median, median survival could not be reliably estimated.
- The analysis of event-free survival (EFS), defined as a failure to obtain a complete remission (CR) within 60 days of initiation of protocol therapy, or relapse, or death from any cause, showed a statistically significant improvement with a median of 8.2 months for midostaurin plus standard chemotherapy versus 3.0 months for placebo plus standard chemotherapy with HR 0.78 (95% CI 0.66, 0.93) and 2 sided p = 0.005. In an exploratory analysis of EFS defined as a failure to obtain a CR any time during induction, or relapse, or death from any cause with failures assigned as an event on study day 1, the median EFS was 10.6 months for midostaurin plus standard chemotherapy versus 5.6 months for placebo plus standard chemotherapy with HR 0.72 (95% CI 0.61, 0.86).
Study 2
- A single-arm, open-label, multicenter trial evaluated the efficacy of midostaurin as a single agent in ASM, SM-AHN, and MCL, collectively referred to as advanced SM. The study enrolled 116 adult patients with relapse or progression to 0, 1, or 2 prior regimens for SM. The study excluded patients with serum creatinine > 2.0 mg/dL, hepatic transaminases > 2.5 x upper limit of normal (ULN) or > 5 x ULN if disease-related, total bilirubin > 1.5 x ULN or > 3 x ULN if disease-related, QTc > 450 msec, cardiovascular disease including left-ventricular ejection fraction < 50%, or any pulmonary infiltrates. In addition, the study excluded patients with acute-stage or life-threatening AHN. Patients received midostaurin 100 mg orally twice daily in 28-day cycles until disease progression or intolerable toxicity.
- Of the 116 patients treated, a study steering committee identified 89 patients who had measurable C-findings and were evaluable for response. The median age in this group was 64 years (range: 25 to 82), 64% of patients were male, and nearly all patients (97%) were Caucasian. Among these patients, 36% had prior therapy for SM, and 82% had the KIT D816V mutation detected at baseline. Their median duration of treatment was 11 months (range: < 1 to 68 months), with treatment ongoing in 17%.
- Efficacy was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles of midostaurin by modified Valent criteria for ASM and SM-AHN (Table 7). Table 7 shows responses to midostaurin according to modified Valent criteria. Confirmed major or partial responses occurred in 46 of 73 patients with a documented KIT D816V mutation, 7 of 16 with wild-type or unknown status with respect to KIT D816V mutation, and 21 of 32 having prior therapy for SM.
- As a post-hoc exploratory analysis, efficacy was also assessed using modified 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Response after 6 cycles of midostaurin was determined using a computational algorithm. The efficacy of midostaurin for MCL was based on the CR results by these criteria. There were 115 patients evaluable for response assessment, of whom 47 (41%) had prior therapy for SM, and 93 (81%) had a documented D816V mutation at baseline. Table 8 provides the results of this analysis. Overall response by modified IWG-MRT-ECNM criteria was reported for 16 (17%) of 93 patients with a documented D816V mutation, and in 8 (17%) of 47 patients having prior therapy for SM.
Study 3
- Study 3 was a single-arm, multicenter, open-label trial of 26 patients with advanced SM. Midostaurin was administered orally at 100 mg twice daily with food. The median age in this group was 64 years, 58% of patients were male and most were Caucasian (81%). Eligibility criteria were similar to Study 2. By Valent criteria per investigator assessment, of 17 patients with SM-AHN, 10 achieved a response (1 partial, 9 major) by 2 cycles that was sustained for at least 8 weeks. Patients who received concomitant corticosteroids were included. Of the 6 patients with MCL, 1 achieved partial response and 1 achieved major response. Median DOR for either group had not been reached, with DOR ranging from 3.4+ to 79.2+ months in patients with SM-AHN and 28.6+ to 32.1+ months in patients with MCL. The subtype of SM in the remaining 3 patients was unconfirmed.
# How Supplied
- Midostaurin 25 mg capsules
- Pale orange oblong soft capsule with red ink imprint ‘PKC NVR’; available in:
- 56 soft capsules………………………………………………………………………………………NDC 0078-0698-99
- Contents: Each carton contains two inner packs, each with 28 capsules (7 blister cards with 4 capsules each)
- 112 soft capsules……………………………………………………………………………………..NDC 0078-0698-19
- Contents: Each carton contains four inner packs, each with 28 capsules (7 blister cards with 4 capsules each)
## Storage
- Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store in the original package to protect from moisture.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient to read the FDA-approved patient labeling (Patient Information).
- Pulmonary Adverse Reactions: Inform patients to seek medical attention for new cough, chest discomfort, or shortness of breath.
- Gastrointestinal Adverse Reactions: Inform patients that midostaurin can cause nausea, vomiting, and diarrhea. Advise patients to contact their healthcare provider if these symptoms occur or are persisting despite supportive medications.
- Embryo-Fetal Toxicity
- Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy.
- Advise male patients with female partners of reproductive potential to use effective contraception during treatment with midostaurin and for 4 months after the last dose.
- Advise females who may have been exposed to midostaurin during pregnancy directly or through male partner receiving midostaurin therapy to contact the Novartis Pharmaceuticals Corporation at 1-888-669-6682 and /or at https://psi.novartis.com/.
- Lactation
- Advise women not to breastfeed during treatment with midostaurin and for at least 4 months after the final dose.
- Infertility
- Advise females and males of reproductive potential that midostaurin may impair fertility.
# Precautions with Alcohol
Alcohol-Midostaurin interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Rydapt
# Look-Alike Drug Names
There is limited information regarding Midostaurin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Midostaurin | |
9866f6e365be054d5256d009fea8303b611bec66 | wikidoc | Mifamurtide | Mifamurtide
# Overview
Mifamurtide (trade name Mepact, marketed by Takeda) is a drug against osteosarcoma, a kind of bone cancer mainly affecting children and young adults, which is lethal in about a third of cases. The drug was approved in Europe in March 2009.
# History
The drug was invented by Ciba-Geigy (now Novartis) in the early 1980s and sold to Jenner Biotherapies in the 1990s. In 2003, IDM Pharma bought the rights and developed it further. IDM Pharma was acquired by Takeda along with mifamurtide in June 2009.
Mifamurtide had already been granted orphan drug status by the U.S. Food and Drug Administration (FDA) in 2001, and the European Medicines Agency (EMA) followed in 2004. It was approved in the 27 European Union member states plus Iceland, Liechtenstein, and Norway by a centralized marketing authorization in March 2009. The drug was denied approval by the FDA in 2007. Mifamurtide has been licensed by the EMA since March, 2009.
# Indications
Mifamurtide is indicated for the treatment of high-grade, nonmetastasizing, resectable osteosarcoma following complete surgical removal in children, adolescents, and young adults, aged two to 30 years. Osteosarcoma is diagnosed in about 1,000 individuals in Europe and the USA per year, most under the age of 30. The drug is used in combination with postoperative, multiagent chemotherapy to kill remaining cancer cells and improve a patient's chance of overall survival.
In a phase-III clinical trial in about 800 newly diagnosed osteosarcoma patients, mifamurtide was combined with the chemotherapeutic agents doxorubicin and methotrexate, with or without cisplatin and ifosfamide. The mortality could be lowered by 30% versus chemotherapy plus placebo. Six years after the treatment, 78% of patients were still alive. This equals an absolute risk reduction of 8% .
# Adverse effects
In a clinical study, mifamurtide was given to 332 subjects (half of whom were under age of 16) and most side effects were found to be mild to moderate in nature. Most patients experience fewer adverse events with subsequent administration. Common side effects include fever (about 90%), vomiting, fatigue and tachycardia (about 50%), infections, anaemia, anorexia, headache, diarrhoea and constipation (>10%).
# Pharmacokinetics
After application of the liposomal infusion, the drug is cleared from the plasma within minutes and is concentrated in lung, liver, spleen, nasopharynx, and thyroid. The terminal half-life is 18 hours. In patients receiving a second treatment after 11–12 weeks, no accumulation effects were observed.
# Pharmacodynamics
Mifamurtide is a fully synthetic derivative of muramyl dipeptide (MDP), the smallest naturally occurring immune stimulatory component of cell walls from Mycobacterium species. It has similar immunostimulatory effects as natural MDP with the advantage of a longer half-life in plasma.
NOD2 is a pattern recognition receptor which is found in several kinds of white blood cells, mainly monocytes and macrophages. It recognises muramyl dipeptide, a component of the cell wall of bacteria. Mifamurtide simulates a bacterial infection by binding to NOD2, activating white cells. This results in an increased production of TNF-α, interleukin 1, interleukin 6, interleukin 8, interleukin 12, and other cytokines, as well as ICAM-1. The activated white cells attack cancer cells, but not, at least in vitro, other cells.
# Interactions
- Theoretical considerations suggest calcineurin inhibitors like ciclosporin and tacrolimus might interact with mifamurtide because of their effect on macrophages.
- High-dose NSAIDs block the mechanism of mifamurtide in vitro.
Consequently, the combination of mifamurtide with these types of drugs is contraindicated. However, mifamurtide can be coadministered with low doses of NSAIDs. No evidence suggests mifamurtide interacts with the studied chemotherapeutics, or with the cytochrome P450 system.
# Chemistry
Mifamurtide is muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic analogue of muramyl dipeptide. The side chains of the molecule give it a longer elimination half-life than the natural substance. The substance is applied encapsulated into liposomes (L-MTP-PE). Being a phospholipid, it accumulates in the lipid bilayer of the liposomes in the infusion.
## Synthesis
One method of synthesis (shown first) is based on N,N'-dicyclohexylcarbodiimide (DCC) assisted esterification of N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine with N-hydroxysuccinimide, followed by a condensation with 2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid in triethylamine (Et3N). A different approach (shown second) uses N-acetylmuramyl-L-alanyl-D-isoglutamine, hydroxysuccinimide and alanyl-2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid; that is, the alanine is introduced in the second step instead of the first. | Mifamurtide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Mifamurtide (trade name Mepact, marketed by Takeda) is a drug against osteosarcoma, a kind of bone cancer mainly affecting children and young adults, which is lethal in about a third of cases. The drug was approved in Europe in March 2009.
# History
The drug was invented by Ciba-Geigy (now Novartis) in the early 1980s and sold to Jenner Biotherapies in the 1990s. In 2003, IDM Pharma bought the rights and developed it further.[1] IDM Pharma was acquired by Takeda along with mifamurtide in June 2009.[2]
Mifamurtide had already been granted orphan drug status by the U.S. Food and Drug Administration (FDA) in 2001, and the European Medicines Agency (EMA) followed in 2004. It was approved in the 27 European Union member states plus Iceland, Liechtenstein, and Norway by a centralized marketing authorization in March 2009. The drug was denied approval by the FDA in 2007.[3][4] Mifamurtide has been licensed by the EMA since March, 2009.[5]
# Indications
Mifamurtide is indicated for the treatment of high-grade, nonmetastasizing, resectable osteosarcoma following complete surgical removal in children, adolescents, and young adults, aged two to 30 years.[1][6][7] Osteosarcoma is diagnosed in about 1,000 individuals in Europe and the USA per year, most under the age of 30.[8] The drug is used in combination with postoperative, multiagent chemotherapy to kill remaining cancer cells and improve a patient's chance of overall survival.[6]
In a phase-III clinical trial in about 800 newly diagnosed osteosarcoma patients, mifamurtide was combined with the chemotherapeutic agents doxorubicin and methotrexate, with or without cisplatin and ifosfamide. The mortality could be lowered by 30% versus chemotherapy plus placebo. Six years after the treatment, 78% of patients were still alive. This equals an absolute risk reduction of 8% .[1]
# Adverse effects
In a clinical study, mifamurtide was given to 332 subjects (half of whom were under age of 16) and most side effects were found to be mild to moderate in nature. Most patients experience fewer adverse events with subsequent administration.[9][10] Common side effects include fever (about 90%), vomiting, fatigue and tachycardia (about 50%), infections, anaemia, anorexia, headache, diarrhoea and constipation (>10%).[1][11]
# Pharmacokinetics
After application of the liposomal infusion, the drug is cleared from the plasma within minutes and is concentrated in lung, liver, spleen, nasopharynx, and thyroid. The terminal half-life is 18 hours. In patients receiving a second treatment after 11–12 weeks, no accumulation effects were observed.[12]
# Pharmacodynamics
Mifamurtide is a fully synthetic derivative of muramyl dipeptide (MDP), the smallest naturally occurring immune stimulatory component of cell walls from Mycobacterium species. It has similar immunostimulatory effects as natural MDP with the advantage of a longer half-life in plasma.
NOD2 is a pattern recognition receptor which is found in several kinds of white blood cells, mainly monocytes and macrophages. It recognises muramyl dipeptide, a component of the cell wall of bacteria. Mifamurtide simulates a bacterial infection by binding to NOD2, activating white cells. This results in an increased production of TNF-α, interleukin 1, interleukin 6, interleukin 8, interleukin 12, and other cytokines, as well as ICAM-1. The activated white cells attack cancer cells, but not, at least in vitro, other cells.[13]
# Interactions
- Theoretical considerations suggest calcineurin inhibitors like ciclosporin and tacrolimus might interact with mifamurtide because of their effect on macrophages.
- High-dose NSAIDs block the mechanism of mifamurtide in vitro.
Consequently, the combination of mifamurtide with these types of drugs is contraindicated. However, mifamurtide can be coadministered with low doses of NSAIDs. No evidence suggests mifamurtide interacts with the studied chemotherapeutics, or with the cytochrome P450 system.[14]
# Chemistry
Mifamurtide is muramyl tripeptide phosphatidylethanolamine (MTP-PE), a synthetic analogue of muramyl dipeptide. The side chains of the molecule give it a longer elimination half-life than the natural substance. The substance is applied encapsulated into liposomes (L-MTP-PE). Being a phospholipid, it accumulates in the lipid bilayer of the liposomes in the infusion.[15]
## Synthesis
One method of synthesis (shown first) is based on N,N'-dicyclohexylcarbodiimide (DCC) assisted esterification of N-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine with N-hydroxysuccinimide, followed by a condensation with 2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid in triethylamine (Et3N).[16] A different approach (shown second) uses N-acetylmuramyl-L-alanyl-D-isoglutamine, hydroxysuccinimide and alanyl-2-aminoethyl-2,3-dipalmitoylglycerylphosphoric acid;[17] that is, the alanine is introduced in the second step instead of the first. | https://www.wikidoc.org/index.php/Mifamurtide | |
c47bdd6cb9c2ed7f2984be245659a86fee31885b | wikidoc | Mithramycin | Mithramycin
Mithramycin is an anti-neoplastic antibiotic. Its major use is as an IV infusion to reduce very high levels of plasma calcium. It inhibits RNA synthesis in osteoclasts. Typically use a dose of
25 microgram per kilogram IV given over four to six hours. This dose can be repeated in 1 to 2 days if necessary. Ca++ levels start falling after 12 hours, with maximal reduction at 48-72 hours.
Hypercalcaemia recurs in days to several weeks. With repeated use, organotoxicity (kidney, liver, haematopoetic system) can become a problem. | Mithramycin
Mithramycin is an anti-neoplastic antibiotic. Its major use is as an IV infusion to reduce very high levels of plasma calcium. It inhibits RNA synthesis in osteoclasts. Typically use a dose of
25 microgram per kilogram IV given over four to six hours. This dose can be repeated in 1 to 2 days if necessary. Ca++ levels start falling after 12 hours, with maximal reduction at 48-72 hours.
Hypercalcaemia recurs in days to several weeks. With repeated use, organotoxicity (kidney, liver, haematopoetic system) can become a problem.
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Mithracin | |
ddb4d147a9b144e820afea4773a408f53dd0835c | wikidoc | Mixing test | Mixing test
The mixing test is a medical laboratory study used to clarify the differential diagnosis of blood clotting abnormalities. Other names for the test include mixing studies, PT mixing study, PTT mixing study, circulating anticoagulant screening test, PT, 50/50, or inhibitor screen.
The test is most often initiated when a patient has an abnormally long prothrombin time (PT) or more usually, a prolonged partial thromboplastin time (PTT), to distinguish whether the underlying problem is a clotting factor deficiency on the one hand, or a factor inhibitor on the other hand.
The test relies on the fact that the circulating level of any coagulation factor must be reduced to a level significantly less than 50% in order to affect the PT or PTT. Thus when the patient's blood is mixed with an equal volume of blood donated by a person known to have normal clotting, the mixture (which will have at least 50% factor activity for all factors) will clot more quickly if the initial disorder was because of a deficiency, while it will not clot any faster if the initial disorder was because of a factor inhibitor.
If the PTT of the mixed blood is normal, factor deficiency is indicated, and further testing will be performed for specific factors. If the PTT of the mixed blood is still prolonged, an inhibitor is suggested, and further studies (typically starting with an assay for lupus anticoagulant) will be performed. This result, however, can also be seen if the patient is taking heparin or another anticoagulant. If the PTT of the mixed blood initially normalized, but becomes prolonged again after a two hour incubation, the test is suggestive of a factor VIII inhibitor (because their effect requires this amount of time to become effective). When a mixing test shows this result, a factor VIII inhibitor assay will be performed. | Mixing test
Template:WikiDoc Cardiology News
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
The mixing test is a medical laboratory study used to clarify the differential diagnosis of blood clotting abnormalities. Other names for the test include mixing studies, PT mixing study, PTT mixing study, circulating anticoagulant screening test, PT, 50/50, or inhibitor screen.
The test is most often initiated when a patient has an abnormally long prothrombin time (PT) or more usually, a prolonged partial thromboplastin time (PTT), to distinguish whether the underlying problem is a clotting factor deficiency on the one hand, or a factor inhibitor on the other hand.
The test relies on the fact that the circulating level of any coagulation factor must be reduced to a level significantly less than 50% in order to affect the PT or PTT. Thus when the patient's blood is mixed with an equal volume of blood donated by a person known to have normal clotting, the mixture (which will have at least 50% factor activity for all factors) will clot more quickly if the initial disorder was because of a deficiency, while it will not clot any faster if the initial disorder was because of a factor inhibitor.
If the PTT of the mixed blood is normal, factor deficiency is indicated, and further testing will be performed for specific factors. If the PTT of the mixed blood is still prolonged, an inhibitor is suggested, and further studies (typically starting with an assay for lupus anticoagulant) will be performed. This result, however, can also be seen if the patient is taking heparin or another anticoagulant. If the PTT of the mixed blood initially normalized, but becomes prolonged again after a two hour incubation, the test is suggestive of a factor VIII inhibitor (because their effect requires this amount of time to become effective). When a mixing test shows this result, a factor VIII inhibitor assay will be performed.
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Mixing_test | |
bfac79b49ac869cc341deacc402ac7ad20504914 | wikidoc | Moclobemide | Moclobemide
# Overview
Moclobemide (sold as Amira, Aurorix, Clobemix , Depnil and Manerix) is a reversible monoamine oxidase inhibitor (MAOI) drug primarily used to treat depression and social anxiety. It is not approved for use in the United States, but is approved in other Western countries such as the UK and Australia (TGA approved in December 2000). It is produced by affiliates of the Hoffmann–La Roche pharmaceutical company. Initially, Aurorix was also marketed by Roche in South Africa, but was withdrawn after its patent rights expired and Cipla Medpro's Depnil and Pharma Dynamic's Clorix became available at half the cost.
No significant rise in blood pressure occurs when moclobemide is combined with amines such as tyramine containing foods or pressor amine drugs, unlike the older non-selective irreversible MAOIs which cause a severe rise in blood pressure with such combination. Due to the lack of anticholinergic, cardiovascular, cognitive and psychomotor impairments moclobemide is advantageous in the elderly as well as those with cardiovascular disease.
# Medical uses
Reversible selective MAOIs such as moclobemide are widely underprescribed due to the misconception that the side effect profile of moclobemide is analogous to that of the irreversible and non-selective MAOIs. MAOIs such as moclobemide are reported to have a relatively fast onset of action compared to other antidepressant drug classes, and have good long-term tolerability in terms of side effects.
Tolerance does not seem to occur; research has found that moclobemide retains its beneficial therapeutic properties in depression for at least a year.
- Unipolar depression. Moclobemide has demonstrated effectiveness and efficacy in the treatment and management of major depressive disorder, with both endogenous and non-endogenous depression responding; in addition moclobemide has a fast onset of action compared to other antidepressants and is significantly more tolerable than the tricyclic antidepressants. Due to a very good safety profile and very low incidence of side effects moclobemide is likely to have a high level of acceptability by individuals suffering from depression. Higher doses (>450 mg/day) may be more effective in severe depression, while patients treated with a lower dose tend to respond less well than those treated with tricyclic antidepressants.
- Bipolar depression. While not generally recommended as a monotherapy for bipolar depression (as with all antidepressants) in one clinical trial it appeared (although statistical significance at the p=0.05 was not reached) as though moclobemide was equally effective as imipramine at reducing depressive symptoms, but had a significantly lower risk of causing a manic switch. This is in line with recent findings that MAOIs as a class are superior to other antidepressants (in terms of both their relatively low rate of manic switching and their efficacy) in the treatment of bipolar depression.
- Dysthymia; moclobemide has been found to be effective in the treatment and management of this depressive disorder.
- Social phobia. Moclobemide has been found to be effective for the treatment of social anxiety disorder in both short and long-term placebo controlled clinical trials. Moclobemide is effective but not as effective as the irreversible MAOIs in the treatment of social phobia. Maximal benefits can take 8 – 12 weeks to manifest. There is a high risk of treatment failure if there is co-morbid alcohol abuse, however. The Australian Medicines Handbook lists social phobia as an accepted but not a licensed indication.
- Smoking cessation. Moclobemide has been tested in heavy dependent smokers against placebo based on the theory that tobacco smoking could be a form of self-medicating of major depression, and moclobemide could therefore help increase abstinence rates due to moclobemide mimicking the MAO-A inhibiting effects of tobacco smoke. Moclobemide was administered for 3 months and then stopped; at 6 months follow-up it was found those who had taken moclobemide for 3 months had a much higher successful quit rate than those in the placebo group. However, at 12-month follow-up the difference between the placebo group and the moclobemide group was no longer significant.
- Panic disorder. Moclobemide is useful in the treatment and management of panic disorder. Panic disorder is mentioned as an accepted but unlicensed indication in the Australian Medicines Handbook.
- ADHD. Two small studies assessing the benefit of moclobemide in people with attention deficit disorder found that moclobemide produced favourable results.
- Fibromyalgia, moclobemide has been found to improve pain and functioning in this group of people.
- Migraine. Moclobemide has been reported to be effective in the treament of migraine and chronic tension headache.
Similar to other MAOIs, reversible MAOIs such as moclobemide may also be effective in a range of other psychiatric disorders. Menopausal flushing may also respond to moclobemide. Moclobemide may also have benefit for some patients with Parkinson's Disease by extending and enhancing the effects of l-dopa.
In efficacy studies for the treatment of major depressive disorder, moclobemide has been found to be significantly more effective than placebo, as effective as the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), and somewhat less effective than the older, irreversible MAOIs phenelzine and tranylcypromine. In terms of tolerability, however, moclobemide was found to be comparable to the SSRIs and better tolerated than the TCAs and older MAOIs. There is some evidence that moclobemide on its own or in combination with other antidepressants such as SSRIs is also effective for treatment resistant depression and that the combination can be administered without the development of serotonin syndrome; however, further research is needed before such a combination can be recommended. Follow-up studies show that ongoing use of antidepressants leads to continuing improvement in depression over time; and also have demonstrated that moclobemide retains its therapeutic efficacy as an antidepressant for at least a year. This long-term efficacy is equivalent to that seen with other antidepressant classes.
People on irreversible MAOIs have to discontinue these antidepressants two weeks before general anesthesia, however, the use of moclobemide due to its reversible nature, would allow such patients to possibly continue antidepressant therapy.
A dexamethasone suppression test (DST) and plasma and urine methoxyhydroxyphenylglycol (MHPG) test can be used to estimate who is likely to respond to moclobemide antidepressant therapy.
## Pregnancy and lactation
The doses of moclobemide in breast milk are very low (0.06% of moclobemide being recovered in breast milk) and therefore it has been concluded that moclobemide is unlikely to have any adverse effect on a suckling baby.
## Children
Use in children is not recommended as there is insufficient data to assess their safety and efficacy in these patients.
## Elderly
Reversible MAOIs such as moclobemide may have advantages in the treatment of depression associated with Alzheimer's disease due to its effect on noradrenaline. Cognitive impairments have been found to improve in people with dementia when depression is treated with moclobemide. Due to its superior safety profile, moclobemide has been recommended as a first line agent for the treatment of depression in the elderly. Due to the side effect profile of moclobemide, it may be a better option for this sub group of people than other antidepressants. Research has found evidence that moclobemide may be able to counter cholinergic induced cognitive impairments thus making moclobemide a good choice in the depression in the elderly and those with dementia.
# Adverse effects
The incidence of adverse events is not correlated with age; however, adverse events occur more often in females than in males. Moclobemide is regarded as a generally safe antidepressant and due to its favorable side effect profile, it can be considered a first-line therapeutic antidepressant. Side effects of moclobemide are exceptionally low, with insomnia, headache and dizziness being the most commonly reported side effects in the initial stages of therapy with moclobemide. Many antidepressants have an adverse effect on sexual function; however, treatment with moclobemide has actually been found to improve sexual function. Moclobemide does not have any adverse effect on cognitive abilities, thus there are no impairments of moclobemide therapy on memory, attention functions nor is ability to drive a motor vehicle affected adversely. In fact, moclobemide has been found to improve cognition, especially memory; this is relevant with regard to the elderly as adverse effects on cognition are of particular concern in this population. People with dementia and comorbid depression also show improvements in cognitive impairments; these improvements are unrelated to alleviation of depression. Alcohol related cognitive impairments are also improved by moclobemide. Improvements in cognition also occur in young depressed people after 6 weeks of treatment. There is a mild impairment in psychometric performance in elderly people but none in younger people. Moclobemide, even at high doses of 600 mg, does not impair the ability to drive a motor vehicle. The tolerability of moclobemide is similar in women and men and it is also well tolerated in the elderly. Moclobemide is tolerated to a similar degree to the SSRI antidepressants, although unlike SSRIs moclobemide does not cause sexual dysfunction and gastrointestinal disturbance is less common. Moclobemide has been found to be superior to tricyclic and irreversible MAOI antidepressants in terms of side effects, as it does not cause anticholinergic, sedative or cardiovascular adverse effects as well as not causing weight gain.
Unlike the irreversible MAOIs there is no evidence of liver toxicity with moclobemide. Moclobemide has a similar efficacy profile compared to other antidepressants but is significantly superior to the tricyclic antidepressants and the classic (unselective or irreversible) MAOIs, in terms of tolerance and safety profile. Moclobemide has little effect on psychomotor functions. Other side effects include, nausea, insomnia, tremor and lightheadedness; orthostatic hypotension is uncommon even among the elderly. Behavioural toxicity or other impairments relating to everyday living does not occur with moclobemide, except in doses of 400 mg or higher, peripheral reaction time may be impaired. Peripheral oedema has been associated with moclobemide.
Most of the side effects are transient disappearing within 2 weeks of treatment. tiredness, headache, restlessness, nervousness and sleep disturbances have been described as side effects from moclobemide therapy. A paradoxical worsening of depression has been reported in some individuals in several studies, and reports of suicidal ideation and suicide as an adverse effect have been reported as a rare adverse effect of moclobemide. Overall, antidepressants decrease the risk of suicide. Moclobemide is believed to have only small proconvulsant effects; however, rarely seizures may occur. Hypertension, has been reported to occur very rarely with moclobemide therapy.
Moclobemide is relatively well tolerated. The following are the potential adverse effects and their respective incidences:
- Nausea
- Dry mouth
- Constipation
- Diarrhoea
- Insomnia
- Dizziness
- Anxiety
- Restlessness
- Difficulties falling asleep
- Nightmares/dreams
- Hallucinations
- Memory disturbances,
- Confusion
- Disorientation
- Delusions
- Increased depression
- Excitation/irritability
- Hypomania
- Mania
- Aggressive behaviour
- Apathy
- Tension
- Suicidal ideation
- Suicidal behaviour
- Migraine
- Extrapyramidal effects
- Tinnitus
- Paraesthesia
- Dysarthria
- Heartburn
- Gastritis
- Meteorism
- Indigestion
- Hypertension
- Bradycardia
- Extrasystoles
- Angina/chest pain
- Phlebetic symptoms
- Flushing
- Exanthema/rash
- Allergic skin reaction
- Itching
- Gingivitis
- Stomatitis
- Dry skin
- Conjunctivitis
- Pruritus
- Urticaria
- Disturbances of micturition (dysuria, polyuria, tenesmus)
- Metrorrhagia
- Prolonged menstruation
- General malaise
- Skeletal/muscular pain
- Altered taste sensations
- Hot flushes/cold sensation
- Photopsia
- Dyspnoea
- Visual disturbances
- Increased hepatic enzymes without associated clinical sequelae.
## Contraindications
Avoid use in:
- Confusional states
- Bipolar disorder (although it seems less likely than imipramine to cause a manic switch)
- Phaeochromocytoma
and caution is recommended in:
- Agitated/excited patients
- Thyrotoxicosis
## Interactions
Moclobemide has fewer interactions than irreversible MAOIs. Cimetidine, however, causes a significant rise in moclobemide levels and therefore if the combination is used, lower doses of moclobemide have been recommended. There is little increase in the effects of alcohol when combined with moclobemide and, in fact, moclobemide causes a reduction in alcohol-related impairments. Moclobemide also interacts with pethidine/meperidine, and dextropropoxyphene. Ephedrine in combination with moclobemide increases the risk of cardiovascular adverse effects. Moclobemide is also likely to interact with warfarin.
Serotonin syndrome has been reported when moclobemide has been taken in combination with other serotonin enhancing drugs; however, due to moclobemide's reversible MAO inhibition, serotonin syndrome is significantly less likely to occur with moclobemide than with older irreversible MAOIs. Serotonin syndrome has been reported when trazodone was abruptly replaced with moclobemide. Taking at the same time or starting moclobemide too soon after discontinuing clomipramine, or other serotonin reuptake inhibitors, such as SSRIs may result in the development of a serotonin syndrome. SNRIs, such as venlafaxine in combination with moclobemide have also been associated with serotonin syndrome. Cimetidine, causes a doubling of the blood plasma levels of moclobemide. Blood plasma levels of trimipramine and maprotiline and possibly other tricyclic antidepressants increase when used in combination with moclobemide and may require dosage adjustments if the combination is used for treatment resistant depression. The elimination of zolmitriptan is reduced by moclobemide and if the combination is used, a dosage reduction of zolmitriptan is recommended. Moclobemide reduces the metabolism of dextromethorphan.
Irreversible MAOIs can cause unpleasant and occasionally dangerous side effects such as a hypertensive crises after intake of food or drink containing indirectly acting sympathomimetic amines such as tyramine. This is sometimes referred to as the 'cheese effect'. These side effects are due to irreversible inhibition of MAO in the gut and vasomotor neurones. However, the reversible MAOI antidepressants such as moclobemide have a very different side effect profile in this regard. The reversible binding to MAO-A by moclobemide allows amines such as tyramine to displace moclobemide from MAO-A allowing its metabolism and removing the risk of a hypertensive crisis that occurs with irreversible MAO inhibition. Of 2300 people in multiple clinical trials who were treated with moclobemide in doses up to 600 mg with no dietary restrictions, none experienced a tyramine-mediated hypertensive reaction. As the pressor effect of moclobemide is so low, dietary restrictions are not necessary in people eating a normal diet, in contrast to irreversible MAOIs. However, some rare cheeses that have a high tyramine level may possibly cause a pressor effect and require caution. The potentiation of the pressor effect of tyramine by moclobemide is only one seventh to one tenth of that of irreversible MAOIs. In order to minimize this potentiation, postprandial administration (taken after meals) of moclobemide is recommended. The combined use of moclobemide and selegiline requires dietary restrictions as the combination can lead to increased sensitivity to the pressor effect of foods containing tyramine.
The combination of moclobemide with prescription or over the counter sympathomimetic drugs is not recommended due to the potential of significant drug interactions. While moclobemide or the irreversible MAO-B selective inhibitor selegiline taken alone has very little pressor effect, and requires no dietry restriction, the combination of seligiline with moclobemide leads to a significant enhancement of the pressor effect and such a combination requires dietary restriction of foods containing high amounts of tyramine. The combination of moclobemide and a reversible MAO-B inhibitor requires tyramine dietary restrictions.
## Overdose
Moclobemide is considered to be less toxic in overdose compared to older antidepressants, such as the tricyclic antidepressants and nonselective, irreversible MAO inhibitors, making it a safer antidepressant in the elderly or people with physical disorders. Of 18 people who overdosed on moclobemide during clinical trials, all recovered fully and moclobemide was judged to be safe for in as well as outpatient use. Intoxications with moclobemide as single agent are usually mild; however, when combined with tricyclic or SSRI antidepressants the overdose much more toxic and potentially fatal. Moclobemide, is preferred by doctors for patients who are at risk of suicide, due to moclobemide's low toxicity in overdose. Patients with mixed intoxications (e.g. with other CNS active drugs) may show severe or life-threatening symptoms and should be hospitalized. Treatment is largely symptomatic and should be aimed at maintenance of the vital functions.
## Withdrawal and tolerance
Withdrawal symptoms appear to be very rare with moclobemide compared to other antidepressants; a single report of relatively mild flu-like symptoms persisting for 7 days after rapid reduction of high dose mocloemide therapy has been reported in one patient. Withdrawal of moclobemide causes a rebound in REM Sleep.
Moclobemide does not prevent withdrawal symptoms from serotonin reuptake inhibitors.
Discontinuation of moclobemide is recommended to be done gradually to minimise side effects (e.g. rapid return of condition being treated and/or the appearance of withdrawal symptoms). Tolerance to the therapeutic effects has been reported in a small number of users of MAOIs including moclobemide.
# Pharmacology
Moclobemide is a benzamide, derivative of morpholine, which acts pharmacologically as a selective, reversible inhibitor of monoamine oxidase A (RIMA), a type of monoamine oxidase inhibitor (MAOI), and increases levels of norepinephrine (noradrenaline), dopamine, and especially serotonin. in neuronal cells as well as in synaptic vesicles; extracellular levels also increase which results in increased monoamine receptor stimulation and suppression of REM sleep, down regulation of 3-adrenoceptors. A single 300 mg dose of moclobemide inhibits 80% of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B (MAO-B), blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. There is also some evidence pointing towards moclobemide possessing neuroprotective properties. There is no cumulative effect of moclobemide centrally when taken long-term. With long-term use of moclobemide, there is a significant down-regulation of B-adrenoceptors. Single or repeated dosing with 100–300 mg of moclobemide leads to a reduction in deaminated metabolites of amines such as 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethylglycol as well as 5-HIAA. Excretion of homovanillic acid and vanillylmandelic acid via urine is also reduced. There is also a temporary increase in prolactin during initial intake of 100–300 mg of moclobemide. L-dihydroxyphenylalanine is also reduced. However, suppression of the serotonin metabolite is less pronounced than the inhibition of the metabolite of noradrenaline which suggest there are other major metabolic pathways for serotonin other than MAO-A.
It has been described as a 'slow binding inhibitor', whereby conformational changes to either moclobemide or the enzyme to MAO-A slowly form a more tightly bound complex, resulting in the non-competitive MAO inhibition by moclobemide. With three times daily dosing the inhibition on MAO-A was relatively constant with moclobemide. The MAO inhibition of moclobemide lasts about 8–10 hours and wears off completely by 24 hours after dosing. The inhibition of MAO-A by moclobemide is 10 times more potent than the irreversible MAOIs phenelzine and approximately equivalent to tranylcypromine and isocarboxazid.
Moclobemide increases levels of extracellular monoamines and decreases levels of their metabolites in rat brains; tolerance to these effects does not seem to occur with chronic use of moclobemide. Moclobemide lacks anticholinergic effects and cognitive impairments can be improved by moclobemide. Moclobemide suppresses the unstimulated release of certain proinflammatory cytokines which are believed to be involved in the pathophysiology of major depression and stimulates the release of anti-inflammatory cytokines. Long-term treatment with moclobemide leads to an increase in cyclic adenosine monophosphate (cAMP) binding to cAMP-dependent protein kinase (PKA).
Moclobemide is chemically unrelated to irreversible MAOI antidepressants and only has a very weak pressor effect of orally administered tyramine. In humans, the n-oxide metabolites of moclobemide and moclobemide itself are the compounds that produce most of the inhibition of MAO-A; other metabolites are significantly less potent than the parent compound.
In healthy people moclobemide has a relatively small suppressing effect on REM sleep; in contrast, depressed people who have been treated with moclobemide, progressively show improved sleep over a 4-week period, with an increase in stage 2 non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. There have been conflicting findings with regard to moclobemide altering cortisol levels and whether moclobemide increases growth hormone levels. Testosterone levels increase significantly with long-term use of moclobemide in depressed males.
Moclobemide also has neuroprotective properties in its demonstrated anti-hypoxia or anti-ischemia effects; there is a possibility that moclobemide may possess similar neuro-rescuing properties, similar to selegiline, however, research is required to determine this. Moclobemide has also been demonstrated in a single dose research study to possess antinociceptive properties.
Platelet MAO is of the MAO-B and this is inhibited only to a small degree in humans; the inhibition is due to low levels of metabolites of moclobemide that have MAO-B inhibiting properties. Moclobemide has been reported to be a mixed MAO-A/MAO-B inhibitor in rats but in man, it has been reported to be a pure MAO-A inhibitor, blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. No reuptake inhibition of any of the neurotransmitters occurs. The pharmacodynamic action encompasses activation, elevation of mood, and improvement of symptoms like dysphoria, fatigue, and difficulties in concentration. The duration and quality of sleep may be improved. In the treatment of depression the antidepressant effect often becomes evident in the first week of therapy (earlier than typically noted with TCAs/SSRIs).
As MAO inhibition returns completely back to normal after 24 hours, which allows for changing to another antidepressant within 24 hours of the last dose taken of moclobemide.
# Pharmacokinetics
In humans moclobemide is rapidly and almost completely absorbed and totally metabolised via the liver. Peak plasma levels occur 0.3 to 2 hours after oral administration. The bioavailability increases during the first week of therapy from 60% to 80% and more. The elimination half-life is around 2 hours. It is moderately bound to plasma proteins, especially albumin. However, the short disposition half life somewhat increases after repeated dosing; moclobemide has an intermediate elimination half life for systemic clearance and an intermediate volume of distribution. Despite its short half-life the pharmacodynamic action of a single dose persists for approximately 16 hours. The drug is almost completely metabolized in the liver; it is a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6 and CYP1A2. Less than 1 percent of the drug is excreted unchanged; 92 percent of the metabolised drug is excreted within the first 12 hours. The main metabolites are the N-oxide Ro 12-5637 formed via morpholine N-oxidation and lactam derivative Ro 12-8095 formed via morpholine C-oxidation; active metabolites are found only in trace amounts. The unchanged drug (less than 1%) as well as the metabolites are excreted renally (in urine). The main degradation pathway of moclobemide is oxidation. About 44 percent of the drug is lost due to the first pass effect through the liver. Age and renal function do not affect the pharmacokinetics of moclobemide. However, patients with significantly reduced liver function require dose reductions due to the significant slowing of metabolism of moclobemide. Food slows the absorption but does not affect the bioavailability of moclobemide.
Steady state concentrations are established after one week. It has been suggested that changes in dose should not be made with a gap of no less than a week. Moclobemide has good penetration across the blood brain barrier with peak plasma levels within the central nervous system occurring 2 hours after administration.
# Animal toxicology
- Acute toxicity: The oral Template:LD50 values in mouse and rat are quite high, indicating a wide therapeutic index. LD50 for mice is 730 mg/kg and for rats 1,300 mg/kg. In dogs doses in excess of 300 mg/kg led to vomiting, salivation, ataxia, and drowsiness.
- Chronic toxicity: In an 18-months-study in rats with 10 mg/kg no signs of chronic toxicity were noted, with 50 mg/kg and 250 mg/kg only a slight loss of weight, and with 250 mg/kg mildly elevated Alkaline phosphatase and Gamma-GT. Studies in dogs revealed no toxicity relevant for humans. No evidence for a possible hepatic or cardiovascular toxicity was found.
# History
Irreversible MAOI antidepressants were discovered accidentally in the 1950s but their popularity declined as their toxicity especially their dangerous food interactions became apparent and rival the tricyclic antidepressants were discovered. Reversible MAOIs were developed in the hope that they would exert efficacy in depressive disorders but with less of the toxicity of the older irreversible compounds; moclobemide's discovery and marketing brought the renewed interest in MAOIs due to an absence of dangerous tyramine food interactions and potent antidepressant effects. In 1992 moclobemide was launched onto the world markets. Moclobemide was the first reversible MAO-A inhibitor to be widely marketed; Moclobemide as well as other newer antidepressants such as the SSRIs lead to changes in prescribing patterns and broadened the treatment options for the management of depressive disorders.
The discovery of moclobemide in 1972 in Switzerland, as an antidepressant came about after it was initially investigated as a possible lipid lowering drug or antibiotic; when tests failed to demonstrate any antibiotic or antilipaemic properties; it was then tested for anti-cholinergic properties to see if it was a possible antidepressant but these tests also proved negative, leading researchers to think it may, in fact, be an antipsychotic; finally its reversible MAO-A properties as well as its lack of tyramine pressor effect. Clinical trials were commenced for moclobemide's effectiveness in the treatment of depression. It was first approved in the UK and Europe as the first reversible and selective inhibitor of MAO-A an is now approved in over 50 countries world wide. Subsequent research found that moclobemide is well tolerated in elderly patients and far superior to tricyclic antidepressants in terms of side effects/tolerability as well as being much safer in overdose; with regard to effectiveness in the treatment of depression, moclobemide was determined to be as effective as all major antidepressant drug classes. There is no need for dietary restrictions in contrast to people on irreversible MAOIs and apart from an important interaction with other serotonergic enhancing agents such as SSRIs and pethidine, there are few serious drug interactions; because of these benefits of moclobemide over existing antidepressant drugs, moclobemide became regarded as a beneficial addition to medical 'prescribing arsenal'. Additionally moclobemide was found to, unlike most other antidepressants on the market, to actually improve all aspects of sexual function. It is the only reversible MAOI in use in clinical practice. The fact that moclobemide's pharmacokinetic properties are unaltered by age, that cognition is improved in the elderly, and moclobemide has low potential for food and drug interactions opened up a new avenue for the treatment of major depressive disorder. Due to a lack of financial incentive, such as the costs of conducting the necessary trials to gain approval, moclobemide is unavailable in the USA pharmaceutical market. | Moclobemide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Moclobemide (sold as Amira, Aurorix,[7] Clobemix , Depnil and Manerix[8]) is a reversible monoamine oxidase inhibitor (MAOI) drug primarily used to treat depression and social anxiety.[9][10][11] It is not approved for use in the United States,[12] but is approved in other Western countries such as the UK[11] and Australia (TGA approved in December 2000).[13] It is produced by affiliates of the Hoffmann–La Roche pharmaceutical company. Initially, Aurorix was also marketed by Roche in South Africa, but was withdrawn after its patent rights expired and Cipla Medpro's Depnil and Pharma Dynamic's Clorix became available at half the cost.
No significant rise in blood pressure occurs when moclobemide is combined with amines such as tyramine containing foods or pressor amine drugs, unlike the older non-selective irreversible MAOIs which cause a severe rise in blood pressure with such combination.[9] Due to the lack of anticholinergic, cardiovascular, cognitive and psychomotor impairments moclobemide is advantageous in the elderly as well as those with cardiovascular disease.[9]
# Medical uses
Reversible selective MAOIs such as moclobemide are widely underprescribed due to the misconception that the side effect profile of moclobemide is analogous to that of the irreversible and non-selective MAOIs.[14] MAOIs such as moclobemide are reported to have a relatively fast onset of action compared to other antidepressant drug classes,[15] and have good long-term tolerability in terms of side effects.[16]
Tolerance does not seem to occur; research has found that moclobemide retains its beneficial therapeutic properties in depression for at least a year.[17]
- Unipolar depression. Moclobemide has demonstrated effectiveness and efficacy in the treatment and management of major depressive disorder,[18] with both endogenous and non-endogenous depression responding; in addition moclobemide has a fast onset of action compared to other antidepressants and is significantly more tolerable than the tricyclic antidepressants.[19] Due to a very good safety profile and very low incidence of side effects moclobemide is likely to have a high level of acceptability by individuals suffering from depression.[20] Higher doses (>450 mg/day) may be more effective in severe depression, while patients treated with a lower dose tend to respond less well than those treated with tricyclic antidepressants.[21]
- Bipolar depression. While not generally recommended as a monotherapy for bipolar depression (as with all antidepressants) in one clinical trial it appeared (although statistical significance at the p=0.05 was not reached) as though moclobemide was equally effective as imipramine at reducing depressive symptoms, but had a significantly lower risk of causing a manic switch.[30] This is in line with recent findings that MAOIs as a class are superior to other antidepressants (in terms of both their relatively low rate of manic switching and their efficacy) in the treatment of bipolar depression.[31]
- Dysthymia; moclobemide has been found to be effective in the treatment and management of this depressive disorder.[32]
- Social phobia. Moclobemide has been found to be effective for the treatment of social anxiety disorder in both short and long-term placebo controlled clinical trials.[33] Moclobemide is effective but not as effective as the irreversible MAOIs in the treatment of social phobia.[34] Maximal benefits can take 8 – 12 weeks to manifest.[35] There is a high risk of treatment failure if there is co-morbid alcohol abuse, however.[36] The Australian Medicines Handbook lists social phobia as an accepted but not a licensed indication.[10]
- Smoking cessation. Moclobemide has been tested in heavy dependent smokers against placebo based on the theory that tobacco smoking could be a form of self-medicating of major depression,[37] and moclobemide could therefore help increase abstinence rates due to moclobemide mimicking the MAO-A inhibiting effects of tobacco smoke. Moclobemide was administered for 3 months and then stopped; at 6 months follow-up it was found those who had taken moclobemide for 3 months had a much higher successful quit rate than those in the placebo group. However, at 12-month follow-up the difference between the placebo group and the moclobemide group was no longer significant.[38]
- Panic disorder. Moclobemide is useful in the treatment and management of panic disorder.[39] Panic disorder is mentioned as an accepted but unlicensed indication in the Australian Medicines Handbook.[10]
- ADHD. Two small studies assessing the benefit of moclobemide in people with attention deficit disorder found that moclobemide produced favourable results.[22]
- Fibromyalgia, moclobemide has been found to improve pain and functioning in this group of people.[40]
- Migraine. Moclobemide has been reported to be effective in the treament of migraine and chronic tension headache.[41][42]
Similar to other MAOIs, reversible MAOIs such as moclobemide may also be effective in a range of other psychiatric disorders.[22][43] Menopausal flushing may also respond to moclobemide.[44] Moclobemide may also have benefit for some patients with Parkinson's Disease by extending and enhancing the effects of l-dopa.[45]
In efficacy studies for the treatment of major depressive disorder, moclobemide has been found to be significantly more effective than placebo, as effective as the tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs), and somewhat less effective than the older, irreversible MAOIs phenelzine and tranylcypromine. In terms of tolerability, however, moclobemide was found to be comparable to the SSRIs and better tolerated than the TCAs and older MAOIs.[12] There is some evidence that moclobemide on its own or in combination with other antidepressants such as SSRIs is also effective for treatment resistant depression and that the combination can be administered without the development of serotonin syndrome; however, further research is needed before such a combination can be recommended.[9][46] Follow-up studies show that ongoing use of antidepressants leads to continuing improvement in depression over time; and also have demonstrated that moclobemide retains its therapeutic efficacy as an antidepressant for at least a year. This long-term efficacy is equivalent to that seen with other antidepressant classes.[14]
People on irreversible MAOIs have to discontinue these antidepressants two weeks before general anesthesia, however, the use of moclobemide due to its reversible nature, would allow such patients to possibly continue antidepressant therapy.[47][48]
A dexamethasone suppression test (DST) and plasma and urine methoxyhydroxyphenylglycol (MHPG) test can be used to estimate who is likely to respond to moclobemide antidepressant therapy.[49]
## Pregnancy and lactation
The doses of moclobemide in breast milk are very low (0.06% of moclobemide being recovered in breast milk) and therefore it has been concluded that moclobemide is unlikely to have any adverse effect on a suckling baby.[8]
## Children
Use in children is not recommended as there is insufficient data to assess their safety and efficacy in these patients.[10][11]
## Elderly
Reversible MAOIs such as moclobemide may have advantages in the treatment of depression associated with Alzheimer's disease due to its effect on noradrenaline.[50] Cognitive impairments have been found to improve in people with dementia when depression is treated with moclobemide.[22] Due to its superior safety profile, moclobemide has been recommended as a first line agent for the treatment of depression in the elderly.[51] Due to the side effect profile of moclobemide, it may be a better option for this sub group of people than other antidepressants.[52] Research has found evidence that moclobemide may be able to counter cholinergic induced cognitive impairments thus making moclobemide a good choice in the depression in the elderly and those with dementia.[53]
# Adverse effects
The incidence of adverse events is not correlated with age; however, adverse events occur more often in females than in males.[54] Moclobemide is regarded as a generally safe antidepressant and due to its favorable side effect profile, it can be considered a first-line therapeutic antidepressant.[55] Side effects of moclobemide are exceptionally low,[20] with insomnia, headache and dizziness being the most commonly reported side effects in the initial stages of therapy with moclobemide.[56] Many antidepressants have an adverse effect on sexual function; however, treatment with moclobemide has actually been found to improve sexual function.[57] Moclobemide does not have any adverse effect on cognitive abilities, thus there are no impairments of moclobemide therapy on memory, attention functions nor is ability to drive a motor vehicle affected adversely.[58] In fact, moclobemide has been found to improve cognition, especially memory; this is relevant with regard to the elderly as adverse effects on cognition are of particular concern in this population. People with dementia and comorbid depression also show improvements in cognitive impairments; these improvements are unrelated to alleviation of depression. Alcohol related cognitive impairments are also improved by moclobemide. Improvements in cognition also occur in young depressed people after 6 weeks of treatment. There is a mild impairment in psychometric performance in elderly people but none in younger people. Moclobemide, even at high doses of 600 mg, does not impair the ability to drive a motor vehicle.[8][59] The tolerability of moclobemide is similar in women and men and it is also well tolerated in the elderly.[60] Moclobemide is tolerated to a similar degree to the SSRI antidepressants, although unlike SSRIs moclobemide does not cause sexual dysfunction and gastrointestinal disturbance is less common. Moclobemide has been found to be superior to tricyclic and irreversible MAOI antidepressants in terms of side effects, as it does not cause anticholinergic, sedative or cardiovascular adverse effects[9] as well as not causing weight gain.[59]
Unlike the irreversible MAOIs there is no evidence of liver toxicity with moclobemide.[61] Moclobemide has a similar efficacy profile compared to other antidepressants but is significantly superior to the tricyclic antidepressants and the classic (unselective or irreversible) MAOIs, in terms of tolerance and safety profile.[62] Moclobemide has little effect on psychomotor functions.[63] Other side effects include, nausea, insomnia, tremor and lightheadedness; orthostatic hypotension is uncommon even among the elderly.[12] Behavioural toxicity or other impairments relating to everyday living does not occur with moclobemide, except in doses of 400 mg or higher, peripheral reaction time may be impaired.[64] Peripheral oedema has been associated with moclobemide.[65]
Most of the side effects are transient disappearing within 2 weeks of treatment.[66] tiredness, headache, restlessness, nervousness and sleep disturbances have been described as side effects from moclobemide therapy.[67] A paradoxical worsening of depression has been reported in some individuals in several studies,[68] and reports of suicidal ideation and suicide as an adverse effect have been reported as a rare adverse effect of moclobemide.[69] Overall, antidepressants decrease the risk of suicide.[70] Moclobemide is believed to have only small proconvulsant effects;[71] however, rarely seizures may occur.[72] Hypertension, has been reported to occur very rarely with moclobemide therapy.[12]
Moclobemide is relatively well tolerated. The following are the potential adverse effects and their respective incidences:[13][73]
- Nausea
- Dry mouth
- Constipation
- Diarrhoea
- Insomnia
- Dizziness
- Anxiety
- Restlessness
- Difficulties falling asleep
- Nightmares/dreams
- Hallucinations
- Memory disturbances,
- Confusion
- Disorientation
- Delusions
- Increased depression
- Excitation/irritability
- Hypomania
- Mania
- Aggressive behaviour
- Apathy
- Tension
- Suicidal ideation
- Suicidal behaviour
- Migraine
- Extrapyramidal effects
- Tinnitus
- Paraesthesia
- Dysarthria
- Heartburn
- Gastritis
- Meteorism
- Indigestion
- Hypertension
- Bradycardia
- Extrasystoles
- Angina/chest pain
- Phlebetic symptoms
- Flushing
- Exanthema/rash
- Allergic skin reaction
- Itching
- Gingivitis
- Stomatitis
- Dry skin
- Conjunctivitis
- Pruritus
- Urticaria
- Disturbances of micturition (dysuria, polyuria, tenesmus)
- Metrorrhagia
- Prolonged menstruation
- General malaise
- Skeletal/muscular pain
- Altered taste sensations
- Hot flushes/cold sensation
- Photopsia
- Dyspnoea
- Visual disturbances
- Increased hepatic enzymes without associated clinical sequelae.
## Contraindications
Avoid use in:[10]
- Confusional states
- Bipolar disorder (although it seems less likely than imipramine to cause a manic switch[30])
- Phaeochromocytoma
and caution is recommended in:[11]
- Agitated/excited patients
- Thyrotoxicosis
## Interactions
Moclobemide has fewer interactions than irreversible MAOIs. Cimetidine, however, causes a significant rise in moclobemide levels and therefore if the combination is used, lower doses of moclobemide have been recommended.[74] There is little increase in the effects of alcohol when combined with moclobemide[74] and, in fact, moclobemide causes a reduction in alcohol-related impairments.[63] Moclobemide also interacts with pethidine/meperidine,[75] and dextropropoxyphene.[62] Ephedrine in combination with moclobemide increases the risk of cardiovascular adverse effects.[76] Moclobemide is also likely to interact with warfarin.[77]
Serotonin syndrome has been reported when moclobemide has been taken in combination with other serotonin enhancing drugs; however, due to moclobemide's reversible MAO inhibition, serotonin syndrome is significantly less likely to occur with moclobemide than with older irreversible MAOIs.[10][78][79] Serotonin syndrome has been reported when trazodone was abruptly replaced with moclobemide.[80] Taking at the same time or starting moclobemide too soon after discontinuing clomipramine, or other serotonin reuptake inhibitors, such as SSRIs may result in the development of a serotonin syndrome.[62][81] SNRIs, such as venlafaxine in combination with moclobemide have also been associated with serotonin syndrome.[82] Cimetidine, causes a doubling of the blood plasma levels of moclobemide.[8] Blood plasma levels of trimipramine and maprotiline and possibly other tricyclic antidepressants increase when used in combination with moclobemide and may require dosage adjustments if the combination is used for treatment resistant depression.[83] The elimination of zolmitriptan is reduced by moclobemide and if the combination is used, a dosage reduction of zolmitriptan is recommended.[84] Moclobemide reduces the metabolism of dextromethorphan.[85]
Irreversible MAOIs can cause unpleasant and occasionally dangerous side effects such as a hypertensive crises after intake of food or drink containing indirectly acting sympathomimetic amines such as tyramine. This is sometimes referred to as the 'cheese effect'. These side effects are due to irreversible inhibition of MAO in the gut and vasomotor neurones. However, the reversible MAOI antidepressants such as moclobemide have a very different side effect profile in this regard.[8] The reversible binding to MAO-A by moclobemide allows amines such as tyramine to displace moclobemide from MAO-A allowing its metabolism and removing the risk of a hypertensive crisis that occurs with irreversible MAO inhibition.[86] Of 2300 people in multiple clinical trials who were treated with moclobemide in doses up to 600 mg with no dietary restrictions, none experienced a tyramine-mediated hypertensive reaction.[60] As the pressor effect of moclobemide is so low, dietary restrictions are not necessary in people eating a normal diet, in contrast to irreversible MAOIs.[9] However, some rare cheeses that have a high tyramine level may possibly cause a pressor effect and require caution.[87] The potentiation of the pressor effect of tyramine by moclobemide is only one seventh to one tenth of that of irreversible MAOIs.[88] In order to minimize this potentiation, postprandial administration (taken after meals) of moclobemide is recommended.[8] The combined use of moclobemide and selegiline requires dietary restrictions as the combination can lead to increased sensitivity to the pressor effect of foods containing tyramine.[89]
The combination of moclobemide with prescription or over the counter sympathomimetic drugs is not recommended due to the potential of significant drug interactions.[90] While moclobemide or the irreversible MAO-B selective inhibitor selegiline taken alone has very little pressor effect, and requires no dietry restriction, the combination of seligiline with moclobemide leads to a significant enhancement of the pressor effect and such a combination requires dietary restriction of foods containing high amounts of tyramine.[91] The combination of moclobemide and a reversible MAO-B inhibitor requires tyramine dietary restrictions.[92]
## Overdose
Moclobemide is considered to be less toxic in overdose compared to older antidepressants, such as the tricyclic antidepressants and nonselective, irreversible MAO inhibitors,[9] making it a safer antidepressant in the elderly or people with physical disorders.[59] Of 18 people who overdosed on moclobemide during clinical trials, all recovered fully and moclobemide was judged to be safe for in as well as outpatient use.[93] Intoxications with moclobemide as single agent are usually mild; however, when combined with tricyclic or SSRI antidepressants the overdose much more toxic and potentially fatal.[94][95] Moclobemide, is preferred by doctors for patients who are at risk of suicide, due to moclobemide's low toxicity in overdose.[96] Patients with mixed intoxications (e.g. with other CNS active drugs) may show severe or life-threatening symptoms and should be hospitalized. Treatment is largely symptomatic and should be aimed at maintenance of the vital functions.
## Withdrawal and tolerance
Withdrawal symptoms appear to be very rare with moclobemide compared to other antidepressants; a single report of relatively mild flu-like symptoms persisting for 7 days after rapid reduction of high dose mocloemide therapy has been reported in one patient.[97] Withdrawal of moclobemide causes a rebound in REM Sleep.[8]
Moclobemide does not prevent withdrawal symptoms from serotonin reuptake inhibitors.[98]
Discontinuation of moclobemide is recommended to be done gradually to minimise side effects (e.g. rapid return of condition being treated and/or the appearance of withdrawal symptoms). Tolerance to the therapeutic effects has been reported in a small number of users of MAOIs including moclobemide.[14]
# Pharmacology
Moclobemide is a benzamide,[12] derivative of morpholine,[99] which acts pharmacologically as a selective, reversible inhibitor of monoamine oxidase A (RIMA),[9] a type of monoamine oxidase inhibitor (MAOI), and increases levels of norepinephrine (noradrenaline), dopamine, and especially serotonin.[100][101] in neuronal cells as well as in synaptic vesicles; extracellular levels also increase which results in increased monoamine receptor stimulation and suppression of REM sleep, down regulation of 3-adrenoceptors. A single 300 mg dose of moclobemide inhibits 80% of monoamine oxidase A (MAO-A) and 30% of monoamine oxidase B (MAO-B), blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. There is also some evidence pointing towards moclobemide possessing neuroprotective properties.[8] There is no cumulative effect of moclobemide centrally when taken long-term.[8] With long-term use of moclobemide, there is a significant down-regulation of B-adrenoceptors.[8] Single or repeated dosing with 100–300 mg of moclobemide leads to a reduction in deaminated metabolites of amines such as 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxyphenylethylglycol as well as 5-HIAA. Excretion of homovanillic acid and vanillylmandelic acid via urine is also reduced. There is also a temporary increase in prolactin during initial intake of 100–300 mg of moclobemide.[8] L-dihydroxyphenylalanine is also reduced.[102] However, suppression of the serotonin metabolite is less pronounced than the inhibition of the metabolite of noradrenaline which suggest there are other major metabolic pathways for serotonin other than MAO-A.[103]
It has been described as a 'slow binding inhibitor', whereby conformational changes to either moclobemide or the enzyme to MAO-A slowly form a more tightly bound complex, resulting in the non-competitive MAO inhibition by moclobemide.[8] With three times daily dosing the inhibition on MAO-A was relatively constant with moclobemide.[104] The MAO inhibition of moclobemide lasts about 8–10 hours and wears off completely by 24 hours after dosing.[8][101] The inhibition of MAO-A by moclobemide is 10 times more potent than the irreversible MAOIs phenelzine and approximately equivalent to tranylcypromine and isocarboxazid.[8]
Moclobemide increases levels of extracellular monoamines and decreases levels of their metabolites in rat brains; tolerance to these effects does not seem to occur with chronic use of moclobemide. Moclobemide lacks anticholinergic effects and cognitive impairments can be improved by moclobemide.[105] Moclobemide suppresses the unstimulated release of certain proinflammatory cytokines which are believed to be involved in the pathophysiology of major depression and stimulates the release of anti-inflammatory cytokines.[106] Long-term treatment with moclobemide leads to an increase in cyclic adenosine monophosphate (cAMP) binding to cAMP-dependent protein kinase (PKA).[107]
Moclobemide is chemically unrelated to irreversible MAOI antidepressants and only has a very weak pressor effect of orally administered tyramine.[108] In humans, the n-oxide metabolites of moclobemide and moclobemide itself are the compounds that produce most of the inhibition of MAO-A; other metabolites are significantly less potent than the parent compound.[8]
In healthy people moclobemide has a relatively small suppressing effect on REM sleep; in contrast, depressed people who have been treated with moclobemide, progressively show improved sleep over a 4-week period, with an increase in stage 2 non-rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep.[8] There have been conflicting findings with regard to moclobemide altering cortisol levels and whether moclobemide increases growth hormone levels.[8] Testosterone levels increase significantly with long-term use of moclobemide in depressed males.[109]
Moclobemide also has neuroprotective properties in its demonstrated anti-hypoxia or anti-ischemia effects; there is a possibility that moclobemide may possess similar neuro-rescuing properties, similar to selegiline, however, research is required to determine this.[8] Moclobemide has also been demonstrated in a single dose research study to possess antinociceptive properties.[110]
Platelet MAO is of the MAO-B and this is inhibited only to a small degree in humans; the inhibition is due to low levels of metabolites of moclobemide that have MAO-B inhibiting properties.[111] Moclobemide has been reported to be a mixed MAO-A/MAO-B inhibitor in rats but in man, it has been reported to be a pure MAO-A inhibitor,[112] blocking the decomposition of norepinephrine, serotonin and, to a lesser extent, dopamine. No reuptake inhibition of any of the neurotransmitters occurs. The pharmacodynamic action encompasses activation, elevation of mood, and improvement of symptoms like dysphoria, fatigue, and difficulties in concentration. The duration and quality of sleep may be improved. In the treatment of depression the antidepressant effect often becomes evident in the first week of therapy (earlier than typically noted with TCAs/SSRIs).
As MAO inhibition returns completely back to normal after 24 hours, which allows for changing to another antidepressant within 24 hours of the last dose taken of moclobemide.[8]
# Pharmacokinetics
In humans moclobemide is rapidly and almost completely absorbed and totally metabolised via the liver.[113] Peak plasma levels occur 0.3 to 2 hours after oral administration. The bioavailability increases during the first week of therapy from 60% to 80% and more. The elimination half-life is around 2 hours.[8][114] It is moderately bound to plasma proteins, especially albumin.[8] However, the short disposition half life somewhat increases after repeated dosing; moclobemide has an intermediate elimination half life for systemic clearance and an intermediate volume of distribution.[113] Despite its short half-life the pharmacodynamic action of a single dose persists for approximately 16 hours. The drug is almost completely metabolized in the liver; it is a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6 and CYP1A2.[115] Less than 1 percent of the drug is excreted unchanged; 92 percent of the metabolised drug is excreted within the first 12 hours.[116] The main metabolites are the N-oxide Ro 12-5637 formed via morpholine N-oxidation and lactam derivative Ro 12-8095 formed via morpholine C-oxidation;[117][118] active metabolites are found only in trace amounts. The unchanged drug (less than 1%) as well as the metabolites are excreted renally (in urine). The main degradation pathway of moclobemide is oxidation.[119] About 44 percent of the drug is lost due to the first pass effect through the liver.[120] Age and renal function do not affect the pharmacokinetics of moclobemide. However, patients with significantly reduced liver function require dose reductions due to the significant slowing of metabolism of moclobemide.[121] Food slows the absorption but does not affect the bioavailability of moclobemide.[8]
Steady state concentrations are established after one week.[113] It has been suggested that changes in dose should not be made with a gap of no less than a week.[122] Moclobemide has good penetration across the blood brain barrier with peak plasma levels within the central nervous system occurring 2 hours after administration.[123]
# Animal toxicology
- Acute toxicity: The oral Template:LD50 values in mouse and rat are quite high, indicating a wide therapeutic index. LD50 for mice is 730 mg/kg and for rats 1,300 mg/kg. In dogs doses in excess of 300 mg/kg led to vomiting, salivation, ataxia, and drowsiness.
- Chronic toxicity: In an 18-months-study in rats with 10 mg/kg no signs of chronic toxicity were noted, with 50 mg/kg and 250 mg/kg only a slight loss of weight, and with 250 mg/kg mildly elevated Alkaline phosphatase and Gamma-GT. Studies in dogs revealed no toxicity relevant for humans. No evidence for a possible hepatic or cardiovascular toxicity was found.
# History
Irreversible MAOI antidepressants were discovered accidentally in the 1950s but their popularity declined as their toxicity especially their dangerous food interactions became apparent and rival the tricyclic antidepressants were discovered. Reversible MAOIs were developed in the hope that they would exert efficacy in depressive disorders but with less of the toxicity of the older irreversible compounds; moclobemide's discovery and marketing brought the renewed interest in MAOIs due to an absence of dangerous tyramine food interactions and potent antidepressant effects.[16][124] In 1992 moclobemide was launched onto the world markets.[125] Moclobemide was the first reversible MAO-A inhibitor to be widely marketed;[126] Moclobemide as well as other newer antidepressants such as the SSRIs lead to changes in prescribing patterns and broadened the treatment options for the management of depressive disorders.[127]
The discovery of moclobemide in 1972 in Switzerland,[12] as an antidepressant came about after it was initially investigated as a possible lipid lowering drug or antibiotic; when tests failed to demonstrate any antibiotic or antilipaemic properties; it was then tested for anti-cholinergic properties to see if it was a possible antidepressant but these tests also proved negative, leading researchers to think it may, in fact, be an antipsychotic; finally its reversible MAO-A properties as well as its lack of tyramine pressor effect. Clinical trials were commenced for moclobemide's effectiveness in the treatment of depression.[128] It was first approved in the UK and Europe as the first reversible and selective inhibitor of MAO-A an is now approved in over 50 countries world wide.[12] Subsequent research found that moclobemide is well tolerated in elderly patients[129] and far superior to tricyclic antidepressants in terms of side effects/tolerability as well as being much safer in overdose; with regard to effectiveness in the treatment of depression, moclobemide was determined to be as effective as all major antidepressant drug classes. There is no need for dietary restrictions in contrast to people on irreversible MAOIs and apart from an important interaction with other serotonergic enhancing agents such as SSRIs and pethidine, there are few serious drug interactions; because of these benefits of moclobemide over existing antidepressant drugs, moclobemide became regarded as a beneficial addition to medical 'prescribing arsenal'.[79][130] Additionally moclobemide was found to, unlike most other antidepressants on the market, to actually improve all aspects of sexual function.[131] It is the only reversible MAOI in use in clinical practice.[8] The fact that moclobemide's pharmacokinetic properties are unaltered by age, that cognition is improved in the elderly, and moclobemide has low potential for food and drug interactions opened up a new avenue for the treatment of major depressive disorder.[8] Due to a lack of financial incentive, such as the costs of conducting the necessary trials to gain approval, moclobemide is unavailable in the USA pharmaceutical market.[12] | https://www.wikidoc.org/index.php/Moclobemide | |
b147f17a706ddfcb872cef82da07c934f274a716 | wikidoc | Modal logic | Modal logic
In formal logic, a modal logic is any logic for handling modalities: concepts like possibility, existence, and necessity. Logics for handling a number of other ideas, such as eventually, formerly, can, could, might, may, must are by extension also called modal logics, since it turns out that these can be treated in similar ways.
A formal modal logic represents modalities using unary modal operators. For example, "Jones's murder was a possibility"; "Jones was possibly murdered"; and "It is possible that Jones was murdered," all contain the notion of possibility; in a modal logic this is represented as an operator, Possibly, attaching to the sentence Jones was murdered.
The basic modal operators are usually written \Box (or L) for Necessarily and \Diamond (or M) for Possibly. In a classical modal logic, each can be expressed by the other and negation:
Thus it is possible that Jones was murdered if and only if it is not necessary that Jones was not murdered.
# Alethic modalities
Necessity and possibility are sometimes called special modalities, from the Latin species. Modal logic was first developed to deal with these concepts, and only afterward was extended to others. For this reason, or perhaps for their familiarity and simplicity, necessity and possibility are often casually treated as the subject matter of modal logic.
A proposition is said to be
- possible if it is not necessarily false (regardless of whether it actually is true or false);
- necessary if it is not possibly false;
- contingent if it is not necessarily false but not necessarily true either. In formal contexts, therefore, contingency refers to a limited case of possibility.
## Logical necessity
There are a number of different alethic modalities: logical possibility is, perhaps, the weakest, since almost anything intelligible is logically possible: Possibly, pigs can fly, Elvis is still alive, and the atomic theory of matter is false.
Likewise, almost nothing is logically impossible: something logically impossible is called a contradiction or a logical falsehood. It is possible that Elvis is alive; but it is impossible that Elvis is alive and is not alive, regardless of what Schrödinger might say. Many logicians also hold that mathematical truths are logically necessary: it is impossible that 2+2 ≠ 4.
Something which is logically necessary is called a logical truth. For example, it is necessary that if Elvis is alive, then he is alive.
## Physical possibility
Something is physically possible if it is permitted by the laws of nature. For example, it is possible for there to be an atom with an atomic number of 150, though there may not in fact be one. On the other hand, it is not possible, in this sense, for there to be an element whose nucleus contains cheese. While it is logically possible to accelerate beyond the speed of light, it is not, according to modern science, physically possible for objects with mass.
## Metaphysical possibility
Philosophers ponder the properties objects have independently of those dictated by scientific laws. For example, it might be metaphysically necessary, as some have thought, that all thinking beings have bodies and can experience the passage of time, or that God exists (or does not exist). Saul Kripke has argued that every person necessarily has the parents they do have: anyone with different parents wouldn't be the same person.
Metaphysical possibility is generally thought to be stronger than bare logical possibility (i.e., fewer things are metaphysically possible than are logically possible). Its exact relation to physical possibility is a matter of some dispute. Philosophers also disagree over whether metaphysical truths are necessary merely "by definition", or whether they reflect some underlying deep facts about the world, or something else entirely.
## Confusion with epistemic modalities
Alethic modalities and epistemic modalities (see below) are often expressed in English using the same words. Thus, "It is possible that bigfoot exists" might mean either "It would be possible for such a creature as a bigfoot to exist," or (more likely), "As far as I know, there may be some bigfoots."
In the former case, the speaker might know that there are not any bigfoots, but is saying that (unlike round squares), there could be some – the existence of bigfoot is not impossible. In the latter case he is saying that there may well be some "right now".
# Epistemic logic
Epistemic modalities (from the Greek episteme, knowledge), deal with the certainty of sentences. The operators are translated as "It is certainly true that..." and "It may (given the available information) be true that..." In ordinary speech both modalities are often expressed in similar words; the following contrasts may help:
A person, Jones, might reasonably say both: (1) "No, it is not possible that Bigfoot exists; I am quite certain of that;" and, (2) "Sure, Bigfoot possibly could exist." What Jones means by (1) is that given all the available information, there is no question remaining as to whether Bigfoot exists. This is an epistemic claim. By (2) he means that things might have been otherwise. He does not mean "it is possible that Bigfoot exists – for all I know." (So he is not contradicting (1).) Rather, he is making the metaphysical claim that it's possible for Bigfoot to exist, even though he doesn't.
From the other direction, Jones might say, (3) "It is possible that Goldbach's conjecture is true; but also possible that it is false," and also (4) "if it is true, then it is necessarily true, and not possibly false." Here Jones means that it is epistemically possible that it is true or false, for all he knows (Goldbach's conjecture has not been proven either true or false). But if there is a proof (heretofore undiscovered), then that would show that it is not logically possible for Goldbach's conjecture to be false—there could be no set of numbers that violated it. Logical possibility is a form of alethic possibility; (4) makes a claim about whether it is possible for a mathematical truth to have been false, but (3) only makes a claim about whether it is possible that the mathematical claim turns out false, for all Jones knows, and so again Jones does not contradict himself. It is worthwhile to observe that Jones is not necessarily correct: It is possible (epistemically) that Goldbach's conjecture is both true and unprovable.
Epistemic possibilities also bear on the actual world in a way that metaphysical possibilities do not. Metaphysical possibilities bear on ways the world might have been, but epistemic possibilities bear on the way the world may be (for all we know). Suppose, for example, that I want to know whether or not to take an umbrella before I leave. If you tell me "It is possible that it is raining outside" – in the sense of epistemic possibility – then that would weigh on whether or not I take the umbrella. But if you just tell me that "It is possible for it to rain outside" – in the sense of metaphysical possibility – then I am no better off for this bit of modal enlightenment.
# Temporal logic
There are several analogous modes of speech, which though less likely to be confused with alethic modalities are still closely related. One is talk of time. It seems reasonable to say that possibly it will rain tomorrow, and possibly it won't; on the other hand, if it rained yesterday, if it really already did so, then it cannot be quite correct to say "It may not have rained yesterday." It seems the past is "fixed," or necessary, in a way the future is not. This is sometimes referred to as accidental necessity.
A standard method for formalizing talk of time is to use two pairs of operators, one for the past and one for the future. For the past, let "It has always been the case that . . ." be equivalent to the box, and let "It was once the case that . . ." be equivalent to the diamond. For the future, let "It will always be the case that . . ." be equivalent to the box, and let "it will eventually be the case that . . ." be equivalent to the diamond. If these two systems are used together, it will, obviously, be necessary to indicate, as by subscripts, which box is which.
Additional binary operators are also relevant to temporal logics, q.v. Linear Temporal Logic.
# Deontic logic
Likewise talk of morality, or of obligation and norms generally, seems to have a modal structure. The difference between "You must do this" and "You may do this" looks a lot like the difference between "This is necessary" and "This is possible." Such logics are called deontic, from the Greek for "duty".
# Other modal logics
Significantly, modal logics can be developed to accommodate most of these idioms; it is the fact of their common logical structure (the use of "intensional" or non-truth-functional sentential operators) that make them all varieties of the same thing. Epistemic logic is arguably best captured in the system "S4"; deontic logic in the system "D", temporal logic in "T" and alethic logic arguably with "S5".
# Interpretations of modal logic
In the most common interpretation of modal logic, one considers "all logically possible worlds". If a statement is true in all possible worlds, then it is a necessary truth. If a statement happens to be true in our world, but is not true in all possible worlds, then it is a contingent truth. A statement that is true in some possible world (not necessarily our own) is called a possible truth.
Whether this "possible worlds idiom" is the best way to interpret modal logic, and how literally this idiom can be taken, is a live issue for metaphysicians. For example, the possible worlds idiom would translate the claim about Bigfoot as "There is some possible world in which Bigfoot exists". To maintain that Bigfoot's existence is possible, but not actual, one could say, "There is some possible world in which Bigfoot exists; but in the actual world, Bigfoot does not exist". But it is unclear what it is that making modal claims commits us to. Are we really alleging the existence of possible worlds, every bit as real as our actual world, just not actual? David Lewis made himself notorious by biting the bullet, asserting that all merely possible worlds are as real as our own, and that what distinguishes our world as actual is simply that it is indeed our world – this world (see Indexicality). That position is a major tenet of "modal realism". Most philosophers decline to endorse such a view, considering it ontologically extravagant, and preferring to seek various ways to paraphrase away the ontological commitments implied by our modal claims.
# Formal rules
Many systems of modal logic, with widely varying properties, have been proposed since C. I. Lewis began working in the area in 1910. Hughes and Cresswell (1996), for example, describe 42 normal and 25 non-normal modal logics. Zeman (1973) describes some systems Hughes and Cresswell omit.
Modern treatments of modal logic begin by augmenting the propositional calculus with two unary operations, one denoting "necessity" and the other "possibility." The notation of Lewis, much employed since, denotes "necessarily p" by a prefixed "box" ( \Box p ) whose scope is established by parentheses. Likewise, a prefixed "diamond" (\Diamond p) denotes "possibly p." Regardless of notation, each of these operators is definable in terms of the other:
- \Box p (necessarily p) is equivalent to \neg \Diamond \neg p ("not possible that not-p")
- \Diamond p (possibly p) is equivalent to \neg \Box \neg p ("not necessarily not-p")
Hence \Box and \Diamond form a dual pair of operators.
In many modal logics, the necessity and possibility operators satisfy the following analogs of de Morgan's laws from Boolean algebra:
Precisely what axioms and rules must be added to the propositional calculus to create a usable system of modal logic is a matter of philosophical opinion, often driven by the theorems one wishes to prove. Many modal logics, known collectively as normal modal logics, include the following rule and axiom:
- N, Necessitation Rule: If p is a theorem (of any system invoking N), then \Box p is likewise a theorem.
- K, Distribution Axiom: \Box (p \rightarrow q) \rightarrow (\Box p \rightarrow \Box q).
The weakest normal modal logic, named K in honor of Saul Kripke, is simply the propositional calculus augmented by \Box , the rule N, and the axiom K. K is weak in that it fails to determine whether a proposition can be necessary but only contingently necessary. That is, it is not a theorem of K that if \Box p is true then \Box \Box p is true, i.e., that necessary truths are "necessarily necessary." If such perplexities are deemed forced and artificial, this defect of K is not a great one. In any case, different answers to such questions yield different systems of modal logic.
Adding axioms to K gives rise to other well-known modal systems. One cannot prove in K that if "p is necessary" then p is true. The axiom T remedies this defect:
- T, Reflexivity Axiom: \Box p \rightarrow p (If p is necessary, then p is the case.) T holds in most but not all modal logics. Zeman (1973) describes a few exceptions, such as S1^0.
Other well-known elementary axioms are:
- 4: \Box p \rightarrow \Box \Box p
- B: p \rightarrow \Box \Diamond p
- D: \Box p \rightarrow \Diamond p
- E: \Diamond p \rightarrow \Box \Diamond p.
These axioms yield the systems:
- K := K + N
- T := K + T
- S4 := T + 4
- S5 := S4 + B or T + E
- D := K + D.
K through S5 form a nested hierarchy of systems, making up the core of normal modal logic. D is primarily of interest to those exploring the deontic interpretation of modal logic.
The commonly employed system S5 simply makes all modal truths necessary. For example, if p is possible, then it is "necessary" that p is possible. Also, if p is necessary, then it is necessary that p is necessary. Although controversial, this is commonly justified on the grounds that S5 is the system obtained if every possible world is possible relative to every other world. Other systems of modal logic have been formulated, in part because S5 does not describe every kind of metaphysical modality of interest. This suggests that talk of possible worlds and their semantics may not do justice to all modalities.
# Development of modal logic
Although Aristotle's logic is almost entirely concerned with the theory of the categorical syllogism, there are passages in his work, such as the famous Sea-Battle Argument in De Interpretatione § 9, that are now seen as anticipations of modal logic and its connection with potentiality and time. Modal logic as a self-aware subject owes much to the writings of the Scholastics, in particular William of Ockham and John Duns Scotus, who reasoned informally in a modal manner, mainly to analyze statements about essence and accident.
C. I. Lewis founded modern modal logic in his 1910 Harvard thesis and in a series of scholarly articles beginning in 1912. This work culminated in his 1932 book Symbolic Logic (with C. H. Langford), which introduced the five systems S1 through S5. The contemporary era in modal logic began in 1959, when Saul Kripke (then only a 19 year old Harvard University undergraduate) introduced the now-standard Kripke semantics for modal logics. These are commonly referred to as "possible worlds" semantics. Kripke and A. N. Prior had previously corresponded at some length.
A. N. Prior created temporal logic, closely related to modal logic, in 1957 by adding modal operators and meaning "henceforth" and "hitherto." Vaughan Pratt introduced dynamic logic in 1976. In 1977, Amir Pnueli proposed using temporal logic to formalise the behaviour of continually operating concurrent programs. Flavors of temporal logic include propositional dynamic logic (PDL), propositional linear temporal logic (PLTL), linear temporal logic (LTL), computational tree logic (CTL), Hennessy-Milner logic, and T.
The mathematical structure of modal logic, namely Boolean algebras augmented with unary operations (often called "modal algebras"), began to emerge with J. C. C. McKinsey's 1941 proof that S2 and S4 are decidable, and reached full flower in the work of Alfred Tarski and his student Bjarni Jonsson (Jonsson and Tarski 1951-52). This work revealed that S4 and S5 are models of interior algebra, a proper extension of Boolean algebra originally designed to capture the properties of the interior and closure operators of topology. Texts on modal logic typically do little more than mention its connections with the study of Boolean algebras and topology. For a thorough survey of the history of formal modal logic and of the associated mathematics, see Goldblatt (2006). | Modal logic
In formal logic, a modal logic is any logic for handling modalities: concepts like possibility, existence, and necessity. Logics for handling a number of other ideas, such as eventually, formerly, can, could, might, may, must are by extension also called modal logics, since it turns out that these can be treated in similar ways.
A formal modal logic represents modalities using unary modal operators. For example, "Jones's murder was a possibility"; "Jones was possibly murdered"; and "It is possible that Jones was murdered," all contain the notion of possibility; in a modal logic this is represented as an operator, Possibly, attaching to the sentence Jones was murdered.
The basic modal operators are usually written <math>\Box</math> (or L) for Necessarily and <math>\Diamond</math> (or M) for Possibly. In a classical modal logic, each can be expressed by the other and negation:
Thus it is possible that Jones was murdered if and only if it is not necessary that Jones was not murdered.
# Alethic modalities
Necessity and possibility are sometimes called special modalities, from the Latin species. Modal logic was first developed to deal with these concepts, and only afterward was extended to others. For this reason, or perhaps for their familiarity and simplicity, necessity and possibility are often casually treated as the subject matter of modal logic.
A proposition is said to be
- possible if it is not necessarily false (regardless of whether it actually is true or false);
- necessary if it is not possibly false;
- contingent if it is not necessarily false but not necessarily true either. In formal contexts, therefore, contingency refers to a limited case of possibility.
## Logical necessity
There are a number of different alethic modalities: logical possibility is, perhaps, the weakest, since almost anything intelligible is logically possible: Possibly, pigs can fly, Elvis is still alive, and the atomic theory of matter is false.
Likewise, almost nothing is logically impossible: something logically impossible is called a contradiction or a logical falsehood. It is possible that Elvis is alive; but it is impossible that Elvis is alive and is not alive, regardless of what Schrödinger might say[1]. Many logicians also hold that mathematical truths are logically necessary: it is impossible that 2+2 ≠ 4.
Something which is logically necessary is called a logical truth. For example, it is necessary that if Elvis is alive, then he is alive.
## Physical possibility
Something is physically possible if it is permitted by the laws of nature. For example, it is possible for there to be an atom with an atomic number of 150, though there may not in fact be one. On the other hand, it is not possible, in this sense, for there to be an element whose nucleus contains cheese. While it is logically possible to accelerate beyond the speed of light, it is not, according to modern science, physically possible for objects with mass.
## Metaphysical possibility
Philosophers ponder the properties objects have independently of those dictated by scientific laws. For example, it might be metaphysically necessary, as some have thought, that all thinking beings have bodies and can experience the passage of time, or that God exists (or does not exist). Saul Kripke has argued that every person necessarily has the parents they do have: anyone with different parents wouldn't be the same person.
Metaphysical possibility is generally thought to be stronger than bare logical possibility (i.e., fewer things are metaphysically possible than are logically possible). Its exact relation to physical possibility is a matter of some dispute. Philosophers also disagree over whether metaphysical truths are necessary merely "by definition", or whether they reflect some underlying deep facts about the world, or something else entirely.
## Confusion with epistemic modalities
Alethic modalities and epistemic modalities (see below) are often expressed in English using the same words. Thus, "It is possible that bigfoot exists" might mean either "It would be possible for such a creature as a bigfoot to exist," or (more likely), "As far as I know, there may be some bigfoots."
In the former case, the speaker might know that there are not any bigfoots, but is saying that (unlike round squares), there could be some – the existence of bigfoot is not impossible. In the latter case he is saying that there may well be some "right now".
# Epistemic logic
Epistemic modalities (from the Greek episteme, knowledge), deal with the certainty of sentences. The operators are translated as "It is certainly true that..." and "It may (given the available information) be true that..." In ordinary speech both modalities are often expressed in similar words; the following contrasts may help:
A person, Jones, might reasonably say both: (1) "No, it is not possible that Bigfoot exists; I am quite certain of that;" and, (2) "Sure, Bigfoot possibly could exist." What Jones means by (1) is that given all the available information, there is no question remaining as to whether Bigfoot exists. This is an epistemic claim. By (2) he means that things might have been otherwise. He does not mean "it is possible that Bigfoot exists – for all I know." (So he is not contradicting (1).) Rather, he is making the metaphysical claim that it's possible for Bigfoot to exist, even though he doesn't.
From the other direction, Jones might say, (3) "It is possible that Goldbach's conjecture is true; but also possible that it is false," and also (4) "if it is true, then it is necessarily true, and not possibly false." Here Jones means that it is epistemically possible that it is true or false, for all he knows (Goldbach's conjecture has not been proven either true or false). But if there is a proof (heretofore undiscovered), then that would show that it is not logically possible for Goldbach's conjecture to be false—there could be no set of numbers that violated it. Logical possibility is a form of alethic possibility; (4) makes a claim about whether it is possible for a mathematical truth to have been false, but (3) only makes a claim about whether it is possible that the mathematical claim turns out false, for all Jones knows, and so again Jones does not contradict himself. It is worthwhile to observe that Jones is not necessarily correct: It is possible (epistemically) that Goldbach's conjecture is both true and unprovable.
Epistemic possibilities also bear on the actual world in a way that metaphysical possibilities do not. Metaphysical possibilities bear on ways the world might have been, but epistemic possibilities bear on the way the world may be (for all we know). Suppose, for example, that I want to know whether or not to take an umbrella before I leave. If you tell me "It is possible that it is raining outside" – in the sense of epistemic possibility – then that would weigh on whether or not I take the umbrella. But if you just tell me that "It is possible for it to rain outside" – in the sense of metaphysical possibility – then I am no better off for this bit of modal enlightenment.
# Temporal logic
There are several analogous modes of speech, which though less likely to be confused with alethic modalities are still closely related. One is talk of time. It seems reasonable to say that possibly it will rain tomorrow, and possibly it won't; on the other hand, if it rained yesterday, if it really already did so, then it cannot be quite correct to say "It may not have rained yesterday." It seems the past is "fixed," or necessary, in a way the future is not. This is sometimes referred to as accidental necessity.
A standard method for formalizing talk of time is to use two pairs of operators, one for the past and one for the future. For the past, let "It has always been the case that . . ." be equivalent to the box, and let "It was once the case that . . ." be equivalent to the diamond. For the future, let "It will always be the case that . . ." be equivalent to the box, and let "it will eventually be the case that . . ." be equivalent to the diamond. If these two systems are used together, it will, obviously, be necessary to indicate, as by subscripts, which box is which.
Additional binary operators are also relevant to temporal logics, q.v. Linear Temporal Logic.
# Deontic logic
Likewise talk of morality, or of obligation and norms generally, seems to have a modal structure. The difference between "You must do this" and "You may do this" looks a lot like the difference between "This is necessary" and "This is possible." Such logics are called deontic, from the Greek for "duty".
# Other modal logics
Significantly, modal logics can be developed to accommodate most of these idioms; it is the fact of their common logical structure (the use of "intensional" or non-truth-functional sentential operators) that make them all varieties of the same thing. Epistemic logic is arguably best captured in the system "S4"; deontic logic in the system "D", temporal logic in "T" and alethic logic arguably with "S5".
# Interpretations of modal logic
In the most common interpretation of modal logic, one considers "all logically possible worlds". If a statement is true in all possible worlds, then it is a necessary truth. If a statement happens to be true in our world, but is not true in all possible worlds, then it is a contingent truth. A statement that is true in some possible world (not necessarily our own) is called a possible truth.
Whether this "possible worlds idiom" is the best way to interpret modal logic, and how literally this idiom can be taken, is a live issue for metaphysicians. For example, the possible worlds idiom would translate the claim about Bigfoot as "There is some possible world in which Bigfoot exists". To maintain that Bigfoot's existence is possible, but not actual, one could say, "There is some possible world in which Bigfoot exists; but in the actual world, Bigfoot does not exist". But it is unclear what it is that making modal claims commits us to. Are we really alleging the existence of possible worlds, every bit as real as our actual world, just not actual? David Lewis made himself notorious by biting the bullet, asserting that all merely possible worlds are as real as our own, and that what distinguishes our world as actual is simply that it is indeed our world – this world (see Indexicality). That position is a major tenet of "modal realism". Most philosophers decline to endorse such a view, considering it ontologically extravagant, and preferring to seek various ways to paraphrase away the ontological commitments implied by our modal claims.
# Formal rules
Many systems of modal logic, with widely varying properties, have been proposed since C. I. Lewis began working in the area in 1910. Hughes and Cresswell (1996), for example, describe 42 normal and 25 non-normal modal logics. Zeman (1973) describes some systems Hughes and Cresswell omit.
Modern treatments of modal logic begin by augmenting the propositional calculus with two unary operations, one denoting "necessity" and the other "possibility." The notation of Lewis, much employed since, denotes "necessarily p" by a prefixed "box" ( <math>\Box p </math>) whose scope is established by parentheses. Likewise, a prefixed "diamond" (<math>\Diamond p</math>) denotes "possibly p." Regardless of notation, each of these operators is definable in terms of the other:
- <math>\Box p</math> (necessarily p) is equivalent to <math>\neg \Diamond \neg p </math> ("not possible that not-p")
- <math>\Diamond p </math> (possibly p) is equivalent to <math>\neg \Box \neg p </math> ("not necessarily not-p")
Hence <math>\Box</math> and <math>\Diamond</math> form a dual pair of operators.
In many modal logics, the necessity and possibility operators satisfy the following analogs of de Morgan's laws from Boolean algebra:
Precisely what axioms and rules must be added to the propositional calculus to create a usable system of modal logic is a matter of philosophical opinion, often driven by the theorems one wishes to prove. Many modal logics, known collectively as normal modal logics, include the following rule and axiom:
- N, Necessitation Rule: If p is a theorem (of any system invoking N), then <math>\Box p</math> is likewise a theorem.
- K, Distribution Axiom: <math> \Box (p \rightarrow q) \rightarrow (\Box p \rightarrow \Box q)</math>.
The weakest normal modal logic, named K in honor of Saul Kripke, is simply the propositional calculus augmented by <math> \Box </math>, the rule N, and the axiom K. K is weak in that it fails to determine whether a proposition can be necessary but only contingently necessary. That is, it is not a theorem of K that if <math> \Box p </math> is true then <math> \Box \Box p </math> is true, i.e., that necessary truths are "necessarily necessary." If such perplexities are deemed forced and artificial, this defect of K is not a great one. In any case, different answers to such questions yield different systems of modal logic.
Adding axioms to K gives rise to other well-known modal systems. One cannot prove in K that if "p is necessary" then p is true. The axiom T remedies this defect:
- T, Reflexivity Axiom: <math> \Box p \rightarrow p </math> (If p is necessary, then p is the case.) T holds in most but not all modal logics. Zeman (1973) describes a few exceptions, such as S1^0.
Other well-known elementary axioms are:
- 4: <math> \Box p \rightarrow \Box \Box p</math>
- B: <math> p \rightarrow \Box \Diamond p</math>
- D: <math> \Box p \rightarrow \Diamond p</math>
- E: <math> \Diamond p \rightarrow \Box \Diamond p.</math>
These axioms yield the systems:
- K := K + N
- T := K + T
- S4 := T + 4
- S5 := S4 + B or T + E
- D := K + D.
K through S5 form a nested hierarchy of systems, making up the core of normal modal logic. D is primarily of interest to those exploring the deontic interpretation of modal logic.
The commonly employed system S5 simply makes all modal truths necessary. For example, if p is possible, then it is "necessary" that p is possible. Also, if p is necessary, then it is necessary that p is necessary. Although controversial, this is commonly justified on the grounds that S5 is the system obtained if every possible world is possible relative to every other world. Other systems of modal logic have been formulated, in part because S5 does not describe every kind of metaphysical modality of interest. This suggests that talk of possible worlds and their semantics may not do justice to all modalities.
# Development of modal logic
Although Aristotle's logic is almost entirely concerned with the theory of the categorical syllogism, there are passages in his work, such as the famous Sea-Battle Argument in De Interpretatione § 9, that are now seen as anticipations of modal logic and its connection with potentiality and time. Modal logic as a self-aware subject owes much to the writings of the Scholastics, in particular William of Ockham and John Duns Scotus, who reasoned informally in a modal manner, mainly to analyze statements about essence and accident.
C. I. Lewis founded modern modal logic in his 1910 Harvard thesis and in a series of scholarly articles beginning in 1912. This work culminated in his 1932 book Symbolic Logic (with C. H. Langford), which introduced the five systems S1 through S5. The contemporary era in modal logic began in 1959, when Saul Kripke (then only a 19 year old Harvard University undergraduate) introduced the now-standard Kripke semantics for modal logics. These are commonly referred to as "possible worlds" semantics. Kripke and A. N. Prior had previously corresponded at some length.
A. N. Prior created temporal logic, closely related to modal logic, in 1957 by adding modal operators [F] and [P] meaning "henceforth" and "hitherto." Vaughan Pratt introduced dynamic logic in 1976. In 1977, Amir Pnueli proposed using temporal logic to formalise the behaviour of continually operating concurrent programs. Flavors of temporal logic include propositional dynamic logic (PDL), propositional linear temporal logic (PLTL), linear temporal logic (LTL), computational tree logic (CTL), Hennessy-Milner logic, and T.
The mathematical structure of modal logic, namely Boolean algebras augmented with unary operations (often called "modal algebras"), began to emerge with J. C. C. McKinsey's 1941 proof that S2 and S4 are decidable, and reached full flower in the work of Alfred Tarski and his student Bjarni Jonsson (Jonsson and Tarski 1951-52). This work revealed that S4 and S5 are models of interior algebra, a proper extension of Boolean algebra originally designed to capture the properties of the interior and closure operators of topology. Texts on modal logic typically do little more than mention its connections with the study of Boolean algebras and topology. For a thorough survey of the history of formal modal logic and of the associated mathematics, see Goldblatt (2006). | https://www.wikidoc.org/index.php/Modal_logic | |
54d760cfcf59eb0278f3ecb5ddbea76b523c59a4 | wikidoc | Mohr's salt | Mohr's salt
Mohr's Salt, or ammonium iron sulfate, is a double salt of iron sulfate and ammonium sulfate, with the formula 22·6H2O.
Mohr's salt is preferred over iron(II) sulfate for titration purposes as it is much less affected by oxygen in the air than iron(II) sulfate, solutions of which tend to oxidise to iron(III). The oxidation of solutions of iron(II) is very pH dependent, occurring much more readily at high pH. The ammonium ions make solutions of Mohr's salt slightly acidic, which prevents this oxidation from occurring. The relevant equation for this is:
The presence of protons keeps this equilibrium to the left, the Fe(II) side.
Mohr's salt is named after the German chemist Karl Friedrich Mohr, who made many important advances in the methodology of titration in the 19th century.
ar:كبريتات أمونيوم حديد ثنائي
de:Ammoniumeisen(II)-sulfat
nl:Mohr's zout | Mohr's salt
Template:Chembox new
Mohr's Salt, or ammonium iron sulfate, is a double salt of iron sulfate and ammonium sulfate, with the formula [NH4]2[Fe][SO4]2·6H2O.
Mohr's salt is preferred over iron(II) sulfate for titration purposes as it is much less affected by oxygen in the air than iron(II) sulfate, solutions of which tend to oxidise to iron(III). The oxidation of solutions of iron(II) is very pH dependent, occurring much more readily at high pH. The ammonium ions make solutions of Mohr's salt slightly acidic, which prevents this oxidation from occurring. The relevant equation for this is:
The presence of protons keeps this equilibrium to the left, the Fe(II) side.
Mohr's salt is named after the German chemist Karl Friedrich Mohr, who made many important advances in the methodology of titration in the 19th century.
ar:كبريتات أمونيوم حديد ثنائي
de:Ammoniumeisen(II)-sulfat
nl:Mohr's zout
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Mohr%27s_salt | |
33ae681976fadc0b440c0d7f7d7a31a40fb444e2 | wikidoc | Moisturizer | Moisturizer
Moisturizers or moisturisers (see spelling differences) are complex mixtures of chemical agents specially designed to make the external layers of the skin (epidermis) softer and more pliable, by increasing its hydration (water content). Naturally occurring skin lipids and sterols as well as artificial or natural oils, humectants, emollients, lubricants, etc. may be part of the composition of commercial skin moisturizers. They usually are available as commercial products for cosmetic and therapeutic uses, but can also be thrown together at home using common pharmacy ingredients.
Besides imparting or restoring normal levels of hydration to the skin, moisturizers can have several additional intended and unintended effects on their users, including building a barrier against the loss of water through the epidermis (skin), repairing scaly, damaged or dry skin resulting from external environmental aggressions or internal changes (such as in acne or naturally dry skin), repairing or postponing the aging effects on the skin, etc.
# Composition
Although simple and effective moisturisers can be prepared from two or three simple chemicals, such as stearate, olive oil, water and glycerin, commercial preparations are astoundingly complex and varied in composition and may include:
- Humectants, such as glycerin, urea, lactic acid and sorbitol;
- Natural moisturising factors (NMF) include low molecular weight substances such as ammonia, aminoacids, glucosamine, creatinine, citrate and ionic solutions such as sodium, potassium, chloride, phosphate, calcium and magnesium.
- Emollients, such as lanolin (the earliest complex organic substances used in facial and body moisturisers, which is extracted from wool). Lanolin acts as a barrier (occlusion effect) against loss of water and also as a softener of stratum corneum, by means of lubrication and smoothing. Other emollients are oil-water emulsions of varying composition and may include several esters and oils such as octyl dodecanol, hexyl decanol, oleyl alcohol,decyl oleate, isopropyl stearate, isopropyl palmitate, isopropyl myristate, hexyl laureate, and dioctyl cyclohexane.
- Emulsifier, preserving and fragrance agents are also part of commercial preparations.
Moisturisers are among the most used and prescribed products for the skin; unfortunately, the cosmetics industry often advertises loudly for scientifically unsubstantiated effects. Physicians, cosmeticians and consumers alike should be aware of the real science behind skin moisturisation, and know what is possible to achieve and what is not. For example, the addition of vitamins (A, B, C, D and E), nutritive agents, proteins and phytotherapeutic agents has been common in the industry, supposedly in order to add to the moisturiser the capability to treat several skin conditions such as cellulitis, age and photo damage, edema, loss of collagen, wrinkles, etc., with little or no scientific evidence for such.
# Adverse effects
Despite claims to the contrary by the cosmetics industry, complex moisturisers may cause a number of adverse effects, including allergic reactions to some of its components, skin irritation, contact dermatitis, characterised by redness, itching, burning and stinging sensations, or even may cause a contrary effect to the desired, i.e. they may actually increase dehydration. When used near sensitive spots, such as the eyes, lips and genitals, these effects may be exaggerated in some persons. Use of plant extracts, some alcohols and proteins may increase the danger of adverse effects. Cosmetic and therapeutic moisturisers should be accompanied by the printed formula in order to inform consumers adequately, as well as physicians, in order to easily and quickly identify the offending component.
# Reference
- Centurion, S.A. et al.: Moisturizers. eMedicine. | Moisturizer
Moisturizers or moisturisers (see spelling differences) are complex mixtures of chemical agents specially designed to make the external layers of the skin (epidermis) softer and more pliable, by increasing its hydration (water content). Naturally occurring skin lipids and sterols as well as artificial or natural oils, humectants, emollients, lubricants, etc. may be part of the composition of commercial skin moisturizers. They usually are available as commercial products for cosmetic and therapeutic uses, but can also be thrown together at home using common pharmacy ingredients.
Besides imparting or restoring normal levels of hydration to the skin, moisturizers can have several additional intended and unintended effects on their users, including building a barrier against the loss of water through the epidermis (skin), repairing scaly, damaged or dry skin resulting from external environmental aggressions or internal changes (such as in acne or naturally dry skin), repairing or postponing the aging effects on the skin, etc.
# Composition
Although simple and effective moisturisers can be prepared from two or three simple chemicals,[citation needed] such as stearate, olive oil, water and glycerin, commercial preparations are astoundingly complex and varied in composition[citation needed] and may include:
- Humectants, such as glycerin, urea, lactic acid and sorbitol;
- Natural moisturising factors (NMF) include low molecular weight substances such as ammonia, aminoacids, glucosamine, creatinine, citrate and ionic solutions such as sodium, potassium, chloride, phosphate, calcium and magnesium.
- Emollients, such as lanolin (the earliest complex organic substances used in facial and body moisturisers, which is extracted from wool). Lanolin acts as a barrier (occlusion effect) against loss of water and also as a softener of stratum corneum, by means of lubrication and smoothing. Other emollients are oil-water emulsions of varying composition and may include several esters and oils such as octyl dodecanol, hexyl decanol, oleyl alcohol,decyl oleate, isopropyl stearate, isopropyl palmitate, isopropyl myristate, hexyl laureate, and dioctyl cyclohexane.
- Emulsifier, preserving and fragrance agents are also part of commercial preparations.
Moisturisers are among the most used and prescribed products for the skin; unfortunately, the cosmetics industry often advertises loudly for scientifically unsubstantiated effects.[citation needed] Physicians, cosmeticians and consumers alike should be aware of the real science behind skin moisturisation, and know what is possible to achieve and what is not.[citation needed] For example, the addition of vitamins (A, B, C, D and E), nutritive agents, proteins and phytotherapeutic agents has been common in the industry, supposedly in order to add to the moisturiser the capability to treat several skin conditions such as cellulitis, age and photo damage, edema, loss of collagen, wrinkles, etc., with little or no scientific evidence for such.[citation needed]
# Adverse effects
Despite claims to the contrary by the cosmetics industry, complex moisturisers may cause a number of adverse effects, including allergic reactions to some of its components, skin irritation, contact dermatitis, characterised by redness, itching, burning and stinging sensations, or even may cause a contrary effect to the desired, i.e. they may actually increase dehydration.[citation needed] When used near sensitive spots, such as the eyes, lips and genitals, these effects may be exaggerated in some persons. Use of plant extracts, some alcohols and proteins may increase the danger of adverse effects. Cosmetic and therapeutic moisturisers should be accompanied by the printed formula in order to inform consumers adequately, as well as physicians, in order to easily and quickly identify the offending component.[citation needed]
# Reference
- Centurion, S.A. et al.: Moisturizers. eMedicine.
# External links
Template:Skin care
- Sun Sweet Skin Moisturizing (All Natural Homemade Skin Care Remedy Recipes)
no:Krem (kosmetikk)
fi:Kosteusvoide
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Moisturizer | |
8f90e6610f2b78115cba710cddd53b15519fb9c0 | wikidoc | Monilethrix | Monilethrix
# Overview
Monilethrix is an autosomal dominant hair disease that results in short, fragile, broken hair that appears beaded. It comes from the Latin word for necklace (monile) and the Greek word for hair (thrix).
# Presentation
The presentation may be of alopecia. Individuals vary in severity of symptoms. Nail deformities may also be present as well as hair follicle keratosis and follicular hyperkeratosis.
# Causes
The genes KRTHB1 (KRT81), KRTHB3 (KRT83), or KRTHB6 (KRT86) that are mutated in this condition code for type II hair cortex keratins.
# Physical examination
## Gallery
### Head
- url = >
- url = >
- url = >
- url = >
### Trunk
- url = >
- url = > | Monilethrix
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2].
# Overview
Monilethrix is an autosomal dominant hair disease that results in short, fragile, broken hair that appears beaded. It comes from the Latin word for necklace (monile) and the Greek word for hair (thrix).
# Presentation
The presentation may be of alopecia. Individuals vary in severity of symptoms. Nail deformities may also be present as well as hair follicle keratosis and follicular hyperkeratosis.
# Causes
The genes KRTHB1 (KRT81), KRTHB3 (KRT83), or KRTHB6 (KRT86) that are mutated in this condition code for type II hair cortex keratins.[1]
# Physical examination
## Gallery
### Head
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=297>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=297>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=297>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=297>
### Trunk
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=297>
- url = http://www.atlasdermatologico.com.br/disease.jsf?diseaseId=297> | https://www.wikidoc.org/index.php/Monilethrix | |
9f01141eb5808775843ef60b8472432d12856e11 | wikidoc | Monobenzone | Monobenzone
# 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
Monobenzone is a hypopigmentation agent that is FDA approved for the treatment of for final depigmentation in extensive vitiligo. Common adverse reactions include achromia of skin, permanent, burning sensation, dermatitis, skin irritation, transient.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Benoquin Cream 20% is indicated for final depigmentation in extensive vitiligo.
- Benoquin Cream 20% is applied topically to permanently depigment normal skin surrounding vitiliginous lesions in patients with disseminated (greater than 50 percent of body surface area) idiopathic vitiligo.
- Benoquin Cream 20% is not recommended in freckling; hyperpigmentation caused by photosensitization following the use of certain perfumes (berlock dermatitis); melasma (chloasma) of pregnancy; or hyperpigmentation resulting from inflammation of the skin. Benoquin Cream 20% is not effective for the treatment of cafe-au-lait spots, pigmented nevi, malignant melanoma or pigmentation resulting from pigments other than melanin (e.g.: bile, silver, or artificial pigments).
- A thin layer of Benoquin Cream 20% should be applied and rubbed into the pigmented area two or three times daily, or as directed by physician. Prolonged exposure to sunlight should be avoided during treatment with Benoquin Cream 20%, or a sunscreen should be used.
- Depigmentation is usually accomplished after one to four months of Benoquin Cream 20% treatment. If satisfactory results are not obtained after four months of Benoquin Cream 20% treatment, the drug should be discontinued. When the desired degree of depigmentation is obtained, Benoquin Cream 20% should be applied only as often as needed to maintain depigmentation (usually only two times weekly).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Monobenzone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Monobenzone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Monobenzone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Monobenzone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Monobenzone in pediatric patients.
# Contraindications
- Benoquin Cream 20% contains a potent depigmenting agent and is not a cosmetic skin bleach. Use of Benoquin Cream 20% is contraindicated in any conditions other than disseminated vitiligo. Benoquin Cream 20% frequently produces irreversible depigmentation, and it must not be used as a substitute for hydroquinone.
- Benoquin Cream 20% is also contraindicated in individuals with a history of sensitivity or allergic reactions to this product, or any of its ingredients.
# Warnings
- Benoquin Cream 20% is a potent depigmenting agent, not a mild cosmetic bleach. Do not use except for final depigmentation in extensive vitiligo.
- Keep this, and all medications out of the reach of children. In case of accidental ingestion, call a physician or a Poison Control Center immediately.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Monobenzone in the drug label.
## Postmarketing Experience
- Mild, transient skin irritation and sensitization, including erythematous and eczematous reactions have occurred following topical application of Benoquin Cream 20%. Although those reactions are usually transient, treatment with Benoquin Cream 20% should be discontinued if irritation, a burning sensation, or dermatitis occur. Areas of normal skin distant to the site of Benoquin Cream 20% application frequently have become depigmented, and irregular, excessive, unsightly, and frequently permanent depigmentation has occurred.
# Drug Interactions
There is limited information regarding Monobenzone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Benoquin Cream 20%. It is also not known whether Benoquin Cream 20% can cause fetal harm when administered to a pregnant woman, or can affect reproduction capacity. Benoquin Cream 20% should be given to a pregnant woman 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 Monobenzone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Monobenzone 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 Benoquin Cream 20% is administered to a nursing woman.
### Pediatric Use
The safety and effectiveness of Benoquin Cream 20% in pediatric patients below the age of 12 years have not been established.
### Geriatic Use
There is no FDA guidance on the use of Monobenzone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Monobenzone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Monobenzone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Monobenzone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Monobenzone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Monobenzone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Monobenzone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Monobenzone in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Monobenzone in the drug label.
# Overdosage
There is limited information regarding Monobenzone overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Monobenzone Pharmacology in the drug label.
## Mechanism of Action
- Benoquin Cream 20% is a depigmenting agent whose mechanism of action is not fully understood.
- The topical application of monobenzone in animals, increases the excretion of melanin from the melanocytes. The same action is thought to be responsible for the depigmenting effect of the drug in humans. Monobenzone may cause destruction of melanocytes and permanent depigmentation. This effect is erratic and may take one to four months to occur while existing melanin is lost with normal sloughing of the stratum corneum. Hyperpigmented skin appears to fade more rapidly than does normal skin, and exposure to sunlight reduces the depigmenting effect of the drug. The histology of the skin after depigmentation with topical monobenzone is the same as that seen in vitiligo; the epidermis is normal except for the absence of identifiable melanocytes.
## Structure
- Monobenzone is the monobenzyl ether of hydroquinone. Monobenzone occurs as a white, almost tasteless crystalline powder, soluble in alcohol and practically insoluble in water.
- Chemically, monobenzone is designated as p-(benzyloxy) phenol; the empirical formula is C13H12O2; molecular weight 200.24. The structural formula is:
- Each gram of Benoquin Cream contains 200 mg of monobenzone USP, in a water-washable base consisting of purified water USP, cetyl alcohol NF, propylene glycol USP, sodium lauryl sulfate NF and white wax NF.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Monobenzone in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Monobenzone in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Monobenzone in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Monobenzone in the drug label.
# How Supplied
- Benoquin Cream 20% in 1 1/4 oz. tubes (35.4 g)
- (NDC 0187-0380-34).
## Storage
- Benoquin Cream 20% should be stored at 25°C (77°F);
- Excursion permitted to 15°C - 30°C (59°F - 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Monobenzone in the drug label.
# Precautions with Alcohol
- Alcohol-Monobenzone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- BENOQUIN®
# Look-Alike Drug Names
There is limited information regarding Monobenzone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Monobenzone
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
Monobenzone is a hypopigmentation agent that is FDA approved for the treatment of for final depigmentation in extensive vitiligo. Common adverse reactions include achromia of skin, permanent, burning sensation, dermatitis, skin irritation, transient.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Benoquin Cream 20% is indicated for final depigmentation in extensive vitiligo.
- Benoquin Cream 20% is applied topically to permanently depigment normal skin surrounding vitiliginous lesions in patients with disseminated (greater than 50 percent of body surface area) idiopathic vitiligo.
- Benoquin Cream 20% is not recommended in freckling; hyperpigmentation caused by photosensitization following the use of certain perfumes (berlock dermatitis); melasma (chloasma) of pregnancy; or hyperpigmentation resulting from inflammation of the skin. Benoquin Cream 20% is not effective for the treatment of cafe-au-lait spots, pigmented nevi, malignant melanoma or pigmentation resulting from pigments other than melanin (e.g.: bile, silver, or artificial pigments).
- A thin layer of Benoquin Cream 20% should be applied and rubbed into the pigmented area two or three times daily, or as directed by physician. Prolonged exposure to sunlight should be avoided during treatment with Benoquin Cream 20%, or a sunscreen should be used.
- Depigmentation is usually accomplished after one to four months of Benoquin Cream 20% treatment. If satisfactory results are not obtained after four months of Benoquin Cream 20% treatment, the drug should be discontinued. When the desired degree of depigmentation is obtained, Benoquin Cream 20% should be applied only as often as needed to maintain depigmentation (usually only two times weekly).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Monobenzone in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Monobenzone in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Monobenzone in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Monobenzone in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Monobenzone in pediatric patients.
# Contraindications
- Benoquin Cream 20% contains a potent depigmenting agent and is not a cosmetic skin bleach. Use of Benoquin Cream 20% is contraindicated in any conditions other than disseminated vitiligo. Benoquin Cream 20% frequently produces irreversible depigmentation, and it must not be used as a substitute for hydroquinone.
- Benoquin Cream 20% is also contraindicated in individuals with a history of sensitivity or allergic reactions to this product, or any of its ingredients.
# Warnings
- Benoquin Cream 20% is a potent depigmenting agent, not a mild cosmetic bleach. Do not use except for final depigmentation in extensive vitiligo.
- Keep this, and all medications out of the reach of children. In case of accidental ingestion, call a physician or a Poison Control Center immediately.
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Monobenzone in the drug label.
## Postmarketing Experience
- Mild, transient skin irritation and sensitization, including erythematous and eczematous reactions have occurred following topical application of Benoquin Cream 20%. Although those reactions are usually transient, treatment with Benoquin Cream 20% should be discontinued if irritation, a burning sensation, or dermatitis occur. Areas of normal skin distant to the site of Benoquin Cream 20% application frequently have become depigmented, and irregular, excessive, unsightly, and frequently permanent depigmentation has occurred.
# Drug Interactions
There is limited information regarding Monobenzone Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with Benoquin Cream 20%. It is also not known whether Benoquin Cream 20% can cause fetal harm when administered to a pregnant woman, or can affect reproduction capacity. Benoquin Cream 20% should be given to a pregnant woman 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 Monobenzone in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Monobenzone 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 Benoquin Cream 20% is administered to a nursing woman.
### Pediatric Use
The safety and effectiveness of Benoquin Cream 20% in pediatric patients below the age of 12 years have not been established.
### Geriatic Use
There is no FDA guidance on the use of Monobenzone with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Monobenzone with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Monobenzone with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Monobenzone in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Monobenzone in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Monobenzone in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Monobenzone in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Topical
### Monitoring
There is limited information regarding Monitoring of Monobenzone in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Monobenzone in the drug label.
# Overdosage
There is limited information regarding Monobenzone overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
There is limited information regarding Monobenzone Pharmacology in the drug label.
## Mechanism of Action
- Benoquin Cream 20% is a depigmenting agent whose mechanism of action is not fully understood.
- The topical application of monobenzone in animals, increases the excretion of melanin from the melanocytes. The same action is thought to be responsible for the depigmenting effect of the drug in humans. Monobenzone may cause destruction of melanocytes and permanent depigmentation. This effect is erratic and may take one to four months to occur while existing melanin is lost with normal sloughing of the stratum corneum. Hyperpigmented skin appears to fade more rapidly than does normal skin, and exposure to sunlight reduces the depigmenting effect of the drug. The histology of the skin after depigmentation with topical monobenzone is the same as that seen in vitiligo; the epidermis is normal except for the absence of identifiable melanocytes.
## Structure
- Monobenzone is the monobenzyl ether of hydroquinone. Monobenzone occurs as a white, almost tasteless crystalline powder, soluble in alcohol and practically insoluble in water.
- Chemically, monobenzone is designated as p-(benzyloxy) phenol; the empirical formula is C13H12O2; molecular weight 200.24. The structural formula is:
- Each gram of Benoquin Cream contains 200 mg of monobenzone USP, in a water-washable base consisting of purified water USP, cetyl alcohol NF, propylene glycol USP, sodium lauryl sulfate NF and white wax NF.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Monobenzone in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Monobenzone in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Monobenzone in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Monobenzone in the drug label.
# How Supplied
- Benoquin Cream 20% in 1 1/4 oz. tubes (35.4 g)
- (NDC 0187-0380-34).
## Storage
- Benoquin Cream 20% should be stored at 25°C (77°F);
- Excursion permitted to 15°C - 30°C (59°F - 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Monobenzone in the drug label.
# Precautions with Alcohol
- Alcohol-Monobenzone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- BENOQUIN®[1]
# Look-Alike Drug Names
There is limited information regarding Monobenzone Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Monobenzone | |
1883468dd314315cdeea7322f2acfc13db174a40 | wikidoc | Monotropism | Monotropism
Monotropism and polytropism are according to Murray, Lesser and Lawson different strategies in distributing attention in the human brain. Monotropism refers to an attention-tunnel (undivided attention or attention-tunnel), while polytropism refers to multiple divided attention in the brain.
The Monotropism hypothesis was developed by Murray, Lesser and Lawson, a Doctor of Philosophy, a mathematician and a social worker, and regards attention-tunnels as the central feature of autism.
Autists don't have the ability to "multi-task".
In this model of mind, mental events compete for and consume attention. In a polytropic mind, many interests have a moderate amount of attention put into them, while in a monotropic mind, the person's attention is put into a few more specialized interests. The theory argues that when many interests are aroused, multiple complex behaviors emerge, but if only a few interests are aroused, fewer—but more intense—behaviors emerge.
# Notes
- ↑ Murray D, Lesser M, Lawson W (2005). "Attention, monotropism and the diagnostic criteria for autism" (PDF). Autism. 9 (2): 139–56. doi:10.1177/1362361305051398. PMID 15857859. Retrieved 2007-07-24.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | Monotropism
Monotropism and polytropism are according to Murray, Lesser and Lawson different strategies in distributing attention in the human brain. Monotropism refers to an attention-tunnel (undivided attention or attention-tunnel), while polytropism refers to multiple divided attention in the brain.
The Monotropism hypothesis was developed by Murray, Lesser and Lawson, a Doctor of Philosophy, a mathematician and a social worker, and regards attention-tunnels as the central feature of autism.
Autists don't have the ability to "multi-task".
In this model of mind, mental events compete for and consume attention. In a polytropic mind, many interests have a moderate amount of attention put into them, while in a monotropic mind, the person's attention is put into a few more specialized interests. The theory argues that when many interests are aroused, multiple complex behaviors emerge, but if only a few interests are aroused, fewer—but more intense—behaviors emerge.[1]
# Notes
- ↑ Murray D, Lesser M, Lawson W (2005). "Attention, monotropism and the diagnostic criteria for autism" (PDF). Autism. 9 (2): 139–56. doi:10.1177/1362361305051398. PMID 15857859. Retrieved 2007-07-24.CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
Template:Neuroscience-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Monotropism | |
3853b97b926f026301a59a95890f79fb8cc0569d | wikidoc | Montelukast | Montelukast
# 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
Montelukast is a leukotriene receptor antagonist that is FDA approved for the {{{indicationType}}} of asthma, exercise-induced bronchoconstriction (EIB), allergic rhinitis (AR). Common adverse reactions include upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Montelukast sodium tablets are indicated for the prophylaxis and chronic treatment of asthma in patients 15 years of age and older.
- Montelukast sodium should be taken once daily in the evening. The following dose is are recommended:
- For adults: one 10-mg tablet.
- There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion.
- Montelukast sodium tablets are indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older.
- For prevention of EIB, a single 10 mg dose of montelukast should be taken at least 2 hours before exercise.
- The following dose is recommended :
- For adults: one 10-mg tablet.
- An additional dose of montelukast should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting ß-agonist. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
- Montelukast sodium tablets are indicated for the relief of symptoms of seasonal allergic rhinitis in patients 15 years of age and older and perennial allergic rhinitis in patients 15 years of age and older.
- For allergic rhinitis, montelukast sodium should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs.
- The following dose for the treatment of symptoms of seasonal allergic rhinitis are recommended:
- For adults: one 10-mg tablet.
- The following dose for the treatment of symptoms of perennial allergic rhinitis are recommended:
- For adults: one 10-mg tablet.
## Off-Label Use and Dosage (Adult)
### Non–Guideline-Supported Use
- Dosing Information
- Oral montelukast 10 mg.
- Dosing Information
- Oral montelukast 10 mg once daily.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Montelukast sodium tablets are indicated for the prophylaxis and chronic treatment of asthma in patients 15 years of age and older.
- Montelukast sodium should be taken once daily in the evening. The following dose is are recommended:
- For adolescents 15 years of age and older: one 10-mg tablet.
- Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established.
- There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion.
- Montelukast sodium tablets are indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older.
- For prevention of EIB, a single 10 mg dose of montelukast should be taken at least 2 hours before exercise.
- The following dose is recommended :
- For adolescents 15 years of age and older: one 10-mg tablet.
- An additional dose of montelukast should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting ß-agonist. Safety and effectiveness in patients younger than 15 years of age have not been established. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
- Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp's montelukast tablet products. However, due to Merck Sharp & Dohme Corp's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
- Montelukast sodium tablets are indicated for the relief of symptoms of seasonal allergic rhinitis in patients 15 years of age and older and perennial allergic rhinitis in patients 15 years of age and older.
- For allergic rhinitis, montelukast sodium should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs.
- The following dose for the treatment of symptoms of seasonal allergic rhinitis are recommended:
- For adolescents 15 years of age and older: one 10-mg tablet.
- Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established.
- The following dose for the treatment of symptoms of perennial allergic rhinitis are recommended:
- For adolescents 15 years of age and older: one 10-mg tablet.
- Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Montelukast in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Oral course of either montelukast 10 mg once daily.
- Dosing Information
- Montelukast 4 mg (younger than 6 years) or 5 mg (older than 6 years) once daily.
# Contraindications
- Hypersensitivity to any component of this product.
# Warnings
### Precautions
- Acute Asthma
- Montelukast sodium is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. Therapy with montelukast sodium can be continued during acute exacerbations of asthma. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled ß-agonist.
- Concomitant Corticosteroid Use
- While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, montelukast sodium should not be abruptly substituted for inhaled or oral corticosteroids.
- Aspirin Sensitivity
- Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast sodium. Although montelukast sodium is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients.
- Neuropsychiatric Events
- Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking montelukast sodium. Post-marketing reports with montelukast use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving montelukast sodium appear consistent with a drug-induced effect.
- Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with montelukast sodium if such events occur.
- Eosinophilic Conditions
- Patients with asthma on therapy with montelukast sodium may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between montelukast sodium and these underlying conditions has not been established.
# 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. In the following description of clinical trials experience, adverse reactions are listed regardless of causality assessment.
- The most common adverse reactions (incidence ≥5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.
- Adults and Adolescents 15 Years of Age and Older with Asthma
- Montelukast sodium has been evaluated for safety in approximately 2950 adult and adolescent patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with montelukast occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:
- TABLE 1: Adverse Experiences Occurring in ≥1% of Patients with an Incidence Greater than that in Patients Treated with Placebo
- The frequency of less common adverse events was comparable between montelukast sodium and placebo.
- The safety profile of montelukast sodium, when administered as a single dose for prevention of EIB in adult and adolescent patients 15 years of age and older, was consistent with the safety profile previously described for montelukast sodium.
- Cumulatively, 569 patients were treated with montelukast sodium for at least 6 months, 480 for one year, and 49 for two years in clinical trials. With prolonged treatment, the adverse experience profile did not significantly change.
- Adults and Adolescents 15 Years of Age and Older with Seasonal Allergic Rhinitis
- Montelukast sodium has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. Montelukast sodium administered once daily in the morning or in the evening had a safety profile similar to that of placebo. In placebo-controlled clinical trials, the following event was reported with montelukast sodium with a frequency ≥ 1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving montelukast sodium vs. 1.5% of patients receiving placebo. In a 4-week, placebo-controlled clinical study, the safety profile was consistent with that observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies.
- Adults and Adolescents 15 Years of Age and Older with Perennial Allergic Rhinitis
- Montelukast sodium has been evaluated for safety in 3357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1632 received montelukast sodium in two, 6-week, clinical studies. Montelukast sodium administered once daily had a safety profile consistent with that observed in patients with seasonal allergic rhinitis and similar to that of placebo. In these two studies, the following events were reported with montelukast sodium with a frequency ≥ 1% and at an incidence greater than placebo: sinusitis, upper respiratory infection, sinus headache, cough, epistaxis, and increased ALT. The incidence of somnolence was similar to that of placebo.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of montelukast sodium. 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.
increased bleeding tendency, thrombocytopenia.
hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration.
agitation including aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tremor.
drowsiness, paraesthesia/hypoesthesia, seizures.
palpitations.
epistaxis, pulmonary eosinophilia.
diarrhea, dyspepsia, nausea, pancreatitis, vomiting.
Cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with montelukast sodium. Most of these occurred in combination with other confounding factors, such as use of other medications, or when montelukast sodium was administered to patients who had underlying potential for liver disease such as alcohol use or other forms of hepatitis.
angioedema, bruising, erythema multiforme, erythema nodosum, pruritus, Stevens-Johnson syndrome/toxic epidermal necrolysis, urticaria.
arthralgia, myalgia including muscle cramps.
edema.
- Patients with asthma on therapy with montelukast sodium may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.
# Drug Interactions
- No dose adjustment is needed when montelukast sodium is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin,
- Warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, montelukast sodium should be used during pregnancy only if clearly needed.
- Teratogenic Effect: No teratogenicity was observed in rats and rabbits at doses approximately 100 and 110 times, respectively, the maximum recommended daily oral dose in adults based on AUCs.
- During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women being treated with montelukast sodium during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and montelukast sodium has not been established.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Montelukast in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Montelukast during labor and delivery.
### Nursing Mothers
- Studies in rats have shown that montelukast is excreted in milk. It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when montelukast sodium is given to a nursing mother.
### Pediatric Use
- The safety and effectiveness in pediatric patients below the age of 12 months with asthma and 6 months with perennial allergic rhinitis have not been established. The safety and effectiveness in pediatric patients below the age of 6 years with exercise-induced bronchoconstriction have not been established.
- Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp's montelukast tablet products. However, due to Merck Sharp & Dohme Corp's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
### Geriatic Use
- Of the total number of subjects in clinical studies of montelukast, 3.5% were 65 years of age and over, and 0.4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetic profile and the oral bioavailability of a single 10-mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required.
### Gender
There is no FDA guidance on the use of Montelukast with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Montelukast with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is recommended in patients with renal insufficiency.
### Hepatic Impairment
- No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Montelukast in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Montelukast in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Montelukast in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Montelukast in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- No specific information is available on the treatment of overdosage with montelukast sodium. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks and, in short-term studies, up to 900 mg/day to patients for approximately a week without clinically important adverse experiences.
- There have been reports of acute overdosage in post-marketing experience and clinical studies with montelukast sodium. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and pediatric patients. There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of montelukast sodium and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity.
### Management
- In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.
- It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Montelukast in the drug label.
# Pharmacology
## Mechanism of Action
- The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis.
- Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.
## Structure
- Montelukast sodium, the active ingredient in montelukast sodium tablets, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor.
- Montelukast sodium is described chemically as -1- phenyl]-3- propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt.
- The empirical formula is C35H35ClNNaO3S, and its molecular weight is 608.18. The structural formula is:
- Montelukast sodium is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile.
- Each 10-mg film-coated montelukast tablet contains 10.4 mg montelukast sodium, which is equivalent to 10 mg of montelukast, and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, disodium edetate and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide and yellow ferric oxide.
## Pharmacodynamics
- Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD4-induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), montelukast sodium inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.
- The effect of montelukast sodium on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received montelukast, a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received montelukast sodium, a mean increase of 0.2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12.5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12.3% in favor of montelukast sodium. The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known.
## Pharmacokinetics
- Absorption
- Montelukast is rapidly absorbed following oral administration. After administration of the 10-mg film-coated tablet to fasted adults, the mean peak montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax). The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal in the morning.
- The safety and efficacy of montelukast in patients with asthma were demonstrated in clinical trials in which the 10-mg film-coated tablet formulation was administered in the evening without regard to the time of food ingestion. The safety and efficacy of montelukast in patients with seasonal allergic rhinitis were demonstrated in clinical trials in which the 10-mg film-coated tablet was administered in the morning or evening without regard to the time of food ingestion.
- The comparative pharmacokinetics of montelukast when administered as two 5-mg chewable tablets versus one 10-mg film-coated tablet have not been evaluated.
- Distribution
- Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages 8 to 11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.
- Metabolism
- Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients.
- In vitro studies using human liver microsomes indicate that CYP3A4, 2C8, and 2C9 are involved in the metabolism of montelukast. At clinically relevant concentrations, 2C8 appears to play a major role in the metabolism of montelukast.
- Elimination
- The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.
- In several studies, the mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (14%).
- Special Populations
- Hepatic Insufficiency
- Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% (90% CI=7%, 85%) higher mean montelukast AUC following a single 10-mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours).
- No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of montelukast in patients with more severe hepatic impairment or with hepatitis have not been evaluated.
- Renal Insufficiency
- Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients.
- Gender
- The pharmacokinetics of montelukast are similar in males and females.
- Race
- Pharmacokinetic differences due to race have not been studied.
- Adolescents and Pediatric Patients
- Pharmacokinetic studies evaluated the systemic exposure of the 10-mg film-coated tablets in young adults and adolescents ≥ 15 years of age.
- The plasma concentration profile of montelukast following administration of the 10-mg film-coated tablet is similar in adolescents ≥ 15 years of age and young adults. The 10-mg film-coated tablet is recommended for use in patients ≥ 15 years of age.
- Drug-Drug Interactions
- Theophylline, Prednisone, and Prednisolone
- Montelukast sodium has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, and prednisolone.
- Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state, did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline . Montelukast at doses of ≥ 100 mg daily dosed to pharmacokinetic steady state, did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone.
- Oral Contraceptives, Terfenadine, Digoxin, and Warfarin
- In drug interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Montelukast at doses of ≥ 100 mg daily dosed to pharmacokinetic steady state did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ ethinyl estradiol 35 mcg. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of terfenadine (a substrate of CYP3A4) or fexofenadine, the carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily; did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP2C9, 3A4 and 1A2) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the International Normalized Ratio (INR).
- Thyroid Hormones, Sedative Hypnotics, Non-Steroidal Anti-Inflammatory Agents, Benzodiazepines, and Decongestants
- Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants.
- Cytochrome P450 (CYP) Enzyme Inducers
- Phenobarbital, which induces hepatic metabolism, decreased the area under the plasma concentration curve (AUC) of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast sodium is recommended. It is reasonable to employ appropriate clinical monitoring when potent CYP enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast sodium.
- Effect of Montelukast on Cytochrome P450 (CYP) Enzymes
- Montelukast is a potent inhibitor of CYP2C8 in vitro. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) in 12 healthy individuals demonstrated that the pharmacokinetics of rosiglitazone are not altered when the drugs are coadministered, indicating that montelukast does not inhibit CYP2C8 in vivo. Therefore, montelukast is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide). Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit CYP 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.
- Cytochrome P450 (CYP) Enzyme Inhibitors
- In vitro studies have shown that montelukast is a substrate of CYP 2C8, 2C9, and 3A4. Co-administration of montelukast with itraconazole, a strong CYP 3A4 inhibitor, resulted in no significant increase in the systemic exposure of montelukast. Data from a clinical drug-drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) demonstrated that gemfibrozil, at a therapeutic dose, increased the systemic exposure of montelukast by 4.4-fold. Co-administration of itraconazole, gemfibrozil, and montelukast did not further increase the systemic exposure of montelukast. Based on available clinical experience, no dosage adjustment of montelukast is required upon co-administration with gemfibrozil.
## Nonclinical Toxicology
- No evidence of tumorigenicity was seen in carcinogenicity studies of either 2 years in Sprague-Dawley rats or 92 weeks in mice at oral gavage doses up to 200 mg/kg/day or 100 mg/kg/day, respectively. The estimated exposure in rats was approximately 120 and 75 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose. The estimated exposure in mice was approximately 45 and 25 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose.
- Montelukast demonstrated no evidence of mutagenic or clastogenic activity in the following assays: the microbial mutagenesis assay, the V-79 mammalian cell mutagenesis assay, the alkaline elution assay in rat hepatocytes, the chromosomal aberration assay in Chinese hamster ovary cells, and in the in vivo mouse bone marrow chromosomal aberration assay.
- In fertility studies in female rats, montelukast produced reductions in fertility and fecundity indices at an oral dose of 200 mg/kg (estimated exposure was approximately 70 times the AUC for adults at the maximum recommended daily oral dose). No effects on female fertility or fecundity were observed at an oral dose of 100 mg/kg (estimated exposure was approximately 20 times the AUC for adults at the maximum recommended daily oral dose). Montelukast had no effects on fertility in male rats at oral doses up to 800 mg/kg (estimated exposure was approximately 160 times the AUC for adults at the maximum recommended daily oral dose).
- Reproductive Toxicology Studies
- No teratogenicity was observed at oral doses up to 400 mg/kg/day and 300 mg/kg/day in rats and rabbits, respectively. These doses were approximately 100 and 110 times the maximum recommended daily oral dose in adults, respectively, based on AUCs. Montelukast crosses the placenta following oral dosing in rats and rabbits.
# Clinical Studies
- Adults and Adolescents 15 Years of Age and Older with Asthma
- Clinical trials in adults and adolescents 15 years of age and older demonstrated there is no additional clinical benefit to montelukast doses above 10 mg once daily.
- The efficacy of montelukast sodium for the chronic treatment of asthma in adults and adolescents 15 years of age and older was demonstrated in two (U.S. and Multinational) similarly designed, randomized, 12-week, double-blind, placebo-controlled trials in 1576 patients (795 treated with montelukast sodium, 530 treated with placebo, and 251 treated with active control). The median age was 33 years (range 15 to 85); 56.8% were females and 43.2% were males. The ethnic/racial distribution in these studies was 71.6% Caucasian, 17.7% Hispanic, 7.2% other origins and 3.5% Black. Patients had mild or moderate asthma and were non-smokers who required approximately 5 puffs of inhaled β-agonist per day on an “as-needed” basis. The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV1) of 66% (approximate range, 40 to 90%). The co-primary endpoints in these trials were FEV1 and daytime asthma symptoms. In both studies after 12 weeks, a random subset of patients receiving montelukast sodium was switched to placebo for an additional 3 weeks of double-blind treatment to evaluate for possible rebound effects.
- The results of the U.S. trial on the primary endpoint, morning FEV1, expressed as mean percent change from baseline averaged over the 12-week treatment period, are shown in FIGURE 1. Compared with placebo, treatment with one montelukast sodium 10-mg tablet daily in the evening resulted in a statistically significant increase in FEV1 percent change from baseline (13.0%-change in the group treated with montelukast sodium vs. 4.2%-change in the placebo group, p<0.001); the change from baseline in FEV1 for montelukast sodium was 0.32 liters compared with 0.10 liters for placebo, corresponding to a between-group difference of 0.22 liters (p<0.001, 95% CI 0.17 liters, 0.27 liters). The results of the Multinational trial on FEV1 were similar.
- FIGURE 1: FEV1 Mean Percent Change from Baseline (U.S. Trial: Montelukast Sodium N=406; Placebo N=270) (ANOVAModel)
- The effect of montelukast sodium on other primary and secondary endpoints, represented by the Multinational study is shown in TABLE 2.
- Results on these endpoints were similar in the US study.
- TABLE 2: Effect of Montelukast sodium on Primary and Secondary Endpoints in a Multinational Placebo-controlled Trial (ANOVA Model)
- Both studies evaluated the effect of montelukast sodium on secondary outcomes, including asthma attack (utilization of health-care resources such as an unscheduled visit to a doctor's office, emergency room, or hospital; or treatment with oral, intravenous, or intramuscular corticosteroid), and use of oral corticosteroids for asthma rescue. In the Multinational study, significantly fewer patients (15.6% of patients) on montelukast sodium experienced asthma attacks compared with patients on placebo (27.3%, p < 0.001). In the US study, 7.8% of patients on montelukast sodium and 10.3% of patients on placebo experienced asthma attacks, but the difference between the two treatment groups was not significant (p = 0.334). In the Multinational study, significantly fewer patients (14.8% of patients) on montelukast sodium were prescribed oral corticosteroids for asthma rescue compared with patients on placebo (25.7%, p < 0.001). In the US study, 6.9% of patients on montelukast sodium and 9.9% of patients on placebo were prescribed oral corticosteroids for asthma rescue, but the difference between the two treatment groups was not significant (p = 0.196).
- Onset of Action and Maintenance of Effects
- In each placebo-controlled trial in adults, the treatment effect of montelukast sodium, measured by daily diary card parameters, including symptom scores, “as-needed” ß-agonist use, and PEFR measurements, was achieved after the first dose and was maintained throughout the dosing interval (24 hours). No significant change in treatment effect was observed during continuous once-daily evening administration in non-placebo-controlled extension trials for up to one year. Withdrawal of montelukast sodium in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma.
- Effects in Patients on Concomitant Inhaled Corticosteroids
- Separate trials in adults evaluated the ability of montelukast sodium to add to the clinical effect of inhaled corticosteroids and to allow inhaled corticosteroid tapering when used concomitantly.
- One randomized, placebo-controlled, parallel-group trial (n=226) enrolled adults with stable asthma with a mean FEV1 of approximately 84% of predicted who were previously maintained on various inhaled corticosteroids (delivered by metered-dose aerosol or dry powder inhalers). The median age was 41.5 years (range 16 to 70); 52.2% were females and 47.8% were males.
- The ethnic/racial distribution in this study was 92.0% Caucasian, 3.5% Black, 2.2% Hispanic, and 2.2% Asian. The types of inhaled corticosteroids and their mean baseline requirements included beclomethasone dipropionate (mean dose, 1203 mcg/day), triamcinolone acetonide (mean dose, 2004 mcg/day), flunisolide (mean dose, 1971 mcg/day), fluticasone propionate (mean dose, 1083 mcg/day), or budesonide (mean dose, 1192 mcg/day). Some of these inhaled corticosteroids were non-U.S.-approved formulations, and doses expressed may not be ex-actuator. The pre-study inhaled corticosteroid requirements were reduced by approximately 37% during a 5- to 7-week placebo run-in period designed to titrate patients toward their lowest effective inhaled corticosteroid dose.
- Treatment with montelukast sodium resulted in a further 47% reduction in mean inhaled corticosteroid dose compared with a mean reduction of 30% in the placebo group over the 12-week active treatment period (p ≤ 0.05). It is not known whether the results of this study can be generalized to patients with asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids.
- In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of montelukast sodium to beclomethasone resulted in statistically significant improvements in FEV1 compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with montelukast sodium or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to montelukast alone or placebo alone as indicated by FEV1, daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-needed” ß-agonist requirements.
- In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) demonstrated that montelukast sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of montelukast sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of montelukast sodium on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated .
- Exercise-Induced Bronchoconstriction(Adults and Adolescents 15 years of age and older)
- The efficacy of montelukast sodium, 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. and Multinational), randomized, double-blind, placebo-controlled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8.5 or 12 hours, and 24 hours following administration of a single dose of study drug (montelukast 10 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV1 following the 2 hours post-dose exercise challenge in all three studies (Study A, Study B, and Study C). In Study A, a single dose of montelukast sodium 10 mg demonstrated a statistically significant protective benefit against EIB when taken 2 hours prior to exercise. Some patients were protected from EIB at 8.5 and 24 hours after administration; however, some patients were not. The results for the mean maximum percent fall at each timepoint in Study A are shown in TABLE 3 and are representative of the results from the other two studies.
- TABLE 3: Mean Maximum Percent Fall in FEV1 Following Exercise Challenge in Study A (N=47) ANOVA Model
- Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp's montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
- The efficacy of montelukast for prevention of EIB in patients below 6 years of age has not been established.
- Daily administration of montelukast for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
- In a 12-week, randomized, double-blind, parallel group study of 110 adult and adolescent asthmatics 15 years of age and older, with a mean baseline FEV1 percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with montelukast sodium, 10 mg, once daily in the evening, resulted in a statistically significant reduction in mean maximal percent fall in FEV1 and mean time to recovery to within 5% of the pre-exercise FEV1. Exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose). This effect was maintained throughout the 12-week treatment period indicating that tolerance did not occur. Montelukast sodium did not, however, prevent clinically significant deterioration in maximal percent fall in FEV1 after exercise (i.e., ≥ 20% decrease from pre-exercise baseline) in 52% of patients studied. In a separate crossover study in adults, a similar effect was observed after two once-daily 10-mg doses of montelukast sodium.
- Seasonal Allergic Rhinitis
- The efficacy of montelukast sodium tablets for the treatment of seasonal allergic rhinitis was investigated in 5 similarly designed, randomized, double-blind, parallel-group, placebo- and active-controlled (loratadine) trials conducted in North America. The 5 trials enrolled a total of 5029 patients, of whom 1799 were treated with montelukast sodium tablets. Patients were 15 to 82 years of age with a history of seasonal allergic rhinitis, a positive skin test to at least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at study entry.
- The period of randomized treatment was 2 weeks in 4 trials and 4 weeks in one trial. The primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing) as assessed by patients on a 0-3 categorical scale.
- Four of the five trials showed a significant reduction in daytime nasal symptoms scores with montelukast sodium 10-mg tablets compared with placebo. The results of one trial are shown below. The median age in this trial was 35.0 years (range 15 to 81); 65.4% were females and 34.6% were males. The ethnic/racial distribution in this study was 83.1% Caucasian, 6.4% other origins, 5.8% Black, and 4.8% Hispanic. The mean changes from baseline in daytime nasal symptoms score in the treatment groups that received montelukast tablets, loratadine, and placebo are shown in TABLE 4. The remaining three trials that demonstrated efficacy showed similar results.
- TABLE 4: Effects of Montelukast on Daytime Nasal Symptoms Score- in a Placebo- and Active-controlled Trial in Patients with Seasonal Allergic Rhinitis (ANCOVA Model)
- Average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing as assessed by patients on a 0-3 categorical scale.
- † Statistically different from placebo (p≤0.001).
- ‡ The study was not designed for statistical comparison between montelukast sodium and the active control (loratadine).
- Perennial Allergic Rhinitis
- The efficacy of montelukast sodium tablets for the treatment of perennial allergic rhinitis was investigated in 2 randomized, double-blind, placebo-controlled studies conducted in North America and Europe. The two studies enrolled a total of 3357 patients, of whom 1632 received montelukast sodium 10-mg tablets. Patients 15 to 82 years of age with perennial allergic rhinitis as confirmed by history and a positive skin test to at least one relevant perennial allergen (dust mites, animal dander, and/or mold spores), who had active symptoms at the time of study entry, were enrolled.
- In the study in which efficacy was demonstrated, the median age was 35 years (range 15 to 81); 64.1% were females and 35.9% were males. The ethnic/racial distribution in this study was 83.2% Caucasian, 8.1% Black, 5.4% Hispanic, 2.3% Asian, and 1.0% other origins. Montelukast sodium 10-mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6-week treatment period (TABLE 5); in this study the primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, and sneezing).
- TABLE 5: Effects of Montelukast Sodium on Daytime Nasal Symptoms Score- in a Placebo-controlled Trial in Patients with Perennial Allergic Rhinitis (ANCOVA Model)
- Average of individual scores of nasal congestion, rhinorrhea, sneezing as assessed by patients on a 0-3 categorical scale.
- †Statistically different from placebo (p ≤ 0.001).
- The other 6-week study evaluated montelukast 10 mg (n=626), placebo (n=609), and an active-control (cetirizine 10 mg; n=120).
- The primary analysis compared the mean change from baseline in daytime nasal symptoms score for montelukast vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between montelukast sodium and the active-control. The primary outcome variable included nasal itching in addition to nasal congestion, rhinorrhea, and sneezing. The estimated difference between montelukast sodium and placebo was -0.04 with a 95% CI of (-0.09, 0.01). The estimated difference between the active-control and placebo was -0.10 with a 95% CI of (-0.19, -0.01).
# How Supplied
- Montelukast sodium 10-mg Film-Coated Tablets are beige, rounded square-shaped tablets, biconvex and debossed 'CL 26' on one side of the tablet and having plain surface on other side. They are supplied as follows:
- Storage
- Store montelukast sodium 10-mg film-coated tablets at 20°C - 25°C (68-77°F), excursions permitted to 15-30°C (59-86°F). Protect from moisture and light. Store in original package.
- Storage for Bulk Bottles
- Store bottles of 500 montelukast 10-mg film-coated tablets at 20°C - 25°C (68-77°F), excursions permitted to 15-30°C (59-86°F). Protect from moisture and light. Store in original container. When product container is subdivided, repackage into a well-closed, light-resistant container.
## Storage
There is limited information regarding Montelukast Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised to take montelukast daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, and to contact their physicians if their asthma is not well controlled.
- Patients should be advised that oral montelukast sodium is not for the treatment of acute asthma attacks. They should have appropriate short-acting inhaled ß-agonist medication available to treat asthma exacerbations. Patients who have exacerbations of asthma after exercise should be instructed to have available for rescue a short-acting inhaled ß-agonist. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
- Patients should be advised that, while using montelukast sodium, medical attention should be sought if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed.
- Patients receiving montelukast sodium should be instructed not to decrease the dose or stop taking any other anti-asthma medications unless instructed by a physician.
- Patients should be instructed to notify their physician if neuropsychiatric events occur while using montelukast sodium.
- Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast.
# Precautions with Alcohol
- Alcohol-Montelukast interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MONTELUKAST®
# Look-Alike Drug Names
- Singulair® — SINEquan®
# Drug Shortage Status
# Price | Montelukast
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]
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# Overview
Montelukast is a leukotriene receptor antagonist that is FDA approved for the {{{indicationType}}} of asthma, exercise-induced bronchoconstriction (EIB), allergic rhinitis (AR). Common adverse reactions include upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Montelukast sodium tablets are indicated for the prophylaxis and chronic treatment of asthma in patients 15 years of age and older.
- Montelukast sodium should be taken once daily in the evening. The following dose is are recommended:
- For adults: one 10-mg tablet.
- There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion.
- Montelukast sodium tablets are indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older.
- For prevention of EIB, a single 10 mg dose of montelukast should be taken at least 2 hours before exercise.
- The following dose is recommended :
- For adults: one 10-mg tablet.
- An additional dose of montelukast should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting ß-agonist. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
- Montelukast sodium tablets are indicated for the relief of symptoms of seasonal allergic rhinitis in patients 15 years of age and older and perennial allergic rhinitis in patients 15 years of age and older.
- For allergic rhinitis, montelukast sodium should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs.
- The following dose for the treatment of symptoms of seasonal allergic rhinitis are recommended:
- For adults: one 10-mg tablet.
- The following dose for the treatment of symptoms of perennial allergic rhinitis are recommended:
- For adults: one 10-mg tablet.
## Off-Label Use and Dosage (Adult)
### Non–Guideline-Supported Use
- Dosing Information
- Oral montelukast 10 mg.
- Dosing Information
- Oral montelukast 10 mg once daily.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Montelukast sodium tablets are indicated for the prophylaxis and chronic treatment of asthma in patients 15 years of age and older.
- Montelukast sodium should be taken once daily in the evening. The following dose is are recommended:
- For adolescents 15 years of age and older: one 10-mg tablet.
- Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established.
- There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion.
- Montelukast sodium tablets are indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older.
- For prevention of EIB, a single 10 mg dose of montelukast should be taken at least 2 hours before exercise.
- The following dose is recommended :
- For adolescents 15 years of age and older: one 10-mg tablet.
- An additional dose of montelukast should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting ß-agonist. Safety and effectiveness in patients younger than 15 years of age have not been established. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
- Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp's montelukast tablet products. However, due to Merck Sharp & Dohme Corp's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
- Montelukast sodium tablets are indicated for the relief of symptoms of seasonal allergic rhinitis in patients 15 years of age and older and perennial allergic rhinitis in patients 15 years of age and older.
- For allergic rhinitis, montelukast sodium should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs.
- The following dose for the treatment of symptoms of seasonal allergic rhinitis are recommended:
- For adolescents 15 years of age and older: one 10-mg tablet.
- Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established.
- The following dose for the treatment of symptoms of perennial allergic rhinitis are recommended:
- For adolescents 15 years of age and older: one 10-mg tablet.
- Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Montelukast in pediatric patients.
### Non–Guideline-Supported Use
- Dosing Information
- Oral course of either montelukast 10 mg once daily.
- Dosing Information
- Montelukast 4 mg (younger than 6 years) or 5 mg (older than 6 years) once daily.
# Contraindications
- Hypersensitivity to any component of this product.
# Warnings
### Precautions
- Acute Asthma
- Montelukast sodium is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. Therapy with montelukast sodium can be continued during acute exacerbations of asthma. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled ß-agonist.
- Concomitant Corticosteroid Use
- While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, montelukast sodium should not be abruptly substituted for inhaled or oral corticosteroids.
- Aspirin Sensitivity
- Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast sodium. Although montelukast sodium is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients.
- Neuropsychiatric Events
- Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking montelukast sodium. Post-marketing reports with montelukast use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving montelukast sodium appear consistent with a drug-induced effect.
- Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with montelukast sodium if such events occur.
- Eosinophilic Conditions
- Patients with asthma on therapy with montelukast sodium may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between montelukast sodium and these underlying conditions has not been established.
# 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. In the following description of clinical trials experience, adverse reactions are listed regardless of causality assessment.
- The most common adverse reactions (incidence ≥5% and greater than placebo; listed in descending order of frequency) in controlled clinical trials were: upper respiratory infection, fever, headache, pharyngitis, cough, abdominal pain, diarrhea, otitis media, influenza, rhinorrhea, sinusitis, otitis.
- Adults and Adolescents 15 Years of Age and Older with Asthma
- Montelukast sodium has been evaluated for safety in approximately 2950 adult and adolescent patients 15 years of age and older in clinical trials. In placebo-controlled clinical trials, the following adverse experiences reported with montelukast occurred in greater than or equal to 1% of patients and at an incidence greater than that in patients treated with placebo:
- TABLE 1: Adverse Experiences Occurring in ≥1% of Patients with an Incidence Greater than that in Patients Treated with Placebo
- The frequency of less common adverse events was comparable between montelukast sodium and placebo.
- The safety profile of montelukast sodium, when administered as a single dose for prevention of EIB in adult and adolescent patients 15 years of age and older, was consistent with the safety profile previously described for montelukast sodium.
- Cumulatively, 569 patients were treated with montelukast sodium for at least 6 months, 480 for one year, and 49 for two years in clinical trials. With prolonged treatment, the adverse experience profile did not significantly change.
- Adults and Adolescents 15 Years of Age and Older with Seasonal Allergic Rhinitis
- Montelukast sodium has been evaluated for safety in 2199 adult and adolescent patients 15 years of age and older in clinical trials. Montelukast sodium administered once daily in the morning or in the evening had a safety profile similar to that of placebo. In placebo-controlled clinical trials, the following event was reported with montelukast sodium with a frequency ≥ 1% and at an incidence greater than placebo: upper respiratory infection, 1.9% of patients receiving montelukast sodium vs. 1.5% of patients receiving placebo. In a 4-week, placebo-controlled clinical study, the safety profile was consistent with that observed in 2-week studies. The incidence of somnolence was similar to that of placebo in all studies.
- Adults and Adolescents 15 Years of Age and Older with Perennial Allergic Rhinitis
- Montelukast sodium has been evaluated for safety in 3357 adult and adolescent patients 15 years of age and older with perennial allergic rhinitis of whom 1632 received montelukast sodium in two, 6-week, clinical studies. Montelukast sodium administered once daily had a safety profile consistent with that observed in patients with seasonal allergic rhinitis and similar to that of placebo. In these two studies, the following events were reported with montelukast sodium with a frequency ≥ 1% and at an incidence greater than placebo: sinusitis, upper respiratory infection, sinus headache, cough, epistaxis, and increased ALT. The incidence of somnolence was similar to that of placebo.
## Postmarketing Experience
- The following adverse reactions have been identified during post-approval use of montelukast sodium. 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.
increased bleeding tendency, thrombocytopenia.
hypersensitivity reactions including anaphylaxis, hepatic eosinophilic infiltration.
agitation including aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, restlessness, somnambulism, suicidal thinking and behavior (including suicide), tremor.
drowsiness, paraesthesia/hypoesthesia, seizures.
palpitations.
epistaxis, pulmonary eosinophilia.
diarrhea, dyspepsia, nausea, pancreatitis, vomiting.
Cases of cholestatic hepatitis, hepatocellular liver-injury, and mixed-pattern liver injury have been reported in patients treated with montelukast sodium. Most of these occurred in combination with other confounding factors, such as use of other medications, or when montelukast sodium was administered to patients who had underlying potential for liver disease such as alcohol use or other forms of hepatitis.
angioedema, bruising, erythema multiforme, erythema nodosum, pruritus, Stevens-Johnson syndrome/toxic epidermal necrolysis, urticaria.
arthralgia, myalgia including muscle cramps.
edema.
- Patients with asthma on therapy with montelukast sodium may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events have been sometimes associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.
# Drug Interactions
- No dose adjustment is needed when montelukast sodium is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin,
- Warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category B
- There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, montelukast sodium should be used during pregnancy only if clearly needed.
- Teratogenic Effect: No teratogenicity was observed in rats and rabbits at doses approximately 100 and 110 times, respectively, the maximum recommended daily oral dose in adults based on AUCs.
- During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women being treated with montelukast sodium during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and montelukast sodium has not been established.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Montelukast in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Montelukast during labor and delivery.
### Nursing Mothers
- Studies in rats have shown that montelukast is excreted in milk. It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when montelukast sodium is given to a nursing mother.
### Pediatric Use
- The safety and effectiveness in pediatric patients below the age of 12 months with asthma and 6 months with perennial allergic rhinitis have not been established. The safety and effectiveness in pediatric patients below the age of 6 years with exercise-induced bronchoconstriction have not been established.
- Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp's montelukast tablet products. However, due to Merck Sharp & Dohme Corp's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
### Geriatic Use
- Of the total number of subjects in clinical studies of montelukast, 3.5% were 65 years of age and over, and 0.4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetic profile and the oral bioavailability of a single 10-mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required.
### Gender
There is no FDA guidance on the use of Montelukast with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Montelukast with respect to specific racial populations.
### Renal Impairment
- No dosage adjustment is recommended in patients with renal insufficiency.
### Hepatic Impairment
- No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Montelukast in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Montelukast in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Montelukast in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Montelukast in the drug label.
# Overdosage
## Acute Overdose
### Signs and Symptoms
- No specific information is available on the treatment of overdosage with montelukast sodium. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks and, in short-term studies, up to 900 mg/day to patients for approximately a week without clinically important adverse experiences.
- There have been reports of acute overdosage in post-marketing experience and clinical studies with montelukast sodium. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and pediatric patients. There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of montelukast sodium and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity.
### Management
- In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required.
- It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.
## Chronic Overdose
There is limited information regarding Chronic Overdose of Montelukast in the drug label.
# Pharmacology
## Mechanism of Action
- The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis.
- Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.
## Structure
- Montelukast sodium, the active ingredient in montelukast sodium tablets, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor.
- Montelukast sodium is described chemically as [R-(E)]-1-[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl] phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl] propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt.
- The empirical formula is C35H35ClNNaO3S, and its molecular weight is 608.18. The structural formula is:
- Montelukast sodium is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile.
- Each 10-mg film-coated montelukast tablet contains 10.4 mg montelukast sodium, which is equivalent to 10 mg of montelukast, and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, hydroxypropyl cellulose, disodium edetate and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide and yellow ferric oxide.
## Pharmacodynamics
- Montelukast causes inhibition of airway cysteinyl leukotriene receptors as demonstrated by the ability to inhibit bronchoconstriction due to inhaled LTD4 in asthmatics. Doses as low as 5 mg cause substantial blockage of LTD4-induced bronchoconstriction. In a placebo-controlled, crossover study (n=12), montelukast sodium inhibited early- and late-phase bronchoconstriction due to antigen challenge by 75% and 57%, respectively.
- The effect of montelukast sodium on eosinophils in the peripheral blood was examined in clinical trials. In patients with asthma aged 2 years and older who received montelukast, a decrease in mean peripheral blood eosinophil counts ranging from 9% to 15% was noted, compared with placebo, over the double-blind treatment periods. In patients with seasonal allergic rhinitis aged 15 years and older who received montelukast sodium, a mean increase of 0.2% in peripheral blood eosinophil counts was noted, compared with a mean increase of 12.5% in placebo-treated patients, over the double-blind treatment periods; this reflects a mean difference of 12.3% in favor of montelukast sodium. The relationship between these observations and the clinical benefits of montelukast noted in the clinical trials is not known.
## Pharmacokinetics
- Absorption
- Montelukast is rapidly absorbed following oral administration. After administration of the 10-mg film-coated tablet to fasted adults, the mean peak montelukast plasma concentration (Cmax) is achieved in 3 to 4 hours (Tmax). The mean oral bioavailability is 64%. The oral bioavailability and Cmax are not influenced by a standard meal in the morning.
- The safety and efficacy of montelukast in patients with asthma were demonstrated in clinical trials in which the 10-mg film-coated tablet formulation was administered in the evening without regard to the time of food ingestion. The safety and efficacy of montelukast in patients with seasonal allergic rhinitis were demonstrated in clinical trials in which the 10-mg film-coated tablet was administered in the morning or evening without regard to the time of food ingestion.
- The comparative pharmacokinetics of montelukast when administered as two 5-mg chewable tablets versus one 10-mg film-coated tablet have not been evaluated.
- Distribution
- Montelukast is more than 99% bound to plasma proteins. The steady state volume of distribution of montelukast averages 8 to 11 liters. Studies in rats with radiolabeled montelukast indicate minimal distribution across the blood-brain barrier. In addition, concentrations of radiolabeled material at 24 hours postdose were minimal in all other tissues.
- Metabolism
- Montelukast is extensively metabolized. In studies with therapeutic doses, plasma concentrations of metabolites of montelukast are undetectable at steady state in adults and pediatric patients.
- In vitro studies using human liver microsomes indicate that CYP3A4, 2C8, and 2C9 are involved in the metabolism of montelukast. At clinically relevant concentrations, 2C8 appears to play a major role in the metabolism of montelukast.
- Elimination
- The plasma clearance of montelukast averages 45 mL/min in healthy adults. Following an oral dose of radiolabeled montelukast, 86% of the radioactivity was recovered in 5-day fecal collections and <0.2% was recovered in urine. Coupled with estimates of montelukast oral bioavailability, this indicates that montelukast and its metabolites are excreted almost exclusively via the bile.
- In several studies, the mean plasma half-life of montelukast ranged from 2.7 to 5.5 hours in healthy young adults. The pharmacokinetics of montelukast are nearly linear for oral doses up to 50 mg. During once-daily dosing with 10-mg montelukast, there is little accumulation of the parent drug in plasma (14%).
- Special Populations
- Hepatic Insufficiency
- Patients with mild-to-moderate hepatic insufficiency and clinical evidence of cirrhosis had evidence of decreased metabolism of montelukast resulting in 41% (90% CI=7%, 85%) higher mean montelukast AUC following a single 10-mg dose. The elimination of montelukast was slightly prolonged compared with that in healthy subjects (mean half-life, 7.4 hours).
- No dosage adjustment is required in patients with mild-to-moderate hepatic insufficiency. The pharmacokinetics of montelukast in patients with more severe hepatic impairment or with hepatitis have not been evaluated.
- Renal Insufficiency
- Since montelukast and its metabolites are not excreted in the urine, the pharmacokinetics of montelukast were not evaluated in patients with renal insufficiency. No dosage adjustment is recommended in these patients.
- Gender
- The pharmacokinetics of montelukast are similar in males and females.
- Race
- Pharmacokinetic differences due to race have not been studied.
- Adolescents and Pediatric Patients
- Pharmacokinetic studies evaluated the systemic exposure of the 10-mg film-coated tablets in young adults and adolescents ≥ 15 years of age.
- The plasma concentration profile of montelukast following administration of the 10-mg film-coated tablet is similar in adolescents ≥ 15 years of age and young adults. The 10-mg film-coated tablet is recommended for use in patients ≥ 15 years of age.
- Drug-Drug Interactions
- Theophylline, Prednisone, and Prednisolone
- Montelukast sodium has been administered with other therapies routinely used in the prophylaxis and chronic treatment of asthma with no apparent increase in adverse reactions. In drug-interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: theophylline, prednisone, and prednisolone.
- Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state, did not cause clinically significant changes in the kinetics of a single intravenous dose of theophylline [predominantly a cytochrome P450 (CYP) 1A2 substrate]. Montelukast at doses of ≥ 100 mg daily dosed to pharmacokinetic steady state, did not cause any clinically significant change in plasma profiles of prednisone or prednisolone following administration of either oral prednisone or intravenous prednisolone.
- Oral Contraceptives, Terfenadine, Digoxin, and Warfarin
- In drug interaction studies, the recommended clinical dose of montelukast did not have clinically important effects on the pharmacokinetics of the following drugs: oral contraceptives (norethindrone 1 mg/ethinyl estradiol 35 mcg), terfenadine, digoxin, and warfarin. Montelukast at doses of ≥ 100 mg daily dosed to pharmacokinetic steady state did not significantly alter the plasma concentrations of either component of an oral contraceptive containing norethindrone 1 mg/ ethinyl estradiol 35 mcg. Montelukast at a dose of 10 mg once daily dosed to pharmacokinetic steady state did not change the plasma concentration profile of terfenadine (a substrate of CYP3A4) or fexofenadine, the carboxylated metabolite, and did not prolong the QTc interval following co-administration with terfenadine 60 mg twice daily; did not change the pharmacokinetic profile or urinary excretion of immunoreactive digoxin; did not change the pharmacokinetic profile of warfarin (primarily a substrate of CYP2C9, 3A4 and 1A2) or influence the effect of a single 30-mg oral dose of warfarin on prothrombin time or the International Normalized Ratio (INR).
- Thyroid Hormones, Sedative Hypnotics, Non-Steroidal Anti-Inflammatory Agents, Benzodiazepines, and Decongestants
- Although additional specific interaction studies were not performed, montelukast was used concomitantly with a wide range of commonly prescribed drugs in clinical studies without evidence of clinical adverse interactions. These medications included thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, and decongestants.
- Cytochrome P450 (CYP) Enzyme Inducers
- Phenobarbital, which induces hepatic metabolism, decreased the area under the plasma concentration curve (AUC) of montelukast approximately 40% following a single 10-mg dose of montelukast. No dosage adjustment for montelukast sodium is recommended. It is reasonable to employ appropriate clinical monitoring when potent CYP enzyme inducers, such as phenobarbital or rifampin, are co-administered with montelukast sodium.
- Effect of Montelukast on Cytochrome P450 (CYP) Enzymes
- Montelukast is a potent inhibitor of CYP2C8 in vitro. However, data from a clinical drug-drug interaction study involving montelukast and rosiglitazone (a probe substrate representative of drugs primarily metabolized by CYP2C8) in 12 healthy individuals demonstrated that the pharmacokinetics of rosiglitazone are not altered when the drugs are coadministered, indicating that montelukast does not inhibit CYP2C8 in vivo. Therefore, montelukast is not anticipated to alter the metabolism of drugs metabolized by this enzyme (e.g., paclitaxel, rosiglitazone, and repaglinide). Based on further in vitro results in human liver microsomes, therapeutic plasma concentrations of montelukast do not inhibit CYP 3A4, 2C9, 1A2, 2A6, 2C19, or 2D6.
- Cytochrome P450 (CYP) Enzyme Inhibitors
- In vitro studies have shown that montelukast is a substrate of CYP 2C8, 2C9, and 3A4. Co-administration of montelukast with itraconazole, a strong CYP 3A4 inhibitor, resulted in no significant increase in the systemic exposure of montelukast. Data from a clinical drug-drug interaction study involving montelukast and gemfibrozil (an inhibitor of both CYP 2C8 and 2C9) demonstrated that gemfibrozil, at a therapeutic dose, increased the systemic exposure of montelukast by 4.4-fold. Co-administration of itraconazole, gemfibrozil, and montelukast did not further increase the systemic exposure of montelukast. Based on available clinical experience, no dosage adjustment of montelukast is required upon co-administration with gemfibrozil.
## Nonclinical Toxicology
- No evidence of tumorigenicity was seen in carcinogenicity studies of either 2 years in Sprague-Dawley rats or 92 weeks in mice at oral gavage doses up to 200 mg/kg/day or 100 mg/kg/day, respectively. The estimated exposure in rats was approximately 120 and 75 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose. The estimated exposure in mice was approximately 45 and 25 times the AUC for adults and children, respectively, at the maximum recommended daily oral dose.
- Montelukast demonstrated no evidence of mutagenic or clastogenic activity in the following assays: the microbial mutagenesis assay, the V-79 mammalian cell mutagenesis assay, the alkaline elution assay in rat hepatocytes, the chromosomal aberration assay in Chinese hamster ovary cells, and in the in vivo mouse bone marrow chromosomal aberration assay.
- In fertility studies in female rats, montelukast produced reductions in fertility and fecundity indices at an oral dose of 200 mg/kg (estimated exposure was approximately 70 times the AUC for adults at the maximum recommended daily oral dose). No effects on female fertility or fecundity were observed at an oral dose of 100 mg/kg (estimated exposure was approximately 20 times the AUC for adults at the maximum recommended daily oral dose). Montelukast had no effects on fertility in male rats at oral doses up to 800 mg/kg (estimated exposure was approximately 160 times the AUC for adults at the maximum recommended daily oral dose).
- Reproductive Toxicology Studies
- No teratogenicity was observed at oral doses up to 400 mg/kg/day and 300 mg/kg/day in rats and rabbits, respectively. These doses were approximately 100 and 110 times the maximum recommended daily oral dose in adults, respectively, based on AUCs. Montelukast crosses the placenta following oral dosing in rats and rabbits.
# Clinical Studies
- Adults and Adolescents 15 Years of Age and Older with Asthma
- Clinical trials in adults and adolescents 15 years of age and older demonstrated there is no additional clinical benefit to montelukast doses above 10 mg once daily.
- The efficacy of montelukast sodium for the chronic treatment of asthma in adults and adolescents 15 years of age and older was demonstrated in two (U.S. and Multinational) similarly designed, randomized, 12-week, double-blind, placebo-controlled trials in 1576 patients (795 treated with montelukast sodium, 530 treated with placebo, and 251 treated with active control). The median age was 33 years (range 15 to 85); 56.8% were females and 43.2% were males. The ethnic/racial distribution in these studies was 71.6% Caucasian, 17.7% Hispanic, 7.2% other origins and 3.5% Black. Patients had mild or moderate asthma and were non-smokers who required approximately 5 puffs of inhaled β-agonist per day on an “as-needed” basis. The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV1) of 66% (approximate range, 40 to 90%). The co-primary endpoints in these trials were FEV1 and daytime asthma symptoms. In both studies after 12 weeks, a random subset of patients receiving montelukast sodium was switched to placebo for an additional 3 weeks of double-blind treatment to evaluate for possible rebound effects.
- The results of the U.S. trial on the primary endpoint, morning FEV1, expressed as mean percent change from baseline averaged over the 12-week treatment period, are shown in FIGURE 1. Compared with placebo, treatment with one montelukast sodium 10-mg tablet daily in the evening resulted in a statistically significant increase in FEV1 percent change from baseline (13.0%-change in the group treated with montelukast sodium vs. 4.2%-change in the placebo group, p<0.001); the change from baseline in FEV1 for montelukast sodium was 0.32 liters compared with 0.10 liters for placebo, corresponding to a between-group difference of 0.22 liters (p<0.001, 95% CI 0.17 liters, 0.27 liters). The results of the Multinational trial on FEV1 were similar.
- FIGURE 1: FEV1 Mean Percent Change from Baseline (U.S. Trial: Montelukast Sodium N=406; Placebo N=270) (ANOVAModel)
- The effect of montelukast sodium on other primary and secondary endpoints, represented by the Multinational study is shown in TABLE 2.
- Results on these endpoints were similar in the US study.
- TABLE 2: Effect of Montelukast sodium on Primary and Secondary Endpoints in a Multinational Placebo-controlled Trial (ANOVA Model)
- Both studies evaluated the effect of montelukast sodium on secondary outcomes, including asthma attack (utilization of health-care resources such as an unscheduled visit to a doctor's office, emergency room, or hospital; or treatment with oral, intravenous, or intramuscular corticosteroid), and use of oral corticosteroids for asthma rescue. In the Multinational study, significantly fewer patients (15.6% of patients) on montelukast sodium experienced asthma attacks compared with patients on placebo (27.3%, p < 0.001). In the US study, 7.8% of patients on montelukast sodium and 10.3% of patients on placebo experienced asthma attacks, but the difference between the two treatment groups was not significant (p = 0.334). In the Multinational study, significantly fewer patients (14.8% of patients) on montelukast sodium were prescribed oral corticosteroids for asthma rescue compared with patients on placebo (25.7%, p < 0.001). In the US study, 6.9% of patients on montelukast sodium and 9.9% of patients on placebo were prescribed oral corticosteroids for asthma rescue, but the difference between the two treatment groups was not significant (p = 0.196).
- Onset of Action and Maintenance of Effects
- In each placebo-controlled trial in adults, the treatment effect of montelukast sodium, measured by daily diary card parameters, including symptom scores, “as-needed” ß-agonist use, and PEFR measurements, was achieved after the first dose and was maintained throughout the dosing interval (24 hours). No significant change in treatment effect was observed during continuous once-daily evening administration in non-placebo-controlled extension trials for up to one year. Withdrawal of montelukast sodium in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma.
- Effects in Patients on Concomitant Inhaled Corticosteroids
- Separate trials in adults evaluated the ability of montelukast sodium to add to the clinical effect of inhaled corticosteroids and to allow inhaled corticosteroid tapering when used concomitantly.
- One randomized, placebo-controlled, parallel-group trial (n=226) enrolled adults with stable asthma with a mean FEV1 of approximately 84% of predicted who were previously maintained on various inhaled corticosteroids (delivered by metered-dose aerosol or dry powder inhalers). The median age was 41.5 years (range 16 to 70); 52.2% were females and 47.8% were males.
- The ethnic/racial distribution in this study was 92.0% Caucasian, 3.5% Black, 2.2% Hispanic, and 2.2% Asian. The types of inhaled corticosteroids and their mean baseline requirements included beclomethasone dipropionate (mean dose, 1203 mcg/day), triamcinolone acetonide (mean dose, 2004 mcg/day), flunisolide (mean dose, 1971 mcg/day), fluticasone propionate (mean dose, 1083 mcg/day), or budesonide (mean dose, 1192 mcg/day). Some of these inhaled corticosteroids were non-U.S.-approved formulations, and doses expressed may not be ex-actuator. The pre-study inhaled corticosteroid requirements were reduced by approximately 37% during a 5- to 7-week placebo run-in period designed to titrate patients toward their lowest effective inhaled corticosteroid dose.
- Treatment with montelukast sodium resulted in a further 47% reduction in mean inhaled corticosteroid dose compared with a mean reduction of 30% in the placebo group over the 12-week active treatment period (p ≤ 0.05). It is not known whether the results of this study can be generalized to patients with asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids.
- In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of montelukast sodium to beclomethasone resulted in statistically significant improvements in FEV1 compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with montelukast sodium or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to montelukast alone or placebo alone as indicated by FEV1, daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-needed” ß-agonist requirements.
- In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) demonstrated that montelukast sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of montelukast sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of montelukast sodium on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated [see Warnings and Precautions (5.3)].
- Exercise-Induced Bronchoconstriction(Adults and Adolescents 15 years of age and older)
- The efficacy of montelukast sodium, 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. and Multinational), randomized, double-blind, placebo-controlled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8.5 or 12 hours, and 24 hours following administration of a single dose of study drug (montelukast 10 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV1 following the 2 hours post-dose exercise challenge in all three studies (Study A, Study B, and Study C). In Study A, a single dose of montelukast sodium 10 mg demonstrated a statistically significant protective benefit against EIB when taken 2 hours prior to exercise. Some patients were protected from EIB at 8.5 and 24 hours after administration; however, some patients were not. The results for the mean maximum percent fall at each timepoint in Study A are shown in TABLE 3 and are representative of the results from the other two studies.
- TABLE 3: Mean Maximum Percent Fall in FEV1 Following Exercise Challenge in Study A (N=47) ANOVA Model
- Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp's montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
- The efficacy of montelukast for prevention of EIB in patients below 6 years of age has not been established.
- Daily administration of montelukast for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
- In a 12-week, randomized, double-blind, parallel group study of 110 adult and adolescent asthmatics 15 years of age and older, with a mean baseline FEV1 percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with montelukast sodium, 10 mg, once daily in the evening, resulted in a statistically significant reduction in mean maximal percent fall in FEV1 and mean time to recovery to within 5% of the pre-exercise FEV1. Exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose). This effect was maintained throughout the 12-week treatment period indicating that tolerance did not occur. Montelukast sodium did not, however, prevent clinically significant deterioration in maximal percent fall in FEV1 after exercise (i.e., ≥ 20% decrease from pre-exercise baseline) in 52% of patients studied. In a separate crossover study in adults, a similar effect was observed after two once-daily 10-mg doses of montelukast sodium.
- Seasonal Allergic Rhinitis
- The efficacy of montelukast sodium tablets for the treatment of seasonal allergic rhinitis was investigated in 5 similarly designed, randomized, double-blind, parallel-group, placebo- and active-controlled (loratadine) trials conducted in North America. The 5 trials enrolled a total of 5029 patients, of whom 1799 were treated with montelukast sodium tablets. Patients were 15 to 82 years of age with a history of seasonal allergic rhinitis, a positive skin test to at least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at study entry.
- The period of randomized treatment was 2 weeks in 4 trials and 4 weeks in one trial. The primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing) as assessed by patients on a 0-3 categorical scale.
- Four of the five trials showed a significant reduction in daytime nasal symptoms scores with montelukast sodium 10-mg tablets compared with placebo. The results of one trial are shown below. The median age in this trial was 35.0 years (range 15 to 81); 65.4% were females and 34.6% were males. The ethnic/racial distribution in this study was 83.1% Caucasian, 6.4% other origins, 5.8% Black, and 4.8% Hispanic. The mean changes from baseline in daytime nasal symptoms score in the treatment groups that received montelukast tablets, loratadine, and placebo are shown in TABLE 4. The remaining three trials that demonstrated efficacy showed similar results.
- TABLE 4: Effects of Montelukast on Daytime Nasal Symptoms Score* in a Placebo- and Active-controlled Trial in Patients with Seasonal Allergic Rhinitis (ANCOVA Model)
- Average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing as assessed by patients on a 0-3 categorical scale.
- † Statistically different from placebo (p≤0.001).
- ‡ The study was not designed for statistical comparison between montelukast sodium and the active control (loratadine).
- Perennial Allergic Rhinitis
- The efficacy of montelukast sodium tablets for the treatment of perennial allergic rhinitis was investigated in 2 randomized, double-blind, placebo-controlled studies conducted in North America and Europe. The two studies enrolled a total of 3357 patients, of whom 1632 received montelukast sodium 10-mg tablets. Patients 15 to 82 years of age with perennial allergic rhinitis as confirmed by history and a positive skin test to at least one relevant perennial allergen (dust mites, animal dander, and/or mold spores), who had active symptoms at the time of study entry, were enrolled.
- In the study in which efficacy was demonstrated, the median age was 35 years (range 15 to 81); 64.1% were females and 35.9% were males. The ethnic/racial distribution in this study was 83.2% Caucasian, 8.1% Black, 5.4% Hispanic, 2.3% Asian, and 1.0% other origins. Montelukast sodium 10-mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6-week treatment period (TABLE 5); in this study the primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, and sneezing).
- TABLE 5: Effects of Montelukast Sodium on Daytime Nasal Symptoms Score* in a Placebo-controlled Trial in Patients with Perennial Allergic Rhinitis (ANCOVA Model)
- Average of individual scores of nasal congestion, rhinorrhea, sneezing as assessed by patients on a 0-3 categorical scale.
- †Statistically different from placebo (p ≤ 0.001).
- The other 6-week study evaluated montelukast 10 mg (n=626), placebo (n=609), and an active-control (cetirizine 10 mg; n=120).
- The primary analysis compared the mean change from baseline in daytime nasal symptoms score for montelukast vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between montelukast sodium and the active-control. The primary outcome variable included nasal itching in addition to nasal congestion, rhinorrhea, and sneezing. The estimated difference between montelukast sodium and placebo was -0.04 with a 95% CI of (-0.09, 0.01). The estimated difference between the active-control and placebo was -0.10 with a 95% CI of (-0.19, -0.01).
# How Supplied
- Montelukast sodium 10-mg Film-Coated Tablets are beige, rounded square-shaped tablets, biconvex and debossed 'CL 26' on one side of the tablet and having plain surface on other side. They are supplied as follows:
- Storage
- Store montelukast sodium 10-mg film-coated tablets at 20°C - 25°C (68-77°F), excursions permitted to 15-30°C (59-86°F). Protect from moisture and light. Store in original package.
- Storage for Bulk Bottles
- Store bottles of 500 montelukast 10-mg film-coated tablets at 20°C - 25°C (68-77°F), excursions permitted to 15-30°C (59-86°F). Protect from moisture and light. Store in original container. When product container is subdivided, repackage into a well-closed, light-resistant container.
## Storage
There is limited information regarding Montelukast Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be advised to take montelukast daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, and to contact their physicians if their asthma is not well controlled.
- Patients should be advised that oral montelukast sodium is not for the treatment of acute asthma attacks. They should have appropriate short-acting inhaled ß-agonist medication available to treat asthma exacerbations. Patients who have exacerbations of asthma after exercise should be instructed to have available for rescue a short-acting inhaled ß-agonist. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB.
- Patients should be advised that, while using montelukast sodium, medical attention should be sought if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed.
- Patients receiving montelukast sodium should be instructed not to decrease the dose or stop taking any other anti-asthma medications unless instructed by a physician.
- Patients should be instructed to notify their physician if neuropsychiatric events occur while using montelukast sodium.
- Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast.
# Precautions with Alcohol
- Alcohol-Montelukast interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- MONTELUKAST®[1]
# Look-Alike Drug Names
- Singulair® — SINEquan®[2]
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Montelukast | |
aeb1c8f64a9f7b58b33b60fddcc20637b34112c6 | wikidoc | Moon facies | Moon facies
Synonyms and keywords: moon face, Cushingoid appearance
# Overview
Moon facies refers to a round, full, puffy face due to extra fluid or fat around the sides of the face.
# Pathophysiology
Fluid and fat deposits along the sides of the face make it look rounder. The fat deposition may be due to obesity or excess cortisol released by the adrenal glands (hyperadrenocorticalism or hypercortisolism).
# Causes
- ACTH releasing pituitary tumor or tumor in the thymus, lung or pancreas
- Adrenal gland tumors that release cortisol
- Allergies
- Cushing's syndrome
- Obesity
- Steroids such asprednisone. It is more common with oral than with injected or inhaled steroids
# Diagnosis
## Head
The face is round, full and puffy and the ears may not be visible when looking at the front of the face. | Moon facies
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: moon face, Cushingoid appearance
# Overview
Moon facies refers to a round, full, puffy face due to extra fluid or fat around the sides of the face.
# Pathophysiology
Fluid and fat deposits along the sides of the face make it look rounder. The fat deposition may be due to obesity or excess cortisol released by the adrenal glands (hyperadrenocorticalism or hypercortisolism).
# Causes
- ACTH releasing pituitary tumor or tumor in the thymus, lung or pancreas
- Adrenal gland tumors that release cortisol
- Allergies
- Cushing's syndrome
- Obesity
- Steroids such asprednisone. It is more common with oral than with injected or inhaled steroids
# Diagnosis
## Head
The face is round, full and puffy and the ears may not be visible when looking at the front of the face. | https://www.wikidoc.org/index.php/Moon_facies | |
9f86b3c3aa061b4ae1d4ecd5fa2b4fb543af64bc | wikidoc | Moro reflex | Moro reflex
# Overview
The Moro reflex, also known as the startle reflex, is one of the infantile reflexes.
It may be observed in incomplete form in premature birth after the 28th week of gestation, and is usually present in complete form by week 34 (third trimester). It is normally present in all infants/newborns up to 4 or 5 months of age, and its absence indicates a profound disorder of the motor system. An absent or inadequate Moro response on one side is found in infants with hemiplegia, brachial plexus palsy, or a fractured clavicle. Persistence of the Moro response beyond 4 or 5 months of age is noted only in infants with severe neurological defects. It was discovered and first described by Austrian pediatrician Ernst Moro (1874-1951).
This reflex is a response to unexpected loud noise or when the infant feels like it is falling. It is believed to be the only unlearned fear in human newborns. The little Albert study used the startle reflex in the famous classical conditioning experiment to make him fear white fuzzy things.
The primary significance of this reflex is in evaluating integration of the central nervous system (CNS), since the reflex involves 4 distinct components:
- Startle
- spreading out the arms (abduction)
- unspreading the arms (adduction)
- Crying (usually)
Absence of any component (except crying) or any asymmetry in the movements is abnormal, as is persistence of the reflex in older infants, children and adults. However, in individuals with cerebral palsy, persistence and exacerbation of this reflex is common.
In adults, the startle reflex is modulating by expressions of observers. | Moro reflex
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The Moro reflex, also known as the startle reflex, is one of the infantile reflexes[1].
It may be observed in incomplete form in premature birth after the 28th week of gestation, and is usually present in complete form by week 34 (third trimester). It is normally present in all infants/newborns up to 4 or 5 months of age, and its absence indicates a profound disorder of the motor system. An absent or inadequate Moro response on one side is found in infants with hemiplegia, brachial plexus palsy, or a fractured clavicle. Persistence of the Moro response beyond 4 or 5 months of age is noted only in infants with severe neurological defects. It was discovered and first described by Austrian pediatrician Ernst Moro (1874-1951).
This reflex is a response to unexpected loud noise or when the infant feels like it is falling. It is believed to be the only unlearned fear in human newborns. The little Albert study used the startle reflex in the famous classical conditioning experiment to make him fear white fuzzy things.
The primary significance of this reflex is in evaluating integration of the central nervous system (CNS), since the reflex involves 4 distinct components:
- Startle
- spreading out the arms (abduction)
- unspreading the arms (adduction)
- Crying (usually)
Absence of any component (except crying) or any asymmetry in the movements is abnormal, as is persistence of the reflex in older infants, children and adults. However, in individuals with cerebral palsy, persistence and exacerbation of this reflex is common[2].
In adults, the startle reflex is modulating by expressions of observers. | https://www.wikidoc.org/index.php/Moro_reflex | |
0e8dd7686c3916ca2e76831a553d180ac50b35cb | wikidoc | Motavizumab | Motavizumab
# Overview
Motavizumab (proposed INN, trade name Numax) is a humanized monoclonal antibody. It is being investigated by MedImmune (today a subsidiary of AstraZeneca) for the prevention of respiratory syncytial virus infection in high-risk infants. As of September 2009, it is undergoing Phase II and III clinical trials.
In June 2010, the FDA Antiviral Drugs Advisory Committee declined to endorse MedImmune's request for licensure of Motavizumab in a 14 to 3 decision. The members of that panel cited several reasons for the decision, and many were concerned that "we're not looking at a product that has evidence of superiority in terms of efficacy" when compared to the already available monoclonal antibody Palivizumab.
In December 2010, AstraZeneca in a stock market statement stated that it would be writing down $445m (£286m) after discontinuing a key development programme for Motavizumab. The company stated that it would no longer develop Motavizumab for the prevention of respiratory syncytial virus (RSV), and as a result was withdrawing its licence application to the US Food and Drug Administration. It added that it would continue to develop Motavizumab for other treatments of RSV. | Motavizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Motavizumab (proposed INN, trade name Numax) is a humanized monoclonal antibody. It is being investigated by MedImmune (today a subsidiary of AstraZeneca) for the prevention of respiratory syncytial virus infection in high-risk infants. As of September 2009[update], it is undergoing Phase II and III clinical trials.[1]
In June 2010, the FDA Antiviral Drugs Advisory Committee declined to endorse MedImmune's request for licensure of Motavizumab in a 14 to 3 decision. The members of that panel cited several reasons for the decision, and many were concerned that "we're not looking at a product that has evidence of superiority in terms of efficacy" when compared to the already available monoclonal antibody Palivizumab.[2]
In December 2010, AstraZeneca in a stock market statement stated that it would be writing down $445m (£286m) after discontinuing a key development programme for Motavizumab. The company stated that it would no longer develop Motavizumab for the prevention of respiratory syncytial virus (RSV), and as a result was withdrawing its licence application to the US Food and Drug Administration. It added that it would continue to develop Motavizumab for other treatments of RSV.[3] | https://www.wikidoc.org/index.php/Motavizumab | |
b6b4d05f9cd316c2bcf1b16ecee21b99d9e2f0f1 | wikidoc | Motor skill | Motor skill
A motor skill is a skill that requires an organism to utilize their skeletal muscles effectively in a goal directed manner. Motor skills and motor control depend upon the proper functioning of the brain, skeleton, joints, and nervous system. Most motor skills are learned throughout the lifespan and can be affected by disabilities. Motor development is the development of action and coordination of one's limbs, as well as the development of strength, posture control, balance, and perceptual skills.
Motor skills are divided into two parts:
- Gross motor skills include lifting one's head, rolling over, sitting up, balancing, crawling, and walking. Gross motor development usually follows a pattern. Generally large muscles develop before smaller ones. Thus, gross motor development is the foundation for developing skills in other areas (such as fine motor skills). Development also generally moves from top to bottom. The first thing a baby usually learns is to control is it eyes.
- Fine motor skills include the ability to manipulate small objects, transfer objects from hand to hand, and various hand-eye coordination tasks. Fine motor skills may involve the use of very precise motor movement in order to achieve an especially delicate task. Some examples of fine motor skills are using the pincer grasp (thumb and forefinger) to pick up small objects, cutting, coloring and writing, and threading beads. Fine motor development refers to the development of skills involving the smaller muscle groups.
Fine Motor Disabilities negatively impact a child's performance in school but have no bearing on their intellectual ability. It strictly speaks to an individual’s struggle to control the small muscles in their hand as they write. Since communication in the form of writing is important and still heavily relied upon in our society and schools, kids with this disability face a variety of obstacles. Simply writing their name is not only time consuming, it may also end up illegible. To make their work legible, these individuals must exert a great deal of focus and energy which leaves very little left over for concentrating on what they are writing about.
# Disabilities affecting motor skills
- ADC
- Alzheimer's disease
- Catatonia
- Cerebral palsy
- Developmental Dyspraxia
- Hypotonia
- Multiple sclerosis
- Parkinson's Disease
- Syphilis | Motor skill
A motor skill is a skill that requires an organism to utilize their skeletal muscles effectively in a goal directed manner. Motor skills and motor control depend upon the proper functioning of the brain, skeleton, joints, and nervous system. Most motor skills are learned throughout the lifespan and can be affected by disabilities. Motor development is the development of action and coordination of one's limbs, as well as the development of strength, posture control, balance, and perceptual skills.
Motor skills are divided into two parts:
- Gross motor skills include lifting one's head, rolling over, sitting up, balancing, crawling, and walking. Gross motor development usually follows a pattern. Generally large muscles develop before smaller ones. Thus, gross motor development is the foundation for developing skills in other areas (such as fine motor skills). Development also generally moves from top to bottom. The first thing a baby usually learns is to control is it eyes.
- Fine motor skills include the ability to manipulate small objects, transfer objects from hand to hand, and various hand-eye coordination tasks. Fine motor skills may involve the use of very precise motor movement in order to achieve an especially delicate task. Some examples of fine motor skills are using the pincer grasp (thumb and forefinger) to pick up small objects, cutting, coloring and writing, and threading beads. Fine motor development refers to the development of skills involving the smaller muscle groups.
Fine Motor Disabilities negatively impact a child's performance in school but have no bearing on their intellectual ability. It strictly speaks to an individual’s struggle to control the small muscles in their hand as they write. Since communication in the form of writing is important and still heavily relied upon in our society and schools, kids with this disability face a variety of obstacles. Simply writing their name is not only time consuming, it may also end up illegible. To make their work legible, these individuals must exert a great deal of focus and energy which leaves very little left over for concentrating on what they are writing about.
# Disabilities affecting motor skills
- ADC
- Alzheimer's disease
- Catatonia
- Cerebral palsy
- Developmental Dyspraxia
- Hypotonia
- Multiple sclerosis
- Parkinson's Disease
- Syphilis | https://www.wikidoc.org/index.php/Motor_Control | |
a2e108ce201c473c56572a5ba14ad34103c6a8f6 | wikidoc | Moxibustion | Moxibustion
Moxibustion (Template:Zh-cp) is an oriental medicine therapy utilizing moxa, or mugwort herb. It plays an important role in the traditional medical systems of China, Japan, Korea, Vietnam, Tibet, and Mongolia. Suppliers usually age the mugwort and grind it up to a fluff; practitioners burn the fluff or process it further into a stick that resembles a (non-smokable) cigar. They can use it indirectly, with acupuncture needles, or sometimes burn it on a patient's skin.
# Terminology
The word "moxa" comes from Japanese mogusa (艾) (the u is not very strongly enunciated). Yomogi (蓬) also serves as a synonym for moxa in Japan. Chinese uses the same character as mogusa, but pronounced differently: ài, also called àiróng (艾絨)(meaning "velvet of ài").
The Chinese character for moxa forms one half of the two making up the Chinese word that often gets translated as "acupuncture" zhēnjiǔ (針灸).
# Theory and practice
Practitioners use moxa to warm regions and acupuncture points with the intention of stimulating circulation through the points and inducing a smoother flow of blood and qi. Research, for example at Mugwort (Encyclopedia of Alternative Medicine by Clare Hanrahan) has shown that mugwort acts as an emmenagogue, meaning that it stimulates blood-flow in the pelvic area and uterus. It is claimed that moxibustion militates against cold and dampness in the body and can serve to turn breech babies
Medical historians believe that moxibustion pre-dated acupuncture, and needling came to supplement moxa after the 2nd century BC. Different schools of acupuncture use moxa in varying degrees. For example a 5-element acupuncturist will use moxa directly on the skin, whilst a TCM-style practitioner will use rolls of moxa and hold them over the point treated. It can also be burnt atop a fine slice of ginger root to prevent scarring.
Practitioners consider moxibustion to be especially effective in the treatment of chronic problems, "deficient conditions" (weakness), and gerontology. Bian Que (fl. circa 500 BC), one of the most famous semi-legendary doctors of Chinese antiquity and the first specialist in moxibustion, discussed the benefits of moxa over acupuncture in his classic work. He asserted that moxa could add new energy to the body and could treat both excess and deficient conditions. On the other hand, he advised against the use of acupuncture in an already deficient (weak) patient, on the grounds that needle manipulation would leak too much energy.
A huge classical work, Gao Huang Shu (膏肓俞), specialises solely in treatment indications for moxa on a single point (穴).
Note that Taoists use scarring moxibustion along with Chinese medical astrology for longevity.
Practitioners may use acupuncture needles made of various materials in combination with moxa, depending on the direction of qi flow they wish to stimulate.
# Parallel uses of mugwort
In North and South America, indigenous peoples regard mugwort as a sacred plant of divination and spiritual healing, as well as a panacea. Mugwort amongst other herbs were often bound into smudge sticks. Europeans placed sprigs of mugwort under pillows to provoke dreams; and the herb had associations with the practice of magic in Anglo-Saxon times. | Moxibustion
Moxibustion (Template:Zh-cp) is an oriental medicine therapy utilizing moxa, or mugwort herb. It plays an important role in the traditional medical systems of China, Japan, Korea, Vietnam, Tibet, and Mongolia. Suppliers usually age the mugwort and grind it up to a fluff; practitioners burn the fluff or process it further into a stick that resembles a (non-smokable) cigar. They can use it indirectly, with acupuncture needles, or sometimes burn it on a patient's skin.
# Terminology
The word "moxa" comes from Japanese mogusa (艾) (the u is not very strongly enunciated). Yomogi (蓬) also serves as a synonym for moxa in Japan. Chinese uses the same character as mogusa, but pronounced differently: ài, also called àiróng (艾絨)(meaning "velvet of ài").
The Chinese character for moxa forms one half of the two making up the Chinese word that often gets translated as "acupuncture" zhēnjiǔ (針灸).
# Theory and practice
Practitioners use moxa to warm regions and acupuncture points with the intention of stimulating circulation through the points and inducing a smoother flow of blood and qi. Research, for example at Mugwort (Encyclopedia of Alternative Medicine by Clare Hanrahan) has shown that mugwort acts as an emmenagogue, meaning that it stimulates blood-flow in the pelvic area and uterus. It is claimed that moxibustion militates against cold and dampness in the body and can serve to turn breech babies [1]
Medical historians believe that moxibustion pre-dated acupuncture, and needling came to supplement moxa after the 2nd century BC. Different schools of acupuncture use moxa in varying degrees. For example a 5-element acupuncturist will use moxa directly on the skin, whilst a TCM-style practitioner will use rolls of moxa and hold them over the point treated. It can also be burnt atop a fine slice of ginger root to prevent scarring.[citation needed]
Practitioners consider moxibustion to be especially effective in the treatment of chronic problems, "deficient conditions" (weakness), and gerontology. Bian Que (fl. circa 500 BC), one of the most famous semi-legendary doctors of Chinese antiquity and the first specialist in moxibustion, discussed the benefits of moxa over acupuncture in his classic work. He asserted that moxa could add new energy to the body and could treat both excess and deficient conditions. On the other hand, he advised against the use of acupuncture in an already deficient (weak) patient, on the grounds that needle manipulation would leak too much energy.
A huge classical work, Gao Huang Shu (膏肓俞), specialises solely in treatment indications for moxa on a single point (穴).
Note that Taoists use scarring moxibustion along with Chinese medical astrology for longevity.
Practitioners may use acupuncture needles made of various materials in combination with moxa, depending on the direction of qi flow they wish to stimulate.
# Parallel uses of mugwort
In North and South America, indigenous peoples regard mugwort as a sacred plant of divination and spiritual healing, as well as a panacea. Mugwort amongst other herbs were often bound into smudge sticks. Europeans placed sprigs of mugwort under pillows to provoke dreams; and the herb had associations with the practice of magic in Anglo-Saxon times. | https://www.wikidoc.org/index.php/Moxa | |
0b540088112cc3f553104d4d9ec2083ba9403501 | wikidoc | Muscle tone | Muscle tone
# Overview
Muscle tone (aka residual muscle tension or tonus) is the continuous and passive partial contraction of the muscles. It helps maintain posture, and it declines during REM sleep. Note that muscular tone is not defined as muscular shaping or the aspect of general Human physical appearance.
# Purpose
Unconscious nerve impulses maintain the muscles in a partially contracted state. If a sudden pull or stretch occurs, the body responds by automatically increasing the muscle's tension, a reflex which helps guard against danger as well as helping to maintain balance.
The presence of near-continuous innervation makes it clear that tonus describes a "default" or "steady state" condition. There is, for the most part, no actual "rest state" insofar as activation is concerned.
In terms of skeletal muscle, both the extensor muscle and flexor muscle use the term tonus to refer to the "at rest" or normal enervation that maintains current positions of bones.
Cardiac muscle and smooth muscle, although not directly connected to the skeleton, also have tonus in the sense that although their contractions are not matched with those of antagonist muscles; their non-contractive state is characterized by (sometimes random) enervation.
# Pathological tonus
Physical disorders can result in abnormally low (hypotonia) or high (hypertonia) muscle tone. Another form of hypertonia is Paratonia, which is associated with dementia.
# Tonus in surgery
In ophthalmology, tonus may be a central consideration in eye surgery, as in the manipulation of extraocular muscles to repair strabismus. Tonicity aberrations are associated with many diseases of the eye (e.g. Adie syndrome). | Muscle tone
# Overview
Muscle tone (aka residual muscle tension or tonus) is the continuous and passive partial contraction of the muscles. It helps maintain posture, and it declines during REM sleep. Note that muscular tone is not defined as muscular shaping or the aspect of general Human physical appearance.
# Purpose
Unconscious nerve impulses maintain the muscles in a partially contracted state. If a sudden pull or stretch occurs, the body responds by automatically increasing the muscle's tension, a reflex which helps guard against danger as well as helping to maintain balance.
The presence of near-continuous innervation makes it clear that tonus describes a "default" or "steady state" condition. There is, for the most part, no actual "rest state" insofar as activation is concerned.
In terms of skeletal muscle, both the extensor muscle and flexor muscle use the term tonus to refer to the "at rest" or normal enervation that maintains current positions of bones.
Cardiac muscle and smooth muscle, although not directly connected to the skeleton, also have tonus in the sense that although their contractions are not matched with those of antagonist muscles; their non-contractive state is characterized by (sometimes random) enervation.
# Pathological tonus
Physical disorders can result in abnormally low (hypotonia) or high (hypertonia) muscle tone. Another form of hypertonia is Paratonia, which is associated with dementia.
# Tonus in surgery
In ophthalmology, tonus may be a central consideration in eye surgery, as in the manipulation of extraocular muscles to repair strabismus. Tonicity aberrations are associated with many diseases of the eye (e.g. Adie syndrome). | https://www.wikidoc.org/index.php/Muscle_tension | |
42f28d343506c250732112d4c785d9ad4981cd30 | wikidoc | Mustard oil | Mustard oil
The term mustard oil is used for two different oils that are made from mustard seeds:
- a fatty vegetable oil resulting from pressing the seeds,
- an essential oil resulting from grinding the seeds, mixing them with water, and extracting the resulting volatile oil by distillation.
# Mustard oil from pressed seeds
This oil has a strong smell, a little like strong cabbage, a hot nutty taste, and is much used for cooking in Orissa, Bengal, Bihar and other areas of India and Bangladesh. In north India, it is mainly used in frying fritters. The oil makes up about 30% of the mustard seeds. It can be produced from black mustard (Brassica nigra), brown Indian mustard (Brassica juncea), and white mustard (Brassica hirta).
Mustard oil is composed mostly of the fatty acids oleic acid, linoleic acid and erucic acid. At 5%, mustard seed oil has the lowest saturated fat content of the edible oils.
In India, mustard oil is generally heated almost to smoking before it is used for cooking; this may be an attempt to reduce the content of noxious substances such as erucic acid, and does reduce the strong smell and taste. , Mustard oil is not considered suitable for human consumption in the United States, Canada and the European Union due to the high content of erucic acid, which is considered noxious, although mustard oil with low erucic acid content is available. To get around the restriction in Western countries, the oil is often sold "for external use only" in stores catering to Indian immigrants, as in North India, mustard oil is also used for rub-downs and massages (see ayurveda), thought to improve blood circulation, muscular development and skin texture; the oil is also antibacterial.
In India, the restrictions on mustard oil are viewed as an attempt by foreign multi-national corporations to replace mustard oil with canola oil, a variety of rapeseed with a low erucic acid content, but often from a genetically modified canola. The East and North Indians have been using it for ages and deny that there is enough evidence for the toxicity of erucic acid, instead maintaining that mustard oil is beneficial to human health because of its low saturated fat content, ideal ratio of omega-3 and omega 6 fatty acids (15g of omega 3 fats per 100g serving), content of antioxidants and vitamin E, as well as being cold-pressed (extracted at 45-50 degrees Celsius).
In northern Italy, it is used in the fruit condiment called mostarda.
# Mustard oil from mixing seeds with water
The pungency of the condiment mustard results when ground mustard seeds are mixed with water, vinegar, or other liquid (or even when chewed). Under these conditions, a chemical reaction between the enzyme myrosinase and a glucosinolate known as sinigrin from the seeds of black mustard (Brassica nigra) or brown Indian mustard (Brassica juncea) produces allyl isothiocyanate. By distillation one can produce a very sharp-tasting essential oil, sometimes called volatile oil of mustard, containing more than 92% allyl isothiocyanate. The pungency of allyl isothiocyanate is due to the activation of the TRPA1 ion channel in sensory neurons. White mustard Brassica hirta does not yield allyl isothiocyanate, but a different and milder isothiocyanate.
Allyl isothiocyanate serves the plant as a defense against herbivores. Since it is harmful to the plant itself, it is stored in the harmless form of a glucosinolate, separate from the myrosinase enzyme. Once the herbivore chews the plant, the noxious allyl isothiocyanate is produced. Allyl isothiocyanate is also responsible for the pungent taste of horseradish and wasabi. It can be produced synthetically, sometimes known as synthetic mustard oil.
Because of the contained allyl isothiocyanate, this type of mustard oil is toxic and irritates the skin and mucous membranes. In very small amounts, it is often used by the food industry for flavoring. It is also used to repel cats and dogs. It will also denature alcohol, making it unfit for human consumption, thus avoiding the taxes collected on alcoholic beverages.
The CAS number of this type of mustard oil is 8007-40-7, and the CAS number of pure allyl isothiocyanate is 57-06-7.
# Use of mustard oil in North Indian cultural activities
Mustard oil, though not very popular as a cooking oil in North India, still is intricately embedded in the culture, used in these contexts:
- It is poured on both sides of threshold when someone important comes home for the first time (e.g. a newly-wedded couple or a son or daughter when returning after a long absence, or succeeding in an exams or election.
- Used as traditional jaggo pot fuel in Punjabi weddings.
- Used as part of home-made cosmetics during mayian. | Mustard oil
The term mustard oil is used for two different oils that are made from mustard seeds:
- a fatty vegetable oil resulting from pressing the seeds,
- an essential oil resulting from grinding the seeds, mixing them with water, and extracting the resulting volatile oil by distillation.
# Mustard oil from pressed seeds
This oil has a strong smell, a little like strong cabbage, a hot nutty taste, and is much used for cooking in Orissa, Bengal, Bihar and other areas of India and Bangladesh. In north India, it is mainly used in frying fritters. The oil makes up about 30% of the mustard seeds. It can be produced from black mustard (Brassica nigra), brown Indian mustard (Brassica juncea), and white mustard (Brassica hirta).
Mustard oil is composed mostly of the fatty acids oleic acid, linoleic acid and erucic acid. At 5%, mustard seed oil has the lowest saturated fat content of the edible oils.
In India, mustard oil is generally heated almost to smoking before it is used for cooking; this may be an attempt to reduce the content of noxious substances such as erucic acid, and does reduce the strong smell and taste. , Mustard oil is not considered suitable for human consumption in the United States, Canada and the European Union due to the high content of erucic acid, which is considered noxious, although mustard oil with low erucic acid content is available. To get around the restriction in Western countries, the oil is often sold "for external use only" in stores catering to Indian immigrants, as in North India, mustard oil is also used for rub-downs and massages (see ayurveda), thought to improve blood circulation, muscular development and skin texture; the oil is also antibacterial.
In India, the restrictions on mustard oil are viewed as an attempt by foreign multi-national corporations to replace mustard oil with canola oil, a variety of rapeseed with a low erucic acid content, but often from a genetically modified canola. The East and North Indians have been using it for ages and deny that there is enough evidence for the toxicity of erucic acid, instead maintaining that mustard oil is beneficial to human health because of its low saturated fat content, ideal ratio of omega-3 and omega 6 fatty acids (15g of omega 3 fats per 100g serving), content of antioxidants and vitamin E, as well as being cold-pressed (extracted at 45-50 degrees Celsius).
In northern Italy, it is used in the fruit condiment called mostarda.
# Mustard oil from mixing seeds with water
The pungency of the condiment mustard results when ground mustard seeds are mixed with water, vinegar, or other liquid (or even when chewed). Under these conditions, a chemical reaction between the enzyme myrosinase and a glucosinolate known as sinigrin from the seeds of black mustard (Brassica nigra) or brown Indian mustard (Brassica juncea) produces allyl isothiocyanate. By distillation one can produce a very sharp-tasting essential oil, sometimes called volatile oil of mustard, containing more than 92% allyl isothiocyanate. The pungency of allyl isothiocyanate is due to the activation of the TRPA1 ion channel in sensory neurons. White mustard Brassica hirta does not yield allyl isothiocyanate, but a different and milder isothiocyanate.
Allyl isothiocyanate serves the plant as a defense against herbivores. Since it is harmful to the plant itself, it is stored in the harmless form of a glucosinolate, separate from the myrosinase enzyme. Once the herbivore chews the plant, the noxious allyl isothiocyanate is produced. Allyl isothiocyanate is also responsible for the pungent taste of horseradish and wasabi. It can be produced synthetically, sometimes known as synthetic mustard oil.
Because of the contained allyl isothiocyanate, this type of mustard oil is toxic and irritates the skin and mucous membranes. In very small amounts, it is often used by the food industry for flavoring. It is also used to repel cats and dogs. It will also denature alcohol, making it unfit for human consumption, thus avoiding the taxes collected on alcoholic beverages.
The CAS number of this type of mustard oil is 8007-40-7, and the CAS number of pure allyl isothiocyanate is 57-06-7.
# Use of mustard oil in North Indian cultural activities
Template:Cleanupsect
Mustard oil, though not very popular as a cooking oil in North India, still is intricately embedded in the culture, used in these contexts:
- It is poured on both sides of threshold when someone important comes home for the first time (e.g. a newly-wedded couple or a son or daughter when returning after a long absence, or succeeding in an exams or election.
- Used as traditional jaggo pot fuel in Punjabi weddings.
- Used as part of home-made cosmetics during mayian.
# External links
- Canadian Food Inspection Agency
- Isolation of Erucic Acid from Mustard Seed Oil by Candida rugosa lipase
- The Mustard Seed Conspiracy by Vandana Shiva in The Ecologist, July 2001
- Tanuja Rastogi (2004) Diet and risk of ischemic heart disease in India. American Journal of Clinical Nutrition, Vol. 79, No. 4, 582-592, April 2004. Retrieved 2007-01-29
- Alternate oils
de:Senföl
nl:Mosterdolie | https://www.wikidoc.org/index.php/Mustard_oil | |
27083ac460be15df73fd939b655892f0fe1c9923 | wikidoc | Mycolactone | Mycolactone
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Mycolactone is a polyketide-derived macrolide produced and secreted by the pathogenic mycobacteria M. ulcerans, M. liflandii, M. pseudoshottsii, and a few M. marinum isolates.
The M. ulcerans toxins comprise a family of polyketide-derived macrolides, mycolactones, which are formed through condensation of two polyketide chains. Each isolate of M. ulcerans produces a characteristic mixture of mycolactone congeners. M. ulcerans strains from different geographic areas produce distinct patterns of mycolactone congeners. The structural heterogeneity in mycolactones is due to variations in the fatty acid side chain. The structure of the core lactone is invariant.
Genes for mycolactone biosynthesis form a contiguous 110-kb cluster (Fig. 1A) on a large plasmid. The lactone core is encoded by two polyketide synthase (Pks) genes, mlsA1 and mlsA2, and a third polyketide synthase gene, mlsB, encodes the fatty acid side chain. Three accessory genes are found in the mycolactone cluster. One of these, MUP053, encodes a p450 monooxygenase that is thought to produce the hydroxyl at C′-12 on the fatty acid side chain. The gene encoding a FabH-like, type III ketosynthase (KS), located upstream of mlsA1, encodes a putative “joinase” (MUP045), and a small type II thioesterase (TE II) gene (MUP037) is located between mlsA2 and mlsB.
Five categories have been described so far:
- Mycolactone A/B (M. ulcerans from Africa, Malaysia, ...)
- Mycolactone C (8 Australian M. ulcerans isolates)
- Mycolactone D (M. ulcerans from Asia)
- Mycolactone E (M. liflandii)
- Mycolactone F (M. pseudoshottsii and M. marinum from Israël) | Mycolactone
Template:Chembox new
Please Take Over This Page and Apply to be Editor-In-Chief for this topic:
There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch.
Mycolactone is a polyketide-derived macrolide produced and secreted by the pathogenic mycobacteria M. ulcerans, M. liflandii, M. pseudoshottsii, and a few M. marinum isolates.
The M. ulcerans toxins comprise a family of polyketide-derived macrolides, mycolactones, which are formed through condensation of two polyketide chains. Each isolate of M. ulcerans produces a characteristic mixture of mycolactone congeners. M. ulcerans strains from different geographic areas produce distinct patterns of mycolactone congeners. The structural heterogeneity in mycolactones is due to variations in the fatty acid side chain. The structure of the core lactone is invariant.[1]
Genes for mycolactone biosynthesis form a contiguous 110-kb cluster (Fig. 1A) on a large plasmid. The lactone core is encoded by two polyketide synthase (Pks) genes, mlsA1 and mlsA2, and a third polyketide synthase gene, mlsB, encodes the fatty acid side chain. Three accessory genes are found in the mycolactone cluster. One of these, MUP053, encodes a p450 monooxygenase that is thought to produce the hydroxyl at C′-12 on the fatty acid side chain. The gene encoding a FabH-like, type III ketosynthase (KS), located upstream of mlsA1, encodes a putative “joinase” (MUP045), and a small type II thioesterase (TE II) gene (MUP037) is located between mlsA2 and mlsB.[1]
Five categories have been described so far:
- Mycolactone A/B (M. ulcerans from Africa, Malaysia, ...)
- Mycolactone C (8 Australian M. ulcerans isolates)
- Mycolactone D (M. ulcerans from Asia)
- Mycolactone E (M. liflandii)[1]
- Mycolactone F (M. pseudoshottsii and M. marinum from Israël)[2] | https://www.wikidoc.org/index.php/Mycolactone | |
ac64100101a8b47ff3b94859f400ea6032d713ba | wikidoc | Tropicamide | Tropicamide
# 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
Tropicamide is an antimuscarinic that is FDA approved for the procedure of causing mydriasis and cycloplegia. Common adverse reactions include blurred vision, burning sensation in eye.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Tropicamide is indicated for mydriasis and cycloplegia for diagnostic procedures.
- Dosage:
- For examination of fundus: 1 to 2 drops 0.5% solution in the eye(s) 15 to 20 min prior to exam
- For mydriasis induction: refractive procedures, 1 to 2 drops 1% solution in the eye(s), may be repeated in 5 min
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tropicamide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tropicamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Tropicamide is indicated for mydriasis and cycloplegia for diagnostic procedures.
- Dosage:
- For examination of fundus: 1 to 2 drops 0.5% solution in the eye(s) 15 to 20 min prior to exam
- For mydriasis induction: refractive procedures, 1 to 2 drops 1% solution in the eye(s), may be repeated in 5 min
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tropicamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tropicamide in pediatric patients.
# Contraindications
- Contraindicated in persons showing hypersensitivity to any component of this preparation.
# Warnings
- FOR TOPICAL OPHTHALMIC USE ONLY. NOT FOR INJECTION.
- This preparation may cause CNS disturbances which may be dangerous in pediatric patients. The possibility of psychotic reactions and behavioral disturbances due to hypersensitivity to anticholinergic drugs should be considered.
- Mydriatics may produce a transient elevation of intraocular pressure.
- Remove contact lenses before using.
# Adverse Reactions
## Clinical Trials Experience
Transient stinging, blurred vision, photophobia and superficial punctuate keratitis have been reported with the use of tropicamide. Increased intraocular pressure has been reported following the use of mydriatics.
Dryness of the mouth, tachycardia, headache, allergic reactions, nausea, vomiting, pallor, central nervous system disturbances and muscle rigidity have been reported with the use of tropicamide. Psychotic reactions, behavioral disturbances, and vasomotor or cardiorespiratory collapse in children have been reported with the use of anticholinergic drugs.
## Postmarketing Experience
There is limited information regarding Tropicamide Postmarketing Experience in the drug label.
# Drug Interactions
Tropicamide may interfere with the antihypertensive action of carbachol, pilocarpine, or ophthalmic cholinesterase inhibitors.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with tropicamide. It is also not known whether tropicamide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Tropicamide should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tropicamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tropicamide 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 tropicamide is administered to a nursing woman.
### Pediatric Use
Tropicamide may rarely cause CNS disturbances which may be dangerous in pediatric patients. Psychotic reactions, behavioral disturbances, and vasomotor or cardiorespiratory collapse in children have been reported with the use of anticholinergic drugs. Keep this and all medications out of the reach of children.
### Geriatic Use
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Tropicamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tropicamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tropicamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tropicamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tropicamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tropicamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Topical (Ophthalmic drops)
### Monitoring
There is limited information regarding Tropicamide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tropicamide and IV administrations.
# Overdosage
There is limited information regarding Tropicamide overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
This anticholinergic preparation blocks the responses of the sphincter muscle of the iris and the ciliary muscle to cholinergic stimulation, dilating the pupil (mydriasis). The stronger preparation (1%) also paralyzes accommodation.
## Structure
The active ingredient is represented by the chemical structure:
## Pharmacodynamics
This preparation acts in 15-30 minutes, and the duration of activity is approximately 3-8 hours. Complete recovery from mydriasis in some individuals may require 24 hours.
## Pharmacokinetics
There is limited information regarding Tropicamide Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There have been no long-term studies done using tropicamide in animals to evaluate carcinogenic potential.
# Clinical Studies
There is limited information regarding Tropicamide Clinical Studies in the drug label.
# How Supplied
Tropicamide Ophthalmic Solution USP, 0.5% and 1% are supplied as sterile solutions in plastic dropper bottles:
- 0.5% NDC 17478-101-12 (15 mL)
- 1% NDC 17478-102-12 (15 mL)
- 1% NDC 17478-102-20 (2 mL)
## Storage
Store at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Do not touch dropper tip to any surface, as this may contaminate the solution. Patient should be advised not to drive or engage in potentially hazardous activities while pupils are dilated.
- Patient may experience sensitivity to light and should protect eyes in bright illumination during dilation.
- Parents should be warned not to get this preparation in their child's mouth and to wash their own hands and the child's hands following administration.
# Precautions with Alcohol
Alcohol-Tropicamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Mydral
- Mydriacyl
- Ocu-Tropic
- Tropicacyl
# Look-Alike Drug Names
There is limited information regarding Tropicamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tropicamide
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
Tropicamide is an antimuscarinic that is FDA approved for the procedure of causing mydriasis and cycloplegia. Common adverse reactions include blurred vision, burning sensation in eye.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
Tropicamide is indicated for mydriasis and cycloplegia for diagnostic procedures.
- Dosage:
- For examination of fundus: 1 to 2 drops 0.5% solution in the eye(s) 15 to 20 min prior to exam
- For mydriasis induction: refractive procedures, 1 to 2 drops 1% solution in the eye(s), may be repeated in 5 min
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tropicamide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tropicamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Tropicamide is indicated for mydriasis and cycloplegia for diagnostic procedures.
- Dosage:
- For examination of fundus: 1 to 2 drops 0.5% solution in the eye(s) 15 to 20 min prior to exam
- For mydriasis induction: refractive procedures, 1 to 2 drops 1% solution in the eye(s), may be repeated in 5 min
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Tropicamide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tropicamide in pediatric patients.
# Contraindications
- Contraindicated in persons showing hypersensitivity to any component of this preparation.
# Warnings
- FOR TOPICAL OPHTHALMIC USE ONLY. NOT FOR INJECTION.
- This preparation may cause CNS disturbances which may be dangerous in pediatric patients. The possibility of psychotic reactions and behavioral disturbances due to hypersensitivity to anticholinergic drugs should be considered.
- Mydriatics may produce a transient elevation of intraocular pressure.
- Remove contact lenses before using.
# Adverse Reactions
## Clinical Trials Experience
Transient stinging, blurred vision, photophobia and superficial punctuate keratitis have been reported with the use of tropicamide. Increased intraocular pressure has been reported following the use of mydriatics.
Dryness of the mouth, tachycardia, headache, allergic reactions, nausea, vomiting, pallor, central nervous system disturbances and muscle rigidity have been reported with the use of tropicamide. Psychotic reactions, behavioral disturbances, and vasomotor or cardiorespiratory collapse in children have been reported with the use of anticholinergic drugs.
## Postmarketing Experience
There is limited information regarding Tropicamide Postmarketing Experience in the drug label.
# Drug Interactions
Tropicamide may interfere with the antihypertensive action of carbachol, pilocarpine, or ophthalmic cholinesterase inhibitors.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Animal reproduction studies have not been conducted with tropicamide. It is also not known whether tropicamide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Tropicamide should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tropicamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tropicamide 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 tropicamide is administered to a nursing woman.
### Pediatric Use
Tropicamide may rarely cause CNS disturbances which may be dangerous in pediatric patients. Psychotic reactions, behavioral disturbances, and vasomotor or cardiorespiratory collapse in children have been reported with the use of anticholinergic drugs. Keep this and all medications out of the reach of children.
### Geriatic Use
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
### Gender
There is no FDA guidance on the use of Tropicamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tropicamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tropicamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tropicamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tropicamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tropicamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Topical (Ophthalmic drops)
### Monitoring
There is limited information regarding Tropicamide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tropicamide and IV administrations.
# Overdosage
There is limited information regarding Tropicamide overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
This anticholinergic preparation blocks the responses of the sphincter muscle of the iris and the ciliary muscle to cholinergic stimulation, dilating the pupil (mydriasis). The stronger preparation (1%) also paralyzes accommodation.
## Structure
The active ingredient is represented by the chemical structure:
## Pharmacodynamics
This preparation acts in 15-30 minutes, and the duration of activity is approximately 3-8 hours. Complete recovery from mydriasis in some individuals may require 24 hours.
## Pharmacokinetics
There is limited information regarding Tropicamide Pharmacokinetics in the drug label.
## Nonclinical Toxicology
There have been no long-term studies done using tropicamide in animals to evaluate carcinogenic potential.
# Clinical Studies
There is limited information regarding Tropicamide Clinical Studies in the drug label.
# How Supplied
Tropicamide Ophthalmic Solution USP, 0.5% and 1% are supplied as sterile solutions in plastic dropper bottles:
- 0.5% NDC 17478-101-12 (15 mL)
- 1% NDC 17478-102-12 (15 mL)
- 1% NDC 17478-102-20 (2 mL)
## Storage
Store at 20° to 25°C (68° to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Do not touch dropper tip to any surface, as this may contaminate the solution. Patient should be advised not to drive or engage in potentially hazardous activities while pupils are dilated.
- Patient may experience sensitivity to light and should protect eyes in bright illumination during dilation.
- Parents should be warned not to get this preparation in their child's mouth and to wash their own hands and the child's hands following administration.
# Precautions with Alcohol
Alcohol-Tropicamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Mydral [1]
- Mydriacyl
- Ocu-Tropic
- Tropicacyl
# Look-Alike Drug Names
There is limited information regarding Tropicamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Mydral | |
a1718684e94bb4cb1e4e771f750c4b21970292a9 | wikidoc | Nitrosamine | Nitrosamine
# Overview
Nitrosamines are chemical compounds of the chemical structure R1N(-R2)-N=O, some of which are carcinogenic.
# Occurrence in food
Nitrosamines are produced from nitrites and secondary amines, which often occur in the form of proteins. Their formation can occur only under certain conditions, including strongly acidic conditions such as that of the human stomach. High temperatures, as in frying, can also enhance the formation of nitrosamines.
The nitrite forms nitrous acid (HNO2), which splits into the nitrosonium cation, N=O+, and the hydroxide anion, OH−. The nitrosonium cation then reacts with an amine to produce nitrosamine.
Nitrosamines are found in many foodstuffs especially beer, fish, fish byproducts, and in meat and cheese products preserved with nitrite pickling salt. The US government established limits on the amount of nitrites used in meat products to decrease cancer risk in the population. There are also rules about adding ascorbic acid or related compounds to meat, because they inhibit nitrosamine formation.
# Occurrence in other consumer products
Nitrosamines can be found in tobacco smoke and latex products. A test of party balloons and condoms indicated that many of them release small amounts of nitrosamines. However, nitrosamines from condoms are not expected to be of toxicological significance.
# Cancer
Nitrosamines can cause cancers in a wide variety of animal species, a feature which suggests that they may also be carcinogenic in humans. Epidemiological data suggests that nitrosamines in preserved food cause stomach cancer.
# Uses
- Rubber products
- Pesticides
- Certain cosmetics
# Examples of nitrosamines
## Tobacco-specific nitrosamines
- N-Nitrosonornicotine (NNN)
- NNK
- NNAL
- NAT
- NAB
- iso-NNAL
- iso-NNAC
## Other nitrosamines
- NDEA
- NDMA | Nitrosamine
# Overview
Nitrosamines are chemical compounds of the chemical structure R1N(-R2)-N=O, some of which are carcinogenic.
# Occurrence in food
Nitrosamines are produced from nitrites and secondary amines, which often occur in the form of proteins. Their formation can occur only under certain conditions, including strongly acidic conditions such as that of the human stomach. High temperatures, as in frying, can also enhance the formation of nitrosamines.
The nitrite forms nitrous acid (HNO2), which splits into the nitrosonium cation, N=O+, and the hydroxide anion, OH−. The nitrosonium cation then reacts with an amine to produce nitrosamine.
Nitrosamines are found in many foodstuffs especially beer, fish, fish byproducts, and in meat and cheese products preserved with nitrite pickling salt. The US government established limits on the amount of nitrites used in meat products to decrease cancer risk in the population. There are also rules about adding ascorbic acid or related compounds to meat, because they inhibit nitrosamine formation.
# Occurrence in other consumer products
Nitrosamines can be found in tobacco smoke and latex products. A test of party balloons and condoms indicated that many of them release small amounts of nitrosamines.[1] However, nitrosamines from condoms are not expected to be of toxicological significance.[1]
# Cancer
Nitrosamines can cause cancers in a wide variety of animal species, a feature which suggests that they may also be carcinogenic in humans. Epidemiological data suggests that nitrosamines in preserved food cause stomach cancer.[2]
# Uses
- Rubber products
- Pesticides
- Certain cosmetics
# Examples of nitrosamines
## Tobacco-specific nitrosamines
- N-Nitrosonornicotine (NNN)
- NNK
- NNAL
- NAT
- NAB
- iso-NNAL
- iso-NNAC
## Other nitrosamines
- NDEA
- NDMA | https://www.wikidoc.org/index.php/N-Nitrosodiethylamine | |
e93f83071b6c005fdb1a8e523f8152b44c78d2e4 | wikidoc | NACA (gene) | NACA (gene)
Nascent-polypeptide-associated complex alpha polypeptide, also known as NACA, is a protein which in humans is encoded by the NACA gene.
# Function
NACA prevents short recently synthesized (i.e., nascent) ribosome-associated polypeptides from inappropriate interactions with cytosolic proteins. NACA binds nascent-polypeptide domains emerging from ribosomes unless it contains a signal peptide which is fully exposed. Depletion of NACA from ribosomes carrying nascent polypeptides allows the signal recognition particle (SRP) to crosslink to polypeptides regardless of whether or not they contain signal peptides or not. In the absence of NACA, proteins lacking signal peptides can be mis-translocated into the endoplasmic reticulum.
The NACA protein is expressed in bone during development and acts as a transcriptional coactivator in conjunction with acidic activators.
# Interactions
NACA has been shown to interact with BTF3, FADD, C-jun, and 3 members of taxilin family. | NACA (gene)
Nascent-polypeptide-associated complex alpha polypeptide, also known as NACA, is a protein which in humans is encoded by the NACA gene.[1][2][3]
# Function
NACA prevents short recently synthesized (i.e., nascent) ribosome-associated polypeptides from inappropriate interactions with cytosolic proteins. NACA binds nascent-polypeptide domains emerging from ribosomes unless it contains a signal peptide which is fully exposed. Depletion of NACA from ribosomes carrying nascent polypeptides allows the signal recognition particle (SRP) to crosslink to polypeptides regardless of whether or not they contain signal peptides or not. In the absence of NACA, proteins lacking signal peptides can be mis-translocated into the endoplasmic reticulum.[2][4]
The NACA protein is expressed in bone during development and acts as a transcriptional coactivator in conjunction with acidic activators.[3]
# Interactions
NACA has been shown to interact with BTF3, FADD,[5] C-jun,[6] and 3 members of taxilin family.[7] | https://www.wikidoc.org/index.php/NACA_(gene) | |
bc8431e6907b8dbca106b3b06add8ad7789b1e62 | wikidoc | NAD+ kinase | NAD+ kinase
NAD+ kinase (EC 2.7.1.23, NADK) is an enzyme that converts nicotinamide adenine dinucleotide (NAD+) into NADP+ through phosphorylating the NAD+ coenzyme. NADP+ is an essential coenzyme that is reduced to NADPH primarily by the pentose phosphate pathway to provide reducing power in biosynthetic processes such as fatty acid biosynthesis and nucleotide synthesis. The structure of the NADK from the archaean Archaeoglobus fulgidus has been determined.
In humans, the genes NADK and MNADK encode NAD+ kinases localized in cytosol and mitochondria, respectively. Similarly, yeast have both cytosolic and mitochondrial isoforms, and the yeast mitochondrial isoform accepts both NAD+ and NADH as substrates for phosphorylation.
# Reaction
ATP + NAD+ \rightleftharpoons ADP + NADP+
# Mechanism
NADK phosphorylates NAD+ at the 2’ position of the ribose ring that carries the adenine moiety. It is highly selective for its substrates, NAD and ATP, and does not tolerate modifications either to the phosphoryl acceptor, NAD, or the pyridine moiety of the phosphoryl donor, ATP. NADK also uses metal ions to coordinate the ATP in the active site. In vitro studies with various divalent metal ions have shown that zinc and manganese are preferred over magnesium, while copper and nickel are not accepted by the enzyme at all. A proposed mechanism involves the 2' alcohol oxygen acting as a nucleophile to attack the gamma-phosphoryl of ATP, releasing ADP.
# Regulation
NADK is highly regulated by the redox state of the cell. Whereas NAD is predominantly found in its oxidized state NAD+, the phosphorylated NADP is largely present in its reduced form, as NADPH. Thus, NADK can modulate responses to oxidative stress by controlling NADP synthesis. Bacterial NADK is shown to be inhibited allosterically by both NADPH and NADH. NADK is also reportedly stimulated by calcium/calmodulin binding in certain cell types, such as neutrophils. NAD kinases in plants and sea urchin eggs have also been found to bind calmodulin.
# Clinical significance
Due to the essential role of NADPH in lipid and DNA biosynthesis and the hyperproliferative nature of most cancers, NADK is an attractive target for cancer therapy. Furthermore, NADPH is required for the antioxidant activities of thioredoxin reductase and glutaredoxin. Thionicotinamide and other nicotinamide analogs are potential inhibitors of NADK, and studies show that treatment of colon cancer cells with thionicotinamide suppresses the cytosolic NADPH pool to increase oxidative stress and synergizes with chemotherapy.
While the role of NADK in increasing the NADPH pool appears to offer protection against apoptosis, there are also cases where NADK activity appears to potentiate cell death. Genetic studies done in human haploid cell lines indicate that knocking out NADK may protect from certain non-apoptotic stimuli. | NAD+ kinase
NAD+ kinase (EC 2.7.1.23, NADK) is an enzyme that converts nicotinamide adenine dinucleotide (NAD+) into NADP+ through phosphorylating the NAD+ coenzyme.[2] NADP+ is an essential coenzyme that is reduced to NADPH primarily by the pentose phosphate pathway to provide reducing power in biosynthetic processes such as fatty acid biosynthesis and nucleotide synthesis.[3] The structure of the NADK from the archaean Archaeoglobus fulgidus has been determined.[1]
In humans, the genes NADK[4] and MNADK[5] encode NAD+ kinases localized in cytosol[4] and mitochondria,[5] respectively. Similarly, yeast have both cytosolic and mitochondrial isoforms, and the yeast mitochondrial isoform accepts both NAD+ and NADH as substrates for phosphorylation.[6][7]
# Reaction
ATP + NAD+ <math>\rightleftharpoons</math> ADP + NADP+
# Mechanism
NADK phosphorylates NAD+ at the 2’ position of the ribose ring that carries the adenine moiety. It is highly selective for its substrates, NAD and ATP, and does not tolerate modifications either to the phosphoryl acceptor, NAD, or the pyridine moiety of the phosphoryl donor, ATP.[4] NADK also uses metal ions to coordinate the ATP in the active site. In vitro studies with various divalent metal ions have shown that zinc and manganese are preferred over magnesium, while copper and nickel are not accepted by the enzyme at all.[4] A proposed mechanism involves the 2' alcohol oxygen acting as a nucleophile to attack the gamma-phosphoryl of ATP, releasing ADP.
# Regulation
NADK is highly regulated by the redox state of the cell. Whereas NAD is predominantly found in its oxidized state NAD+, the phosphorylated NADP is largely present in its reduced form, as NADPH.[8][9] Thus, NADK can modulate responses to oxidative stress by controlling NADP synthesis. Bacterial NADK is shown to be inhibited allosterically by both NADPH and NADH.[10] NADK is also reportedly stimulated by calcium/calmodulin binding in certain cell types, such as neutrophils.[11] NAD kinases in plants and sea urchin eggs have also been found to bind calmodulin.[12][13]
# Clinical significance
Due to the essential role of NADPH in lipid and DNA biosynthesis and the hyperproliferative nature of most cancers, NADK is an attractive target for cancer therapy. Furthermore, NADPH is required for the antioxidant activities of thioredoxin reductase and glutaredoxin.[14][15] Thionicotinamide and other nicotinamide analogs are potential inhibitors of NADK,[16] and studies show that treatment of colon cancer cells with thionicotinamide suppresses the cytosolic NADPH pool to increase oxidative stress and synergizes with chemotherapy.[17]
While the role of NADK in increasing the NADPH pool appears to offer protection against apoptosis, there are also cases where NADK activity appears to potentiate cell death. Genetic studies done in human haploid cell lines indicate that knocking out NADK may protect from certain non-apoptotic stimuli.[18] | https://www.wikidoc.org/index.php/NAD%2B_kinase | |
a6c681e7260e729e125575c00fc8c356707051ef | wikidoc | NAIP (gene) | NAIP (gene)
Baculoviral IAP repeat-containing protein 1 is a protein that in humans is encoded by the NAIP gene.
This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. This copy of the gene is full length; additional copies with truncations and internal deletions are also present in this region of chromosome 5q13. It is thought that this gene is a modifier of spinal muscular atrophy caused by mutations in a neighboring gene, SMN1.
The protein encoded by this gene contains regions of homology to two baculovirus inhibitor of apoptosis proteins, and it is able to suppress apoptosis induced by various signals. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. | NAIP (gene)
Baculoviral IAP repeat-containing protein 1 is a protein that in humans is encoded by the NAIP gene.[1][2]
This gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four genes and repetitive elements which make it prone to rearrangements and deletions. The repetitiveness and complexity of the sequence have also caused difficulty in determining the organization of this genomic region. This copy of the gene is full length; additional copies with truncations and internal deletions are also present in this region of chromosome 5q13. It is thought that this gene is a modifier of spinal muscular atrophy caused by mutations in a neighboring gene, SMN1.
The protein encoded by this gene contains regions of homology to two baculovirus inhibitor of apoptosis proteins, and it is able to suppress apoptosis induced by various signals. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[2] | https://www.wikidoc.org/index.php/NAIP_(gene) | |
6d6ba2e30cc8906d96fc2b3fbc069cbafe825dcc | wikidoc | NAPA (gene) | NAPA (gene)
N-ethylmaleimide-sensitive factor Attachment Protein Alpha, also known as SNAP-α, is a protein that is involved in the intra-cellular trafficking and fusing of vesicles to target membranes in cells.
# Function
The 'SNARE hypothesis' is a model explaining the process of docking and fusion of vesicles to their target membranes. According to this model, membrane proteins from the vesicle (v-SNAREs) and proteins from the target membrane (t-SNAREs) govern the specificity of vesicle targeting and docking through mutual recognition. Once the 2 classes of SNAREs bind to each other, they form a complex that recruits the general elements of the fusion apparatus, namely NSF (N-ethylmaleimide-sensitive factor) and SNAPs (soluble NSF-attachment proteins), to the site of membrane fusion, thereby forming the 20S fusion complex. Alpha- and gamma-SNAP are found in a wide range of tissues and act synergistically in intra-Golgi transport. The sequence of the predicted 295-amino acid human protein encoded by NAPA shares 37%, 60%, and 67% identity with the sequences of yeast, Drosophila, and squid alpha-SNAP, respectively. Platelets contain some of the same proteins, including NSF, p115/TAP, alpha-SNAP (this protein), gamma-SNAP, and the t-SNAREs syntaxin-2 and syntaxin-4, that are used in many vesicular transport processes in other cell types. Platelet exocytosis uses a molecular mechanism similar to that used by other secretory cells, such as neurons, although the proteins used by the platelet and their modes of regulation may be quite different.
# Clinical significance
NAPA is abnormally expressed in fetuses of both IVF and ICSI, which may contribute to the increased risk of birth defects in these methods of assisted reproductive technology, ART.
# Interactions
NAPA has been shown to interact with:
- NSF,
- SNAP23,
- STX1A,
- STX4,
- STX5.
- ORAI1, STIM1. | NAPA (gene)
N-ethylmaleimide-sensitive factor Attachment Protein Alpha, also known as SNAP-α, is a protein that is involved in the intra-cellular trafficking and fusing of vesicles to target membranes in cells.[1]
# Function
The 'SNARE hypothesis' is a model explaining the process of docking and fusion of vesicles to their target membranes. According to this model, membrane proteins from the vesicle (v-SNAREs) and proteins from the target membrane (t-SNAREs) govern the specificity of vesicle targeting and docking through mutual recognition. Once the 2 classes of SNAREs bind to each other, they form a complex that recruits the general elements of the fusion apparatus, namely NSF (N-ethylmaleimide-sensitive factor) and SNAPs (soluble NSF-attachment proteins), to the site of membrane fusion, thereby forming the 20S fusion complex. Alpha- and gamma-SNAP are found in a wide range of tissues and act synergistically in intra-Golgi transport. The sequence of the predicted 295-amino acid human protein encoded by NAPA shares 37%, 60%, and 67% identity with the sequences of yeast, Drosophila, and squid alpha-SNAP, respectively. Platelets contain some of the same proteins, including NSF, p115/TAP, alpha-SNAP (this protein), gamma-SNAP, and the t-SNAREs syntaxin-2 and syntaxin-4, that are used in many vesicular transport processes in other cell types. Platelet exocytosis uses a molecular mechanism similar to that used by other secretory cells, such as neurons, although the proteins used by the platelet and their modes of regulation may be quite different.[citation needed]
# Clinical significance
NAPA is abnormally expressed in fetuses of both IVF and ICSI, which may contribute to the increased risk of birth defects in these methods of assisted reproductive technology, ART.[2]
# Interactions
NAPA has been shown to interact with:
- NSF,[3][4]
- SNAP23,[5]
- STX1A,[3][6]
- STX4,[5]
- STX5.[5][7]
- ORAI1, STIM1.[8] | https://www.wikidoc.org/index.php/NAPA_(gene) | |
b6c35d4f2a7233c302a9bbc42a694cc58787d82e | wikidoc | NFIB (gene) | NFIB (gene)
# Embryonic Development
The NFIB gene is a part of the NFI gene complex that includes three other genes (NFIA, NFIC and NFIX). The NFIB gene is a protein coding gene that also serves as a transcription factor. This gene is essential in embryonic development and it works together with its gene complex to initiate tissue differentiation in the fetus. NFIB has the highest concentrations in the lung, skeletal muscle and heart but is also found in the areas of the developing liver, kidneys and brain.
Through knockout experiments, researchers found that mice without the NFIB gene have severely underdeveloped lungs. This mutation does not seem to cause spontaneous abortions because in utero the fetus does not use its lungs for respiration. However, this becomes lethal once the fetus is born and has to take its first breath. It is thought that NFIB plays a role in down regulating the transcription factors TGF-β1 and Shh in normal gestation because they remained high in knockout experiments. The absence of NFIB also leads to insufficient amounts of surfactant being produced which is one reason why the mice cannot breathe once it is born. The knockout experiments demonstrated that NFIB has a significant role in fore-brain development. NFIB is typically found in pontine nuclei of the CNS, the cerebral cortex and the white matter of the brain and without NFIB these areas are dramatically affected.
Absence of one copy is associated with macrocephaly and intellectual disability. This associated was confirmed in mouse modelswhere deletion of one copy resulted in enlargement of the brain while preserving its overall organisation.
# General Information
Nuclear factor 1 B-type is a protein that in humans is encoded by the NFIB gene. | NFIB (gene)
# Embryonic Development
The NFIB gene is a part of the NFI gene complex that includes three other genes (NFIA, NFIC and NFIX).[1][2] The NFIB gene is a protein coding gene that also serves as a transcription factor.[3] This gene is essential in embryonic development and it works together with its gene complex to initiate tissue differentiation in the fetus. NFIB has the highest concentrations in the lung, skeletal muscle and heart but is also found in the areas of the developing liver, kidneys and brain.[1]
Through knockout experiments, researchers found that mice without the NFIB gene have severely underdeveloped lungs.[2][4] This mutation does not seem to cause spontaneous abortions because in utero the fetus does not use its lungs for respiration. However, this becomes lethal once the fetus is born and has to take its first breath. It is thought that NFIB plays a role in down regulating the transcription factors TGF-β1 and Shh in normal gestation because they remained high in knockout experiments.[2] The absence of NFIB also leads to insufficient amounts of surfactant being produced which is one reason why the mice cannot breathe once it is born.[2] The knockout experiments demonstrated that NFIB has a significant role in fore-brain development. NFIB is typically found in pontine nuclei of the CNS, the cerebral cortex and the white matter of the brain and without NFIB these areas are dramatically affected.[1][4]
Absence of one copy is associated with macrocephaly and intellectual disability. This associated was confirmed in mouse modelswhere deletion of one copy resulted in enlargement of the brain while preserving its overall organisation.
[5]
# General Information
Nuclear factor 1 B-type is a protein that in humans is encoded by the NFIB gene.[6][7] | https://www.wikidoc.org/index.php/NFIB_(gene) | |
d5fa489f1a9e3d42fc34b38ec8216ad7b70d293a | wikidoc | Nitroethane | Nitroethane
Nitroethane is an organic compound having the chemical formula C2H5NO2. Similar in many regards to nitromethane, nitroethane is an oily liquid at standard temperature and pressure. Pure nitroethane is colourless, and has a fruity odor. It is a high volume chemical, with over 1 million pounds of nitroethane being produced or imported into the United States of America per year.
# Uses
Nitroethane is most commonly used as a solvent for artificial polymers such as styrene, and particularly for dissolving cyanoacrylate adhesives. It has been used as a component in artificial nail remover and in overhead ceiling sealant sprays, although it is not common in such applications. Nitroethane is also used as a fuel additive for increasing the octane rating of gasoline, as a pure fuel in certain drag racing vehicles, and as a propellant.
In addition, nitroethane finds use as a reagent in various syntheses, primarily in organic chemistry (for example, in the artificial synthesis of piperonal and phenylacetone) and for production of pharmaceutical compounds. Among the compounds for which nitroethane is useful, both methamphetamine and MDMA may be synthesized using nitroethane as an essential precursor; for this reason, nitroethane has been designated a List I precursor chemical under the Controlled Substances Act in the USA.
# Toxicity
Nitroethane is suspected for damage to the genes and nervous system. Typical TLV/TWA 100 ppm. Typical STEL 150 ppm. Skin contact with nitroethane is known to cause dermatitis in human beings; and in animal studies, the effects of nitroethane exposure were observed to include lacrimation; dyspnea, pulmonary rales, edema; liver, kidney injury; and narcosis.
Also, there have been instances of nitroethane poisoning in children due to accidental ingestion of artificial nail remover.
The LD50 for rats is reported as 1100 mg/kg. | Nitroethane
Nitroethane is an organic compound having the chemical formula C2H5NO2. Similar in many regards to nitromethane, nitroethane is an oily liquid at standard temperature and pressure. Pure nitroethane is colourless, and has a fruity odor. It is a high volume chemical, with over 1 million pounds of nitroethane being produced or imported into the United States of America per year.[1]
# Uses
Nitroethane is most commonly used as a solvent for artificial polymers such as styrene, and particularly for dissolving cyanoacrylate adhesives.[2] It has been used as a component in artificial nail remover and in overhead ceiling sealant sprays, although it is not common in such applications. Nitroethane is also used as a fuel additive for increasing the octane rating of gasoline, as a pure fuel in certain drag racing vehicles, and as a propellant.[3]
In addition, nitroethane finds use as a reagent in various syntheses, primarily in organic chemistry (for example, in the artificial synthesis of piperonal and phenylacetone) and for production of pharmaceutical compounds. Among the compounds for which nitroethane is useful, both methamphetamine and MDMA may be synthesized using nitroethane as an essential precursor; for this reason, nitroethane has been designated a List I precursor chemical under the Controlled Substances Act in the USA.
# Toxicity
Nitroethane is suspected for damage to the genes and nervous system. Typical TLV/TWA 100 ppm. Typical STEL 150 ppm. Skin contact with nitroethane is known to cause dermatitis in human beings; and in animal studies, the effects of nitroethane exposure were observed to include lacrimation; dyspnea, pulmonary rales, edema; liver, kidney injury; and narcosis.[4]
Also, there have been instances of nitroethane poisoning in children due to accidental ingestion of artificial nail remover.[5]
The LD50 for rats is reported as 1100 mg/kg.[6] | https://www.wikidoc.org/index.php/NN-Dimethyl-P-Toluidine | |
be9c242c7a8c7102be2cfb0b3d58623d11d5c725 | wikidoc | NPH insulin | NPH insulin
Neutral Protamine Hagedorn was created in 1946 when Nordisk formulated "isophane" porcine insulin by adding Neutral Protamine Hagedorn or NPH.
This is a suspension of crystalline zinc insulin combined with the positively charged polypeptide, protamine. It has an intermediate duration of action, longer than that of regular insulin, but shorter than ultralente.
# History
Hans Christian Hagedorn (1888-1971) and August Krogh (1874-1949) obtained the rights for insulin from Banting and Best in Toronto. In 1923 they formed Nordisk Insulinlaboratorium, and in 1926 with August Kongsted he obtained a Danish Royal Charters as a non-profit foundation.
In 1936 Hagedorn and B. Norman Jensen discovered that the effects of injected insulin could be prolonged by the addition of protamine obtained from the "milt" or semen of river trout. The insulin would be added to the protamine, but the solution would have to be brought to pH 7 for injection. Canada later produced ZPI insulin, a mixture of zinc, protamine and porcine insulin. This mixture only needed to be shaken before injection.
In 1946 Nordisk was able to form crystals of protamine and insulin and marketed it in 1950 as NPH insulin. NPH insulin has the advantage that it can be mixed with an insulin that has a faster onset to complement its longer lasting action.
Eventually all animal insulins were replaced by human recombinant insulin. Human insulin is also complexed with NPH.
# Timeline
- 1926 Nordisk receives Danish charter to produce insulin
- 1936 Hagedorn discovers that adding protamine to insulin prolongs the effect of insulin
- 1936 Canadians D.M. Scott and A.M. Fisher formulate zinc insulin mixture and license to Novo
- 1946 Nordisk crystallizes a protamine and insulin mixture
- 1950 Nordisk markets NPH insulin
- 1953 Nordisk markets "Lente" zinc insulin mixtures | NPH insulin
Neutral Protamine Hagedorn was created in 1946 when Nordisk formulated "isophane" porcine insulin by adding Neutral Protamine Hagedorn or NPH.
This is a suspension of crystalline zinc insulin combined with the positively charged polypeptide, protamine. It has an intermediate duration of action, longer than that of regular insulin, but shorter than ultralente.
# History
Hans Christian Hagedorn (1888-1971) and August Krogh (1874-1949) obtained the rights for insulin from Banting and Best in Toronto. In 1923 they formed Nordisk Insulinlaboratorium, and in 1926 with August Kongsted he obtained a Danish Royal Charters as a non-profit foundation.
In 1936 Hagedorn and B. Norman Jensen discovered that the effects of injected insulin could be prolonged by the addition of protamine obtained from the "milt" or semen of river trout. The insulin would be added to the protamine, but the solution would have to be brought to pH 7 for injection. Canada later produced ZPI insulin, a mixture of zinc, protamine and porcine insulin. This mixture only needed to be shaken before injection.
In 1946 Nordisk was able to form crystals of protamine and insulin and marketed it in 1950 as NPH insulin. NPH insulin has the advantage that it can be mixed with an insulin that has a faster onset to complement its longer lasting action.
Eventually all animal insulins were replaced by human recombinant insulin. Human insulin is also complexed with NPH.
# Timeline
- 1926 Nordisk receives Danish charter to produce insulin
- 1936 Hagedorn discovers that adding protamine to insulin prolongs the effect of insulin
- 1936 Canadians D.M. Scott and A.M. Fisher formulate zinc insulin mixture and license to Novo
- 1946 Nordisk crystallizes a protamine and insulin mixture
- 1950 Nordisk markets NPH insulin
- 1953 Nordisk markets "Lente" zinc insulin mixtures | https://www.wikidoc.org/index.php/NPH_insulin | |
c8b39ed513ddfd6357b150af5c12b4d92f4093c1 | wikidoc | NUMB (gene) | NUMB (gene)
Protein numb homolog is a protein that in humans is encoded by the NUMB gene.
The protein encoded by this gene plays a role in the determination of cell fates during development. The encoded protein, whose degradation is induced in a proteasome-dependent manner by MDM2, is a membrane-bound protein that has been shown to associate with EPS15, LNX1, and NOTCH1. Four transcript variants encoding different isoforms have been found for this gene.
The protein Numb is coded for by the gene, NUMB, whose mechanism appears to be evolutionarily conserved. Numb has been extensively studied in both invertebrates and mammals, though its function is best understood in Drosophila. Numb plays a crucial role in asymmetrical cell division during development, allowing for differential cell fate specification in the central and peripheral nervous systems. During neurogenesis, Numb localizes to one side of the mother cell such that it is distributed selectively to one daughter cell. This asymmetric division allows a daughter cell containing Numb to acquire a different fate than the other daughter cell.
# Gene
The numb gene protein product controls binary cell fate decisions in the peripheral and central nervous systems of both invertebrates and mammals during neurogenesis. During cell division, Numb is asymmetrically localized to one end of the progenitor cell and subsequently segregates to only one daughter cell where it intrinsically determines cell fate. Numb protein signaling plays a key role in binary cell fate decisions following asymmetric cell divisions. One daughter cell, generally that receiving the Numb, is able to adopt a neuronal fate and innervate the developing nervous system. The other daughter cell becomes a progenitor cell to fill the lost role of the parent cell and maintain proliferation. In addition to its role in proliferation and differentiation, Numb has also been shown to play a role in tumorigenesis and the response of neural progenitors to chemotactic cues during migration.
In mammals, there are four alternatively spliced forms of the Numb protein. In addition, there is a Numb homolog called “Numb-like,” or NUMBL. Numb proteins in mammals are not as well understood as their fly counterparts. The various forms of Numb have differential progenitor-promoting and differentiation-promoting functions. More research is necessary to understand the complex relationships between these forms of Numb and their functions.
# Asymmetic localization
In both invertebrates and mammals, Numb is localized using the Pins/GαI complex and the PAR complex of Bazooka (Par3 in mammals), Par6, and aPKC (atypical protein kinase C). In the sensory organ precursor (SOP) cell, the PAR proteins localize to the posterior pole of the cell, and the Pins/GαI complex is localized to the anterior pole of the cell. This results in an anterior/posterior cell division with daughter cells of similar size. In neuroblasts, both complexes are localized to the apical cortex, causing apical/basal cell division and daughter cells exhibiting strong size asymmetry. In the SOP, one mechanism for Numb localization has been proposed based on the PAR complex. It states that a complex phosphorylation cascade enables aPKC to phosphorylate Numb in the pre-mitotic cell, decreasing its affinity for the plasma membrane. This releases Numb from the aPKC pole, increasing its presence in the non-aPKC pole. This establishes the asymmetric distribution of Numb, with the Numb/Pon crescent on one side of the mother cell.
Another proposed component of the localization complex is Partner of Numb (PON), which is asymmetrically localized during mitosis and acts as an adaptor protein by binding and mediating the anchoring of Numb. The localization of PON is controlled by either Insc or the Frizzled-Wnt signaling pathway.
# Role in cell proliferation and differentiation
## Differentiation through inhibition of notch signaling
Numb’s primary function in cell differentiation is as an inhibitor of Notch signaling which is essential for maintaining self-renewal potential in stem and progenitor cells. Notch is a transmembrane signaling receptor that is activated by DSL family ligands. Notch binds the ligands Delta and Serrate in Drosophila. The human ligands are Delta-like and Jagged, respectively. These ligands are themselves integral membrane proteins. Following ligand binding of the Notch receptor, the intracellular fragment of Notch (NICD, or notch intracellular domain) is released into the cytoplasm and transported to the nucleus, where it can form a complex with binding partners such as EP300 and histone acetyltransferase and act as a transcription factor for Notch target genes. Among the Notch target genes are members of the HES and HEY gene families whose protein products can act as transcriptional repressors for tissue-specific transcription factors, thus maintaining the cell’s potential for self-renewal.
## Inhibition of notch signaling through the ubiquitination pathway
Numb exerts its functional role on cell fate decisions by antagonizing Notch signaling activities. The molecular mechanisms underlying this relationship appear to rely on the ubiquitination of the membrane bound Notch1 receptor and the subsequent degradation of its NICD following receptor activation. In support of this, Numb’s ability to ubiquinate Notch1 directly correlated with its functional inhibition of Notch1 signaling activities. The ubiquitination pathway directs protein recycling by directly tagging specific proteins for proteasome degradation. Through a multi-step process, free ubiquitin is first attached to an activating enzyme (E1) and then transferred to a conjugating enzyme (E2) which partners with a ligase (E3) which functions as an adaptor to selectively transfer the ubiquitin to specific protein substrates. Numb expression was found to selectively tag the membrane Notch1 receptor for ubiquitination through the interaction of its Phosphotyrosine-binding domain with the E3 ubiquitin ligase Itch. Numb and Itch work in concert to promote the ubiquitination of the full-length membrane-tethered Notch receptor prior to activation. However, Numb only appears to promote the degradation of the NICD cleavage product following receptor activation, targeting it for proteasome degradation and preventing its translocation to the nucleus.
## Inhibition of notch signaling through sanpodo
Numb acts as an antagonist for Notch by causing its selective endocytosis and degradation. Another mechanism proposed for how this is accomplished in Drosophila involves a protein called Sanpodo. Sanpodo is a protein that associates with both Notch and Numb. It is located at the plasma membrane and is necessary for Notch activation, promoting Notch cleavage and NICD signaling in the nucleus. Numb converts Sanpodo from an activator to an inhibitor of Notch signaling, magnifying the differences in Notch signaling between different daughter cells. In daughter cells containing Numb, Sanpodo allows Numb to inhibit Notch. In daughter cells with no Numb, Sanpodo potentiates Notch signaling. Sanpodo therefore allows cells to maintain Notch signaling at a below- or above-threshold level.
# Numb in Drosophila
Numb has been studied most extensively in Drosophila, in particular in the context of their sensory organ precursors and ganglion mother cells.
## External sensory organ development
The Drosophila external sensory organ is a sensory structure in the peripheral nervous system that consists of four cells; a neuron, a sheath cell that surrounds the dendrite, and hair and socket cells, which are considered the “outer” support cells. All four cell fates are descendants of the sensory organ precursor (SOP) cell. In response to the proper cues, SOPs first divide into two secondary precursor cells. The posterior daughter cell is called the pIIa cell and the anterior daughter cell is called the pIIb. The pIIa cell divides to produce a bristle cell and a socket cell, while the pIIb cell divides to produce a neuron and a glial cell. The asymmetric division of the SOP into daughter cells with distinct fates is dependent upon the distribution of Numb. Numb is distributed uniformly in the cytoplasm until mitotic division, when it is selectively localized to the anterior pole of the cell. Thus, Numb is selectively segregated into the pIIb daughter cell upon division of the SOP.
Loss of Numb function causes inappropriate differentiation of SOP cells into all pIIa cells, producing four outer support cells and no neurons or glia. In SOP loss of function Numb mutants, flies have a significant decrease in sensory neurons, leaving them “numb.” Gain of function Notch mutants express a similar phenotype. Ectopic expression of Numb during SOP division has the opposite effect, producing all pIIb cells and no outer support cells. In support of previous experiments demonstrating the role of Numb in Notch signaling inhibition, functional loss of Notch signaling components result in SOP division into two pIIb cells, suggesting Numb promotes acquisition of the pIIb cell fate through inhibition of Notch signaling. Thus, the asymmetric distribution of Numb into IIb secondary precursors during SOP division is necessary for daughter cells to acquire distinct cell fates.
## Ganglion mother cell
A ganglion mother cell (GMC) is the cell derived from the division of a neuroblast in the Drosophila central nervous system. The neuroblast divides to produce two cells, a progenitor cell like the mother neuroblast and a GMC that will divide to produce neurons. The mother neuroblast divides along the apical-basal axis, with Numb localizing basally and ending up in the GMC.
# Numb in mammals
## Alternative splicing to support proliferation and differentiation
In mice embryos mutant for Numb, early neurons emerge in the expected spatial and temporal pattern but fail to maintain a sufficient pool of proliferating progenitors and nearly deplete the population of dividing cells shortly after the onset of neurogenesis. These embryos display precocious neuron production in the forebrain and defects in neural tube closure, dying around embryonic day 11.5. These studies suggest a functional role of mammalian Numb in promoting progenitor cell fate during neurogenesis, which directly opposes the proposed role of Numb in invertebrates. However, other studies have shown overexpression of Numb in the mammalian neural crest MONC-1 stem cell line biases neuronal differentiation, consistent with what is observed in drosophila.
Unlike the invertebrate Numb gene, the mammalian Numb gene undergoes alternative splicing to produce at least four functionally different Numb isoforms. While asymmetric divisions alone can produce sufficient neuron populations in Drosophilia, mammalian brains are much more advanced and require larger populations of neurons that can’t be established to asymmetric divisions alone. Thus, mammalian cortical progenitors must first need to undergo symmetric divisions to expand the progenitor pool before they can undergo later asymmetric divisions for neuronal generations. The mammalian brain has accounted for this by producing isoforms of Numb that maintain progenitor populations in addition to those which support neuronal differentiation.
Studies using the mouse embryonic P19 cell line have shown isoforms with the short proline rich region (PRR) domain promote neuronal differentiation, while those with the long PRR domain promote cell proliferation and prevent differentiation. The p71 and p72 isoforms, which contain the PRR insert, are primarily expressed in actively dividing tissues and are down regulated during differentiation suggesting these isoforms promote cell proliferation (Dho et al., 1999). In contrast, the Drosophilia Numb gene encodes a 66 kDa protein. Consistent with the finding that Numb only supports differentiation and not proliferation in asymmetric division, the 66 kDa Drosophilia protein is analogous to a shorter mammalian isoform lacking the PRR insert and thus promoting cell differentiation.
# Role in cancer and tumorigenesis
In several types of cancer, a loss of Numb expression has been demonstrated. This is well-established in breast cancer, where a loss of Numb correlates with a worse prognosis. Numb loss has also been demonstrated in Non-small-cell lung carcinoma, salivary gland carcinoma, and chronic myelogenous leukemia. Restoration of Numb function, or manipulation of enzymes in the ubiquitin mechanism, are some possible research directions for the treatment of certain cancer types.
## Role in mammary carcinomas
In approximately half of all human mammary carcinomas, Numb-mediated suppression of Notch signaling is lost due to Numb ubiquitination, tagging it for proteasomal degradation. Numb acts as an oncogene suppressor, inhibiting tumor cell proliferation through suppression of Notch signaling. Increased Notch signaling is observed in tumors where Numb activity has been lost and retrovirally mediated transient overexpression of Numb protein in these tumors restored basal levels of Notch signaling and significantly reduced their colony-forming abilities. Thus, the biological antagonism between Notch and Numb signaling that controls the proliferative/differentiative balance of many cell lineages appears to play a role in human breast carcinogenesis and perhaps other types of tumorigenesis. Pharmalogical inhibition of Notch signaling or enhancement of Numb signaling could be a source of treatment for cancer patients in the future.
Numb has been posited to have a role in tumor-suppression, through its ability to regulate Notch and TP53. Numb binds and inhibits the E3-ligase Mdm2 that is responsible for TP53 ubiquitination and degradation. The ablation of Numb in a cell leads to a decrease in TP53, causing impaired apoptosis and cell cycle checkpoint response. Restoring Numb levels also restores TP53 expression and tumor suppressant abilities.
# Role in cell migration
Neural precursors are generated in proliferative zones, before migrating to directed locations where they undergo maturation and become functional neurons. Studies in Drosophilia first suggested Numb played a role in cell migration when mutants displayed defective glial migration along axonal tracts. Since then, a mechanism has been discovered through which Numb binds chemotactic signaling receptors, forming a scaffold for atypical PKC (aPKC) recruitment to the receptor complex. Once activated, aPKC phosphorylates Numb, thus promoting a positive feed-forward response that potentiates Numb-chemotactic receptor binding and subsequent endosomal complex formation. Endocytosis supports the relocalization of the chemotactic receptor to the front of the cell to promote receptor-mediated directional migration in response to receptor activation.
Brain-derived neurotrophic factor is among the chemotactic factors that stimulate Numb-mediated chemotaxis during cell migration. BDNF can function as a chemotactic factor for neural precursors during migration by activating TrkB receptors. Numb binds to TrkB receptors to act as an endocytic regulator of TrkB and promote aPKC activation by acting as a scaffolding protein. Once phosphorylated, aPKC can also phosphorylate Numb to increase its efficacy for binding TrkB, thus promoting the precursor’s chemotactic sensitivity to BDNF.
# Interactions
Numb has demonstrated protein-protein interactions with Adaptor-related protein complex 2, alpha 1, Mdm2, L1, DPYSL2, SIAH1, P53 and LNX1. | NUMB (gene)
Protein numb homolog is a protein that in humans is encoded by the NUMB gene.
The protein encoded by this gene plays a role in the determination of cell fates during development. The encoded protein, whose degradation is induced in a proteasome-dependent manner by MDM2, is a membrane-bound protein that has been shown to associate with EPS15, LNX1, and NOTCH1. Four transcript variants encoding different isoforms have been found for this gene.[1]
The protein Numb is coded for by the gene, NUMB, whose mechanism appears to be evolutionarily conserved.[2] Numb has been extensively studied in both invertebrates and mammals, though its function is best understood in Drosophila. Numb plays a crucial role in asymmetrical cell division during development, allowing for differential cell fate specification in the central and peripheral nervous systems. During neurogenesis, Numb localizes to one side of the mother cell such that it is distributed selectively to one daughter cell. This asymmetric division allows a daughter cell containing Numb to acquire a different fate than the other daughter cell.
# Gene
The numb gene protein product controls binary cell fate decisions in the peripheral and central nervous systems of both invertebrates and mammals during neurogenesis.[3] During cell division, Numb is asymmetrically localized to one end of the progenitor cell and subsequently segregates to only one daughter cell where it intrinsically determines cell fate.[3] Numb protein signaling plays a key role in binary cell fate decisions following asymmetric cell divisions. One daughter cell, generally that receiving the Numb, is able to adopt a neuronal fate and innervate the developing nervous system. The other daughter cell becomes a progenitor cell to fill the lost role of the parent cell and maintain proliferation. In addition to its role in proliferation and differentiation, Numb has also been shown to play a role in tumorigenesis and the response of neural progenitors to chemotactic cues during migration.
In mammals, there are four alternatively spliced forms of the Numb protein. In addition, there is a Numb homolog called “Numb-like,” or NUMBL. Numb proteins in mammals are not as well understood as their fly counterparts. The various forms of Numb have differential progenitor-promoting and differentiation-promoting functions.[4] More research is necessary to understand the complex relationships between these forms of Numb and their functions.
# Asymmetic localization
In both invertebrates and mammals, Numb is localized using the Pins/GαI complex and the PAR complex of Bazooka (Par3 in mammals), Par6, and aPKC (atypical protein kinase C). In the sensory organ precursor (SOP) cell, the PAR proteins localize to the posterior pole of the cell, and the Pins/GαI complex is localized to the anterior pole of the cell. This results in an anterior/posterior cell division with daughter cells of similar size. In neuroblasts, both complexes are localized to the apical cortex, causing apical/basal cell division and daughter cells exhibiting strong size asymmetry.[5] In the SOP, one mechanism for Numb localization has been proposed based on the PAR complex. It states that a complex phosphorylation cascade enables aPKC to phosphorylate Numb in the pre-mitotic cell, decreasing its affinity for the plasma membrane. This releases Numb from the aPKC pole, increasing its presence in the non-aPKC pole.[6] This establishes the asymmetric distribution of Numb, with the Numb/Pon crescent on one side of the mother cell.
Another proposed component of the localization complex is Partner of Numb (PON), which is asymmetrically localized during mitosis and acts as an adaptor protein by binding and mediating the anchoring of Numb. The localization of PON is controlled by either Insc or the Frizzled-Wnt signaling pathway.[7]
# Role in cell proliferation and differentiation
## Differentiation through inhibition of notch signaling
Numb’s primary function in cell differentiation is as an inhibitor of Notch signaling which is essential for maintaining self-renewal potential in stem and progenitor cells. Notch is a transmembrane signaling receptor that is activated by DSL family ligands. Notch binds the ligands Delta and Serrate in Drosophila. The human ligands are Delta-like and Jagged, respectively. These ligands are themselves integral membrane proteins. Following ligand binding of the Notch receptor, the intracellular fragment of Notch (NICD, or notch intracellular domain) is released into the cytoplasm and transported to the nucleus, where it can form a complex with binding partners such as EP300 and histone acetyltransferase and act as a transcription factor for Notch target genes.[8] Among the Notch target genes are members of the HES and HEY gene families whose protein products can act as transcriptional repressors for tissue-specific transcription factors, thus maintaining the cell’s potential for self-renewal.
## Inhibition of notch signaling through the ubiquitination pathway
Numb exerts its functional role on cell fate decisions by antagonizing Notch signaling activities. The molecular mechanisms underlying this relationship appear to rely on the ubiquitination of the membrane bound Notch1 receptor and the subsequent degradation of its NICD following receptor activation.[9] In support of this, Numb’s ability to ubiquinate Notch1 directly correlated with its functional inhibition of Notch1 signaling activities. The ubiquitination pathway directs protein recycling by directly tagging specific proteins for proteasome degradation. Through a multi-step process, free ubiquitin is first attached to an activating enzyme (E1) and then transferred to a conjugating enzyme (E2) which partners with a ligase (E3) which functions as an adaptor to selectively transfer the ubiquitin to specific protein substrates. Numb expression was found to selectively tag the membrane Notch1 receptor for ubiquitination through the interaction of its Phosphotyrosine-binding domain with the E3 ubiquitin ligase Itch. Numb and Itch work in concert to promote the ubiquitination of the full-length membrane-tethered Notch receptor prior to activation. However, Numb only appears to promote the degradation of the NICD cleavage product following receptor activation, targeting it for proteasome degradation and preventing its translocation to the nucleus.
## Inhibition of notch signaling through sanpodo
Numb acts as an antagonist for Notch by causing its selective endocytosis and degradation.[10] Another mechanism proposed for how this is accomplished in Drosophila involves a protein called Sanpodo. Sanpodo is a protein that associates with both Notch and Numb. It is located at the plasma membrane and is necessary for Notch activation, promoting Notch cleavage and NICD signaling in the nucleus.[5] Numb converts Sanpodo from an activator to an inhibitor of Notch signaling, magnifying the differences in Notch signaling between different daughter cells. In daughter cells containing Numb, Sanpodo allows Numb to inhibit Notch. In daughter cells with no Numb, Sanpodo potentiates Notch signaling. Sanpodo therefore allows cells to maintain Notch signaling at a below- or above-threshold level.[2]
# Numb in Drosophila
Numb has been studied most extensively in Drosophila, in particular in the context of their sensory organ precursors and ganglion mother cells.
## External sensory organ development
The Drosophila external sensory organ is a sensory structure in the peripheral nervous system that consists of four cells; a neuron, a sheath cell that surrounds the dendrite, and hair and socket cells, which are considered the “outer” support cells. All four cell fates are descendants of the sensory organ precursor (SOP) cell. In response to the proper cues, SOPs first divide into two secondary precursor cells. The posterior daughter cell is called the pIIa cell and the anterior daughter cell is called the pIIb. The pIIa cell divides to produce a bristle cell and a socket cell, while the pIIb cell divides to produce a neuron and a glial cell. The asymmetric division of the SOP into daughter cells with distinct fates is dependent upon the distribution of Numb. Numb is distributed uniformly in the cytoplasm until mitotic division, when it is selectively localized to the anterior pole of the cell. Thus, Numb is selectively segregated into the pIIb daughter cell upon division of the SOP.[11]
Loss of Numb function causes inappropriate differentiation of SOP cells into all pIIa cells, producing four outer support cells and no neurons or glia.[12] In SOP loss of function Numb mutants, flies have a significant decrease in sensory neurons, leaving them “numb.” Gain of function Notch mutants express a similar phenotype.[13] Ectopic expression of Numb during SOP division has the opposite effect, producing all pIIb cells and no outer support cells. In support of previous experiments demonstrating the role of Numb in Notch signaling inhibition, functional loss of Notch signaling components result in SOP division into two pIIb cells, suggesting Numb promotes acquisition of the pIIb cell fate through inhibition of Notch signaling.[12] Thus, the asymmetric distribution of Numb into IIb secondary precursors during SOP division is necessary for daughter cells to acquire distinct cell fates.[11]
## Ganglion mother cell
A ganglion mother cell (GMC) is the cell derived from the division of a neuroblast in the Drosophila central nervous system. The neuroblast divides to produce two cells, a progenitor cell like the mother neuroblast and a GMC that will divide to produce neurons. The mother neuroblast divides along the apical-basal axis, with Numb localizing basally and ending up in the GMC.[14]
# Numb in mammals
## Alternative splicing to support proliferation and differentiation
In mice embryos mutant for Numb, early neurons emerge in the expected spatial and temporal pattern but fail to maintain a sufficient pool of proliferating progenitors and nearly deplete the population of dividing cells shortly after the onset of neurogenesis.[15] These embryos display precocious neuron production in the forebrain and defects in neural tube closure, dying around embryonic day 11.5.[16] These studies suggest a functional role of mammalian Numb in promoting progenitor cell fate during neurogenesis, which directly opposes the proposed role of Numb in invertebrates. However, other studies have shown overexpression of Numb in the mammalian neural crest MONC-1 stem cell line biases neuronal differentiation, consistent with what is observed in drosophila.[17]
Unlike the invertebrate Numb gene, the mammalian Numb gene undergoes alternative splicing to produce at least four functionally different Numb isoforms. While asymmetric divisions alone can produce sufficient neuron populations in Drosophilia, mammalian brains are much more advanced and require larger populations of neurons that can’t be established to asymmetric divisions alone.[18] Thus, mammalian cortical progenitors must first need to undergo symmetric divisions to expand the progenitor pool before they can undergo later asymmetric divisions for neuronal generations. The mammalian brain has accounted for this by producing isoforms of Numb that maintain progenitor populations in addition to those which support neuronal differentiation.
Studies using the mouse embryonic P19 cell line have shown isoforms with the short proline rich region (PRR) domain promote neuronal differentiation, while those with the long PRR domain promote cell proliferation and prevent differentiation.[19] The p71 and p72 isoforms, which contain the PRR insert, are primarily expressed in actively dividing tissues and are down regulated during differentiation suggesting these isoforms promote cell proliferation (Dho et al., 1999). In contrast, the Drosophilia Numb gene encodes a 66 kDa protein.[17] Consistent with the finding that Numb only supports differentiation and not proliferation in asymmetric division, the 66 kDa Drosophilia protein is analogous to a shorter mammalian isoform lacking the PRR insert and thus promoting cell differentiation.[17]
# Role in cancer and tumorigenesis
In several types of cancer, a loss of Numb expression has been demonstrated. This is well-established in breast cancer, where a loss of Numb correlates with a worse prognosis.[20] Numb loss has also been demonstrated in Non-small-cell lung carcinoma, salivary gland carcinoma, and chronic myelogenous leukemia. Restoration of Numb function, or manipulation of enzymes in the ubiquitin mechanism, are some possible research directions for the treatment of certain cancer types.[2]
## Role in mammary carcinomas
In approximately half of all human mammary carcinomas, Numb-mediated suppression of Notch signaling is lost due to Numb ubiquitination, tagging it for proteasomal degradation.[20] Numb acts as an oncogene suppressor, inhibiting tumor cell proliferation through suppression of Notch signaling. Increased Notch signaling is observed in tumors where Numb activity has been lost and retrovirally mediated transient overexpression of Numb protein in these tumors restored basal levels of Notch signaling and significantly reduced their colony-forming abilities. Thus, the biological antagonism between Notch and Numb signaling that controls the proliferative/differentiative balance of many cell lineages appears to play a role in human breast carcinogenesis and perhaps other types of tumorigenesis. Pharmalogical inhibition of Notch signaling or enhancement of Numb signaling could be a source of treatment for cancer patients in the future.
Numb has been posited to have a role in tumor-suppression, through its ability to regulate Notch and TP53. Numb binds and inhibits the E3-ligase Mdm2 that is responsible for TP53 ubiquitination and degradation. The ablation of Numb in a cell leads to a decrease in TP53, causing impaired apoptosis and cell cycle checkpoint response. Restoring Numb levels also restores TP53 expression and tumor suppressant abilities.[2]
# Role in cell migration
Neural precursors are generated in proliferative zones, before migrating to directed locations where they undergo maturation and become functional neurons. Studies in Drosophilia first suggested Numb played a role in cell migration when mutants displayed defective glial migration along axonal tracts. Since then, a mechanism has been discovered through which Numb binds chemotactic signaling receptors, forming a scaffold for atypical PKC (aPKC) recruitment to the receptor complex.[21] Once activated, aPKC phosphorylates Numb, thus promoting a positive feed-forward response that potentiates Numb-chemotactic receptor binding and subsequent endosomal complex formation. Endocytosis supports the relocalization of the chemotactic receptor to the front of the cell to promote receptor-mediated directional migration in response to receptor activation.
Brain-derived neurotrophic factor is among the chemotactic factors that stimulate Numb-mediated chemotaxis during cell migration.[21] BDNF can function as a chemotactic factor for neural precursors during migration by activating TrkB receptors. Numb binds to TrkB receptors to act as an endocytic regulator of TrkB and promote aPKC activation by acting as a scaffolding protein. Once phosphorylated, aPKC can also phosphorylate Numb to increase its efficacy for binding TrkB, thus promoting the precursor’s chemotactic sensitivity to BDNF.
# Interactions
Numb has demonstrated protein-protein interactions with Adaptor-related protein complex 2, alpha 1,[22] Mdm2,[23][24] L1,[22] DPYSL2,[22] SIAH1,[25] P53[24] and LNX1.[26] | https://www.wikidoc.org/index.php/NUMB_(gene) | |
88128c928dda7e3d28b03ca484d6c5629ea46dff | wikidoc | Nadi (yoga) | Nadi (yoga)
# Early Reference
An early version of the nadi system is mentioned in the Chandogya Upanishad, which says:
# Ida, Pingala and Sushumna
Amongst these ducts or nadis, three are of the utmost importance: the Medullar Shushumna, which interpenetrates the cerebrospinal axis from the perineum to the juncture of the lamboid and sagittal suture of the cranium, the lunar Serpentine Ida of the left side, of a pale color, negative polarity; the solar Serpentine Pingala of the right side, red color, positive polarity. Those are the main nadis, but in some tantric texts more than 72,000 nadis are cited . They all start from the central channel of the chakras to the periphery where they gradually become thinner.
The Sat-Cakra-Narupana, one of the earliest text on nadis and chakra, explicitally refer to these three main nadis, calling them Sasi, Mihira, Susumna.
In the space outside the Meru,
placed on the left and the right,
are the two Nadis, Sasi and Mihira.
The Nadi Susumna, whose substance
is the threefold Gunas,
is in the middle.
She is the form of Moon, Sun, and Fire;
Her body, a string of blooming Dhatura flowers,
extends from the middle of the Kanda to the Head,
and the Vajra inside Her extends,
shining, from the Medhra to the Head.
# Functions and Activities
Nadis are thought to carry a life force energy known as prana in Sanskrit, or qi in Chinese-based systems. In particular prana (active) is supposed to circulate inside Pingala, while apana(passive) is supposed to circulate inside Ida. Inside Sushumna is supposed to circulate kundalini when awakened.
The Ida and Pingala nadis are often seen as referring to the two hemispheres of the brain. Pingala is the extroverted(Active), solar nadi, and corresponds to the right hand side of the body and the left hand side of the brain. Ida is the introverted, lunar nadi, and corresponds to the left hand side of the body and the right hand side of the brain (crossing occurs in the optical chiasma). These nadis are also said to have an extrasensory function, playing a part in empathic and instinctive responses.
The two nadis are believed to be stimulated through different practices, including Pranayama, which involves alternate breathing through left and right nostrils, which would alternately stimulate respectively the left and right sides of the brain. The word nadi comes from the Sanskrit root nad meaning "channel", "stream", or "flow". The rhythmical breathing and special breathing techniques are supposed to influence the flow of these nadis or energetic currents. According to this kind of interpretation (which is the Yoga interpretation) the breathing techniques will purify and develop these two energetic currents and will lead to breathing special exercises whose goal is to awake kundalini.
# Western tradition and Interpretations
Sometimes the three main nadis (Ida, Pingala and Sushumna) are related to the Caduceus of Hermes: "the two snakes of which symbolize the kundalini or serpent-fire which is presently to be set in motion along those channels, while the wings typify the power of conscious flight through higher planes which the development of that fire confers".. In this framework of mystic western esotericism welded with yoga concepts, sometimes the three nadis are related and named as alchemical sulphur and alchemical mercury
"In the East, the symbol of the two serpents twisting on the rod corresponds to the two currents Pingala and Ida which coil around the Merudanda: the first is red, hot and dry, likened to the Sun and the Alchemic Sulphur; the second, Ida, is cold and wet, like the Alchemic Mercury and is correlated with the Moon for its silver pallor." | Nadi (yoga)
Template:IAST (Sanskrit: channel or vein; Tamil: psychic nerve) are the channels through which, in traditional Indian medicine and spiritual science, the energies of the subtle body are said to flow. They connect at special points of intensity called chakras. Nadis seems to correspond to the meridians of traditional Chinese medicine.
# Early Reference
An early version of the nadi system is mentioned in the Chandogya Upanishad, which says:
# Ida, Pingala and Sushumna
Amongst these ducts or nadis, three are of the utmost importance: the Medullar Shushumna, which interpenetrates the cerebrospinal axis from the perineum to the juncture of the lamboid and sagittal suture of the cranium, the lunar Serpentine Ida of the left side, of a pale color, negative polarity; the solar Serpentine Pingala of the right side, red color, positive polarity.[2] Those are the main nadis, but in some tantric texts more than 72,000 nadis are cited [3]. They all start from the central channel of the chakras to the periphery where they gradually become thinner[citation needed].
The Sat-Cakra-Narupana, one of the earliest text on nadis and chakra, explicitally refer to these three main nadis, calling them Sasi, Mihira, Susumna.
In the space outside the Meru,
placed on the left and the right,
are the two Nadis, Sasi and Mihira.
The Nadi Susumna, whose substance
is the threefold Gunas,
is in the middle.
She is the form of Moon, Sun, and Fire;
Her body, a string of blooming Dhatura flowers,
extends from the middle of the Kanda to the Head,
and the Vajra inside Her extends,
shining, from the Medhra to the Head.
[4]
# Functions and Activities
Nadis are thought to carry a life force energy known as prana in Sanskrit, or qi in Chinese-based systems. In particular prana (active) is supposed to circulate inside Pingala, while apana(passive) is supposed to circulate inside Ida. Inside Sushumna is supposed to circulate kundalini when awakened. [5]
The Ida and Pingala nadis are often seen as referring to the two hemispheres of the brain. Pingala is the extroverted(Active), solar nadi, and corresponds to the right hand side of the body and the left hand side of the brain. Ida is the introverted, lunar nadi, and corresponds to the left hand side of the body and the right hand side of the brain (crossing occurs in the optical chiasma). These nadis are also said to have an extrasensory function, playing a part in empathic and instinctive responses.
The two nadis are believed to be stimulated through different practices, including Pranayama, which involves alternate breathing through left and right nostrils, which would alternately stimulate respectively the left and right sides of the brain. The word nadi comes from the Sanskrit root nad meaning "channel", "stream", or "flow". The rhythmical breathing and special breathing techniques are supposed to influence the flow of these nadis or energetic currents. According to this kind of interpretation (which is the Yoga interpretation) the breathing techniques will purify and develop these two energetic currents and will lead to breathing special exercises whose goal is to awake kundalini.
# Western tradition and Interpretations
Sometimes the three main nadis (Ida, Pingala and Sushumna) are related to the Caduceus of Hermes: "the two snakes of which symbolize the kundalini or serpent-fire which is presently to be set in motion along those channels, while the wings typify the power of conscious flight through higher planes which the development of that fire confers".[6]. In this framework of mystic western esotericism welded with yoga concepts, sometimes the three nadis are related and named as alchemical sulphur and alchemical mercury [7][8]
"In the East, the symbol of the two serpents twisting on the rod corresponds to the two currents Pingala and Ida which coil around the Merudanda: the first is red, hot and dry, likened to the Sun and the Alchemic Sulphur; the second, Ida, is cold and wet, like the Alchemic Mercury and is correlated with the Moon for its silver pallor."
[9] | https://www.wikidoc.org/index.php/Nadi_(yoga) | |
57e5e3721e66f2ae4bd69a8bb160f3dfdd9a72da | wikidoc | Naldemedine | Naldemedine
# 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
Naldemedine is a opioid antagonist that is FDA approved for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. Common adverse reactions include abdominal pain, diarrhea, nausea, and gastroenteritis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Naldemedine is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.
- The recommended dosage of Naldemedine is 0.2 mg orally once daily with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Naldemedine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Naldemedine Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Naldemedine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Naldemedine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Naldemedine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Naldemedine is contraindicated in:
- Patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation.
- Patients with a history of a hypersensitivity reaction to Naldemedine. Reactions have included bronchospasm and rash.
# Warnings
- Cases of gastrointestinal perforation have been reported with use of another peripherally acting opioid antagonist in patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies, or peritoneal metastases). Take into account the overall risk-benefit profile when using Naldemedine in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue Naldemedine in patients who develop this symptom.
- Clusters of symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, increased lacrimation, hot flush/flushing, pyrexia, sneezing, feeling cold, abdominal pain, diarrhea, nausea, and vomiting have occurred in patients treated with Naldemedine.
- Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Take into account the overall risk-benefit profile when using Naldemedine in such patients. Monitor for symptoms of opioid withdrawal in such patients.
# 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 data described below reflect exposure to Naldemedine in 1163 patients in clinical trials, including 487 patients with exposures greater than six months and 203 patients with exposures of 12 months.
- The following safety data are derived from three double-blind, placebo-controlled trials in patients with OIC and chronic non-cancer pain: two 12-week studies (Studies 1 and 2) and one 52-week study (Study 3).
- In Studies 1 and 2, patients on laxatives were required to discontinue their use prior to study enrollment. All patients were restricted to bisacodyl rescue treatment during the study. In Study 3, approximately 60% of patients in both treatment groups were on a laxative regimen at baseline; patients were allowed to continue using their laxative regimen throughout the study duration. The safety profile of Naldemedine relative to placebo was similar regardless of laxative use.
- Tables 1 and 2 list common adverse reactions occurring in at least 2% of patients receiving Naldemedine and at an incidence greater than placebo. Table 1 shows pooled 12-week data from Studies 1 and 2. Table 2 shows 12-week data from Study 3.
- Adverse reactions up to 12 months in Study 3 are similar to those listed in Tables 1 and 2 (diarrhea: 11% vs. 5%, abdominal pain: 8% vs. 3%, and nausea: 8% vs. 6% for Naldemedine and placebo, respectively).
Opioid Withdrawal
- In Studies 1, 2 and 3, adverse reactions consistent with opioid withdrawal were based on investigator assessment and adjudicated based upon the occurrence of at least 3 adverse reactions potentially related to opioid withdrawal with onset of a constellation of those symptoms occurring on the same day or within one day of each other.
- Adverse reactions of possible opioid withdrawal could include non-gastrointestinal (GI) symptoms (e.g., hyperhidrosis, hot flush or flushing, chills, tremor, tachycardia, anxiety, agitation, yawning, rhinorrhea, increased lacrimation, sneezing, feeling cold, and pyrexia), GI symptoms (e.g., vomiting, diarrhea, or abdominal pain), or both GI and non-GI symptoms.
- In pooled Studies 1 and 2, the incidence of adverse reactions of opioid withdrawal was 1% (8/542) for Naldemedine and 1% (3/546) for placebo. In Study 3 (52-week data), the incidence was 3% (20/621) for Naldemedine and 1% (9/619) for placebo. Most Naldemedine treated subjects experienced nearly equal incidence of GI only or both GI and non-GI symptoms.
Less Common Adverse Reactions:
- Two patients developed symptoms of hypersensitivity following a single dose of Naldemedine. One patient reported bronchospasm and another rash.
## Postmarketing Experience
There is limited information regarding Naldemedine Postmarketing Experience in the drug label.
# Drug Interactions
- Table 3 includes drugs with clinically important drug interactions with Naldemedine and instructions for preventing or managing the interaction.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no available data with Naldemedine in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. There is a potential for opioid withdrawal in a fetus when Naldemedine is used in pregnant women. Naldemedine should be used during pregnancy only if the potential benefit justifies the potential risk.
- In a rat embryo-fetal development study following oral administration of Naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 23,000 times the human area under the plasma-concentration time curve (AUC) at the recommended human dose of 0.2 mg/day, no developmental abnormalities were observed. In rabbits, there were no adverse effects on embryo-fetal development following oral administration of Naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 226 times the human AUC at the recommended human dose of 0.2 mg/day. No effects on pre- and postnatal development were observed in rats at exposures 12 times human exposures at the recommended human dose.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
- Naldemedine crosses the placenta, and may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier.
Data (Animal)
- In rats, there were no adverse effects on embryo-fetal development following oral administration of Naldemedine during the period of organogenesis at doses up to 1000 mg/kg/day (approximately 23,000 times the human exposures (AUC) at the recommended human dose). In rabbits, there were no adverse effects on embryo-fetal development following oral administration of Naldemedine during the period of organogenesis at doses up to 100 mg/kg/day (approximately 226 times the human exposures (AUC) at the recommended human dose). At 400 mg/kg/day (approximately 844 times the human exposures (AUC) at the recommended human dose), effects in maternal animals included body weight loss/decreased body weight gain and food consumption, fetal loss, and premature delivery. Decreased fetal body weights at this dose may be related to the maternal toxicity observed.
- In the pre- and postnatal development study, pregnant rats were administered Naldemedine at oral doses up to 1000 mg/kg/day from gestation day 7 through lactation day 20. No effects on pre- and postnatal development were observed in rats at 1 mg/kg/day (approximately 12 times the human exposures (AUC) at the recommended human dose). A single dam died at parturition at 1000 mg/kg/day, and decreased body weights/body weight gain and food consumption, poor nursing, and total litter loss were noted at 30 and 1000 mg/kg/day (approximately 626 and 17,000 times the human exposures (AUC) at the recommended human dose, respectively). Decreases in the offspring viability index on Day 4 after birth were noted at 30 and 1000 mg/kg/day, and low body weights and delayed pinna unfolding in pups were noted at 1000 mg/kg/day.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Naldemedine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Naldemedine during labor and delivery.
### Nursing Mothers
Risk Summary
- There is no information regarding the presence of Naldemedine in human milk, the effects on the breastfed infant, or the effects on milk production. Naldemedine was present in the milk of rats. Because of the potential for serious adverse reactions, including opioid withdrawal in breastfed infants, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. If drug is discontinued in order to minimize drug exposure to a breastfed infant, advise women that breastfeeding may be resumed 3 days after the final dose of Naldemedine.
Data
- Drug-related radioactivity was transferred into milk of lactating rats following a single oral dose of 1 mg/kg -Naldemedine.
### Pediatric Use
- The safety and effectiveness of Naldemedine have not been established in pediatric patients.
### Geriatic Use
- Of 1163 patients in clinical studies exposed to Naldemedine, 183 (16%) were 65 years of age and over, while 37 (3%) were 75 years and over. No overall differences in safety or effectiveness between these and younger patients were observed, but greater sensitivity of some older individuals cannot be ruled out. In a population pharmacokinetic analysis, no age-related alterations in the pharmacokinetics of Naldemedine were observed.
### Gender
There is no FDA guidance on the use of Naldemedine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Naldemedine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Naldemedine in patients with renal impairment.
### Hepatic Impairment
- The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of Naldemedine has not been evaluated. Avoid use of Naldemedine in patients with severe hepatic impairment. No dose adjustment of Naldemedine is required in patients with mild or moderate hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Naldemedine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Naldemedine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Alteration of analgesic dosing regimen prior to initiating Naldemedine is not required.
- Patients receiving opioids for less than 4 weeks may be less responsive to Naldemedine.
- Discontinue Naldemedine if treatment with the opioid pain medication is also discontinued.
### Monitoring
- Increased frequency of spontaneous bowel movements is indicative of efficacy.
- Development of severe, persistent, or worsening abdominal pain.
- Symptoms of opioid withdrawal.
# IV Compatibility
There is limited information regarding the compatibility of Naldemedine and IV administrations.
# Overdosage
- Single doses of Naldemedine up to 100 mg (500 times the recommended dose) and multiple doses of up to 30 mg (150 times the recommended dose) for 10 days have been administered to healthy subjects in clinical studies. Dose-dependent increases in gastrointestinal-related adverse reactions, including abdominal pain, diarrhea, and nausea, were observed.
- Single doses of Naldemedine up to 3 mg (15 times the recommended dose) and multiple doses of 0.4 mg (twice the recommended dose) for 28 days have been administered to patients with OIC in clinical studies. Dose-dependent increases in gastrointestinal-related adverse reactions, including abdominal pain, diarrhea, nausea, and vomiting, were observed. Also, chills, hyperhidrosis, and dizziness were reported more frequently at 1 and 3 mg doses and hyperhidrosis at the 0.4 mg dose.
- No antidote for Naldemedine is known. Hemodialysis is not an effective means to remove Naldemedine from the blood.
# Pharmacology
## Mechanism of Action
- Naldemedine is an opioid antagonist with binding affinities for mu-, delta-, and kappa-opioid receptors. Naldemedine functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids.
- Naldemedine is a derivative of naltrexone to which a side chain has been added that increases the molecular weight and the polar surface area, thereby reducing its ability to cross the blood-brain barrier (BBB).
- Naldemedine is also a substrate of the P-glycoprotein (P-gp) efflux transporter. Based on these properties, the CNS penetration of Naldemedine is expected to be negligible at the recommended dose levels, limiting the potential for interference with centrally-mediated opioid analgesia.
## Structure
## Pharmacodynamics
- Use of opioids induces slowing of gastrointestinal motility and transit. Antagonism of gastrointestinal mu-opioid receptors by Naldemedine inhibits opioid-induced delay of gastrointestinal transit time.
Effect on Cardiac Repolarization
- At a dose up to 5-times the recommended dose, Naldemedine does not prolong the QT interval to any clinically relevant extent.
## Pharmacokinetics
Absorption
- Following oral administration, Naldemedine is absorbed with the time to achieve peak concentrations (Tmax) of approximately 0.75 hours in a fasted state. Across the range of doses evaluated, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose-proportional or almost dose-proportional manner. Accumulation was minimal following multiple daily doses of Naldemedine.
Food Effect
- A high-fat meal decreased the rate, but not the extent of Naldemedine absorption. The Cmax was decreased by approximately 35% and time to achieve Cmax was delayed from 0.75 hours in the fasted state to 2.5 hours in the fed state, whereas there was no meaningful change in the AUC in the fed state.
Distribution
- Plasma protein binding of Naldemedine in humans is 93% to 94%. The mean apparent volume of distribution during the terminal phase (Vz/F) is 155 L.
Elimination
- The terminal elimination half-life of Naldemedine is 11 hours.
Metabolism
- Naldemedine is primarily metabolized by CYP3A to nor-Naldemedine, with minor contribution from UGT1A3 to form Naldemedine 3-G. Nor-Naldemedine and Naldemedine 3-G have been shown to have antagonistic activity for opioid receptors, with less potent effect than Naldemedine.
- Following oral administration of -labeled Naldemedine, the primary metabolite in plasma was nor-Naldemedine, with a relative exposure compared to Naldemedine of approximately 9% to 13%. Naldemedine 3-G was a minor metabolite in plasma, with a relative exposure to Naldemedine of less than 3%.
- Naldemedine also undergoes cleavage in the GI tract to form benzamidine and Naldemedine carboxylic acid.
Excretion
- Following oral administration of -labeled Naldemedine, the total amount of radioactivity excreted in the urine and feces was 57% and 35% of the administered dose of Naldemedine, respectively. The amount of Naldemedine excreted unchanged in the urine was approximately 16% to 18% of the administered dose. Benzamidine was the most predominant metabolite excreted in the urine and feces, representing approximately 32% and 20% of the administered dose of Naldemedine, respectively. The percentage of unchanged drug in feces has not been estimated.
Use in Specific Populations
Age: Geriatric Population, Sex, Race/Ethnicity
- A population pharmacokinetic analysis from clinical studies with Naldemedine did not identify a clinically meaningful effect of age, sex, or race on the pharmacokinetics of Naldemedine.
Renal Impairment
- The pharmacokinetics of Naldemedine after administration of a 0.2 mg single oral dose of Naldemedine was studied in 8 subjects with mild (n=8, estimated glomerular filtration rate of 60 to 89 mL/min/1.73 m2), moderate (n=8, eGFR 30 to 59 mL/min/1.73 m2), and severe (n=6, eGFR less than 30 mL/min/1.73 m2) renal impairment, and subjects with end-stage renal disease (ESRD) requiring hemodialysis (n=8), and compared to healthy subjects with normal renal function (n=8, estimated creatinine clearance of at least 90 mL/min). The pharmacokinetics of Naldemedine between subjects in all groups were similar.
- Plasma concentrations of Naldemedine in subjects with ESRD requiring hemodialysis were similar when Naldemedine was administered either pre- or post-hemodialysis, indicating that Naldemedine was not removed from the blood by hemodialysis.
Hepatic Impairment
- The effect of hepatic impairment on the pharmacokinetics of a 0.2 mg single oral dose of Naldemedine was studied in subjects with hepatic impairment classified as mild (n=8, Child-Pugh Class A) or moderate (n=8, Child-Pugh Class B) and compared with healthy subjects with normal hepatic function (n=8). The pharmacokinetics of Naldemedine between subjects in all groups were similar.
- The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of Naldemedine was not evaluated.
Drug Interaction Studies
Effect of Naldemedine on Other Drugs
- In in vitro studies at clinically relevant concentrations, Naldemedine did not inhibit the major CYP enzymes (including CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A11 isozymes) and is not an inhibitor of transporters (including OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BCRP, or P-gp). Naldemedine did not cause significant induction of CYP1A2, CYP2B6, CYP3A4, UGT1A2, UGT1A6, or UGT2B7 isozymes.
Effect of Other Drugs on Naldemedine
- Naldemedine is primarily metabolized by CYP3A4 enzyme with minor contribution from UGT1A3. Naldemedine is a substrate of P-gp. The effects of co-administered drugs on the pharmacokinetics of Naldemedine are summarized in Figure 1.
## Nonclinical Toxicology
Carcinogenesis
- In 2-year carcinogenicity studies, there were no drug-related neoplastic findings following oral administration of Naldemedine to mice and rats at doses up to 100 mg/kg/day (approximately 17,500 and 6,300 times the human exposures (AUC) at the recommended human dose, respectively).
Mutagenesis
- Naldemedine was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, a chromosomal aberration assay with cultured Chinese hamster lung cells, and an in vivo micronucleus assay with rat bone marrow cells.
Impairment of Fertility
- Naldemedine was found to have no effect on fertility or reproductive performance in male and female rats at oral doses up to 1000 mg/kg/day (approximately 17,000 times the human exposures (AUC) at the recommended human dose). In female rats, prolongation of diestrous phase was noted at 10 mg/kg/day (approximately 179 times the human exposures (AUC) at the recommended human dose).
# Clinical Studies
- Naldemedine was evaluated in two replicate, 12-week, randomized, double-blind, placebo-controlled trials (Study 1 and Study 2) in which Naldemedine was used without laxatives in patients with OIC and chronic non-cancer pain.
- Patients receiving a stable opioid morphine equivalent daily dose of at least 30 mg for at least 4 weeks before enrollment and self-reported OIC were eligible for clinical trial participation.
- Patients with evidence of significant structural abnormalities of the GI tract were not enrolled in these trials.
- In Studies 1 and 2, patients had to either be not using laxatives or willing to discontinue laxative use at the time of screening and willing to use only the provided rescue laxatives during the screening and treatment periods.
- In Studies 1 and 2, OIC was confirmed through a two-week run in period and was defined as no more than 4 spontaneous bowel movements (SBMs) total over 14 consecutive days and less than 3 SBMs in a given week with at least 25% of the SBMs associated with one or more of the following conditions: (1) straining; (2) hard or lumpy stools; (3) having a sensation of incomplete evacuation; and (4) having a sensation of anorectal obstruction/blockage.
- An SBM was defined as a bowel movement (BM) without rescue laxative taken within the past 24 hours. Patients with no BMs over the 7 consecutive days prior to and during the 2 week screening period or patients who have never taken laxatives were excluded.
- In the screening and treatment periods, bisacodyl was used as rescue laxative if patients had not had a BM for 72 hours and were allowed one-time use of an enema, if after 24 hours of taking bisacodyl they still had not had a BM.
- A total of 547 patients in Study 1 and 553 patients in Study 2 were randomized in a 1:1 ratio to receive Naldemedine 0.2 mg once daily or placebo for 12 weeks. Study medication was administered without regard to meals.
- The mean age of subjects in Studies 1 and 2 was 54 years; 59% were women; and 80% were white. The most common types of pain in Studies 1 and 2 were back or neck pain (61%). The mean baseline number of SBMs was 1.3 and 1.2 per week for Studies 1 and 2, respectively.
- Prior to enrollment, patients were using their current opioid for a mean duration of approximately 5 years. A wide range of types of opioids were used. The mean baseline opioid morphine equivalent daily dosage was 132 mg and 121 mg per day for Studies 1 and 2, respectively.
- The efficacy of Naldemedine was assessed in Studies 1 and 2 using a responder analysis. A responder was defined as a patient who had at least 3 SBMs per week and a change from baseline of at least 1 SBM per week for at least 9 out of the 12 weeks and 3 out of the last 4 weeks in Studies 1 and 2.
- The responder rates in Studies 1 and 2 are shown in Table 4.
- In Studies 1 and 2, the mean increase in frequency of SBMs per week from baseline to the last 2 weeks of the 12-week treatment period was 3.1 for Naldemedine vs. 2.0 for placebo (difference 1.0, 95% CI 0.6, 1.5), and 3.3 for Naldemedine vs. 2.1 for placebo (difference 1.2, 95% CI 0.8, 1.7), respectively.
- During week 1 of the treatment period, the mean increase in frequency of SBMs per week from baseline was 3.3 for Naldemedine vs. 1.3 for placebo (difference 2.0, 95% CI 1.5, 2.5) in Study 1 and 3.7 for Naldemedine vs. 1.6 for placebo (difference 2.1, 95% CI 1.5, 2.6) in Study 2.
- The mean increase in the frequency of complete SBM (CSBM) per week from baseline to the last 2 weeks of 12-week treatment period was 2.3 for Naldemedine vs. 1.5 for placebo (difference 0.8, 95% CI 0.4, 1.2) in Study 1 and 2.6 for Naldemedine vs. 1.6 for placebo (difference 1.1, 95% CI 0.6, 1.5) in Study 2. A CSBM was defined as a SBM that was associated with a sense of complete evacuation.
- The change in the frequency of SBMs without straining per week from baseline to the last 2 weeks of the treatment period was 1.3 for Naldemedine vs. 0.7 for placebo (difference 0.6, 95% CI 0.2, 0.9) in Study 1 and 1.8 for Naldemedine vs. 1.1 for placebo (difference 0.7, 95% CI 0.3, 1.2) in Study 2.
# How Supplied
- Naldemedine is supplied as 0.2 mg Naldemedine tablets in:
- bottle of 30 tablets - NDC 59011-523-30
- bottle of 90 tablets - NDC 59011-523-90
## Storage
- Store Naldemedine in light resistant container at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Administration
- Advise patients to discontinue Naldemedine if treatment with the opioid pain medication is also discontinued.
Gastrointestinal Perforation
- Advise patients to discontinue Naldemedine and to promptly seek medical attention if they develop unusually severe, persistent or worsening abdominal pain.
Opioid Withdrawal
- Advise patients that clusters of symptoms consistent with opioid withdrawal may occur while taking Naldemedine and to contact their healthcare provider if these symptoms occur.
Pregnancy
- Advise females of reproductive potential, who become pregnant or are planning to become pregnant, that the use of Naldemedine during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood-brain barrier.
Lactation
- Advise women that breastfeeding is not recommended during treatment with Naldemedine and for 3 days after the final dose.
# Precautions with Alcohol
Alcohol-Naldemedine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Symproic
# Look-Alike Drug Names
There is limited information regarding Naldemedine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Naldemedine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[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
Naldemedine is a opioid antagonist that is FDA approved for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation. Common adverse reactions include abdominal pain, diarrhea, nausea, and gastroenteritis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Naldemedine is indicated for the treatment of opioid-induced constipation (OIC) in adult patients with chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (e.g., weekly) opioid dosage escalation.
- The recommended dosage of Naldemedine is 0.2 mg orally once daily with or without food.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Naldemedine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Naldemedine Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Naldemedine FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Naldemedine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Naldemedine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Naldemedine is contraindicated in:
- Patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation.
- Patients with a history of a hypersensitivity reaction to Naldemedine. Reactions have included bronchospasm and rash.
# Warnings
- Cases of gastrointestinal perforation have been reported with use of another peripherally acting opioid antagonist in patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies, or peritoneal metastases). Take into account the overall risk-benefit profile when using Naldemedine in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue Naldemedine in patients who develop this symptom.
- Clusters of symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, increased lacrimation, hot flush/flushing, pyrexia, sneezing, feeling cold, abdominal pain, diarrhea, nausea, and vomiting have occurred in patients treated with Naldemedine.
- Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal or reduced analgesia. Take into account the overall risk-benefit profile when using Naldemedine in such patients. Monitor for symptoms of opioid withdrawal in such patients.
# 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 data described below reflect exposure to Naldemedine in 1163 patients in clinical trials, including 487 patients with exposures greater than six months and 203 patients with exposures of 12 months.
- The following safety data are derived from three double-blind, placebo-controlled trials in patients with OIC and chronic non-cancer pain: two 12-week studies (Studies 1 and 2) and one 52-week study (Study 3).
- In Studies 1 and 2, patients on laxatives were required to discontinue their use prior to study enrollment. All patients were restricted to bisacodyl rescue treatment during the study. In Study 3, approximately 60% of patients in both treatment groups were on a laxative regimen at baseline; patients were allowed to continue using their laxative regimen throughout the study duration. The safety profile of Naldemedine relative to placebo was similar regardless of laxative use.
- Tables 1 and 2 list common adverse reactions occurring in at least 2% of patients receiving Naldemedine and at an incidence greater than placebo. Table 1 shows pooled 12-week data from Studies 1 and 2. Table 2 shows 12-week data from Study 3.
- Adverse reactions up to 12 months in Study 3 are similar to those listed in Tables 1 and 2 (diarrhea: 11% vs. 5%, abdominal pain: 8% vs. 3%, and nausea: 8% vs. 6% for Naldemedine and placebo, respectively).
Opioid Withdrawal
- In Studies 1, 2 and 3, adverse reactions consistent with opioid withdrawal were based on investigator assessment and adjudicated based upon the occurrence of at least 3 adverse reactions potentially related to opioid withdrawal with onset of a constellation of those symptoms occurring on the same day or within one day of each other.
- Adverse reactions of possible opioid withdrawal could include non-gastrointestinal (GI) symptoms (e.g., hyperhidrosis, hot flush or flushing, chills, tremor, tachycardia, anxiety, agitation, yawning, rhinorrhea, increased lacrimation, sneezing, feeling cold, and pyrexia), GI symptoms (e.g., vomiting, diarrhea, or abdominal pain), or both GI and non-GI symptoms.
- In pooled Studies 1 and 2, the incidence of adverse reactions of opioid withdrawal was 1% (8/542) for Naldemedine and 1% (3/546) for placebo. In Study 3 (52-week data), the incidence was 3% (20/621) for Naldemedine and 1% (9/619) for placebo. Most Naldemedine treated subjects experienced nearly equal incidence of GI only or both GI and non-GI symptoms.
Less Common Adverse Reactions:
- Two patients developed symptoms of hypersensitivity following a single dose of Naldemedine. One patient reported bronchospasm and another rash.
## Postmarketing Experience
There is limited information regarding Naldemedine Postmarketing Experience in the drug label.
# Drug Interactions
- Table 3 includes drugs with clinically important drug interactions with Naldemedine and instructions for preventing or managing the interaction.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no available data with Naldemedine in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. There is a potential for opioid withdrawal in a fetus when Naldemedine is used in pregnant women. Naldemedine should be used during pregnancy only if the potential benefit justifies the potential risk.
- In a rat embryo-fetal development study following oral administration of Naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 23,000 times the human area under the plasma-concentration time curve (AUC) at the recommended human dose of 0.2 mg/day, no developmental abnormalities were observed. In rabbits, there were no adverse effects on embryo-fetal development following oral administration of Naldemedine during the period of organogenesis at doses resulting in systemic exposure approximately 226 times the human AUC at the recommended human dose of 0.2 mg/day. No effects on pre- and postnatal development were observed in rats at exposures 12 times human exposures at the recommended human dose.
- The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Fetal/Neonatal Adverse Reactions
- Naldemedine crosses the placenta, and may precipitate opioid withdrawal in a fetus due to the immature fetal blood-brain barrier.
Data (Animal)
- In rats, there were no adverse effects on embryo-fetal development following oral administration of Naldemedine during the period of organogenesis at doses up to 1000 mg/kg/day (approximately 23,000 times the human exposures (AUC) at the recommended human dose). In rabbits, there were no adverse effects on embryo-fetal development following oral administration of Naldemedine during the period of organogenesis at doses up to 100 mg/kg/day (approximately 226 times the human exposures (AUC) at the recommended human dose). At 400 mg/kg/day (approximately 844 times the human exposures (AUC) at the recommended human dose), effects in maternal animals included body weight loss/decreased body weight gain and food consumption, fetal loss, and premature delivery. Decreased fetal body weights at this dose may be related to the maternal toxicity observed.
- In the pre- and postnatal development study, pregnant rats were administered Naldemedine at oral doses up to 1000 mg/kg/day from gestation day 7 through lactation day 20. No effects on pre- and postnatal development were observed in rats at 1 mg/kg/day (approximately 12 times the human exposures (AUC) at the recommended human dose). A single dam died at parturition at 1000 mg/kg/day, and decreased body weights/body weight gain and food consumption, poor nursing, and total litter loss were noted at 30 and 1000 mg/kg/day (approximately 626 and 17,000 times the human exposures (AUC) at the recommended human dose, respectively). Decreases in the offspring viability index on Day 4 after birth were noted at 30 and 1000 mg/kg/day, and low body weights and delayed pinna unfolding in pups were noted at 1000 mg/kg/day.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Naldemedine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Naldemedine during labor and delivery.
### Nursing Mothers
Risk Summary
- There is no information regarding the presence of Naldemedine in human milk, the effects on the breastfed infant, or the effects on milk production. Naldemedine was present in the milk of rats. Because of the potential for serious adverse reactions, including opioid withdrawal in breastfed infants, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. If drug is discontinued in order to minimize drug exposure to a breastfed infant, advise women that breastfeeding may be resumed 3 days after the final dose of Naldemedine.
Data
- Drug-related radioactivity was transferred into milk of lactating rats following a single oral dose of 1 mg/kg [carbonyl-14C]-Naldemedine.
### Pediatric Use
- The safety and effectiveness of Naldemedine have not been established in pediatric patients.
### Geriatic Use
- Of 1163 patients in clinical studies exposed to Naldemedine, 183 (16%) were 65 years of age and over, while 37 (3%) were 75 years and over. No overall differences in safety or effectiveness between these and younger patients were observed, but greater sensitivity of some older individuals cannot be ruled out. In a population pharmacokinetic analysis, no age-related alterations in the pharmacokinetics of Naldemedine were observed.
### Gender
There is no FDA guidance on the use of Naldemedine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Naldemedine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Naldemedine in patients with renal impairment.
### Hepatic Impairment
- The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of Naldemedine has not been evaluated. Avoid use of Naldemedine in patients with severe hepatic impairment. No dose adjustment of Naldemedine is required in patients with mild or moderate hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Naldemedine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Naldemedine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Alteration of analgesic dosing regimen prior to initiating Naldemedine is not required.
- Patients receiving opioids for less than 4 weeks may be less responsive to Naldemedine.
- Discontinue Naldemedine if treatment with the opioid pain medication is also discontinued.
### Monitoring
- Increased frequency of spontaneous bowel movements is indicative of efficacy.
- Development of severe, persistent, or worsening abdominal pain.
- Symptoms of opioid withdrawal.
# IV Compatibility
There is limited information regarding the compatibility of Naldemedine and IV administrations.
# Overdosage
- Single doses of Naldemedine up to 100 mg (500 times the recommended dose) and multiple doses of up to 30 mg (150 times the recommended dose) for 10 days have been administered to healthy subjects in clinical studies. Dose-dependent increases in gastrointestinal-related adverse reactions, including abdominal pain, diarrhea, and nausea, were observed.
- Single doses of Naldemedine up to 3 mg (15 times the recommended dose) and multiple doses of 0.4 mg (twice the recommended dose) for 28 days have been administered to patients with OIC in clinical studies. Dose-dependent increases in gastrointestinal-related adverse reactions, including abdominal pain, diarrhea, nausea, and vomiting, were observed. Also, chills, hyperhidrosis, and dizziness were reported more frequently at 1 and 3 mg doses and hyperhidrosis at the 0.4 mg dose.
- No antidote for Naldemedine is known. Hemodialysis is not an effective means to remove Naldemedine from the blood.
# Pharmacology
## Mechanism of Action
- Naldemedine is an opioid antagonist with binding affinities for mu-, delta-, and kappa-opioid receptors. Naldemedine functions as a peripherally-acting mu-opioid receptor antagonist in tissues such as the gastrointestinal tract, thereby decreasing the constipating effects of opioids.
- Naldemedine is a derivative of naltrexone to which a side chain has been added that increases the molecular weight and the polar surface area, thereby reducing its ability to cross the blood-brain barrier (BBB).
- Naldemedine is also a substrate of the P-glycoprotein (P-gp) efflux transporter. Based on these properties, the CNS penetration of Naldemedine is expected to be negligible at the recommended dose levels, limiting the potential for interference with centrally-mediated opioid analgesia.
## Structure
## Pharmacodynamics
- Use of opioids induces slowing of gastrointestinal motility and transit. Antagonism of gastrointestinal mu-opioid receptors by Naldemedine inhibits opioid-induced delay of gastrointestinal transit time.
Effect on Cardiac Repolarization
- At a dose up to 5-times the recommended dose, Naldemedine does not prolong the QT interval to any clinically relevant extent.
## Pharmacokinetics
Absorption
- Following oral administration, Naldemedine is absorbed with the time to achieve peak concentrations (Tmax) of approximately 0.75 hours in a fasted state. Across the range of doses evaluated, the maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose-proportional or almost dose-proportional manner. Accumulation was minimal following multiple daily doses of Naldemedine.
Food Effect
- A high-fat meal decreased the rate, but not the extent of Naldemedine absorption. The Cmax was decreased by approximately 35% and time to achieve Cmax was delayed from 0.75 hours in the fasted state to 2.5 hours in the fed state, whereas there was no meaningful change in the AUC in the fed state.
Distribution
- Plasma protein binding of Naldemedine in humans is 93% to 94%. The mean apparent volume of distribution during the terminal phase (Vz/F) is 155 L.
Elimination
- The terminal elimination half-life of Naldemedine is 11 hours.
Metabolism
- Naldemedine is primarily metabolized by CYP3A to nor-Naldemedine, with minor contribution from UGT1A3 to form Naldemedine 3-G. Nor-Naldemedine and Naldemedine 3-G have been shown to have antagonistic activity for opioid receptors, with less potent effect than Naldemedine.
- Following oral administration of [14C]-labeled Naldemedine, the primary metabolite in plasma was nor-Naldemedine, with a relative exposure compared to Naldemedine of approximately 9% to 13%. Naldemedine 3-G was a minor metabolite in plasma, with a relative exposure to Naldemedine of less than 3%.
- Naldemedine also undergoes cleavage in the GI tract to form benzamidine and Naldemedine carboxylic acid.
Excretion
- Following oral administration of [14C]-labeled Naldemedine, the total amount of radioactivity excreted in the urine and feces was 57% and 35% of the administered dose of Naldemedine, respectively. The amount of Naldemedine excreted unchanged in the urine was approximately 16% to 18% of the administered dose. Benzamidine was the most predominant metabolite excreted in the urine and feces, representing approximately 32% and 20% of the administered dose of Naldemedine, respectively. The percentage of unchanged drug in feces has not been estimated.
Use in Specific Populations
Age: Geriatric Population, Sex, Race/Ethnicity
- A population pharmacokinetic analysis from clinical studies with Naldemedine did not identify a clinically meaningful effect of age, sex, or race on the pharmacokinetics of Naldemedine.
Renal Impairment
- The pharmacokinetics of Naldemedine after administration of a 0.2 mg single oral dose of Naldemedine was studied in 8 subjects with mild (n=8, estimated glomerular filtration rate [eGFR] of 60 to 89 mL/min/1.73 m2), moderate (n=8, eGFR 30 to 59 mL/min/1.73 m2), and severe (n=6, eGFR less than 30 mL/min/1.73 m2) renal impairment, and subjects with end-stage renal disease (ESRD) requiring hemodialysis (n=8), and compared to healthy subjects with normal renal function (n=8, estimated creatinine clearance of at least 90 mL/min). The pharmacokinetics of Naldemedine between subjects in all groups were similar.
- Plasma concentrations of Naldemedine in subjects with ESRD requiring hemodialysis were similar when Naldemedine was administered either pre- or post-hemodialysis, indicating that Naldemedine was not removed from the blood by hemodialysis.
Hepatic Impairment
- The effect of hepatic impairment on the pharmacokinetics of a 0.2 mg single oral dose of Naldemedine was studied in subjects with hepatic impairment classified as mild (n=8, Child-Pugh Class A) or moderate (n=8, Child-Pugh Class B) and compared with healthy subjects with normal hepatic function (n=8). The pharmacokinetics of Naldemedine between subjects in all groups were similar.
- The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of Naldemedine was not evaluated.
Drug Interaction Studies
Effect of Naldemedine on Other Drugs
- In in vitro studies at clinically relevant concentrations, Naldemedine did not inhibit the major CYP enzymes (including CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, or CYP4A11 isozymes) and is not an inhibitor of transporters (including OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BCRP, or P-gp). Naldemedine did not cause significant induction of CYP1A2, CYP2B6, CYP3A4, UGT1A2, UGT1A6, or UGT2B7 isozymes.
Effect of Other Drugs on Naldemedine
- Naldemedine is primarily metabolized by CYP3A4 enzyme with minor contribution from UGT1A3. Naldemedine is a substrate of P-gp. The effects of co-administered drugs on the pharmacokinetics of Naldemedine are summarized in Figure 1.
## Nonclinical Toxicology
Carcinogenesis
- In 2-year carcinogenicity studies, there were no drug-related neoplastic findings following oral administration of Naldemedine to mice and rats at doses up to 100 mg/kg/day (approximately 17,500 and 6,300 times the human exposures (AUC) at the recommended human dose, respectively).
Mutagenesis
- Naldemedine was not genotoxic in the in vitro bacterial reverse mutation (Ames) assay, a chromosomal aberration assay with cultured Chinese hamster lung cells, and an in vivo micronucleus assay with rat bone marrow cells.
Impairment of Fertility
- Naldemedine was found to have no effect on fertility or reproductive performance in male and female rats at oral doses up to 1000 mg/kg/day (approximately 17,000 times the human exposures (AUC) at the recommended human dose). In female rats, prolongation of diestrous phase was noted at 10 mg/kg/day (approximately 179 times the human exposures (AUC) at the recommended human dose).
# Clinical Studies
- Naldemedine was evaluated in two replicate, 12-week, randomized, double-blind, placebo-controlled trials (Study 1 and Study 2) in which Naldemedine was used without laxatives in patients with OIC and chronic non-cancer pain.
- Patients receiving a stable opioid morphine equivalent daily dose of at least 30 mg for at least 4 weeks before enrollment and self-reported OIC were eligible for clinical trial participation.
- Patients with evidence of significant structural abnormalities of the GI tract were not enrolled in these trials.
- In Studies 1 and 2, patients had to either be not using laxatives or willing to discontinue laxative use at the time of screening and willing to use only the provided rescue laxatives during the screening and treatment periods.
- In Studies 1 and 2, OIC was confirmed through a two-week run in period and was defined as no more than 4 spontaneous bowel movements (SBMs) total over 14 consecutive days and less than 3 SBMs in a given week with at least 25% of the SBMs associated with one or more of the following conditions: (1) straining; (2) hard or lumpy stools; (3) having a sensation of incomplete evacuation; and (4) having a sensation of anorectal obstruction/blockage.
- An SBM was defined as a bowel movement (BM) without rescue laxative taken within the past 24 hours. Patients with no BMs over the 7 consecutive days prior to and during the 2 week screening period or patients who have never taken laxatives were excluded.
- In the screening and treatment periods, bisacodyl was used as rescue laxative if patients had not had a BM for 72 hours and were allowed one-time use of an enema, if after 24 hours of taking bisacodyl they still had not had a BM.
- A total of 547 patients in Study 1 and 553 patients in Study 2 were randomized in a 1:1 ratio to receive Naldemedine 0.2 mg once daily or placebo for 12 weeks. Study medication was administered without regard to meals.
- The mean age of subjects in Studies 1 and 2 was 54 years; 59% were women; and 80% were white. The most common types of pain in Studies 1 and 2 were back or neck pain (61%). The mean baseline number of SBMs was 1.3 and 1.2 per week for Studies 1 and 2, respectively.
- Prior to enrollment, patients were using their current opioid for a mean duration of approximately 5 years. A wide range of types of opioids were used. The mean baseline opioid morphine equivalent daily dosage was 132 mg and 121 mg per day for Studies 1 and 2, respectively.
- The efficacy of Naldemedine was assessed in Studies 1 and 2 using a responder analysis. A responder was defined as a patient who had at least 3 SBMs per week and a change from baseline of at least 1 SBM per week for at least 9 out of the 12 weeks and 3 out of the last 4 weeks in Studies 1 and 2.
- The responder rates in Studies 1 and 2 are shown in Table 4.
- In Studies 1 and 2, the mean increase in frequency of SBMs per week from baseline to the last 2 weeks of the 12-week treatment period was 3.1 for Naldemedine vs. 2.0 for placebo (difference 1.0, 95% CI 0.6, 1.5), and 3.3 for Naldemedine vs. 2.1 for placebo (difference 1.2, 95% CI 0.8, 1.7), respectively.
- During week 1 of the treatment period, the mean increase in frequency of SBMs per week from baseline was 3.3 for Naldemedine vs. 1.3 for placebo (difference 2.0, 95% CI 1.5, 2.5) in Study 1 and 3.7 for Naldemedine vs. 1.6 for placebo (difference 2.1, 95% CI 1.5, 2.6) in Study 2.
- The mean increase in the frequency of complete SBM (CSBM) per week from baseline to the last 2 weeks of 12-week treatment period was 2.3 for Naldemedine vs. 1.5 for placebo (difference 0.8, 95% CI 0.4, 1.2) in Study 1 and 2.6 for Naldemedine vs. 1.6 for placebo (difference 1.1, 95% CI 0.6, 1.5) in Study 2. A CSBM was defined as a SBM that was associated with a sense of complete evacuation.
- The change in the frequency of SBMs without straining per week from baseline to the last 2 weeks of the treatment period was 1.3 for Naldemedine vs. 0.7 for placebo (difference 0.6, 95% CI 0.2, 0.9) in Study 1 and 1.8 for Naldemedine vs. 1.1 for placebo (difference 0.7, 95% CI 0.3, 1.2) in Study 2.
# How Supplied
- Naldemedine is supplied as 0.2 mg Naldemedine tablets in:
- bottle of 30 tablets - NDC 59011-523-30
- bottle of 90 tablets - NDC 59011-523-90
## Storage
- Store Naldemedine in light resistant container at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Administration
- Advise patients to discontinue Naldemedine if treatment with the opioid pain medication is also discontinued.
Gastrointestinal Perforation
- Advise patients to discontinue Naldemedine and to promptly seek medical attention if they develop unusually severe, persistent or worsening abdominal pain.
Opioid Withdrawal
- Advise patients that clusters of symptoms consistent with opioid withdrawal may occur while taking Naldemedine and to contact their healthcare provider if these symptoms occur.
Pregnancy
- Advise females of reproductive potential, who become pregnant or are planning to become pregnant, that the use of Naldemedine during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood-brain barrier.
Lactation
- Advise women that breastfeeding is not recommended during treatment with Naldemedine and for 3 days after the final dose.
# Precautions with Alcohol
Alcohol-Naldemedine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Symproic
# Look-Alike Drug Names
There is limited information regarding Naldemedine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Naldemedine | |
8aa30aa5c52dd2a7634d5ccf808564dc6f97a670 | wikidoc | Naphazoline | Naphazoline
# 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
Naphazoline is a Alpha-Adrenergic Agonist that is FDA approved for the treatment of as a topical ocular vasoconstrictor. Common adverse reactions include Mydriasis, increased redness, increased intraocular pressure, irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indication
- Naphazoline Hydrochloride Ophthalmic Solution is indicated for use as a topical ocular vasoconstrictor.
### Dosage
- Instill one or two drops in the conjunctival sac(s) every three to four hours as needed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Naphazoline in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Naphazoline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Naphazoline in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Naphazoline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Naphazoline in pediatric patients.
# Contraindications
- Contraindicated in the presence of an anatomically narrow angle or in narrow angle glaucoma or in persons who have shown hypersensitivity to any component of this preparation.
# Warnings
- Patients under therapy with MAO inhibitors may experience a severe hypertensive crisis if given a sympathomimetic drug. Use in children, especially infants, may result in CNS depression leading to coma and marked reduction in body temperature.
### Precautions
- For topical ophthalmic use only. Use with caution in presence of hypertension, cardiovascular abnormalities, hyperglycemia (diabetes), hyperthyroidism, infection or injury.
# Adverse Reactions
## Clinical Trials Experience
- Mydriasis, increased redness, irritation, discomfort, blurring, punctate keratitis, lacrimation, increased intraocular pressure.
- Dizziness, headache, nausea, sweating, nervousness, drowsiness, weakness, hypertension, cardiac irregularities, and hyperglycemia.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Naphazoline in the drug label.
# Drug Interactions
- Concurrent use of maprotiline or tricyclic antidepressants and naphazoline may also potentiate the pressor effect of naphazoline. Patients under therapy with MAO inhibitors may experience a severe hypertensive crisis if given a sympathomimetic drug.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with naphazoline. It is also not known whether naphazoline can cause harm when administered to a pregnant women or can affect reproduction capacity. Naphazoline should be given to a pregnant women 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 Naphazoline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Naphazoline during labor and delivery.
### Nursing Mothers
- It is not known whether naphazoline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when naphazoline is administered to a nursing women.
### Pediatric Use
- Safety and effectiveness in the pediatric population have not been established
### Geriatic Use
There is no FDA guidance on the use of Naphazoline with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Naphazoline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Naphazoline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Naphazoline in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Naphazoline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Naphazoline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Naphazoline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Instill one or two drops in the conjunctival sac(s) every three to four hours as needed.
### Monitoring
There is limited information regarding Monitoring of Naphazoline in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Naphazoline in the drug label.
# Overdosage
There is limited information regarding Overdose of Naphazoline in the drug label.
# Pharmacology
## Mechanism of Action
- Naphazoline constricts the vascular system of the conjunctiva. It is presumed that this effect is due to direct stimulation of the drug upon the alpha adrenergic receptors in the arterioles of the conjunctiva resulting in decreased conjunctival congestion. Naphazoline belongs to the imidazoline class of sympathomimetics.
## Structure
- Naphazoline Hydrochloride, an ocular vasoconstrictor, is an imidazoline derivative sympathomimetic amine. It occurs as a white, odorless crystalline powder having a bitter taste and is freely soluble in water and in alcohol. The active ingredient is represented by the structural formula:
- Chemical Name:
- Each mL contains:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Naphazoline in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Naphazoline in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Naphazoline in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Naphazoline in the drug label.
# How Supplied
- Naphazoline Hydrochloride Ophthalmic Solution, USP, is supplied as a sterile 0.1% solution in 15 mL plastic dropper bottles.
## Storage
- Store at 20° to 25°C (68° to 77°F) .
Keep container tightly closed.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
Principal Display Panel Text for Container Label:
Naphazoline Hydrochloride Ophthalmic Solution, USP 0.1%
15 mL
Sterile
Rx only
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be advised to discontinue the drug and consult the physician if relief is not obtained within 48 hours of therapy, if irritation, blurring or redness persists or increases, or if symptoms of systemic absorption occur, i.e., dizziness, headache, nausea, decrease in body temperature, or drowsiness.
- To prevent contaminating the dropper tip and solution, do not touch any surface, the eyelids or the surrounding area with the dropper tip of the bottle. If solution changes color or becomes cloudy, do not use.
# Precautions with Alcohol
- Alcohol-Naphazoline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- AK-Con®
# Look-Alike Drug Names
There is limited information regarding Naphazoline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Naphazoline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rabin Bista, 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
Naphazoline is a Alpha-Adrenergic Agonist that is FDA approved for the treatment of as a topical ocular vasoconstrictor. Common adverse reactions include Mydriasis, increased redness, increased intraocular pressure, irritation.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Indication
- Naphazoline Hydrochloride Ophthalmic Solution is indicated for use as a topical ocular vasoconstrictor.
### Dosage
- Instill one or two drops in the conjunctival sac(s) every three to four hours as needed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Naphazoline in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Naphazoline in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Naphazoline in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Naphazoline in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Naphazoline in pediatric patients.
# Contraindications
- Contraindicated in the presence of an anatomically narrow angle or in narrow angle glaucoma or in persons who have shown hypersensitivity to any component of this preparation.
# Warnings
- Patients under therapy with MAO inhibitors may experience a severe hypertensive crisis if given a sympathomimetic drug. Use in children, especially infants, may result in CNS depression leading to coma and marked reduction in body temperature.
### Precautions
- For topical ophthalmic use only. Use with caution in presence of hypertension, cardiovascular abnormalities, hyperglycemia (diabetes), hyperthyroidism, infection or injury.
# Adverse Reactions
## Clinical Trials Experience
- Mydriasis, increased redness, irritation, discomfort, blurring, punctate keratitis, lacrimation, increased intraocular pressure.
- Dizziness, headache, nausea, sweating, nervousness, drowsiness, weakness, hypertension, cardiac irregularities, and hyperglycemia.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Naphazoline in the drug label.
# Drug Interactions
- Concurrent use of maprotiline or tricyclic antidepressants and naphazoline may also potentiate the pressor effect of naphazoline. Patients under therapy with MAO inhibitors may experience a severe hypertensive crisis if given a sympathomimetic drug.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with naphazoline. It is also not known whether naphazoline can cause harm when administered to a pregnant women or can affect reproduction capacity. Naphazoline should be given to a pregnant women 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 Naphazoline in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Naphazoline during labor and delivery.
### Nursing Mothers
- It is not known whether naphazoline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when naphazoline is administered to a nursing women.
### Pediatric Use
- Safety and effectiveness in the pediatric population have not been established
### Geriatic Use
There is no FDA guidance on the use of Naphazoline with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Naphazoline with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Naphazoline with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Naphazoline in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Naphazoline in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Naphazoline in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Naphazoline in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Instill one or two drops in the conjunctival sac(s) every three to four hours as needed.
### Monitoring
There is limited information regarding Monitoring of Naphazoline in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Naphazoline in the drug label.
# Overdosage
There is limited information regarding Overdose of Naphazoline in the drug label.
# Pharmacology
## Mechanism of Action
- Naphazoline constricts the vascular system of the conjunctiva. It is presumed that this effect is due to direct stimulation of the drug upon the alpha adrenergic receptors in the arterioles of the conjunctiva resulting in decreased conjunctival congestion. Naphazoline belongs to the imidazoline class of sympathomimetics.
## Structure
- Naphazoline Hydrochloride, an ocular vasoconstrictor, is an imidazoline derivative sympathomimetic amine. It occurs as a white, odorless crystalline powder having a bitter taste and is freely soluble in water and in alcohol. The active ingredient is represented by the structural formula:
- Chemical Name:
- Each mL contains:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Naphazoline in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Naphazoline in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Naphazoline in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Naphazoline in the drug label.
# How Supplied
- Naphazoline Hydrochloride Ophthalmic Solution, USP, is supplied as a sterile 0.1% solution in 15 mL plastic dropper bottles.
## Storage
- Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].
Keep container tightly closed.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
Principal Display Panel Text for Container Label:
Naphazoline Hydrochloride Ophthalmic Solution, USP 0.1%
15 mL
Sterile
Rx only
### Ingredients and Appearance
# Patient Counseling Information
- Patients should be advised to discontinue the drug and consult the physician if relief is not obtained within 48 hours of therapy, if irritation, blurring or redness persists or increases, or if symptoms of systemic absorption occur, i.e., dizziness, headache, nausea, decrease in body temperature, or drowsiness.
- To prevent contaminating the dropper tip and solution, do not touch any surface, the eyelids or the surrounding area with the dropper tip of the bottle. If solution changes color or becomes cloudy, do not use.
# Precautions with Alcohol
- Alcohol-Naphazoline interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- AK-Con®[1]
# Look-Alike Drug Names
There is limited information regarding Naphazoline Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Naphazoline | |
8dfea190a54683cb69494c01539771be9a286e1e | wikidoc | Naphthalene | Naphthalene
Naphthalene (not to be confused with naphtha) (also known as naphthalin, naphthaline, moth ball, tar camphor, white tar, or albocarbon), is a crystalline, aromatic, white, solid hydrocarbon, best known as the primary ingredient of mothballs. Naphthalene is volatile, forming a flammable vapor. Its molecules consist of two fused benzene rings. It is manufactured from coal tar, and converted to phthalic anhydride for the manufacture of plastics, dyes and solvents. It is also used as an antiseptic and insecticide, especially in mothballs. p-Dichlorobenzene is now often used instead of naphthalene as a mothball substitute. Naphthalene easily sublimates at room temperature.
# History
In 1819-1820, at least two chemists reported a white solid with a pungent odor derived from the distillation of coal tar. In 1821, John Kidd described many of this substance's properties and the means of its production, and proposed the name naphthaline, as it had been derived from a kind of naphtha (a broad term encompassing any volatile, flammable liquid hydrocarbon mixture, including coal tar). Naphthaline's chemical formula was determined by Michael Faraday in 1826. The structure of two fused benzene rings was proposed by Emil Erlenmeyer in 1866, and confirmed by Carl Graebe three years later.
# Structure and reactivity
A naphthalene molecule is composed of two fused benzene rings. (In organic chemistry, rings are fused if they share two or more atoms.) Accordingly, naphthalene is classified as a benzenoid polycyclic aromatic hydrocarbon (PAH). Naphthalene has three resonance structures, which are shown in the drawing below. Naphthalene has two sets of equivalent hydrogens. The alpha positions are positions 1, 4, 5, and 8 on the drawing below. The beta positions are positions 2, 3, 6, and 7.
Unlike benzene, the carbon-carbon bonds in naphthalene are not of the same length. The bonds C1–C2, C3–C4, C5–C6 and C7–C8 are about 1.36 Å (136 pm) in length, whereas all the other carbon-carbon bonds are about 1.42 Å (142 pm) in length. This has been verified by x-ray diffraction and can be expected from the resonance structures, where the bonds C1–C2, C3–C4, C5–C6 and C7–C8 are double in two of the three structures, whereas all the others are double in only one.
Resonace structures of naphthalene
Like benzene,naphthalene can undergo electrophilic aromatic substitution. For many electrophilic aromatic substitution reactions, naphthalene is more reactive than benzene, reacting under milder conditions than does benzene. For example, whereas both benzene and naphthalene react with chlorine in the presence of a ferric chloride or aluminium chloride catalyst, naphthalene and chlorine can react to form 1-chloronaphthalene even without a catalyst. Similarly, while both benzene and naphthalene can be alkylated using Friedel-Crafts reactions, naphthalene can also be alkylated by reaction with alkenes or alcohols, with sulfuric or phosphoric acid as the catalyst.
Two isomeric are possible for mono-substituted naphthalenes, corresponding to substitution at an alpha or beta position. Usually, electrophiles attack at the alpha position. The selectivity for alpha over beta substitution can be rationalized in terms of the resonance structures of the intermediate: for the alpha substitution intermediate, seven resonance structures can be drawn, of which four preserve an aromatic ring. For beta substitution, the intermediate has only six resonance structures, and only two of these are aromatic. Sulfonation, however, gives a mixture of the "alpha" product 1-naphthalenesulfonic acid and the "beta" product 2-naphthalenesulfonic acid, with the ratio dependent on reaction conditions.
Naphthalene can be hydrogenated under high pressure with metal catalysts to give 1,2,3,4-tetrahydronaphthalene, a solvent sold under the trade name Tetralin. Further hydrogenation yields decahydronaphthalene or Decalin (C10H18). Oxidation of naphthalene with chromate or permanganate, or catalytic oxidation with O2 and a vanadium catalyst, gives phthalic acid.
# Production
Most naphthalene is derived from coal tar. From the 1960s until the 1990s, significant amounts of naphthalene were also produced from heavy petroleum fractions during petroleum refining, but today petroleum-derived naphthalene represents only a minor component of naphthalene production.
Naphthalene is the most abundant single component of coal tar. While the composition of coal tar varies with the coal from which it is produced, typical coal tar is about 10% naphthalene by weight. In industrial practice, distillation of coal tar yields an oil containing about 50% naphthalene, along with a variety of other aromatic compounds. This oil, after being washed with aqueous sodium hydroxide to remove acidic components, chiefly various phenols, and with sulfuric acid to remove basic components, is fractionally distilled to isolate naphthalene. The crude naphthalene resulting from this process is about 95% naphthalene by weight. The chief impurity is the sulfur-containing aromatic compound benzothiophene. Petroleum-derived naphthalene is usually purer than that derived from coal tar. Where purer naphthalene is required, crude naphthalene can be further purified by recrystallizing it from any of a variety of solvents.
# Incidence in nature
Trace amounts of naphthalene are produced by magnolias and specific types of deer. Naphthalene has also been found in the Formosan subterranean termite, possibly as a repellant against "ants, poisonous fungi and nematode worms."
# Uses
Naphthalene's most familiar use is as a household fumigant, such as in mothballs. In a sealed container containing naphthalene pellets, naphthalene vapors build up to levels toxic to both the adult and larval forms of many moths that are destructive to textiles. Other fumigant uses of naphthalene include use in soil as a fumigant pesticide, and in attic spaces to repel animals and insects.
In the past, naphthalene was administered orally to kill parasitic worms in livestock.
Larger volumes of naphthalene are used as a chemical intermediate to produce other chemicals. The single largest use of naphthalene is the industrial production of phthalic anhydride, although more phthalic anhydride is made from o-xylene than from naphthalene. Other naphthalene-derived chemicals include alkyl naphthalene sulfonate surfactants, and the insecticide carbaryl. Naphthalenes substituted with combinations of strongly electron-donating functional groups, such as alcohols and amines, and strongly electron-withdrawing groups, especially sulfonic acids, are intermediates in the preparation of many synthetic dyes. The hydrogenated naphthalenes tetrahydronaphthalene (Tetralin) and decahydronaphthalene (Decalin) are used as low-volatility solvents.
Naphthalene vapour can also slow the onset of rust, such as the use of moth balls in a tool box.
# Health effects
In humans, exposure to large amounts of naphthalene may damage or destroy red blood cells. This condition is known as hemolytic anemia. Humans, particularly children, have developed this condition after ingesting mothballs or deodorant blocks containing naphthalene. Symptoms of this condition include fatigue, lack of appetite, restlessness, and pale skin. Exposure to large amounts of naphthalene may also cause nausea, vomiting, diarrhea, blood in the urine, and jaundice (yellow coloration of the skin).
When the U.S. National Toxicology Program exposed male and female rats and mice to naphthalene vapors on weekdays for two years, male and female rats exhibited: evidence of carcinogenic activity, based on increased incidences of adenoma and neuroblastoma of the nose, female mice exhibited some evidence of carcinogenic activity, based on increased incidences of alveolar and bronchiolar adenomas of the lung, and male mice exhibited no evidence of carcinogenic activity.
The International Agency for Research on Cancer (IARC) classifies naphthalene as possibly carcinogenic to humans . The IARC also points out that acute exposure causes cataracts in humans, rats, rabbits, and mice, and that hemolytic anemia, described above, can occur in children and infants after oral or inhalation exposure or after maternal exposure during pregnancy.
Over 400 million people have an inherited condition called glucose-6-phosphate dehydrogenase deficiency. For these people, exposure to naphthalene is more harmful and may cause hemolytic anemia at lower doses. | Naphthalene
Template:Chembox new
Naphthalene (not to be confused with naphtha) (also known as naphthalin, naphthaline, moth ball, tar camphor, white tar, or albocarbon), is a crystalline, aromatic, white, solid hydrocarbon, best known as the primary ingredient of mothballs. Naphthalene is volatile, forming a flammable vapor. Its molecules consist of two fused benzene rings. It is manufactured from coal tar, and converted to phthalic anhydride for the manufacture of plastics, dyes and solvents. It is also used as an antiseptic and insecticide, especially in mothballs. p-Dichlorobenzene is now often used instead of naphthalene as a mothball substitute. Naphthalene easily sublimates at room temperature.
# History
In 1819-1820, at least two chemists reported a white solid with a pungent odor derived from the distillation of coal tar. In 1821, John Kidd described many of this substance's properties and the means of its production, and proposed the name naphthaline, as it had been derived from a kind of naphtha (a broad term encompassing any volatile, flammable liquid hydrocarbon mixture, including coal tar).[1] Naphthaline's chemical formula was determined by Michael Faraday in 1826. The structure of two fused benzene rings was proposed by Emil Erlenmeyer in 1866, and confirmed by Carl Graebe three years later.
# Structure and reactivity
A naphthalene molecule is composed of two fused benzene rings. (In organic chemistry, rings are fused if they share two or more atoms.) Accordingly, naphthalene is classified as a benzenoid polycyclic aromatic hydrocarbon (PAH). Naphthalene has three resonance structures, which are shown in the drawing below. Naphthalene has two sets of equivalent hydrogens. The alpha positions are positions 1, 4, 5, and 8 on the drawing below. The beta positions are positions 2, 3, 6, and 7.
Unlike benzene, the carbon-carbon bonds in naphthalene are not of the same length. The bonds C1–C2, C3–C4, C5–C6 and C7–C8 are about 1.36 Å (136 pm) in length, whereas all the other carbon-carbon bonds are about 1.42 Å (142 pm) in length. This has been verified by x-ray diffraction and can be expected from the resonance structures, where the bonds C1–C2, C3–C4, C5–C6 and C7–C8 are double in two of the three structures, whereas all the others are double in only one.
Resonace structures of naphthalene
Like benzene,naphthalene can undergo electrophilic aromatic substitution. For many electrophilic aromatic substitution reactions, naphthalene is more reactive than benzene, reacting under milder conditions than does benzene. For example, whereas both benzene and naphthalene react with chlorine in the presence of a ferric chloride or aluminium chloride catalyst, naphthalene and chlorine can react to form 1-chloronaphthalene even without a catalyst. Similarly, while both benzene and naphthalene can be alkylated using Friedel-Crafts reactions, naphthalene can also be alkylated by reaction with alkenes or alcohols, with sulfuric or phosphoric acid as the catalyst.
Two isomeric are possible for mono-substituted naphthalenes, corresponding to substitution at an alpha or beta position. Usually, electrophiles attack at the alpha position. The selectivity for alpha over beta substitution can be rationalized in terms of the resonance structures of the intermediate: for the alpha substitution intermediate, seven resonance structures can be drawn, of which four preserve an aromatic ring. For beta substitution, the intermediate has only six resonance structures, and only two of these are aromatic. Sulfonation, however, gives a mixture of the "alpha" product 1-naphthalenesulfonic acid and the "beta" product 2-naphthalenesulfonic acid, with the ratio dependent on reaction conditions.
Naphthalene can be hydrogenated under high pressure with metal catalysts to give 1,2,3,4-tetrahydronaphthalene, a solvent sold under the trade name Tetralin. Further hydrogenation yields decahydronaphthalene or Decalin (C10H18). Oxidation of naphthalene with chromate or permanganate, or catalytic oxidation with O2 and a vanadium catalyst, gives phthalic acid.
# Production
Most naphthalene is derived from coal tar. From the 1960s until the 1990s, significant amounts of naphthalene were also produced from heavy petroleum fractions during petroleum refining, but today petroleum-derived naphthalene represents only a minor component of naphthalene production.
Naphthalene is the most abundant single component of coal tar. While the composition of coal tar varies with the coal from which it is produced, typical coal tar is about 10% naphthalene by weight. In industrial practice, distillation of coal tar yields an oil containing about 50% naphthalene, along with a variety of other aromatic compounds. This oil, after being washed with aqueous sodium hydroxide to remove acidic components, chiefly various phenols, and with sulfuric acid to remove basic components, is fractionally distilled to isolate naphthalene. The crude naphthalene resulting from this process is about 95% naphthalene by weight. The chief impurity is the sulfur-containing aromatic compound benzothiophene. Petroleum-derived naphthalene is usually purer than that derived from coal tar. Where purer naphthalene is required, crude naphthalene can be further purified by recrystallizing it from any of a variety of solvents.
# Incidence in nature
Trace amounts of naphthalene are produced by magnolias and specific types of deer. Naphthalene has also been found in the Formosan subterranean termite, possibly as a repellant against "ants, poisonous fungi and nematode worms." [1]
# Uses
Naphthalene's most familiar use is as a household fumigant, such as in mothballs. In a sealed container containing naphthalene pellets, naphthalene vapors build up to levels toxic to both the adult and larval forms of many moths that are destructive to textiles. Other fumigant uses of naphthalene include use in soil as a fumigant pesticide, and in attic spaces to repel animals and insects.
In the past, naphthalene was administered orally to kill parasitic worms in livestock.
Larger volumes of naphthalene are used as a chemical intermediate to produce other chemicals. The single largest use of naphthalene is the industrial production of phthalic anhydride, although more phthalic anhydride is made from o-xylene than from naphthalene. Other naphthalene-derived chemicals include alkyl naphthalene sulfonate surfactants, and the insecticide carbaryl. Naphthalenes substituted with combinations of strongly electron-donating functional groups, such as alcohols and amines, and strongly electron-withdrawing groups, especially sulfonic acids, are intermediates in the preparation of many synthetic dyes. The hydrogenated naphthalenes tetrahydronaphthalene (Tetralin) and decahydronaphthalene (Decalin) are used as low-volatility solvents.
Naphthalene vapour can also slow the onset of rust, such as the use of moth balls in a tool box.
# Health effects
In humans, exposure to large amounts of naphthalene may damage or destroy red blood cells. This condition is known as hemolytic anemia. Humans, particularly children, have developed this condition after ingesting mothballs or deodorant blocks containing naphthalene. Symptoms of this condition include fatigue, lack of appetite, restlessness, and pale skin. Exposure to large amounts of naphthalene may also cause nausea, vomiting, diarrhea, blood in the urine, and jaundice (yellow coloration of the skin).
When the U.S. National Toxicology Program exposed male and female rats and mice to naphthalene vapors on weekdays for two years,[2] male and female rats exhibited: evidence of carcinogenic activity, based on increased incidences of adenoma and neuroblastoma of the nose, female mice exhibited some evidence of carcinogenic activity, based on increased incidences of alveolar and bronchiolar adenomas of the lung, and male mice exhibited no evidence of carcinogenic activity.
The International Agency for Research on Cancer (IARC)[3] classifies naphthalene as possibly carcinogenic to humans [Group 2B]. The IARC also points out that acute exposure causes cataracts in humans, rats, rabbits, and mice, and that hemolytic anemia, described above, can occur in children and infants after oral or inhalation exposure or after maternal exposure during pregnancy.
Over 400 million people have an inherited condition called glucose-6-phosphate dehydrogenase deficiency. For these people, exposure to naphthalene is more harmful and may cause hemolytic anemia at lower doses. | https://www.wikidoc.org/index.php/Naphthalene | |
017897ed6f7fe9a3604eb83185f811f7c3fff195 | wikidoc | Naproxcinod | Naproxcinod
# Overview
Naproxcinod (nitronaproxen) is a non-steroidal anti-inflammatory drug (NSAID) developed by the French pharmaceutical company NicOx. It is a derivative of naproxen with a nitroxybutyl ester to allow it to also act as a nitric oxide (NO) donor. This second mechanism of action makes naproxcinod the first in a new class of drugs, the cyclooxygenase inhibiting nitric oxide donators (CINODs), that are hoped to produce similar analgesic efficacy to traditional NSAIDs, but with less gastrointestinal and cardiovascular side effects.
On December 2006, Scientific American distinguished naproxcinod as one of the ten most promising treatments for the world's biggest health threats; however, in 2010 the U.S. Food and Drug Administration determined that further clinical trials would be needed to obtain approval.
# Current situation in pain treatment
Many people are currently relying on traditional non-steroidal anti-inflammatory drugs and COX-2 inhibitors (for example celecoxib) to treat chronic pain and inflammation. COX-2 inhibitors have been associated with an increased risk of serious cardiovascular events such as strokes or heart attacks. Therefore, there is an unmet need for safer medications. This need is particularly acute among patients with high cardiovascular risk like hypertension which represents 50% of osteoarthritis sufferers.
# Indications
Three phase III clinical trials led by NicOx have shown that naproxcinod was effective to treat pain against knee osteoarthritis and hip osteoarthrtis. A phase II study showed no significant differences in efficacy between naproxcinod and the COX-2 inhibitor rofecoxib in the treatment of pain.
In osteoarthritis, a 750 mg dose is equipotent to 500 mg of naproxen for the treatment of inflammation but with the added benefit of attenuating the cardiovascular effects traditionally associated with NSAIDs.
In July 2010 the FDA decided not to approve naproxcinod.
# Mechanism of action
Naproxcinoid is metabolized to naproxen and a nitric oxide donating moiety. NO has various cardiovascular effects, including vasodilatory and platelet-inhibitory actions as well as the inhibition of vascular smooth muscle proliferation that serves to maintain normal vascular tone.
# Safety profile
## Blood pressure profile
According to some expertsTemplate:Who, cardiovascular risks induced by COX-2 inhibitors are caused by increases in blood pressure. Naproxcinod demonstrated in a clinical trial with 916 patients to have a blood pressure profile similar to placebo. Two phase II randomized controlled trials have shown a decreased systolic blood pressure by 2.1 mmHg after patients took naproxcinod (375 mg or 750 mg twice daily) for six weeks. These effects were especially pronounced in hypertensive populations.
### Clinical relevance of small increase in blood pressure
During an U.S. Food and Drug Administration (FDA) COX-2 advisory committee meeting, doctors have underlined the important role of small increase in blood pressure. They cited the CAMELOT trial which has concluded that even a small decrease in systolic blood pressure of 5 mmHg could lead to a reduction of 31% in cardiovascular events. Clinical studies about rofecoxib have shown that this drug increases the systolic blood pressure.
A 2005 analysis shows that a blood pressure decrease of 3.1 mmHG could avoid over 30,000 deaths from stroke and 2,000 deaths from coronary disease, resulting in more than 449,000 person years of life saved and 1.4 billion US$ in direct health care cost savings.
## Gastrointestinal safety
Non-steroidal antiinflammatory drugs have also been associated with gastrointestinal risks such as bleedings. Early studies demonstrated that naproxcinod had a better gastrointestinal profile than naproxen, especially for the gastroduodenal mucosa, but a 2009 review has found only a slight and possibly not clinically relevant reduction of gastrointestinal side-effects.
# Contraindications and adverse effects
Similarly to NSAIDs, adverse effects of naproxcinod include gastrointestinal bleedings.
# Commercialization
Naproxcinod completed the pivotal phase III studies needed for a New Drug Application (NDA). As a result, NicOx submitted its project to the FDA in September 2009. In July 2010, the FDA decided not to approve naproxcinod without further clinical trials.
NicOx has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA) in December 2009. | Naproxcinod
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Naproxcinod (nitronaproxen) is a non-steroidal anti-inflammatory drug (NSAID) developed by the French pharmaceutical company NicOx. It is a derivative of naproxen with a nitroxybutyl ester to allow it to also act as a nitric oxide (NO) donor. This second mechanism of action makes naproxcinod the first in a new class of drugs, the cyclooxygenase inhibiting nitric oxide donators (CINODs), that are hoped to produce similar analgesic efficacy to traditional NSAIDs, but with less gastrointestinal and cardiovascular side effects.[1][2]
On December 2006, Scientific American distinguished naproxcinod as one of the ten most promising treatments for the world's biggest health threats;[3] however, in 2010 the U.S. Food and Drug Administration determined that further clinical trials would be needed to obtain approval.[4]
# Current situation in pain treatment
Many people are currently relying on traditional non-steroidal anti-inflammatory drugs and COX-2 inhibitors (for example celecoxib) to treat chronic pain and inflammation. COX-2 inhibitors have been associated with an increased risk of serious cardiovascular events such as strokes or heart attacks.[5] Therefore, there is an unmet need for safer medications. This need is particularly acute among patients with high cardiovascular risk like hypertension which represents 50% of osteoarthritis sufferers.[citation needed]
# Indications
Three phase III clinical trials led by NicOx have shown that naproxcinod was effective to treat pain against knee osteoarthritis[6][7][8] and hip osteoarthrtis.[9] A phase II study showed no significant differences in efficacy between naproxcinod and the COX-2 inhibitor rofecoxib in the treatment of pain.[10]
In osteoarthritis, a 750 mg dose is equipotent to 500 mg of naproxen for the treatment of inflammation but with the added benefit of attenuating the cardiovascular effects traditionally associated with NSAIDs.[11]
In July 2010 the FDA decided not to approve naproxcinod.[4]
# Mechanism of action
Naproxcinoid is metabolized to naproxen and a nitric oxide donating moiety. NO has various cardiovascular effects, including vasodilatory and platelet-inhibitory actions as well as the inhibition of vascular smooth muscle proliferation that serves to maintain normal vascular tone.[11]
# Safety profile
## Blood pressure profile
According to some expertsTemplate:Who, cardiovascular risks induced by COX-2 inhibitors are caused by increases in blood pressure. Naproxcinod demonstrated in a clinical trial with 916 patients to have a blood pressure profile similar to placebo.[11] Two phase II randomized controlled trials have shown a decreased systolic blood pressure by 2.1 mmHg after patients took naproxcinod (375 mg or 750 mg twice daily) for six weeks. These effects were especially pronounced in hypertensive populations.[10][12]
### Clinical relevance of small increase in blood pressure
During an U.S. Food and Drug Administration (FDA) COX-2 advisory committee meeting, doctors have underlined the important role of small increase in blood pressure.[13] They cited the CAMELOT trial which has concluded that even a small decrease in systolic blood pressure of 5 mmHg could lead to a reduction of 31% in cardiovascular events.[14] Clinical studies about rofecoxib have shown that this drug increases the systolic blood pressure.[15]
A 2005 analysis shows that a blood pressure decrease of 3.1 mmHG could avoid over 30,000 deaths from stroke and 2,000 deaths from coronary disease, resulting in more than 449,000 person years of life saved and 1.4 billion US$ in direct health care cost savings.[16]
## Gastrointestinal safety
Non-steroidal antiinflammatory drugs have also been associated with gastrointestinal risks such as bleedings. Early studies demonstrated that naproxcinod had a better gastrointestinal profile than naproxen, especially for the gastroduodenal mucosa,[17][18] but a 2009 review has found only a slight and possibly not clinically relevant reduction of gastrointestinal side-effects.[19][20]
# Contraindications and adverse effects
Similarly to NSAIDs, adverse effects of naproxcinod include gastrointestinal bleedings.[19][20]
# Commercialization
Naproxcinod completed the pivotal phase III studies needed for a New Drug Application (NDA). As a result, NicOx submitted its project to the FDA in September 2009.[21] In July 2010, the FDA decided not to approve naproxcinod without further clinical trials.[4]
NicOx has submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA) in December 2009.[22] | https://www.wikidoc.org/index.php/Naproxcinod | |
500ef7a1febffb288f79435b90bac637aae2e03e | wikidoc | Ropivacaine | Ropivacaine
# Disclaimer
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# Overview
Ropivacaine is a local anesthetic that is FDA approved for the {{{indicationType}}} of cesarean section - local anesthetic lumbar epidural block, epidural anesthesia - surgical procedure, labor pain, local anesthetic nerve block - surgical procedure, postoperative pain. Common adverse reactions include cardiovascular: fetal bradycardia (12.1% ), hypotension (32% to 37% ), dermatologic: pruritus (5.1% ), gastrointestinal: nausea (24.8% .), vomiting (11.6% ), musculoskeletal: backache (4% to 40% ), neurologic: headache (5.1% ), paresthesia (5.6% ), other: fever (9.2% ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Local anesthetic lumbar epidural block
- 20 to 30 mL of 0.5% solution (100 to 150 mg) OR 15 to 20 mL of 0.75% solution (113 to 150 mg)
- Surgical procedure
- 15 to 30 mL (75 to 150 mg) of 0.5% solution
- Lumbar Epidural 10 to 20 mL (20 to 40 mg) of 0.2% solution
- Continuous lumbar Epidural infusion, 6 to 14 mL/hr (12 to 28 mg/hr) of 0.2% solution
- Incremental lumbar Epidural injections (top-up), 10 to 15 mL/hr (20 to 30 mg/hr) of 0.2% solution
- Surgical procedure: Field block 1 to 40 mL of 0.5% solution (5 to 200 mg)
- Surgical procedure: Major nerve block 35 to 50 mL of 0.5% solution (175 to 250 mg) OR 10 to 40 mL of 0.75% solution (75 to 300 mg)
- Lumbar or thoracic EpiduraL continuous infusion
- 6 to 14 mL/hr (12 to 28 mg/hr) of a 0.2% (2 mg/mL) solution
- Local Infiltration
- 1 to 100 mL (2 to 200 mg) of a 0.2% (2 mg/mL) solution OR 1 to 40 mL (5 to 200 mg) of a 0.5% (5 mg/mL) solution
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Pain
- Peribulbar infiltration of local anesthetic
- Spinal anesthesia - Surgical procedure
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Ropivacaine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy in pediatric patients has not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ropivacaine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ropivacaine in pediatric patients.
# Contraindications
- Naropin is contraindicated in patients with a known hypersensitivity to ropivacaine or to any local anesthetic agent of the amide type.
# Warnings
- In performing Naropin blocks, unintended intravenous injection is possible and may result in cardiac arrhythmia or cardiac arrest. - The potential for successful resuscitation has not been studied in humans. There have been rare reports of cardiac arrest during the use of Naropin for epidural anesthesia or peripheral nerve blockade, the majority of which occurred after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult.
- Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome.
- Naropin should be administered in incremental doses. It is not recommended for emergency situations, where a fast onset of surgical anesthesia is necessary. Historically, pregnant patients were reported to have a high risk for cardiac arrhythmias, cardiac/circulatory arrest and death when 0.75% bupivacaine (another member of the amino amide class of local anesthetics) was inadvertently rapidly injected intravenously.
- Prior to receiving major blocks the general condition of the patient should be optimized and the patient should have an i.v. line inserted.
- All necessary precautions should be taken to avoid intravascular injection. Local anesthetics should only be administered by clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after ensuring the immediate (without delay) availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies (see also Adverse Reactions, Precautions, and Management of Local Anesthetic Emergencies). Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. Solutions of Naropin should not be used for the production of obstetrical paracervical block anesthesia, retrobulbar block, or spinal anesthesia (subarachnoid block) due to insufficient data to support such use. Intravenous regional anesthesia (bier block) should not be performed due to a lack of clinical experience and the risk of attaining toxic blood levels of ropivacaine.
- It is essential that aspiration for blood, or cerebrospinal fluid (where applicable), be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection.
- A well-known risk of epidural anesthesia may be an unintentional subarachnoid injection of local anesthetic. Two clinical studies have been performed to verify the safety of Naropin at a volume of 3 mL injected into the subarachnoid space since this dose represents an incremental epidural volume that could be unintentionally injected. The 15 and 22.5 mg doses injected resulted in sensory levels as high as T5 and T4, respectively. Anesthesia to pinprick started in the sacral dermatomes in 2 to 3 minutes, extended to the T10 level in 10 to 13 minutes and lasted for approximately 2 hours. The results of these two clinical studies showed that a 3 mL dose did not produce any serious adverse events when spinal anesthesia blockade was achieved.
- Naropin should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive.
- Patients treated withclass III antiarrhythmic drugs (eg, amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.
# Adverse Reactions
## Clinical Trials Experience
- Reactions to ropivacaine are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs may be associated with excessive plasma levels, which may be due to overdosage, unintentional intravascular injection or slow metabolic degradation.
- The reported adverse events are derived from clinical studies conducted in the U.S. and other countries. The reference drug was usually bupivacaine. The studies used a variety of premedications, sedatives, and surgical procedures of varying length. A total of 3,988 patients have been exposed to Naropin at concentrations up to 1% in clinical trials. Each patient was counted once for each type of adverse event.
- For the indications of epidural administration in surgery, cesarean section, post-operative pain management, peripheral nerve block, and local infiltration, the following treatment-emergent adverse events were reported with an incidence of ≥5% in all clinical studies (N=3988): hypotension (37%),nausea (24.8%), vomiting (11.6%), bradycardia (9.3%), fever (9.2%), pain (8%), postoperative complications (7.1%), anemia (6.1%),paresthesia (5.6%),headache (5.1%), pruritus (5.1%), and back pain (5%).
- Urinary retention, dizziness, rigors, hypertension, tachycardia,anxiety, oliguria, hypoesthesia, chest pain, hypokalemia, dyspnea, cramps, and urinary tract infection.
- The reported adverse events are derived from controlled clinical studies with Naropin (concentrations ranged from 0.125% to 1% for Naropin and 0.25% to 0.75% for bupivacaine) in the U.S. and other countries involving 3,094 patients. Table 3A and 3B list adverse events (number and percentage) that occurred in at least 1% of Naropin-treated patients in these studies. The majority of patients receiving concentrations higher than 5 mg/mL (0.5%) were treated with Naropin.
- The following adverse events were reported during the Naropin clinical program in more than one patient (N=3988), occurred at an overall incidence of <1%, and were considered relevant:
- Application Site Reactions - injection site pain
- Cardiovascular System - vasovagal reaction, syncope, postural hypotension, non-specific ECG abnormalities
- Female Reproductive - poor progression of labor, uterine atony
- Gastrointestinal System - fecal incontinence, tenesmus, neonatal vomiting
- General and Other Disorders - hypothermia, malaise, asthenia, accident and/or injury
- Hearing and Vestibular - tinnitus, hearing abnormalities
- Heart Rate and Rhythm - extrasystoles, non-specific arrhythmias, atrial fibrillation
- Liver and Biliary System - jaundice
- Metabolic Disorders - hypomagnesemia
- Musculoskeletal System - myalgia
- Myo/Endo/Pericardium - ST segment changes, myocardial infarction
- Nervous System - tremor, Horner’s syndrome, paresis, dyskinesia, neuropathy, vertigo, coma, convulsion, hypokinesia, hypotonia, ptosis, stupor
- Psychiatric Disorders - agitation, confusion, somnolence, nervousness, amnesia, hallucination, emotional lability, insomnia, nightmares
- Respiratory System - bronchospasm, coughing
- Skin Disorders - rash, urticaria
- Urinary System Disorders - urinary incontinence, micturition disorder
- Vascular - deep vein thrombosis, phlebitis, pulmonary embolism
- Vision - vision abnormalities
- For the indication epidural anesthesia for surgery, the 15 most common adverse events were compared between different concentrations of Naropin and bupivacaine. Table 4 is based on data from trials in the U.S. and other countries where Naropin was administered as an epidural anesthetic for surgery.
- Using data from the same studies, the number (%) of patients experiencing hypotension is displayed by patient age, drug and concentration in Table 5.
- In Table 6, the adverse events for Naropin are broken down by gender.
- The most commonly encountered acute adverse experiences that demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose-related and due to high plasma levels that may result from overdosage, rapid absorption from the injection site, diminished tolerance or from unintentional intravascular injection of the local anesthetic solution. - In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea ("Total or High Spinal"). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Factors influencing plasma protein binding, such as acidosis, systemic diseases that alter protein production or competition with other drugs for protein binding sites, may diminish individual tolerance.
- Epidural administration of Naropin has, in some cases, as with other local anesthetics, been associated with transient increases in temperature to >38.5°C. This occurred more frequently at doses of Naropin >16 mg/h.
- These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils.
- The incidence of convulsions associated with the use of local anesthetics varies with the route of administration and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations.
- The incidence of adverse neurological reactions associated with the use of local anesthetics may be related to the total dose and concentration of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the drug. During lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur.
- Subsequent adverse effects may depend partially on the amount of drug administered intrathecally as well as the physiological and physical effects of a dural puncture. These observations may include spinal block of varying magnitude (including high or total spinal block), hypotension secondary to spinal block, urinary retention, loss of bladder and bowel control (fecal and urinary incontinence), and loss of perineal sensation and sexual function. Signs and symptoms of subarachnoid block typically start within 2 to 3 minutes of injection. Doses of 15 and 22.5 mg of Naropin resulted in sensory levels as high as T5 and T4, respectively. Analgesia started in the sacral dermatomes in 2 to 3 minutes and extended to the T10 level in 10 to 13 minutes and lasted for approximately 2 hours. Other neurological effects following unintentional subarachnoid administration during epidural anesthesia may include persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities, and loss of sphincter control; all of which may have slow, incomplete or no recovery. Headache, septic meningitis, meningismus, slowing of labor, increased incidence of forceps delivery, or cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid have been reported (see Dosage and Administration discussion of Lumbar Epidural Block). A high spinal is characterized by paralysis of the arms, loss of consciousness, respiratory paralysis and bradycardia.
- High doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and possibly cardiac arrest (see Warnings, Precautions, And Overdosage).
- Allergic type reactions are rare and may occur as a result of sensitivity to the local anesthetic (see Warnings). These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid symptomatology (including severe hypotension). Cross-sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitively established.
## Postmarketing Experience
There is limited information regarding Ropivacaine Postmarketing Experience in the drug label.
# Drug Interactions
- Specific trials studying the interaction between ropivacaine and class III antiarrhythmic drugs (eg, amiodarone) have not been performed, but caution is advised (see Warnings).
- Naropin should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Naropin, can interact with Naropin leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in vivo plasma clearance of ropivacaine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction toxicity studies have been performed in pregnant New Zealand white rabbits and Sprague-Dawley rats. During gestation days 6 to 18, rabbits received 1.3, 4.2, or 13 mg/kg/day subcutaneously. In rats, subcutaneous doses of 5.3, 11 and 26 mg/kg/day were administered during gestation days 6 to 15. No teratogenic effects were observed in rats and rabbits at the highest doses tested. The highest doses of 13 mg/kg/day (rabbits) and 26 mg/kg/day (rats) are approximately 1/3 of the maximum recommended human dose (epidural, 770 mg/24 hours) based on a mg/m2 basis. In 2 prenatal and postnatal studies, the female rats were dosed daily from day 15 of gestation to day 20 postpartum.
- The doses were 5.3, 11 and 26 mg/kg/day subcutaneously. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring.
- In another study with rats, the males were dosed daily for 9 weeks before mating and during mating. The females were dosed daily for 2 weeks before mating and then during the mating, pregnancy, and lactation, up to day 42 post coitus. At 23 mg/kg/day, an increased loss of pups was observed during the first 3 days postpartum. The effect was considered secondary to impaired maternal care due to maternal toxicity.
- There are no adequate or well-controlled studies in pregnant women of the effects of Naropin on the developing fetus. Naropin should only be used during pregnancy if the benefits outweigh the risk.
- Teratogenicity studies in rats and rabbits did not show evidence of any adverse effects on organogenesis or early fetal development in rats (26 mg/kg sc) or rabbits (13 mg/kg). The doses used were approximately equal to total daily dose based on body surface area. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring in 2 perinatal and postnatal studies in rats, at dose levels equivalent to the maximum recommended human dose based on body surface area. In another study at 23 mg/kg, an increased pup loss was seen during the first 3 days postpartum, which was considered secondary to impaired maternal care due to maternal toxicity.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ropivacaine in women who are pregnant.
### Labor and Delivery
- Local anesthetics, including ropivacaine, rapidly cross the placenta, and when used for epidural block can cause varying degrees of maternal, fetal and neonatal toxicity (see Clinical Pharmacology And Pharmacokinetics). The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function.
- Maternal hypotension has resulted from regional anesthesia with Naropin for obstetrical pain relief. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient's legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural anesthesia has been reported to prolong the second stage of labor by removing the patient's reflex urge to bear down or by interfering with motor function. Spontaneous vertex delivery occurred more frequently in patients receiving Naropin than in those receiving bupivacaine
### Nursing Mothers
- Some local anesthetic drugs are excreted in human milk and caution should be exercised when they are administered to a nursing woman. The excretion of ropivacaine or its metabolites in human milk has not been studied. Based on the milk/plasma concentration ratio in rats, the estimated daily dose to a pup will be about 4% of the dose given to the mother. Assuming that the milk/plasma concentration in humans is of the same order, the total Naropin dose to which the baby is exposed by breast-feeding is far lower than by exposure in utero in pregnant women at term (see Precautions).
### Pediatric Use
- The safety and efficacy of Naropin in pediatric patients have not been established.
### Geriatic Use
- Of the 2,978 subjects that were administered Naropin Injection in 71 controlled and uncontrolled clinical studies, 803 patients (27%) were 65 years of age or older which includes 127 patients (4%) 75 years of age and over. Naropin Injection was found to be safe and effective in the patients in these studies. Clinical data in one published article indicate that differences in various pharmacodynamic measures were observed with increasing age. In one study, the upper level of analgesia increased with age, the maximum decrease of mean arterial pressure (MAP) declined with age during the first hour after epidural administration, and the intensity of motor blockade increased with age.
- This drug and its metabolites are known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased hepatic, renal, or cardiac function, as well as concomitant disease. Therefore, care should be taken in dose selection, starting at the low end of the dosage range, and it may be useful to monitor renal function (see Pharmacokinetics, Elimination).
### Gender
There is no FDA guidance on the use of Ropivacaine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ropivacaine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ropivacaine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ropivacaine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ropivacaine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ropivacaine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Ropivacaine Administration in the drug label.
### Monitoring
There is limited information regarding Ropivacaine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ropivacaine and IV administrations.
# Overdosage
- Acute emergencies from local anesthetics are generally related to high plasma levels encountered, or large doses administered, during therapeutic use of local anesthetics or to unintended subarachnoid or intravascular injection of local anesthetic solution (see adverse reactions, Warnings, and Precautions).
- Therapy with Naropin should be discontinued at the first sign of toxicity. No specific information is available for the treatment of toxicity with Naropin; therefore, treatment should be symptomatic and supportive. The first consideration is prevention, best accomplished by incremental injection of Naropin, careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic and during continuous infusion. At the first sign of change in mental status, oxygen should be administered.
- The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Circulation should be assisted as necessary. This may prevent convulsions if they have not already occurred.
- If necessary, use drugs to control convulsions. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force).
- Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome.
- The mean dosages of ropivacaine producing seizures, after intravenous infusion in dogs, nonpregnant and pregnant sheep were 4.9, 6.1 and 5.9 mg/kg, respectively. These doses were associated with peak arterial total plasma concentrations of 11.4, 4.3 and 5 mcg/mL, respectively.
- In human volunteers given intravenous Naropin, the mean (min-max) maximum tolerated total and free arterial plasma concentrations were 4.3 (3.4 to 5.3) and 0.6 (0.3 to 0.9) mcg/mL respectively, at which time moderate CNS symptoms (muscle twitching) were noted.
- Clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia and acidosis within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen, which may avoid cardiac arrest.
- If difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated, endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask.
- The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels should be accomplished. Resuscitation of obstetrical patients may take longer than resuscitation of non-pregnant patients and closed-chest cardiac compression may be ineffective. Rapid delivery of the fetus may improve the response to resuscitative efforts.
# Pharmacology
## Mechanism of Action
- Ropivacaine is a member of the amino amide class of local anesthetics and is supplied as the pure S-(-)-enantiomer. Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows
- Pain,
- Temperature
- Touch,
- Proprioception,
- Skeletal muscle tone.
## Structure
- Naropin® Injection contains ropivacaine HCl which is a member of the amino amide class of local anesthetics. Naropin Injection is a sterile, isotonic solution that contains the enantiomerically pure drug substance, sodium chloride for isotonicity and Water for Injection. Sodium hydroxide and/or hydrochloric acid may be used for pH adjustment. It is administered parenterally.
Ropivacaine HCl is chemically described as S-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate. The drug substance is a white crystalline powder, with a molecular formula of C17H26N2OHClH2O, molecular weight of 328.89 and the following structural formula:
- At 25°C ropivacaine HCl has a solubility of 53.8 mg/mL in water, a distribution ratio between n-octanol and phosphate buffer at pH 7.4 of 14:1 and a pKa of 8.07 in 0.1 M KCl solution. The pKa of ropivacaine is approximately the same as bupivacaine (8.1) and is similar to that of mepivacaine (7.7). However, ropivacaine has an intermediate degree of lipid solubility compared to bupivacaine and mepivacaine.
Naropin Injection is preservative-free and is available in single dose containers in 2 (0.2%), 5 (0.5%), 7.5 (0.75%) and 10 mg/mL (1%) concentrations. The specific gravity of Naropin Injection solutions range from 1.002 to 1.005 at 25°C.
## Pharmacodynamics
- Studies in humans have demonstrated that, unlike most other local anesthetics, the presence of epinephrine has no major effect on either the time of onset or the duration of action of ropivacaine. Likewise, addition of epinephrine to ropivacaine has no effect on limiting systemic absorption of ropivacaine.
- Systemic absorption of local anesthetics can produce effects on the central nervous and cardiovascular systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance have been reported. Toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure.
- Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. Apparent central stimulation is usually manifested as restlessness, tremors and shivering, progressing to convulsions, followed by depression and coma, progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage.
- In 2 clinical pharmacology studies (total n=24) ropivacaine and bupivacaine were infused (10 mg/min) in human volunteers until the appearance of CNS symptoms, eg, visual or hearing disturbances, perioral numbness, tingling and others. Similar symptoms were seen with both drugs. In 1 study, the mean ± SD maximum tolerated intravenous dose of ropivacaine infused (124 ± 38 mg) was significantly higher than that of bupivacaine (99 ± 30 mg) while in the other study the doses were not different (115 ± 29 mg of ropivacaine and 103 ± 30 mg of bupivacaine). In the latter study, the number of subjects reporting each symptom was similar for both drugs with the exception of muscle twitching which was reported by more subjects with bupivacaine than ropivacaine at comparable intravenous doses. At the end of the infusion, ropivacaine in both studies caused significantly less depression of cardiac conductivity (less QRS widening) than bupivacaine. Ropivacaine and bupivacaine caused evidence of depression of cardiac contractility, but there were no changes in cardiac output.
- Clinical data in one published article indicate that differences in various pharmacodynamic measures were observed with increasing age. In one study, the upper level of analgesia increased with age, the maximum decrease of mean arterial pressure (MAP) declined with age during the first hour after epidural administration, and the intensity of motor blockade increased with age. However, no pharmacokinetic differences were observed between elderly and younger patients.
- In non-clinical pharmacology studies comparing ropivacaine and bupivacaine in several animal species, the cardiac toxicity of ropivacaine was less than that of bupivacaine, although both were considerably more toxic than lidocaine. Arrhythmogenic and cardio-depressant effects were seen in animals at significantly higher doses of ropivacaine than bupivacaine. The incidence of successful resuscitation was not significantly different between the ropivacaine and bupivacaine groups.
## Pharmacokinetics
- The systemic concentration of ropivacaine is dependent on the total dose and concentration of drug administered, the route of administration, the patient's hemodynamic/circulatory condition, and the vascularity of the administration site.
From the epidural space, ropivacaine shows complete and biphasic absorption. The half-lives of the 2 phases, (mean ± SD) are 14 ± 7 minutes and 4.2 ± 0.9 h, respectively. The slow absorption is the rate limiting factor in the elimination of ropivacaine that explains why the terminal half-life is longer after epidural than after intravenous administration. Ropivacaine shows dose-proportionality up to the highest intravenous dose studied, 80 mg, corresponding to a mean ± SD peak plasma concentration of 1.9 ± 0.3 mcg/mL.
- In some patients after a 300 mg dose for brachial plexus block, free plasma concentrations of ropivacaine may approach the threshold for CNS toxicity (see Precautions). At a dose of greater than 300 mg, for local infiltration, the terminal half-life may be longer (>30 hours).
- After intravascular infusion, ropivacaine has a steady state volume of distribution of 41 ± 7 liters. Ropivacaine is 94% protein bound, mainly to α1-acid glycoprotein. An increase in total plasma concentrations during continuous epidural infusion has been observed, related to a postoperative increase of α1-acid glycoprotein. Variations in unbound, ie, pharmacologically active, concentrations have been less than in total plasma concentration. Ropivacaine readily crosses the placenta and equilibrium in regard to unbound concentration will be rapidly reached (see PRECAUTIONS, Labor and Delivery).
- Ropivacaine is extensively metabolized in the liver, predominantly by aromatic hydroxylation mediated by cytochrome P4501A to 3-hydroxy ropivacaine. After a single IV dose approximately 37% of the total dose is excreted in the urine as both free and conjugated 3-hydroxy ropivacaine. Low concentrations of 3-hydroxy ropivacaine have been found in the plasma. Urinary excretion of the 4-hydroxy ropivacaine, and both the 3-hydroxy N-de-alkylated (3-OH-PPX) and 4-hydroxy N-de-alkylated (4-OH-PPX) metabolites account for less than 3% of the dose. An additional metabolite, 2-hydroxy-methyl-ropivacaine, has been identified but not quantified in the urine. The N-de-alkylated metabolite of ropivacaine (PPX) and 3-OH-ropivacaine are the major metabolites excreted in the urine during epidural infusion. Total PPX concentration in the plasma was about half as that of total ropivacaine; however, mean unbound concentrations of PPX were about 7 to 9 times higher than that of unbound ropivacaine following continuous epidural infusion up to 72 hours. Unbound PPX, 3-hydroxy and 4-hydroxy ropivacaine, have a pharmacological activity in animal models less than that of ropivacaine. There is no evidence of in vivo racemization in urine of ropivacaine.
- The kidney is the main excretory organ for most local anesthetic metabolites. In total, 86% of the ropivacaine dose is excreted in the urine after intravenous administration of which only 1% relates to unchanged drug. After intravenous administration ropivacaine has a mean ± SD total plasma clearance of 387 ± 107 mL/min, an unbound plasma clearance of 7.2 ± 1.6 L/min, and a renal clearance of 1 mL/min. The mean ± SD terminal half-life is 1.8 ± 0.7 h after intravascular administration and 4.2 ± 1 h after epidural administration (see Absorption).
## Nonclinical Toxicology
There is limited information regarding Ropivacaine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Ropivacaine Clinical Studies in the drug label.
# How Supplied
- The solubility of ropivacaine is limited at pH above 6. Thus, care must be taken as precipitation may occur if Naropin is mixed with alkaline solutions.
- Disinfecting agents containing heavy metals, which cause release of respective ions (mercury, zinc, copper, etc.) should not be used for skin or mucous membrane disinfection since they have been related to incidents of swelling and edema.
When chemical disinfection of the container surface is desired, either isopropyl alcohol (91%) or ethyl alcohol (70%) is recommended. It is recommended that chemical disinfection be accomplished by wiping the ampule or vial stopper thoroughly with cotton or gauze that has been moistened with the recommended alcohol just prior to use. When a container is required to have a sterile outside, a Sterile-Pak should be chosen. Glass containers may, as an alternative, be autoclaved once. Stability has been demonstrated using a targeted F0 of 7 minutes at 121°C.
- Solutions should be stored at 20º to 25°C (68º to 77°F) .
- These products are intended for single use and are free from preservatives. Any solution remaining from an opened container should be discarded promptly. In addition, continuous infusion bottles should not be left in place for more than 24 hours.
## Storage
There is limited information regarding Ropivacaine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ropivacaine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Ropivacaine 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 Ropivacaine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Ropivacaine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ropivacaine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2]
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# Overview
Ropivacaine is a local anesthetic that is FDA approved for the {{{indicationType}}} of cesarean section - local anesthetic lumbar epidural block, epidural anesthesia - surgical procedure, labor pain, local anesthetic nerve block - surgical procedure, postoperative pain. Common adverse reactions include cardiovascular: fetal bradycardia (12.1% ), hypotension (32% to 37% ), dermatologic: pruritus (5.1% ), gastrointestinal: nausea (24.8% .), vomiting (11.6% ), musculoskeletal: backache (4% to 40% ), neurologic: headache (5.1% ), paresthesia (5.6% ), other: fever (9.2% ).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Local anesthetic lumbar epidural block
- 20 to 30 mL of 0.5% solution (100 to 150 mg) OR 15 to 20 mL of 0.75% solution (113 to 150 mg)
- Surgical procedure
- 15 to 30 mL (75 to 150 mg) of 0.5% solution
- Lumbar Epidural 10 to 20 mL (20 to 40 mg) of 0.2% solution
- Continuous lumbar Epidural infusion, 6 to 14 mL/hr (12 to 28 mg/hr) of 0.2% solution
- Incremental lumbar Epidural injections (top-up), 10 to 15 mL/hr (20 to 30 mg/hr) of 0.2% solution
- Surgical procedure: Field block 1 to 40 mL of 0.5% solution (5 to 200 mg)
- Surgical procedure: Major nerve block 35 to 50 mL of 0.5% solution (175 to 250 mg) OR 10 to 40 mL of 0.75% solution (75 to 300 mg)
- Lumbar or thoracic EpiduraL continuous infusion
- 6 to 14 mL/hr (12 to 28 mg/hr) of a 0.2% (2 mg/mL) solution
- Local Infiltration
- 1 to 100 mL (2 to 200 mg) of a 0.2% (2 mg/mL) solution OR 1 to 40 mL (5 to 200 mg) of a 0.5% (5 mg/mL) solution
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
- Pain
- Peribulbar infiltration of local anesthetic
- Spinal anesthesia - Surgical procedure
### Non–Guideline-Supported Use
- There is limited information regarding Off-Label Non–Guideline-Supported Use of Ropivacaine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Safety and efficacy in pediatric patients has not been established
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ropivacaine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ropivacaine in pediatric patients.
# Contraindications
- Naropin is contraindicated in patients with a known hypersensitivity to ropivacaine or to any local anesthetic agent of the amide type.
# Warnings
- In performing Naropin blocks, unintended intravenous injection is possible and may result in cardiac arrhythmia or cardiac arrest. * The potential for successful resuscitation has not been studied in humans. There have been rare reports of cardiac arrest during the use of Naropin for epidural anesthesia or peripheral nerve blockade, the majority of which occurred after unintentional accidental intravascular administration in elderly patients and in patients with concomitant heart disease. In some instances, resuscitation has been difficult.
- Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome.
- Naropin should be administered in incremental doses. It is not recommended for emergency situations, where a fast onset of surgical anesthesia is necessary. Historically, pregnant patients were reported to have a high risk for cardiac arrhythmias, cardiac/circulatory arrest and death when 0.75% bupivacaine (another member of the amino amide class of local anesthetics) was inadvertently rapidly injected intravenously.
- Prior to receiving major blocks the general condition of the patient should be optimized and the patient should have an i.v. line inserted.
- All necessary precautions should be taken to avoid intravascular injection. Local anesthetics should only be administered by clinicians who are well versed in the diagnosis and management of dose-related toxicity and other acute emergencies which might arise from the block to be employed, and then only after ensuring the immediate (without delay) availability of oxygen, other resuscitative drugs, cardiopulmonary resuscitative equipment, and the personnel resources needed for proper management of toxic reactions and related emergencies (see also Adverse Reactions, Precautions, and Management of Local Anesthetic Emergencies). Delay in proper management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest and, possibly, death. Solutions of Naropin should not be used for the production of obstetrical paracervical block anesthesia, retrobulbar block, or spinal anesthesia (subarachnoid block) due to insufficient data to support such use. Intravenous regional anesthesia (bier block) should not be performed due to a lack of clinical experience and the risk of attaining toxic blood levels of ropivacaine.
- It is essential that aspiration for blood, or cerebrospinal fluid (where applicable), be done prior to injecting any local anesthetic, both the original dose and all subsequent doses, to avoid intravascular or subarachnoid injection. However, a negative aspiration does not ensure against an intravascular or subarachnoid injection.
- A well-known risk of epidural anesthesia may be an unintentional subarachnoid injection of local anesthetic. Two clinical studies have been performed to verify the safety of Naropin at a volume of 3 mL injected into the subarachnoid space since this dose represents an incremental epidural volume that could be unintentionally injected. The 15 and 22.5 mg doses injected resulted in sensory levels as high as T5 and T4, respectively. Anesthesia to pinprick started in the sacral dermatomes in 2 to 3 minutes, extended to the T10 level in 10 to 13 minutes and lasted for approximately 2 hours. The results of these two clinical studies showed that a 3 mL dose did not produce any serious adverse events when spinal anesthesia blockade was achieved.
- Naropin should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive.
- Patients treated withclass III antiarrhythmic drugs (eg, amiodarone) should be under close surveillance and ECG monitoring considered, since cardiac effects may be additive.
# Adverse Reactions
## Clinical Trials Experience
- Reactions to ropivacaine are characteristic of those associated with other amide-type local anesthetics. A major cause of adverse reactions to this group of drugs may be associated with excessive plasma levels, which may be due to overdosage, unintentional intravascular injection or slow metabolic degradation.
- The reported adverse events are derived from clinical studies conducted in the U.S. and other countries. The reference drug was usually bupivacaine. The studies used a variety of premedications, sedatives, and surgical procedures of varying length. A total of 3,988 patients have been exposed to Naropin at concentrations up to 1% in clinical trials. Each patient was counted once for each type of adverse event.
- For the indications of epidural administration in surgery, cesarean section, post-operative pain management, peripheral nerve block, and local infiltration, the following treatment-emergent adverse events were reported with an incidence of ≥5% in all clinical studies (N=3988): hypotension (37%),nausea (24.8%), vomiting (11.6%), bradycardia (9.3%), fever (9.2%), pain (8%), postoperative complications (7.1%), anemia (6.1%),paresthesia (5.6%),headache (5.1%), pruritus (5.1%), and back pain (5%).
- Urinary retention, dizziness, rigors, hypertension, tachycardia,anxiety, oliguria, hypoesthesia, chest pain, hypokalemia, dyspnea, cramps, and urinary tract infection.
- The reported adverse events are derived from controlled clinical studies with Naropin (concentrations ranged from 0.125% to 1% for Naropin and 0.25% to 0.75% for bupivacaine) in the U.S. and other countries involving 3,094 patients. Table 3A and 3B list adverse events (number and percentage) that occurred in at least 1% of Naropin-treated patients in these studies. The majority of patients receiving concentrations higher than 5 mg/mL (0.5%) were treated with Naropin.
- The following adverse events were reported during the Naropin clinical program in more than one patient (N=3988), occurred at an overall incidence of <1%, and were considered relevant:
- Application Site Reactions - injection site pain
- Cardiovascular System - vasovagal reaction, syncope, postural hypotension, non-specific ECG abnormalities
- Female Reproductive - poor progression of labor, uterine atony
- Gastrointestinal System - fecal incontinence, tenesmus, neonatal vomiting
- General and Other Disorders - hypothermia, malaise, asthenia, accident and/or injury
- Hearing and Vestibular - tinnitus, hearing abnormalities
- Heart Rate and Rhythm - extrasystoles, non-specific arrhythmias, atrial fibrillation
- Liver and Biliary System - jaundice
- Metabolic Disorders - hypomagnesemia
- Musculoskeletal System - myalgia
- Myo/Endo/Pericardium - ST segment changes, myocardial infarction
- Nervous System - tremor, Horner’s syndrome, paresis, dyskinesia, neuropathy, vertigo, coma, convulsion, hypokinesia, hypotonia, ptosis, stupor
- Psychiatric Disorders - agitation, confusion, somnolence, nervousness, amnesia, hallucination, emotional lability, insomnia, nightmares
- Respiratory System - bronchospasm, coughing
- Skin Disorders - rash, urticaria
- Urinary System Disorders - urinary incontinence, micturition disorder
- Vascular - deep vein thrombosis, phlebitis, pulmonary embolism
- Vision - vision abnormalities
- For the indication epidural anesthesia for surgery, the 15 most common adverse events were compared between different concentrations of Naropin and bupivacaine. Table 4 is based on data from trials in the U.S. and other countries where Naropin was administered as an epidural anesthetic for surgery.
- Using data from the same studies, the number (%) of patients experiencing hypotension is displayed by patient age, drug and concentration in Table 5.
- In Table 6, the adverse events for Naropin are broken down by gender.
- The most commonly encountered acute adverse experiences that demand immediate countermeasures are related to the central nervous system and the cardiovascular system. These adverse experiences are generally dose-related and due to high plasma levels that may result from overdosage, rapid absorption from the injection site, diminished tolerance or from unintentional intravascular injection of the local anesthetic solution. * In addition to systemic dose-related toxicity, unintentional subarachnoid injection of drug during the intended performance of lumbar epidural block or nerve blocks near the vertebral column (especially in the head and neck region) may result in underventilation or apnea ("Total or High Spinal"). Also, hypotension due to loss of sympathetic tone and respiratory paralysis or underventilation due to cephalad extension of the motor level of anesthesia may occur. This may lead to secondary cardiac arrest if untreated. Factors influencing plasma protein binding, such as acidosis, systemic diseases that alter protein production or competition with other drugs for protein binding sites, may diminish individual tolerance.
- Epidural administration of Naropin has, in some cases, as with other local anesthetics, been associated with transient increases in temperature to >38.5°C. This occurred more frequently at doses of Naropin >16 mg/h.
- These are characterized by excitation and/or depression. Restlessness, anxiety, dizziness, tinnitus, blurred vision or tremors may occur, possibly proceeding to convulsions. However, excitement may be transient or absent, with depression being the first manifestation of an adverse reaction. This may quickly be followed by drowsiness merging into unconsciousness and respiratory arrest. Other central nervous system effects may be nausea, vomiting, chills, and constriction of the pupils.
- The incidence of convulsions associated with the use of local anesthetics varies with the route of administration and the total dose administered. In a survey of studies of epidural anesthesia, overt toxicity progressing to convulsions occurred in approximately 0.1% of local anesthetic administrations.
- The incidence of adverse neurological reactions associated with the use of local anesthetics may be related to the total dose and concentration of local anesthetic administered and are also dependent upon the particular drug used, the route of administration, and the physical status of the patient. Many of these observations may be related to local anesthetic techniques, with or without a contribution from the drug. During lumbar epidural block, occasional unintentional penetration of the subarachnoid space by the catheter or needle may occur.
- Subsequent adverse effects may depend partially on the amount of drug administered intrathecally as well as the physiological and physical effects of a dural puncture. These observations may include spinal block of varying magnitude (including high or total spinal block), hypotension secondary to spinal block, urinary retention, loss of bladder and bowel control (fecal and urinary incontinence), and loss of perineal sensation and sexual function. Signs and symptoms of subarachnoid block typically start within 2 to 3 minutes of injection. Doses of 15 and 22.5 mg of Naropin resulted in sensory levels as high as T5 and T4, respectively. Analgesia started in the sacral dermatomes in 2 to 3 minutes and extended to the T10 level in 10 to 13 minutes and lasted for approximately 2 hours. Other neurological effects following unintentional subarachnoid administration during epidural anesthesia may include persistent anesthesia, paresthesia, weakness, paralysis of the lower extremities, and loss of sphincter control; all of which may have slow, incomplete or no recovery. Headache, septic meningitis, meningismus, slowing of labor, increased incidence of forceps delivery, or cranial nerve palsies due to traction on nerves from loss of cerebrospinal fluid have been reported (see Dosage and Administration discussion of Lumbar Epidural Block). A high spinal is characterized by paralysis of the arms, loss of consciousness, respiratory paralysis and bradycardia.
- High doses or unintentional intravascular injection may lead to high plasma levels and related depression of the myocardium, decreased cardiac output, heart block, hypotension, bradycardia, ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, and possibly cardiac arrest (see Warnings, Precautions, And Overdosage).
- Allergic type reactions are rare and may occur as a result of sensitivity to the local anesthetic (see Warnings). These reactions are characterized by signs such as urticaria, pruritus, erythema, angioneurotic edema (including laryngeal edema), tachycardia, sneezing, nausea, vomiting, dizziness, syncope, excessive sweating, elevated temperature, and possibly, anaphylactoid symptomatology (including severe hypotension). Cross-sensitivity among members of the amide-type local anesthetic group has been reported. The usefulness of screening for sensitivity has not been definitively established.
## Postmarketing Experience
There is limited information regarding Ropivacaine Postmarketing Experience in the drug label.
# Drug Interactions
- Specific trials studying the interaction between ropivacaine and class III antiarrhythmic drugs (eg, amiodarone) have not been performed, but caution is advised (see Warnings).
- Naropin should be used with caution in patients receiving other local anesthetics or agents structurally related to amide-type local anesthetics, since the toxic effects of these drugs are additive. Cytochrome P4501A2 is involved in the formation of 3-hydroxy ropivacaine, the major metabolite. In vivo, the plasma clearance of ropivacaine was reduced by 70% during coadministration of fluvoxamine (25 mg bid for 2 days), a selective and potent CYP1A2 inhibitor. Thus strong inhibitors of cytochrome P4501A2, such as fluvoxamine, given concomitantly during administration of Naropin, can interact with Naropin leading to increased ropivacaine plasma levels. Caution should be exercised when CYP1A2 inhibitors are coadministered. Possible interactions with drugs known to be metabolized by CYP1A2 via competitive inhibition such as theophylline and imipramine may also occur. Coadministration of a selective and potent inhibitor of CYP3A4, ketoconazole (100 mg bid for 2 days with ropivacaine infusion administered 1 hour after ketoconazole) caused a 15% reduction in in vivo plasma clearance of ropivacaine.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): B
- Reproduction toxicity studies have been performed in pregnant New Zealand white rabbits and Sprague-Dawley rats. During gestation days 6 to 18, rabbits received 1.3, 4.2, or 13 mg/kg/day subcutaneously. In rats, subcutaneous doses of 5.3, 11 and 26 mg/kg/day were administered during gestation days 6 to 15. No teratogenic effects were observed in rats and rabbits at the highest doses tested. The highest doses of 13 mg/kg/day (rabbits) and 26 mg/kg/day (rats) are approximately 1/3 of the maximum recommended human dose (epidural, 770 mg/24 hours) based on a mg/m2 basis. In 2 prenatal and postnatal studies, the female rats were dosed daily from day 15 of gestation to day 20 postpartum.
- The doses were 5.3, 11 and 26 mg/kg/day subcutaneously. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring.
- In another study with rats, the males were dosed daily for 9 weeks before mating and during mating. The females were dosed daily for 2 weeks before mating and then during the mating, pregnancy, and lactation, up to day 42 post coitus. At 23 mg/kg/day, an increased loss of pups was observed during the first 3 days postpartum. The effect was considered secondary to impaired maternal care due to maternal toxicity.
- There are no adequate or well-controlled studies in pregnant women of the effects of Naropin on the developing fetus. Naropin should only be used during pregnancy if the benefits outweigh the risk.
- Teratogenicity studies in rats and rabbits did not show evidence of any adverse effects on organogenesis or early fetal development in rats (26 mg/kg sc) or rabbits (13 mg/kg). The doses used were approximately equal to total daily dose based on body surface area. There were no treatment-related effects on late fetal development, parturition, lactation, neonatal viability, or growth of the offspring in 2 perinatal and postnatal studies in rats, at dose levels equivalent to the maximum recommended human dose based on body surface area. In another study at 23 mg/kg, an increased pup loss was seen during the first 3 days postpartum, which was considered secondary to impaired maternal care due to maternal toxicity.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ropivacaine in women who are pregnant.
### Labor and Delivery
- Local anesthetics, including ropivacaine, rapidly cross the placenta, and when used for epidural block can cause varying degrees of maternal, fetal and neonatal toxicity (see Clinical Pharmacology And Pharmacokinetics). The incidence and degree of toxicity depend upon the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus and neonate involve alterations of the central nervous system, peripheral vascular tone and cardiac function.
- Maternal hypotension has resulted from regional anesthesia with Naropin for obstetrical pain relief. Local anesthetics produce vasodilation by blocking sympathetic nerves. Elevating the patient's legs and positioning her on her left side will help prevent decreases in blood pressure. The fetal heart rate also should be monitored continuously, and electronic fetal monitoring is highly advisable. Epidural anesthesia has been reported to prolong the second stage of labor by removing the patient's reflex urge to bear down or by interfering with motor function. Spontaneous vertex delivery occurred more frequently in patients receiving Naropin than in those receiving bupivacaine
### Nursing Mothers
- Some local anesthetic drugs are excreted in human milk and caution should be exercised when they are administered to a nursing woman. The excretion of ropivacaine or its metabolites in human milk has not been studied. Based on the milk/plasma concentration ratio in rats, the estimated daily dose to a pup will be about 4% of the dose given to the mother. Assuming that the milk/plasma concentration in humans is of the same order, the total Naropin dose to which the baby is exposed by breast-feeding is far lower than by exposure in utero in pregnant women at term (see Precautions).
### Pediatric Use
- The safety and efficacy of Naropin in pediatric patients have not been established.
### Geriatic Use
- Of the 2,978 subjects that were administered Naropin Injection in 71 controlled and uncontrolled clinical studies, 803 patients (27%) were 65 years of age or older which includes 127 patients (4%) 75 years of age and over. Naropin Injection was found to be safe and effective in the patients in these studies. Clinical data in one published article indicate that differences in various pharmacodynamic measures were observed with increasing age. In one study, the upper level of analgesia increased with age, the maximum decrease of mean arterial pressure (MAP) declined with age during the first hour after epidural administration, and the intensity of motor blockade increased with age.
- This drug and its metabolites are known to be excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Elderly patients are more likely to have decreased hepatic, renal, or cardiac function, as well as concomitant disease. Therefore, care should be taken in dose selection, starting at the low end of the dosage range, and it may be useful to monitor renal function (see Pharmacokinetics, Elimination).
### Gender
There is no FDA guidance on the use of Ropivacaine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ropivacaine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ropivacaine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ropivacaine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ropivacaine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ropivacaine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
There is limited information regarding Ropivacaine Administration in the drug label.
### Monitoring
There is limited information regarding Ropivacaine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Ropivacaine and IV administrations.
# Overdosage
- Acute emergencies from local anesthetics are generally related to high plasma levels encountered, or large doses administered, during therapeutic use of local anesthetics or to unintended subarachnoid or intravascular injection of local anesthetic solution (see adverse reactions, Warnings, and Precautions).
- Therapy with Naropin should be discontinued at the first sign of toxicity. No specific information is available for the treatment of toxicity with Naropin; therefore, treatment should be symptomatic and supportive. The first consideration is prevention, best accomplished by incremental injection of Naropin, careful and constant monitoring of cardiovascular and respiratory vital signs and the patient’s state of consciousness after each local anesthetic and during continuous infusion. At the first sign of change in mental status, oxygen should be administered.
- The first step in the management of systemic toxic reactions, as well as underventilation or apnea due to unintentional subarachnoid injection of drug solution, consists of immediate attention to the establishment and maintenance of a patent airway and effective assisted or controlled ventilation with 100% oxygen with a delivery system capable of permitting immediate positive airway pressure by mask. Circulation should be assisted as necessary. This may prevent convulsions if they have not already occurred.
- If necessary, use drugs to control convulsions. Intravenous barbiturates, anticonvulsant agents, or muscle relaxants should only be administered by those familiar with their use. Immediately after the institution of these ventilatory measures, the adequacy of the circulation should be evaluated. Supportive treatment of circulatory depression may require administration of intravenous fluids, and, when appropriate, a vasopressor dictated by the clinical situation (such as ephedrine or epinephrine to enhance myocardial contractile force).
- Should cardiac arrest occur, prolonged resuscitative efforts may be required to improve the probability of a successful outcome.
- The mean dosages of ropivacaine producing seizures, after intravenous infusion in dogs, nonpregnant and pregnant sheep were 4.9, 6.1 and 5.9 mg/kg, respectively. These doses were associated with peak arterial total plasma concentrations of 11.4, 4.3 and 5 mcg/mL, respectively.
- In human volunteers given intravenous Naropin, the mean (min-max) maximum tolerated total and free arterial plasma concentrations were 4.3 (3.4 to 5.3) and 0.6 (0.3 to 0.9) mcg/mL respectively, at which time moderate CNS symptoms (muscle twitching) were noted.
- Clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia and acidosis within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen, which may avoid cardiac arrest.
- If difficulty is encountered in the maintenance of a patent airway or if prolonged ventilatory support (assisted or controlled) is indicated, endotracheal intubation, employing drugs and techniques familiar to the clinician, may be indicated after initial administration of oxygen by mask.
- The supine position is dangerous in pregnant women at term because of aortocaval compression by the gravid uterus. Therefore, during treatment of systemic toxicity, maternal hypotension or fetal bradycardia following regional block, the parturient should be maintained in the left lateral decubitus position if possible, or manual displacement of the uterus off the great vessels should be accomplished. Resuscitation of obstetrical patients may take longer than resuscitation of non-pregnant patients and closed-chest cardiac compression may be ineffective. Rapid delivery of the fetus may improve the response to resuscitative efforts.
# Pharmacology
## Mechanism of Action
- Ropivacaine is a member of the amino amide class of local anesthetics and is supplied as the pure S-(-)-enantiomer. Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows
- Pain,
- Temperature
- Touch,
- Proprioception,
- Skeletal muscle tone.
## Structure
- Naropin® Injection contains ropivacaine HCl which is a member of the amino amide class of local anesthetics. Naropin Injection is a sterile, isotonic solution that contains the enantiomerically pure drug substance, sodium chloride for isotonicity and Water for Injection. Sodium hydroxide and/or hydrochloric acid may be used for pH adjustment. It is administered parenterally.
Ropivacaine HCl is chemically described as S-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate. The drug substance is a white crystalline powder, with a molecular formula of C17H26N2O•HCl•H2O, molecular weight of 328.89 and the following structural formula:
- At 25°C ropivacaine HCl has a solubility of 53.8 mg/mL in water, a distribution ratio between n-octanol and phosphate buffer at pH 7.4 of 14:1 and a pKa of 8.07 in 0.1 M KCl solution. The pKa of ropivacaine is approximately the same as bupivacaine (8.1) and is similar to that of mepivacaine (7.7). However, ropivacaine has an intermediate degree of lipid solubility compared to bupivacaine and mepivacaine.
Naropin Injection is preservative-free and is available in single dose containers in 2 (0.2%), 5 (0.5%), 7.5 (0.75%) and 10 mg/mL (1%) concentrations. The specific gravity of Naropin Injection solutions range from 1.002 to 1.005 at 25°C.
## Pharmacodynamics
- Studies in humans have demonstrated that, unlike most other local anesthetics, the presence of epinephrine has no major effect on either the time of onset or the duration of action of ropivacaine. Likewise, addition of epinephrine to ropivacaine has no effect on limiting systemic absorption of ropivacaine.
- Systemic absorption of local anesthetics can produce effects on the central nervous and cardiovascular systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance have been reported. Toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure.
- Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. Apparent central stimulation is usually manifested as restlessness, tremors and shivering, progressing to convulsions, followed by depression and coma, progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage.
- In 2 clinical pharmacology studies (total n=24) ropivacaine and bupivacaine were infused (10 mg/min) in human volunteers until the appearance of CNS symptoms, eg, visual or hearing disturbances, perioral numbness, tingling and others. Similar symptoms were seen with both drugs. In 1 study, the mean ± SD maximum tolerated intravenous dose of ropivacaine infused (124 ± 38 mg) was significantly higher than that of bupivacaine (99 ± 30 mg) while in the other study the doses were not different (115 ± 29 mg of ropivacaine and 103 ± 30 mg of bupivacaine). In the latter study, the number of subjects reporting each symptom was similar for both drugs with the exception of muscle twitching which was reported by more subjects with bupivacaine than ropivacaine at comparable intravenous doses. At the end of the infusion, ropivacaine in both studies caused significantly less depression of cardiac conductivity (less QRS widening) than bupivacaine. Ropivacaine and bupivacaine caused evidence of depression of cardiac contractility, but there were no changes in cardiac output.
- Clinical data in one published article indicate that differences in various pharmacodynamic measures were observed with increasing age. In one study, the upper level of analgesia increased with age, the maximum decrease of mean arterial pressure (MAP) declined with age during the first hour after epidural administration, and the intensity of motor blockade increased with age. However, no pharmacokinetic differences were observed between elderly and younger patients.
- In non-clinical pharmacology studies comparing ropivacaine and bupivacaine in several animal species, the cardiac toxicity of ropivacaine was less than that of bupivacaine, although both were considerably more toxic than lidocaine. Arrhythmogenic and cardio-depressant effects were seen in animals at significantly higher doses of ropivacaine than bupivacaine. The incidence of successful resuscitation was not significantly different between the ropivacaine and bupivacaine groups.
## Pharmacokinetics
- The systemic concentration of ropivacaine is dependent on the total dose and concentration of drug administered, the route of administration, the patient's hemodynamic/circulatory condition, and the vascularity of the administration site.
From the epidural space, ropivacaine shows complete and biphasic absorption. The half-lives of the 2 phases, (mean ± SD) are 14 ± 7 minutes and 4.2 ± 0.9 h, respectively. The slow absorption is the rate limiting factor in the elimination of ropivacaine that explains why the terminal half-life is longer after epidural than after intravenous administration. Ropivacaine shows dose-proportionality up to the highest intravenous dose studied, 80 mg, corresponding to a mean ± SD peak plasma concentration of 1.9 ± 0.3 mcg/mL.
- In some patients after a 300 mg dose for brachial plexus block, free plasma concentrations of ropivacaine may approach the threshold for CNS toxicity (see Precautions). At a dose of greater than 300 mg, for local infiltration, the terminal half-life may be longer (>30 hours).
- After intravascular infusion, ropivacaine has a steady state volume of distribution of 41 ± 7 liters. Ropivacaine is 94% protein bound, mainly to α1-acid glycoprotein. An increase in total plasma concentrations during continuous epidural infusion has been observed, related to a postoperative increase of α1-acid glycoprotein. Variations in unbound, ie, pharmacologically active, concentrations have been less than in total plasma concentration. Ropivacaine readily crosses the placenta and equilibrium in regard to unbound concentration will be rapidly reached (see PRECAUTIONS, Labor and Delivery).
- Ropivacaine is extensively metabolized in the liver, predominantly by aromatic hydroxylation mediated by cytochrome P4501A to 3-hydroxy ropivacaine. After a single IV dose approximately 37% of the total dose is excreted in the urine as both free and conjugated 3-hydroxy ropivacaine. Low concentrations of 3-hydroxy ropivacaine have been found in the plasma. Urinary excretion of the 4-hydroxy ropivacaine, and both the 3-hydroxy N-de-alkylated (3-OH-PPX) and 4-hydroxy N-de-alkylated (4-OH-PPX) metabolites account for less than 3% of the dose. An additional metabolite, 2-hydroxy-methyl-ropivacaine, has been identified but not quantified in the urine. The N-de-alkylated metabolite of ropivacaine (PPX) and 3-OH-ropivacaine are the major metabolites excreted in the urine during epidural infusion. Total PPX concentration in the plasma was about half as that of total ropivacaine; however, mean unbound concentrations of PPX were about 7 to 9 times higher than that of unbound ropivacaine following continuous epidural infusion up to 72 hours. Unbound PPX, 3-hydroxy and 4-hydroxy ropivacaine, have a pharmacological activity in animal models less than that of ropivacaine. There is no evidence of in vivo racemization in urine of ropivacaine.
- The kidney is the main excretory organ for most local anesthetic metabolites. In total, 86% of the ropivacaine dose is excreted in the urine after intravenous administration of which only 1% relates to unchanged drug. After intravenous administration ropivacaine has a mean ± SD total plasma clearance of 387 ± 107 mL/min, an unbound plasma clearance of 7.2 ± 1.6 L/min, and a renal clearance of 1 mL/min. The mean ± SD terminal half-life is 1.8 ± 0.7 h after intravascular administration and 4.2 ± 1 h after epidural administration (see Absorption).
## Nonclinical Toxicology
There is limited information regarding Ropivacaine Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Ropivacaine Clinical Studies in the drug label.
# How Supplied
- The solubility of ropivacaine is limited at pH above 6. Thus, care must be taken as precipitation may occur if Naropin is mixed with alkaline solutions.
- Disinfecting agents containing heavy metals, which cause release of respective ions (mercury, zinc, copper, etc.) should not be used for skin or mucous membrane disinfection since they have been related to incidents of swelling and edema.
When chemical disinfection of the container surface is desired, either isopropyl alcohol (91%) or ethyl alcohol (70%) is recommended. It is recommended that chemical disinfection be accomplished by wiping the ampule or vial stopper thoroughly with cotton or gauze that has been moistened with the recommended alcohol just prior to use. When a container is required to have a sterile outside, a Sterile-Pak should be chosen. Glass containers may, as an alternative, be autoclaved once. Stability has been demonstrated using a targeted F0 of 7 minutes at 121°C.
- Solutions should be stored at 20º to 25°C (68º to 77°F) [see USP Controlled Room Temperature].
- These products are intended for single use and are free from preservatives. Any solution remaining from an opened container should be discarded promptly. In addition, continuous infusion bottles should not be left in place for more than 24 hours.
## Storage
There is limited information regarding Ropivacaine Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Ropivacaine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Ropivacaine 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 Ropivacaine Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Ropivacaine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Naropin | |
c8a5a6a21209eaf339754046f336fda641da2e10 | wikidoc | Nasal cycle | Nasal cycle
The nasal cycle is the rhythmic, alternating side-to-side fluctuation in nasal airflow. It is known to be regulated by the autonomic nervous system probably from the centres located in brainstem.
Nasal Cycle is the name given by western medicine for the readily noticeable pattern in human breathing - we do not breath equally (50:50) using both nostrils. At any given time, either the left or the right nostril is more actively breathing. Further, this one-sidedness reverses on a periodic basis. Much research has been done on the duration of nasal cycle.
Although readily noticeable, for some reason, this phenomenon has received very little attention under Western Medicine. The phenomenon was first noted by Kayser, a German rhinologist in Breslau, 1895.
On the other hand, this alternate-nostril-breathing is central to various breathing practices such as Pranayama, in Yoga and also in various systems of Alternative medicines. As per these systems, breathing pattern is directly linked to the working of our minds. Balancing the left and right sides of the mind is ultimately desired.
In the field of Neurosciences, researchers can measure 'how active' each cerebral hemisphere is, at baseline and while performing specific tasks. It has been known for a long time that an ultradian rhythm of alternating cerebral hemispheric activity exists in humans and animals. At any given time, either the left OR the right hemisphere of the brain is 'more active' than the other and this hemispherical dominance changes periodically. Recent findings in neuroscience have revealed that the nasal cycle is intricately linked to the ultradian rhythm of alternating cerebral hemispheric activity. Whenever the nasal cycle switches sides, the hemispheric dominance also seems to change. Although a clear association between the two has been established, causality is still arguable - whether the nostril-change causes the change in hemispherical-predominance or vice-versa. | Nasal cycle
The nasal cycle is the rhythmic, alternating side-to-side fluctuation in nasal airflow. It is known to be regulated by the autonomic nervous system probably from the centres located in brainstem. [1]
Nasal Cycle is the name given by western medicine for the readily noticeable pattern in human breathing - we do not breath equally (50:50) using both nostrils. At any given time, either the left or the right nostril is more actively breathing. Further, this one-sidedness reverses on a periodic basis. Much research has been done on the duration of nasal cycle.[2]
Although readily noticeable, for some reason, this phenomenon has received very little attention under Western Medicine. The phenomenon was first noted by Kayser, a German rhinologist in Breslau, 1895. [3]
On the other hand, this alternate-nostril-breathing is central to various breathing practices such as Pranayama, in Yoga and also in various systems of Alternative medicines. As per these systems, breathing pattern is directly linked to the working of our minds. Balancing the left and right sides of the mind is ultimately desired.
In the field of Neurosciences, researchers can measure 'how active' each cerebral hemisphere is, at baseline and while performing specific tasks. It has been known for a long time that an ultradian rhythm of alternating cerebral hemispheric activity exists in humans and animals. At any given time, either the left OR the right hemisphere of the brain is 'more active' than the other and this hemispherical dominance changes periodically. Recent findings in neuroscience[4] have revealed that the nasal cycle is intricately linked to the ultradian rhythm of alternating cerebral hemispheric activity. Whenever the nasal cycle switches sides, the hemispheric dominance also seems to change. Although a clear association between the two has been established, causality is still arguable - whether the nostril-change causes the change in hemispherical-predominance or vice-versa. | https://www.wikidoc.org/index.php/Nasal_cycle | |
2632cd839e38a94269fe4c5d0d853ff55980b685 | wikidoc | Nasopharynx | Nasopharynx
# Overview
The nasopharynx (nasal part of the pharynx) lies behind the nose and above the level of the soft palate: it differs from the and laryngeal parts of the pharynx in that its cavity always remains patent (open).
In front it communicates through the choanae with the nasal cavities.
On its lateral wall is the pharyngeal ostium of the auditory tube, somewhat triangular in shape, and bounded behind by a firm prominence, the torus or cushion, caused by the medial end of the cartilage of the tube which elevates the mucous membrane.
A vertical fold of mucous membrane, the salpingopharyngeal fold, stretches from the lower part of the torus; it contains the Salpingopharyngeus muscle.
A second and smaller fold, the salpingopalatine fold, stretches from the upper part of the torus to the palate.
Behind the ostium of the auditory tube is a deep recess, the pharyngeal recess (fossa of Rosenmüller).
On the posterior wall is a prominence, best marked in childhood, produced by a mass of lymphoid tissue, which is known as the pharyngeal tonsil.
Above the pharyngeal tonsil, in the middle line, an irregular flask-shaped depression of the mucous membrane sometimes extends up as far as the basilar process of the occipital bone; it is known as the pharyngeal bursa.
# Additional images
- Nose and nasal cavities
- External and middle ear, opened from the front. Right side. | Nasopharynx
Template:Infobox Anatomy
# Overview
The nasopharynx (nasal part of the pharynx) lies behind the nose and above the level of the soft palate: it differs from the and laryngeal parts of the pharynx in that its cavity always remains patent (open).
In front it communicates through the choanae with the nasal cavities.
On its lateral wall is the pharyngeal ostium of the auditory tube, somewhat triangular in shape, and bounded behind by a firm prominence, the torus or cushion, caused by the medial end of the cartilage of the tube which elevates the mucous membrane.
A vertical fold of mucous membrane, the salpingopharyngeal fold, stretches from the lower part of the torus; it contains the Salpingopharyngeus muscle.
A second and smaller fold, the salpingopalatine fold, stretches from the upper part of the torus to the palate.
Behind the ostium of the auditory tube is a deep recess, the pharyngeal recess (fossa of Rosenmüller).
On the posterior wall is a prominence, best marked in childhood, produced by a mass of lymphoid tissue, which is known as the pharyngeal tonsil.
Above the pharyngeal tonsil, in the middle line, an irregular flask-shaped depression of the mucous membrane sometimes extends up as far as the basilar process of the occipital bone; it is known as the pharyngeal bursa.
# Additional images
- Nose and nasal cavities
- External and middle ear, opened from the front. Right side. | https://www.wikidoc.org/index.php/Nasal_part_of_the_pharynx | |
9f65819abf7ef4df8786a7a17b29ddf3d55e986f | wikidoc | Nasal polyp | Nasal polyp
# Overview
Nasal polyps are polypoidal masses arising mainly from the mucous membranes of the nose and paranasal sinuses.
# Diagnosis
They are overgrowths of the mucosa that frequently accompany allergic rhinitis. They are freely moveable and non-tender. Nasal polyps are usually classified into antrochoanal polyps and ethmoidal polyps. Antrochoanal polyps arise from the maxillary sinuses and are much less common, ethmoidal polyps arise from the ethmoidal sinuses. Antrochoanal polyps are usually single and unilateral whereas ethmoidal polyps are multiple and bilateral.
## History and Symptoms
Symptoms of polyps include nasal block, sinusitis, anosmia or loss of smell, and secondary infection leading to headache.
## Physical Examination
### Ear Nose and Throat
The pathogenesis of nasal polyps is unknown. Nasal polyps are most commonly thought to be caused by allergy and rarely by cystic fibrosis although a significant number are associated with non-allergic adult asthma or no respiratory or allergic trigger that can be demonstrated.
These polyps have no relationship with colonic or uterine polyps. Irregular unilateral polyps particularly associated with pain or bleeding will require urgent investigation as they may represent an intranasal tumour.
## CT
CT images demonstrate a right nasal polyp
# Treatment
Nasal polyps are most often treated with steroids, topical or oral, but can also be treated with surgical methods.
Pre-post surgery, sinus rinses with a warm water (240ml / 8oz) mixed with a small amount (teaspoon) of salts (sodium chloride & sodium bicarbonate) can be very helpful to clear the sinuses. This method can be also used as a preventative measure to discourage the polyps from growing back and should be used in combination with a nasal steroid.
Mometasone furoate, commonly available as a nasal spray for treating common allergy symptoms, has been indicated in the United States by the FDA for the treatment of nasal polyps since December 2004. | Nasal polyp
# Overview
Nasal polyps are polypoidal masses arising mainly from the mucous membranes of the nose and paranasal sinuses.
# Diagnosis
They are overgrowths of the mucosa that frequently accompany allergic rhinitis. They are freely moveable and non-tender. Nasal polyps are usually classified into antrochoanal polyps and ethmoidal polyps. Antrochoanal polyps arise from the maxillary sinuses and are much less common, ethmoidal polyps arise from the ethmoidal sinuses. Antrochoanal polyps are usually single and unilateral whereas ethmoidal polyps are multiple and bilateral.
## History and Symptoms
Symptoms of polyps include nasal block, sinusitis, anosmia or loss of smell, and secondary infection leading to headache. [1]
## Physical Examination
### Ear Nose and Throat
The pathogenesis of nasal polyps is unknown. Nasal polyps are most commonly thought to be caused by allergy and rarely by cystic fibrosis although a significant number are associated with non-allergic adult asthma or no respiratory or allergic trigger that can be demonstrated.
These polyps have no relationship with colonic or uterine polyps. Irregular unilateral polyps particularly associated with pain or bleeding will require urgent investigation as they may represent an intranasal tumour.
## CT
CT images demonstrate a right nasal polyp
-
-
# Treatment
Nasal polyps are most often treated with steroids, topical or oral, but can also be treated with surgical methods.
Pre-post surgery, sinus rinses with a warm water (240ml / 8oz) mixed with a small amount (teaspoon) of salts (sodium chloride & sodium bicarbonate) can be very helpful to clear the sinuses. This method can be also used as a preventative measure to discourage the polyps from growing back and should be used in combination with a nasal steroid.
Mometasone furoate, commonly available as a nasal spray for treating common allergy symptoms, has been indicated in the United States by the FDA for the treatment of nasal polyps since December 2004.
# External links
- Nasal Polyps emedicine.com
- Nasal polyps: Signs and symptoms mayoclinic.com
Template:Respiratory pathology
de:Nasenpolyp
Template:WikiDoc Sources
- ↑ http://picasaweb.google.com/mcmumbi/USMLEIIImages | https://www.wikidoc.org/index.php/Nasal_polyp | |
c0945f869f1e5cee1e473f601079bf5d06340f0e | wikidoc | Nasal voice | Nasal voice
A nasal voice is a type of speaking voice characterized by speech with a "nasal" quality to it. It can also occur naturally because of genetic variation. In vocal context, the opposite of nasal is adenoidal or denasal.
Nasal speech can be divided into hypo-nasal or hyper-nasal.
# Hypo-nasal speech
- Hypo-nasal speech is when there is a lack of appropriate nasal airflow during speech resulting in speech much as if someone has a bad cold.
Causes of hypo-nasal speech include anything that causes nasal obstruction including, but not limited to:
- adenoid hypertrophy
- turbinate hypertrophy
- allergies
- sinus infections
- viral upper respiratory infection
- deviated septum
# Hyper-nasal speech
Hyper-nasal speech is inappropriate increased airflow through the nose during speech, especially with plosives and fricatives (syllables that begin with a consonant).
Examples of hyper-nasal speech include cleft palate and velopharyngeal insufficiency.
# People described as having nasal voices
- Fran Drescher
- Ray Romano
- Neil Young
- Bob Dylan
- John Lennon
- Billy Corgan
- The character Janice on the popular sitcom Friends
- Katie Carlile
- The character Clyde Donovan and Kyle Schwartz in the animated show South Park | Nasal voice
A nasal voice is a type of speaking voice characterized by speech with a "nasal" quality to it. It can also occur naturally because of genetic variation. In vocal context, the opposite of nasal is adenoidal or denasal.
Nasal speech can be divided into hypo-nasal or hyper-nasal.
# Hypo-nasal speech
- Hypo-nasal speech is when there is a lack of appropriate nasal airflow during speech resulting in speech much as if someone has a bad cold.
Causes of hypo-nasal speech include anything that causes nasal obstruction including, but not limited to:
- adenoid hypertrophy
- turbinate hypertrophy
- allergies
- sinus infections
- viral upper respiratory infection
- deviated septum
# Hyper-nasal speech
Hyper-nasal speech is inappropriate increased airflow through the nose during speech, especially with plosives and fricatives (syllables that begin with a consonant).
Examples of hyper-nasal speech include cleft palate and velopharyngeal insufficiency.
# People described as having nasal voices
- Fran Drescher
- Ray Romano
- Neil Young
- Bob Dylan
- John Lennon
- Billy Corgan
- The character Janice on the popular sitcom Friends
- Katie Carlile
- The character Clyde Donovan and Kyle Schwartz in the animated show South Park
# External links
- Nasal Speech Section of VoiceInfo.org
Template:Disease-stub
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Nasal_voice | |
2ab430ca1b2df764741efbb84fc878361cb60d9f | wikidoc | Nateglinide | Nateglinide
# 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
Nateglinide is a antidiabetic , endocrine metabolic-hypoglycemic agent and meglitinide that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia and upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Starlix® (nateglinide) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
### Dosing Information
- Nateglinide should be taken 1 to 30 minutes prior to meals.
- The recommended starting and maintenance dose of Starlix, alone or in combination with metformin or a thiazolidinedione, is 120 mg three times daily before meals.
- The 60-mg dose of Starlix, either alone or in combination with metformin or a thiazolidinedione, may be used in patients who are near goal HbA1C when treatment is initiated.
- No special dose adjustments are usually necessary. However, greater sensitivity of some individuals to Starlix therapy cannot be ruled out.
- No dosage adjustment is necessary in patients with mild-to-severe renal insufficiency or in patients with mild hepatic insufficiency. Dosing of patients with moderate-to-severe hepatic dysfunction has not been studied. Therefore, Starlix should be used with caution in patients with moderate-to-severe liver disease.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nateglinide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nateglinide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Nateglinide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nateglinide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nateglinide in pediatric patients.
# Contraindications
- Nateglinide is contraindicated in patients with:
- Known hypersensitivity to the drug or its inactive ingredients.
- Type 1 diabetes.
- Diabetic ketoacidosis. This condition should be treated with insulin.
# Warnings
### PRECAUTIONS
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Starlix or any other antidiabetic drug.
- Hypoglycemia:
- All oral blood glucose lowering drugs that are absorbed systemically are capable of producing hypoglycemia. The frequency of hypoglycemia is related to the severity of the diabetes, the level of glycemic control, and other patient characteristics. Geriatric patients, malnourished patients, and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose lowering effect of these treatments. The risk of hypoglycemia may be increased by strenuous physical exercise, ingestion of alcohol, insufficient caloric intake on an acute or chronic basis, or combinations with other oral antidiabetic agents. Hypoglycemia may be difficult to recognize in patients with autonomic neuropathy and/or those who use beta-blockers. Starlix® (nateglinide) should be administered prior to meals to reduce the risk of hypoglycemia. Patients who skip meals should also skip their scheduled dose of Starlix to reduce the risk of hypoglycemia.
- Hepatic Impairment:
- Starlix should be used with caution in patients with moderate-to-severe liver disease because such patients have not been studied.
- Loss of Glycemic Control:
- Transient loss of glycemic control may occur with fever, infection, trauma, or surgery. Insulin therapy may be needed instead of Starlix therapy at such times. Secondary failure, or reduced effectiveness of Starlix over a period of time, may occur.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, approximately 2,600 patients with Type 2 diabetes were treated with Starlix® (nateglinide). Of these, approximately 1,335 patients were treated for 6 months or longer and approximately 190 patients for one year or longer.
- Hypoglycemia was relatively uncommon in all treatment arms of the clinical trials. Only 0.3% of Starlix patients discontinued due to hypoglycemia. Symptoms suggestive of hypoglycemia have been observed after administration of nateglinide. These symptoms included sweating, trembling, dizziness, increased appetite, palpitations, nausea, fatigue, and weakness.
- Gastrointestinal symptoms, especially diarrhea and nausea, were no more common in patients using the combination of Starlix and metformin than in patients receiving metformin alone. Likewise, peripheral edema was no more common in patients using the combination of Starlix and rosiglitazone than in patients receiving rosiglitazone alone. The following table lists events that occurred more frequently in Starlix patients than placebo patients in controlled clinical trials.
- During post-marketing experience, rare cases of hypersensitivity reactions such as rash, itching and urticaria have been reported. Similarly, cases of jaundice, cholestatic hepatitis and elevated liver enzymes have been reported.
- Uric Acid: There were increases in mean uric acid levels for patients treated with Starlix alone, Starlix in combination with metformin, metformin alone, and glyburide alone. The respective differences from placebo were 0.29 mg/dL, 0.45 mg/dL, 0.28 mg/dL, and 0.19 mg/dL. The clinical significance of these findings is unknown.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Nateglinide in the drug label.
# Drug Interactions
- Response to therapies should be periodically assessed with glucose values and HbA1C levels.
- Nateglinide is highly bound to plasma proteins (98%), mainly albumin. In vitro displacement studies with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, acetylsalicylic acid, tolbutamide, and metformin showed no influence on the extent of nateglinide protein binding. Similarly, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, acetylsalicylic acid, and tolbutamide in vitro. However, prudent evaluation of individual cases is warranted in the clinical setting.
- Certain drugs, including nonsteroidal anti-inflammatory agents (NSAIDs), salicylates, monoamine oxidase inhibitors, non-selective beta-adrenergic-blocking agents, guanethidine, and CYP2C9 inhibitors (e.g. fluconazole, amiodarone, miconazole, oxandrolone) may potentiate the hypoglycemic action of Starlix and other oral antidiabetic drugs.
- Certain drugs including thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, rifampin, phenytoin and dietary supplements (St John’s wort) may reduce the hypoglycemic action of Starlix and other oral antidiabetic drugs. Somatostatin analogues may potentiate or attenuate the hypoglycemic action of Starlix.
- When these drugs are administered to or withdrawn from patients receiving Starlix, the patient should be observed closely for changes in glycemic control.
- The pharmacokinetics of nateglinide were not affected by the composition of a meal (high protein, fat, or carbohydrate). However, peak plasma levels were significantly reduced when Starlix was administered 10 minutes prior to a liquid meal. Starlix did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Nateglinide was not teratogenic in rats at doses up to 1000 mg/kg (approximately 60 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). In the rabbit, embryonic development was adversely affected and the incidence of gallbladder agenesis or small gallbladder was increased at a dose of 500 mg/kg (approximately 40 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). There are no adequate and well-controlled studies in pregnant women. Starlix should not be used during pregnancy.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nateglinide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nateglinide during labor and delivery.
### Nursing Mothers
- Studies in lactating rats showed that nateglinide is excreted in the milk; the AUC0-48h ratio in milk to plasma was approximately 1:4. During the peri- and postnatal period body weights were lower in offspring of rats administered nateglinide at 1000 mg/kg (approximately 60 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). It is not known whether Starlix is excreted in human milk. Because many drugs are excreted in human milk, Starlix should not be administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Nateglinide with respect to pediatric patients.
### Geriatic Use
- No differences were observed in safety or efficacy of Starlix between patients age 65 and over, and those under age 65. However, greater sensitivity of some older individuals to Starlix therapy cannot be ruled out.
### Gender
There is no FDA guidance on the use of Nateglinide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nateglinide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nateglinide in patients with renal impairment.
### Hepatic Impairment
- Starlix should be used with caution in patients with moderate-to-severe liver disease because such patients have not been studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nateglinide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nateglinide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Nateglinide in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Nateglinide in the drug label.
# Overdosage
- In a clinical study in patients with Type 2 diabetes, Starlix® (nateglinide) was administered in increasing doses up to 720 mg a day for 7 days and there were no clinically significant adverse events reported. There have been no instances of overdose with Starlix in clinical trials. However, an overdose may result in an exaggerated glucose-lowering effect with the development of hypoglycemic symptoms. Hypoglycemic symptoms without loss of consciousness or neurological findings should be treated with oral glucose and adjustments in dosage and/or meal patterns. Severe hypoglycemic reactions with coma, seizure, or other neurological symptoms should be treated with intravenous glucose. As nateglinide is highly protein bound, dialysis is not an efficient means of removing it from the blood.
# Pharmacology
## Mechanism of Action
- Nateglinide is an amino-acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K+ATP) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle.
## Structure
- Starlix® (nateglinide) is an oral antidiabetic agent used in the management of Type 2 diabetes mellitus . Starlix, (-)-N--D-phenylalanine, is structurally unrelated to the oral sulfonylurea insulin secretagogues.
The structural formula is as shown:
## Pharmacodynamics
- Starlix is rapidly absorbed and stimulates pancreatic insulin secretion within 20 minutes of oral administration. When Starlix is dosed three times daily before meals there is a rapid rise in plasma insulin, with peak levels approximately 1 hour after dosing and a fall to baseline by 4 hours after dosing.
- In a double-blind, controlled clinical trial in which Starlix was administered before each of three meals, plasma glucose levels were determined over a 12-hour, daytime period after 7 weeks of treatment. Starlix was administered 10 minutes before meals. The meals were based on standard diabetic weight maintenance menus with the total caloric content based on each subject’s height. Starlix produced statistically significant decreases in fasting and postprandial glycemia compared to placebo.
## Pharmacokinetics
- Following oral administration immediately prior to a meal, nateglinide is rapidly absorbed with mean peak plasma drug concentrations (Cmax) generally occurring within 1 hour (Tmax) after dosing. When administered to patients with Type 2 diabetes over the dosage range 60 mg to 240 mg three times a day for one week, nateglinide demonstrated linear pharmacokinetics for both AUC (area under the time/plasma concentration curve) and Cmax. Tmax was also found to be independent of dose in this patient population. Absolute bioavailability is estimated to be approximately 73%. When given with or after meals, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterized by a decrease in Cmax and a delay in time to peak plasma concentration (Tmax). Plasma profiles are characterized by multiple plasma concentration peaks when nateglinide is administered under fasting conditions. This effect is diminished when nateglinide is taken prior to a meal.
- Based on data following intravenous (IV) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 liters in healthy subjects. Nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to a lesser extent α1 acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1-10 µg/mL.
- Nateglinide is metabolized by the mixed-function oxidase system prior to elimination. The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent antidiabetic agents than nateglinide. The isoprene minor metabolite possesses potency similar to that of the parent compound nateglinide.
- In vitro data demonstrate that nateglinide is predominantly metabolized by cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%).
- Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Within 6 hours after dosing, approximately 75% of the administered 14C-nateglinide was recovered in the urine. Eighty-three percent of the 14C-nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14C-nateglinide was excreted in the urine as parent compound. In all studies of healthy volunteers and patients with Type 2 diabetes, nateglinide plasma concentrations declined rapidly with an average elimination half-life of approximately 1.5 hours. Consistent with this short elimination half-life, there was no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for 7 days.
- In vitro drug metabolism studies indicate that Starlix is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). Starlix is a potential inhibitor of the CYP2C9 isoenzyme in vivo as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. Inhibition of CYP3A4 metabolic reactions was not detected in in vitro experiments.
- Glyburide:
- In a randomized, multiple-dose crossover study, patients with Type 2 diabetes were administered 120 mg Starlix three times a day before meals for 1 day in combination with glyburide 10 mg daily. There were no clinically relevant alterations in the pharmacokinetics of either agent.
- Metformin:
- When Starlix 120 mg three times daily before meals was administered in combination with metformin 500 mg three times daily to patients with Type 2 diabetes, there were no clinically relevant changes in the pharmacokinetics of either agent.
- Digoxin:
- When Starlix 120 mg before meals was administered in combination with a single 1-mg dose of digoxin to healthy volunteers, there were no clinically relevant changes in the pharmacokinetics of either agent.
- Warfarin:
- When healthy subjects were administered Starlix 120 mg three times daily before meals for four days in combination with a single dose of warfarin 30 mg on day 2, there were no alterations in the pharmacokinetics of either agent. Prothrombin time was not affected.
- Diclofenac:
- Administration of morning and lunch doses of Starlix 120 mg in combination with a single 75-mg dose of diclofenac in healthy volunteers resulted in no significant changes to the pharmacokinetics of either agent.
- Geriatric:
- Age did not influence the pharmacokinetic properties of nateglinide. Therefore, no dose adjustments are necessary for elderly patients.
- Gender:
- No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. Therefore, no dose adjustment based on gender is necessary.
- Race:
- Results of a population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide.
- Renal Impairment:
- Compared to healthy matched subjects, patients with Type 2 diabetes and moderate-to-severe renal insufficiency (CrCl 15-50 mL/min) not on dialysis displayed similar apparent clearance, AUC, and Cmax. Patients with Type 2 diabetes and renal failure on dialysis exhibited reduced overall drug exposure. However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.
- Hepatic Impairment:
- The peak and total exposure of nateglinide in non-diabetic subjects with mild hepatic insufficiency were increased by 30% compared to matched healthy subjects. Starlix® (nateglinide) should be used with caution in patients with chronic liver disease.
## Nonclinical Toxicology
### Carcinogenesis/Mutagenesis/Impairment of Fertility
- Carcinogenicity: A two-year carcinogenicity study in Sprague-Dawley rats was performed with oral doses of nateglinide up to 900 mg/kg/day, which produced AUC exposures in male and female rats approximately 30 and 40 times the human therapeutic exposure respectively with a recommended Starlix dose of 120 mg, three times daily before meals. A two-year carcinogenicity study in B6C3F1 mice was performed with oral doses of nateglinide up to 400 mg/kg/day, which produced AUC exposures in male and female mice approximately 10 and 30 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals. No evidence of a tumorigenic response was found in either rats or mice.
- Nateglinide was not genotoxic in the in vitro Ames test, mouse lymphoma assay, chromosome aberration assay in Chinese hamster lung cells, or in the in vivo mouse micronucleus test.
- Fertility was unaffected by administration of nateglinide to rats at doses up to 600 mg/kg (approximately 16 times the human therapeutic exposure with a recommended Starlix dose of 120 mg three times daily before meals).
# Clinical Studies
- A total of 3,566 patients were randomized in nine double-blind, placebo- or active-controlled studies 8 to 24 weeks in duration to evaluate the safety and efficacy of Starlix® (nateglinide). 3,513 patients had efficacy values beyond baseline. In these studies Starlix was administered up to 30 minutes before each of three main meals daily.
- In a randomized, double-blind, placebo-controlled, 24-week study, patients with Type 2 diabetes with HbA1C ≥ 6.8% on diet alone were randomized to receive either Starlix (60 mg or 120 mg three times daily before meals) or placebo. Baseline HbA1C ranged from 7.9% to 8.1% and 77.8% of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue that medication for at least 2 months before randomization. The addition of Starlix before meals resulted in statistically significant reductions in mean HbA1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 1). The reductions in HbA1C and FPG were similar for patients naïve to, and those previously exposed to, antidiabetic medications.
- In this study, one episode of severe hypoglycemia (plasma glucose < 36 mg/dL) was reported in a patient treated with Starlix 120 mg three times daily before meals. No patients experienced hypoglycemia that required third party assistance. Patients treated with Starlix had statistically significant mean increases in weight compared to placebo (see Table 1).
- In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive Starlix (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of Starlix 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Starlix monotherapy resulted in significant reductions in mean HbA1C and mean FPG compared to placebo that were similar to the results of the study reported above (see Table 2).
- Glyburide
- In a 24-week, double-blind, active-controlled trial, patients with Type 2 diabetes who had been on a sulfonylurea for ≥ 3 months and who had a baseline HbA1C ≥ 6.5% were randomized to receive Starlix (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to Starlix had significant increases in mean HbA1C and mean FPG at endpoint compared to patients randomized to glyburide.
- Metformin
- In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive Starlix (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of Starlix 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue medication for at least 2 months before randomization. The reductions in mean HbA1C and mean FPG at endpoint with metformin monotherapy were significantly greater than the reductions in these variables with Starlix monotherapy (see Table 2). Relative to placebo, Starlix monotherapy was associated with significant increases in mean weight whereas metformin monotherapy was associated with significant decreases in mean weight. Among the subset of patients naïve to antidiabetic therapy, the reductions in mean HbA1C and mean FPG for Starlix monotherapy were similar to those for metformin monotherapy (see Table 2). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA1C in the Starlix monotherapy group increased slightly from baseline, whereas HbA1C was reduced in the metformin monotherapy group (see Table 2).
- Metformin
- In the active and placebo-controlled study of metformin and Starlix described above, the combination of Starlix and metformin resulted in statistically significantly greater reductions in HbA1C and FPG compared to either Starlix or metformin monotherapy (see Table 2). Starlix, alone or in combination with metformin, significantly reduced the prandial glucose elevation from pre-meal to 2-hours post-meal compared to placebo and metformin alone.
- In this study, one episode of severe hypoglycemia (plasma glucose ≤ 36 mg/dL) was reported in a patient receiving the combination of Starlix and metformin and four episodes of severe hypoglycemia were reported in a single patient in the metformin treatment arm. No patient experienced an episode of hypoglycemia that required third party assistance. Compared to placebo, Starlix monotherapy was associated with a statistically significant increase in weight, while no significant change in weight was observed with combined Starlix and metformin therapy (see Table 2).
- In another 24-week, double-blind, placebo-controlled trial, patients with Type 2 diabetes with HbA1C ≥ 6.8% after treatment with metformin (≥ 1500 mg daily for ≥ 1 month) were first entered into a four week run-in period of metformin monotherapy (2000 mg daily) and then randomized to receive Starlix (60 mg or 120 mg three times daily before meals) or placebo in addition to metformin. Combination therapy with Starlix and metformin was associated with statistically significantly greater reductions in HbA1C compared to metformin monotherapy (-0.4% and -0.6% for Starlix 60 mg and Starlix 120 mg plus metformin, respectively).
- Rosiglitazone
- A 24-week, double blind multicenter, placebo-controlled trial was performed in patients with Type 2 diabetes not adequately controlled after a therapeutic response to rosiglitazone monotherapy 8 mg daily. The addition of Starlix (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA1C compared to rosiglitazone monotherapy. The difference was -0.77% at 24 weeks. The mean change in weight from baseline was about +3 kg for patients treated with Starlix plus rosiglitazone vs about +1 kg for patients treated with placebo plus rosiglitazone.
- Glyburide
- In a 12-week study of patients with Type 2 diabetes inadequately controlled on glyburide 10 mg once daily, the addition of Starlix (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.
# How Supplied
Starlix® (nateglinide) tablets
60 mg
Pink, round, beveled edge tablet with “STARLIX” debossed on one side and “60” on the other.
Bottles of 100……………………………………………….NDC 0078-0351-05
120 mg
Yellow, ovaloid tablet with “STARLIX” debossed on one side and “120” on the other.
Bottles of 100……………………………………………….NDC 0078-0352-05
Manufactured by:
Novartis Singapore
Pharmaceutical Manufacturing Pte. Ltd., Singapore 637461
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
©Novartis
T2013-06
January 2013
## Storage
- Store at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF).
- Dispense in a tight container, USP.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of the potential risks and benefits of Starlix and of alternative modes of therapy. The risks and management of hypoglycemia should be explained. Patients should be instructed to take Starlix 1 to 30 minutes before ingesting a meal, but to skip their scheduled dose if they skip the meal so that the risk of hypoglycemia will be reduced. Drug interactions should be discussed with patients. Patients should be informed of potential drug-drug interactions with Starlix.
# Precautions with Alcohol
- Hypoglycemia: All oral blood glucose lowering drugs that are absorbed systemically are capable of producing hypoglycemia. The frequency of hypoglycemia is related to the severity of the diabetes, the level of glycemic control, and other patient characteristics. Geriatric patients, malnourished patients, and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose lowering effect of these treatments. The risk of hypoglycemia may be increased by strenuous physical exercise, ingestion of alcohol, insufficient caloric intake on an acute or chronic basis, or combinations with other oral antidiabetic agents. Hypoglycemia may be difficult to recognize in patients with autonomic neuropathy and/or those who use beta-blockers. Starlix® (nateglinide) should be administered prior to meals to reduce the risk of hypoglycemia. Patients who skip meals should also skip their scheduled dose of Starlix to reduce the risk of hypoglycemia.
# Brand Names
- Starlix®
# Look-Alike Drug Names
There is limited information regarding Nateglinide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nateglinide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
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# Overview
Nateglinide is a antidiabetic , endocrine metabolic-hypoglycemic agent and meglitinide that is FDA approved for the treatment of type 2 diabetes mellitus. Common adverse reactions include hypoglycemia and upper respiratory infection.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Starlix® (nateglinide) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
### Dosing Information
- Nateglinide should be taken 1 to 30 minutes prior to meals.
- The recommended starting and maintenance dose of Starlix, alone or in combination with metformin or a thiazolidinedione, is 120 mg three times daily before meals.
- The 60-mg dose of Starlix, either alone or in combination with metformin or a thiazolidinedione, may be used in patients who are near goal HbA1C when treatment is initiated.
- No special dose adjustments are usually necessary. However, greater sensitivity of some individuals to Starlix therapy cannot be ruled out.
- No dosage adjustment is necessary in patients with mild-to-severe renal insufficiency or in patients with mild hepatic insufficiency. Dosing of patients with moderate-to-severe hepatic dysfunction has not been studied. Therefore, Starlix should be used with caution in patients with moderate-to-severe liver disease.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nateglinide in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nateglinide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Nateglinide in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nateglinide in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nateglinide in pediatric patients.
# Contraindications
- Nateglinide is contraindicated in patients with:
- Known hypersensitivity to the drug or its inactive ingredients.
- Type 1 diabetes.
- Diabetic ketoacidosis. This condition should be treated with insulin.
# Warnings
### PRECAUTIONS
- There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Starlix or any other antidiabetic drug.
- Hypoglycemia:
- All oral blood glucose lowering drugs that are absorbed systemically are capable of producing hypoglycemia. The frequency of hypoglycemia is related to the severity of the diabetes, the level of glycemic control, and other patient characteristics. Geriatric patients, malnourished patients, and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose lowering effect of these treatments. The risk of hypoglycemia may be increased by strenuous physical exercise, ingestion of alcohol, insufficient caloric intake on an acute or chronic basis, or combinations with other oral antidiabetic agents. Hypoglycemia may be difficult to recognize in patients with autonomic neuropathy and/or those who use beta-blockers. Starlix® (nateglinide) should be administered prior to meals to reduce the risk of hypoglycemia. Patients who skip meals should also skip their scheduled dose of Starlix to reduce the risk of hypoglycemia.
- Hepatic Impairment:
- Starlix should be used with caution in patients with moderate-to-severe liver disease because such patients have not been studied.
- Loss of Glycemic Control:
- Transient loss of glycemic control may occur with fever, infection, trauma, or surgery. Insulin therapy may be needed instead of Starlix therapy at such times. Secondary failure, or reduced effectiveness of Starlix over a period of time, may occur.
# Adverse Reactions
## Clinical Trials Experience
- In clinical trials, approximately 2,600 patients with Type 2 diabetes were treated with Starlix® (nateglinide). Of these, approximately 1,335 patients were treated for 6 months or longer and approximately 190 patients for one year or longer.
- Hypoglycemia was relatively uncommon in all treatment arms of the clinical trials. Only 0.3% of Starlix patients discontinued due to hypoglycemia. Symptoms suggestive of hypoglycemia have been observed after administration of nateglinide. These symptoms included sweating, trembling, dizziness, increased appetite, palpitations, nausea, fatigue, and weakness.
- Gastrointestinal symptoms, especially diarrhea and nausea, were no more common in patients using the combination of Starlix and metformin than in patients receiving metformin alone. Likewise, peripheral edema was no more common in patients using the combination of Starlix and rosiglitazone than in patients receiving rosiglitazone alone. The following table lists events that occurred more frequently in Starlix patients than placebo patients in controlled clinical trials.
- During post-marketing experience, rare cases of hypersensitivity reactions such as rash, itching and urticaria have been reported. Similarly, cases of jaundice, cholestatic hepatitis and elevated liver enzymes have been reported.
- Uric Acid: There were increases in mean uric acid levels for patients treated with Starlix alone, Starlix in combination with metformin, metformin alone, and glyburide alone. The respective differences from placebo were 0.29 mg/dL, 0.45 mg/dL, 0.28 mg/dL, and 0.19 mg/dL. The clinical significance of these findings is unknown.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Nateglinide in the drug label.
# Drug Interactions
- Response to therapies should be periodically assessed with glucose values and HbA1C levels.
- Nateglinide is highly bound to plasma proteins (98%), mainly albumin. In vitro displacement studies with highly protein-bound drugs such as furosemide, propranolol, captopril, nicardipine, pravastatin, glyburide, warfarin, phenytoin, acetylsalicylic acid, tolbutamide, and metformin showed no influence on the extent of nateglinide protein binding. Similarly, nateglinide had no influence on the serum protein binding of propranolol, glyburide, nicardipine, warfarin, phenytoin, acetylsalicylic acid, and tolbutamide in vitro. However, prudent evaluation of individual cases is warranted in the clinical setting.
- Certain drugs, including nonsteroidal anti-inflammatory agents (NSAIDs), salicylates, monoamine oxidase inhibitors, non-selective beta-adrenergic-blocking agents, guanethidine, and CYP2C9 inhibitors (e.g. fluconazole, amiodarone, miconazole, oxandrolone) may potentiate the hypoglycemic action of Starlix and other oral antidiabetic drugs.
- Certain drugs including thiazides, corticosteroids, thyroid products, sympathomimetics, somatropin, rifampin, phenytoin and dietary supplements (St John’s wort) may reduce the hypoglycemic action of Starlix and other oral antidiabetic drugs. Somatostatin analogues may potentiate or attenuate the hypoglycemic action of Starlix.
- When these drugs are administered to or withdrawn from patients receiving Starlix, the patient should be observed closely for changes in glycemic control.
- The pharmacokinetics of nateglinide were not affected by the composition of a meal (high protein, fat, or carbohydrate). However, peak plasma levels were significantly reduced when Starlix was administered 10 minutes prior to a liquid meal. Starlix did not have any effect on gastric emptying in healthy subjects as assessed by acetaminophen testing.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Nateglinide was not teratogenic in rats at doses up to 1000 mg/kg (approximately 60 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). In the rabbit, embryonic development was adversely affected and the incidence of gallbladder agenesis or small gallbladder was increased at a dose of 500 mg/kg (approximately 40 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). There are no adequate and well-controlled studies in pregnant women. Starlix should not be used during pregnancy.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nateglinide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nateglinide during labor and delivery.
### Nursing Mothers
- Studies in lactating rats showed that nateglinide is excreted in the milk; the AUC0-48h ratio in milk to plasma was approximately 1:4. During the peri- and postnatal period body weights were lower in offspring of rats administered nateglinide at 1000 mg/kg (approximately 60 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals). It is not known whether Starlix is excreted in human milk. Because many drugs are excreted in human milk, Starlix should not be administered to a nursing woman.
### Pediatric Use
There is no FDA guidance on the use of Nateglinide with respect to pediatric patients.
### Geriatic Use
- No differences were observed in safety or efficacy of Starlix between patients age 65 and over, and those under age 65. However, greater sensitivity of some older individuals to Starlix therapy cannot be ruled out.
### Gender
There is no FDA guidance on the use of Nateglinide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nateglinide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nateglinide in patients with renal impairment.
### Hepatic Impairment
- Starlix should be used with caution in patients with moderate-to-severe liver disease because such patients have not been studied.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nateglinide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nateglinide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
### Monitoring
There is limited information regarding Monitoring of Nateglinide in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Nateglinide in the drug label.
# Overdosage
- In a clinical study in patients with Type 2 diabetes, Starlix® (nateglinide) was administered in increasing doses up to 720 mg a day for 7 days and there were no clinically significant adverse events reported. There have been no instances of overdose with Starlix in clinical trials. However, an overdose may result in an exaggerated glucose-lowering effect with the development of hypoglycemic symptoms. Hypoglycemic symptoms without loss of consciousness or neurological findings should be treated with oral glucose and adjustments in dosage and/or meal patterns. Severe hypoglycemic reactions with coma, seizure, or other neurological symptoms should be treated with intravenous glucose. As nateglinide is highly protein bound, dialysis is not an efficient means of removing it from the blood.
# Pharmacology
## Mechanism of Action
- Nateglinide is an amino-acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. Nateglinide interacts with the ATP-sensitive potassium (K+ATP) channel on pancreatic beta-cells. The subsequent depolarization of the beta cell opens the calcium channel, producing calcium influx and insulin secretion. The extent of insulin release is glucose dependent and diminishes at low glucose levels. Nateglinide is highly tissue selective with low affinity for heart and skeletal muscle.
## Structure
- Starlix® (nateglinide) is an oral antidiabetic agent used in the management of Type 2 diabetes mellitus [also known as non-insulin dependent diabetes mellitus (NIDDM) or adult-onset diabetes]. Starlix, (-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine, is structurally unrelated to the oral sulfonylurea insulin secretagogues.
The structural formula is as shown:
## Pharmacodynamics
- Starlix is rapidly absorbed and stimulates pancreatic insulin secretion within 20 minutes of oral administration. When Starlix is dosed three times daily before meals there is a rapid rise in plasma insulin, with peak levels approximately 1 hour after dosing and a fall to baseline by 4 hours after dosing.
- In a double-blind, controlled clinical trial in which Starlix was administered before each of three meals, plasma glucose levels were determined over a 12-hour, daytime period after 7 weeks of treatment. Starlix was administered 10 minutes before meals. The meals were based on standard diabetic weight maintenance menus with the total caloric content based on each subject’s height. Starlix produced statistically significant decreases in fasting and postprandial glycemia compared to placebo.
## Pharmacokinetics
- Following oral administration immediately prior to a meal, nateglinide is rapidly absorbed with mean peak plasma drug concentrations (Cmax) generally occurring within 1 hour (Tmax) after dosing. When administered to patients with Type 2 diabetes over the dosage range 60 mg to 240 mg three times a day for one week, nateglinide demonstrated linear pharmacokinetics for both AUC (area under the time/plasma concentration curve) and Cmax. Tmax was also found to be independent of dose in this patient population. Absolute bioavailability is estimated to be approximately 73%. When given with or after meals, the extent of nateglinide absorption (AUC) remains unaffected. However, there is a delay in the rate of absorption characterized by a decrease in Cmax and a delay in time to peak plasma concentration (Tmax). Plasma profiles are characterized by multiple plasma concentration peaks when nateglinide is administered under fasting conditions. This effect is diminished when nateglinide is taken prior to a meal.
- Based on data following intravenous (IV) administration of nateglinide, the steady-state volume of distribution of nateglinide is estimated to be approximately 10 liters in healthy subjects. Nateglinide is extensively bound (98%) to serum proteins, primarily serum albumin, and to a lesser extent α1 acid glycoprotein. The extent of serum protein binding is independent of drug concentration over the test range of 0.1-10 µg/mL.
- Nateglinide is metabolized by the mixed-function oxidase system prior to elimination. The major routes of metabolism are hydroxylation followed by glucuronide conjugation. The major metabolites are less potent antidiabetic agents than nateglinide. The isoprene minor metabolite possesses potency similar to that of the parent compound nateglinide.
- In vitro data demonstrate that nateglinide is predominantly metabolized by cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%).
- Nateglinide and its metabolites are rapidly and completely eliminated following oral administration. Within 6 hours after dosing, approximately 75% of the administered 14C-nateglinide was recovered in the urine. Eighty-three percent of the 14C-nateglinide was excreted in the urine with an additional 10% eliminated in the feces. Approximately 16% of the 14C-nateglinide was excreted in the urine as parent compound. In all studies of healthy volunteers and patients with Type 2 diabetes, nateglinide plasma concentrations declined rapidly with an average elimination half-life of approximately 1.5 hours. Consistent with this short elimination half-life, there was no apparent accumulation of nateglinide upon multiple dosing of up to 240 mg three times daily for 7 days.
- In vitro drug metabolism studies indicate that Starlix is predominantly metabolized by the cytochrome P450 isozyme CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). Starlix is a potential inhibitor of the CYP2C9 isoenzyme in vivo as indicated by its ability to inhibit the in vitro metabolism of tolbutamide. Inhibition of CYP3A4 metabolic reactions was not detected in in vitro experiments.
- Glyburide:
- In a randomized, multiple-dose crossover study, patients with Type 2 diabetes were administered 120 mg Starlix three times a day before meals for 1 day in combination with glyburide 10 mg daily. There were no clinically relevant alterations in the pharmacokinetics of either agent.
- Metformin:
- When Starlix 120 mg three times daily before meals was administered in combination with metformin 500 mg three times daily to patients with Type 2 diabetes, there were no clinically relevant changes in the pharmacokinetics of either agent.
- Digoxin:
- When Starlix 120 mg before meals was administered in combination with a single 1-mg dose of digoxin to healthy volunteers, there were no clinically relevant changes in the pharmacokinetics of either agent.
- Warfarin:
- When healthy subjects were administered Starlix 120 mg three times daily before meals for four days in combination with a single dose of warfarin 30 mg on day 2, there were no alterations in the pharmacokinetics of either agent. Prothrombin time was not affected.
- Diclofenac:
- Administration of morning and lunch doses of Starlix 120 mg in combination with a single 75-mg dose of diclofenac in healthy volunteers resulted in no significant changes to the pharmacokinetics of either agent.
- Geriatric:
- Age did not influence the pharmacokinetic properties of nateglinide. Therefore, no dose adjustments are necessary for elderly patients.
- Gender:
- No clinically significant differences in nateglinide pharmacokinetics were observed between men and women. Therefore, no dose adjustment based on gender is necessary.
- Race:
- Results of a population pharmacokinetic analysis including subjects of Caucasian, Black, and other ethnic origins suggest that race has little influence on the pharmacokinetics of nateglinide.
- Renal Impairment:
- Compared to healthy matched subjects, patients with Type 2 diabetes and moderate-to-severe renal insufficiency (CrCl 15-50 mL/min) not on dialysis displayed similar apparent clearance, AUC, and Cmax. Patients with Type 2 diabetes and renal failure on dialysis exhibited reduced overall drug exposure. However, hemodialysis patients also experienced reductions in plasma protein binding compared to the matched healthy volunteers.
- Hepatic Impairment:
- The peak and total exposure of nateglinide in non-diabetic subjects with mild hepatic insufficiency were increased by 30% compared to matched healthy subjects. Starlix® (nateglinide) should be used with caution in patients with chronic liver disease.
## Nonclinical Toxicology
### Carcinogenesis/Mutagenesis/Impairment of Fertility
- Carcinogenicity: A two-year carcinogenicity study in Sprague-Dawley rats was performed with oral doses of nateglinide up to 900 mg/kg/day, which produced AUC exposures in male and female rats approximately 30 and 40 times the human therapeutic exposure respectively with a recommended Starlix dose of 120 mg, three times daily before meals. A two-year carcinogenicity study in B6C3F1 mice was performed with oral doses of nateglinide up to 400 mg/kg/day, which produced AUC exposures in male and female mice approximately 10 and 30 times the human therapeutic exposure with a recommended Starlix dose of 120 mg, three times daily before meals. No evidence of a tumorigenic response was found in either rats or mice.
- Nateglinide was not genotoxic in the in vitro Ames test, mouse lymphoma assay, chromosome aberration assay in Chinese hamster lung cells, or in the in vivo mouse micronucleus test.
- Fertility was unaffected by administration of nateglinide to rats at doses up to 600 mg/kg (approximately 16 times the human therapeutic exposure with a recommended Starlix dose of 120 mg three times daily before meals).
# Clinical Studies
- A total of 3,566 patients were randomized in nine double-blind, placebo- or active-controlled studies 8 to 24 weeks in duration to evaluate the safety and efficacy of Starlix® (nateglinide). 3,513 patients had efficacy values beyond baseline. In these studies Starlix was administered up to 30 minutes before each of three main meals daily.
- In a randomized, double-blind, placebo-controlled, 24-week study, patients with Type 2 diabetes with HbA1C ≥ 6.8% on diet alone were randomized to receive either Starlix (60 mg or 120 mg three times daily before meals) or placebo. Baseline HbA1C ranged from 7.9% to 8.1% and 77.8% of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue that medication for at least 2 months before randomization. The addition of Starlix before meals resulted in statistically significant reductions in mean HbA1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 1). The reductions in HbA1C and FPG were similar for patients naïve to, and those previously exposed to, antidiabetic medications.
- In this study, one episode of severe hypoglycemia (plasma glucose < 36 mg/dL) was reported in a patient treated with Starlix 120 mg three times daily before meals. No patients experienced hypoglycemia that required third party assistance. Patients treated with Starlix had statistically significant mean increases in weight compared to placebo (see Table 1).
- In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive Starlix (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of Starlix 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Starlix monotherapy resulted in significant reductions in mean HbA1C and mean FPG compared to placebo that were similar to the results of the study reported above (see Table 2).
- Glyburide
- In a 24-week, double-blind, active-controlled trial, patients with Type 2 diabetes who had been on a sulfonylurea for ≥ 3 months and who had a baseline HbA1C ≥ 6.5% were randomized to receive Starlix (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to Starlix had significant increases in mean HbA1C and mean FPG at endpoint compared to patients randomized to glyburide.
- Metformin
- In another randomized, double-blind, 24-week, active- and placebo-controlled study, patients with Type 2 diabetes were randomized to receive Starlix (120 mg three times daily before meals), metformin 500 mg (three times daily), a combination of Starlix 120 mg (three times daily before meals) and metformin 500 mg (three times daily), or placebo. Baseline HbA1C ranged from 8.3% to 8.4%. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue medication for at least 2 months before randomization. The reductions in mean HbA1C and mean FPG at endpoint with metformin monotherapy were significantly greater than the reductions in these variables with Starlix monotherapy (see Table 2). Relative to placebo, Starlix monotherapy was associated with significant increases in mean weight whereas metformin monotherapy was associated with significant decreases in mean weight. Among the subset of patients naïve to antidiabetic therapy, the reductions in mean HbA1C and mean FPG for Starlix monotherapy were similar to those for metformin monotherapy (see Table 2). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA1C in the Starlix monotherapy group increased slightly from baseline, whereas HbA1C was reduced in the metformin monotherapy group (see Table 2).
- Metformin
- In the active and placebo-controlled study of metformin and Starlix described above, the combination of Starlix and metformin resulted in statistically significantly greater reductions in HbA1C and FPG compared to either Starlix or metformin monotherapy (see Table 2). Starlix, alone or in combination with metformin, significantly reduced the prandial glucose elevation from pre-meal to 2-hours post-meal compared to placebo and metformin alone.
- In this study, one episode of severe hypoglycemia (plasma glucose ≤ 36 mg/dL) was reported in a patient receiving the combination of Starlix and metformin and four episodes of severe hypoglycemia were reported in a single patient in the metformin treatment arm. No patient experienced an episode of hypoglycemia that required third party assistance. Compared to placebo, Starlix monotherapy was associated with a statistically significant increase in weight, while no significant change in weight was observed with combined Starlix and metformin therapy (see Table 2).
- In another 24-week, double-blind, placebo-controlled trial, patients with Type 2 diabetes with HbA1C ≥ 6.8% after treatment with metformin (≥ 1500 mg daily for ≥ 1 month) were first entered into a four week run-in period of metformin monotherapy (2000 mg daily) and then randomized to receive Starlix (60 mg or 120 mg three times daily before meals) or placebo in addition to metformin. Combination therapy with Starlix and metformin was associated with statistically significantly greater reductions in HbA1C compared to metformin monotherapy (-0.4% and -0.6% for Starlix 60 mg and Starlix 120 mg plus metformin, respectively).
- Rosiglitazone
- A 24-week, double blind multicenter, placebo-controlled trial was performed in patients with Type 2 diabetes not adequately controlled after a therapeutic response to rosiglitazone monotherapy 8 mg daily. The addition of Starlix (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA1C compared to rosiglitazone monotherapy. The difference was -0.77% at 24 weeks. The mean change in weight from baseline was about +3 kg for patients treated with Starlix plus rosiglitazone vs about +1 kg for patients treated with placebo plus rosiglitazone.
- Glyburide
- In a 12-week study of patients with Type 2 diabetes inadequately controlled on glyburide 10 mg once daily, the addition of Starlix (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.
# How Supplied
Starlix® (nateglinide) tablets
60 mg
Pink, round, beveled edge tablet with “STARLIX” debossed on one side and “60” on the other.
Bottles of 100……………………………………………….NDC 0078-0351-05
120 mg
Yellow, ovaloid tablet with “STARLIX” debossed on one side and “120” on the other.
Bottles of 100……………………………………………….NDC 0078-0352-05
Manufactured by:
Novartis Singapore
Pharmaceutical Manufacturing Pte. Ltd., Singapore 637461
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
©Novartis
T2013-06
January 2013
## Storage
- Store at 25ºC (77ºF); excursions permitted to 15ºC-30ºC (59ºF-86ºF).
- Dispense in a tight container, USP.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Patients should be informed of the potential risks and benefits of Starlix and of alternative modes of therapy. The risks and management of hypoglycemia should be explained. Patients should be instructed to take Starlix 1 to 30 minutes before ingesting a meal, but to skip their scheduled dose if they skip the meal so that the risk of hypoglycemia will be reduced. Drug interactions should be discussed with patients. Patients should be informed of potential drug-drug interactions with Starlix.
# Precautions with Alcohol
- Hypoglycemia: All oral blood glucose lowering drugs that are absorbed systemically are capable of producing hypoglycemia. The frequency of hypoglycemia is related to the severity of the diabetes, the level of glycemic control, and other patient characteristics. Geriatric patients, malnourished patients, and those with adrenal or pituitary insufficiency or severe renal impairment are more susceptible to the glucose lowering effect of these treatments. The risk of hypoglycemia may be increased by strenuous physical exercise, ingestion of alcohol, insufficient caloric intake on an acute or chronic basis, or combinations with other oral antidiabetic agents. Hypoglycemia may be difficult to recognize in patients with autonomic neuropathy and/or those who use beta-blockers. Starlix® (nateglinide) should be administered prior to meals to reduce the risk of hypoglycemia. Patients who skip meals should also skip their scheduled dose of Starlix to reduce the risk of hypoglycemia.
# Brand Names
- Starlix®
# Look-Alike Drug Names
There is limited information regarding Nateglinide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nateglinide | |
9ad6915d5bc01999352e777d8673cf545ad2f957 | wikidoc | Natural gas | Natural gas
Natural gas is a gaseous fossil fuel consisting primarily of methane but including significant quantities of ethane, butane, propane, carbon dioxide, nitrogen, helium and hydrogen sulfide. It is found in oil fields and natural gas fields, and in coal beds (as coalbed methane). When methane-rich gases are produced by the anaerobic decay of non-fossil organic material, these are referred to as biogas. Sources of biogas include swamps, marshes, and landfills (see landfill gas), as well as sewage sludge and manure by way of anaerobic digesters, in addition to enteric fermentation particularly in cattle. Natural gas is often informally referred to as simply gas, especially when compared to other energy sources such as electricity. Before natural gas can be used as a fuel, it must undergo extensive processing to remove almost all materials other than methane. The by-products of that processing include ethane, propane, butanes, pentanes and higher molecular weight hydrocarbons, elemental sulfur, and sometimes helium and nitrogen.
## Chemical composition
The primary component of natural gas is methane (CH4), the shortest and lightest hydrocarbon molecule. It also contains heavier gaseous hydrocarbons such as ethane (C2H6), propane (C3H8) and butane (C4H10), as well as other sulfur containing gases, in varying amounts, see also natural gas condensate. Natural gas also contains and is the primary market source of helium.
Nitrogen, helium, carbon dioxide and trace amounts of hydrogen sulfide, water and odorants can also be present
. Mercury is also present in small amounts in natural gas extracted from some fields. The exact composition of natural gas varies between gas fields.
Organosulfur compounds and hydrogen sulfide are common contaminants which must be removed prior to most uses. Gas with a significant amount of sulfur impurities, such as hydrogen sulfide, is termed sour gas; gas with sulfur or carbon dioxide impurities is acid gas. Processed natural gas that is available to end-users is tasteless and odorless, however, before gas is distributed to end-users, it is odorized by adding small amounts of odorants (mixtures of t-butyl mercaptan, isopropyl mercaptan, tetrahydrothiophene, dimethyl sulfide and other sulfur compounds), to assist in leak detection. Processed natural gas is, in itself, harmless to the human body, however, natural gas is a simple asphyxiant and can kill if it displaces air to the point where the oxygen content will not support life.
Natural gas can also be hazardous to life and property through an explosion. Natural gas is lighter than air, and so tends to escape into the atmosphere. But when natural gas is confined, such as within a house, gas concentrations can reach explosive mixtures and, if ignited, result in blasts that could destroy buildings. Methane has a lower explosive limit of 5% in air, and an upper explosive limit of 15%.
Explosive concerns with compressed natural gas used in vehicles are almost non-existent, due to the escaping nature of the gas, and the need to maintain concentrations between 5% and 15% to trigger explosions.
## Energy content, statistics and pricing
Quantities of natural gas are measured in normal cubic meters (corresponding to 0°C at 101.325 kPaA) or in standard cubic feet (corresponding to 60°F and 14.73 PSIA).
The gross heat of combustion of one normal cubic meter of commercial quality natural gas is around 39 megajoules (≈10.8 kWh), but this can vary by several percent.
In US units, one standard cubic foot of natural gas produces around 1,030 British Thermal Units (BTUs). The actual heating value when the water formed does not condense is the net heat of combustion and can be as much as 10% less.
The price of natural gas varies greatly depending on location and type of consumer, but as of 2007 a price of $7 per 1000 cubic feet is typical in the United States. This corresponds to around $7 per million BTU's, or around $7 per gigajoule. Natural gas in the United States is traded as a futures contract on the New York Mercantile Exchange. Each contract is for 10,000 MMBTU (gigajoules), or 10 billion BTU's. Thus, if the price of gas is $7 per million BTU's on the NYMEX, the contract is worth $70,000. In the United States, at retail, natural gas is often sold in units of therms (th); 1 therm = 100,000 BTU. Gas meters measure the volume of gas used, and this is converted to therms by multiplying the volume by the energy content of the gas used during that period, which varies slightly over time. Wholesale transactions are generally done in decatherms (Dth), or in thousand decatherms (MDth), or in million decatherms (MMDth). A million decatherms is roughly a billion cubic feet of natural gas.
Natural gas is also traded as a commodity in Europe, principally at the United Kingdom NBP and related European hubs, such as the TTF in the Netherlands.
In the rest of the world, LNG and LPG is traded in metric tons or mmBTU as spot deliveries. Long term contracts are signed in metric tons - and to convert from one system to the other requires should better be described here, than a very isolated market. A cubic foot is a volumetric measure, MT is weight. The LNG and LPG is transported by special ships/containers, as the gas is liquified - LPG cryonic. The specification of each LNG/LPG cargo will usually contain the energy content, but this information is in general not available to the public.
# Natural gas processing
The image below is a schematic block flow diagram of a typical natural gas processing plant. It shows the various unit processes used to convert raw natural gas into sales gas pipelined to the end user markets.
The block flow diagram also shows how processing of the raw natural gas yields byproduct sulfur, byproduct ethane, and natural gas liquids (NGL) propane, butanes and natural gasoline (denoted as pentanes +).
# Storage and transport
The major difficulty in the use of natural gas is transportation and storage because of its low density. Natural gas pipelines are economical, but are impractical across oceans. Many existing pipelines in North America are close to reaching their capacity, prompting some politicians representing colder areas to speak publicly of potential shortages.
LNG carriers can be used to transport liquefied natural gas (LNG) across oceans, while tank trucks can carry liquefied or compressed natural gas (CNG) over shorter distances. They may transport natural gas directly to end-users, or to distribution points such as pipelines for further transport. These may have a higher cost, requiring additional facilities for liquefaction or compression at the production point, and then gasification or decompression at end-use facilities or into a pipeline.
In the past, the natural gas which was recovered in the course of recovering petroleum could not be profitably sold, and was simply burned at the oil field (known as flaring). This wasteful practice is now illegal in many countries. Additionally, companies now recognize that value for the gas may be achieved with LNG, CNG, or other transportation methods to end-users in the future. The gas is now re-injected back into the formation for later recovery. This also assists oil pumping by keeping underground pressures higher. In Saudi Arabia, in the late 1970s, a "Master Gas System" was created, ending the need for flaring. The natural gas is used to generate electricity and heat for desalinization. Similarly, some landfills that also discharge methane gases have been set up to capture the methane and generate electricity.
Natural gas is often stored in underground caverns formed inside depleted gas reservoirs from previous gas wells, salt domes, or in tanks as liquefied natural gas. The gas is injected during periods of low demand and extracted during periods of higher demand. Storage near the ultimate end-users helps to best meet volatile demands, but this may not always be practicable.
With 15 nations accounting for 84% of the world-wide production, access to natural gas has become a significant factor in international economics and politics. In this respect, control over the pipelines is a major strategic factor.
# Use
## Power generation
Natural gas is a major source of electricity generation through the use of gas turbines and steam turbines. Particularly high efficiencies can be achieved through combining gas turbines with a steam turbine in combined cycle mode. Natural gas burns cleaner than other fossil fuels, such as oil and coal, and produces less carbon dioxide per unit energy released. For an equivalent amount of heat, burning natural gas produces about 30% less carbon dioxide than burning petroleum and about 45% less than burning coal. Combined cycle power generation using natural gas is thus the cleanest source of power available using fossil fuels, and this technology is widely used wherever gas can be obtained at a reasonable cost. Fuel cell technology may eventually provide cleaner options for converting natural gas into electricity, but as yet it is not price-competitive. Also, the natural gas supply is expected to peak around the year 2030, 20 years after the peak of oil. It is also projected that the world's supply of natural gas could be exhausted around the year 2085.
## Hydrogen
Natural gas can be used to produce hydrogen, with one common method being the hydrogen reformer. Hydrogen has various applications: it is a primary feedstock for the chemical industry, a hydrogenating agent, an important commodity for oil refineries, and a fuel source in hydrogen vehicles.
## Natural gas vehicles
Compressed natural gas (methane) is used as a clean alternative to other automobile fuels such as gasoline (petrol) and diesel. As of 2005, the countries with the largest number of natural gas vehicles were Argentina, Brazil, Pakistan, Italy, India and Bangladesh. The energy efficiency is generally equal to that of gasoline engines, but lower compared with modern diesel engines. Benzine vehicles converted to run on gas suffer of the low-compression ratio their engines have, resulting in a cropping of delivered power while running on natural gas (10%-15%). CNG factory-made engines, however, use a higher compression ratio, due to the high number of octane (120-130) of this fuel.
Liquified petroleum gas (a propane and butane blend) is also used to fuel vehicles. LPG and CNG vehicle fuel systems are not compatible. CNG also requires higher pressure tanks which are typically much heavier than those used for LPG.
## Residential domestic use
Natural gas is supplied to homes, where it is used for such purposes as cooking in natural gas-powered ranges and/or ovens, natural gas-heated clothes dryers, heating/cooling and central heating. Home or other building heating may include boilers, furnaces, and water heaters. CNG is used in rural homes without connections to piped-in public utility services, or with portable grills. However, due to CNG being less economical than LPG, LPG (Propane) is the dominant source of rural gas.
## Fertilizer
Natural gas is a major feedstock for the production of ammonia, via the Haber process, for use in fertilizer production.
## Aviation
Russian aircraft manufacturer Tupolev is currently running a development program to produce LNG- and hydrogen-powered aircraft. The program has been running since the mid-1970s, and seeks to develop LNG and hydrogen variants of the Tu-204 and Tu-334 passenger aircraft, and also the Tu-330 cargo aircraft. It claims that at current market prices, an LNG-powered aircraft would cost 5,000 roubles less to operate per ton, roughly equivalent to 60%, with considerable reductions to carbon monoxide, hydrocarbon and nitrogen oxide emissions.
## Other
Natural gas is also used in the manufacture of fabrics, glass, steel, plastics, paint, and other products.
# Sources
## Natural gas
Natural gas is commercially produced from oil fields and natural gas fields. Gas produced from oil wells is called casinghead gas or associated gas. The natural gas industry is producing gas from increasingly more challenging resource types: sour gas, tight gas, shale gas and coalbed methane.
The world's largest gas field by far is Qatar's offshore North Field, estimated to have 25 trillion cubic metres (900 trillion cubic feet) of gas in place - enough to last more than 200 years at optimum production levels. The second largest natural gas field is the South Pars Gas Field in Iranian waters in the Persian Gulf. Connected to Qatar's North Field, it has estimated reserves of 8 to 14 trillion cubic metres (280-500 trillion cubic feet) of gas; see List of natural gas fields.
## Town gas
Town gas is a mixture of methane and other gases, mainly the highly toxic carbon monoxide, that can be used in a similar way to natural gas and can be produced by treating coal chemically. This is a historic technology, still used as 'best solution' in some local circumstances, although coal gasification is not usually economic at current gas prices. However, depending upon infrastructure considerations, it remains a future possibility.
## Biogas
Methanogenic archaea are responsible for all biological sources of methane, some in symbiotic relationships with other life forms, including termites, ruminants, and cultivated crops. Methane released directly into the atmosphere would be considered a pollutant, however, methane in the atmosphere is oxidised, producing carbon dioxide and water. Methane in the atmosphere has a half life of seven years, meaning that every seven years, half of the methane present is converted to carbon dioxide and water.
Future sources of methane, the principal component of natural gas, include landfill gas, biogas and methane hydrate. Biogas, and especially landfill gas, are already used in some areas, but their use could be greatly expanded. Landfill gas is a type of biogas, but biogas usually refers to gas produced from organic material that has not been mixed with other waste.
Landfill gas is created from the decomposition of waste in landfills. If the gas is not removed, the pressure may get so high that it works its way to the surface, causing damage to the landfill structure, unpleasant odor, vegetation die-off and an explosion hazard. The gas can be vented to the atmosphere, flared or burned to produce electricity or heat. Experimental systems were being proposed for use in parts Hertfordshire, UK and Lyon in France.
Once water vapor is removed, about half of landfill gas is methane. Almost all of the rest is carbon dioxide, but there are also small amounts of nitrogen, oxygen and hydrogen. There are usually trace amounts of hydrogen sulfide and siloxanes, but their concentration varies widely. Landfill gas cannot be distributed through natural gas pipelines unless it is cleaned up to the same quality. It is usually more economical to combust the gas on site or within a short distance of the landfill using a dedicated pipeline. Water vapor is often removed, even if combusting the gas on site. If low temperatures condense out the water from the gas, siloxanes can be lowered as well because they tend to condense out with the water vapour. Other non-methane components may also be removed in order to meet emission standards, to prevent fouling of the equipment or for environmental considerations. Co-firing landfill gas with natural gas improves combustion, which lowers emissions.
Biogas is usually produced using agricultural waste materials, such as otherwise unusable parts of plants and manure. Biogas can also be produced by separating organic materials from waste that otherwise goes to landfills. This is more efficient than just capturing the landfill gas it produces. Using materials that would otherwise generate no income, or even cost money to get rid of, improves the profitability and energy balance of biogas production.
Anaerobic lagoons produce biogas from manure, while biogas reactors can be used for manure or plant parts. Like landfill gas, biogas is mostly methane and carbon dioxide, with small amounts of nitrogen, oxygen and hydrogen. However, with the exception of pesticides, there are usually lower levels of contaminants.
## Hydrates
A speculative source of enormous quantities of methane is from methane hydrate, found under sediments in the oceans. However, as of 2006 no technology has been developed to recover it economically.
# Safety
In any form, a minute amount of odorant such as t-butyl mercaptan, with a rotting-cabbage-like smell, is added to the otherwise colorless and odorless gas, so that leaks can be detected before a fire or explosion occurs. Sometimes a related compound, thiophane is used, with a rotten-egg smell. Adding odorant to natural gas began in the United States after the 1937 New London School explosion. The buildup of gas in the school went unnoticed, killing three hundred students and faculty when it ignited. Odorants are considered non-toxic in the extremely low concentrations occurring in natural gas delivered to the end user.
In mines, where methane seeping from rock formations has no odor, sensors are used, and mining apparatuses have been specifically developed to avoid ignition sources, e.g., the Davy lamp.
Explosions caused by natural gas leaks occur a few times each year. Individual homes, small businesses and boats are most frequently affected when an internal leak builds up gas inside the structure. Frequently, the blast will be enough to significantly damage a building but leave it standing. In these cases, the people inside tend to have minor to moderate injuries. Occasionally, the gas can collect in high enough quantities to cause a deadly explosion, disintegrating one or more buildings in the process. The gas usually dissipates readily outdoors, but can sometimes collect in dangerous quantities if weather conditions are right. However, considering the tens of millions of structures that use the fuel, the individual risk of using natural gas is very low.
Some gas fields yield sour gas containing hydrogen sulfide (H2S). This untreated gas is toxic. Amine gas treating, an industrial scale process which removes acidic gaseous components, is often used to remove hydrogen sulfide from natural gas.
Extraction of natural gas (or oil) leads to decrease in pressure in the reservoir. This in turn may lead to subsidence at ground level. Subsidence may affect ecosystems, waterways, sewer and water supply systems, foundations, etc.
Natural Gas heating systems are the leading cause of carbon monoxide deaths in the United States, according to the U.S. Consumer Product Safety Commission. When a natural gas heating system malfunctions, it produces odorless carbon monoxide. With no fumes or smoke to give warning, poisoning victims are easily asphyxiated by the carbon monoxide. | Natural gas
Natural gas is a gaseous fossil fuel consisting primarily of methane but including significant quantities of ethane, butane, propane, carbon dioxide, nitrogen, helium and hydrogen sulfide.[1] It is found in oil fields and natural gas fields, and in coal beds (as coalbed methane). When methane-rich gases are produced by the anaerobic decay of non-fossil organic material, these are referred to as biogas. Sources of biogas include swamps, marshes, and landfills (see landfill gas), as well as sewage sludge and manure by way of anaerobic digesters, in addition to enteric fermentation particularly in cattle. Natural gas is often informally referred to as simply gas, especially when compared to other energy sources such as electricity. Before natural gas can be used as a fuel, it must undergo extensive processing to remove almost all materials other than methane. The by-products of that processing include ethane, propane, butanes, pentanes and higher molecular weight hydrocarbons, elemental sulfur, and sometimes helium and nitrogen.
## Chemical composition
The primary component of natural gas is methane (CH4), the shortest and lightest hydrocarbon molecule. It also contains heavier gaseous hydrocarbons such as ethane (C2H6), propane (C3H8) and butane (C4H10), as well as other sulfur containing gases, in varying amounts, see also natural gas condensate. Natural gas also contains and is the primary market source of helium.
Nitrogen, helium, carbon dioxide and trace amounts of hydrogen sulfide, water and odorants can also be present
[2]. Mercury is also present in small amounts in natural gas extracted from some fields[3]. The exact composition of natural gas varies between gas fields.
Organosulfur compounds and hydrogen sulfide are common contaminants which must be removed prior to most uses. Gas with a significant amount of sulfur impurities, such as hydrogen sulfide, is termed sour gas; gas with sulfur or carbon dioxide impurities is acid gas. Processed natural gas that is available to end-users is tasteless and odorless, however, before gas is distributed to end-users, it is odorized by adding small amounts of odorants (mixtures of t-butyl mercaptan, isopropyl mercaptan, tetrahydrothiophene, dimethyl sulfide and other sulfur compounds), to assist in leak detection. Processed natural gas is, in itself, harmless to the human body, however, natural gas is a simple asphyxiant and can kill if it displaces air to the point where the oxygen content will not support life.
Natural gas can also be hazardous to life and property through an explosion. Natural gas is lighter than air, and so tends to escape into the atmosphere. But when natural gas is confined, such as within a house, gas concentrations can reach explosive mixtures and, if ignited, result in blasts that could destroy buildings. Methane has a lower explosive limit of 5% in air, and an upper explosive limit of 15%.
Explosive concerns with compressed natural gas used in vehicles are almost non-existent, due to the escaping nature of the gas, and the need to maintain concentrations between 5% and 15% to trigger explosions.
## Energy content, statistics and pricing
Quantities of natural gas are measured in normal cubic meters (corresponding to 0°C at 101.325 kPaA) or in standard cubic feet (corresponding to 60°F and 14.73 PSIA).
The gross heat of combustion of one normal cubic meter of commercial quality natural gas is around 39 megajoules (≈10.8 kWh), but this can vary by several percent.
In US units, one standard cubic foot of natural gas produces around 1,030 British Thermal Units (BTUs). The actual heating value when the water formed does not condense is the net heat of combustion and can be as much as 10% less.
The price of natural gas varies greatly depending on location and type of consumer, but as of 2007 a price of $7 per 1000 cubic feet is typical in the United States. This corresponds to around $7 per million BTU's, or around $7 per gigajoule. Natural gas in the United States is traded as a futures contract on the New York Mercantile Exchange. Each contract is for 10,000 MMBTU (gigajoules), or 10 billion BTU's. Thus, if the price of gas is $7 per million BTU's on the NYMEX, the contract is worth $70,000. In the United States, at retail, natural gas is often sold in units of therms (th); 1 therm = 100,000 BTU. Gas meters measure the volume of gas used, and this is converted to therms by multiplying the volume by the energy content of the gas used during that period, which varies slightly over time. Wholesale transactions are generally done in decatherms (Dth), or in thousand decatherms (MDth), or in million decatherms (MMDth). A million decatherms is roughly a billion cubic feet of natural gas.
Natural gas is also traded as a commodity in Europe, principally at the United Kingdom NBP and related European hubs, such as the TTF in the Netherlands.
In the rest of the world, LNG and LPG is traded in metric tons or mmBTU as spot deliveries. Long term contracts are signed in metric tons - and to convert from one system to the other requires should better be described here, than a very isolated market. A cubic foot is a volumetric measure, MT is weight. The LNG and LPG is transported by special ships/containers, as the gas is liquified - LPG cryonic. The specification of each LNG/LPG cargo will usually contain the energy content, but this information is in general not available to the public.
# Natural gas processing
The image below is a schematic block flow diagram of a typical natural gas processing plant. It shows the various unit processes used to convert raw natural gas into sales gas pipelined to the end user markets.
The block flow diagram also shows how processing of the raw natural gas yields byproduct sulfur, byproduct ethane, and natural gas liquids (NGL) propane, butanes and natural gasoline (denoted as pentanes +).[4][5][6][7][8]
# Storage and transport
The major difficulty in the use of natural gas is transportation and storage because of its low density. Natural gas pipelines are economical, but are impractical across oceans. Many existing pipelines in North America are close to reaching their capacity, prompting some politicians representing colder areas to speak publicly of potential shortages.
LNG carriers can be used to transport liquefied natural gas (LNG) across oceans, while tank trucks can carry liquefied or compressed natural gas (CNG) over shorter distances. They may transport natural gas directly to end-users, or to distribution points such as pipelines for further transport. These may have a higher cost, requiring additional facilities for liquefaction or compression at the production point, and then gasification or decompression at end-use facilities or into a pipeline.
In the past, the natural gas which was recovered in the course of recovering petroleum could not be profitably sold, and was simply burned at the oil field (known as flaring). This wasteful practice is now illegal in many countries. Additionally, companies now recognize that value for the gas may be achieved with LNG, CNG, or other transportation methods to end-users in the future. The gas is now re-injected back into the formation for later recovery. This also assists oil pumping by keeping underground pressures higher. In Saudi Arabia, in the late 1970s, a "Master Gas System" was created, ending the need for flaring. The natural gas is used to generate electricity and heat for desalinization. Similarly, some landfills that also discharge methane gases have been set up to capture the methane and generate electricity.
Natural gas is often stored in underground caverns formed inside depleted gas reservoirs from previous gas wells, salt domes, or in tanks as liquefied natural gas. The gas is injected during periods of low demand and extracted during periods of higher demand. Storage near the ultimate end-users helps to best meet volatile demands, but this may not always be practicable.
With 15 nations accounting for 84% of the world-wide production, access to natural gas has become a significant factor in international economics and politics. In this respect, control over the pipelines is a major strategic factor.[9]
# Use
## Power generation
Natural gas is a major source of electricity generation through the use of gas turbines and steam turbines. Particularly high efficiencies can be achieved through combining gas turbines with a steam turbine in combined cycle mode. Natural gas burns cleaner than other fossil fuels, such as oil and coal, and produces less carbon dioxide per unit energy released. For an equivalent amount of heat, burning natural gas produces about 30% less carbon dioxide than burning petroleum and about 45% less than burning coal.[10] Combined cycle power generation using natural gas is thus the cleanest source of power available using fossil fuels, and this technology is widely used wherever gas can be obtained at a reasonable cost. Fuel cell technology may eventually provide cleaner options for converting natural gas into electricity, but as yet it is not price-competitive. Also, the natural gas supply is expected to peak around the year 2030, 20 years after the peak of oil. It is also projected that the world's supply of natural gas could be exhausted around the year 2085.
## Hydrogen
Natural gas can be used to produce hydrogen, with one common method being the hydrogen reformer. Hydrogen has various applications: it is a primary feedstock for the chemical industry, a hydrogenating agent, an important commodity for oil refineries, and a fuel source in hydrogen vehicles.
## Natural gas vehicles
Compressed natural gas (methane) is used as a clean alternative to other automobile fuels such as gasoline (petrol) and diesel. As of 2005, the countries with the largest number of natural gas vehicles were Argentina, Brazil, Pakistan, Italy, India and Bangladesh.[11] The energy efficiency is generally equal to that of gasoline engines, but lower compared with modern diesel engines. Benzine vehicles converted to run on gas suffer of the low-compression ratio their engines have, resulting in a cropping of delivered power while running on natural gas (10%-15%). CNG factory-made engines, however, use a higher compression ratio, due to the high number of octane (120-130) of this fuel.
Liquified petroleum gas (a propane and butane blend) is also used to fuel vehicles. LPG and CNG vehicle fuel systems are not compatible. CNG also requires higher pressure tanks which are typically much heavier than those used for LPG.
## Residential domestic use
Natural gas is supplied to homes, where it is used for such purposes as cooking in natural gas-powered ranges and/or ovens, natural gas-heated clothes dryers, heating/cooling and central heating. Home or other building heating may include boilers, furnaces, and water heaters. CNG is used in rural homes without connections to piped-in public utility services, or with portable grills. However, due to CNG being less economical than LPG, LPG (Propane) is the dominant source of rural gas.
## Fertilizer
Natural gas is a major feedstock for the production of ammonia, via the Haber process, for use in fertilizer production.
## Aviation
Russian aircraft manufacturer Tupolev is currently running a development program to produce LNG- and hydrogen-powered aircraft.[12] The program has been running since the mid-1970s, and seeks to develop LNG and hydrogen variants of the Tu-204 and Tu-334 passenger aircraft, and also the Tu-330 cargo aircraft. It claims that at current market prices, an LNG-powered aircraft would cost 5,000 roubles less to operate per ton, roughly equivalent to 60%, with considerable reductions to carbon monoxide, hydrocarbon and nitrogen oxide emissions.
## Other
Natural gas is also used in the manufacture of fabrics, glass, steel, plastics, paint, and other products.
# Sources
## Natural gas
Natural gas is commercially produced from oil fields and natural gas fields. Gas produced from oil wells is called casinghead gas or associated gas. The natural gas industry is producing gas from increasingly more challenging resource types: sour gas, tight gas, shale gas and coalbed methane.
The world's largest gas field by far is Qatar's offshore North Field, estimated to have 25 trillion cubic metres[13] (900 trillion cubic feet) of gas in place - enough to last more than 200 years at optimum production levels. The second largest natural gas field is the South Pars Gas Field in Iranian waters in the Persian Gulf. Connected to Qatar's North Field, it has estimated reserves of 8 to 14 trillion cubic metres[14] (280-500 trillion cubic feet) of gas; see List of natural gas fields.
## Town gas
Town gas is a mixture of methane and other gases, mainly the highly toxic carbon monoxide, that can be used in a similar way to natural gas and can be produced by treating coal chemically. This is a historic technology, still used as 'best solution' in some local circumstances, although coal gasification is not usually economic at current gas prices. However, depending upon infrastructure considerations, it remains a future possibility.
## Biogas
Methanogenic archaea are responsible for all biological sources of methane, some in symbiotic relationships with other life forms, including termites, ruminants, and cultivated crops. Methane released directly into the atmosphere would be considered a pollutant, however, methane in the atmosphere is oxidised, producing carbon dioxide and water. Methane in the atmosphere has a half life of seven years, meaning that every seven years, half of the methane present is converted to carbon dioxide and water.
Future sources of methane, the principal component of natural gas, include landfill gas, biogas and methane hydrate. Biogas, and especially landfill gas, are already used in some areas, but their use could be greatly expanded. Landfill gas is a type of biogas, but biogas usually refers to gas produced from organic material that has not been mixed with other waste.
Landfill gas is created from the decomposition of waste in landfills. If the gas is not removed, the pressure may get so high that it works its way to the surface, causing damage to the landfill structure, unpleasant odor, vegetation die-off and an explosion hazard. The gas can be vented to the atmosphere, flared or burned to produce electricity or heat. Experimental systems were being proposed for use in parts Hertfordshire, UK and Lyon in France.
Once water vapor is removed, about half of landfill gas is methane. Almost all of the rest is carbon dioxide, but there are also small amounts of nitrogen, oxygen and hydrogen. There are usually trace amounts of hydrogen sulfide and siloxanes, but their concentration varies widely. Landfill gas cannot be distributed through natural gas pipelines unless it is cleaned up to the same quality. It is usually more economical to combust the gas on site or within a short distance of the landfill using a dedicated pipeline. Water vapor is often removed, even if combusting the gas on site. If low temperatures condense out the water from the gas, siloxanes can be lowered as well because they tend to condense out with the water vapour. Other non-methane components may also be removed in order to meet emission standards, to prevent fouling of the equipment or for environmental considerations. Co-firing landfill gas with natural gas improves combustion, which lowers emissions.
Biogas is usually produced using agricultural waste materials, such as otherwise unusable parts of plants and manure. Biogas can also be produced by separating organic materials from waste that otherwise goes to landfills. This is more efficient than just capturing the landfill gas it produces. Using materials that would otherwise generate no income, or even cost money to get rid of, improves the profitability and energy balance of biogas production.
Anaerobic lagoons produce biogas from manure, while biogas reactors can be used for manure or plant parts. Like landfill gas, biogas is mostly methane and carbon dioxide, with small amounts of nitrogen, oxygen and hydrogen. However, with the exception of pesticides, there are usually lower levels of contaminants.
## Hydrates
A speculative source of enormous quantities of methane is from methane hydrate, found under sediments in the oceans. However, as of 2006 no technology has been developed to recover it economically.
# Safety
In any form, a minute amount of odorant such as t-butyl mercaptan, with a rotting-cabbage-like smell, is added to the otherwise colorless and odorless gas, so that leaks can be detected before a fire or explosion occurs. Sometimes a related compound, thiophane is used, with a rotten-egg smell. Adding odorant to natural gas began in the United States after the 1937 New London School explosion. The buildup of gas in the school went unnoticed, killing three hundred students and faculty when it ignited. Odorants are considered non-toxic in the extremely low concentrations occurring in natural gas delivered to the end user.
In mines, where methane seeping from rock formations has no odor, sensors are used, and mining apparatuses have been specifically developed to avoid ignition sources, e.g., the Davy lamp.
Explosions caused by natural gas leaks occur a few times each year. Individual homes, small businesses and boats are most frequently affected when an internal leak builds up gas inside the structure. Frequently, the blast will be enough to significantly damage a building but leave it standing. In these cases, the people inside tend to have minor to moderate injuries. Occasionally, the gas can collect in high enough quantities to cause a deadly explosion, disintegrating one or more buildings in the process. The gas usually dissipates readily outdoors, but can sometimes collect in dangerous quantities if weather conditions are right. However, considering the tens of millions of structures that use the fuel, the individual risk of using natural gas is very low.
Some gas fields yield sour gas containing hydrogen sulfide (H2S). This untreated gas is toxic. Amine gas treating, an industrial scale process which removes acidic gaseous components, is often used to remove hydrogen sulfide from natural gas.
[15]
Extraction of natural gas (or oil) leads to decrease in pressure in the reservoir. This in turn may lead to subsidence at ground level. Subsidence may affect ecosystems, waterways, sewer and water supply systems, foundations, etc.
Natural Gas heating systems are the leading cause of carbon monoxide deaths in the United States, according to the U.S. Consumer Product Safety Commission. When a natural gas heating system malfunctions, it produces odorless carbon monoxide. With no fumes or smoke to give warning, poisoning victims are easily asphyxiated by the carbon monoxide. | https://www.wikidoc.org/index.php/Natural_gas | |
3d68143729aa77be9ad723c29dc255f9e6ea782b | wikidoc | Thiothixene | Thiothixene
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# Black Box Warning
# Overview
Thiothixene is a antipsychotic, central nervous system agent and thioxanthene that is FDA approved for the treatment of schizophrenia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, orthostatic hypotension, diminished sweating, constipation, xerostomia, akathisia, dizziness, tardive dystonia, dystonia, extrapyramidal disease, parkinsonian, somnolence, tardive dyskinesia, blurred vision, urinary retention and nasal congestion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Thiothixene capsules are effective in the management of schizophrenia. Thiothixene capsules have not been evaluated in the management of behavioral complications in patients with mental retardation.
### Dosing Information
- Dosage of thiothixene capsules should be individually adjusted depending on the chronicity and severity of the symptoms of schizophrenia. In general, small doses should be used initially and gradually increased to the optimal effective level, based on patient response.
- Some patients have been successfully maintained on once a day thiothixene capsule therapy.
- In milder conditions, an initial dose of 2 mg three times daily is recommended. If indicated, a subsequent increase to 15 mg/day total daily dose is often effective.
- In more severe conditions, an initial dose of 5 mg twice daily is recommended.
- The usual optimal dose is 20 mg to 30 mg daily. If indicated, an increase to 60 mg/day total daily dose is often effective. Exceeding a total daily dose of 60 mg rarely increases the beneficial response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thiothixene in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Thiothixene in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Thiothixene capsules are effective in the management of schizophrenia for children 12 years and older.
- The use of thiothixene capsules in children under 12 years of age is not recommended because safe conditions for its use have not been established.
### Dosing Information
- Initial dose of 2 mg X 3/day and then increase to 20/day to 30 mg/day with a maximum of 60 mg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thiothixene in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Thiothixene in pediatric patients.
# Contraindications
- Thiothixene capsules are contraindicated in patients with circulatory collapse, comatose states, central nervous system depression due to any cause, and blood dyscrasias. Thiothixene is contraindicated in individuals who have shown hypersensitivity to the drug. It is not known whether there is a cross sensitivity between the thioxanthenes and the phenothiazine derivatives, but this possibility should be considered.
# Warnings
- Elderly patients with dementia-related Psychosis treated with antipsychotic drugs are at an increased risk of death. Thiothixene is not approved for the treatment of patients with dementia-related Psychosis.
- Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
- Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
(For further information about the description of tardive dyskinesia and its clinical detection, please refer to INFORMATION FOR PATIENTS IN THE PRECAUTIONS section, and to the ADVERSE REACTIONS section.)
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
- Safe use of thiothixene during pregnancy has not been established. Therefore, this drug should be given to pregnant patients only when, in the judgment of the physician, the expected benefits from the treatment exceed the possible risks to mother and fetus. Animal reproduction studies and clinical experience to date have not demonstrated any teratogenic effects.
- In the animal reproduction studies with thiothixene, there was some decrease in conception rate and litter size, and an increase in resorption rate in rats and rabbits. Similar findings have been reported with other psychotropic agents. After repeated oral administration of thiothixene to rats (5 to 15 mg/kg/day), rabbits (3 to 50 mg/kg/day), and monkeys (1 to 3 mg/kg/day) before and during gestation, no teratogenic effects were seen.
- The use of thiothixene in children under 12 years of age is not recommended because safe conditions for its use have not been established.
- As is true with many CNS drugs, thiothixene may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery, especially during the first few days of therapy. Therefore, the patient should be cautioned accordingly.
- As in the case of other CNS-acting drugs, patients receiving thiothixene should be cautioned about the possible additive effects (which may include hypotension) with CNS depressants and with alcohol.
### PRECAUTIONS
- An antiemetic effect was observed in animal studies with thiothixene; since this effect may also occur in man, it is possible that thiothixene may mask signs of overdosage of toxic drugs and may obscure conditions such as intestinal obstruction and brain tumor.
- In consideration of the known capability of thiothixene and certain other psychotropic drugs to precipitate convulsions, extreme caution should be used in patients with a history of convulsive disorders or those in a state of alcohol withdrawal, since it may lower the convulsive threshold. Although thiothixene potentiates the actions of the barbiturates, the dosage of the anticonvulsant therapy should not be reduced when thiothixene is administered concurrently.
- Though exhibiting rather weak anticholinergic properties, thiothixene should be used with caution in patients who might be exposed to extreme heat or who are receiving atropine or related drugs.
- Use with caution in patients with cardiovascular disease.
- Caution as well as careful adjustment of the dosages is indicated when thiothixene is used in conjunction with other CNS depressants.
- Also, careful observation should be made for pigmentary retinopathy and lenticular pigmentation (fine lenticular pigmentation has been noted in a small number of patients treated with thiothixene for prolonged periods). Blood dyscrasias (agranulocytosis, pancytopenia, thrombocytopenic purpura), and liver damage (jaundice, biliary stasis), have been reported with related drugs.
- Antipsychotic drugs, including thiothixene3, elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.
### Leukopenia, Neutropenia and Agranulocytosis
- In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.
- Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of thiothixene should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
- Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue thiothixene and have their WBC followed until recovery.
# Adverse Reactions
## Clinical Trials Experience
- NOTE: Not all of the following adverse reactions have been reported with thiothixene. However, since thiothixene has certain chemical and pharmacologic similarities to the phenothiazines, all of the known side effects and toxicity associated with phenothiazine therapy should be borne in mind when thiothixene is used.
- Tachycardia, hypotension, light-headedness, and syncope. In the event hypotension occurs, epinephrine should not be used as a pressor agent since a paradoxical further lowering of blood pressure may result. Nonspecific EKG changes have been observed in some patients receiving thiothixene. These changes are usually reversible and frequently disappear on continued thiothixene therapy. The incidence of these changes is lower than that observed with some phenothiazines. The clinical significance of these changes is not known.
- Drowsiness, usually mild, may occur although it usually subsides with continuation of thiothixene therapy. The incidence of sedation appears similar to that of the piperazine group of phenothiazines but less than that of certain aliphatic phenothiazines. Restlessness, agitation and insomnia have been noted with thiothixene. Seizures and paradoxical exacerbation of psychotic symptoms have occurred with thiothixene infrequently.
- Hyperreflexia has been reported in infants delivered from mothers having received structurally related drugs.
- In addition, phenothiazine derivatives have been associated with cerebral edema and cerebrospinal fluid abnormalities.
- Extrapyramidal symptoms, such as pseudoparkinsonism, akathisia and dystonia have been reported. Management of these extrapyramidal symptoms depends upon the type and severity. Rapid relief of acute symptoms may require the use of an injectable antiparkinson agent. More slowly emerging symptoms may be managed by reducing the dosage of thiothixene and/or administering an oral antiparkinson agent.
- Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
- As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy with thiothixene, or may occur after drug therapy has been discontinued. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities.
- Since early detection of tardive dyskinesia is important, patients should be monitored on an ongoing basis. It has been reported that fine vermicular movement of the tongue may be an early sign of the syndrome. If this or any other presentation of the syndrome is observed, the clinician should consider possible discontinuation of antipsychotic medication.
- Elevations of serum transaminase and alkaline phosphatase, usually transient, have been infrequently observed in some patients. No clinically confirmed cases of jaundice attributable to thiothixene have been reported.
- As is true with certain other psychotropic drugs, leukopenia and leucocytosis, which are usually transient, can occur occasionally with thiothixene. Other antipsychotic drugs have been associated with agranulocytosis, eosinophilia, hemolytic anemia, thrombocytopenia and pancytopenia.
- Rash, pruritus, urticaria, photosensitivity and rare cases of anaphylaxis have been reported with thiothixene. Undue exposure to sunlight should be avoided. Although not experienced with thiothixene, exfoliative dermatitis and contact dermatitis (in nursing personnel) have been reported with certain phenothiazines.
- Hyperprolactinemia3, lactation, menstrual irregularities, moderate breast enlargement and amenorrhea have occurred in a small percentage of females receiving thiothixene. If persistent, this may necessitate a reduction in dosage or the discontinuation of therapy. Phenothiazines have been associated with false positive pregnancy tests, gynecomastia, hypoglycemia, hyperglycemia and glycosuria.
- Dry mouth, blurred vision, nasal congestion, constipation, increased sweating, increased salivation and impotence have occurred infrequently with thiothixene therapy. Phenothiazines have been associated with miosis, mydriasis, and adynamic ileus.
- Hyperpyrexia, anorexia, nausea, vomiting, diarrhea, increase in appetite and weight, weakness or fatigue, polydipsia, and peripheral edema.
- Although not reported with thiothixene, evidence indicates there is a relationship between phenothiazine therapy and the occurrence of a systemic lupus erythematosus-like syndrome.
- Please refer to the text regarding NMS in the WARNINGS section.
- NOTE: Sudden deaths have occasionally been reported in patients who have received certain phenothiazine derivatives. In some cases the cause of death was apparently cardiac arrest or asphyxia due to failure of the cough reflex. In others, the cause could not be determined nor could it be established that death was due to phenothiazine administration.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Thiothixene in the drug label.
# Drug Interactions
- Hepatic microsomal enzyme inducing agents, such as carbamazepine, were found to significantly increase the clearance of thiothixene. Patients receiving these drugs should be observed for signs of reduced thiothixene effectiveness4,5.
- Due to a possible additive effect with hypotensive agents, patients receiving these drugs should be observed closely for signs of excessive hypotension when thiothixene is added to their drug regimen.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS): C
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Thiothixene in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Thiothixene during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Thiothixene with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Thiothixene with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Thiothixene with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Thiothixene with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Thiothixene with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Thiothixene in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Thiothixene in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Thiothixene in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Thiothixene in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intramuscular
### Monitoring
There is limited information regarding Monitoring of Thiothixene in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Thiothixene in the drug label.
# Overdosage
- Manifestations include muscular twitching, drowsiness and dizziness. Symptoms of gross overdosage may include CNS depression, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbances of gait, or coma.
- Essentially symptomatic and supportive. Early gastric lavage is helpful. Keep patient under careful observation and maintain an open airway, since involvement of the extrapyramidal system may produce dysphagia and respiratory difficulty in severe overdosage. If hypotension occurs, the standard measures for managing circulatory shock should be used (I.V. fluids and/or vasoconstrictors).
- If a vasoconstrictor is needed, norepinephrine and phenylephrine are the most suitable drugs. Other pressor agents, including epinephrine, are not recommended, since phenothiazine derivatives may reverse the usual pressor action of these agents and cause further lowering of blood pressure.
- If CNS depression is marked, symptomatic treatment is indicated. Extrapyramidal symptoms may be treated with antiparkinson drugs.
- There are no data on the use of peritoneal or hemodialysis, but they are known to be of little value in phenothiazine intoxication.
# Pharmacology
## Mechanism of Action
- Thiothixene is an antipsychotic of the thioxanthene series. Thiothixene possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines.
## Structure
- Thiothixene is a thioxanthene derivative. Specifically, it is the cis isomer of N,N-dimethyl-9-thioxanthene-2-sulfonamide. It may be represented by the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Thiothixene in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Thiothixene in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Thiothixene in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Thiothixene in the drug label.
# How Supplied
Thiothixene Capsules, USP are available containing 1 mg, 2 mg, 5 mg or 10 mg of thiothixene, USP.
The 1 mg capsule is a hard-shell gelatin capsule with a caramel opaque cap and a powder blue opaque body filled with white to off-white powder. The capsule is axially imprinted with MYLAN over 1001 in black ink on both the cap and body. They are available as follows:
NDC 0378-1001-01
bottles of 100 capsules
The 2 mg capsule is a hard-shell gelatin capsule with a caramel opaque cap and a yellow opaque body filled with white to off-white powder. The capsule is axially imprinted with MYLAN over 2002 in black ink on both the cap and body. They are available as follows:
NDC 0378-2002-01
bottles of 100 capsules
NDC 0378-2002-10
bottles of 1000 capsules
The 5 mg capsule is a hard-shell gelatin capsule with a caramel opaque cap and a white opaque body filled with white to off-white powder. The capsule is axially imprinted with MYLAN over 3005 in black ink on both the cap and body. They are available as follows:
NDC 0378-3005-01
bottles of 100 capsules
NDC 0378-3005-10
bottles of 1000 capsules
The 10 mg capsule is a hard-shell gelatin capsule with a caramel opaque cap and a peach opaque body filled with white to off-white powder. The capsule is axially imprinted with MYLAN over 5010 in black ink on both the cap and body. They are available as follows:
NDC 0378-5010-01
bottles of 100 capsules
NDC 0378-5010-10
bottles of 1000 capsules
## Storage
- Store at 20° to 25°C (68° to 77°F).
- Protect from light.
- Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 0378-1001-01
Thiothixene
Capsules, USP
1 mg
Rx only 100 Capsules
Each capsule contains:
Thiothixene, USP 1 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
-ut of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from light.
Dosage - In mild conditions:
6 mg to 15 mg daily. In severe
conditions: 10 mg to 60 mg daily.
Usual Optimal Dosage: 20 mg to
30 mg daily. See insert.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
RM1001A10
NDC 0378-2002-01
Thiothixene
Capsules, USP
2 mg
Rx only 100 Capsules
Each capsule contains:
Thiothixene, USP 2 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
-ut of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from light.
Dosage - In mild conditions:
6 mg to 15 mg daily. In severe
conditions: 10 mg to 60 mg daily.
Usual Optimal Dosage: 20 mg to
30 mg daily. See insert.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
RM2002A8
NDC 0378-3005-01
Thiothixene
Capsules, USP
5 mg
Rx only 100 Capsules
Each capsule contains:
Thiothixene, USP 5 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
-ut of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from light.
Dosage - In mild conditions:
6 mg to 15 mg daily. In severe
conditions: 10 mg to 60 mg daily.
Usual Optimal Dosage: 20 mg to
30 mg daily. See insert.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
RM3005A9
NDC 0378-5010-01
Thiothixene
Capsules, USP
10 mg
Rx only 100 Capsules
Each capsule contains:
Thiothixene, USP 10 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
-ut of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from light.
Dosage - In mild conditions:
6 mg to 15 mg daily. In severe
conditions: 10 mg to 60 mg daily.
Usual Optimal Dosage: 20 mg to
30 mg daily. See insert.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
RM5010A9
# Patient Counseling Information
- Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.
# Precautions with Alcohol
- Alcohol-Thiothixene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Navane®
# Look-Alike Drug Names
- Navane® - Norvasc®
# Drug Shortage Status
# Price | Thiothixene
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.
# Black Box Warning
# Overview
Thiothixene is a antipsychotic, central nervous system agent and thioxanthene that is FDA approved for the treatment of schizophrenia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypotension, orthostatic hypotension, diminished sweating, constipation, xerostomia, akathisia, dizziness, tardive dystonia, dystonia, extrapyramidal disease, parkinsonian, somnolence, tardive dyskinesia, blurred vision, urinary retention and nasal congestion.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Thiothixene capsules are effective in the management of schizophrenia. Thiothixene capsules have not been evaluated in the management of behavioral complications in patients with mental retardation.
### Dosing Information
- Dosage of thiothixene capsules should be individually adjusted depending on the chronicity and severity of the symptoms of schizophrenia. In general, small doses should be used initially and gradually increased to the optimal effective level, based on patient response.
- Some patients have been successfully maintained on once a day thiothixene capsule therapy.
- In milder conditions, an initial dose of 2 mg three times daily is recommended. If indicated, a subsequent increase to 15 mg/day total daily dose is often effective.
- In more severe conditions, an initial dose of 5 mg twice daily is recommended.
- The usual optimal dose is 20 mg to 30 mg daily. If indicated, an increase to 60 mg/day total daily dose is often effective. Exceeding a total daily dose of 60 mg rarely increases the beneficial response.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thiothixene in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Thiothixene in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- Thiothixene capsules are effective in the management of schizophrenia for children 12 years and older.
- The use of thiothixene capsules in children under 12 years of age is not recommended because safe conditions for its use have not been established.
### Dosing Information
- Initial dose of 2 mg X 3/day and then increase to 20/day to 30 mg/day with a maximum of 60 mg/day.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Thiothixene in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Thiothixene in pediatric patients.
# Contraindications
- Thiothixene capsules are contraindicated in patients with circulatory collapse, comatose states, central nervous system depression due to any cause, and blood dyscrasias. Thiothixene is contraindicated in individuals who have shown hypersensitivity to the drug. It is not known whether there is a cross sensitivity between the thioxanthenes and the phenothiazine derivatives, but this possibility should be considered.
# Warnings
- Elderly patients with dementia-related Psychosis treated with antipsychotic drugs are at an increased risk of death. Thiothixene is not approved for the treatment of patients with dementia-related Psychosis.
- Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs, including thiothixene. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.
- Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses.
- There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
- Given these considerations, antipsychotics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to antipsychotic drugs, and 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.
- If signs and symptoms of tardive dyskinesia appear in a patient on antipsychotics, drug discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.
(For further information about the description of tardive dyskinesia and its clinical detection, please refer to INFORMATION FOR PATIENTS IN THE PRECAUTIONS section, and to the ADVERSE REACTIONS section.)
- A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs, including thiothixene. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
- The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.
- The management of NMS should include 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
- If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.
- Safe use of thiothixene during pregnancy has not been established. Therefore, this drug should be given to pregnant patients only when, in the judgment of the physician, the expected benefits from the treatment exceed the possible risks to mother and fetus. Animal reproduction studies and clinical experience to date have not demonstrated any teratogenic effects.
- In the animal reproduction studies with thiothixene, there was some decrease in conception rate and litter size, and an increase in resorption rate in rats and rabbits. Similar findings have been reported with other psychotropic agents. After repeated oral administration of thiothixene to rats (5 to 15 mg/kg/day), rabbits (3 to 50 mg/kg/day), and monkeys (1 to 3 mg/kg/day) before and during gestation, no teratogenic effects were seen.
- The use of thiothixene in children under 12 years of age is not recommended because safe conditions for its use have not been established.
- As is true with many CNS drugs, thiothixene may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery, especially during the first few days of therapy. Therefore, the patient should be cautioned accordingly.
- As in the case of other CNS-acting drugs, patients receiving thiothixene should be cautioned about the possible additive effects (which may include hypotension) with CNS depressants and with alcohol.
### PRECAUTIONS
- An antiemetic effect was observed in animal studies with thiothixene; since this effect may also occur in man, it is possible that thiothixene may mask signs of overdosage of toxic drugs and may obscure conditions such as intestinal obstruction and brain tumor.
- In consideration of the known capability of thiothixene and certain other psychotropic drugs to precipitate convulsions, extreme caution should be used in patients with a history of convulsive disorders or those in a state of alcohol withdrawal, since it may lower the convulsive threshold. Although thiothixene potentiates the actions of the barbiturates, the dosage of the anticonvulsant therapy should not be reduced when thiothixene is administered concurrently.
- Though exhibiting rather weak anticholinergic properties, thiothixene should be used with caution in patients who might be exposed to extreme heat or who are receiving atropine or related drugs.
- Use with caution in patients with cardiovascular disease.
- Caution as well as careful adjustment of the dosages is indicated when thiothixene is used in conjunction with other CNS depressants.
- Also, careful observation should be made for pigmentary retinopathy and lenticular pigmentation (fine lenticular pigmentation has been noted in a small number of patients treated with thiothixene for prolonged periods). Blood dyscrasias (agranulocytosis, pancytopenia, thrombocytopenic purpura), and liver damage (jaundice, biliary stasis), have been reported with related drugs.
- Antipsychotic drugs, including thiothixene3, elevate prolactin levels; the elevation persists during chronic administration. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with a previously detected breast cancer. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported, the clinical significance of elevated serum prolactin levels is unknown for most patients. An increase in mammary neoplasms has been found in rodents after chronic administration of antipsychotic drugs. Neither clinical studies nor epidemiologic studies conducted to date, however, have shown an association between chronic administration of these drugs and mammary tumorigenesis; the available evidence is considered too limited to be conclusive at this time.
### Leukopenia, Neutropenia and Agranulocytosis
- In clinical trial and/or post-marketing experience, events of leukopenia/neutropenia and agranulocytosis have been reported temporally related to antipsychotic agents.
- Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of thiothixene should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
- Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue thiothixene and have their WBC followed until recovery.
# Adverse Reactions
## Clinical Trials Experience
- NOTE: Not all of the following adverse reactions have been reported with thiothixene. However, since thiothixene has certain chemical and pharmacologic similarities to the phenothiazines, all of the known side effects and toxicity associated with phenothiazine therapy should be borne in mind when thiothixene is used.
- Tachycardia, hypotension, light-headedness, and syncope. In the event hypotension occurs, epinephrine should not be used as a pressor agent since a paradoxical further lowering of blood pressure may result. Nonspecific EKG changes have been observed in some patients receiving thiothixene. These changes are usually reversible and frequently disappear on continued thiothixene therapy. The incidence of these changes is lower than that observed with some phenothiazines. The clinical significance of these changes is not known.
- Drowsiness, usually mild, may occur although it usually subsides with continuation of thiothixene therapy. The incidence of sedation appears similar to that of the piperazine group of phenothiazines but less than that of certain aliphatic phenothiazines. Restlessness, agitation and insomnia have been noted with thiothixene. Seizures and paradoxical exacerbation of psychotic symptoms have occurred with thiothixene infrequently.
- Hyperreflexia has been reported in infants delivered from mothers having received structurally related drugs.
- In addition, phenothiazine derivatives have been associated with cerebral edema and cerebrospinal fluid abnormalities.
- Extrapyramidal symptoms, such as pseudoparkinsonism, akathisia and dystonia have been reported. Management of these extrapyramidal symptoms depends upon the type and severity. Rapid relief of acute symptoms may require the use of an injectable antiparkinson agent. More slowly emerging symptoms may be managed by reducing the dosage of thiothixene and/or administering an oral antiparkinson agent.
- Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
- As with all antipsychotic agents, tardive dyskinesia may appear in some patients on long-term therapy with thiothixene, or may occur after drug therapy has been discontinued. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of tongue, puffing of cheeks, puckering of mouth, chewing movements). Sometimes these may be accompanied by involuntary movements of extremities.
- Since early detection of tardive dyskinesia is important, patients should be monitored on an ongoing basis. It has been reported that fine vermicular movement of the tongue may be an early sign of the syndrome. If this or any other presentation of the syndrome is observed, the clinician should consider possible discontinuation of antipsychotic medication.
- Elevations of serum transaminase and alkaline phosphatase, usually transient, have been infrequently observed in some patients. No clinically confirmed cases of jaundice attributable to thiothixene have been reported.
- As is true with certain other psychotropic drugs, leukopenia and leucocytosis, which are usually transient, can occur occasionally with thiothixene. Other antipsychotic drugs have been associated with agranulocytosis, eosinophilia, hemolytic anemia, thrombocytopenia and pancytopenia.
- Rash, pruritus, urticaria, photosensitivity and rare cases of anaphylaxis have been reported with thiothixene. Undue exposure to sunlight should be avoided. Although not experienced with thiothixene, exfoliative dermatitis and contact dermatitis (in nursing personnel) have been reported with certain phenothiazines.
- Hyperprolactinemia3, lactation, menstrual irregularities, moderate breast enlargement and amenorrhea have occurred in a small percentage of females receiving thiothixene. If persistent, this may necessitate a reduction in dosage or the discontinuation of therapy. Phenothiazines have been associated with false positive pregnancy tests, gynecomastia, hypoglycemia, hyperglycemia and glycosuria.
- Dry mouth, blurred vision, nasal congestion, constipation, increased sweating, increased salivation and impotence have occurred infrequently with thiothixene therapy. Phenothiazines have been associated with miosis, mydriasis, and adynamic ileus.
- Hyperpyrexia, anorexia, nausea, vomiting, diarrhea, increase in appetite and weight, weakness or fatigue, polydipsia, and peripheral edema.
- Although not reported with thiothixene, evidence indicates there is a relationship between phenothiazine therapy and the occurrence of a systemic lupus erythematosus-like syndrome.
- Please refer to the text regarding NMS in the WARNINGS section.
- NOTE: Sudden deaths have occasionally been reported in patients who have received certain phenothiazine derivatives. In some cases the cause of death was apparently cardiac arrest or asphyxia due to failure of the cough reflex. In others, the cause could not be determined nor could it be established that death was due to phenothiazine administration.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Thiothixene in the drug label.
# Drug Interactions
- Hepatic microsomal enzyme inducing agents, such as carbamazepine, were found to significantly increase the clearance of thiothixene. Patients receiving these drugs should be observed for signs of reduced thiothixene effectiveness4,5.
- Due to a possible additive effect with hypotensive agents, patients receiving these drugs should be observed closely for signs of excessive hypotension when thiothixene is added to their drug regimen.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category
Pregnancy Category (AUS): C
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Thiothixene in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Thiothixene during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Thiothixene with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Thiothixene with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Thiothixene with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Thiothixene with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Thiothixene with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Thiothixene in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Thiothixene in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Thiothixene in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Thiothixene in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intramuscular
### Monitoring
There is limited information regarding Monitoring of Thiothixene in the drug label.
- Description
# IV Compatibility
There is limited information regarding IV Compatibility of Thiothixene in the drug label.
# Overdosage
- Manifestations include muscular twitching, drowsiness and dizziness. Symptoms of gross overdosage may include CNS depression, rigidity, weakness, torticollis, tremor, salivation, dysphagia, hypotension, disturbances of gait, or coma.
- Essentially symptomatic and supportive. Early gastric lavage is helpful. Keep patient under careful observation and maintain an open airway, since involvement of the extrapyramidal system may produce dysphagia and respiratory difficulty in severe overdosage. If hypotension occurs, the standard measures for managing circulatory shock should be used (I.V. fluids and/or vasoconstrictors).
- If a vasoconstrictor is needed, norepinephrine and phenylephrine are the most suitable drugs. Other pressor agents, including epinephrine, are not recommended, since phenothiazine derivatives may reverse the usual pressor action of these agents and cause further lowering of blood pressure.
- If CNS depression is marked, symptomatic treatment is indicated. Extrapyramidal symptoms may be treated with antiparkinson drugs.
- There are no data on the use of peritoneal or hemodialysis, but they are known to be of little value in phenothiazine intoxication.
# Pharmacology
## Mechanism of Action
- Thiothixene is an antipsychotic of the thioxanthene series. Thiothixene possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines.
## Structure
- Thiothixene is a thioxanthene derivative. Specifically, it is the cis isomer of N,N-dimethyl-9-[3-(4-methyl-1-piperazinyl)propylidene]thioxanthene-2-sulfonamide. It may be represented by the following structural formula:
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Thiothixene in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Thiothixene in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Thiothixene in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Thiothixene in the drug label.
# How Supplied
Thiothixene Capsules, USP are available containing 1 mg, 2 mg, 5 mg or 10 mg of thiothixene, USP.
The 1 mg capsule is a hard-shell gelatin capsule with a caramel opaque cap and a powder blue opaque body filled with white to off-white powder. The capsule is axially imprinted with MYLAN over 1001 in black ink on both the cap and body. They are available as follows:
NDC 0378-1001-01
bottles of 100 capsules
The 2 mg capsule is a hard-shell gelatin capsule with a caramel opaque cap and a yellow opaque body filled with white to off-white powder. The capsule is axially imprinted with MYLAN over 2002 in black ink on both the cap and body. They are available as follows:
NDC 0378-2002-01
bottles of 100 capsules
NDC 0378-2002-10
bottles of 1000 capsules
The 5 mg capsule is a hard-shell gelatin capsule with a caramel opaque cap and a white opaque body filled with white to off-white powder. The capsule is axially imprinted with MYLAN over 3005 in black ink on both the cap and body. They are available as follows:
NDC 0378-3005-01
bottles of 100 capsules
NDC 0378-3005-10
bottles of 1000 capsules
The 10 mg capsule is a hard-shell gelatin capsule with a caramel opaque cap and a peach opaque body filled with white to off-white powder. The capsule is axially imprinted with MYLAN over 5010 in black ink on both the cap and body. They are available as follows:
NDC 0378-5010-01
bottles of 100 capsules
NDC 0378-5010-10
bottles of 1000 capsules
## Storage
- Store at 20° to 25°C (68° to 77°F).
- Protect from light.
- Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
# Images
## Drug Images
## Package and Label Display Panel
### PRINCIPAL DISPLAY PANEL
NDC 0378-1001-01
Thiothixene
Capsules, USP
1 mg
Rx only 100 Capsules
Each capsule contains:
Thiothixene, USP 1 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
out of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from light.
Dosage - In mild conditions:
6 mg to 15 mg daily. In severe
conditions: 10 mg to 60 mg daily.
Usual Optimal Dosage: 20 mg to
30 mg daily. See insert.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
RM1001A10
NDC 0378-2002-01
Thiothixene
Capsules, USP
2 mg
Rx only 100 Capsules
Each capsule contains:
Thiothixene, USP 2 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
out of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from light.
Dosage - In mild conditions:
6 mg to 15 mg daily. In severe
conditions: 10 mg to 60 mg daily.
Usual Optimal Dosage: 20 mg to
30 mg daily. See insert.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
RM2002A8
NDC 0378-3005-01
Thiothixene
Capsules, USP
5 mg
Rx only 100 Capsules
Each capsule contains:
Thiothixene, USP 5 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
out of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from light.
Dosage - In mild conditions:
6 mg to 15 mg daily. In severe
conditions: 10 mg to 60 mg daily.
Usual Optimal Dosage: 20 mg to
30 mg daily. See insert.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
RM3005A9
NDC 0378-5010-01
Thiothixene
Capsules, USP
10 mg
Rx only 100 Capsules
Each capsule contains:
Thiothixene, USP 10 mg
Dispense in a tight, light-resistant
container as defined in the USP
using a child-resistant closure.
Keep container tightly closed.
Keep this and all medication
out of the reach of children.
Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room
Temperature.]
Protect from light.
Dosage - In mild conditions:
6 mg to 15 mg daily. In severe
conditions: 10 mg to 60 mg daily.
Usual Optimal Dosage: 20 mg to
30 mg daily. See insert.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
RM5010A9
# Patient Counseling Information
- Given the likelihood that some patients exposed chronically to antipsychotics will develop tardive dyskinesia, it is advised that all patients in whom chronic use is contemplated be given, if possible, full information about this risk. The decision to inform patients and/or their guardians must obviously take into account the clinical circumstances and the competency of the patient to understand the information provided.
# Precautions with Alcohol
- Alcohol-Thiothixene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Navane®
# Look-Alike Drug Names
- Navane® - Norvasc®
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Navane | |
3f8fe1e77da12203df17266ed810ee400e456864 | wikidoc | Vinorelbine | Vinorelbine
# Disclaimer
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# Black Box Warning
# Overview
Vinorelbine is an antineoplastic that is FDA approved for the treatment of single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with unresectable, advanced nonsmall cell lung cancer (NSCLC). There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, injection site reaction, diarrhea, nausea, vomiting, asthenia, neuromyopathy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Vinorelbine Injection USP is indicated as a single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with unresectable, advanced nonsmall cell lung cancer (NSCLC). In patients with Stage IV NSCLC, Vinorelbine Injection USP is indicated as a single agent or in combination with cisplatin. In Stage III NSCLC, Vinorelbine Injection USP is indicated in combination with cisplatin.
- The usual initial dose of single-agent vinorelbine injection is 30 mg/m2 administered weekly. The recommended method of administration is an intravenous injection over 6 to 10 minutes. In controlled trials, single-agent vinorelbine injection was given weekly until progression or dose-limiting toxicity.
- Vinorelbine Injection in Combination with Cisplatin
- Vinorelbine injection may be administered weekly at a dose of 25 mg/m2 in combination with cisplatin given every 4 weeks at a dose of 100 mg/m2.
- Blood counts should be checked weekly to determine whether dose reductions of vinorelbine injection and/or cisplatin are necessary. In the SWOG study, most patients required a 50% dose reduction of vinorelbine injection at day 15 of each cycle and a 50% dose reduction of cisplatin by cycle 3.
- Vinorelbine injection may also be administered weekly at a dose of 30 mg/m2 in combination with cisplatin, given on days 1 and 29, then every 6 weeks at a dose of 120 mg/m2.
- The dosage should be adjusted according to hematologic toxicity or hepatic insufficiency, whichever results in the lower dose for the corresponding starting dose of vinorelbine injection.
- Granulocyte counts should be ≥1000 cells/mm3 prior to the administration of vinorelbine injection. Adjustments in the dosage of vinorelbine injection should be based on granulocyte counts obtained on the day of treatment according to TABLE 5.
- Dose Modifications for Concurrent Hematologic Toxicity and Hepatic =====Insufficiency=====
- In patients with both hematologic toxicity and hepatic insufficiency, the lower of the doses based on the corresponding starting dose of vinorelbine injection determined fromTABLE 5andTABLE 6should be administered.
- No dose adjustments for vinorelbine injection are required for renal insufficiency. Appropriate dose reductions for cisplatin should be made when vinorelbine injection is used in combination.
- If grade ≥2 neurotoxicity develops, vinorelbine injection should be discontinued.
- Caution—vinorelbine injection must be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any vinorelbine injection is injected. Leakage into surrounding tissue during intravenous administration of vinorelbine injection may cause considerable irritation, local tissue necrosis, and/or thrombophlebitis. If extravasation occurs, the injection should be discontinued immediately, and any remaining portion of the dose should then be introduced into another vein. Since there are no established guidelines for the treatment of extravasation injuries with vinorelbine injection, institutional guidelines may be used. The ONS Chemotherapy Guidelines provide additional recommendations for the prevention of extravasation injuries.1
- As with other toxic compounds, caution should be exercised in handling and preparing the solution of vinorelbine injection. Skin reactions may occur with accidental exposure. The use of gloves is recommended. If the solution of vinorelbine injection contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. Severe irritation of the eye has been reported with accidental contamination of the eye with another vinca alkaloid. If this happens with vinorelbine injection, the eye should be flushed with water immediately and thoroughly.
- Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published.2–8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
- Vinorelbine injection is a clear, colorless to pale yellow solution. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If particulate matter is seen, vinorelbine injection should not be administered.
- Vinorelbine injection must be diluted in either a syringe or IV bag using one of the recommended solutions. The diluted vinorelbine injection should be administered over 6 to 10 minutes into the side port of a free-flowing IV closest to the IV bag followed by flushing with at least 75 to 125 mL of one of the solutions. Diluted vinorelbine injection may be used for up to 24 hours under normal room light when stored in polypropylene syringes or polyvinyl chloride bags at 5° to 30°C (41° to 86°F)
- The calculated dose of vinorelbine injection should be diluted to a concentration between 1.5 and 3 mg/mL. The following solutions may be used for dilution:
- 5% Dextrose Injection, USP
- 0.9% Sodium Chloride Injection, USP
- The calculated dose of vinorelbine injection should be diluted to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution:
- 5% Dextrose Injection, USP
- 0.9% Sodium Chloride Injection, USP
- 0.45% Sodium Chloride Injection, USP
- 5% Dextrose and 0.45% Sodium Chloride Injection, USP
- Ringer's Injection, USP
- Lactated Ringer's Injection, USP
- Unopened vials of vinorelbine injection are stable until the date indicated on the package when stored under refrigeration at 2° to 8°C (36° to 46°F) and protected from light in the carton. Unopened vials of vinorelbine injection are stable at temperatures up to 25°C (77°F) for up to 72 hours. This product should not be frozen.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vinorelbine in adult patients.
### Non–Guideline-Supported Use
- Breast cancer
- Carcinoma of cervix
- Carcinoma of esophagus
- Head and neck cancer
- Hodgkin's disease
- Kaposi's sarcoma
- Malignant tumor of salivary gland
- Non-Hodgkin's lymphoma
- Non-small cell lung cancer
- Ovarian cancer, Advanced, previously treated
- Small cell carcinoma of lung
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Vinorelbine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vinorelbine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vinorelbine in pediatric patients.
# Contraindications
- Administration of vinorelbine tartrate injection is contraindicated in patients with pretreatment granulocyte counts <1000 cells/mm3
# Warnings
- Vinorelbine tartrate should be administered in carefully adjusted doses by or under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.
- Patients treated with vinorelbine tartrate should be frequently monitored for myelosuppression both during and after therapy. Granulocytopenia is dose-limiting. Granulocyte nadirs occur between 7 and 10 days after dosing with granulocyte count recovery usually within the following 7 to 14 days.
- Complete blood counts with differentials should be performed and results reviewed prior to administering each dose of vinorelbine tartrate. Vinorelbine tartrate should not be administered to patients with granulocyte counts <1000 cells/mm3. Patients developing severe granulocytopenia should be monitored carefully for evidence of infection and/or fever.
- Acute shortness of breath and severe bronchospasm have been reported infrequently, following the administration of vinorelbine tartrate and other vinca alkaloids, most commonly when the vinca alkaloid was used in combination with mitomycin. These adverse events may require treatment with supplemental oxygen, bronchodilators, and/or corticosteroids, particularly when there is pre-existing pulmonary dysfunction.
- Reported cases of interstitial pulmonary changes and acute respiratory distress syndrome (ARDS), most of which were fatal, occurred in patients treated with single-agent vinorelbine tartrate. The mean time to onset of these symptoms after vinorelbine administration was 1 week (range 3 to 8 days). Patients with alterations in their baseline pulmonary symptoms or with new onset of dyspnea, cough, hypoxia, or other symptoms should be evaluated promptly.
- Vinorelbine tartrate has been reported to cause severe constipation (e.g., Grade 3 to 4), paralytic ileus, intestinal obstruction, necrosis, and/or perforation. Some events have been fatal.
# Adverse Reactions
## Clinical Trials Experience
- The pattern of adverse reactions is similar whether vinorelbine tartrate is used as a single agent or in combination. Adverse reactions from studies with single-agent and combination use of vinorelbine tartrate are summarized in Tables 2 to 4.
- Data in the following table are based on the experience of 365 patients (143 patients with NSCLC; 222 patients with advanced breast cancer) treated with IV vinorelbine tartrate as a single agent in 3 clinical studies. The dosing schedule in each study was 30 mg/m2 vinorelbine tartrate on a weekly basis.
- Granulocytopenia is the major dose-limiting toxicity with vinorelbine tartrate. Dose adjustments are required for hematologic toxicity and hepatic insufficiency. Granulocytopenia was generally reversible and not cumulative over time. Granulocyte nadirs occurred 7 to 10 days after the dose, with granulocyte recovery usually within the following 7 to 14 days. Granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of patients. Septic deaths occurred in approximately 1% of patients. Prophylactic hematologic growth factors have not been routinely used with vinorelbine tartrate. If medically necessary, growth factors may be administered at recommended doses no earlier than 24 hours after the administration of cytotoxic chemotherapy. Growth factors should not be administered in the period 24 hours before the administration of chemotherapy.
- Whole blood and/or packed red blood cells were administered to 18% of patients who received vinorelbine tartrate.
- Loss of deep tendon reflexes occurred in less than 5% of patients. The development of severe peripheral neuropathy was infrequent (1%) and generally reversible.
- Like other anticancer vinca alkaloids, vinorelbine tartrate is a moderate vesicant. Injection site reactions, including erythema, pain at injection site, and vein discoloration, occurred in approximately one third of patients; 5% were severe. Chemical phlebitis along the vein proximal to the site of injection was reported in 10% of patients.
- Prophylactic administration of antiemetics was not routine in patients treated with single-agent vinorelbine tartrate. Due to the low incidence of severe nausea and vomiting with single-agent vinorelbine tartrate, the use of serotonin antagonists is generally not required.
- Transient elevations of liver enzymes were reported without clinical symptoms.
- Chest pain was reported in 5% of patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumor within the chest. There have been rare reports of myocardial infarction.
- Shortness of breath was reported in 3% of patients; it was severe in 2%. Interstitial pulmonary changes were documented.
- Fatigue occurred in 27% of patients. It was usually mild or moderate but tended to increase with cumulative dosing.
- Other toxicities that have been reported in less than 5% of patients include jaw pain, myalgia, arthralgia, and rash. Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in <1% of patients.
- Adverse events for combination use are summarized inTABLES 3 and 4.
- Vinorelbine Tartrate in Combination with Cisplatin
- Vinorelbine Tartrate plus Cisplatin versus Single-Agent Cisplatin (Table 3)
- Myelosuppression was the predominant toxicity in patients receiving combination therapy, Grade 3 and 4 granulocytopenia of 82% compared to 5% in the single-agent cisplatin arm. Fever and/or sepsis related to granulocytopenia occurred in 11% of patients on vinorelbine tartrate and cisplatin compared to 0% on the cisplatin arm.
- Four patients on the combination died of granulocytopenia-related sepsis.
- During this study, the use of granulocyte colony-stimulating factor ( filgrastim) was permitted, but not mandated, after the first course of treatment for patients who experienced Grade 3 or 4 granulocytopenia (≤1000 cells/mm3) or in those who developed neutropenic fever between cycles of chemotherapy. Beginning 24 hours after completion of chemotherapy, G-CSF was started at a dose of 5 mcg/kg per day and continued until the total granulocyte count was >1000 cells/mm3 on 2 successive determinations. G-CSF was not administered on the day of treatment.
- Grade 3 and 4 anemia occurred more frequently in the combination arm compared to control, 24% vs. 8%, respectively. Thrombocytopenia occurred in 6% of patients treated with vinorelbine tartrate plus cisplatin compared to 2% of patients treated with cisplatin.
- The incidence of severe non-hematologic toxicity was similar among the patients in both treatment groups. Patients receiving vinorelbine tartrate plus cisplatin compared to single-agent cisplatin experienced more Grade 3 and/or 4 peripheral numbness (2% vs. <1%), phlebitis/thrombosis/embolism (3% vs. <1%), and infection (6% vs. <1%). Grade 3 to 4-constipation and/or ileus occurred in 3% of patients treated with combination therapy and in 1% of patients treated with cisplatin.
- Seven deaths were reported on the combination arm; 2 were related to cardiac ischemia, 1 massive cerebrovascular accident, 1 multisystem failure due to an overdose of vinorelbine tartrate, and 3 from febrile neutropenia. One death, secondary to respiratory infection unrelated to granulocytopenia, occurred with single-agent cisplatin.
- Vinorelbine Tartrate plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine Tartrate (Table 4)
- Myelosuppression, specifically Grade 3 and 4 granulocytopenia, was significantly greater with the combination of vinorelbine tartrate plus cisplatin (79%) than with either single-agent vinorelbine tartrate (53%) or vindesine plus cisplatin (48%), P<0.0001. Hospitalization due to documented sepsis occurred in 4.4% of patients treated with vinorelbine tartrate plus cisplatin; 2% of patients treated with vindesine and cisplatin, and 4% of patients treated with single-agent vinorelbine tartrate. Grade 3 and 4 thrombocytopenia was infrequent in patients receiving combination chemotherapy and no events were reported with single-agent vinorelbine tartrate.
- The incidence of Grade 3 and/or 4 nausea and vomiting, alopecia, and renal toxicity were reported more frequently in the cisplatin-containing combinations compared to single-agent vinorelbine tartrate. Severe local reactions occurred in 2% of patients treated with combinations containing vinorelbine tartrate; none were observed in the vindesine plus cisplatin arm. Grade 3 and 4 neurotoxicity was significantly more frequent in patients receiving vindesine plus cisplatin (17%) compared to vinorelbine tartrate plus cisplatin (7%) and single-agent vinorelbine tartrate (9%) (P< 0.005). Cisplatin did not appear to increase the incidence of neurotoxicity observed with single-agent vinorelbine tartrate.
## Postmarketing Experience
- In addition to the adverse events reported from clinical trials, the following events have been identified during post-approval use of vinorelbine tartrate. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to vinorelbine tartrate.
- Body as a Whole
- Systemic allergic reactions reported as anaphylaxis, pruritus, urticaria, and angioedema; flushing; and radiation recall events such as dermatitis and esophagitis have been reported.
- Hematologic
- Thromboembolic events, including pulmonary embolus and deep venous thrombosis, have been reported primarily in seriously ill and debilitated patients with known predisposing risk factors for these events.
- Neurologic
- Peripheral neurotoxicities such as, but not limited to, muscle weakness and disturbance of gait, have been observed in patients with and without prior symptoms. There may be increased potential for neurotoxicity in patients with pre-existing neuropathy, regardless of etiology, who receive vinorelbine tartrate. Vestibular and auditory deficits have been observed with vinorelbine tartrate, usually when used in combination with cisplatin.
- Skin
- Injection site reactions, including localized rash and urticaria, blister formation, and skin sloughing have been observed in clinical practice. Some of these reactions may be delayed in appearance.
- Gastrointestinal
- Dysphagia, mucositis, and pancreatitis have been reported.
- Cardiovascular
- Hypertension, hypotension, vasodilation, tachycardia, and pulmonary edema have been reported.
- Pulmonary
- Pneumonia has been reported.
- Musculoskeletal
- Headache has been reported, with and without other musculoskeletal aches and pains.
- Other
- Pain in tumor-containing tissue, back pain, and abdominal pain have been reported. Electrolyte abnormalities, including hyponatremia with or without the syndrome of inappropriate ADH secretion, have been reported in seriously ill and debilitated patients.
- Combination Use
- Patients with prior exposure to paclitaxel and who have demonstrated neuropathy should be monitored closely for new or worsening neuropathy. Patients who have experienced neuropathy with previous drug regimens should be monitored for symptoms of neuropathy while receiving vinorelbine tartrate. Vinorelbine tartrate may result in radiosensitizing effects with prior or concomitant radiation therapy.
# Drug Interactions
There is limited information regarding Vinorelbine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Vinorelbine tartrate may cause fetal harm if administered to a pregnant woman. A single dose of vinorelbine has been shown to be embryo- and/or fetotoxic in mice and rabbits at doses of 9 mg/m2 and 5.5 mg/m2, respectively (one third and one sixth the human dose). At nonmaternotoxic doses, fetal weight was reduced and ossification was delayed. There are no studies in pregnant women. If vinorelbine tartrate is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with vinorelbine tartrate.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vinorelbine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vinorelbine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Vinorelbine with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Vinorelbine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Vinorelbine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Vinorelbine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vinorelbine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Vinorelbine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Vinorelbine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vinorelbine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vinorelbine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Patients with prior exposure to paclitaxel and who have demonstrated neuropathy should be monitored closely for new or worsening neuropathy. Patients who have experienced neuropathy with previous drug regimens should be monitored for symptoms of neuropathy while receiving vinorelbine tartrate.
Patients treated with vinorelbine tartrate should be frequently monitored for myelosuppression both during and after therapy
- Patients developing severe granulocytopenia should be monitored carefully for evidence of infection and/or fever.
# IV Compatibility
There is limited information regarding IV Compatibility of Vinorelbine in the drug label.
# Overdosage
- There is no known antidote for overdoses of vinorelbine tartrate. Overdoses involving quantities up to 10 times the recommended dose (30 mg/m2) have been reported. The toxicities described were consistent with those listed in theADVERSE REACTIONSsection including paralytic ileus, stomatitis, and esophagitis. Bone marrow aplasia, sepsis, and paresis have also been reported.
- Fatalities have occurred following overdose of vinorelbine tartrate. If overdosage occurs, general supportive measures together with appropriate blood transfusions, growth factors, and antibiotics should be instituted as deemed necessary by the physician.
# Pharmacology
There is limited information regarding Vinorelbine Pharmacology in the drug label.
## Mechanism of Action
- Vinorelbine is a vinca alkaloid that interferes with microtubule assembly. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units, vindoline and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for vinorelbine.
- The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, vinorelbine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca++-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. In intact tectal plates from mouse embryos, vinorelbine, vincristine, and vinblastine inhibited mitotic microtubule formation at the same concentration (2 µM), inducing a blockade of cells at metaphase.
- Vincristine produced depolymerization of axonal microtubules at 5 µM, but vinblastine and vinorelbine did not have this effect until concentrations of 30 µM and 40 µM, respectively. These data suggest relative selectivity of vinorelbine for mitotic microtubules.
## Structure
- Vinorelbine Injection USP is for intravenous administration. Each vial contains vinorelbine tartrate, USP equivalent to 10 mg (1-mL vial) or 50 mg (5-mL vial) vinorelbine in Water for Injection. No preservatives or other additives are present. The aqueous solution is sterile and nonpyrogenic.
- Vinorelbine tartrate, USP is a semi-synthetic vinca alkaloid with antitumor activity. The chemical name is 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine .
- Vinorelbine tartrate, USP has the following structure:
- Vinorelbine tartrate, USP is a white to yellow or light brown amorphous powder. The aqueous solubility is >1000 mg/mL in distilled water. The pH of Vinorelbine Injection USP is approximately 3.5.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Vinorelbine in the drug label.
## Pharmacokinetics
- The pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/m2 in 4 clinical trials. Doses were administered by 15- to 20-minute constant-rate infusions. Following intravenous administration, vinorelbine concentration in plasma decays in a triphasic manner.
- The initial rapid decline primarily represents distribution of drug to peripheral compartments followed by metabolism and excretion of the drug during subsequent phases. The prolonged terminal phase is due to relatively slow efflux of vinorelbine from peripheral compartments. The terminal phase half-life averages 27.7 to 43.6 hours and the mean plasma clearance ranges from 0.97 to 1.26 L/h per kg. Steady-state volume of distribution (Vss) values range from 25.4 to 40.1 L/kg.
- Vinorelbine demonstrated high binding to human platelets and lymphocytes. The free fraction was approximately 0.11 in pooled human plasma over a concentration range of 234 to 1169 ng/mL. The binding to plasma constituents in cancer patients ranged from 79.6% to 91.2%. Vinorelbine binding was not altered in the presence of cisplatin, 5-fluorouracil, or doxorubicin.
- Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine.
- Therapeutic doses of vinorelbine tartrate (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes.
- The effects of renal or hepatic dysfunction on the disposition of vinorelbine have not been assessed, but based on experience with other anticancer vinca alkaloids, dose adjustments are recommended for patients with impaired hepatic function.
- The disposition of radiolabeled vinorelbine given intravenously was studied in a limited number of patients. Approximately 18% and 46% of the administered dose was recovered in the urine and in the feces, respectively. Incomplete recovery in humans is consistent with results in animals where recovery is incomplete, even after prolonged sampling times. A separate study of the urinary excretion of vinorelbine using specific chromatographic analytical methodology showed that 10.9% ± 0.7% of a 30 mg/m2 intravenous dose was excreted unchanged in the urine.
- The influence of age on the pharmacokinetics of vinorelbine was examined using data from 44 cancer patients (average age, 56.7 ± 7.8 years; range, 41 to 74 years; with 12 patients ≥60 years and 6 patients ≥65 years) in 3 studies. CL (the mean plasma clearance), t1/2 (the terminal phase half-life), and VZ (the volume of distribution during terminal phase) were independent of age. A separate pharmacokinetic study was conducted in 10 elderly patients with metastatic breast cancer (age range, 66 to 81 years; 3 patients >75 years; normal liver function tests) receiving vinorelbine 30 mg/m2 intravenously. CL, Vss, and t1/2 were similar to those reported for younger adult patients in previous studies. No relationship between age, systemic exposure (AUCo-∞), and hematological toxicity was observed.
- The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin with vinorelbine tartrate.
- Data from 1 randomized clinical study (211 evaluable patients) with single-agent vinorelbine tartrate and 2 randomized clinical trials (1044 patients) using vinorelbine tartrate combined with cisplatin support the use of vinorelbine tartrate in patients with advanced nonsmall cell lung cancer (NSCLC).
- Single-agent vinorelbine tartrate was studied in a North American, randomized clinical trial in which patients with Stage IV NSCLC, no prior chemotherapy, and Karnofsky Performance Status ≥70 were treated with vinorelbine tartrate (30 mg/m2) weekly or 5-fluorouracil (5-FU) (425 mg/m2 IV bolus) plus leucovorin (LV) (20 mg/m2 IV bolus) daily for 5 days every 4 weeks. A total of 211 patients were randomized at a 2:1 ratio to vinorelbine tartrate (143) or 5-FU/LV (68). Vinorelbine tartrate showed improved survival time compared to 5-FU/LV. In an intent-to-treat analysis, the median survival time was 30 weeks versus 22 weeks for patients receiving vinorelbine tartrate versus 5-FU/LV, respectively (P = 0.06). The 1-year survival rates were 24% (±4% SE) for vinorelbine tartrate and 16% (±5% SE) for the 5-FU/LV group, using the Kaplan-Meier product-limit estimates. The median survival time with 5-FU/LV was similar to or slightly better than that usually observed in untreated patients with advanced NSCLC, suggesting that the difference was not related to some unknown detrimental effect of 5-FU/LV therapy.
- The response rates (all partial responses) for vinorelbine tartrate and 5-FU/LV were 12% and 3%, respectively.
- Vinorelbine Tartrate in Combination with Cisplatin: Vinorelbine Tartrate plus Cisplatin versus Single-Agent Cisplatin
- A Phase III open-label, randomized study was conducted which compared vinorelbine tartrate (25 mg/m2 per week) plus cisplatin (100 mg/m2 every 4 weeks) to single-agent cisplatin (100 mg/m2 every 4 weeks) in patients with Stage IV or Stage IIIb NSCLC patients with malignant pleural effusion or multiple lesions in more than one lobe who were not previously treated with chemotherapy. Patients included in the study had a performance status of 0 or 1, and 34% had received prior surgery and/or radiotherapy.
- Characteristics of the 432 randomized patients are provided in TABLE 1. Two hundred and twelve patients received vinorelbine tartrate plus cisplatin and 210 received single-agent cisplatin. The primary objective of this trial was to compare survival between the 2 treatment groups. Survival (FIGURE 1) for patients receiving vinorelbine tartrate plus cisplatin was significantly better compared to the patients who received single-agent cisplatin. The results of this trial are summarized in TABLE 1.
- Vinorelbine Tartrate plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine Tartrate
- In a large European clinical trial, 612 patients with Stage III or IV NSCLC, no prior chemotherapy, and WHO Performance Status of 0, 1, or 2 were randomized to treatment with single-agent vinorelbine tartrate (30 mg/m2 per week), vinorelbine tartrate (30 mg/m2 per week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks), and vindesine (3 mg/m2 per week for 7 weeks, then every other week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks). Patient characteristics are provided in TABLE 1. Survival was longer in patients treated with vinorelbine tartrate plus cisplatin compared to those treated with vindesine plus cisplatin (FIGURE 2). Study results are summarized in TABLE 1.
- A dose-ranging study of vinorelbine tartrate (20, 25, or 30 mg/m2 per week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks) in 32 patients with NSCLC demonstrated a median survival of 10.2 months. There were no responses at the lowest dose level; the response rate was 33% in the 21 patients treated at the 2 highest dose levels.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Vinorelbine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Vinorelbine in the drug label.
# How Supplied
- Vinorelbine Injection UPS is a clear, colorless to pale yellow solution in water for injection, containing 10 mg vinorelbine tartrate, USP per mL. Vinorelbine Injection USP is available as follows:
## Storage
- Store the vials under refrigeration at 2° to 8°C (36° to 46°F) in the carton. - Protect from light. DO NOT FREEZE.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Vinorelbine Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Vinorelbine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VINORELBINE ®
# Look-Alike Drug Names
There is limited information regarding Vinorelbine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Vinorelbine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2]
# Disclaimer
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# Black Box Warning
# Overview
Vinorelbine is an antineoplastic that is FDA approved for the treatment of single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with unresectable, advanced nonsmall cell lung cancer (NSCLC). There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia, injection site reaction, diarrhea, nausea, vomiting, asthenia, neuromyopathy.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Vinorelbine Injection USP is indicated as a single agent or in combination with cisplatin for the first-line treatment of ambulatory patients with unresectable, advanced nonsmall cell lung cancer (NSCLC). In patients with Stage IV NSCLC, Vinorelbine Injection USP is indicated as a single agent or in combination with cisplatin. In Stage III NSCLC, Vinorelbine Injection USP is indicated in combination with cisplatin.
- The usual initial dose of single-agent vinorelbine injection is 30 mg/m2 administered weekly. The recommended method of administration is an intravenous injection over 6 to 10 minutes. In controlled trials, single-agent vinorelbine injection was given weekly until progression or dose-limiting toxicity.
- Vinorelbine Injection in Combination with Cisplatin
- Vinorelbine injection may be administered weekly at a dose of 25 mg/m2 in combination with cisplatin given every 4 weeks at a dose of 100 mg/m2.
- Blood counts should be checked weekly to determine whether dose reductions of vinorelbine injection and/or cisplatin are necessary. In the SWOG study, most patients required a 50% dose reduction of vinorelbine injection at day 15 of each cycle and a 50% dose reduction of cisplatin by cycle 3.
- Vinorelbine injection may also be administered weekly at a dose of 30 mg/m2 in combination with cisplatin, given on days 1 and 29, then every 6 weeks at a dose of 120 mg/m2.
- The dosage should be adjusted according to hematologic toxicity or hepatic insufficiency, whichever results in the lower dose for the corresponding starting dose of vinorelbine injection.
- Granulocyte counts should be ≥1000 cells/mm3 prior to the administration of vinorelbine injection. Adjustments in the dosage of vinorelbine injection should be based on granulocyte counts obtained on the day of treatment according to TABLE 5.
- Dose Modifications for Concurrent Hematologic Toxicity and Hepatic =====Insufficiency=====
- In patients with both hematologic toxicity and hepatic insufficiency, the lower of the doses based on the corresponding starting dose of vinorelbine injection determined fromTABLE 5andTABLE 6should be administered.
- No dose adjustments for vinorelbine injection are required for renal insufficiency. Appropriate dose reductions for cisplatin should be made when vinorelbine injection is used in combination.
- If grade ≥2 neurotoxicity develops, vinorelbine injection should be discontinued.
- Caution—vinorelbine injection must be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any vinorelbine injection is injected. Leakage into surrounding tissue during intravenous administration of vinorelbine injection may cause considerable irritation, local tissue necrosis, and/or thrombophlebitis. If extravasation occurs, the injection should be discontinued immediately, and any remaining portion of the dose should then be introduced into another vein. Since there are no established guidelines for the treatment of extravasation injuries with vinorelbine injection, institutional guidelines may be used. The ONS Chemotherapy Guidelines provide additional recommendations for the prevention of extravasation injuries.1
- As with other toxic compounds, caution should be exercised in handling and preparing the solution of vinorelbine injection. Skin reactions may occur with accidental exposure. The use of gloves is recommended. If the solution of vinorelbine injection contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water. Severe irritation of the eye has been reported with accidental contamination of the eye with another vinca alkaloid. If this happens with vinorelbine injection, the eye should be flushed with water immediately and thoroughly.
- Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published.2–8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
- Vinorelbine injection is a clear, colorless to pale yellow solution. Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If particulate matter is seen, vinorelbine injection should not be administered.
- Vinorelbine injection must be diluted in either a syringe or IV bag using one of the recommended solutions. The diluted vinorelbine injection should be administered over 6 to 10 minutes into the side port of a free-flowing IV closest to the IV bag followed by flushing with at least 75 to 125 mL of one of the solutions. Diluted vinorelbine injection may be used for up to 24 hours under normal room light when stored in polypropylene syringes or polyvinyl chloride bags at 5° to 30°C (41° to 86°F)
- The calculated dose of vinorelbine injection should be diluted to a concentration between 1.5 and 3 mg/mL. The following solutions may be used for dilution:
- 5% Dextrose Injection, USP
- 0.9% Sodium Chloride Injection, USP
- The calculated dose of vinorelbine injection should be diluted to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution:
- 5% Dextrose Injection, USP
- 0.9% Sodium Chloride Injection, USP
- 0.45% Sodium Chloride Injection, USP
- 5% Dextrose and 0.45% Sodium Chloride Injection, USP
- Ringer's Injection, USP
- Lactated Ringer's Injection, USP
- Unopened vials of vinorelbine injection are stable until the date indicated on the package when stored under refrigeration at 2° to 8°C (36° to 46°F) and protected from light in the carton. Unopened vials of vinorelbine injection are stable at temperatures up to 25°C (77°F) for up to 72 hours. This product should not be frozen.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vinorelbine in adult patients.
### Non–Guideline-Supported Use
- Breast cancer[1]
- Carcinoma of cervix[2]
- Carcinoma of esophagus[3]
- Head and neck cancer[4]
- Hodgkin's disease[5]
- Kaposi's sarcoma[6]
- Malignant tumor of salivary gland[7]
- Non-Hodgkin's lymphoma[8]
- Non-small cell lung cancer[9]
- Ovarian cancer, Advanced, previously treated[10]
- Small cell carcinoma of lung[11]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Vinorelbine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Vinorelbine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Vinorelbine in pediatric patients.
# Contraindications
- Administration of vinorelbine tartrate injection is contraindicated in patients with pretreatment granulocyte counts <1000 cells/mm3
# Warnings
- Vinorelbine tartrate should be administered in carefully adjusted doses by or under the supervision of a physician experienced in the use of cancer chemotherapeutic agents.
- Patients treated with vinorelbine tartrate should be frequently monitored for myelosuppression both during and after therapy. Granulocytopenia is dose-limiting. Granulocyte nadirs occur between 7 and 10 days after dosing with granulocyte count recovery usually within the following 7 to 14 days.
- Complete blood counts with differentials should be performed and results reviewed prior to administering each dose of vinorelbine tartrate. Vinorelbine tartrate should not be administered to patients with granulocyte counts <1000 cells/mm3. Patients developing severe granulocytopenia should be monitored carefully for evidence of infection and/or fever.
- Acute shortness of breath and severe bronchospasm have been reported infrequently, following the administration of vinorelbine tartrate and other vinca alkaloids, most commonly when the vinca alkaloid was used in combination with mitomycin. These adverse events may require treatment with supplemental oxygen, bronchodilators, and/or corticosteroids, particularly when there is pre-existing pulmonary dysfunction.
- Reported cases of interstitial pulmonary changes and acute respiratory distress syndrome (ARDS), most of which were fatal, occurred in patients treated with single-agent vinorelbine tartrate. The mean time to onset of these symptoms after vinorelbine administration was 1 week (range 3 to 8 days). Patients with alterations in their baseline pulmonary symptoms or with new onset of dyspnea, cough, hypoxia, or other symptoms should be evaluated promptly.
- Vinorelbine tartrate has been reported to cause severe constipation (e.g., Grade 3 to 4), paralytic ileus, intestinal obstruction, necrosis, and/or perforation. Some events have been fatal.
# Adverse Reactions
## Clinical Trials Experience
- The pattern of adverse reactions is similar whether vinorelbine tartrate is used as a single agent or in combination. Adverse reactions from studies with single-agent and combination use of vinorelbine tartrate are summarized in Tables 2 to 4.
- Data in the following table are based on the experience of 365 patients (143 patients with NSCLC; 222 patients with advanced breast cancer) treated with IV vinorelbine tartrate as a single agent in 3 clinical studies. The dosing schedule in each study was 30 mg/m2 vinorelbine tartrate on a weekly basis.
- Granulocytopenia is the major dose-limiting toxicity with vinorelbine tartrate. Dose adjustments are required for hematologic toxicity and hepatic insufficiency. Granulocytopenia was generally reversible and not cumulative over time. Granulocyte nadirs occurred 7 to 10 days after the dose, with granulocyte recovery usually within the following 7 to 14 days. Granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of patients. Septic deaths occurred in approximately 1% of patients. Prophylactic hematologic growth factors have not been routinely used with vinorelbine tartrate. If medically necessary, growth factors may be administered at recommended doses no earlier than 24 hours after the administration of cytotoxic chemotherapy. Growth factors should not be administered in the period 24 hours before the administration of chemotherapy.
- Whole blood and/or packed red blood cells were administered to 18% of patients who received vinorelbine tartrate.
- Loss of deep tendon reflexes occurred in less than 5% of patients. The development of severe peripheral neuropathy was infrequent (1%) and generally reversible.
- Like other anticancer vinca alkaloids, vinorelbine tartrate is a moderate vesicant. Injection site reactions, including erythema, pain at injection site, and vein discoloration, occurred in approximately one third of patients; 5% were severe. Chemical phlebitis along the vein proximal to the site of injection was reported in 10% of patients.
- Prophylactic administration of antiemetics was not routine in patients treated with single-agent vinorelbine tartrate. Due to the low incidence of severe nausea and vomiting with single-agent vinorelbine tartrate, the use of serotonin antagonists is generally not required.
- Transient elevations of liver enzymes were reported without clinical symptoms.
- Chest pain was reported in 5% of patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumor within the chest. There have been rare reports of myocardial infarction.
- Shortness of breath was reported in 3% of patients; it was severe in 2%. Interstitial pulmonary changes were documented.
- Fatigue occurred in 27% of patients. It was usually mild or moderate but tended to increase with cumulative dosing.
- Other toxicities that have been reported in less than 5% of patients include jaw pain, myalgia, arthralgia, and rash. Hemorrhagic cystitis and the syndrome of inappropriate ADH secretion were each reported in <1% of patients.
- Adverse events for combination use are summarized inTABLES 3 and 4.
- Vinorelbine Tartrate in Combination with Cisplatin
- Vinorelbine Tartrate plus Cisplatin versus Single-Agent Cisplatin (Table 3)
- Myelosuppression was the predominant toxicity in patients receiving combination therapy, Grade 3 and 4 granulocytopenia of 82% compared to 5% in the single-agent cisplatin arm. Fever and/or sepsis related to granulocytopenia occurred in 11% of patients on vinorelbine tartrate and cisplatin compared to 0% on the cisplatin arm.
- Four patients on the combination died of granulocytopenia-related sepsis.
- During this study, the use of granulocyte colony-stimulating factor ([G-CSF] filgrastim) was permitted, but not mandated, after the first course of treatment for patients who experienced Grade 3 or 4 granulocytopenia (≤1000 cells/mm3) or in those who developed neutropenic fever between cycles of chemotherapy. Beginning 24 hours after completion of chemotherapy, G-CSF was started at a dose of 5 mcg/kg per day and continued until the total granulocyte count was >1000 cells/mm3 on 2 successive determinations. G-CSF was not administered on the day of treatment.
- Grade 3 and 4 anemia occurred more frequently in the combination arm compared to control, 24% vs. 8%, respectively. Thrombocytopenia occurred in 6% of patients treated with vinorelbine tartrate plus cisplatin compared to 2% of patients treated with cisplatin.
- The incidence of severe non-hematologic toxicity was similar among the patients in both treatment groups. Patients receiving vinorelbine tartrate plus cisplatin compared to single-agent cisplatin experienced more Grade 3 and/or 4 peripheral numbness (2% vs. <1%), phlebitis/thrombosis/embolism (3% vs. <1%), and infection (6% vs. <1%). Grade 3 to 4-constipation and/or ileus occurred in 3% of patients treated with combination therapy and in 1% of patients treated with cisplatin.
- Seven deaths were reported on the combination arm; 2 were related to cardiac ischemia, 1 massive cerebrovascular accident, 1 multisystem failure due to an overdose of vinorelbine tartrate, and 3 from febrile neutropenia. One death, secondary to respiratory infection unrelated to granulocytopenia, occurred with single-agent cisplatin.
- Vinorelbine Tartrate plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine Tartrate (Table 4)
- Myelosuppression, specifically Grade 3 and 4 granulocytopenia, was significantly greater with the combination of vinorelbine tartrate plus cisplatin (79%) than with either single-agent vinorelbine tartrate (53%) or vindesine plus cisplatin (48%), P<0.0001. Hospitalization due to documented sepsis occurred in 4.4% of patients treated with vinorelbine tartrate plus cisplatin; 2% of patients treated with vindesine and cisplatin, and 4% of patients treated with single-agent vinorelbine tartrate. Grade 3 and 4 thrombocytopenia was infrequent in patients receiving combination chemotherapy and no events were reported with single-agent vinorelbine tartrate.
- The incidence of Grade 3 and/or 4 nausea and vomiting, alopecia, and renal toxicity were reported more frequently in the cisplatin-containing combinations compared to single-agent vinorelbine tartrate. Severe local reactions occurred in 2% of patients treated with combinations containing vinorelbine tartrate; none were observed in the vindesine plus cisplatin arm. Grade 3 and 4 neurotoxicity was significantly more frequent in patients receiving vindesine plus cisplatin (17%) compared to vinorelbine tartrate plus cisplatin (7%) and single-agent vinorelbine tartrate (9%) (P< 0.005). Cisplatin did not appear to increase the incidence of neurotoxicity observed with single-agent vinorelbine tartrate.
## Postmarketing Experience
- In addition to the adverse events reported from clinical trials, the following events have been identified during post-approval use of vinorelbine tartrate. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to vinorelbine tartrate.
- Body as a Whole
- Systemic allergic reactions reported as anaphylaxis, pruritus, urticaria, and angioedema; flushing; and radiation recall events such as dermatitis and esophagitis have been reported.
- Hematologic
- Thromboembolic events, including pulmonary embolus and deep venous thrombosis, have been reported primarily in seriously ill and debilitated patients with known predisposing risk factors for these events.
- Neurologic
- Peripheral neurotoxicities such as, but not limited to, muscle weakness and disturbance of gait, have been observed in patients with and without prior symptoms. There may be increased potential for neurotoxicity in patients with pre-existing neuropathy, regardless of etiology, who receive vinorelbine tartrate. Vestibular and auditory deficits have been observed with vinorelbine tartrate, usually when used in combination with cisplatin.
- Skin
- Injection site reactions, including localized rash and urticaria, blister formation, and skin sloughing have been observed in clinical practice. Some of these reactions may be delayed in appearance.
- Gastrointestinal
- Dysphagia, mucositis, and pancreatitis have been reported.
- Cardiovascular
- Hypertension, hypotension, vasodilation, tachycardia, and pulmonary edema have been reported.
- Pulmonary
- Pneumonia has been reported.
- Musculoskeletal
- Headache has been reported, with and without other musculoskeletal aches and pains.
- Other
- Pain in tumor-containing tissue, back pain, and abdominal pain have been reported. Electrolyte abnormalities, including hyponatremia with or without the syndrome of inappropriate ADH secretion, have been reported in seriously ill and debilitated patients.
- Combination Use
- Patients with prior exposure to paclitaxel and who have demonstrated neuropathy should be monitored closely for new or worsening neuropathy. Patients who have experienced neuropathy with previous drug regimens should be monitored for symptoms of neuropathy while receiving vinorelbine tartrate. Vinorelbine tartrate may result in radiosensitizing effects with prior or concomitant radiation therapy.
# Drug Interactions
There is limited information regarding Vinorelbine Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Vinorelbine tartrate may cause fetal harm if administered to a pregnant woman. A single dose of vinorelbine has been shown to be embryo- and/or fetotoxic in mice and rabbits at doses of 9 mg/m2 and 5.5 mg/m2, respectively (one third and one sixth the human dose). At nonmaternotoxic doses, fetal weight was reduced and ossification was delayed. There are no studies in pregnant women. If vinorelbine tartrate is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with vinorelbine tartrate.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Vinorelbine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Vinorelbine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Vinorelbine with respect to nursing mothers.
### Pediatric Use
There is no FDA guidance on the use of Vinorelbine with respect to pediatric patients.
### Geriatic Use
There is no FDA guidance on the use of Vinorelbine with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Vinorelbine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Vinorelbine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Vinorelbine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Vinorelbine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Vinorelbine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Vinorelbine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
- Patients with prior exposure to paclitaxel and who have demonstrated neuropathy should be monitored closely for new or worsening neuropathy. Patients who have experienced neuropathy with previous drug regimens should be monitored for symptoms of neuropathy while receiving vinorelbine tartrate.
Patients treated with vinorelbine tartrate should be frequently monitored for myelosuppression both during and after therapy
- Patients developing severe granulocytopenia should be monitored carefully for evidence of infection and/or fever.
# IV Compatibility
There is limited information regarding IV Compatibility of Vinorelbine in the drug label.
# Overdosage
- There is no known antidote for overdoses of vinorelbine tartrate. Overdoses involving quantities up to 10 times the recommended dose (30 mg/m2) have been reported. The toxicities described were consistent with those listed in theADVERSE REACTIONSsection including paralytic ileus, stomatitis, and esophagitis. Bone marrow aplasia, sepsis, and paresis have also been reported.
- Fatalities have occurred following overdose of vinorelbine tartrate. If overdosage occurs, general supportive measures together with appropriate blood transfusions, growth factors, and antibiotics should be instituted as deemed necessary by the physician.
# Pharmacology
There is limited information regarding Vinorelbine Pharmacology in the drug label.
## Mechanism of Action
- Vinorelbine is a vinca alkaloid that interferes with microtubule assembly. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units, vindoline and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for vinorelbine.
- The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, vinorelbine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin-dependent Ca++-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. In intact tectal plates from mouse embryos, vinorelbine, vincristine, and vinblastine inhibited mitotic microtubule formation at the same concentration (2 µM), inducing a blockade of cells at metaphase.
- Vincristine produced depolymerization of axonal microtubules at 5 µM, but vinblastine and vinorelbine did not have this effect until concentrations of 30 µM and 40 µM, respectively. These data suggest relative selectivity of vinorelbine for mitotic microtubules.
## Structure
- Vinorelbine Injection USP is for intravenous administration. Each vial contains vinorelbine tartrate, USP equivalent to 10 mg (1-mL vial) or 50 mg (5-mL vial) vinorelbine in Water for Injection. No preservatives or other additives are present. The aqueous solution is sterile and nonpyrogenic.
- Vinorelbine tartrate, USP is a semi-synthetic vinca alkaloid with antitumor activity. The chemical name is 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine [R-(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)].
- Vinorelbine tartrate, USP has the following structure:
- Vinorelbine tartrate, USP is a white to yellow or light brown amorphous powder. The aqueous solubility is >1000 mg/mL in distilled water. The pH of Vinorelbine Injection USP is approximately 3.5.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Vinorelbine in the drug label.
## Pharmacokinetics
- The pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/m2 in 4 clinical trials. Doses were administered by 15- to 20-minute constant-rate infusions. Following intravenous administration, vinorelbine concentration in plasma decays in a triphasic manner.
- The initial rapid decline primarily represents distribution of drug to peripheral compartments followed by metabolism and excretion of the drug during subsequent phases. The prolonged terminal phase is due to relatively slow efflux of vinorelbine from peripheral compartments. The terminal phase half-life averages 27.7 to 43.6 hours and the mean plasma clearance ranges from 0.97 to 1.26 L/h per kg. Steady-state volume of distribution (Vss) values range from 25.4 to 40.1 L/kg.
- Vinorelbine demonstrated high binding to human platelets and lymphocytes. The free fraction was approximately 0.11 in pooled human plasma over a concentration range of 234 to 1169 ng/mL. The binding to plasma constituents in cancer patients ranged from 79.6% to 91.2%. Vinorelbine binding was not altered in the presence of cisplatin, 5-fluorouracil, or doxorubicin.
- Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine.
- Therapeutic doses of vinorelbine tartrate (30 mg/m2) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes.
- The effects of renal or hepatic dysfunction on the disposition of vinorelbine have not been assessed, but based on experience with other anticancer vinca alkaloids, dose adjustments are recommended for patients with impaired hepatic function.
- The disposition of radiolabeled vinorelbine given intravenously was studied in a limited number of patients. Approximately 18% and 46% of the administered dose was recovered in the urine and in the feces, respectively. Incomplete recovery in humans is consistent with results in animals where recovery is incomplete, even after prolonged sampling times. A separate study of the urinary excretion of vinorelbine using specific chromatographic analytical methodology showed that 10.9% ± 0.7% of a 30 mg/m2 intravenous dose was excreted unchanged in the urine.
- The influence of age on the pharmacokinetics of vinorelbine was examined using data from 44 cancer patients (average age, 56.7 ± 7.8 years; range, 41 to 74 years; with 12 patients ≥60 years and 6 patients ≥65 years) in 3 studies. CL (the mean plasma clearance), t1/2 (the terminal phase half-life), and VZ (the volume of distribution during terminal phase) were independent of age. A separate pharmacokinetic study was conducted in 10 elderly patients with metastatic breast cancer (age range, 66 to 81 years; 3 patients >75 years; normal liver function tests) receiving vinorelbine 30 mg/m2 intravenously. CL, Vss, and t1/2 were similar to those reported for younger adult patients in previous studies. No relationship between age, systemic exposure (AUCo-∞), and hematological toxicity was observed.
- The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin with vinorelbine tartrate.
- Data from 1 randomized clinical study (211 evaluable patients) with single-agent vinorelbine tartrate and 2 randomized clinical trials (1044 patients) using vinorelbine tartrate combined with cisplatin support the use of vinorelbine tartrate in patients with advanced nonsmall cell lung cancer (NSCLC).
- Single-agent vinorelbine tartrate was studied in a North American, randomized clinical trial in which patients with Stage IV NSCLC, no prior chemotherapy, and Karnofsky Performance Status ≥70 were treated with vinorelbine tartrate (30 mg/m2) weekly or 5-fluorouracil (5-FU) (425 mg/m2 IV bolus) plus leucovorin (LV) (20 mg/m2 IV bolus) daily for 5 days every 4 weeks. A total of 211 patients were randomized at a 2:1 ratio to vinorelbine tartrate (143) or 5-FU/LV (68). Vinorelbine tartrate showed improved survival time compared to 5-FU/LV. In an intent-to-treat analysis, the median survival time was 30 weeks versus 22 weeks for patients receiving vinorelbine tartrate versus 5-FU/LV, respectively (P = 0.06). The 1-year survival rates were 24% (±4% SE) for vinorelbine tartrate and 16% (±5% SE) for the 5-FU/LV group, using the Kaplan-Meier product-limit estimates. The median survival time with 5-FU/LV was similar to or slightly better than that usually observed in untreated patients with advanced NSCLC, suggesting that the difference was not related to some unknown detrimental effect of 5-FU/LV therapy.
- The response rates (all partial responses) for vinorelbine tartrate and 5-FU/LV were 12% and 3%, respectively.
- Vinorelbine Tartrate in Combination with Cisplatin: Vinorelbine Tartrate plus Cisplatin versus Single-Agent Cisplatin
- A Phase III open-label, randomized study was conducted which compared vinorelbine tartrate (25 mg/m2 per week) plus cisplatin (100 mg/m2 every 4 weeks) to single-agent cisplatin (100 mg/m2 every 4 weeks) in patients with Stage IV or Stage IIIb NSCLC patients with malignant pleural effusion or multiple lesions in more than one lobe who were not previously treated with chemotherapy. Patients included in the study had a performance status of 0 or 1, and 34% had received prior surgery and/or radiotherapy.
- Characteristics of the 432 randomized patients are provided in TABLE 1. Two hundred and twelve patients received vinorelbine tartrate plus cisplatin and 210 received single-agent cisplatin. The primary objective of this trial was to compare survival between the 2 treatment groups. Survival (FIGURE 1) for patients receiving vinorelbine tartrate plus cisplatin was significantly better compared to the patients who received single-agent cisplatin. The results of this trial are summarized in TABLE 1.
- Vinorelbine Tartrate plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine Tartrate
- In a large European clinical trial, 612 patients with Stage III or IV NSCLC, no prior chemotherapy, and WHO Performance Status of 0, 1, or 2 were randomized to treatment with single-agent vinorelbine tartrate (30 mg/m2 per week), vinorelbine tartrate (30 mg/m2 per week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks), and vindesine (3 mg/m2 per week for 7 weeks, then every other week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks). Patient characteristics are provided in TABLE 1. Survival was longer in patients treated with vinorelbine tartrate plus cisplatin compared to those treated with vindesine plus cisplatin (FIGURE 2). Study results are summarized in TABLE 1.
- A dose-ranging study of vinorelbine tartrate (20, 25, or 30 mg/m2 per week) plus cisplatin (120 mg/m2 days 1 and 29, then every 6 weeks) in 32 patients with NSCLC demonstrated a median survival of 10.2 months. There were no responses at the lowest dose level; the response rate was 33% in the 21 patients treated at the 2 highest dose levels.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Vinorelbine in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Vinorelbine in the drug label.
# How Supplied
- Vinorelbine Injection UPS is a clear, colorless to pale yellow solution in water for injection, containing 10 mg vinorelbine tartrate, USP per mL. Vinorelbine Injection USP is available as follows:
## Storage
- Store the vials under refrigeration at 2° to 8°C (36° to 46°F) in the carton. * Protect from light. DO NOT FREEZE.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Vinorelbine Patient Counseling Information in the drug label.
# Precautions with Alcohol
- Alcohol-Vinorelbine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- VINORELBINE ®[12]
# Look-Alike Drug Names
There is limited information regarding Vinorelbine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Navelbine | |
2082b8007940a8379b4b8d89504f309f2419534d | wikidoc | Necitumumab | Necitumumab
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# Black Box Warning
# Overview
Necitumumab is an epidermal growth factor receptor (EGFR) antagonist that is FDA approved for the treatment of patients with metastatic squamous non-small cell lung cancer (first-line treatment in combination with gemcitabine and cisplatin). There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash and hypomagnesemia (≥30%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Squamous Non-Small Cell Lung Cancer (NSCLC)
- Necitumumab is indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer.
- Limitation of Use: Necitumumab is not indicated for treatment of non-squamous non-small cell lung cancer.
- Recommended Dose and Schedule
- The recommended dose of Necitumumab is 800 mg administered as an intravenous infusion over 60 minutes on Days 1 and 8 of each 3-week cycle prior to gemcitabine and cisplatin infusion. Continue Necitumumab until disease progression or unacceptable toxicity.
- Premedication
- For patients who have experienced a previous Grade 1 or 2 infusion-related reaction (IRR), pre-medicate with diphenhydramine hydrochloride (or equivalent) prior to all subsequent Necitumumab infusions.
- For patients who have experienced a second Grade 1 or 2 occurrence of IRR, pre-medicate for all subsequent infusions, with diphenhydramine hydrochloride (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each Necitumumab infusion.
- Dose Modifications
- Infusion-Related Reactions (IRR)
- Reduce the infusion rate of Necitumumab by 50% for Grade 1 IRR.
- Stop the infusion for Grade 2 IRR until signs and symptoms have resolved to Grade 0 or 1; resume Necitumumab at 50% reduced rate for all subsequent infusions.
- Permanently discontinue Necitumumab for Grade 3 or 4 IRR.
- Dermatologic Toxicity
- Withhold Necitumumab for Grade 3 rash or acneiform rash until symptoms resolve to Grade ≤2, then resume Necitumumab at reduced dose of 400 mg for at least 1 treatment cycle. If symptoms do not worsen, may increase dose to 600 mg and 800 mg in subsequent cycles.
- Permanently discontinue Necitumumab if:
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Necitumumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Necitumumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Necitumumab have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Necitumumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Necitumumab in pediatric patients.
# Contraindications
None
# Warnings
Cardiopulmonary arrest or sudden death occurred in 15 (3%) of 538 patients treated with Necitumumab plus gemcitabine and cisplatin as compared to 3 (0.6%) of 541 patients treated with gemcitabine and cisplatin alone in Study 1. Twelve of the fifteen patients died within 30 days of the last dose of Necitumumab and had comorbid conditions including history of coronary artery disease (n=3), hypomagnesemia (n=4), chronic obstructive pulmonary disease (n=7), and hypertension (n=5). Eleven of the 12 patients had an unwitnessed death. Patients with significant coronary artery disease, myocardial infarction within 6 months, uncontrolled hypertension, and uncontrolled congestive heart failure were not enrolled in Study 1. The incremental risk of cardiopulmonary arrest or sudden death in patients with a history of coronary artery disease, congestive heart failure, or arrhythmias as compared to those without these comorbid conditions is not known.
Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium prior to each infusion of Necitumumab during treatment and after Necitumumab administration for at least 8 weeks after the last dose. Withhold Necitumumab for Grade 3 or 4 electrolyte abnormalities; subsequent cycles of Necitumumab may be administered in these patients once electrolyte abnormalities have improved to Grade ≤2. Replete electrolytes as medically appropriate.
Hypomagnesemia occurred in 83% of 461/538 patients with available laboratory results treated with Necitumumab as compared to 70% of 457/541 patients with available laboratory results treated with gemcitabine and cisplatin alone in Study 1. Hypomagnesemia was severe (Grade 3 or 4) in 20% of the patients treated with Necitumumab compared to 7% of the patients treated with gemcitabine and cisplatin alone. The median time to development of hypomagnesemia and accompanying electrolyte abnormalities was 6 weeks (25th percentile 4 weeks; 75th percentile 9 weeks) after initiation of Necitumumab. Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each infusion of Necitumumab during treatment and for at least 8 weeks following the completion of Necitumumab. Withhold Necitumumab for Grade 3 or 4 electrolyte abnormalities; subsequent cycles of Necitumumab may be administered in these patients once hypomagnesemia and related electrolyte abnormalities have improved to Grade ≤2. Replete electrolytes as medically appropriate.
Venous and arterial thromboembolic events (VTE and ATE), some fatal, were observed with Necitumumab in combination with gemcitabine and cisplatin. In Study 1, the incidence of VTE was 9% in patients receiving Necitumumab plus gemcitabine and cisplatin versus 5% in patients receiving gemcitabine and cisplatin alone and the incidence of Grade 3 or higher VTE was 5% versus 3%, respectively. The incidence of fatal VTEs was similar between arms (0.2% versus 0.2%). The most common VTEs were pulmonary embolism (5%) and deep-vein thrombosis (2%).
The incidence of ATEs of any grade was 5% versus 4% and the incidence of Grade 3 or higher ATE was 4% versus 2% in the Necitumumab containing and gemcitabine and cisplatin arms, respectively, in Study 1. The most common ATEs were cerebral stroke and ischemia (2%) and myocardial infarction (1%).
In an exploratory analysis of Study 1, the relative risk of VTE or ATE was approximately 3-fold higher in patients with a reported history of VTE or ATE than in patients with no reported history of VTE or ATE.
Discontinue Necitumumab for patients with serious or life threatening VTE or ATE.
Dermatologic toxicities, including rash, dermatitis acneiform, acne, dry skin, pruritus, generalized rash, skin fissures, maculo-papular rash and erythema, occurred in 79% of patients receiving Necitumumab in Study 1. Skin toxicity was severe in 8% of patients. Skin toxicity usually developed within the first 2 weeks of therapy and resolved within 17 weeks after onset. For Grade 3 skin reactions, modify the dose of Necitumumab. Limit sun exposure.
Discontinue Necitumumab for severe (Grade 4) skin reactions, or for Grade 3 skin induration/fibrosis.
In Study 1, 1.5% of Necitumumab treated patients experienced IRRs of any severity with 0.4% Grade 3 IRR. No patients received premedication for IRR for the first dose of Necitumumab in Study 1. Most IRRs occurred after the first or second administration of Necitumumab. Monitor patients during and following Necitumumab infusion for signs and symptoms of IRR. Discontinue Necitumumab for serious or life-threatening IRR.
Necitumumab is not indicated for the treatment of patients with non-squamous NSCLC. In a study of Necitumumab plus pemetrexed and cisplatin (PC) versus PC alone (Study 2), patients treated with Necitumumab and PC experienced more serious (51% versus 41%) and fatal toxicities (16% versus 10%) and cardiopulmonary arrest/sudden death within 30 days of the last study drug (3.3% versus 1.3%) compared to patients who received PC alone.
Based on animal data and its mechanism of action, Necitumumab can cause fetal harm when administered to a pregnant woman. Disruption or depletion of EGFR in animal models results in impairment of embryofetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR signaling has resulted in embryolethality as well as post-natal death in animals. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Necitumumab and for three months following the final dose.
# Adverse Reactions
## Clinical Trials Experience
The following adverse drug reactions are discussed in greater detail in other sections of the label:
- Cardiopulmonary Arrest
- Hypomagnesemia
- Venous and Arterial Thromboembolic Events
- Dermatologic Toxicities
- Infusion-Related Reactions
- Non-Squamous NSCLC - Increased Toxicity and Increased Mortality
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 Necitumumab was evaluated in two randomized, open-label trials comparing Necitumumab plus gemcitabine and cisplatin to gemcitabine and cisplatin alone in patients with squamous NSCLC (Study 1), and Necitumumab plus pemetrexed and cisplatin to pemetrexed and cisplatin alone in patients with non-squamous NSCLC (Study 2). Since the data in Study 2 demonstrated similar incidence of adverse reactions over control as observed in Study 1, the safety data from Study 1 alone is described below.
For patients who received at least 1 dose of treatment in Study 1, the median age was 62 years (range 32 to 84), 83% were male; 84% were Caucasian; and 92% were smokers. Baseline ECOG performance status was 0 or 1 for 91%, and 2 for 9% of patients; 90% had metastatic disease in 2 or more sites. Patients received Necitumumab 800 mg intravenously on days 1 and 8 of each 21 day cycle in combination with up to six cycles of gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin (75 mg/m2 on day 1). Patients received Necitumumab until progressive disease or unacceptable toxicity.
Patients in the gemcitabine and cisplatin alone arm received a maximum of 6 cycles, while patients in the Necitumumab plus gemcitabine and cisplatin arm demonstrating at least stable disease were permitted to continue to receive additional cycles of Necitumumab until disease progression or unacceptable toxicity. The median duration of exposure to Necitumumab in 538 patients who received at least 1 dose of treatment in Study 1 was 4.6 months (range 0.5 months to 34 months), including 182 patients exposed for at least 6 months and 41 patients exposed for greater than 1 year. Patients were monitored for safety until 30 days after treatment discontinuation and resolution of treatment-emergent adverse events.
The most common adverse reactions (all grades) observed in Necitumumab-treated patients at a rate of ≥15% and ≥2% higher than gemcitabine and cisplatin alone were rash (44%), vomiting (29%), diarrhea (16%), and dermatitis acneiform (15%). The most common severe (Grade 3 or higher) adverse events that occurred at a ≥2% higher rate in Necitumumab-treated patients compared to patients treated with gemcitabine and cisplatin alone were venous thromboembolic events (5%; including pulmonary embolism), rash (4%), and vomiting (3%).
TABLE 1 contains selected adverse drug reactions observed in Study 1 at an incidence of ≥5% in the Necitumumab arm and at ≥2% higher incidence than the control arm.
- Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% All Grades or a ≥2% Grade 3-4 Difference Between Arms in Patients Receiving Necitumumab in Study 1
PORTRAZZA: Necitumumab's Brand name
Clinically relevant adverse reactions (all grades) reported in ≥1% and <5% of patients treated with Necitumumab were: dysphagia (3%), oropharyngeal pain (1%), muscle spasms (2%), phlebitis (2%), and hypersensitivity/IRR (1.5%).
In Study 1, 12% of the patients on the Necitumumab arm discontinued study treatment due to an adverse reaction. The most common Necitumumab related toxicity leading to Necitumumab discontinuation was skin rash (1%).
TABLE 2 contains selected electrolyte abnormalities observed in Study 1 according to laboratory assessment at an incidence of >10% in the Necitumumab arm and at >2% higher incidence than the control arm.
The median time to onset of hypomagnesemia was 6 weeks (25th percentile 4 weeks; 75th percentile 9 weeks). Hypomagnesemia was reported as resolved in 43% of the patients who received Necitumumab. In Study 1, 32% of the patients in the Necitumumab arm and 16% of the patients who received gemcitabine and cisplatin alone received magnesium replacement.
- Table 2: Electrolyte Abnormalities according to Laboratory Assessment at Incidence Rate >10% and a >2% Difference between Arms in Patients Receiving Necitumumab in Study 1(a)
PORTRAZZA: Necitumumab's Brand name
As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, treatment-emergent anti-necitumumab antibodies (ADA) were detected in 4.1% (33/814) of patients using an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 1.4% (11/814) of patients post exposure to Necitumumab. No relationship was found between the presence of ADA and incidence of infusion-related reactions. The impact of ADA on efficacy (overall survival) could not be assessed due to the limited number of patients with treatment-emergent ADA. In Study 1, the exposure to necitumumab was lower in patients with ADA post-treatment than in patients without detectable ADA.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Necitumumab with the incidences of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Necitumumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Necitumumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
- Risk Summary
- Based on animal data and its mechanism of action, Necitumumab can cause fetal harm when administered to a pregnant woman. Disruption or depletion of EGFR in animal models results in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR signaling has resulted in embryolethality as well as post-natal death in animals. No animal reproduction studies have been conducted with necitumumab. There are no available data for Necitumumab exposure in pregnant women. Advise pregnant women of the potential risk to a fetus, and the risk to postnatal development.
- 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.
- Data
- Animal Data
- No animal studies have been conducted to evaluate the effect of necitumumab on reproduction and fetal development; however, based on its mechanism of action, Necitumumab can cause fetal harm or developmental anomalies. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development) and can cause developmental anomalies and early death in surviving fetuses. Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling. Human IgG1 is known to cross the placenta; therefore, necitumumab has the potential to be transmitted from the mother to the developing fetus.
- In monkeys, administration of a chimeric anti-EGFR antibody that binds to an epitope overlapping that of necitumumab during the period of organogenesis resulted in detectable exposure of the antibody in the amniotic fluid and in the serum of embryos from treated dams. While no fetal malformations or other clear teratogenic effects occurred in offspring, there was an increased incidence of embryolethality and abortions.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Necitumumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Necitumumab during labor and delivery.
### Nursing Mothers
There is no information regarding the presence of necitumumab in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from Necitumumab, advise a nursing woman not to breastfeed during treatment with Necitumumab and for three months following the final dose.
### Pediatric Use
The safety and effectiveness of Necitumumab have not been established in pediatric patients.
### Geriatic Use
Of the 545 patients in the Necitumumab plus gemcitabine and cisplatin arm in Study 1, 213 (39%) were 65 years and over, while 108 (20%) were 70 years and over. In an exploratory subgroup analysis of Study 1, the hazard ratio for overall survival in patients 70 years or older was 1.03 (95% CI: 0.75, 1.42). Of the adverse reactions listed in TABLE 1, there was a higher incidence (≥3%) of venous thromboembolic events including pulmonary embolism in patients age 70 and over compared to those who were younger than age 70.
### Gender
There is no FDA guidance on the use of Necitumumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Necitumumab with respect to specific racial populations.
### Renal Impairment
No formal studies have been conducted to evaluate the effect of renal impairment on the exposure to necitumumab. Renal function has no influence on the exposure to necitumumab based on the population pharmacokinetic analysis of data from clinical trials.
### Hepatic Impairment
No formal studies have been conducted to evaluate the effect of hepatic impairment on the exposure to necitumumab. Mild or moderate hepatic impairment has no influence on the exposure to necitumumab based on the population pharmacokinetic analysis. No patients with severe hepatic impairment were enrolled in the clinical trials with Necitumumab.
### Females of Reproductive Potential and Males
- Contraception
- Females: Based on its mechanism of action, Necitumumab can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Necitumumab and for three months following the final dose.
### Immunocompromised Patients
There is no FDA guidance one the use of Necitumumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Preparation
Inspect vial contents for particulate matter and discoloration prior to dilution. Discard the vial if particulate matter or discoloration is identified. Store vials in a refrigerator at 2° to 8°C (36˚ to 46˚F) until time of use. Keep the vial in the outer carton in order to protect from light.
- Dilute the required volume of Necitumumab with 0.9% Sodium Chloride Injection, USP in an intravenous infusion container to a final volume of 250 mL. Do not use solutions containing dextrose.
- Gently invert the container to ensure adequate mixing.
- DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medication.
- Store diluted infusion solution for no more than 24 hours at 2° to 8°C (36° to 46°F), or no more than 4 hours at room temperature (up to 25°C ).
- Discard vial with any unused portion of Necitumumab.
- Administration
Visually inspect the diluted solution for particulate matter and discoloration prior to administration. If particulate matter or discoloration is identified, discard the solution.
Administer diluted Necitumumab infusion via infusion pump over 60 minutes through a separate infusion line. Flush the line with 0.9% Sodium Chloride Injection, USP at the end of the infusion.
### Monitoring
There is limited information regarding Necitumumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Necitumumab and IV administrations.
# Overdosage
There has been limited experience with Necitumumab overdose in human clinical trials.
The highest dose of Necitumumab studied clinically in a human dose-escalation Phase 1 study was 1000 mg once a week and once every other week. Two out of 9 patients in the every other week cohort experienced dose-limiting toxicities (e.g., a combination of Grade 3 headache, vomiting, and nausea). There is no known antidote for Necitumumab overdose.
# Pharmacology
## Mechanism of Action
Necitumumab is a recombinant human lgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands. Expression and activation of EGFR has been correlated with malignant progression, induction of angiogenesis, and inhibition of apoptosis. Binding of necitumumab induces EGFR internalization and degradation in vitro. In vitro, binding of necitumumab also led to antibody-dependent cellular cytotoxicity (ADCC) in EGFR-expressing cells.
In in vivo studies using xenograft models of human cancer, including non-small cell lung carcinoma, administration of necitumumab to implanted mice resulted in increased antitumor activity in combination with gemcitabine and cisplatin as compared to mice receiving gemcitabine and cisplatin alone.
## Structure
Necitumumab is an anti-EGFR recombinant human monoclonal antibody of the IgG1 kappa isotype that specifically binds to the ligand binding site of the human EGFR. Necitumumab has an approximate molecular weight of 144.8 kDa. Necitumumab is produced in genetically engineered mammalian NS0 cells.
Necitumumab is a sterile, preservative free, clear to slightly opalescent and colorless to slightly yellow solution. Necitumumab is available in single-dose vials for intravenous infusion following dilution. Each vial contains 800 mg Necitumumab in 50 mL (16 mg/mL).
Each mL contains necitumumab (16 mg), citric acid anhydrous (0.256 mg), glycine (9.984 mg), mannitol (9.109 mg), polysorbate 80 (0.1 mg), sodium chloride (2.338 mg), sodium citrate dihydrate (2.55 mg), and water for injection, pH 6.0.
## Pharmacodynamics
There is limited information regarding Necitumumab Pharmacodynamics in the drug label.
## Pharmacokinetics
Based on population pharmacokinetic (popPK) analysis of serum concentration data from patients in clinical studies with Necitumumab, necitumumab exhibits dose-dependent kinetics. Following the administration of Necitumumab 800 mg on Days 1 and 8 of each 21 day cycle, the estimated mean total systemic clearance (CLtot) at steady state is 14.1 mL/h (CV=39%), the steady state volume of distribution (Vss) is 7.0 L (CV=31%) and the elimination half-life is approximately 14 days. The predicted time to reach steady state is approximately 100 days.
Specific Populations
- Effect of Age, Body Weight, Sex and Race:
- Based on the popPK analysis with data obtained in 807 patients, age (range 19-84 years), sex (75% males), and race (85% Whites) have no effect on the systemic exposure of necitumumab.
- Body weight is identified as a covariate in the popPK analysis; however, weight-based dosing is not expected to significantly decrease the variability in exposure. No dose adjustment based on body weight is necessary.
- Renal Impairment
- Patients with Renal Impairment — PopPK analysis did not identify a correlation between necitumumab exposure and renal function as assessed by estimated creatinine clearance ranging from 11-250 mL/min.
- Hepatic Impairment
- Patients with Hepatic Impairment — PopPK analysis did not identify a correlation between the exposure of necitumumab and hepatic function as assessed by alanine aminotransferase (ranging from 2-615 U/L), aspartate transaminase (ranging from 1.2-619 U/L) and total bilirubin (ranging from 0.1-106 μmol/L).
Drug Interactions
- Effect of Necitumumab on Gemcitabine and Cisplatin
- In 12 patients with advanced solid tumors who received gemcitabine and cisplatin in combination with Necitumumab, the geometric mean dose-normalized AUC of gemcitabine was increased by 22% and Cmax increased by 63% compared to administration of gemcitabine and cisplatin alone while exposure to cisplatin was unchanged.
- Effect of Gemcitabine and Cisplatin on Necitumumab
- Concomitant administration of gemcitabine and cisplatin had no effect on the exposure of necitumumab.
In Study 1, the CLtot of necitumumab was 26% higher and Css,ave was 34% lower in patients who tested positive for anti-necitumumab antibodies (ADA) post-treatment than patients who tested negative for ADA post-treatment.
## Nonclinical Toxicology
No studies have been performed to assess the potential of necitumumab for carcinogenicity or genotoxicity.
Fertility studies have not been performed with necitumumab.
# Clinical Studies
Study 1 was a randomized, multi-center open-label, controlled trial conducted in 1093 patients receiving gemcitabine and cisplatin first-line chemotherapy for metastatic squamous NSCLC. Patients were randomized (1:1) to receive Necitumumab plus gemcitabine and cisplatin or gemcitabine and cisplatin alone. Stratification factors were ECOG performance status (0, 1 versus 2) and geographic region (North America, Europe, and Australia versus South America, South Africa, and India versus Eastern Asia). Gemcitabine (1250 mg/m2, Days 1 and 8) plus cisplatin (75 mg/m2, Day 1) were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Necitumumab (800 mg by intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered prior to gemcitabine and cisplatin. Patients demonstrating at least stable disease on Necitumumab plus gemcitabine and cisplatin were to continue Necitumumab as a single agent in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of chemotherapy or if chemotherapy was discontinued for toxicity.
Of the 1093 randomized patients, the median age was 62 years (range 32 to 86), 83% were male; 84% were Caucasian; and 91% were smokers. The majority of the patients (87%) were enrolled in North America, Europe and Australia, 36 patients (3%) were enrolled at clinical sites in the U.S., 6% of the patients were enrolled in South America, South Africa and India and 8% enrolled at clinical sites in Eastern Asia. Baseline ECOG performance status was 0 or 1 for 91%, and 2 for 9% of patients; 91% had metastatic disease in 2 or more sites. In the Necitumumab plus gemcitabine and cisplatin arm, 51% of patients continued Necitumumab after completion or discontinuation of chemotherapy. Use of post-study systemic therapy was 47% in the Necitumumab plus gemcitabine and cisplatin arm, and 45% in the gemcitabine and cisplatin arm.
The main outcome measure was overall survival (OS). Investigator-assessed progression-free survival (PFS) and overall response rate (ORR) were also assessed. Overall survival and PFS were statistically significantly improved in patients randomized to receive Necitumumab plus gemcitabine and cisplatin compared to gemcitabine and cisplatin alone. There was no difference in ORR between arms, with an ORR of 31% (95% CI 27, 35) for Necitumumab plus gemcitabine and cisplatin arm and an ORR of 29% (95% CI 25, 33) for gemcitabine and cisplatin arm, p-value 0.40.
Efficacy results are shown in TABLE 3 and FIGURE 1.
- Table 3: Efficacy Results for Metastatic Squamous Non-Small Cell Lung Cancer
PORTRAZZA: Necitumumab's Brand name
- Figure 1: Kaplan-Meier Curves of Overall Survival in Patients with Metastatic Squamous Non-Small Cell Lung Cancer
PORTRAZZA: Necitumumab's Brand name
Lack of efficacy of Necitumumab in combination with pemetrexed and cisplatin for the treatment of patients with metastatic non-squamous non-small cell lung cancer was determined in one randomized, open-label, multicenter trial (Study 2). The study was closed prematurely after 633 patients were enrolled due to increased incidence of death due to any cause and of thromboembolic events in the Necitumumab arm. Patients with no prior chemotherapy for metastatic disease were randomized (1:1) to receive Necitumumab plus pemetrexed and cisplatin or pemetrexed and cisplatin alone. Stratification factors were smoking status (non-smokers versus light smokers versus smokers), ECOG performance status (0 - 1 versus 2), histology (adenocarcinoma/large cell versus others), and geographic region. Necitumumab (800 mg, Days 1 and 8 of each 3-week cycle) was administered prior to pemetrexed and cisplatin. Patients demonstrating at least stable disease on Necitumumab plus pemetrexed and cisplatin were to continue Necitumumab as a single agent in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of chemotherapy.
Of the 633 patients, 315 were randomized to Necitumumab plus pemetrexed and cisplatin arm and 318 in the pemetrexed and cisplatin arm. The median age was 61 years, 67 % were male, 93% were Caucasian and 94% had ECOG PS 0 or 1. More than 75% were smokers and 89% had adenocarcinoma histology.
The main efficacy outcome was OS. Progression-free survival and ORR were also assessed. Addition of Necitumumab to pemetrexed and cisplatin did not improve OS ; PFS or ORR (31% in the Necitumumab plus pemetrexed and cisplatin arm and 32% in the pemetrexed and cisplatin alone arm).
# How Supplied
Necitumumab is supplied in single-dose vials as a sterile, preservative-free solution:
- 800 mg/50 mL (16 mg/mL) NDC 0002-7716-01
## Storage
Store vials in a refrigerator at 2° to 8°C (36° to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light. DO NOT FREEZE OR SHAKE the vial.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Hypomagnesemia
- Advise patients of risk of decreased blood levels of magnesium, potassium and calcium. Take medicines to replace the electrolytes exactly as advised by the physician.
- Venous and Arterial Thromboembolic Events
- Advise patients of increased risk of venous and arterial thromboembolic events.
- Skin reactions
- Advise patients to minimize sun exposure with protective clothing and use of sunscreen while receiving Necitumumab.
- Infusion-Related Reactions
- Advise patients to report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.
- Embryo-Fetal Toxicity
- Advise pregnant women of the potential risk to a fetus.
- Advise females of reproductive potential to use effective contraception during treatment with Necitumumab and for three months following final dose.
- Lactation
- Advise women not to breastfeed during treatment with Necitumumab and for three months following the final dose.
# Precautions with Alcohol
Alcohol-Necitumumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
PORTRAZZA™
# Look-Alike Drug Names
There is limited information regarding Necitumumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Necitumumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2]
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# Black Box Warning
# Overview
Necitumumab is an epidermal growth factor receptor (EGFR) antagonist that is FDA approved for the treatment of patients with metastatic squamous non-small cell lung cancer (first-line treatment in combination with gemcitabine and cisplatin). There is a Black Box Warning for this drug as shown here. Common adverse reactions include rash and hypomagnesemia (≥30%).
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Squamous Non-Small Cell Lung Cancer (NSCLC)
- Necitumumab is indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with metastatic squamous non-small cell lung cancer.
- Limitation of Use: Necitumumab is not indicated for treatment of non-squamous non-small cell lung cancer.
- Recommended Dose and Schedule
- The recommended dose of Necitumumab is 800 mg administered as an intravenous infusion over 60 minutes on Days 1 and 8 of each 3-week cycle prior to gemcitabine and cisplatin infusion. Continue Necitumumab until disease progression or unacceptable toxicity.
- Premedication
- For patients who have experienced a previous Grade 1 or 2 infusion-related reaction (IRR), pre-medicate with diphenhydramine hydrochloride (or equivalent) prior to all subsequent Necitumumab infusions.
- For patients who have experienced a second Grade 1 or 2 occurrence of IRR, pre-medicate for all subsequent infusions, with diphenhydramine hydrochloride (or equivalent), acetaminophen (or equivalent), and dexamethasone (or equivalent) prior to each Necitumumab infusion.
- Dose Modifications
- Infusion-Related Reactions (IRR)
- Reduce the infusion rate of Necitumumab by 50% for Grade 1 IRR.
- Stop the infusion for Grade 2 IRR until signs and symptoms have resolved to Grade 0 or 1; resume Necitumumab at 50% reduced rate for all subsequent infusions.
- Permanently discontinue Necitumumab for Grade 3 or 4 IRR.
- Dermatologic Toxicity
- Withhold Necitumumab for Grade 3 rash or acneiform rash until symptoms resolve to Grade ≤2, then resume Necitumumab at reduced dose of 400 mg for at least 1 treatment cycle. If symptoms do not worsen, may increase dose to 600 mg and 800 mg in subsequent cycles.
- Permanently discontinue Necitumumab if:
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Necitumumab in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Necitumumab in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
The safety and effectiveness of Necitumumab have not been established in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Necitumumab in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Necitumumab in pediatric patients.
# Contraindications
None
# Warnings
Cardiopulmonary arrest or sudden death occurred in 15 (3%) of 538 patients treated with Necitumumab plus gemcitabine and cisplatin as compared to 3 (0.6%) of 541 patients treated with gemcitabine and cisplatin alone in Study 1. Twelve of the fifteen patients died within 30 days of the last dose of Necitumumab and had comorbid conditions including history of coronary artery disease (n=3), hypomagnesemia (n=4), chronic obstructive pulmonary disease (n=7), and hypertension (n=5). Eleven of the 12 patients had an unwitnessed death. Patients with significant coronary artery disease, myocardial infarction within 6 months, uncontrolled hypertension, and uncontrolled congestive heart failure were not enrolled in Study 1. The incremental risk of cardiopulmonary arrest or sudden death in patients with a history of coronary artery disease, congestive heart failure, or arrhythmias as compared to those without these comorbid conditions is not known.
Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium prior to each infusion of Necitumumab during treatment and after Necitumumab administration for at least 8 weeks after the last dose. Withhold Necitumumab for Grade 3 or 4 electrolyte abnormalities; subsequent cycles of Necitumumab may be administered in these patients once electrolyte abnormalities have improved to Grade ≤2. Replete electrolytes as medically appropriate.
Hypomagnesemia occurred in 83% of 461/538 patients with available laboratory results treated with Necitumumab as compared to 70% of 457/541 patients with available laboratory results treated with gemcitabine and cisplatin alone in Study 1. Hypomagnesemia was severe (Grade 3 or 4) in 20% of the patients treated with Necitumumab compared to 7% of the patients treated with gemcitabine and cisplatin alone. The median time to development of hypomagnesemia and accompanying electrolyte abnormalities was 6 weeks (25th percentile 4 weeks; 75th percentile 9 weeks) after initiation of Necitumumab. Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each infusion of Necitumumab during treatment and for at least 8 weeks following the completion of Necitumumab. Withhold Necitumumab for Grade 3 or 4 electrolyte abnormalities; subsequent cycles of Necitumumab may be administered in these patients once hypomagnesemia and related electrolyte abnormalities have improved to Grade ≤2. Replete electrolytes as medically appropriate.
Venous and arterial thromboembolic events (VTE and ATE), some fatal, were observed with Necitumumab in combination with gemcitabine and cisplatin. In Study 1, the incidence of VTE was 9% in patients receiving Necitumumab plus gemcitabine and cisplatin versus 5% in patients receiving gemcitabine and cisplatin alone and the incidence of Grade 3 or higher VTE was 5% versus 3%, respectively. The incidence of fatal VTEs was similar between arms (0.2% versus 0.2%). The most common VTEs were pulmonary embolism (5%) and deep-vein thrombosis (2%).
The incidence of ATEs of any grade was 5% versus 4% and the incidence of Grade 3 or higher ATE was 4% versus 2% in the Necitumumab containing and gemcitabine and cisplatin arms, respectively, in Study 1. The most common ATEs were cerebral stroke and ischemia (2%) and myocardial infarction (1%).
In an exploratory analysis of Study 1, the relative risk of VTE or ATE was approximately 3-fold higher in patients with a reported history of VTE or ATE than in patients with no reported history of VTE or ATE.
Discontinue Necitumumab for patients with serious or life threatening VTE or ATE.
Dermatologic toxicities, including rash, dermatitis acneiform, acne, dry skin, pruritus, generalized rash, skin fissures, maculo-papular rash and erythema, occurred in 79% of patients receiving Necitumumab in Study 1. Skin toxicity was severe in 8% of patients. Skin toxicity usually developed within the first 2 weeks of therapy and resolved within 17 weeks after onset. For Grade 3 skin reactions, modify the dose of Necitumumab. Limit sun exposure.
Discontinue Necitumumab for severe (Grade 4) skin reactions, or for Grade 3 skin induration/fibrosis.
In Study 1, 1.5% of Necitumumab treated patients experienced IRRs of any severity with 0.4% Grade 3 IRR. No patients received premedication for IRR for the first dose of Necitumumab in Study 1. Most IRRs occurred after the first or second administration of Necitumumab. Monitor patients during and following Necitumumab infusion for signs and symptoms of IRR. Discontinue Necitumumab for serious or life-threatening IRR.
Necitumumab is not indicated for the treatment of patients with non-squamous NSCLC. In a study of Necitumumab plus pemetrexed and cisplatin (PC) versus PC alone (Study 2), patients treated with Necitumumab and PC experienced more serious (51% versus 41%) and fatal toxicities (16% versus 10%) and cardiopulmonary arrest/sudden death within 30 days of the last study drug (3.3% versus 1.3%) compared to patients who received PC alone.
Based on animal data and its mechanism of action, Necitumumab can cause fetal harm when administered to a pregnant woman. Disruption or depletion of EGFR in animal models results in impairment of embryofetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR signaling has resulted in embryolethality as well as post-natal death in animals. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Necitumumab and for three months following the final dose.
# Adverse Reactions
## Clinical Trials Experience
The following adverse drug reactions are discussed in greater detail in other sections of the label:
- Cardiopulmonary Arrest
- Hypomagnesemia
- Venous and Arterial Thromboembolic Events
- Dermatologic Toxicities
- Infusion-Related Reactions
- Non-Squamous NSCLC - Increased Toxicity and Increased Mortality
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 Necitumumab was evaluated in two randomized, open-label trials comparing Necitumumab plus gemcitabine and cisplatin to gemcitabine and cisplatin alone in patients with squamous NSCLC (Study 1), and Necitumumab plus pemetrexed and cisplatin to pemetrexed and cisplatin alone in patients with non-squamous NSCLC (Study 2). Since the data in Study 2 demonstrated similar incidence of adverse reactions over control as observed in Study 1, the safety data from Study 1 alone is described below.
For patients who received at least 1 dose of treatment in Study 1, the median age was 62 years (range 32 to 84), 83% were male; 84% were Caucasian; and 92% were smokers. Baseline ECOG performance status was 0 or 1 for 91%, and 2 for 9% of patients; 90% had metastatic disease in 2 or more sites. Patients received Necitumumab 800 mg intravenously on days 1 and 8 of each 21 day cycle in combination with up to six cycles of gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin (75 mg/m2 on day 1). Patients received Necitumumab until progressive disease or unacceptable toxicity.
Patients in the gemcitabine and cisplatin alone arm received a maximum of 6 cycles, while patients in the Necitumumab plus gemcitabine and cisplatin arm demonstrating at least stable disease were permitted to continue to receive additional cycles of Necitumumab until disease progression or unacceptable toxicity. The median duration of exposure to Necitumumab in 538 patients who received at least 1 dose of treatment in Study 1 was 4.6 months (range 0.5 months to 34 months), including 182 patients exposed for at least 6 months and 41 patients exposed for greater than 1 year. Patients were monitored for safety until 30 days after treatment discontinuation and resolution of treatment-emergent adverse events.
The most common adverse reactions (all grades) observed in Necitumumab-treated patients at a rate of ≥15% and ≥2% higher than gemcitabine and cisplatin alone were rash (44%), vomiting (29%), diarrhea (16%), and dermatitis acneiform (15%). The most common severe (Grade 3 or higher) adverse events that occurred at a ≥2% higher rate in Necitumumab-treated patients compared to patients treated with gemcitabine and cisplatin alone were venous thromboembolic events (5%; including pulmonary embolism), rash (4%), and vomiting (3%).
TABLE 1 contains selected adverse drug reactions observed in Study 1 at an incidence of ≥5% in the Necitumumab arm and at ≥2% higher incidence than the control arm.
- Table 1: Adverse Reactions Occurring at Incidence Rate ≥5% All Grades or a ≥2% Grade 3-4 Difference Between Arms in Patients Receiving Necitumumab in Study 1
PORTRAZZA: Necitumumab's Brand name
Clinically relevant adverse reactions (all grades) reported in ≥1% and <5% of patients treated with Necitumumab were: dysphagia (3%), oropharyngeal pain (1%), muscle spasms (2%), phlebitis (2%), and hypersensitivity/IRR (1.5%).
In Study 1, 12% of the patients on the Necitumumab arm discontinued study treatment due to an adverse reaction. The most common Necitumumab related toxicity leading to Necitumumab discontinuation was skin rash (1%).
TABLE 2 contains selected electrolyte abnormalities observed in Study 1 according to laboratory assessment at an incidence of >10% in the Necitumumab arm and at >2% higher incidence than the control arm.
The median time to onset of hypomagnesemia was 6 weeks (25th percentile 4 weeks; 75th percentile 9 weeks). Hypomagnesemia was reported as resolved in 43% of the patients who received Necitumumab. In Study 1, 32% of the patients in the Necitumumab arm and 16% of the patients who received gemcitabine and cisplatin alone received magnesium replacement.
- Table 2: Electrolyte Abnormalities according to Laboratory Assessment at Incidence Rate >10% and a >2% Difference between Arms in Patients Receiving Necitumumab in Study 1(a)
PORTRAZZA: Necitumumab's Brand name
As with all therapeutic proteins, there is the potential for immunogenicity. In clinical trials, treatment-emergent anti-necitumumab antibodies (ADA) were detected in 4.1% (33/814) of patients using an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 1.4% (11/814) of patients post exposure to Necitumumab. No relationship was found between the presence of ADA and incidence of infusion-related reactions. The impact of ADA on efficacy (overall survival) could not be assessed due to the limited number of patients with treatment-emergent ADA. In Study 1, the exposure to necitumumab was lower in patients with ADA post-treatment than in patients without detectable ADA.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Necitumumab with the incidences of antibodies to other products may be misleading.
## Postmarketing Experience
There is limited information regarding Necitumumab Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Necitumumab Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): N
- Risk Summary
- Based on animal data and its mechanism of action, Necitumumab can cause fetal harm when administered to a pregnant woman. Disruption or depletion of EGFR in animal models results in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR signaling has resulted in embryolethality as well as post-natal death in animals. No animal reproduction studies have been conducted with necitumumab. There are no available data for Necitumumab exposure in pregnant women. Advise pregnant women of the potential risk to a fetus, and the risk to postnatal development.
- 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.
- Data
- Animal Data
- No animal studies have been conducted to evaluate the effect of necitumumab on reproduction and fetal development; however, based on its mechanism of action, Necitumumab can cause fetal harm or developmental anomalies. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development) and can cause developmental anomalies and early death in surviving fetuses. Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling. Human IgG1 is known to cross the placenta; therefore, necitumumab has the potential to be transmitted from the mother to the developing fetus.
- In monkeys, administration of a chimeric anti-EGFR antibody that binds to an epitope overlapping that of necitumumab during the period of organogenesis resulted in detectable exposure of the antibody in the amniotic fluid and in the serum of embryos from treated dams. While no fetal malformations or other clear teratogenic effects occurred in offspring, there was an increased incidence of embryolethality and abortions.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Necitumumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Necitumumab during labor and delivery.
### Nursing Mothers
There is no information regarding the presence of necitumumab in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from Necitumumab, advise a nursing woman not to breastfeed during treatment with Necitumumab and for three months following the final dose.
### Pediatric Use
The safety and effectiveness of Necitumumab have not been established in pediatric patients.
### Geriatic Use
Of the 545 patients in the Necitumumab plus gemcitabine and cisplatin arm in Study 1, 213 (39%) were 65 years and over, while 108 (20%) were 70 years and over. In an exploratory subgroup analysis of Study 1, the hazard ratio for overall survival in patients 70 years or older was 1.03 (95% CI: 0.75, 1.42). Of the adverse reactions listed in TABLE 1, there was a higher incidence (≥3%) of venous thromboembolic events including pulmonary embolism in patients age 70 and over compared to those who were younger than age 70.
### Gender
There is no FDA guidance on the use of Necitumumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Necitumumab with respect to specific racial populations.
### Renal Impairment
No formal studies have been conducted to evaluate the effect of renal impairment on the exposure to necitumumab. Renal function has no influence on the exposure to necitumumab based on the population pharmacokinetic analysis of data from clinical trials.
### Hepatic Impairment
No formal studies have been conducted to evaluate the effect of hepatic impairment on the exposure to necitumumab. Mild or moderate hepatic impairment has no influence on the exposure to necitumumab based on the population pharmacokinetic analysis. No patients with severe hepatic impairment were enrolled in the clinical trials with Necitumumab.
### Females of Reproductive Potential and Males
- Contraception
- Females: Based on its mechanism of action, Necitumumab can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with Necitumumab and for three months following the final dose.
### Immunocompromised Patients
There is no FDA guidance one the use of Necitumumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Preparation
Inspect vial contents for particulate matter and discoloration prior to dilution. Discard the vial if particulate matter or discoloration is identified. Store vials in a refrigerator at 2° to 8°C (36˚ to 46˚F) until time of use. Keep the vial in the outer carton in order to protect from light.
- Dilute the required volume of Necitumumab with 0.9% Sodium Chloride Injection, USP in an intravenous infusion container to a final volume of 250 mL. Do not use solutions containing dextrose.
- Gently invert the container to ensure adequate mixing.
- DO NOT FREEZE OR SHAKE the infusion solution. DO NOT dilute with other solutions or co-infuse with other electrolytes or medication.
- Store diluted infusion solution for no more than 24 hours at 2° to 8°C (36° to 46°F), or no more than 4 hours at room temperature (up to 25°C [77°F]).
- Discard vial with any unused portion of Necitumumab.
- Administration
Visually inspect the diluted solution for particulate matter and discoloration prior to administration. If particulate matter or discoloration is identified, discard the solution.
Administer diluted Necitumumab infusion via infusion pump over 60 minutes through a separate infusion line. Flush the line with 0.9% Sodium Chloride Injection, USP at the end of the infusion.
### Monitoring
There is limited information regarding Necitumumab Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Necitumumab and IV administrations.
# Overdosage
There has been limited experience with Necitumumab overdose in human clinical trials.
The highest dose of Necitumumab studied clinically in a human dose-escalation Phase 1 study was 1000 mg once a week and once every other week. Two out of 9 patients in the every other week cohort experienced dose-limiting toxicities (e.g., a combination of Grade 3 headache, vomiting, and nausea). There is no known antidote for Necitumumab overdose.
# Pharmacology
## Mechanism of Action
Necitumumab is a recombinant human lgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR) and blocks the binding of EGFR to its ligands. Expression and activation of EGFR has been correlated with malignant progression, induction of angiogenesis, and inhibition of apoptosis. Binding of necitumumab induces EGFR internalization and degradation in vitro. In vitro, binding of necitumumab also led to antibody-dependent cellular cytotoxicity (ADCC) in EGFR-expressing cells.
In in vivo studies using xenograft models of human cancer, including non-small cell lung carcinoma, administration of necitumumab to implanted mice resulted in increased antitumor activity in combination with gemcitabine and cisplatin as compared to mice receiving gemcitabine and cisplatin alone.
## Structure
Necitumumab is an anti-EGFR recombinant human monoclonal antibody of the IgG1 kappa isotype that specifically binds to the ligand binding site of the human EGFR. Necitumumab has an approximate molecular weight of 144.8 kDa. Necitumumab is produced in genetically engineered mammalian NS0 cells.
Necitumumab is a sterile, preservative free, clear to slightly opalescent and colorless to slightly yellow solution. Necitumumab is available in single-dose vials for intravenous infusion following dilution. Each vial contains 800 mg Necitumumab in 50 mL (16 mg/mL).
Each mL contains necitumumab (16 mg), citric acid anhydrous (0.256 mg), glycine (9.984 mg), mannitol (9.109 mg), polysorbate 80 (0.1 mg), sodium chloride (2.338 mg), sodium citrate dihydrate (2.55 mg), and water for injection, pH 6.0.
## Pharmacodynamics
There is limited information regarding Necitumumab Pharmacodynamics in the drug label.
## Pharmacokinetics
Based on population pharmacokinetic (popPK) analysis of serum concentration data from patients in clinical studies with Necitumumab, necitumumab exhibits dose-dependent kinetics. Following the administration of Necitumumab 800 mg on Days 1 and 8 of each 21 day cycle, the estimated mean total systemic clearance (CLtot) at steady state is 14.1 mL/h (CV=39%), the steady state volume of distribution (Vss) is 7.0 L (CV=31%) and the elimination half-life is approximately 14 days. The predicted time to reach steady state is approximately 100 days.
Specific Populations
- Effect of Age, Body Weight, Sex and Race:
- Based on the popPK analysis with data obtained in 807 patients, age (range 19-84 years), sex (75% males), and race (85% Whites) have no effect on the systemic exposure of necitumumab.
- Body weight is identified as a covariate in the popPK analysis; however, weight-based dosing is not expected to significantly decrease the variability in exposure. No dose adjustment based on body weight is necessary.
- Renal Impairment
- Patients with Renal Impairment — PopPK analysis did not identify a correlation between necitumumab exposure and renal function as assessed by estimated creatinine clearance ranging from 11-250 mL/min.
- Hepatic Impairment
- Patients with Hepatic Impairment — PopPK analysis did not identify a correlation between the exposure of necitumumab and hepatic function as assessed by alanine aminotransferase (ranging from 2-615 U/L), aspartate transaminase (ranging from 1.2-619 U/L) and total bilirubin (ranging from 0.1-106 μmol/L).
Drug Interactions
- Effect of Necitumumab on Gemcitabine and Cisplatin
- In 12 patients with advanced solid tumors who received gemcitabine and cisplatin in combination with Necitumumab, the geometric mean dose-normalized AUC of gemcitabine was increased by 22% and Cmax increased by 63% compared to administration of gemcitabine and cisplatin alone while exposure to cisplatin was unchanged.
- Effect of Gemcitabine and Cisplatin on Necitumumab
- Concomitant administration of gemcitabine and cisplatin had no effect on the exposure of necitumumab.
In Study 1, the CLtot of necitumumab was 26% higher and Css,ave was 34% lower in patients who tested positive for anti-necitumumab antibodies (ADA) post-treatment than patients who tested negative for ADA post-treatment.
## Nonclinical Toxicology
No studies have been performed to assess the potential of necitumumab for carcinogenicity or genotoxicity.
Fertility studies have not been performed with necitumumab.
# Clinical Studies
Study 1 was a randomized, multi-center open-label, controlled trial conducted in 1093 patients receiving gemcitabine and cisplatin first-line chemotherapy for metastatic squamous NSCLC. Patients were randomized (1:1) to receive Necitumumab plus gemcitabine and cisplatin or gemcitabine and cisplatin alone. Stratification factors were ECOG performance status (0, 1 versus 2) and geographic region (North America, Europe, and Australia versus South America, South Africa, and India versus Eastern Asia). Gemcitabine (1250 mg/m2, Days 1 and 8) plus cisplatin (75 mg/m2, Day 1) were administered every 3 weeks (1 cycle) for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Necitumumab (800 mg by intravenous infusion on Days 1 and 8 of each 3-week cycle) was administered prior to gemcitabine and cisplatin. Patients demonstrating at least stable disease on Necitumumab plus gemcitabine and cisplatin were to continue Necitumumab as a single agent in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of chemotherapy or if chemotherapy was discontinued for toxicity.
Of the 1093 randomized patients, the median age was 62 years (range 32 to 86), 83% were male; 84% were Caucasian; and 91% were smokers. The majority of the patients (87%) were enrolled in North America, Europe and Australia, 36 patients (3%) were enrolled at clinical sites in the U.S., 6% of the patients were enrolled in South America, South Africa and India and 8% enrolled at clinical sites in Eastern Asia. Baseline ECOG performance status was 0 or 1 for 91%, and 2 for 9% of patients; 91% had metastatic disease in 2 or more sites. In the Necitumumab plus gemcitabine and cisplatin arm, 51% of patients continued Necitumumab after completion or discontinuation of chemotherapy. Use of post-study systemic therapy was 47% in the Necitumumab plus gemcitabine and cisplatin arm, and 45% in the gemcitabine and cisplatin arm.
The main outcome measure was overall survival (OS). Investigator-assessed progression-free survival (PFS) and overall response rate (ORR) were also assessed. Overall survival and PFS were statistically significantly improved in patients randomized to receive Necitumumab plus gemcitabine and cisplatin compared to gemcitabine and cisplatin alone. There was no difference in ORR between arms, with an ORR of 31% (95% CI 27, 35) for Necitumumab plus gemcitabine and cisplatin arm and an ORR of 29% (95% CI 25, 33) for gemcitabine and cisplatin arm, p-value 0.40.
Efficacy results are shown in TABLE 3 and FIGURE 1.
- Table 3: Efficacy Results for Metastatic Squamous Non-Small Cell Lung Cancer
PORTRAZZA: Necitumumab's Brand name
- Figure 1: Kaplan-Meier Curves of Overall Survival in Patients with Metastatic Squamous Non-Small Cell Lung Cancer
PORTRAZZA: Necitumumab's Brand name
Lack of efficacy of Necitumumab in combination with pemetrexed and cisplatin for the treatment of patients with metastatic non-squamous non-small cell lung cancer was determined in one randomized, open-label, multicenter trial (Study 2). The study was closed prematurely after 633 patients were enrolled due to increased incidence of death due to any cause and of thromboembolic events in the Necitumumab arm. Patients with no prior chemotherapy for metastatic disease were randomized (1:1) to receive Necitumumab plus pemetrexed and cisplatin or pemetrexed and cisplatin alone. Stratification factors were smoking status (non-smokers versus light smokers versus smokers), ECOG performance status (0 - 1 versus 2), histology (adenocarcinoma/large cell versus others), and geographic region. Necitumumab (800 mg, Days 1 and 8 of each 3-week cycle) was administered prior to pemetrexed and cisplatin. Patients demonstrating at least stable disease on Necitumumab plus pemetrexed and cisplatin were to continue Necitumumab as a single agent in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of chemotherapy.
Of the 633 patients, 315 were randomized to Necitumumab plus pemetrexed and cisplatin arm and 318 in the pemetrexed and cisplatin arm. The median age was 61 years, 67 % were male, 93% were Caucasian and 94% had ECOG PS 0 or 1. More than 75% were smokers and 89% had adenocarcinoma histology.
The main efficacy outcome was OS. Progression-free survival and ORR were also assessed. Addition of Necitumumab to pemetrexed and cisplatin did not improve OS [HR=1.01; 95%CI (0.84, 1.21); p-value = 0.96)]; PFS [HR=0.96; 95% CI (0.8, 1.16)] or ORR (31% in the Necitumumab plus pemetrexed and cisplatin arm and 32% in the pemetrexed and cisplatin alone arm).
# How Supplied
Necitumumab is supplied in single-dose vials as a sterile, preservative-free solution:
- 800 mg/50 mL (16 mg/mL) NDC 0002-7716-01
## Storage
Store vials in a refrigerator at 2° to 8°C (36° to 46°F) until time of use. Keep the vial in the outer carton in order to protect from light. DO NOT FREEZE OR SHAKE the vial.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Hypomagnesemia
- Advise patients of risk of decreased blood levels of magnesium, potassium and calcium. Take medicines to replace the electrolytes exactly as advised by the physician.
- Venous and Arterial Thromboembolic Events
- Advise patients of increased risk of venous and arterial thromboembolic events.
- Skin reactions
- Advise patients to minimize sun exposure with protective clothing and use of sunscreen while receiving Necitumumab.
- Infusion-Related Reactions
- Advise patients to report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.
- Embryo-Fetal Toxicity
- Advise pregnant women of the potential risk to a fetus.
- Advise females of reproductive potential to use effective contraception during treatment with Necitumumab and for three months following final dose.
- Lactation
- Advise women not to breastfeed during treatment with Necitumumab and for three months following the final dose.
# Precautions with Alcohol
Alcohol-Necitumumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
PORTRAZZA™
# Look-Alike Drug Names
There is limited information regarding Necitumumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Necitumumab | |
942b88fc576d92089ea61ba369a3a967630d8fb9 | wikidoc | Neostigmine | Neostigmine
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# Overview
Neostigmine is an antidote, cholinergic cholinesterase inhibitor and autonomic central nervous system agent that is FDA approved for the treatment of the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery. Common adverse reactions include hypotension, nausea and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- BLOXIVERZ is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery.
### Dosing Information
- BLOXIVERZ should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses of BLOXIVERZ should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of BLOXIVERZ and should be used to determine the need for additional doses.
- BLOXIVERZ is for intravenous use only and should be injected slowly over a period of at least 1 minute. The BLOXIVERZ dosage is weight-based .
- Prior to BLOXIVERZ administration and until complete recovery of normal ventilation, the patient should be well ventilated and a patent airway maintained. Satisfactory recovery should be judged by adequacy of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation.
- An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with BLOXIVERZ
- Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using BLOXIVERZ.
- There must be a twitch response to the first stimulus in the TOF of at least 10% of its baseline level, i.e., the response prior to NMBA administration, prior to the administration of BLOXIVERZ.
- Prior to administration, visually inspect BLOXIVERZ for particulate matter and discoloration.
- BLOXIVERZ should be injected slowly by intravenous route over a period of at least 1 minute.
- A 0.03 mg/kg to 0.07 mg/kg dose of BLOXIVERZ will generally achieve a TOF twitch ratio of 90% (TOF0.9) within 10 to 20 minutes of administration. Dose selection should be based on the extent of spontaneous recovery that has occurred at the time of administration, the half-life of the NMBA being reversed, and whether there is a need to rapidly reverse the NMBA.
- The 0.03 mg/kg dose is recommended for:
- Reversal of NMBAs with shorter half-lives, e.g., rocuronium, or
- When the first twitch response to the TOF stimulus is substantially greater than 10% of baseline or when a second twitch is present.
- The 0.07 mg/kg dose is recommended for
- NMBAs with longer half-lives, e.g., vecuronium and pancuronium, or
- When the first twitch response is relatively weak, i.e., not substantially greater than 10% of baseline or
- There is need for more rapid recovery.
- TOF monitoring should continue to be used to evaluate the extent of recovery of neuromuscular function and the possible need for an additional dose of BLOXIVERZ.
- TOF monitoring alone should not be relied upon to determine the adequacy of reversal of neuromuscular blockade as related to a patient’s ability to adequately ventilate and maintain a patent airway following tracheal extubation.
- Patients should continue to be monitored for adequacy of reversal from NMBAs for a period of time that would assure full recovery based on the patient’s medical condition and the pharmacokinetics of neostigmine and the NMBA used.
The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less.
- An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with BLOXIVERZ. The anticholinergic agent should be administered intravenously using a separate syringe. In the presence of bradycardia, it is recommended that the anticholinergic agent be administered prior to BLOXIVERZ.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Neostigmine in adult patients.
### Non–Guideline-Supported Use
- Myasthenia gravis, When oral therapy is impractical
- Paralytic ileus - Postoperative complication
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- BLOXIVERZ is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery.
### Dosing Information
- Adult guidelines should be followed when BLOXIVERZ is administered to pediatric patients. Pediatric patients require BLOXIVERZ doses similar to those for adult patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Neostigmine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Neostigmine in pediatric patients.
# Contraindications
- BLOXIVERZ is contraindicated in patients with:
- Known hypersensitivity to neostigmine methylsulfate (known hypersensitivity reactions have included urticaria, angioedema, erythema multiforme, generalized rash, facial swelling, peripheral edema, pyrexia, flushing, hypotension, bronchospasm, bradycardia and anaphylaxis).
- With peritonitis or mechanical obstruction of the intestinal or urinary tract.
# Warnings
- Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to BLOXIVERZ to lessen the risk of bradycardia.
- BLOXIVERZ should be used with caution in patients with coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or myasthenia gravis. Because of the known pharmacology of neostigmine methylsulfate as an acetylcholinesterase inhibitor, cardiovascular effects such as bradycardia, hypotension or dysrhythmia would be anticipated. In patients with certain cardiovascular conditions such as coronary artery disease, cardiac arrhythmias or recent acute coronary syndrome, the risk of blood pressure and heart rate complications may be increased. Risk of these complications may also be increased in patients with myasthenia gravis. Standard antagonism with anticholinergics (e.g., atropine) is generally successful to mitigate the risk of cardiovascular complications.
- Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available.
- Large doses of BLOXIVERZ administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of BLOXIVERZ should be reduced if recovery from neuromuscular blockade is nearly complete.
- It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of BLOXIVERZ. Both conditions result in extreme muscle weakness but require radically different treatment.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reactions to neostigmine methylsulfate are most often attributable to exaggerated pharmacological effects, in particular, at muscarinic receptor sites. The use of an anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, may prevent or mitigate these reactions.
- Quantitative adverse event data are available from trials of neostigmine methylsulfate in which 200 adult patients were exposed to the product. The following table lists the adverse reactions that occurred with an overall frequency of 1% or greater.
## Postmarketing Experience
- The following adverse reactions have been identified during parenteral use of neostigmine methylsulfate. 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.
# Drug Interactions
- The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. Use with caution when using BLOXIVERZ with other drugs which may alter the activity of metabolizing enzymes or transporters.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- It is not known whether neostigmine methylsulfate can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. BLOXIVERZ should be given to a pregnant woman only if clearly needed.
- Animal reproduction studies have not been conducted with neostigmine methylsulfate.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Neostigmine in women who are pregnant.
### Labor and Delivery
- The effect of BLOXIVERZ on the mother and fetus with regard to labor, delivery, the need for forceps delivery or other intervention or resuscitation of the newborn, is not known.
- Cholinesterase inhibitor drugs may induce premature labor when given intravenously to pregnant women near term.
### Nursing Mothers
- It is not known whether neostigmine methylsulfate is excreted in human milk. Caution should be exercised when BLOXIVERZ is administered to a nursing woman.
### Pediatric Use
- BLOXIVERZ is approved for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery in pediatric patients of all ages.
- Recovery of neuromuscular activity occurs more rapidly with smaller doses of cholinesterase inhibitors in infants and children than in adults. However, infants and small children may be at greater risk of complications from incomplete reversal of neuromuscular blockade due to decreased respiratory reserve. The risks associated with incomplete reversal outweigh any risk from giving higher doses of BLOXIVERZ (up to 0.07 mg/kg or up to a total of 5 mg, whichever is less).
- The dose of BLOXIVERZ required to reverse neuromuscular blockade in children varies between 0.03 mg - 0.07 mg/kg, the same dose range shown to be effective in adults, and should be selected using the same criteria as used for adult patients.
- Since the blood pressure in pediatric patients, particularly infants and neonates, is sensitive to changes in heart rate, the effects of an anticholinergic agent (e.g., atropine) should be observed prior to administration of neostigmine to lessen the probability of bradycardia and hypotension.
### Geriatic Use
- Because elderly patients are more likely to have decreased renal function, BLOXIVERZ should be used with caution and monitored for a longer period in elderly patients. The duration of action of neostigmine methylsulfate is prolonged in the elderly; however, elderly patients also experience slower spontaneous recovery from neuromuscular blocking agents. Therefore, dosage adjustments are not generally needed in geriatric patients; however, they should be monitored for longer periods than younger adults to assure additional doses of BLOXIVERZ are not required. The duration of monitoring should be predicated on the anticipated duration of action for the NMBA used on the patient.
### Gender
There is no FDA guidance on the use of Neostigmine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Neostigmine with respect to specific racial populations.
### Renal Impairment
- Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects.
- Although no adjustments to BLOXIVERZ dosing appear to be warranted in patients with impaired renal function, they should be closely monitored to assure the effects of the neuromuscular blocking agent, particularly one cleared by the kidneys, do not persist beyond those of BLOXIVERZ. In this regard, the interval for re-dosing the neuromuscular blocking agent during the surgical procedure may be useful in determining whether, and to what extent, post-operative monitoring needs to be extended.
### Hepatic Impairment
- The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment have not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. No adjustments to the dosing of BLOXIVERZ appear to be warranted in patients with hepatic insufficiency. However, patients should be carefully monitored if hepatically cleared neuromuscular blocking agents were used during their surgical procedure as their duration of action may be prolonged by hepatic insufficiency whereas BLOXIVERZ, which undergoes renal elimination, will not likely be affected. This could result in the effects of the neuromuscular blocking agent outlasting those of BLOXIVERZ. This same situation may arise if the neuromuscular blocking agent has active metabolites. In this regard, the interval for re-dosing the neuromuscular blocking agent during the surgical procedure may be useful in determining whether, and to what extent, post-operative monitoring needs to be extended.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Neostigmine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Neostigmine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Neostigmine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Neostigmine and IV administrations.
# Overdosage
- Muscarinic symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia) may appear with overdosage of BLOXIVERZ (cholinergic crisis), but may be managed by the use of additional atropine or glycopyrrolate. The possibility of iatrogenic overdose can be lessened by carefully monitoring the muscle twitch response to peripheral nerve stimulation. Should overdosage occur, ventilation should be supported by artificial means until the adequacy of spontaneous respiration is assured, and cardiac function should be monitored.
- Overdosage of BLOXIVERZ can cause cholinergic crisis, which is characterized by increasing muscle weakness, and through involvement of the muscles of respiration, may result in death. Myasthenic crisis, due to an increase in the severity of the disease, is also accompanied by extreme muscle weakness and may be difficult to distinguish from cholinergic crisis on a symptomatic basis. However, such differentiation is extremely important because increases in the dose of BLOXIVERZ or other drugs in this class, in the presence of cholinergic crisis or of a refractory or “insensitive” state, could have grave consequences. The two types of crises may be differentiated by the use of edrophonium chloride as well as by clinical judgment.
- Treatment of the two conditions differs radically. Whereas the presence of myasthenic crisis requires more intensive anticholinesterase therapy, cholinergic crisis calls for the prompt withdrawal of all drugs of this type. The immediate use of atropine in cholinergic crisis is also recommended. Atropine may also be used to lessen gastrointestinal side effects or other muscarinic reactions; but such use, by masking signs of overdosage, can lead to inadvertent induction of cholinergic crisis.
# Pharmacology
## Mechanism of Action
- Neostigmine methylsulfate is a competitive cholinesterase inhibitor. By reducing the breakdown of acetylcholine, neostigmine methylsulfate induces an increase in acetylcholine in the synaptic cleft which competes for the same binding site as nondepolarizing neuromuscular blocking agents, and reverses the neuromuscular blockade.
## Structure
- Neostigmine methylsulfate, a cholinesterase inhibitor, is (m-hydroxyphenyl) trimethylammonium methylsulfate dimethylcarbamate. The structural formula is:
- Neostigmine methylsulfate is a white crystalline powder and is very soluble in water and soluble in alcohol. BLOXIVERZ is a sterile, nonpyrogenic solution intended for intravenous use.
- Each mL of the 0.5 mg/mL strength contains neostigmine methylsulfate 0.5 mg, phenol 4.5 mg (used as preservative) and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to a value of 5.5.
- Each mL of the 1 mg/mL strength contains neostigmine methylsulfate 1 mg, phenol 4.5 mg (used as preservative), and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to achieve a value of 5.5.
## Pharmacodynamics
- Neostigmine methylsulfate-induced increases in acetylcholine levels results in the potentiation of both muscarinic and nicotinic cholinergic activity. The resulting elevation of acetylcholine competes with nondepolarizing neuromuscular blocking agents to reverse neuromuscular blockade. Neostigmine methylsulfate does not readily cross the blood-brain barrier and, therefore, does not significantly affect cholinergic function in the central nervous system.
## Pharmacokinetics
- Following intravenous injection, the observed neostigmine methylsulfate volume of distribution is reported between 0.12 and 1.4 L/kg. Protein binding of neostigmine methylsulfate to human serum albumin ranges from 15 to 25%.
- Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver.
- Following intravenous injection, the reported elimination half-life of neostigmine methylsulfate is between 24 and 113 minutes. Total body clearance of neostigmine methylsulfate is reported between 1.14 and 16.7 mL/min/kg.
- Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects; elimination half-life for normal, transplant and anephric patients were 79.8 ± 48.6, 104.7 ± 64 and 181 ± 54 min (mean ± SD), respectively.
- The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment has not been studied.
- Elimination half-life of neostigmine methylsulfate in infants (2-10 months), children (1-6 years) and adults (29-48 years) were 39 ± 5 min, 48 ± 16 min, and 67 ± 8 min (mean ± SD), respectively. Observed neostigmine methylsulfate clearance for infants, children and adults were 14 ± 3, 11 ± 3 and 10 ± 2 mL/min/kg (mean ± SD), respectively.
- The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term animal studies have not been performed to evaluate the carcinogenic potential of neostigmine.
- Neostigmine methylsulfate was not mutagenic or clastogenic when evaluated in an in vitro bacterial reverse mutation assay (Ames test), an in vitro Chinese hamster ovary cell chromosomal aberration assay, or an in vivo mouse bone marrow micronucleus assay.
- Studies on the effect of neostigmine methylsulfate on fertility have not been performed.
# Clinical Studies
- The evidence for the efficacy of neostigmine methylsulfate for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery is derived from the published literature. Randomized, spontaneous-recovery or placebo-controlled studies using similar efficacy endpoints evaluated a total of 404 adult and 80 pediatric patients undergoing various surgical procedures. Patients had reductions in their recovery time from neuromuscular blockade with neostigmine methylsulfate treatment compared to spontaneous recovery.
# How Supplied
- BLOXIVERZ (Neostigmine Methylsulfate Injection, USP) is available in the following:
The vial stopper is not made with natural rubber latex.
Manufactured for:
Éclat Pharmaceuticals
Chesterfield, MO 63005 USA
## Storage
- BLOXIVERZ should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
- Protect from light. Store in carton until time of use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Neostigmine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Neostigmine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Bloxiverz
# Look-Alike Drug Names
There is limited information regarding Neostigmine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Neostigmine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Adeel Jamil, M.D. [2]
# Disclaimer
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# Overview
Neostigmine is an antidote, cholinergic cholinesterase inhibitor and autonomic central nervous system agent that is FDA approved for the treatment of the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery. Common adverse reactions include hypotension, nausea and vomiting.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- BLOXIVERZ is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery.
### Dosing Information
- BLOXIVERZ should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Doses of BLOXIVERZ should be individualized, and a peripheral nerve stimulator should be used to determine the time of initiation of BLOXIVERZ and should be used to determine the need for additional doses.
- BLOXIVERZ is for intravenous use only and should be injected slowly over a period of at least 1 minute. The BLOXIVERZ dosage is weight-based [see Dosage and Administration (2.2)].
- Prior to BLOXIVERZ administration and until complete recovery of normal ventilation, the patient should be well ventilated and a patent airway maintained. Satisfactory recovery should be judged by adequacy of skeletal muscle tone and respiratory measurements in addition to the response to peripheral nerve stimulation.
- An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with BLOXIVERZ [see Dosage and Administration (2.4)]
- Peripheral nerve stimulation devices capable of delivering a train-of-four (TOF) stimulus are essential to effectively using BLOXIVERZ.
- There must be a twitch response to the first stimulus in the TOF of at least 10% of its baseline level, i.e., the response prior to NMBA administration, prior to the administration of BLOXIVERZ.
- Prior to administration, visually inspect BLOXIVERZ for particulate matter and discoloration.
- BLOXIVERZ should be injected slowly by intravenous route over a period of at least 1 minute.
- A 0.03 mg/kg to 0.07 mg/kg dose of BLOXIVERZ will generally achieve a TOF twitch ratio of 90% (TOF0.9) within 10 to 20 minutes of administration. Dose selection should be based on the extent of spontaneous recovery that has occurred at the time of administration, the half-life of the NMBA being reversed, and whether there is a need to rapidly reverse the NMBA.
- The 0.03 mg/kg dose is recommended for:
- Reversal of NMBAs with shorter half-lives, e.g., rocuronium, or
- When the first twitch response to the TOF stimulus is substantially greater than 10% of baseline or when a second twitch is present.
- The 0.07 mg/kg dose is recommended for
- NMBAs with longer half-lives, e.g., vecuronium and pancuronium, or
- When the first twitch response is relatively weak, i.e., not substantially greater than 10% of baseline or
- There is need for more rapid recovery.
- TOF monitoring should continue to be used to evaluate the extent of recovery of neuromuscular function and the possible need for an additional dose of BLOXIVERZ.
- TOF monitoring alone should not be relied upon to determine the adequacy of reversal of neuromuscular blockade as related to a patient’s ability to adequately ventilate and maintain a patent airway following tracheal extubation.
- Patients should continue to be monitored for adequacy of reversal from NMBAs for a period of time that would assure full recovery based on the patient’s medical condition and the pharmacokinetics of neostigmine and the NMBA used.
The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less.
- An anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, should be administered prior to or concomitantly with BLOXIVERZ. The anticholinergic agent should be administered intravenously using a separate syringe. In the presence of bradycardia, it is recommended that the anticholinergic agent be administered prior to BLOXIVERZ.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Neostigmine in adult patients.
### Non–Guideline-Supported Use
- Myasthenia gravis, When oral therapy is impractical
- Paralytic ileus - Postoperative complication
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
- BLOXIVERZ is a cholinesterase inhibitor indicated for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery.
### Dosing Information
- Adult guidelines should be followed when BLOXIVERZ is administered to pediatric patients. Pediatric patients require BLOXIVERZ doses similar to those for adult patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Neostigmine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Neostigmine in pediatric patients.
# Contraindications
- BLOXIVERZ is contraindicated in patients with:
- Known hypersensitivity to neostigmine methylsulfate (known hypersensitivity reactions have included urticaria, angioedema, erythema multiforme, generalized rash, facial swelling, peripheral edema, pyrexia, flushing, hypotension, bronchospasm, bradycardia and anaphylaxis).
- With peritonitis or mechanical obstruction of the intestinal or urinary tract.
# Warnings
- Neostigmine has been associated with bradycardia. Atropine sulfate or glycopyrrolate should be administered prior to BLOXIVERZ to lessen the risk of bradycardia.
- BLOXIVERZ should be used with caution in patients with coronary artery disease, cardiac arrhythmias, recent acute coronary syndrome or myasthenia gravis. Because of the known pharmacology of neostigmine methylsulfate as an acetylcholinesterase inhibitor, cardiovascular effects such as bradycardia, hypotension or dysrhythmia would be anticipated. In patients with certain cardiovascular conditions such as coronary artery disease, cardiac arrhythmias or recent acute coronary syndrome, the risk of blood pressure and heart rate complications may be increased. Risk of these complications may also be increased in patients with myasthenia gravis. Standard antagonism with anticholinergics (e.g., atropine) is generally successful to mitigate the risk of cardiovascular complications.
- Because of the possibility of hypersensitivity, atropine and medications to treat anaphylaxis should be readily available.
- Large doses of BLOXIVERZ administered when neuromuscular blockade is minimal can produce neuromuscular dysfunction. The dose of BLOXIVERZ should be reduced if recovery from neuromuscular blockade is nearly complete.
- It is important to differentiate between myasthenic crisis and cholinergic crisis caused by overdosage of BLOXIVERZ. Both conditions result in extreme muscle weakness but require radically different treatment.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- Adverse reactions to neostigmine methylsulfate are most often attributable to exaggerated pharmacological effects, in particular, at muscarinic receptor sites. The use of an anticholinergic agent, e.g., atropine sulfate or glycopyrrolate, may prevent or mitigate these reactions.
- Quantitative adverse event data are available from trials of neostigmine methylsulfate in which 200 adult patients were exposed to the product. The following table lists the adverse reactions that occurred with an overall frequency of 1% or greater.
## Postmarketing Experience
- The following adverse reactions have been identified during parenteral use of neostigmine methylsulfate. 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.
# Drug Interactions
- The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. Use with caution when using BLOXIVERZ with other drugs which may alter the activity of metabolizing enzymes or transporters.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- It is not known whether neostigmine methylsulfate can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. BLOXIVERZ should be given to a pregnant woman only if clearly needed.
- Animal reproduction studies have not been conducted with neostigmine methylsulfate.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Neostigmine in women who are pregnant.
### Labor and Delivery
- The effect of BLOXIVERZ on the mother and fetus with regard to labor, delivery, the need for forceps delivery or other intervention or resuscitation of the newborn, is not known.
- Cholinesterase inhibitor drugs may induce premature labor when given intravenously to pregnant women near term.
### Nursing Mothers
- It is not known whether neostigmine methylsulfate is excreted in human milk. Caution should be exercised when BLOXIVERZ is administered to a nursing woman.
### Pediatric Use
- BLOXIVERZ is approved for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery in pediatric patients of all ages.
- Recovery of neuromuscular activity occurs more rapidly with smaller doses of cholinesterase inhibitors in infants and children than in adults. However, infants and small children may be at greater risk of complications from incomplete reversal of neuromuscular blockade due to decreased respiratory reserve. The risks associated with incomplete reversal outweigh any risk from giving higher doses of BLOXIVERZ (up to 0.07 mg/kg or up to a total of 5 mg, whichever is less).
- The dose of BLOXIVERZ required to reverse neuromuscular blockade in children varies between 0.03 mg - 0.07 mg/kg, the same dose range shown to be effective in adults, and should be selected using the same criteria as used for adult patients. [see Clinical Pharmacology (12.3)]
- Since the blood pressure in pediatric patients, particularly infants and neonates, is sensitive to changes in heart rate, the effects of an anticholinergic agent (e.g., atropine) should be observed prior to administration of neostigmine to lessen the probability of bradycardia and hypotension.
### Geriatic Use
- Because elderly patients are more likely to have decreased renal function, BLOXIVERZ should be used with caution and monitored for a longer period in elderly patients. The duration of action of neostigmine methylsulfate is prolonged in the elderly; however, elderly patients also experience slower spontaneous recovery from neuromuscular blocking agents. Therefore, dosage adjustments are not generally needed in geriatric patients; however, they should be monitored for longer periods than younger adults to assure additional doses of BLOXIVERZ are not required. The duration of monitoring should be predicated on the anticipated duration of action for the NMBA used on the patient.
### Gender
There is no FDA guidance on the use of Neostigmine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Neostigmine with respect to specific racial populations.
### Renal Impairment
- Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects.
- Although no adjustments to BLOXIVERZ dosing appear to be warranted in patients with impaired renal function, they should be closely monitored to assure the effects of the neuromuscular blocking agent, particularly one cleared by the kidneys, do not persist beyond those of BLOXIVERZ. In this regard, the interval for re-dosing the neuromuscular blocking agent during the surgical procedure may be useful in determining whether, and to what extent, post-operative monitoring needs to be extended.
### Hepatic Impairment
- The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment have not been studied. Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver. No adjustments to the dosing of BLOXIVERZ appear to be warranted in patients with hepatic insufficiency. However, patients should be carefully monitored if hepatically cleared neuromuscular blocking agents were used during their surgical procedure as their duration of action may be prolonged by hepatic insufficiency whereas BLOXIVERZ, which undergoes renal elimination, will not likely be affected. This could result in the effects of the neuromuscular blocking agent outlasting those of BLOXIVERZ. This same situation may arise if the neuromuscular blocking agent has active metabolites. In this regard, the interval for re-dosing the neuromuscular blocking agent during the surgical procedure may be useful in determining whether, and to what extent, post-operative monitoring needs to be extended.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Neostigmine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Neostigmine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Neostigmine Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Neostigmine and IV administrations.
# Overdosage
- Muscarinic symptoms (nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia) may appear with overdosage of BLOXIVERZ (cholinergic crisis), but may be managed by the use of additional atropine or glycopyrrolate. The possibility of iatrogenic overdose can be lessened by carefully monitoring the muscle twitch response to peripheral nerve stimulation. Should overdosage occur, ventilation should be supported by artificial means until the adequacy of spontaneous respiration is assured, and cardiac function should be monitored.
- Overdosage of BLOXIVERZ can cause cholinergic crisis, which is characterized by increasing muscle weakness, and through involvement of the muscles of respiration, may result in death. Myasthenic crisis, due to an increase in the severity of the disease, is also accompanied by extreme muscle weakness and may be difficult to distinguish from cholinergic crisis on a symptomatic basis. However, such differentiation is extremely important because increases in the dose of BLOXIVERZ or other drugs in this class, in the presence of cholinergic crisis or of a refractory or “insensitive” state, could have grave consequences. The two types of crises may be differentiated by the use of edrophonium chloride as well as by clinical judgment.
- Treatment of the two conditions differs radically. Whereas the presence of myasthenic crisis requires more intensive anticholinesterase therapy, cholinergic crisis calls for the prompt withdrawal of all drugs of this type. The immediate use of atropine in cholinergic crisis is also recommended. Atropine may also be used to lessen gastrointestinal side effects or other muscarinic reactions; but such use, by masking signs of overdosage, can lead to inadvertent induction of cholinergic crisis.
# Pharmacology
## Mechanism of Action
- Neostigmine methylsulfate is a competitive cholinesterase inhibitor. By reducing the breakdown of acetylcholine, neostigmine methylsulfate induces an increase in acetylcholine in the synaptic cleft which competes for the same binding site as nondepolarizing neuromuscular blocking agents, and reverses the neuromuscular blockade.
## Structure
- Neostigmine methylsulfate, a cholinesterase inhibitor, is (m-hydroxyphenyl) trimethylammonium methylsulfate dimethylcarbamate. The structural formula is:
- Neostigmine methylsulfate is a white crystalline powder and is very soluble in water and soluble in alcohol. BLOXIVERZ is a sterile, nonpyrogenic solution intended for intravenous use.
- Each mL of the 0.5 mg/mL strength contains neostigmine methylsulfate 0.5 mg, phenol 4.5 mg (used as preservative) and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to a value of 5.5.
- Each mL of the 1 mg/mL strength contains neostigmine methylsulfate 1 mg, phenol 4.5 mg (used as preservative), and sodium acetate trihydrate 0.2 mg, in water for injection. The pH is adjusted, when necessary, with acetic acid/sodium hydroxide to achieve a value of 5.5.
## Pharmacodynamics
- Neostigmine methylsulfate-induced increases in acetylcholine levels results in the potentiation of both muscarinic and nicotinic cholinergic activity. The resulting elevation of acetylcholine competes with nondepolarizing neuromuscular blocking agents to reverse neuromuscular blockade. Neostigmine methylsulfate does not readily cross the blood-brain barrier and, therefore, does not significantly affect cholinergic function in the central nervous system.
## Pharmacokinetics
- Following intravenous injection, the observed neostigmine methylsulfate volume of distribution is reported between 0.12 and 1.4 L/kg. Protein binding of neostigmine methylsulfate to human serum albumin ranges from 15 to 25%.
- Neostigmine methylsulfate is metabolized by microsomal enzymes in the liver.
- Following intravenous injection, the reported elimination half-life of neostigmine methylsulfate is between 24 and 113 minutes. Total body clearance of neostigmine methylsulfate is reported between 1.14 and 16.7 mL/min/kg.
- Elimination half-life of neostigmine methylsulfate was prolonged in anephric patients compared to normal subjects; elimination half-life for normal, transplant and anephric patients were 79.8 ± 48.6, 104.7 ± 64 and 181 ± 54 min (mean ± SD), respectively.
- The pharmacokinetics of neostigmine methylsulfate in patients with hepatic impairment has not been studied.
- Elimination half-life of neostigmine methylsulfate in infants (2-10 months), children (1-6 years) and adults (29-48 years) were 39 ± 5 min, 48 ± 16 min, and 67 ± 8 min (mean ± SD), respectively. Observed neostigmine methylsulfate clearance for infants, children and adults were 14 ± 3, 11 ± 3 and 10 ± 2 mL/min/kg (mean ± SD), respectively.
- The pharmacokinetic interaction between neostigmine methylsulfate and other drugs has not been studied.
## Nonclinical Toxicology
### Carcinogenesis, Mutagenesis, Impairment of Fertility
- Long-term animal studies have not been performed to evaluate the carcinogenic potential of neostigmine.
- Neostigmine methylsulfate was not mutagenic or clastogenic when evaluated in an in vitro bacterial reverse mutation assay (Ames test), an in vitro Chinese hamster ovary cell chromosomal aberration assay, or an in vivo mouse bone marrow micronucleus assay.
- Studies on the effect of neostigmine methylsulfate on fertility have not been performed.
# Clinical Studies
- The evidence for the efficacy of neostigmine methylsulfate for the reversal of the effects of non-depolarizing neuromuscular blocking agents after surgery is derived from the published literature. Randomized, spontaneous-recovery or placebo-controlled studies using similar efficacy endpoints evaluated a total of 404 adult and 80 pediatric patients undergoing various surgical procedures. Patients had reductions in their recovery time from neuromuscular blockade with neostigmine methylsulfate treatment compared to spontaneous recovery.
# How Supplied
- BLOXIVERZ (Neostigmine Methylsulfate Injection, USP) is available in the following:
The vial stopper is not made with natural rubber latex.
Manufactured for:
Éclat Pharmaceuticals
Chesterfield, MO 63005 USA
## Storage
- BLOXIVERZ should be stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F).
- Protect from light. Store in carton until time of use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Neostigmine Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Neostigmine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Bloxiverz
# Look-Alike Drug Names
There is limited information regarding Neostigmine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Neostigmine | |
31299ad22b6793eae929eba39a53afc59046d986 | wikidoc | Nephrostomy | Nephrostomy
# Overview
A nephrostomy is an artificial opening created between the kidney and the skin which allows for the drainage of urine directly from the upper part of the urinary system (renal pelvis).
# Indications
A nephrostomy is performed whenever a blockage keeps urine from passing from the kidneys, through the ureter and into the urinary bladder. Without another way for urine to drain, pressure would rise within the urinary system and the kidneys would be damaged.
The most common cause of blockage necessitating a nephrostomy is cancer, especially ovarian cancer and colon cancer. Nephrostomies may also be required to treat pyonephrosis and kidney stones.
# Procedure
Nephrostomies are created by surgeons or interventional radiologists and typically consist of a catheter which pierces the skin and rests in the urinary tract.
Urine is collected in an external bag which can be emptied as often as necessary.
# Complications
- Acute bleeding (< 5%)
- Delayed hemorrhage (< 0.5%)
- Emergency arterial embolization of the kidney (< 0.5%)
- Failed access (< 5%)
- Infection leading to septicemia (< 1%)
- Intraperitoneal injury (< 1%)
- Mortality (< 0.05%)
- Nephrectomy (< 0.2%)
- Perforation of the collecting system (< 30%)
- Periorgan injury, including bowel perforation, splenic injury, and liver injury (< 1%)
- Pleural effusion, hydrothorax, and pneumothorax (< 13%)
- Significant loss of functioning renal tissue (< 1%) | Nephrostomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A nephrostomy is an artificial opening created between the kidney and the skin which allows for the drainage of urine directly from the upper part of the urinary system (renal pelvis).
# Indications
A nephrostomy is performed whenever a blockage keeps urine from passing from the kidneys, through the ureter and into the urinary bladder. Without another way for urine to drain, pressure would rise within the urinary system and the kidneys would be damaged.
The most common cause of blockage necessitating a nephrostomy is cancer, especially ovarian cancer and colon cancer. Nephrostomies may also be required to treat pyonephrosis and kidney stones[1].
# Procedure
Nephrostomies are created by surgeons or interventional radiologists and typically consist of a catheter which pierces the skin and rests in the urinary tract.
Urine is collected in an external bag which can be emptied as often as necessary[1].
# Complications
- Acute bleeding (< 5%)
- Delayed hemorrhage (< 0.5%)
- Emergency arterial embolization of the kidney (< 0.5%)
- Failed access (< 5%)
- Infection leading to septicemia (< 1%)
- Intraperitoneal injury (< 1%)
- Mortality (< 0.05%)
- Nephrectomy (< 0.2%)
- Perforation of the collecting system (< 30%)
- Periorgan injury, including bowel perforation, splenic injury, and liver injury (< 1%)
- Pleural effusion, hydrothorax, and pneumothorax (< 13%)
- Significant loss of functioning renal tissue (< 1%) | https://www.wikidoc.org/index.php/Nephrostomy | |
a798344db964be63e4a3e57ee6bd8ef79ad6588e | wikidoc | Nerve agent | Nerve agent
Nerve agents (also known as nerve gases, though these chemicals are liquid at room temperature) are a class of phosphorus-containing organic chemicals (organophosphates) that disrupt the mechanism by which nerves transfer messages to organs. The disruption is caused by blocking acetylcholinesterase, an enzyme that normally relaxes the activity of acetylcholine, a neurotransmitter.
As chemical weapons, they are classified as weapons of mass destruction by the United Nations according to UN Resolution 687, and their production and stockpiling was outlawed by the Chemical Weapons Convention of 1993; the Chemical Weapons Convention officially took effect on April 29, 1997.
Poisoning by a nerve agent leads to contraction of pupils, profuse salivation, convulsions, involuntary urination and defecation, and eventual death by asphyxiation as control is lost over respiratory muscles. Some nerve agents are readily vaporized or aerosolized and the primary portal of entry into the body is the respiratory system. Nerve agents can also be absorbed through the skin, requiring that those likely to be subjected to such agents wear a full body suit in addition to a respirator.
# Biological effects
As their name suggests, nerve agents attack the nervous system of the human body. All such agents function the same way: by interrupting the breakdown of the neurotransmitters that signal muscles to contract, preventing them from relaxing.
Initial symptoms following exposure to sarin (and other nerve agents) are a runny nose, tightness in the chest and constriction of the pupils. Soon after, the victim will then have difficulty breathing, and will experience nausea and drooling. As the victim continues to lose control of his or her bodily functions, he or she will involuntarily salivate, lacrimate, urinate, defecate, experience gastrointestinal pain, and emesis (vomiting). This phase is followed by twitching and jerking, and ultimately the victim will become comatose and suffocate as a consequence of convulsive spasms.
The effects of nerve agents are very long lasting and cumulative (increased successive exposures), and survivors of nerve agent poisoning almost invariably suffer chronic neurological damage.
## Mechanism of action
When a normally functioning motor nerve is stimulated it releases the neurotransmitter acetylcholine, which transmits the impulse to a muscle or organ. Once the impulse is sent, the enzyme acetylcholine esterase immediately breaks down the acetylcholine in order to allow the muscle or organ to relax.
Nerve agents disrupt the nervous system by inhibiting the enzyme acetylcholine esterase by forming a covalent bond with the site of the enzyme where acetylcholine normally undergoes hydrolysis (breaks down). The result is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted, and muscle contractions do not stop.
This same action also occurs at the gland and organ levels, resulting in uncontrolled drooling, tearing of the eyes (lacrimation), and excess production of mucous from the nose (rhinorrhea).
## Antidotes
Atropine and related anticholinergic drugs (some synthetic anticholinergics, such as biperiden may counteract the central symptoms of nerve agent poisoning better than atropine, since they pass the blood-brain barrier better than atropine) act as antidotes to nerve agent poisoning because they block acetylcholine receptors, but they are poisonous in their own right. While they will save the life of a person affected with nerve agents, that person may be incapacitated briefly or for an extended period of time, depending on the amount of exposure. The endpoint of atropine administration is the clearing of bronchial secretions. Atropine for field use by military personnel is often loaded in an autoinjector, for ease of use in stressful conditions (See Mark I NAAK).
Pralidoxime chloride, also known as 2-PAM chloride, is also used as an antidote. Rather than counteracting the initial effects of the nerve agent on the nervous system like atropine, pralidoxime chloride actually re-activates the poisoned enzyme (acetylcholinesterase) by "scavenging" the phosphoryl rest attached on the functional hydroxyl group of the enzyme. Though safer to use, it takes a longer time to have an effect.
Recent scientific breakthroughs have seen antidotes being produced in the milk of genetically modified goats.
# Classes
There are two main classes of nerve agents. The members of the two classes share similar properties, and are given both a common name (such as sarin), and a two-character NATO identifier (such as GB).
## G-Series
The G-series is thus named because German scientists first synthesized them. All of the compounds in this class were discovered and synthesized during or soon after World War II, led by Dr. Gerhard Schrader (later under the employment of I.G. Farben).
This series is the first and oldest family of nerve agents. The first nerve agent ever synthesised was GA (tabun) in 1936. GB (sarin) was discovered next in 1938, followed by GD (soman) in 1944 and finally the more obscure GF (cyclosarin) in 1949. GB was the only G agent that was fielded by the USA as a munition, specifically in rockets, aerial bombs, howitzer rounds, and gun rounds.
## V-Series
The V-series is the second family of nerve agents (the V apparently standing for "venomous"), and also contains four members: VE, VG, VM, VX. The most studied agent in this family, VX, was invented in the 1950s at Porton Down in the United Kingdom. The other agents in this series have not been studied extensively, and information about them is limited. It is known, however, that the V-series agents are about 10 times more toxic than the G-agent sarin (GB).
All of the V-agents are persistent agents, meaning that these agents do not degrade or wash away easily, and can therefore remain on clothes and other surfaces for long periods. In use, this allows the V-agents to be used to blanket terrain to guide or curtail the movement of enemy ground forces. The consistency of these agents is similar to oil; as a result, the contact hazard for V-agents is primarily - but not exclusively - dermal. VX was the only V-series agent that was fielded by the USA as a munition, consisting of rockets, artillery shells, and landmines.
## Novichok agents
The Novichok (Russian for "newcomer") agents are a recently developed series of organophosphate compounds developed in the Soviet Union. The advantage to using new agents is that they have never been previously encountered. As a result:
- potentially, no specific treaties banning their possession or use exist
- existing detection and warning devices cannot detect these agents on the battlefield
- existing protective equipment (eg gasmasks) will not protect troops from being poisoned
## Insecticides
A number of insecticides, the phenothiazines, organophosphates such as dichlorvos, malathion and parathion, are nerve agents. The metabolism of insects is sufficiently different from mammals that these compounds have little effect on humans and other mammals at proper doses; but there is considerable concern about the effects of long-term exposure to these chemicals by farm workers and animals alike. At high enough doses, however, acute toxicity and death can occur through the same mechanism as other nerve agents. Organophosphate pesticide poisoning is a major cause of disability in many developing countries, and is often the preferred method of suicide. BMJ
Lately, concern has also been expressed that commercial pilots, flight attendants, and frequent fliers are being poisoned by the organophosphate jet engine oil leaking into the aircraft air conditioning system.
# History
## The discovery of nerve agents
This first class of nerve agents, the so-called G-Series, was accidentally discovered in Germany on December 23, 1936 by a research team headed by Dr. Gerhard Schrader. Since 1934, Schrader had been in charge of a laboratory in Leverkusen to develop new types of insecticides for IG Farben. While working toward his goal of improved insecticide, Schrader experimented with numerous fluorine-containing compounds, eventually leading to the preparation of tabun.
In experiments, tabun was extremely potent against insects: as little as 5 ppm of tabun killed all the leaf lice he used in his initial experiment. In January 1937, Schrader observed the effects of nerve agents on human beings first-hand when a drop of tabun spilled onto a lab bench. Within minutes he and his laboratory assistant began to experience miosis (constriction of the pupils of the eyes), dizziness, and severe shortness of breath. It took them three weeks to recover fully.
In 1935 the Nazi leadership had passed a decree that required all inventions of possible military significance to be reported to the Ministry of War, so in May of 1937 Schrader sent a sample of tabun to the chemical warfare (CW) section of the Army Weapons Office in Berlin-Spandau. Dr. Schrader was summoned to the Wehrmacht chemical lab in Berlin to give a demonstration, after which Schrader's patent application and all related research was classified. Colonel Rüdiger, head of the CW section, ordered the construction of new laboratories for the further investigation of tabun and other organophosphate compounds, and Schrader soon moved to a new laboratory at Wuppertal-Elberfeld in the Ruhr valley to continue his research in secret throughout World War II.
Three of the most widely known agents, sarin (GB), soman (GD), and tabun (GA) were also developed during this period for use as chemical warfare agents, but were not used in combat. Cyclosarin (GF) was developed somewhat later, in 1949, by the same team. The prefix "G" was used in the names of all the chemicals because they were of German origin.
## The Nazi mass production of tabun
In 1939, a pilot plant for tabun production was set up at Munster-Lager, on Luneberg heath near the German Army proving grounds at Raubkammer. In January 1940, construction began on a secret plant, code named "Hochwerk" (High factory), for the production of tabun at Dyherrnfurth an der Oder (now Brzeg Dolny in Poland), on the Oder River 40 km (24.9 miles) from Breslau (now Wrocław) in Silesia.
The plant was large, covering an area of 2.4 by 0.8 km (1.5 by 0.5 miles), and was completely self-contained, synthesizing all intermediates as well as the final product, tabun. The factory even had an underground plant for filling munitions, which were then stored at Krappitz (now Krapowice) in Upper Silesia. The plant was operated by Anorgana GmbH, a subsidiary of IG Farben, as were all other chemical weapon agent production plants in Germany at the time.
Because of the plant's deep secrecy and the difficult nature of the production process, it took from January 1940 until June 1942 for the plant to become fully operational. Many of tabun's chemical precursors were so corrosive that reaction chambers not lined with quartz or silver soon became useless. Tabun itself was so hazardous that the final processes had to be performed while enclosed in double glass-lined chambers with a stream of pressurized air circulating between the walls.
3,000 German nationals were employed at Hochwerk, all equipped with respirators and clothing constructed of a poly-layered rubber/cloth/rubber sandwich that was destroyed after the tenth wearing. Despite all precautions, there were over 300 accidents before production even began, and at least 10 workers died during the 2.5 years of operation. Some incidents cited in A Higher Form of Killing: The Secret History of Chemical and Biological Warfare are as follows:
- Four pipe fitters had liquid tabun drain onto them; they died before their rubber suits could be removed.
- A worker had 2 liters of tabun pour down the neck of his rubber suit; he died within 2 minutes.
- Seven workers were hit in the face with a stream of tabun of such force that the liquid was forced behind their respirators; only two survived despite heroic resuscitation measures.
The plant produced between 10,000 and 30,000 tons of tabun before its capture by the Soviet Army .
## Nerve agents in Nazi Germany
In mid-1939, sarin was invented, and the formula for the agent was passed to the Chemical Warfare section of the German Army Weapons Office, which ordered that it be brought into mass production for wartime use. A number of pilot plants were built, and a high-production facility was under construction (but was not finished) by the end of World War II. Estimates for total sarin production by Nazi Germany range from 500 kg to 10 tons.
During that time, German intelligence believed that the Allies also knew of these compounds, assuming that because these compounds were not discussed in the Allies' scientific journals information about them was being suppressed. Though sarin, tabun and soman were incorporated into artillery shells, the German government ultimately decided not to use nerve agents against Allied targets. The Allies didn't learn of these agents until shells filled with them were captured towards the end of the war.
This is detailed in Joseph Borkin's book The Crime and Punishment of IG Farben:
Speer, who was strongly opposed to the introduction of tabun, flew Otto Ambros, I.G.'s authority on poison gas as well as synthetic rubber, to the meeting. Hitler asked Ambros, "What is the other side doing about poison gas?" Ambros explained that the enemy, because of its greater access to ethylene, probably had a greater capacity to produce mustard gas than Germany did. Hitler interrupted to explain that he was not referring to traditional poison gases: "I understand that the countries with petroleum are in a position to make more , but Germany has a special gas, tabun. In this we have a monopoly in Germany." He specifically wanted to know whether the enemy had access to such a gas and what it was doing in this area. To Hitler's disappointment Ambros replied, "I have justified reasons to assume that tabun, too, is known abroad. I know that tabun was publicized as early as 1902, that Sarin was patented, and that these substances appeared in patents. (...) Ambros was informing Hitler of an extraordinary fact about one of Germany's most secret weapons. The essential nature of tabun and sarin had already been disclosed in the technical journals as far back as 1902, and I.G. had patented both products in 1937 and 1938. Ambros then warned Hitler that if Germany used tabun, it must face the possibility that the Allies could produce this gas in much larger quantities. Upon receiving this discouraging report, Hitler abruptly left the meeting. The nerve gases would not be used, for the time being at least, although they would continue to be produced and tested.
## The secret gets out
After World War II, the Allies recovered German artillery shells containing the three German nerve agents of the day, prompting further research into nerve agents by the former Allies. In 1952, researchers in Porton Down, England invented the VX nerve agent, but soon abandoned the project. In 1958 the British government traded their VX technology with the United States of America in exchange for information on thermonuclear weapons; by 1961 the US was producing large amounts of VX, and performed its own nerve agent research. This research produced three more agents; the four agents (VE, VG, VM, VX) are collectively known as the "V-Series" class of nerve agents.
## Since World War II
To date, the only large scale use of chemical weapons, including nerve agents, was Iraq's chemical war against Iran (Iran-Iraq war of 1981-1988); the Kurdish village of Halabja was exposed to chemical weapons, reportedly including tabun. Nerve agents were not used by Iraq in the Gulf War, though a number of U.S. and UK personnel were exposed to them when the Khamisiyah chemical depot was destroyed. This and the widespread use of anticholinergic drugs as a protective treatment against nerve gas attack has been proposed as a possible cause of Gulf war syndrome.
One of the most widely publicised uses of nerve agents was the 1995 terrorist attack in which operatives of the group Aum Shinrikyo released sarin into the Tokyo subway system (see Sarin gas attack on the Tokyo subway).
## Ocean disposal of chemical weapons
In 1972, The United States Congress banned the practice of disposing chemical weapons into the ocean. However 32,000 tons of nerve and mustard agents had already been dumped into the ocean waters off of the United States by the U.S. Army. According to a 1998 report created by William Brankowitz, a deputy project manager in the U.S. Army Chemical Materials Agency, the Army created at least 26 chemical weapons dumpsites in the ocean off of at least 11 states on both the west and east coasts. Additionally due to poor records, currently they only know the rough whereabouts of half of them.
It is unknown how these dumps of chemical weapons have affected the ocean ecology—it may be responsible for some of the decline in fish populations over the past decades, but no evidence has yet proved a causal relationship between dumping and fish population decline. The steel containers they are contained within face a variable rate of decay and no one is really certain where or how deep they were dumped. If a nerve agent leaks into the ocean, it can last up to six weeks, during which time it will kill every susceptible organism it touches before it breaks down into its nonlethal chemical components.
# Popular culture
As a weapon of fear and terror, nerve agents are quickly becoming a staple in the plots of television, cinema, and video games. In most implementations of this plot, a shadowy terrorist organization obtains a quantity of nerve agent and threatens to release it in a population center.
A fictional nerve agent, ZV, is an integral part of the story line for John Lange's (a pseudonym of Michael Crichton) 1972 novel Binary. The effects of this agent were the same as the V-series agents and the book mentions these other agents although it does not mention other existing binary nerve agents such as the G-series or VX.
In Mobile Suit Zeta Gundam, a fictional nerve agent called G3 is used against space colonists by the Earth Federation's Titans organization, setting off a chain of events culminating in the destruction of said group.
Nerve agents are among the armaments of the future Colonial Marines in the 1986 film Aliens, in which the character Vasquez suggests the use of fictional "CN-20" against an alien hive.
In the 1996 action movie, The Rock, a retired US Marine Brigadier General blackmails the government by threatening to attack San Francisco with rockets armed with VX gas. The film contained numerous inaccuracies, not the least of which including the description (and visual effects) of how VX affects a person: "your muscles freeze, you can't breathe, you spasm so hard you break your own back, spit your guts out--but that's after your skin melts off." Unlike the movie, atropine carried by actual U.S. military personnel is in the form of a sprung "auto-injector" which is applied to the thigh (not a long needle jabbed into the heart), and it is always followed by another injector containing 2-PAM Chloride. Also, and perhaps more glaringly erroneous (though theatrically horrific), VX does not melt skin.
In the 2002 movie XXX, a terrorist group called Anarchy-99 produces a fictitious binary nerve agent called "Silent Night," which decomposed and became harmless when passed through water.
In the movie Saw II, sarin is the nerve agent that the Jigsaw Killer uses as part of his game. However, his brief description of sarin's effects is inaccurate, as is much of the film's representation of how it works: it is highly improbable that the characters exposed to the gas would remain unaffected as long as they did. In addition, as sarin is an irreversible anticholinesterase inhibitor, its effects are permanent; no antidote, even if it were to exist, would be effective unless administered immediately following exposure.
This plot device was adopted by video game designers as well. For example, Tom Clancy's Rainbow Six 3: Raven Shield featured terrorists that attempted to poison the food supply with VX nerve agent. Also, it was the new deadly threat in Syphon Filter: Dark Mirror, where the nerve gas, Project Dark Mirror, was said to blend with oxygen, making it more lethal.
Before long, nerve agents began to appear on television. For example, VX was featured in the British television series Spooks as part of a simulated attack on the center of London, and recently, on season 5 of the primetime FOX series, 24, Russian separatists manage to use a fictional, vaporised variant of VX called "Sentox VX-1" on several targets in Los Angeles.
The Doctor Who story The Mind of Evil involves the hijacking of a nerve gas missile destined to be destroyed, and in the later story Terror of the Zygons a Scottish village is drugged with a nerve gas agent. Sarin was also featured in a later series of Spooks.
Author Greg Iles uses nerve agents sarin and soman in the plot for his World War II thriller Black Cross.
The South African post-grunge band Seether was first known as "Saron Gas".
The Canadian industrial band Skinny Puppy wrote a song called "VX Gas Attack" (from the album VIVISectVI) which deals lyrically with the Iraqi VX bomb attack on Iran in 1988.
In the Gulf War biography Jarhead, the protagonist, Anthony Swofford, is given an atropine autoinjector to counter VX gas.
In the horror sci-fi film 28 Weeks Later Doyle has to cover his face to stop himself breathing in nerve gas while trying to jump start a car.
In the book World War Z, the Russian government drops VX Gas on hordes of refugees to reveal any carrying the zombie virus.
In the Steven Spielberg film Close Encounters of the Third Kind nerve gas is used as an excuse for the evacuation of the UFO landing site.
In the episode I Spy Apocalypse of the second series of spooks an EERIE exercise uses the gas as a test to evaluate the performance of the team under pressure. The gas is never released but the team are sealed on the grid and so believe that it has wiped out London .
# Footnotes
- ↑ Goats Can Foil Gas Attack
- ↑ Jump up to: 2.0 2.1 FM 3-8 Chemical Reference handbook; US Army; 1967
- ↑ Jump up to: 3.0 3.1 , Frederick Sidell | Nerve agent
Template:Chemical warfare vert
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
Nerve agents (also known as nerve gases, though these chemicals are liquid at room temperature) are a class of phosphorus-containing organic chemicals (organophosphates) that disrupt the mechanism by which nerves transfer messages to organs. The disruption is caused by blocking acetylcholinesterase, an enzyme that normally relaxes the activity of acetylcholine, a neurotransmitter.
As chemical weapons, they are classified as weapons of mass destruction by the United Nations according to UN Resolution 687, and their production and stockpiling was outlawed by the Chemical Weapons Convention of 1993; the Chemical Weapons Convention officially took effect on April 29, 1997.
[1]
Poisoning by a nerve agent leads to contraction of pupils, profuse salivation, convulsions, involuntary urination and defecation, and eventual death by asphyxiation as control is lost over respiratory muscles. Some nerve agents are readily vaporized or aerosolized and the primary portal of entry into the body is the respiratory system. Nerve agents can also be absorbed through the skin, requiring that those likely to be subjected to such agents wear a full body suit in addition to a respirator.
# Biological effects
As their name suggests, nerve agents attack the nervous system of the human body. All such agents function the same way: by interrupting the breakdown of the neurotransmitters that signal muscles to contract, preventing them from relaxing.
Initial symptoms following exposure to sarin (and other nerve agents) are a runny nose, tightness in the chest and constriction of the pupils. Soon after, the victim will then have difficulty breathing, and will experience nausea and drooling. As the victim continues to lose control of his or her bodily functions, he or she will involuntarily salivate, lacrimate, urinate, defecate, experience gastrointestinal pain, and emesis (vomiting). This phase is followed by twitching and jerking, and ultimately the victim will become comatose and suffocate as a consequence of convulsive spasms.
The effects of nerve agents are very long lasting and cumulative (increased successive exposures), and survivors of nerve agent poisoning almost invariably suffer chronic neurological damage.
## Mechanism of action
When a normally functioning motor nerve is stimulated it releases the neurotransmitter acetylcholine, which transmits the impulse to a muscle or organ. Once the impulse is sent, the enzyme acetylcholine esterase immediately breaks down the acetylcholine in order to allow the muscle or organ to relax.
Nerve agents disrupt the nervous system by inhibiting the enzyme acetylcholine esterase by forming a covalent bond with the site of the enzyme where acetylcholine normally undergoes hydrolysis (breaks down). The result is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted, and muscle contractions do not stop.
This same action also occurs at the gland and organ levels, resulting in uncontrolled drooling, tearing of the eyes (lacrimation), and excess production of mucous from the nose (rhinorrhea).
## Antidotes
Atropine and related anticholinergic drugs (some synthetic anticholinergics, such as biperiden may counteract the central symptoms of nerve agent poisoning better than atropine, since they pass the blood-brain barrier better than atropine) act as antidotes to nerve agent poisoning because they block acetylcholine receptors, but they are poisonous in their own right. While they will save the life of a person affected with nerve agents, that person may be incapacitated briefly or for an extended period of time, depending on the amount of exposure. The endpoint of atropine administration is the clearing of bronchial secretions. Atropine for field use by military personnel is often loaded in an autoinjector, for ease of use in stressful conditions (See Mark I NAAK).
Pralidoxime chloride, also known as 2-PAM chloride, is also used as an antidote. Rather than counteracting the initial effects of the nerve agent on the nervous system like atropine, pralidoxime chloride actually re-activates the poisoned enzyme (acetylcholinesterase) by "scavenging" the phosphoryl rest attached on the functional hydroxyl group of the enzyme. Though safer to use, it takes a longer time to have an effect.
Recent scientific breakthroughs have seen antidotes being produced in the milk of genetically modified goats.[1]
# Classes
There are two main classes of nerve agents. The members of the two classes share similar properties, and are given both a common name (such as sarin), and a two-character NATO identifier (such as GB).
## G-Series
The G-series is thus named because German scientists first synthesized them. All of the compounds in this class were discovered and synthesized during or soon after World War II, led by Dr. Gerhard Schrader (later under the employment of I.G. Farben).
This series is the first and oldest family of nerve agents. The first nerve agent ever synthesised was GA (tabun) in 1936. GB (sarin) was discovered next in 1938, followed by GD (soman) in 1944 and finally the more obscure GF (cyclosarin) in 1949. GB was the only G agent that was fielded by the USA as a munition, specifically in rockets, aerial bombs, howitzer rounds, and gun rounds[2].
## V-Series
The V-series is the second family of nerve agents (the V apparently standing for "venomous"), and also contains four members: VE, VG, VM, VX. The most studied agent in this family, VX, was invented in the 1950s at Porton Down in the United Kingdom. The other agents in this series have not been studied extensively, and information about them is limited. It is known, however, that the V-series agents are about 10 times more toxic than the G-agent sarin (GB).
All of the V-agents are persistent agents, meaning that these agents do not degrade or wash away easily, and can therefore remain on clothes and other surfaces for long periods. In use, this allows the V-agents to be used to blanket terrain to guide or curtail the movement of enemy ground forces. The consistency of these agents is similar to oil; as a result, the contact hazard for V-agents is primarily - but not exclusively - dermal. VX was the only V-series agent that was fielded by the USA as a munition, consisting of rockets, artillery shells, and landmines[2].
## Novichok agents
The Novichok (Russian for "newcomer") agents are a recently developed series of organophosphate compounds developed in the Soviet Union. The advantage to using new agents is that they have never been previously encountered. As a result:
- potentially, no specific treaties banning their possession or use exist
- existing detection and warning devices cannot detect these agents on the battlefield
- existing protective equipment (eg gasmasks) will not protect troops from being poisoned
## Insecticides
A number of insecticides, the phenothiazines, organophosphates such as dichlorvos, malathion and parathion, are nerve agents. The metabolism of insects is sufficiently different from mammals that these compounds have little effect on humans and other mammals at proper doses; but there is considerable concern about the effects of long-term exposure to these chemicals by farm workers and animals alike. At high enough doses, however, acute toxicity and death can occur through the same mechanism as other nerve agents. Organophosphate pesticide poisoning is a major cause of disability in many developing countries, and is often the preferred method of suicide. BMJ
Lately, concern has also been expressed that commercial pilots, flight attendants, and frequent fliers are being poisoned by the organophosphate jet engine oil leaking into the aircraft air conditioning system. [3]
# History
## The discovery of nerve agents
This first class of nerve agents, the so-called G-Series, was accidentally discovered in Germany on December 23, 1936 by a research team headed by Dr. Gerhard Schrader. Since 1934, Schrader had been in charge of a laboratory in Leverkusen to develop new types of insecticides for IG Farben. While working toward his goal of improved insecticide, Schrader experimented with numerous fluorine-containing compounds, eventually leading to the preparation of tabun.
In experiments, tabun was extremely potent against insects: as little as 5 ppm of tabun killed all the leaf lice he used in his initial experiment. In January 1937, Schrader observed the effects of nerve agents on human beings first-hand when a drop of tabun spilled onto a lab bench. Within minutes he and his laboratory assistant began to experience miosis (constriction of the pupils of the eyes), dizziness, and severe shortness of breath. It took them three weeks to recover fully.
In 1935 the Nazi leadership had passed a decree that required all inventions of possible military significance to be reported to the Ministry of War, so in May of 1937 Schrader sent a sample of tabun to the chemical warfare (CW) section of the Army Weapons Office in Berlin-Spandau. Dr. Schrader was summoned to the Wehrmacht chemical lab in Berlin to give a demonstration, after which Schrader's patent application and all related research was classified. Colonel Rüdiger, head of the CW section, ordered the construction of new laboratories for the further investigation of tabun and other organophosphate compounds, and Schrader soon moved to a new laboratory at Wuppertal-Elberfeld in the Ruhr valley to continue his research in secret throughout World War II.
Three of the most widely known agents, sarin (GB), soman (GD), and tabun (GA) were also developed during this period for use as chemical warfare agents, but were not used in combat. Cyclosarin (GF) was developed somewhat later, in 1949, by the same team. The prefix "G" was used in the names of all the chemicals because they were of German origin[3].
## The Nazi mass production of tabun
In 1939, a pilot plant for tabun production was set up at Munster-Lager, on Luneberg heath near the German Army proving grounds at Raubkammer. In January 1940, construction began on a secret plant, code named "Hochwerk" (High factory), for the production of tabun at Dyherrnfurth an der Oder (now Brzeg Dolny in Poland), on the Oder River 40 km (24.9 miles) from Breslau (now Wrocław) in Silesia.
The plant was large, covering an area of 2.4 by 0.8 km (1.5 by 0.5 miles), and was completely self-contained, synthesizing all intermediates as well as the final product, tabun. The factory even had an underground plant for filling munitions, which were then stored at Krappitz (now Krapowice) in Upper Silesia. The plant was operated by Anorgana GmbH, a subsidiary of IG Farben, as were all other chemical weapon agent production plants in Germany at the time.
Because of the plant's deep secrecy and the difficult nature of the production process, it took from January 1940 until June 1942 for the plant to become fully operational. Many of tabun's chemical precursors were so corrosive that reaction chambers not lined with quartz or silver soon became useless. Tabun itself was so hazardous that the final processes had to be performed while enclosed in double glass-lined chambers with a stream of pressurized air circulating between the walls.
3,000 German nationals were employed at Hochwerk, all equipped with respirators and clothing constructed of a poly-layered rubber/cloth/rubber sandwich that was destroyed after the tenth wearing. Despite all precautions, there were over 300 accidents before production even began, and at least 10 workers died during the 2.5 years of operation. Some incidents cited in A Higher Form of Killing: The Secret History of Chemical and Biological Warfare are as follows:
- Four pipe fitters had liquid tabun drain onto them; they died before their rubber suits could be removed.
- A worker had 2 liters of tabun pour down the neck of his rubber suit; he died within 2 minutes.
- Seven workers were hit in the face with a stream of tabun of such force that the liquid was forced behind their respirators; only two survived despite heroic resuscitation measures.
The plant produced between 10,000 and 30,000 tons of tabun before its capture by the Soviet Army [3].
## Nerve agents in Nazi Germany
In mid-1939, sarin was invented, and the formula for the agent was passed to the Chemical Warfare section of the German Army Weapons Office, which ordered that it be brought into mass production for wartime use. A number of pilot plants were built, and a high-production facility was under construction (but was not finished) by the end of World War II. Estimates for total sarin production by Nazi Germany range from 500 kg to 10 tons.
During that time, German intelligence believed that the Allies also knew of these compounds, assuming that because these compounds were not discussed in the Allies' scientific journals information about them was being suppressed. Though sarin, tabun and soman were incorporated into artillery shells, the German government ultimately decided not to use nerve agents against Allied targets. The Allies didn't learn of these agents until shells filled with them were captured towards the end of the war.
This is detailed in Joseph Borkin's book The Crime and Punishment of IG Farben:
Speer, who was strongly opposed to the introduction of tabun, flew Otto Ambros, I.G.'s authority on poison gas as well as synthetic rubber, to the meeting. Hitler asked Ambros, "What is the other side doing about poison gas?" Ambros explained that the enemy, because of its greater access to ethylene, probably had a greater capacity to produce mustard gas than Germany did. Hitler interrupted to explain that he was not referring to traditional poison gases: "I understand that the countries with petroleum are in a position to make more [mustard gas], but Germany has a special gas, tabun. In this we have a monopoly in Germany." He specifically wanted to know whether the enemy had access to such a gas and what it was doing in this area. To Hitler's disappointment Ambros replied, "I have justified reasons to assume that tabun, too, is known abroad. I know that tabun was publicized as early as 1902, that Sarin was patented, and that these substances appeared in patents. (...) Ambros was informing Hitler of an extraordinary fact about one of Germany's most secret weapons. The essential nature of tabun and sarin had already been disclosed in the technical journals as far back as 1902, and I.G. had patented both products in 1937 and 1938. Ambros then warned Hitler that if Germany used tabun, it must face the possibility that the Allies could produce this gas in much larger quantities. Upon receiving this discouraging report, Hitler abruptly left the meeting. The nerve gases would not be used, for the time being at least, although they would continue to be produced and tested.
## The secret gets out
After World War II, the Allies recovered German artillery shells containing the three German nerve agents of the day, prompting further research into nerve agents by the former Allies. In 1952, researchers in Porton Down, England invented the VX nerve agent, but soon abandoned the project. In 1958 the British government traded their VX technology with the United States of America in exchange for information on thermonuclear weapons; by 1961 the US was producing large amounts of VX, and performed its own nerve agent research. This research produced three more agents; the four agents (VE, VG, VM, VX) are collectively known as the "V-Series" class of nerve agents.
## Since World War II
To date, the only large scale use of chemical weapons, including nerve agents, was Iraq's chemical war against Iran (Iran-Iraq war of 1981-1988); the Kurdish village of Halabja was exposed to chemical weapons, reportedly including tabun. Nerve agents were not used by Iraq in the Gulf War, though a number of U.S. and UK personnel were exposed to them when the Khamisiyah chemical depot was destroyed. This and the widespread use of anticholinergic drugs as a protective treatment against nerve gas attack has been proposed as a possible cause of Gulf war syndrome.
One of the most widely publicised uses of nerve agents was the 1995 terrorist attack in which operatives of the group Aum Shinrikyo released sarin into the Tokyo subway system (see Sarin gas attack on the Tokyo subway).
## Ocean disposal of chemical weapons
In 1972, The United States Congress banned the practice of disposing chemical weapons into the ocean. However 32,000 tons of nerve and mustard agents had already been dumped into the ocean waters off of the United States by the U.S. Army. According to a 1998 report created by William Brankowitz, a deputy project manager in the U.S. Army Chemical Materials Agency, the Army created at least 26 chemical weapons dumpsites in the ocean off of at least 11 states on both the west and east coasts. Additionally due to poor records, currently they only know the rough whereabouts of half of them.
It is unknown how these dumps of chemical weapons have affected the ocean ecology—it may be responsible for some of the decline in fish populations over the past decades, but no evidence has yet proved a causal relationship between dumping and fish population decline. The steel containers they are contained within face a variable rate of decay and no one is really certain where or how deep they were dumped. If a nerve agent leaks into the ocean, it can last up to six weeks, during which time it will kill every susceptible organism it touches before it breaks down into its nonlethal chemical components.
# Popular culture
As a weapon of fear and terror, nerve agents are quickly becoming a staple in the plots of television, cinema, and video games. In most implementations of this plot, a shadowy terrorist organization obtains a quantity of nerve agent and threatens to release it in a population center.
A fictional nerve agent, ZV, is an integral part of the story line for John Lange's (a pseudonym of Michael Crichton) 1972 novel Binary. The effects of this agent were the same as the V-series agents and the book mentions these other agents although it does not mention other existing binary nerve agents such as the G-series or VX.
In Mobile Suit Zeta Gundam, a fictional nerve agent called G3 is used against space colonists by the Earth Federation's Titans organization, setting off a chain of events culminating in the destruction of said group.
Nerve agents are among the armaments of the future Colonial Marines in the 1986 film Aliens, in which the character Vasquez suggests the use of fictional "CN-20" against an alien hive.
In the 1996 action movie, The Rock, a retired US Marine Brigadier General blackmails the government by threatening to attack San Francisco with rockets armed with VX gas. The film contained numerous inaccuracies, not the least of which including the description (and visual effects) of how VX affects a person: "your muscles freeze, you can't breathe, you spasm so hard you break your own back, spit your guts out--but that's after your skin melts off." Unlike the movie, atropine carried by actual U.S. military personnel is in the form of a sprung "auto-injector" which is applied to the thigh (not a long needle jabbed into the heart), and it is always followed by another injector containing 2-PAM Chloride. Also, and perhaps more glaringly erroneous (though theatrically horrific), VX does not melt skin.
In the 2002 movie XXX, a terrorist group called Anarchy-99 produces a fictitious binary nerve agent called "Silent Night," which decomposed and became harmless when passed through water.
In the movie Saw II, sarin is the nerve agent that the Jigsaw Killer uses as part of his game. However, his brief description of sarin's effects is inaccurate, as is much of the film's representation of how it works: it is highly improbable that the characters exposed to the gas would remain unaffected as long as they did. In addition, as sarin is an irreversible anticholinesterase inhibitor, its effects are permanent; no antidote, even if it were to exist, would be effective unless administered immediately following exposure.
This plot device was adopted by video game designers as well. For example, Tom Clancy's Rainbow Six 3: Raven Shield featured terrorists that attempted to poison the food supply with VX nerve agent. Also, it was the new deadly threat in Syphon Filter: Dark Mirror, where the nerve gas, Project Dark Mirror, was said to blend with oxygen, making it more lethal.
Before long, nerve agents began to appear on television. For example, VX was featured in the British television series Spooks as part of a simulated attack on the center of London, and recently, on season 5 of the primetime FOX series, 24, Russian separatists manage to use a fictional, vaporised variant of VX called "Sentox VX-1" on several targets in Los Angeles.
The Doctor Who story The Mind of Evil involves the hijacking of a nerve gas missile destined to be destroyed, and in the later story Terror of the Zygons a Scottish village is drugged with a nerve gas agent. Sarin was also featured in a later series of Spooks.
Author Greg Iles uses nerve agents sarin and soman in the plot for his World War II thriller Black Cross.
The South African post-grunge band Seether was first known as "Saron Gas".
The Canadian industrial band Skinny Puppy wrote a song called "VX Gas Attack" (from the album VIVISectVI) which deals lyrically with the Iraqi VX bomb attack on Iran in 1988.
In the Gulf War biography Jarhead, the protagonist, Anthony Swofford, is given an atropine autoinjector to counter VX gas.
In the horror sci-fi film 28 Weeks Later Doyle has to cover his face to stop himself breathing in nerve gas while trying to jump start a car.
In the book World War Z, the Russian government drops VX Gas on hordes of refugees to reveal any carrying the zombie virus.
In the Steven Spielberg film Close Encounters of the Third Kind nerve gas is used as an excuse for the evacuation of the UFO landing site.
In the episode I Spy Apocalypse of the second series of spooks an EERIE exercise uses the gas as a test to evaluate the performance of the team under pressure. The gas is never released but the team are sealed on the grid and so believe that it has wiped out London .
# Footnotes
- ↑ Goats Can Foil Gas Attack
- ↑ Jump up to: 2.0 2.1 FM 3-8 Chemical Reference handbook; US Army; 1967
- ↑ Jump up to: 3.0 3.1 [1], Frederick Sidell | https://www.wikidoc.org/index.php/Nerve_agent | |
bdc30ec60134ee1fa424057636d4cba1b70c156c | wikidoc | Optic nerve | Optic nerve
# Anatomy
The optic nerve is the second of twelve paired cranial nerves but is considered to be part of the central nervous system as it is derived from an outpouching of the diencephalon during embryonic development. Consequently, the fibers are covered with myelin produced by oligodendrocytes rather than the Schwann cells of the peripheral nervous system. Similarly, the optic nerve is ensheathed in all three meningeal layers (dura, arachnoid, and pia mater) rather than the epineurium, perineurium, and endoneurium found in peripheral nerves. This is an important issue, as fiber tracks of the mammalian central nervous system (as opposed to the peripheral nervous system) are incapable of regeneration and hence optic nerve damage produces irreversible blindness. The fibers from the retina run along the optic nerve to nine primary visual nuclei in the brain, from whence a major relay inputs into the primary visual cortex.
The optic nerve is composed of retinal ganglion cell axons and support cells. It leaves the orbit (eye) via the optic canal, running postero-medially towards the optic chiasm where there is a partial decussation (crossing) of fibers from the temporal visual fields of both eyes. Most of the axons of the optic nerve terminate in the lateral geniculate nucleus from where information is relayed to the visual cortex. Its diameter increases from about 1.6 mm within the eye, to 3.5 mm in the orbit to 4.5 mm within the cranial space. The optic nerve component lengths are 1 mm in the globe, 25 mm in the orbit, 9 mm in the optic canal and 16 mm in the cranial space before joining the optic chiasm. There, partial decussation occurs and about 53% of the fibers cross to form the optic tracts. Most of these fibers terminate in the lateral geniculate body.
From the lateral geniculate body, fibers of the optic radiation pass to the visual cortex in the occipital lobe of the brain. More specifically, fibers carrying information from the contralateral superior visual field traverse Meyer's loop to terminate in the lingual gyrus below the calcarine fissure in the occipital lobe, and fibers carrying information from the contralateral inferior visual field terminate more superiorly.
# Physiology
The optic nerve contains 1.2 million nerve fibers. This number is low compared to the roughly 100 million photoreceptors in the retina, and implies that substantial pre-processing takes place in the retina before the signals are sent to the brain through the optic nerve.
The eye's blind spot is a result of the absence of retina where the optic nerve leaves the eye. This is because there are no photoreceptors in this area.
# Role in disease
Damage to the optic nerve typically causes permanent and potentially severe loss of vision, as well as an abnormal pupillary reflex, which is diagnostically important. The type of visual field loss will depend on which portions of the optic nerve were damaged. Generally speaking:
- Damage before the optic chiasm causes loss of vision in the visual field of the same side only.
- Damage in the chiasm causes loss of vision laterally in both visual fields (bitemporal hemianopia). It may occur in large pituitary adenomata.
- Damage after the chiasm causes loss of vision on one side but affecting both visual fields: the visual field affected is located on the opposite side of the lesion.
Injury to the optic nerve can be the result of congenital or inheritable problems like Leber's Hereditary Optic Neuropathy, glaucoma, trauma, toxicity, inflammation, ischemia, infection (very rarely), or compression from tumors or aneurysms. By far, the three most common injuries to the optic nerve are from glaucoma, optic neuritis (especially in those younger than 50 years of age) and anterior ischemic optic neuropathy (usually in those older than 50).
Glaucoma is a group of diseases involving loss of retinal ganglion cells causing optic neuropathy in a pattern of peripheral vision loss, initially sparing central vision.
Optic neuritis is inflammation of the optic nerve. It is associated with a number of diseases, most notably multiple sclerosis.
Anterior Ischemic Optic Neuropathy is a particular type of infarct that affects patients with an anatomical predisposition and cardiovascular risk factors.
Ophthalmologists, particularly those sub specialists who are neuro-ophthalmologists, are often best suited to diagnose and treat diseases of the optic nerve.
The International Foundation for Optic Nerve Diseases IFOND sponsors research and information on a variety of optic nerve disorders and may provide general direction.
# Additional images
- MRI scan of human eye showing optic nerve.
- The ophthalmic artery and its branches. (optic nerve is yellow)
- Dura mater and its processes exposed by removing part of the right half of the skull, and the brain.
- Tentorium cerebelli from above.
- Superficial dissection of brain-stem. Lateral view.
- Dissection of brain-stem. Lateral view.
- Mesal aspect of a brain sectioned in the median sagittal plane.
- Scheme showing central connections of the optic nerves and optic tracts.
- The fornix and corpus callosum from below.
- Nerves of the orbit. Seen from above.
- Nerves of the orbit, and the ciliary ganglion. Side view.
- The arteries of the choroid and iris. The greater part of the sclera has been removed.
- The veins of the choroid.
- The terminal portion of the optic nerve and its entrance into the eyeball, in horizontal section. | Optic nerve
Template:Infobox Nerve
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Anatomy
The optic nerve is the second of twelve paired cranial nerves but is considered to be part of the central nervous system as it is derived from an outpouching of the diencephalon during embryonic development. Consequently, the fibers are covered with myelin produced by oligodendrocytes rather than the Schwann cells of the peripheral nervous system. Similarly, the optic nerve is ensheathed in all three meningeal layers (dura, arachnoid, and pia mater) rather than the epineurium, perineurium, and endoneurium found in peripheral nerves. This is an important issue, as fiber tracks of the mammalian central nervous system (as opposed to the peripheral nervous system) are incapable of regeneration and hence optic nerve damage produces irreversible blindness. The fibers from the retina run along the optic nerve to nine primary visual nuclei in the brain, from whence a major relay inputs into the primary visual cortex.
The optic nerve is composed of retinal ganglion cell axons and support cells. It leaves the orbit (eye) via the optic canal, running postero-medially towards the optic chiasm where there is a partial decussation (crossing) of fibers from the temporal visual fields of both eyes. Most of the axons of the optic nerve terminate in the lateral geniculate nucleus from where information is relayed to the visual cortex. Its diameter increases from about 1.6 mm within the eye, to 3.5 mm in the orbit to 4.5 mm within the cranial space. The optic nerve component lengths are 1 mm in the globe, 25 mm in the orbit, 9 mm in the optic canal and 16 mm in the cranial space before joining the optic chiasm. There, partial decussation occurs and about 53% of the fibers cross to form the optic tracts. Most of these fibers terminate in the lateral geniculate body.
From the lateral geniculate body, fibers of the optic radiation pass to the visual cortex in the occipital lobe of the brain. More specifically, fibers carrying information from the contralateral superior visual field traverse Meyer's loop to terminate in the lingual gyrus below the calcarine fissure in the occipital lobe, and fibers carrying information from the contralateral inferior visual field terminate more superiorly.
# Physiology
The optic nerve contains 1.2 million nerve fibers. This number is low compared to the roughly 100 million photoreceptors in the retina,[1] and implies that substantial pre-processing takes place in the retina before the signals are sent to the brain through the optic nerve.
The eye's blind spot is a result of the absence of retina where the optic nerve leaves the eye. This is because there are no photoreceptors in this area.
# Role in disease
Damage to the optic nerve typically causes permanent and potentially severe loss of vision, as well as an abnormal pupillary reflex, which is diagnostically important. The type of visual field loss will depend on which portions of the optic nerve were damaged. Generally speaking:
- Damage before the optic chiasm causes loss of vision in the visual field of the same side only.
- Damage in the chiasm causes loss of vision laterally in both visual fields (bitemporal hemianopia). It may occur in large pituitary adenomata.
- Damage after the chiasm causes loss of vision on one side but affecting both visual fields: the visual field affected is located on the opposite side of the lesion.
Injury to the optic nerve can be the result of congenital or inheritable problems like Leber's Hereditary Optic Neuropathy, glaucoma, trauma, toxicity, inflammation, ischemia, infection (very rarely), or compression from tumors or aneurysms. By far, the three most common injuries to the optic nerve are from glaucoma, optic neuritis (especially in those younger than 50 years of age) and anterior ischemic optic neuropathy (usually in those older than 50).
Glaucoma is a group of diseases involving loss of retinal ganglion cells causing optic neuropathy in a pattern of peripheral vision loss, initially sparing central vision.
Optic neuritis is inflammation of the optic nerve. It is associated with a number of diseases, most notably multiple sclerosis.
Anterior Ischemic Optic Neuropathy is a particular type of infarct that affects patients with an anatomical predisposition and cardiovascular risk factors.
Ophthalmologists, particularly those sub specialists who are neuro-ophthalmologists, are often best suited to diagnose and treat diseases of the optic nerve.
The International Foundation for Optic Nerve Diseases IFOND sponsors research and information on a variety of optic nerve disorders and may provide general direction.
# Additional images
- MRI scan of human eye showing optic nerve.
- The ophthalmic artery and its branches. (optic nerve is yellow)
- Dura mater and its processes exposed by removing part of the right half of the skull, and the brain.
- Tentorium cerebelli from above.
- Superficial dissection of brain-stem. Lateral view.
- Dissection of brain-stem. Lateral view.
- Mesal aspect of a brain sectioned in the median sagittal plane.
- Scheme showing central connections of the optic nerves and optic tracts.
- The fornix and corpus callosum from below.
- Nerves of the orbit. Seen from above.
- Nerves of the orbit, and the ciliary ganglion. Side view.
- The arteries of the choroid and iris. The greater part of the sclera has been removed.
- The veins of the choroid.
- The terminal portion of the optic nerve and its entrance into the eyeball, in horizontal section. | https://www.wikidoc.org/index.php/Nerve_head | |
0f4c0f0a5b84ff01264716dfb1edcca34dcc094b | wikidoc | Neurulation | Neurulation
# Overview
Neurulation is a part of organogenesis in vertebrate embryos. Steps of neurulation include the formation of the dorsal nerve cord, and the eventual formation of the central nervous system. The process begins when the notochord induces the formation of the central nervous system (CNS) by signaling the ectoderm germ layer above it to form the thick and flat neural plate. The neural plate folds in upon itself to form the neural tube, which will later differentiate into the spinal cord and the brain, eventually forming the central nervous system.
Different portions of the neural tube form by two different processes, called primary and secondary neurulation, in different species.
- In primary neurulation, the neural plate creases inward until the edges come in contact and fuse.
- In secondary neurulation, the tube forms by hollowing out of the interior of a solid precursor.
# Primary neurulation
## Induction
Primary neurulation occurs in response to soluble growth factors secreted by the notochord. Ectodermal cells are induced to form neuroectoderm from a variety of signals. Ectoderm sends and receives signals of BMP4 (bone morphogenic protein) and cells which receive BMP4 signal develop into epidermis. The inhibitory signals chordin, noggin and follistatin are needed to form neural plate. These inhibitory signals are created and emitted by the notochord. Cells which do not receive BMP4 signaling due to the effects of the inhibitory signals will develop into the anterior neuroectoderm cells of the neural plate. Cells which receive FGF (fibroblast growth factor) in addition to the inhibitory signals form posterior neural plate cells.
## Shape Change
The cells of the neural plate are signaled to become high-columnar and can be identified through microscopy as different from the surrounding epiblastic ectoderm. The cells move laterally and away from the central axis and change into a truncated pyramid shape. This pyramid shape is achieved through tubulin and actin in the apical portion of the cell which constricts as they move. The variation in cell shapes is partially determined by the location of the nucleus within the cell, causing bulging in areas of the cells forcing the height and shape of the cell to change.
## Folding
The process of the flat neural plate folding into the cylindrical neural tube is termed primary neurulation. As a result of the cellular shape changes, the neural plate forms the medial hinge point (MHP). The expanding epidermis puts pressure on the MHP and causes the neural plate to fold resulting in neural folds and the creation of the neural groove. The neural folds form dorsolateral hinge points (DLHP) and pressure on this hinge causes the neural folds to meet and fuse at the midline. The fusion requires the regulation of cell adhesion molecules. The neural plate switches from E-cadherin expression to N-cadherin and N-CAM expression to recognize each other as the same tissue and close the tube. This change in expression stops the binding of the neural tube to the epidermis.
The notochord plays an integral role in the development of the neural tube. Prior to neurulation, during the migration of epiblastic endoderm cells towards the hypoblastic endoderm, the notochordal process opens into an arch termed the notochordal plate and attaches overlying neuroepithelium of the neural plate. The notochordal plate then serves as an anchor for the neural plate and pushes the two edges of the plate upwards while keeping the middle section anchored. Some of the notochodral cells become incorporated into the center section neural plate to later form the floor plate of the neural tube. The notochord plate separates and forms the solid notochord.
The folding of the neural tube to form an actual tube does not occur all at once. Instead, it begins approximately at the level of the fourth somite at Carnegie stage 9 (around Embryonic day 20 in humans). The lateral edges of the neural plate touch in the midline and join together. This continues both cranially (toward the head) and caudally (toward the tail). The openings that are formed at the cranial and caudal regions are termed the cranial and caudal neuropores. In human embryos, the cranial neuropore closes approximately on day 25 and the caudal neuropore on day 27 (Carnegie stages 11 and 13 respectively). Failure of the cranial and caudal neuropore closure results in conditions called anecephaly and spina bifida, respectively. Additionally, failure of the neural tube to close through out the length of the body results in a condition called craniorachischisis.
## Patterning
After SHh from the notochord induces its formation, the floor plate of the incipient neural tube also secretes SHH. After closure, the neural tube forms a basal plate or floor plate and an alar plate or roof plate in response to the combined effects of Shh and factors including BMP4 secreted by the roof plate. The basal plate forms most of the ventral portion of the nervous system, including the motor portion of the spinal cord and brain stem; the alar plate forms the dorsal portions, devoted mostly to sensory processing.
The dorsal epidermis expresses BMP4 and BMP7. The roof plate of the neural tube responds to those signals to express more BMP4 and other TGF-b signals to form a dorsal/ventral gradient among the neural tube. The notochord expresses Sonic Hedgehog (Shh). The floor plate responds to Shh by producing its own Shh and forming a gradient. These gradients allows for the differential expression of transcription factors.
## Complexities of the model
In actuality, the folding of the neural tube is still not entirely understood and is still being studied. The simplistic model of the closure occurring in one step cranially and caudally does not explain the high frequency of neural tube defects. Proposed theories include closure of the neural tube occurs in regions, rather than entirely linearly.
# Secondary Neurulation
In secondary neurulation, the neural ectoderm and some cells from the endoderm form the medullary cord. The medullary cord condenses, separates and then forms cavities. These cavities then merge to form a single tube. Secondary Neurulation occurs in the posterior section of most animals but it is better expressed in birds. Tubes from both primary and secondary neurulation eventually connect.
# Early brain development
The anterior segment of the neural tube forms the three main parts of the brain: the forebrain, midbrain, and the hindbrain. Formation of these structures begins with a swelling of the neural tube in a pattern specified by Hox genes. Ion pumps are used to increase the fluid pressure within the tube and create a bulge. A blockage between the brain and the spinal cord prevents the fluid accumulation from leaking out. These brain regions further divide into subregions. The hindbrain divides into different segments called rhombomeres. Neural crest cells form ganglia above each rhombomere. The neural tube becomes the germinal neuroepithelium and serves as a source of new neurons during brain development. The brain develops from the inside-out.
# Non-neural ectoderm tissue
Mesoderm surrounding the notochord at the sides will develop into the somites (future muscles, bones, and contributes to the formation of limbs of the vertebrate).
# Neural crest cells
Masses of tissue called the neural crest that are located at the very edges of the lateral plates of the folding neural tube separate from the neural tube and migrate to become a variety of different but important cells.
Neural crest cells will migrate through the embryo and will give rise to several cell populations, including pigment cells and the cells of the peripheral nervous system.
# Neural tube defects
Neural tube defects are among the most common and disabling birth defects, occurring in roughly 1 in every 500 live births.
In spina bifida the open ends of the neural tube (the neuropores) fail to close as they should during the fourth week of gestation. This can lead to paralysis beneath the affected region of the spinal cord. Sufferers may require crutches or wheelchairs to move about, and may also suffer from lack of bladder and bowel control. | Neurulation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Neurulation is a part of organogenesis in vertebrate embryos. Steps of neurulation include the formation of the dorsal nerve cord, and the eventual formation of the central nervous system. The process begins when the notochord induces the formation of the central nervous system (CNS) by signaling the ectoderm germ layer above it to form the thick and flat neural plate. The neural plate folds in upon itself to form the neural tube, which will later differentiate into the spinal cord and the brain, eventually forming the central nervous system.
Different portions of the neural tube form by two different processes, called primary and secondary neurulation, in different species.
- In primary neurulation, the neural plate creases inward until the edges come in contact and fuse.
- In secondary neurulation, the tube forms by hollowing out of the interior of a solid precursor.
# Primary neurulation
## Induction
Primary neurulation occurs in response to soluble growth factors secreted by the notochord. Ectodermal cells are induced to form neuroectoderm from a variety of signals. Ectoderm sends and receives signals of BMP4 (bone morphogenic protein) and cells which receive BMP4 signal develop into epidermis. The inhibitory signals chordin, noggin and follistatin are needed to form neural plate. These inhibitory signals are created and emitted by the notochord. Cells which do not receive BMP4 signaling due to the effects of the inhibitory signals will develop into the anterior neuroectoderm cells of the neural plate. Cells which receive FGF (fibroblast growth factor) in addition to the inhibitory signals form posterior neural plate cells.
## Shape Change
The cells of the neural plate are signaled to become high-columnar and can be identified through microscopy as different from the surrounding epiblastic ectoderm. The cells move laterally and away from the central axis and change into a truncated pyramid shape. This pyramid shape is achieved through tubulin and actin in the apical portion of the cell which constricts as they move. The variation in cell shapes is partially determined by the location of the nucleus within the cell, causing bulging in areas of the cells forcing the height and shape of the cell to change.
## Folding
The process of the flat neural plate folding into the cylindrical neural tube is termed primary neurulation. As a result of the cellular shape changes, the neural plate forms the medial hinge point (MHP). The expanding epidermis puts pressure on the MHP and causes the neural plate to fold resulting in neural folds and the creation of the neural groove. The neural folds form dorsolateral hinge points (DLHP) and pressure on this hinge causes the neural folds to meet and fuse at the midline. The fusion requires the regulation of cell adhesion molecules. The neural plate switches from E-cadherin expression to N-cadherin and N-CAM expression to recognize each other as the same tissue and close the tube. This change in expression stops the binding of the neural tube to the epidermis.
The notochord plays an integral role in the development of the neural tube. Prior to neurulation, during the migration of epiblastic endoderm cells towards the hypoblastic endoderm, the notochordal process opens into an arch termed the notochordal plate and attaches overlying neuroepithelium of the neural plate. The notochordal plate then serves as an anchor for the neural plate and pushes the two edges of the plate upwards while keeping the middle section anchored. Some of the notochodral cells become incorporated into the center section neural plate to later form the floor plate of the neural tube. The notochord plate separates and forms the solid notochord.
The folding of the neural tube to form an actual tube does not occur all at once. Instead, it begins approximately at the level of the fourth somite at Carnegie stage 9 (around Embryonic day 20 in humans). The lateral edges of the neural plate touch in the midline and join together. This continues both cranially (toward the head) and caudally (toward the tail). The openings that are formed at the cranial and caudal regions are termed the cranial and caudal neuropores. In human embryos, the cranial neuropore closes approximately on day 25 and the caudal neuropore on day 27 (Carnegie stages 11 and 13 respectively). Failure of the cranial and caudal neuropore closure results in conditions called anecephaly and spina bifida, respectively. Additionally, failure of the neural tube to close through out the length of the body results in a condition called craniorachischisis.
## Patterning
After SHh from the notochord induces its formation, the floor plate of the incipient neural tube also secretes SHH. After closure, the neural tube forms a basal plate or floor plate and an alar plate or roof plate in response to the combined effects of Shh and factors including BMP4 secreted by the roof plate. The basal plate forms most of the ventral portion of the nervous system, including the motor portion of the spinal cord and brain stem; the alar plate forms the dorsal portions, devoted mostly to sensory processing.
The dorsal epidermis expresses BMP4 and BMP7. The roof plate of the neural tube responds to those signals to express more BMP4 and other TGF-b signals to form a dorsal/ventral gradient among the neural tube. The notochord expresses Sonic Hedgehog (Shh). The floor plate responds to Shh by producing its own Shh and forming a gradient. These gradients allows for the differential expression of transcription factors.
## Complexities of the model
In actuality, the folding of the neural tube is still not entirely understood and is still being studied. The simplistic model of the closure occurring in one step cranially and caudally does not explain the high frequency of neural tube defects. Proposed theories include closure of the neural tube occurs in regions, rather than entirely linearly.
# Secondary Neurulation
In secondary neurulation, the neural ectoderm and some cells from the endoderm form the medullary cord. The medullary cord condenses, separates and then forms cavities. These cavities then merge to form a single tube. Secondary Neurulation occurs in the posterior section of most animals but it is better expressed in birds. Tubes from both primary and secondary neurulation eventually connect.
# Early brain development
The anterior segment of the neural tube forms the three main parts of the brain: the forebrain, midbrain, and the hindbrain. Formation of these structures begins with a swelling of the neural tube in a pattern specified by Hox genes. Ion pumps are used to increase the fluid pressure within the tube and create a bulge. A blockage between the brain and the spinal cord prevents the fluid accumulation from leaking out. These brain regions further divide into subregions. The hindbrain divides into different segments called rhombomeres. Neural crest cells form ganglia above each rhombomere. The neural tube becomes the germinal neuroepithelium and serves as a source of new neurons during brain development. The brain develops from the inside-out.
# Non-neural ectoderm tissue
Mesoderm surrounding the notochord at the sides will develop into the somites (future muscles, bones, and contributes to the formation of limbs of the vertebrate).
# Neural crest cells
Masses of tissue called the neural crest that are located at the very edges of the lateral plates of the folding neural tube separate from the neural tube and migrate to become a variety of different but important cells.
Neural crest cells will migrate through the embryo and will give rise to several cell populations, including pigment cells and the cells of the peripheral nervous system.
# Neural tube defects
Neural tube defects are among the most common and disabling birth defects, occurring in roughly 1 in every 500 live births.[1]
In spina bifida the open ends of the neural tube (the neuropores) fail to close as they should during the fourth week of gestation. This can lead to paralysis beneath the affected region of the spinal cord. Sufferers may require crutches or wheelchairs to move about, and may also suffer from lack of bladder and bowel control. | https://www.wikidoc.org/index.php/Neural_tube_defect,_folate-sensitive | |
164c76693d490494bf5a03f60882185db9e5621f | wikidoc | Neurogenins | Neurogenins
Neurogenins are a family of bHLH transcription factors involved in specifying neuronal differentiation. They are related to Drosophila atonal.
The neurogenins (ngns) make up one of these atonal-related gene families. In neural crest cells, the atonal-related neurogenin family is particularly important for the sensory lineage (neurogenins are essential for the formation of dorsal root ganglia), while the achaete-scute homologue ash1 (Mash1) is important for aspects of autonomic neurogenesis (Mash1 is essential for noradrenergic differentiation).
# Neurogenin-1
Neurogenin 1 (Ngn1) is a Class-A basic-helix-loop-helix (bHLH) transcription factor that acts as a regulator for neuronal differentiation, and acts by binding to enhancer regulatory elements on genes that encode transcriptional regulators of neurogenesis. In order for Ngn1 to bind with high fidelity with genomic DNA, it must dimerize with another bHLH protein. Ngn1 is a proneural gene because its expression is seen prior to neural lineage determination, indicating it plays a role in neuronal differentiation.
## Neuronal Differentiation
In E14 rats, when Ngn1 is present in the cerebral cortex, it binds to the CBP/p300/Smad1 transcriptional co-activator complex, which recruits it to the enhancer box upstream of the gene in the promoter for neuronal genes. Binding of Ngn1, to the enhancer box, induces the transcription factor NeuroD to bind to its own enhancer boxes, inducing the genes involved in neuronal differentiation.
### Regulation by BMP
Bone-morphogenetic-protein (BMP) signaling is responsible for the expression of the transcriptional co-activators CBP, p300, and Smad1. In the presence of Ngn1, BMPs promote neuronal differentiation in stem cells through binding of all endogenous CBP/p300/Smad1 to Ngn1, and being recruited toward the neuronal promoters, causing neuronal differentiation. In the embryonic forebrain, Ngn1 is associated with dorsal patterning and cell fate specification, with the patterning molecules and proneural proteins establishing the spatial domains of both proneural and homeodomain protein expression. This is critical for the initiation of neurogenesis.
### Regulation by LIF
In the presence of Ngn1, the leukemia inhibitory factor (LIF) pathway is inhibited by Ngn1 blocking STAT activation. Normally, the STAT binding site promotes GFAP transcription through binding the STAT1/3 complex, which is activated through the LIF pathway.
## Glial Differentiation
Along with supporting neuronal differentiation, when expressed in embryonic neural tissue, Ngn1 also acts to inhibit glial differentiation. In the absence of Ngn1, the CBP/p300/Smad1 transcriptional co-activator complex is recruited to and binds to activated STAT1/3, which in turn causes the expression of GFAP, causing glial differentiation. In the presence of Ngn1, inhibition of gliogenesis occurs through Ngn1 binding to the CBP/p300/Smad1 transcriptional co-activator complex, recruiting it away from STAT1/3.
### Regulation by BMP
In cases of low levels of Ngn1, BMPs promote glial differentiation. Since Ngn1 is the limiting factor, CBP/p300/Smad1 is able to interact with STAT1/3 and induce gliogenesis.
### Regulation by Notch
Activation of the notch pathway, causes the inhibition of proneural bHLH genes, such as Ngn1, which allows for the CBP/p300/Smad1 to interact with STAT1/3 and induce gliogenesis. Along with the embryonic rat, it was also seen in zebrafish that the repression of Ngn1 by Notch, promotes glial lineage in neural crest and central nervous system formation through the inhibition of neuronal differentiation. In addition to the Notch pathway activating the transcriptional factors involved in the promotion of gliogenesis, it is possible that these same factors are involved in the inhibition of other fates.
### Regulation by LIF
In the absence of Ngn1, the LIF pathway is able to activate STAT1/3, which allows for the promotion of GFAP transcription via the STAT binding site. The promotion of GFAP transcription induced glial differentiation.
# Neurogenin-2
Neurogenin 2 (Ngn2) is a bHLH transcription factor involved in both neurogenesis and neural specification. This protein binds to enhancer-box regulatory elements on the promoters of many genes related to neurogenesis and neural specification. For sufficient DNA binding, Ngn2 must form a dimer with an enhancer protein.
## Neurogenesis and Glial Inhibition
Ngn2 is a transcription factor that both increases expression of proneural genes and drives neural fate by inhibiting expression of glial genes in neural progenitor cells (NPCs). This was observed in mice lacking Ngn2 and mash-1 (another proneural bHLH transcription factor), which have more glia in the cortex and decreased capacity to generate neurons. Olig2 expression in what will become NPCs precedes Ngn2 and promotes its expression. During the switch from neural progenitor fate to glial fate, Ngn2 is downregulated and Nkx2.2, which inhibits proneural genes, is upregulated. Glial fate switch was reduced by inhibiting Nkx2.2 and Olig2 in neural progenitors while allowing the expression of Ngn2. The ability of Olig2 to induce expression of Ngn2 is reduced when Nkx2.2 is expressed.
## Neural Specification
In mice that lack Ngn2, there are less motor neurons and ventral interneurons present, indicating that Ngn2 plays a role in specification of these neurons.
### Interaction of Ngn2 with LIM homeodomain transcription factors leads to ventral neural fate
### Pan-neuronal fate
Heterodimerized Ngn2/enhancer protein complex can bind to enhancer boxes to promote transcription of genes related to a non-specified neuronal fate.
### V2 interneuron fate
When an enhancer box of a promoter that has been bound by the Ngn-2/enhancer protein complex is also bound by a dimer of the adaptor nuclear LIM interactor (NLI) bound to two LIM homeobox protein 3 (Lhx3), genes related to V2 interneuron identity are expressed.
### Motor neuron fate
A dimer of the adaptor NLI bound to two islet 1 (Isl1) proteins and each Isl1 is bound by Lhx3 is called the LIM-homeodomain (LIM-HD) transcription complex. When an enhancer box of a promoter that has been bound by the heterodimerized Ngn2/E-protein complex, the LIM-HD transcription complex is able to bind to drive expression of genes related to motor neuron fate, but only if Ngn2 has been properly phosphorylated.
Ngn2 has two serines, S231 and S234, which can be phosphorylated by glycogen synthase kinase 3 (Gsk3). The importance of this phosphorylation was determined by using mice that express a mutated form of Ngn2 protein which has the serines from the previously mentioned phosphorylation sites mutated into alanines, which cannot be phosphorylated. These mutant mice have a decreased number of motor neurons and an increased number of V2 interneurons, suggesting that phosphorylation is necessary for driving expression of genes related to motor neuron fate but not V2 interneuron fate and non-specified neural fate.
# Neurogenin-3
Neurogenin 3 (Ngn3) is another member of the bHLH family of transcription factors. Ngn3 functions in the differentiation of endocrine pancreas cells. Although its key function is in the pancreas, intestinal cells and neural cells express Ngn3 as well. Several studies have highlighted the importance of Ngn3 for differentiation of endocrine cells. In mice, Ngn3 is present in cells as the pancreas begins to bud and glucagon cells are formed. There are several pathways that Ngn3 works through.
Ngn3 is a crucial component in pancreatic development and plays a supporting role in intestinal as well as neuronal cell development. Studies have demonstrated that knockout of Ngn3 in mice leads to death shortly after birth possibly due to after effects of severe diabetes. Further studies are taking place to investigate Ngn3’s possible role as a treatment for diabetes and regeneration of cells in the pancreas.
Neurogenin 3 (NGN3) is expressed by 2-10% of acinar and duct cells in the histologically normal adult human pancreas. NGN3+ cells isolated from cultured exocrine tissue by coexpressed cell surface glycoprotein CD133 have a transcriptome consistent with exocrine dedifferentiation, a phenotype that resembles endocrine progenitor cells during development, and a capacity for endocrine differentiation in vitro. Human and rodent exocrine cells have been reprogrammed into cells with an islet cell-like phenotype following direct expression of NGN3 or manipulation that leads to its expression.
## Phases of pancreatic development
The development of the pancreas is broken up into three phases, primary phase, secondary phase, and tertiary phase. Ngn3 is active in the primary and secondary phase. In the primary phase Ngn3 assists in α cell differentiation and in the secondary phase another wave of Ngn3 assists in differentiation of β cells, pancreatic polypeptide cells, and δ cells. Differentiation is marked as complete after the secondary phase. Ngn3 allows for the commitment of pancreatic progenitor cells to become an endocrine multipotent pro-precursor.
## Modulation via notch pathway
The Notch pathway is one of the key modulators of Ngn3. The binding of Delta and Serrate, activation ligands for the Notch pathway, activates the Notch surface molecule. This allows the Notch intracellular domain to activate RBK-Jκ to translocate into the nucleus. This complex then activates hairy and enhancer of split (HES)-type proteins, which are inhibitors of Ngn3. The cells that allow the Notch/RBK-Jκ complex to enter are the ones that will not be differentiated into pancreatic cells because Ngn3 is suppressed. It’s important to mention that Ngn3 has three HES1 binding sites adjacent to the TATA box sequence that allow for the regulation of this transcription factor.
## Downstream targets of Ngn3
### NeuroD
Ngn3 can also activate the neurogenic differentiation factor 1(NeuroD1) like most of its other family members through the enhancer boxes present in its structure. Being that NeuroD1 is expressed along with Ngn3 in differentiating cells, it is considered one of the transcription factors downstream targets.
### Pax4
Another important target is paired box gene 4 (Pax4), which plays a major role in β cell and δ cell differentiation. Ngn3 works hand-in-hand with HNF1α to activate the Pax4 promoter to induce specific cell differentiation.
### Nkx2.2
Another transcription factor that may be a downstream target of Ngn3 is Nkx2.2 because it’s often coexpressed with it. Studies have shown that disrupting Nkx2.2 expression results in problems with α and β cell differentiation. | Neurogenins
Neurogenins are a family of bHLH transcription factors involved in specifying neuronal differentiation. They are related to Drosophila atonal.
The neurogenins (ngns) make up one of these atonal-related gene families. In neural crest cells, the atonal-related neurogenin family is particularly important for the sensory lineage (neurogenins are essential for the formation of dorsal root ganglia), while the achaete-scute homologue ash1 (Mash1) is important for aspects of autonomic neurogenesis (Mash1 is essential for noradrenergic differentiation).[1]
# Neurogenin-1
Neurogenin 1 (Ngn1) is a Class-A basic-helix-loop-helix (bHLH) transcription factor that acts as a regulator for neuronal differentiation, and acts by binding to enhancer regulatory elements on genes that encode transcriptional regulators of neurogenesis. In order for Ngn1 to bind with high fidelity with genomic DNA, it must dimerize with another bHLH protein.[2] Ngn1 is a proneural gene because its expression is seen prior to neural lineage determination, indicating it plays a role in neuronal differentiation.[3]
## Neuronal Differentiation
In E14 rats, when Ngn1 is present in the cerebral cortex, it binds to the CBP/p300/Smad1 transcriptional co-activator complex, which recruits it to the enhancer box upstream of the gene in the promoter for neuronal genes. Binding of Ngn1, to the enhancer box, induces the transcription factor NeuroD to bind to its own enhancer boxes, inducing the genes involved in neuronal differentiation.[4]
### Regulation by BMP
Bone-morphogenetic-protein (BMP) signaling is responsible for the expression of the transcriptional co-activators CBP, p300, and Smad1.[4] In the presence of Ngn1, BMPs promote neuronal differentiation in stem cells through binding of all endogenous CBP/p300/Smad1 to Ngn1, and being recruited toward the neuronal promoters, causing neuronal differentiation.[4] In the embryonic forebrain, Ngn1 is associated with dorsal patterning and cell fate specification, with the patterning molecules and proneural proteins establishing the spatial domains of both proneural and homeodomain protein expression. This is critical for the initiation of neurogenesis.[5]
### Regulation by LIF
In the presence of Ngn1, the leukemia inhibitory factor (LIF) pathway is inhibited by Ngn1 blocking STAT activation. Normally, the STAT binding site promotes GFAP transcription through binding the STAT1/3 complex, which is activated through the LIF pathway.[4]
## Glial Differentiation
Along with supporting neuronal differentiation, when expressed in embryonic neural tissue, Ngn1 also acts to inhibit glial differentiation.[6] In the absence of Ngn1, the CBP/p300/Smad1 transcriptional co-activator complex is recruited to and binds to activated STAT1/3, which in turn causes the expression of GFAP, causing glial differentiation. In the presence of Ngn1, inhibition of gliogenesis occurs through Ngn1 binding to the CBP/p300/Smad1 transcriptional co-activator complex, recruiting it away from STAT1/3.[4]
### Regulation by BMP
In cases of low levels of Ngn1, BMPs promote glial differentiation. Since Ngn1 is the limiting factor, CBP/p300/Smad1 is able to interact with STAT1/3 and induce gliogenesis.[4]
### Regulation by Notch
Activation of the notch pathway, causes the inhibition of proneural bHLH genes, such as Ngn1, which allows for the CBP/p300/Smad1 to interact with STAT1/3 and induce gliogenesis.[4] Along with the embryonic rat, it was also seen in zebrafish that the repression of Ngn1 by Notch, promotes glial lineage in neural crest and central nervous system formation through the inhibition of neuronal differentiation.[3][7] In addition to the Notch pathway activating the transcriptional factors involved in the promotion of gliogenesis, it is possible that these same factors are involved in the inhibition of other fates.
### Regulation by LIF
In the absence of Ngn1, the LIF pathway is able to activate STAT1/3, which allows for the promotion of GFAP transcription via the STAT binding site. The promotion of GFAP transcription induced glial differentiation.[4]
# Neurogenin-2
Neurogenin 2 (Ngn2) is a bHLH transcription factor involved in both neurogenesis and neural specification. This protein binds to enhancer-box regulatory elements on the promoters of many genes related to neurogenesis and neural specification. For sufficient DNA binding, Ngn2 must form a dimer with an enhancer protein.[8]
## Neurogenesis and Glial Inhibition
Ngn2 is a transcription factor that both increases expression of proneural genes and drives neural fate by inhibiting expression of glial genes in neural progenitor cells (NPCs). This was observed in mice lacking Ngn2 and mash-1 (another proneural bHLH transcription factor), which have more glia in the cortex and decreased capacity to generate neurons. Olig2 expression in what will become NPCs precedes Ngn2 and promotes its expression.[4] During the switch from neural progenitor fate to glial fate, Ngn2 is downregulated and Nkx2.2, which inhibits proneural genes, is upregulated.[9] Glial fate switch was reduced by inhibiting Nkx2.2 and Olig2 in neural progenitors while allowing the expression of Ngn2. The ability of Olig2 to induce expression of Ngn2 is reduced when Nkx2.2 is expressed.[10]
## Neural Specification
In mice that lack Ngn2, there are less motor neurons and ventral interneurons present, indicating that Ngn2 plays a role in specification of these neurons.[11]
### Interaction of Ngn2 with LIM homeodomain transcription factors leads to ventral neural fate
### Pan-neuronal fate
Heterodimerized Ngn2/enhancer protein complex can bind to enhancer boxes to promote transcription of genes related to a non-specified neuronal fate.[11]
### V2 interneuron fate
When an enhancer box of a promoter that has been bound by the Ngn-2/enhancer protein complex is also bound by a dimer of the adaptor nuclear LIM interactor (NLI) bound to two LIM homeobox protein 3 (Lhx3), genes related to V2 interneuron identity are expressed.[11]
### Motor neuron fate
A dimer of the adaptor NLI bound to two islet 1 (Isl1) proteins and each Isl1 is bound by Lhx3 is called the LIM-homeodomain (LIM-HD) transcription complex. When an enhancer box of a promoter that has been bound by the heterodimerized Ngn2/E-protein complex, the LIM-HD transcription complex is able to bind to drive expression of genes related to motor neuron fate, but only if Ngn2 has been properly phosphorylated.[11]
Ngn2 has two serines, S231 and S234, which can be phosphorylated by glycogen synthase kinase 3 (Gsk3). The importance of this phosphorylation was determined by using mice that express a mutated form of Ngn2 protein which has the serines from the previously mentioned phosphorylation sites mutated into alanines, which cannot be phosphorylated. These mutant mice have a decreased number of motor neurons and an increased number of V2 interneurons, suggesting that phosphorylation is necessary for driving expression of genes related to motor neuron fate but not V2 interneuron fate and non-specified neural fate.[11]
# Neurogenin-3
Neurogenin 3 (Ngn3) is another member of the bHLH family of transcription factors. Ngn3 functions in the differentiation of endocrine pancreas cells. Although its key function is in the pancreas, intestinal cells and neural cells express Ngn3 as well. Several studies have highlighted the importance of Ngn3 for differentiation of endocrine cells. In mice, Ngn3 is present in cells as the pancreas begins to bud and glucagon cells are formed. There are several pathways that Ngn3 works through.[12][13][14][15]
Ngn3 is a crucial component in pancreatic development and plays a supporting role in intestinal as well as neuronal cell development. Studies have demonstrated that knockout of Ngn3 in mice leads to death shortly after birth possibly due to after effects of severe diabetes.[12] Further studies are taking place to investigate Ngn3’s possible role as a treatment for diabetes and regeneration of cells in the pancreas.[12][14]
Neurogenin 3 (NGN3) is expressed by 2-10% of acinar and duct cells in the histologically normal adult human pancreas. NGN3+ cells isolated from cultured exocrine tissue by coexpressed cell surface glycoprotein CD133 have a transcriptome consistent with exocrine dedifferentiation, a phenotype that resembles endocrine progenitor cells during development, and a capacity for endocrine differentiation in vitro.[16] Human [17] and rodent [18][19][20][21][22][23][24][25][26] exocrine cells have been reprogrammed into cells with an islet cell-like phenotype following direct expression of NGN3 or manipulation that leads to its expression.
## Phases of pancreatic development
The development of the pancreas is broken up into three phases, primary phase, secondary phase, and tertiary phase. Ngn3 is active in the primary and secondary phase. In the primary phase Ngn3 assists in α cell differentiation and in the secondary phase another wave of Ngn3 assists in differentiation of β cells, pancreatic polypeptide cells, and δ cells. Differentiation is marked as complete after the secondary phase. Ngn3 allows for the commitment of pancreatic progenitor cells to become an endocrine multipotent pro-precursor.[12]
## Modulation via notch pathway
The Notch pathway is one of the key modulators of Ngn3. The binding of Delta and Serrate, activation ligands for the Notch pathway, activates the Notch surface molecule. This allows the Notch intracellular domain to activate RBK-Jκ to translocate into the nucleus. This complex then activates hairy and enhancer of split (HES)-type proteins, which are inhibitors of Ngn3. The cells that allow the Notch/RBK-Jκ complex to enter are the ones that will not be differentiated into pancreatic cells because Ngn3 is suppressed. It’s important to mention that Ngn3 has three HES1 binding sites adjacent to the TATA box sequence that allow for the regulation of this transcription factor.[12]
## Downstream targets of Ngn3
### NeuroD
Ngn3 can also activate the neurogenic differentiation factor 1(NeuroD1) like most of its other family members through the enhancer boxes present in its structure. Being that NeuroD1 is expressed along with Ngn3 in differentiating cells, it is considered one of the transcription factors downstream targets.[12]
### Pax4
Another important target is paired box gene 4 (Pax4), which plays a major role in β cell and δ cell differentiation. Ngn3 works hand-in-hand with HNF1α to activate the Pax4 promoter to induce specific cell differentiation.[12]
### Nkx2.2
Another transcription factor that may be a downstream target of Ngn3 is Nkx2.2 because it’s often coexpressed with it. Studies have shown that disrupting Nkx2.2 expression results in problems with α and β cell differentiation.[13][14] | https://www.wikidoc.org/index.php/Neurogenins | |
d849da24a6b41aec1640335d52fa28785d8c92d1 | wikidoc | Neuroglobin | Neuroglobin
Neuroglobin is a member of the vertebrate globin family involved in cellular oxygen homeostasis. It is an intracellular hemoprotein expressed in the central and peripheral nervous system, cerebrospinal fluid, retina and endocrine tissues. Neuroglobin is a monomer that reversibly binds oxygen with an affinity higher than that of hemoglobin. It also increases oxygen availability to brain tissue and provides protection under hypoxic or ischemic conditions, potentially limiting brain damage. Neuroglobin were in the past found only in vertebrate neurons, but recently in 2013, were found in the neurons of unrelated protostomes, like photosynthesis acoel as well as radiata such as jelly fish. In addition to neurons, neuroglobin is present in astrocytes in certain pathologies of the rodent brain and in the physiological seal brain. This is thought to be due to convergent evolution. It is of ancient evolutionary origin, and is homologous to nerve globins of invertebrates. Recent research confirmed the presence of human neuroglobin protein in cerebrospinal fluid (CSF).
Neuroglobin was first identified by Thorsten Burmester et al. in 2000.
The 3D structure of human neuroglobin was determined in 2003. The next year, murine neuroglobin was determined at a higher resolution.
A practical treatment for carbon monoxide poisoning based on binding of CO by neuroglobin (Ngb) with a mutated distal histidine (H64Q) appears to be possible. | Neuroglobin
Neuroglobin is a member of the vertebrate globin family involved in cellular oxygen homeostasis. It is an intracellular hemoprotein expressed in the central and peripheral nervous system, cerebrospinal fluid, retina and endocrine tissues. Neuroglobin is a monomer that reversibly binds oxygen with an affinity higher than that of hemoglobin. It also increases oxygen availability to brain tissue and provides protection under hypoxic or ischemic conditions, potentially limiting brain damage. Neuroglobin were in the past found only in vertebrate neurons, but recently in 2013, were found in the neurons of unrelated protostomes, like photosynthesis acoel as well as radiata such as jelly fish. In addition to neurons, neuroglobin is present in astrocytes in certain pathologies of the rodent brain[1][2] and in the physiological seal brain.[3] This is thought to be due to convergent evolution.[4] It is of ancient evolutionary origin, and is homologous to nerve globins of invertebrates. Recent research confirmed the presence of human neuroglobin protein in cerebrospinal fluid (CSF).[5]
Neuroglobin was first identified by Thorsten Burmester et al. in 2000.[6]
The 3D structure of human neuroglobin was determined in 2003.[7] The next year, murine neuroglobin was determined at a higher resolution.[8]
A practical treatment for carbon monoxide poisoning based on binding of CO by neuroglobin (Ngb) with a mutated distal histidine (H64Q) appears to be possible.[9] | https://www.wikidoc.org/index.php/Neuroglobin | |
446c5c27be79674c321239092cc719bdb4969799 | wikidoc | Neurogranin | Neurogranin
Neurogranin is a calmodulin-binding protein expressed primarily in the brain, particularly in dendritic spines, and participating in the protein kinase C signaling pathway. Neurogranin is the main postsynaptic protein regulating the availability of calmodulin, binding to it in the absence of calcium. Phosphorylation by protein kinase C lowers its binding ability. NRGN gene expression is controlled by thyroid hormones. Human neurogranin consists of 78 amino acids.
One study tells of potential link of neurogranin gene to the heightened risk of schizophrenia in males, another study gives evidence of lowered neurogranin immunoreactivity in the brains of people suffering from schizophrenia.
Prior to its identification in the bovine and rat brain in 1991, neurogranin was known as a putative protein kinase C-phosphorylated protein named p17. Human neurogranin was cloned in 1997 and turned out to be 96% identical to the rat protein. | Neurogranin
Neurogranin is a calmodulin-binding protein expressed primarily in the brain, particularly in dendritic spines, and participating in the protein kinase C signaling pathway. Neurogranin is the main postsynaptic protein regulating the availability of calmodulin, binding to it in the absence of calcium. Phosphorylation by protein kinase C lowers its binding ability. NRGN gene expression is controlled by thyroid hormones.[1] Human neurogranin consists of 78 amino acids.
One study tells of potential link of neurogranin gene to the heightened risk of schizophrenia in males,[2] another study gives evidence of lowered neurogranin immunoreactivity in the brains of people suffering from schizophrenia.[3]
Prior to its identification in the bovine and rat brain in 1991,[4] neurogranin was known as a putative protein kinase C-phosphorylated protein named p17. Human neurogranin was cloned in 1997 and turned out to be 96% identical to the rat protein.[5] | https://www.wikidoc.org/index.php/Neurogranin | |
991e7dcc84b0431ceda422b1099fa9d8c693992f | wikidoc | Neuropraxia | Neuropraxia
# Overview
Neurapraxia is part of Seddon's classification scheme used to classify nerve damage.
It is a transient episode of motor paralysis with little or no sensory or autonomic dysfunction.
Neurapraxia describes nerve damage in which there is no disruption of the nerve or its sheath. In this case there is an interruption in conduction of the impulse down the nerve fiber, and recovery takes place without true regeneration, as Wallerian degeneration does not occur. This is the mildest form of nerve injury. This is probably a biochemical lesion caused by concussion or shock-like injuries to the fiber. In the case of the role nerve, neurapraxia is brought about by compression or relatively mild, blunt blows, including some low-velocity missile injuries close to the nerve. There is a temporary loss of function which is reversible within hours to months of the injury ( the average is 6-8 weeks ). There is frequently greater involvement of motor than sensory function with autonomic function being retained.
This form of nerve-impulse interruption should not be ignored and the patient should refer to a physician as soon as possible. In sports neurapraxia is common and happens to most athletes during their sports life-span. Patients should also refrain from playing sports or putting stress on the injured area. Since sensation of that part of the body will be lost, any further damage or injury done will not be noticed or felt as profoundly as usual, and damage might go unnoticed.
de:Neurapraxie | Neuropraxia
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Neurapraxia is part of Seddon's classification scheme used to classify nerve damage.
It is a transient episode of motor paralysis with little or no sensory or autonomic dysfunction.
Neurapraxia describes nerve damage in which there is no disruption of the nerve or its sheath. In this case there is an interruption in conduction of the impulse down the nerve fiber, and recovery takes place without true regeneration, as Wallerian degeneration does not occur. This is the mildest form of nerve injury. This is probably a biochemical lesion caused by concussion or shock-like injuries to the fiber. In the case of the role nerve, neurapraxia is brought about by compression or relatively mild, blunt blows, including some low-velocity missile injuries close to the nerve. There is a temporary loss of function which is reversible within hours to months of the injury ( the average is 6-8 weeks ). There is frequently greater involvement of motor than sensory function with autonomic function being retained.
This form of nerve-impulse interruption should not be ignored and the patient should refer to a physician as soon as possible. In sports neurapraxia is common and happens to most athletes during their sports life-span. Patients should also refrain from playing sports or putting stress on the injured area. Since sensation of that part of the body will be lost, any further damage or injury done will not be noticed or felt as profoundly as usual, and damage might go unnoticed.
de:Neurapraxie
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Neuropraxia | |
4161f1da8626b014b04930afa9ca90de8924f00e | wikidoc | Neurotensin | Neurotensin
Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. Neurotensin was first isolated from extracts of bovine hypothalamus based on its ability to cause a visible vasodilation in the exposed cutaneous regions of anesthetized rats.
Neurotensin is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens. It induces a variety of effects, including analgesia, hypothermia and increased locomotor activity. It is also involved in regulation of dopamine pathways. In the periphery, neurotensin is found in enteroendocrine cells of the small intestine, where it leads to secretion and smooth muscle contraction.
# Sequence and biosynthesis
Neurotensin shares significant sequence similarity in its 6 C-terminal amino acids with several other neuropeptides, including neuromedin N (which is derived from the same precursor). This C-terminal region is responsible for the full biological activity, the N-terminal portion having a modulatory role. The neurotensin/neuromedin N precursor can also be processed to produce large 125–138 amino acid peptides with the neurotensin or neuromedin N sequence at their C terminus. These large peptides appear to be less potent than their smaller counterparts, but are also less sensitive to degradation and may represent endogenous, long-lasting activators in a number of pathophysiological situations.
The sequence of bovine neurotensin was determined to be pyroGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH. Neurotensin is synthesized as part of a 169 or 170 amino acid precursor protein that also contains the related neuropeptide neuromedin N. The peptide coding domains are located in tandem near the carboxyl terminal end of the precursor and are bounded and separated by paired basic amino acid (lysine-arginine) processing sites.
# Clinical significance
Neurotensin is a potent mitogen for colorectal cancer.
Neurotensin has been implicated in the modulation of dopamine signaling, and produces a spectrum of pharmacological effects resembling those of antipsychotic drugs, leading to the suggestion that neurotensin may be an endogenous neuroleptic. Neurotensin-deficient mice display defects in responses to several antipsychotic drugs consistent with the idea that neurotensin signaling is a key component underlying at least some antipsychotic drug actions. These mice exhibit modest defects in prepulse inhibition (PPI) of the startle reflex, a model that has been widely used to investigate antipsychotic drug action in animals. Antipsychotic drug administration augments PPI under certain conditions. Comparisons between normal and neurotensin-deficient mice revealed striking differences in the ability of different antipsychotic drugs to augment PPI. While the atypical antipsychotic drug clozapine augmented PPI normally in neurotensin-deficient mice, the conventional antipsychotic haloperidol and the newer atypical antipsychotic quetiapine were ineffective in these mice, in contrast to normal mice where these drugs significantly augmented PPI. These results suggest that certain antipsychotic drugs require neurotensin for at least some of their effects. Neurotensin-deficient mice also display defects in striatal activation following haloperidol, but not clozapine administration in comparison to normal wild type mice, indicating that striatal neurotensin is required for the full spectrum of neuronal responses to a subset of antipsychotic drugs.
Neurotensin is an endogenous neuropeptide involved in thermoregulation that can induce hypothermia and neuroprotection in experimental models of cerebral ischemia. | Neurotensin
Neurotensin is a 13 amino acid neuropeptide that is implicated in the regulation of luteinizing hormone and prolactin release and has significant interaction with the dopaminergic system. Neurotensin was first isolated from extracts of bovine hypothalamus based on its ability to cause a visible vasodilation in the exposed cutaneous regions of anesthetized rats.[1]
Neurotensin is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens. It induces a variety of effects, including analgesia, hypothermia and increased locomotor activity. It is also involved in regulation of dopamine pathways. In the periphery, neurotensin is found in enteroendocrine cells of the small intestine, where it leads to secretion and smooth muscle contraction.[2]
# Sequence and biosynthesis
Neurotensin shares significant sequence similarity in its 6 C-terminal amino acids with several other neuropeptides, including neuromedin N (which is derived from the same precursor). This C-terminal region is responsible for the full biological activity, the N-terminal portion having a modulatory role. The neurotensin/neuromedin N precursor can also be processed to produce large 125–138 amino acid peptides with the neurotensin or neuromedin N sequence at their C terminus. These large peptides appear to be less potent than their smaller counterparts, but are also less sensitive to degradation and may represent endogenous, long-lasting activators in a number of pathophysiological situations.
The sequence of bovine neurotensin was determined to be pyroGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu-OH.[3] Neurotensin is synthesized as part of a 169 or 170 amino acid precursor protein that also contains the related neuropeptide neuromedin N.[4][5] The peptide coding domains are located in tandem near the carboxyl terminal end of the precursor and are bounded and separated by paired basic amino acid (lysine-arginine) processing sites.
# Clinical significance
Neurotensin is a potent mitogen for colorectal cancer.[6]
Neurotensin has been implicated in the modulation of dopamine signaling, and produces a spectrum of pharmacological effects resembling those of antipsychotic drugs, leading to the suggestion that neurotensin may be an endogenous neuroleptic. Neurotensin-deficient mice display defects in responses to several antipsychotic drugs consistent with the idea that neurotensin signaling is a key component underlying at least some antipsychotic drug actions.[7] These mice exhibit modest defects in prepulse inhibition (PPI) of the startle reflex, a model that has been widely used to investigate antipsychotic drug action in animals. Antipsychotic drug administration augments PPI under certain conditions. Comparisons between normal and neurotensin-deficient mice revealed striking differences in the ability of different antipsychotic drugs to augment PPI. While the atypical antipsychotic drug clozapine augmented PPI normally in neurotensin-deficient mice, the conventional antipsychotic haloperidol and the newer atypical antipsychotic quetiapine were ineffective in these mice, in contrast to normal mice where these drugs significantly augmented PPI. These results suggest that certain antipsychotic drugs require neurotensin for at least some of their effects. Neurotensin-deficient mice also display defects in striatal activation following haloperidol, but not clozapine administration in comparison to normal wild type mice, indicating that striatal neurotensin is required for the full spectrum of neuronal responses to a subset of antipsychotic drugs.[8]
Neurotensin is an endogenous neuropeptide involved in thermoregulation that can induce hypothermia and neuroprotection in experimental models of cerebral ischemia.[9] | https://www.wikidoc.org/index.php/Neurotensin | |
acf684a2c09bf97238214a8016e842efc9b0390b | wikidoc | Neuroticism | Neuroticism
Neuroticism is a fundamental personality trait in the study of psychology. It can be defined as an enduring tendency to experience negative emotional states. Individuals who score high on neuroticism are more likely than the average to experience such feelings as anxiety, anger, guilt, and clinical depression. They respond more poorly to environmental stress, and are more likely to interpret ordinary situations as threatening, and minor frustrations as hopelessly difficult. They are often self-conscious and shy, and they may have trouble controlling urges and delaying gratification. Neuroticism is related to emotional intelligence, which involves emotional regulation, motivation, and interpersonal skills. It is also considered to be a predisposition for traditional neuroses, such as phobias and other anxiety disorders.
# Emotional stability
On the opposite end of the spectrum, individuals who score low in neuroticism are more emotionally stable and less reactive to stress. They tend to be calm, even tempered, and less likely to feel tense or rattled. Although they are low in negative emotion, they are not necessarily high on positive emotion. That is an element of the independent trait of extraversion. Neurotic extraverts, for example, would experience high levels of both positive and negative emotional states, a kind of "emotional roller coaster." Individuals who score low on neuroticism (particularly those who are also high on extraversion) generally report more happiness and satisfaction with their lives.
# Measurement
Neuroticism is typically viewed as a continuous trait, rather than a distinct type of person. People vary in their level of neuroticism, with a small minority of individuals scoring extremely high or extremely low on the dimension. Because most people cluster around the average, neuroticism test scores approximate a normal distribution, given a large enough sample of people. Neuroticism is one of the most studied personality traits in psychology, and this has resulted in a wealth of data and statistical analysis. It is measured on the EPQ, the NEO PI-R, and other personality inventories.
# Physiology
Neuroticism appears to be related to physiological differences in the brain. Hans Eysenck theorized that neuroticism is a function of activity in the limbic system, and research suggests that people who score highly on measures of neuroticism have a more reactive sympathetic nervous system, and are more sensitive to environmental stimulation.
Behavioral genetics researchers have found that a substantial portion of the variability on measures of neuroticism can be attributed to genetic factors.
A study with positron emission tomography has found that healthy subjects that score high on the NEO PI-R neuroticism dimension tend to have high altanserin binding in the frontolimbic region of the brain — an indication that these subjects tend to have more of the 5-HT2A receptor in that location.
Another study has found that healthy subjects with a high neuroticism score tend to have higher DASB binding in the thalamus, — with DASB being a ligand that binds to the serotonin transporter protein.
Another neuroimaging study using magnetic resonance imaging to measure brain volume found that the brain volume was negatively correlated to NEO PI-R neuroticism when correcting for possible effects of intracranial volume, sex, and age.
Other studies have associated neuroticism with genetic variations, e.g., with 5-HTTLPR — a polymorphism in the serotonin transporter gene.
However, not all studies find such an association.
A genome-wide association study (GWA study) has pointed single-nucleotide polymorphisms in the MDGA2 gene as associated with neuroticism.
Another GWA study gave some evidence that the rs362584 polymorphism in the SNAP25 gene was associated with neuroticism.
# Geography
Neuroticism, along with other personality traits, has been mapped across states in the USA.
People in eastern states such as New York, New Jersey, West Virginia, and Mississippi tend to score high on neuroticism, whereas people in many western states, such as Utah, Colorado, South Dakota, Oregon, and Arizona score lower on average.
People in states that are higher in neuroticism also tend to have higher rates of heart disease and lower life expectancy. | Neuroticism
Neuroticism is a fundamental personality trait in the study of psychology. It can be defined as an enduring tendency to experience negative emotional states. Individuals who score high on neuroticism are more likely than the average to experience such feelings as anxiety, anger, guilt, and clinical depression.[1] They respond more poorly to environmental stress, and are more likely to interpret ordinary situations as threatening, and minor frustrations as hopelessly difficult. They are often self-conscious and shy, and they may have trouble controlling urges and delaying gratification. Neuroticism is related to emotional intelligence, which involves emotional regulation, motivation, and interpersonal skills.[2] It is also considered to be a predisposition for traditional neuroses, such as phobias and other anxiety disorders.
# Emotional stability
On the opposite end of the spectrum, individuals who score low in neuroticism are more emotionally stable and less reactive to stress. They tend to be calm, even tempered, and less likely to feel tense or rattled. Although they are low in negative emotion, they are not necessarily high on positive emotion. That is an element of the independent trait of extraversion. Neurotic extraverts, for example, would experience high levels of both positive and negative emotional states, a kind of "emotional roller coaster." Individuals who score low on neuroticism (particularly those who are also high on extraversion) generally report more happiness and satisfaction with their lives.
# Measurement
Neuroticism is typically viewed as a continuous trait, rather than a distinct type of person. People vary in their level of neuroticism, with a small minority of individuals scoring extremely high or extremely low on the dimension. Because most people cluster around the average, neuroticism test scores approximate a normal distribution, given a large enough sample of people. Neuroticism is one of the most studied personality traits in psychology, and this has resulted in a wealth of data and statistical analysis. It is measured on the EPQ, the NEO PI-R, and other personality inventories.
# Physiology
Neuroticism appears to be related to physiological differences in the brain. Hans Eysenck theorized that neuroticism is a function of activity in the limbic system, and research suggests that people who score highly on measures of neuroticism have a more reactive sympathetic nervous system, and are more sensitive to environmental stimulation.[3]
Behavioral genetics researchers have found that a substantial portion of the variability on measures of neuroticism can be attributed to genetic factors.[4]
A study with positron emission tomography has found that healthy subjects that score high on the NEO PI-R neuroticism dimension tend to have high altanserin binding in the frontolimbic region of the brain — an indication that these subjects tend to have more of the 5-HT2A receptor in that location.[5]
Another study has found that healthy subjects with a high neuroticism score tend to have higher DASB binding in the thalamus, — with DASB being a ligand that binds to the serotonin transporter protein.[6]
Another neuroimaging study using magnetic resonance imaging to measure brain volume found that the brain volume was negatively correlated to NEO PI-R neuroticism when correcting for possible effects of intracranial volume, sex, and age.[7]
Other studies have associated neuroticism with genetic variations, e.g., with 5-HTTLPR — a polymorphism in the serotonin transporter gene.[8]
However, not all studies find such an association.[9]
A genome-wide association study (GWA study) has pointed single-nucleotide polymorphisms in the MDGA2 gene as associated with neuroticism.[10]
Another GWA study gave some evidence that the rs362584 polymorphism in the SNAP25 gene was associated with neuroticism.[11]
# Geography
Neuroticism, along with other personality traits, has been mapped across states in the USA.[12]
People in eastern states such as New York, New Jersey, West Virginia, and Mississippi tend to score high on neuroticism, whereas people in many western states, such as Utah, Colorado, South Dakota, Oregon, and Arizona score lower on average.
People in states that are higher in neuroticism also tend to have higher rates of heart disease and lower life expectancy. | https://www.wikidoc.org/index.php/Neuroticism | |
0dd157e1b39ce81287c6473b54e34c6371ea980a | wikidoc | Nicergoline | Nicergoline
# Overview
Nicergoline (INN, marketed under the trade name Sermion) is an ergot derivative used to treat senile dementia and other disorders with vascular origins. It has been found to increase mental agility and enhance clarity and perception. It decreases vascular resistance and increases arterial blood flow in the brain, improving the utilization of oxygen and glucose by brain cells. It has similar vasoactive properties in other areas of the body, particularly the lungs.
It is used for vascular disorders such as cerebral thrombosis and atherosclerosis, arterial blockages in the limbs, Raynaud's disease, vascular migraines, and retinopathy.
Nicergoline has been registered in over fifty countries and has been used for more than three decades for the treatment of cognitive, affective, and behavioral disorders of older people.
# Clinical Uses
Nicerogline is used in the following cases:
- Acute and chronic cerebral metabolic-vascular disorders (cerebral arteriosclerosis, thrombosis and cerebral embolism, transitory cerebral ischaemia). Acute and chronic peripheral metabolic-vascular disorders (organic and functional arteriopathies of the limbs), Raynaud’s disease and other syndromes caused by altered peripheral irrigation.
- Migraines of vascular origin
- Coadjutant therapy in clinical situations accompanied by platelet hyper-aggregability, arterial tension.
- Corio-retinal vascular disorders: diabetic retinopathy, macular degeneration and retinal angiosclerosis
- Oto-vestibular problems of a vascular nature: dizziness, auditory hallucinations, hypoacusis.
Dosages for known conditions are usually administered at 5–10 mg three times a day, however anti-aging preventative purposes may want to consider 5 mg once or twice a day more adequate.
# Contraindications
Persons suffering from acute bleeding, myocardial infarction (heart conditions), hypertension, bradycardia or using alpha or beta receptor agonists should consult with their physician before use.
Although toxicology studies have not shown nicergoline to have any teratogenic effect, the use of this medicine during pregnancy should be limited to those cases where it is absolutely necessary.
On 28 June 2013 the European Medicines Agency recommended restricting the use of medicines containing ergot derivatives, including Nicergoline. They stated that "these medicines should no longer be used to treat several conditions involving blood circulation problems or problems with memory and sensation, or to prevent migraine headaches, since the risks are greater than the benefits in these indications. This is based on a review of data showing an increased risk of fibrosis (formation of excess connective tissue that can damage organs and body structures) and ergotism (symptoms of ergot poisoning, such as spasms and obstructed blood circulation) with these medicines." ()
Nicergoline is considered unsafe in porphyria.
# Adverse Effects
The side effects of nicergoline are usually limited to nausea, hot flushes, mild gastric upset, hypotension and dizziness. At high dosages bradycardia, increased appetite, agitation, diarrhea and perspiration have been known to occur. A single case of acute interstitial nephritis has been reported.
# Interactions
Nicergoline is known to enhance the cardiac depressive effects of propranolol. At high dosages, it is advisable to seek one’s physician's guidance if combining with potent vasodilators such as bromocriptine, Gingko biloba, picamilon, vinpocetine or xantinol nicotinate.
# Mechanism of Action
Nicergoline is an ergot alkaloid derivative that acts as a potent and selective alpha-1A adrenergic receptor antagonist. The IC50 of nicergoline in vitro has been reported to be 0.2 nM. The primary action of nicergoline is to increase arterial blood flow by vasodilation. Furthermore, it is known that nicergoline inhibits platelet aggregation. Studies have shown that nicergoline also increases nerve growth factor in the aged brain. | Nicergoline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nicergoline (INN, marketed under the trade name Sermion) is an ergot derivative used to treat senile dementia and other disorders with vascular origins. It has been found to increase mental agility and enhance clarity and perception. It decreases vascular resistance and increases arterial blood flow in the brain, improving the utilization of oxygen and glucose by brain cells. It has similar vasoactive properties in other areas of the body, particularly the lungs.
It is used for vascular disorders such as cerebral thrombosis and atherosclerosis, arterial blockages in the limbs, Raynaud's disease, vascular migraines, and retinopathy.
Nicergoline has been registered in over fifty countries and has been used for more than three decades for the treatment of cognitive, affective, and behavioral disorders of older people.[1]
# Clinical Uses
Nicerogline is used in the following cases:
- Acute and chronic cerebral metabolic-vascular disorders (cerebral arteriosclerosis, thrombosis and cerebral embolism, transitory cerebral ischaemia). Acute and chronic peripheral metabolic-vascular disorders (organic and functional arteriopathies of the limbs), Raynaud’s disease and other syndromes caused by altered peripheral irrigation.
- Migraines of vascular origin
- Coadjutant therapy in clinical situations accompanied by platelet hyper-aggregability, arterial tension.
- Corio-retinal vascular disorders: diabetic retinopathy, macular degeneration and retinal angiosclerosis
- Oto-vestibular problems of a vascular nature: dizziness, auditory hallucinations, hypoacusis.
Dosages for known conditions are usually administered at 5–10 mg three times a day, however anti-aging preventative purposes may want to consider 5 mg once or twice a day more adequate.[2]
# Contraindications
Persons suffering from acute bleeding, myocardial infarction (heart conditions), hypertension, bradycardia or using alpha or beta receptor agonists should consult with their physician before use.
Although toxicology studies have not shown nicergoline to have any teratogenic effect, the use of this medicine during pregnancy should be limited to those cases where it is absolutely necessary.
On 28 June 2013 the European Medicines Agency recommended restricting the use of medicines containing ergot derivatives, including Nicergoline. They stated that "these medicines should no longer be used to treat several conditions involving blood circulation problems or problems with memory and sensation, or to prevent migraine headaches, since the risks are greater than the benefits in these indications. This is based on a review of data showing an increased risk of fibrosis (formation of excess connective tissue that can damage organs and body structures) and ergotism (symptoms of ergot poisoning, such as spasms and obstructed blood circulation) with these medicines." (http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/06/news_detail_001832.jsp&mid=WC0b01ac058004d5c1b)
Nicergoline is considered unsafe in porphyria.[3]
# Adverse Effects
The side effects of nicergoline are usually limited to nausea, hot flushes, mild gastric upset, hypotension and dizziness.[3] At high dosages bradycardia, increased appetite, agitation, diarrhea and perspiration have been known to occur. A single case of acute interstitial nephritis has been reported.[4]
# Interactions
Nicergoline is known to enhance the cardiac depressive effects of propranolol.[3] At high dosages, it is advisable to seek one’s physician's guidance if combining with potent vasodilators such as bromocriptine, Gingko biloba, picamilon, vinpocetine or xantinol nicotinate.
# Mechanism of Action
Nicergoline is an ergot alkaloid derivative that acts as a potent and selective alpha-1A adrenergic receptor antagonist.[5] The IC50 of nicergoline in vitro has been reported to be 0.2 nM.[6] The primary action of nicergoline is to increase arterial blood flow by vasodilation. Furthermore, it is known that nicergoline inhibits platelet aggregation. Studies have shown that nicergoline also increases nerve growth factor in the aged brain. | https://www.wikidoc.org/index.php/Nicergoline | |
f384ee6f9e2f8e17d0d2f9ba153afadae58134ce | wikidoc | Nick Tatham | Nick Tatham
Nick Tatham (born June 11, 1983 in Hong Kong) is a British singer/songwright who has dealt with Tourette syndrome for most of his life whilst writing and recording critically-acclaimed ballads, pop songs and other assorted modern music.
He can play both the guitar and piano to a professional standard - something which is made even more incredible by the fact that he is completely self-taught. His talent has been publicly-recognised.
Nick is currently signed to the En Masse Music & Publishing Ltd. label in the south of England and he has appeared in several television documentaries, most notably on the BBC. He also received the "Meridian Tonight Young Hero Award", live on TV in 2002, for his contributions to local music and his constant optimism and strength in dealing with his condition. Nick made his feature film debut in 2004 with Richard Booth's Live for the Moment, a drama which chronicled the life of a person with Tourette's syndrome. Although the condition cannot be cured in the literal sense (it can only be controlled through medication), when Nick sings or composes music, his whole body changes and he "becomes a different person".
# Discography
- Tourette Blues (2000)
- Love is All Around (2002)
- Nick Tatham (demo recordings) (2005 & 2006)
# Music videos
- Different (single) (2006), directed by Richard Booth
# Notes
- ↑ CD Times. Nick Tatham - Love Is All Around
- ↑ Tourette Syndrome Association - UK. Tatham
- ↑ TSA. Victories: Tatham (PDF) | Nick Tatham
Nick Tatham (born June 11, 1983 in Hong Kong) is a British singer/songwright who has dealt with Tourette syndrome for most of his life whilst writing and recording critically-acclaimed ballads, pop songs and other assorted modern music.[1]
He can play both the guitar and piano to a professional standard - something which is made even more incredible by the fact that he is completely self-taught. His talent has been publicly-recognised.[2]
Nick is currently signed to the En Masse Music & Publishing Ltd. label in the south of England and he has appeared in several television documentaries, most notably on the BBC. He also received the "Meridian Tonight Young Hero Award", live on TV in 2002, for his contributions to local music and his constant optimism and strength in dealing with his condition.[3] Nick made his feature film debut in 2004 with Richard Booth's Live for the Moment, a drama which chronicled the life of a person with Tourette's syndrome. Although the condition cannot be cured in the literal sense (it can only be controlled through medication), when Nick sings or composes music, his whole body changes and he "becomes a different person".
# Discography
- Tourette Blues (2000)
- Love is All Around (2002)
- Nick Tatham (demo recordings) (2005 & 2006)
# Music videos
- Different (single) (2006), directed by Richard Booth
# Notes
- ↑ CD Times. Nick Tatham - Love Is All Around
- ↑ Tourette Syndrome Association - UK. Tatham
- ↑ TSA. Victories: Tatham (PDF)
# External links
- Nick Tatham's official website
- Template:Imdb name
- Song clips
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Nick_Tatham | |
66e6eba16f6c913638cfb88ca1cbaeba1530cfc2 | wikidoc | Niclosamide | Niclosamide
# Overview
Niclosamide is a teniacide ("tenia-" referring to tapeworm) in the anthelmintic family especially effective against cestodes that infect humans.
It is stressed that while anthelmintics are a drug familiy used to treat worm infections, Niclosamide is used specifically to treat tapeworms and is not effective against worms such as pinworms or roundworms.
It is a chewable tablet taken orally, dosage depending on type of worm and patient's age and/or weight.
Niclosamide molecules are lethal to tapeworms upon contact.
# Category
Anthelmintic
# US Brand Names
NICLOCIDE®, YOMESAN® (DISCONTINUED)
# FDA Package Insert
Clinical Pharmacology
# Mechanism of Action
Niclosamide uncouples oxidative phosphorylation in the tapeworm. | Niclosamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Niclosamide is a teniacide ("tenia-" referring to tapeworm) in the anthelmintic family especially effective against cestodes that infect humans.
It is stressed that while anthelmintics are a drug familiy used to treat worm infections, Niclosamide is used specifically to treat tapeworms and is not effective against worms such as pinworms or roundworms.
It is a chewable tablet taken orally, dosage depending on type of worm and patient's age and/or weight.
Niclosamide molecules are lethal to tapeworms upon contact.
# Category
Anthelmintic
# US Brand Names
NICLOCIDE®, YOMESAN® (DISCONTINUED)
# FDA Package Insert
Clinical Pharmacology
# Mechanism of Action
Niclosamide uncouples oxidative phosphorylation in the tapeworm.[1] | https://www.wikidoc.org/index.php/Niclosamide | |
96fa3c858f88196f2f93fcefcbabdcdadba7b202 | wikidoc | Nicocodeine | Nicocodeine
Nicocodeine (Lyopect®, Tusscodin®) is an opiate derivative, closely related to dihydrocodeine and the codeine analogue of nicomorphine developed as a cough suppressant and analgesic. It is not commonly used in most countries, but has activity similar to other opiates. Nicocodeine and nicomorphine were introduced in the late 1950s by Lannacher Heilmittel of Austria. Nicocodeine is metabolised in the liver by demethylation to produce nicomorphine, also known as 6-nicotinoylmorphine, and subsequently further metabolised to morphine. Side effects are similar to those of other opiates and include itching, nausea and respiratory depression.
Nicocodeine is regulated in most cases as is codeine and similar weak opiate drugs like ethylmorphine, benzylmorphine, dihydrocodeine and its other close derivatives like acetyldihydrocodeine (although not the stronger hydrocodone or oxycodone, which are regulated like morphine) and others of this class in the laws of countries and the Single Convention On Narcotic Drugs. One notable example is the fact that nicocodeine is a Schedule I/Narcotic controlled substance in the United States along with heroin as nicocodeine was never introduced to medical use in the United States.
Nicodicodeine is a similar drug which is to nicocodeine as codeine is to dihydrocodeine. The metabolites of nicodicodeine include dihydromorphine where nicocodeine is turned into morphine as noted above.
Nicocodeine cough medicines are available as syrups, extended-release syrups, and sublingual drops. Analgesic preparations are also in the form of sublingial drops and tablets for oral administration. Nicocodeine is approximately the same strength as hydrocodone.
CAS number of hydrochloride: 58263-01-7 | Nicocodeine
Nicocodeine (Lyopect®, Tusscodin®) is an opiate derivative, closely related to dihydrocodeine and the codeine analogue of nicomorphine developed as a cough suppressant and analgesic. It is not commonly used in most countries, but has activity similar to other opiates. Nicocodeine and nicomorphine were introduced in the late 1950s by Lannacher Heilmittel of Austria. Nicocodeine is metabolised in the liver by demethylation to produce nicomorphine, also known as 6-nicotinoylmorphine, and subsequently further metabolised to morphine. Side effects are similar to those of other opiates and include itching, nausea and respiratory depression.
Nicocodeine is regulated in most cases as is codeine and similar weak opiate drugs like ethylmorphine, benzylmorphine, dihydrocodeine and its other close derivatives like acetyldihydrocodeine (although not the stronger hydrocodone or oxycodone, which are regulated like morphine) and others of this class in the laws of countries and the Single Convention On Narcotic Drugs. One notable example is the fact that nicocodeine is a Schedule I/Narcotic controlled substance in the United States along with heroin as nicocodeine was never introduced to medical use in the United States.
Nicodicodeine is a similar drug which is to nicocodeine as codeine is to dihydrocodeine. The metabolites of nicodicodeine include dihydromorphine where nicocodeine is turned into morphine as noted above.
Nicocodeine cough medicines are available as syrups, extended-release syrups, and sublingual drops. Analgesic preparations are also in the form of sublingial drops and tablets for oral administration. Nicocodeine is approximately the same strength as hydrocodone.
CAS number of hydrochloride: 58263-01-7
Template:Pharm-stub
Template:Opioids
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Nicocodeine | |
ba9dfc14a55dfba43ebbae1641b3f957891eca74 | wikidoc | Nidovirales | Nidovirales
The Nidovirales are an order of viruses with vertebrate hosts. They include the Coronaviridae, along with the genera Arterivirus and Okavirus in separate families.
This group consists of viruses which have (+) sense single stranded RNA genomes. It contains the virus which has the largest known non segmented RNA genome; this is the mouse hepatitis virus (MHV) which has a genome of 31.5kb. These genomes share the structure of eukaryotic mRNA and so the viruses can use some host cell proteins during replication and gene expression which occurs in the cytoplasm of the host cell. Unlike many viruses they do not have any polymerase in the virus particle as the genome can be read directly as mRNA when it first enters the host cell.
This group of viruses express the structural proteins separately from the non-structural ones. The structural proteins are encoded at the 3’ region of the genome and are expressed from a set of subgenomic mRNAs. These viruses encode one main proteinase and between one and three accessory proteinases which are mainly involved in expressing the replicase gene. These proteinases are also responsible for activating/inactivating specific proteins at the correct time in the virus life cycle and so ensure replication occurs at the right time. There are still a large number of proteins which have been identified on the genomes of nidovirales but whose function has not yet been determined. | Nidovirales
The Nidovirales are an order of viruses with vertebrate hosts. They include the Coronaviridae,[1] [2] along with the genera Arterivirus [3] and Okavirus in separate families.
This group consists of viruses which have (+) sense single stranded RNA genomes. It contains the virus which has the largest known non segmented RNA genome; this is the mouse hepatitis virus (MHV) which has a genome of 31.5kb. These genomes share the structure of eukaryotic mRNA and so the viruses can use some host cell proteins during replication and gene expression which occurs in the cytoplasm of the host cell. Unlike many viruses they do not have any polymerase in the virus particle as the genome can be read directly as mRNA when it first enters the host cell.
This group of viruses express the structural proteins separately from the non-structural ones. The structural proteins are encoded at the 3’ region of the genome and are expressed from a set of subgenomic mRNAs. These viruses encode one main proteinase and between one and three accessory proteinases which are mainly involved in expressing the replicase gene. These proteinases are also responsible for activating/inactivating specific proteins at the correct time in the virus life cycle and so ensure replication occurs at the right time. There are still a large number of proteins which have been identified on the genomes of nidovirales but whose function has not yet been determined. | https://www.wikidoc.org/index.php/Nidovirales | |
32ed06f447fa00332f5d7088428a84223ee08826 | wikidoc | Nikethamide | Nikethamide
# Overview
Nikethamide is a stimulant which mainly affects the respiratory cycle. Widely known by its former trade name of Coramine, it was used in the mid-twentieth century as a medical countermeasure against tranquilizer overdoses, before the advent of endotracheal intubation and positive-pressure lung expansion. It is now considered to be of no value for such purposes, and may be dangerous.
In alternate terminology, it is known as nicotinic acid diethylamide, which meaningfully emphasizes its laboratory origins, and of which its common name is derived as a blend.
# Former and current medical use
Coramine was used by suspected serial killer John Bodkin Adams when treating patient Gertrude Hullett, whom he was suspected of murdering. However, the toxicity of nikethamide is quite low (Template:LD50 rabbits 650 mg/Kg oral, LD50 rats 240 mg/Kg s.c.).
Theodor Morell, Adolf Hitler's personal physician, would inject the German ruler with Coramine when Hitler was unduly sedated with barbiturates. In addition, Morell would use Coramine as part of an all-purpose "tonic" for Hitler.
It is available as a short-acting over-the-counter drug in several South American and European countries, combined with glucose in form of lozenges. It is especially useful for mountain climbers to increase endurance at high altitudes. Contraindications include hypertension, cardiovascular pathologies and epilepsy.
# Use in sports
In some sports, nikethamide is listed by the World Anti-Doping Agency as a banned substance. Croatian tennis player Marin Čilić was suspended from competition for nine months after he tested positive for nikethamide in April 2013. This ban was later reduced to four months after Cilic appealed and claimed he had unintentionally ingested it in a glucose tablet bought at a pharmacy. Polish kart driver Igor Walilko was given a two-year ban, later reduced to eighteen month, from competition in 2010 due to testing positive for nikethamide after a win in Germany in July, 2010. | Nikethamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nikethamide is a stimulant which mainly affects the respiratory cycle. Widely known by its former trade name of Coramine, it was used in the mid-twentieth century as a medical countermeasure against tranquilizer overdoses, before the advent of endotracheal intubation and positive-pressure lung expansion. It is now considered to be of no value for such purposes, and may be dangerous.[1]
In alternate terminology, it is known as nicotinic acid diethylamide, which meaningfully emphasizes its laboratory origins, and of which its common name is derived as a blend.
# Former and current medical use
Coramine was used by suspected serial killer John Bodkin Adams when treating patient Gertrude Hullett, whom he was suspected of murdering.[2] However, the toxicity of nikethamide is quite low (Template:LD50 rabbits 650 mg/Kg oral, LD50 rats 240 mg/Kg s.c.).
Theodor Morell, Adolf Hitler's personal physician, would inject the German ruler with Coramine when Hitler was unduly sedated with barbiturates. In addition, Morell would use Coramine as part of an all-purpose "tonic" for Hitler.[3]
It is available as a short-acting over-the-counter drug in several South American and European countries, combined with glucose in form of lozenges. It is especially useful for mountain climbers to increase endurance at high altitudes. Contraindications include hypertension, cardiovascular pathologies and epilepsy.[4]
# Use in sports
In some sports, nikethamide is listed by the World Anti-Doping Agency as a banned substance. Croatian tennis player Marin Čilić was suspended from competition for nine months after he tested positive for nikethamide in April 2013.[5] This ban was later reduced to four months after Cilic appealed and claimed he had unintentionally ingested it in a glucose tablet bought at a pharmacy.[6] Polish kart driver Igor Walilko was given a two-year ban, later reduced to eighteen month, from competition in 2010 due to testing positive for nikethamide after a win in Germany in July, 2010.[7] | https://www.wikidoc.org/index.php/Nikethamide | |
d50b47c1a26bcead39a693e4ab99bed1c371cb5a | wikidoc | Nilvadipine | Nilvadipine
# Overview
Nilvadipine is a calcium channel blocker (CCB) used for the treatment of hypertension and chronic major cerebral artery occlusion.
Pathohistochemical studies have revealed that the volume of the infarction in the middle cerebral artery occlusion model could be decreased by nilvadipine.
Nilvadipine was tested in clinical trial as a possible treatment for Alzheimer's Disease in Ireland by the Roskamp Institute, Florida, USA and Trinity College, Ireland.
Following this study, an international research consortium led by Trinity College Dublin (Ireland) in May 2011 announced the selection for funding of a large-scale European clinical trial of Nilvadipine, an Alzheimer’s disease drug developed at the Roskamp Institute in Sarasota. More than 500 Alzheimer’s patients will participate in the multicenter Phase III clinical trial designed to study the effectiveness of Nilvadipine. | Nilvadipine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nilvadipine is a calcium channel blocker (CCB) used for the treatment of hypertension and chronic major cerebral artery occlusion.
Pathohistochemical studies have revealed that the volume of the infarction in the middle cerebral artery occlusion model could be decreased by nilvadipine.
Nilvadipine was tested in clinical trial as a possible treatment for Alzheimer's Disease in Ireland by the Roskamp Institute, Florida, USA and Trinity College, Ireland.[1]
Following this study, an international research consortium led by Trinity College Dublin (Ireland) in May 2011 announced the selection for funding of a large-scale European clinical trial of Nilvadipine, an Alzheimer’s disease drug developed at the Roskamp Institute in Sarasota. More than 500 Alzheimer’s patients will participate in the multicenter Phase III clinical trial designed to study the effectiveness of Nilvadipine.[2] | https://www.wikidoc.org/index.php/Nilvadipine | |
559f49135a4063d8a538bfe8e46a07cb82368d94 | wikidoc | Nimetazepam | Nimetazepam
Nimetazepam (marketed under brand name Erimin®) is a hypnotic drug which is a benzodiazepine derivative. It possesses strong hypnotic, anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It is sold in 5 mg tablets known as Erimin-5. It is used to treat insomnia.
Nimetazepam has a reputation for being particularly subject to abuse (known as 'Happy 5', sold as an Ecstasy replacement without a hangover), especially by persons addicted to amphetamines or opiates. For this reason it is no longer sold in most Western nations, but is still a significant drug of abuse in some Asian countries such as Japan and Malaysia. Nimetazepam is the only benzodiazepine to be subject to legal restrictions in Malaysia, and due to its scarcity, many tablets sold on the black market are in fact counterfeits containing other benzodiazepines such as diazepam or nitrazepam instead.
In a rat study Nimetazepam showed greater damage to the fetus, as did nitrazepam and especially temazepam when compared against other benzodiazepines. Diazepam however showed relatively weak fetal toxicities. | Nimetazepam
Nimetazepam (marketed under brand name Erimin®) is a hypnotic drug which is a benzodiazepine derivative. It possesses strong hypnotic, anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It is sold in 5 mg tablets known as Erimin-5. It is used to treat insomnia.
Nimetazepam has a reputation for being particularly subject to abuse (known as 'Happy 5', sold as an Ecstasy replacement without a hangover), especially by persons addicted to amphetamines or opiates. For this reason it is no longer sold in most Western nations, but is still a significant drug of abuse in some Asian countries such as Japan and Malaysia. Nimetazepam is the only benzodiazepine to be subject to legal restrictions in Malaysia, and due to its scarcity, many tablets sold on the black market are in fact counterfeits containing other benzodiazepines such as diazepam or nitrazepam instead.[1]
In a rat study Nimetazepam showed greater damage to the fetus, as did nitrazepam and especially temazepam when compared against other benzodiazepines. Diazepam however showed relatively weak fetal toxicities.[2] | https://www.wikidoc.org/index.php/Nimetazepam | |
ea630c9111e9885e6df2784fa2cf22166fd6c6ec | wikidoc | Pentostatin | Pentostatin
# 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
Pentostatin is an antineoplastic agent that is FDA approved for the treatment of untreated or alpha-interferon-refractory hairy cell leukemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include disorder of skin, pruritus, abdominal pain, diarrhea, nausea, vomiting, anemia, leukopenia, thrombocytopenia, myalgia, headache, fever, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Pentostatin is indicated as single-agent treatment for both untreated and alpha-interferon-refractory hairy cell leukemia patients with active disease as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.
# Dosage
- It is recommended that patients receive hydration with 500 to 1,000 mL of 5% Dextrose in 0.5 Normal Saline or equivalent before Pentostatin administration. An additional 500 mL of 5% Dextrose or equivalent should be administered after Pentostatin is given.
- The recommended dosage of Pentostatin for the treatment of hairy cell leukemia is 4 mg/m2 every other week. Pentostatin may be administered intravenously by bolus injection or diluted in a larger volume and given over 20 to 30 minutes. (See Preparation of Intravenous Solution.)
- Higher doses are not recommended.
- No extravasation injuries were reported in clinical studies.
- The optimal duration of treatment has not been determined. In the absence of major toxicity and with observed continuing improvement, the patient should be treated until a complete response has been achieved. Although not established as required, the administration of two additional doses has been recommended following the achievement of a complete response.
- All patients receiving Pentostatin at 6 months should be assessed for response to treatment. If the patient has not achieved a complete or partial response, treatment with Pentostatin should be discontinued.
- If the patient has achieved a partial response, Pentostatin treatment should be continued in an effort to achieve a complete response. At any time thereafter that a complete response is achieved, two additional doses of Pentostatin are recommended. Pentostatin treatment should then be stopped. If the best response to treatment at the end of 12 months is a partial response, it is recommended that treatment with Pentostatin be stopped.
- Withholding or discontinuation of individual doses may be needed when severe adverse reactions occur. Drug treatment should be withheld in patients with severe rash, and withheld or discontinued in patients showing evidence of nervous system toxicity.
- Pentostatin treatment should be withheld in patients with active infection occurring during the treatment but may be resumed when the infection is controlled.
- Patients who have elevated serum creatinine should have their dose withheld and a creatinine clearance determined. There are insufficient data to recommend a starting or a subsequent dose for patients with impaired renal function (creatinine clearance <60 mL/min).
- Patients with impaired renal function should be treated only when the potential benefit justifies the potential risk. Two patients with impaired renal function (creatinine clearances 50 to 60 mL/min) achieved complete response without unusual adverse events when treated with 2 mg/m2.
- No dosage reduction is recommended at the start of therapy with Pentostatin in patients with anemia, neutropenia, or thrombocytopenia. In addition, dosage reductions are not recommended during treatment in patients with anemia and thrombocytopenia if patients can be otherwise supported hematologically. Pentostatin should be temporarily withheld if the absolute neutrophil count falls during treatment below 200 cells/mm3 in a patient who had an initial neutrophil count greater than 500 cells/mm3 and may be resumed when the count returns to predose levels.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pentostatin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pentostatin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pentostatin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pentostatin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pentostatin in pediatric patients.
# Contraindications
- Pentostatin is contraindicated in patients who have demonstrated hypersensitivity to Pentostatin.
# Warnings
- Patients with hairy cell leukemia may experience myelosuppression primarily during the first few courses of treatment. Patients with infections prior to Pentostatin treatment have in some cases developed worsening of their condition leading to death, whereas others have achieved complete response. Patients with infection should be treated only when the potential benefit of treatment justifies the potential risk to the patient. Efforts should be made to control the infection before treatment is initiated or resumed.
- In patients with progressive hairy cell leukemia, the initial courses of Pentostatin treatment were associated with worsening of neutropenia. Therefore, frequent monitoring of complete blood counts during this time is necessary. If severe neutropenia continues beyond the initial cycles, patients should be evaluated for disease status, including a bone marrow examination.
- Elevations in liver function tests occurred during treatment with Pentostatin and were generally reversible.
- Renal toxicity was observed at higher doses in early studies; however, in patients treated at the recommended dose, elevations in serum creatinine were usually minor and reversible. There were some patients who began treatment with normal renal function who had evidence of mild to moderate toxicity at a final assessment.
- Rashes, occasionally severe, were commonly reported and may worsen with continued treatment. Withholding of treatment may be required.
- Acute pulmonary edema and hypotension, leading to death, have been reported in the literature in patients treated with pentostatin in combination with carmustine, etoposide and high dose cyclophosphamide as part of the ablative regimen for bone marrow transplant.
# Adverse Reactions
## Clinical Trials Experience
- Most patients treated for hairy cell leukemia in the five NCI-sponsored Phase 2 studies and the Phase 3 SWOG study experienced an adverse event. The following table lists the most frequently occurring adverse events in patients treated with Pentostatin (both frontline and IFN-refractory patients) compared with IFN (frontline only), regardless of drug association. The drug association of some adverse events is uncertain as they may be associated with the disease itself (eg, infection, hematologic suppression), but other events, such as the gastrointestinal symptoms, rashes, and abnormal liver function tests, can in many cases be attributed to the drug. Most adverse events that were assessed for severity were either mild or moderate, and diminished in frequency with continued therapy.
- The total incidence for all types of infections is considerably higher for both treatment groups in the SWOG 8691 study than is listed in the table above. An intent-to-treat analysis of infections found that 38% of patients treated with Pentostatin and 34% of patients treated with IFN averaged 2.4 and 1.9 documented infections during treatment, respectively. The following table lists the different types of infections that were reported as adverse events during the initial phase of the SWOG study. There were no apparent differences in the types of infection between the 2 treatment groups, with the possible exception of herpes zoster which was reported more frequently for Pentostatin (8%) than for IFN (1%).
- The drug relatedness of the adverse events listed below cannot be excluded. The following adverse events occurred in 3% to 10% of Pentostatin-treated patients in the initial phase of the SWOG study:
- Body as a Whole—Chest Pain, Death, Face edema, peripheral edema
- Cardiovascular System—Hemorrhage, Hypotension
- Digestive System—Dental Abnormalities, Dyspepsia, Flatulence, Gingivitis
- Hemic and Lymphatic System—Agranulocytosis
- Laboratory Deviations—Elevated Creatinine
- Musculoskeletal System—Arthralgia
- Nervous System—Confusion, Dizziness, Insomnia, Paresthesia, Somnolence
- Psychobiologic Function—Anxiety, Depression, Nervousness
- Respiratory System—Asthma
- Skin & Appendages—Skin Dry, Urticaria
- The remaining adverse events which occurred in less than 3% of Pentostatin-treated patients during the initial phase of the SWOG study:
- Body as a Whole—Flu-like Symptoms, Hangover Effect, Neoplasm
- Cardiovascular System—Angina Pectoris, Arrhythmia, A-V Block, Bradycardia, Extrasystoles Ventricular, Heart Arrest, Heart Failure, hypertension, pericardial effusion, phlebitis, pulmonary embolus, sinus arrest, tachycardia, thrombophlebitis Deep, vasculitis
- Digestive System—Constipation, Dysphagia, Glossitis, Ileus
- Hemic and Lymphatic System—Acute Leukemia, Anemia-Hemolytic, Aplastic Anemia
- Laboratory Deviations—Hypercalcemia, Hyponatremia
- Musculoskeletal System—arthritis, Gout
- Nervous System—Amnesia, Ataxia, Convulsions, Dreaming Abnormal, dysarthria, encephalitis, hyperkinesia, meningism, neuralgia, neuritis, neuropathy, paralysis, Syncope, twitching, Vertigo
- Psychobiologic Function—Decrease/Loss Libido, Emotional Lability, Hallucination, Hostility, Neurosis, Thinking Abnormal
- Respiratory System—Bronchospasm, Larynx Edema
- Skin and Appendages—Acne, Alopecia, Eczema, Petechial Rash, Photosensitivity Reaction
- Special Senses—Amblyopia, Deafness, Earache, Eyes Dry, Labyrinthitis, Lacrimation Disorder, Nonreactive Eye, Photophobia, Retinopathy, Tinnitus, Unusual Taste, Vision Abnormal, Watery Eyes
- Urogenital System—Amenorrhea, Breast Lump, Impotence, Kidney Function Abnormal, Nephropathy, Renal Failure, Renal Insufficiency, Renal Stone
- One patient with hairy cell leukemia treated with Pentostatin during another clinical study developed unilateral uveitis with vision loss.
- Nineteen (5%) patients withdrew from the Phase 3 SWOG 8691 study because of adverse events; 9 during initial Pentostatin treatment, 4 during Pentostatin crossover, 5 during initial IFN treatment, and 1 during both initial IFN treatment and Pentostatin crossover. In the Phase 2 studies in IFN-refractory hairy cell leukemia, 11% of patients withdrew from treatment with Pentostatin due to an adverse event.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Pentostatin in the drug label.
# Drug Interactions
- Allopurinol and Pentostatin are both associated with skin rashes. Based on clinical studies in 25 refractory patients who received both Pentostatin and allopurinol, the combined use of Pentostatin and allopurinol did not appear to produce a higher incidence of skin rashes than observed with Pentostatin alone. There has been a report of one patient who received both drugs and experienced a hypersensitivity vasculitis that resulted in death. It was unclear whether this adverse event and subsequent death resulted from the drug combination.
- Biochemical studies have demonstrated that pentostatin enhances the effects of vidarabine, a purine nucleoside with antiviral activity. The combined use of vidarabine and Pentostatin may result in an increase in adverse reactions associated with each drug. The therapeutic benefit of the drug combination has not been established.
- The combined use of Pentostatin and fludarabine phosphate is not recommended because it may be associated with an increased risk of fatal pulmonary toxicity (see WARNINGS).
- Acute pulmonary edema and hypotension, leading to death, have been reported in the literature in patients treated with pentostatin in combination with carmustine, etoposide and high dose cyclophosphamide as part of the ablative regimen for bone marrow transplant.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Pentostatin can cause fetal harm when administered to a pregnant woman. Pentostatin was administered intravenously at doses of 0, 0.01, 0.1, or 0.75 mg/kg/day (0, 0.06, 0.6, and 4.5 mg/m2) to pregnant rats on days 6 through 15 of gestation. Drug-related maternal toxicity occurred at doses of 0.1 and 0.75 mg/kg/day (0.6 and 4.5 mg/m2). Teratogenic effects were observed at 0.75 mg/kg/day (4.5 mg/m2) manifested by increased incidence of various skeletal malformations. In a dose range-finding study, pentostatin was administered intravenously to rats at doses of 0, 0.05, 0.1, 0.5, 0.75, or 1 mg/kg/day (0, 0.3, 0.6, 3, 4.5, 6 mg/m2), on days 6 through 15 of gestation. Fetal malformations that were observed were an omphalocele at 0.05 mg/kg (0.3 mg/m2), gastroschisis at 0.75 mg/kg and 1 mg/kg (4.5 and 6 mg/m2), and a flexure defect of the hindlimbs at 0.75 mg/kg (4.5 mg/m2). Pentostatin was also shown to be teratogenic in mice when administered as a single 2 mg/kg (6 mg/m2) intraperitoneal injection on day 7 of gestation. Pentostatin was not teratogenic in rabbits when administered intravenously on days 6 through 18 of gestation at doses of 0, 0.005, 0.01, or 0.02 mg/kg/day (0, 0.015, 0.03, or 0.06 mg/m2); however maternal toxicity, abortions, early deliveries, and deaths occurred in all drug-treated groups. There are no adequate and well-controlled studies in pregnant women. If Pentostatin is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential receiving Pentostatin should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pentostatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pentostatin during labor and delivery.
### Nursing Mothers
- It is not known whether Pentostatin 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 pentostatin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of Pentostatin to the mother.
### Pediatric Use
- Safety and effectiveness in children or adolescents have not been established.
### Geriatic Use
There is no FDA guidance on the use of Pentostatin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Pentostatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pentostatin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pentostatin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pentostatin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pentostatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pentostatin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Pentostatin in the drug label.
# IV Compatibility
Preparation of Intravenous Solution
- Procedures for proper handling and disposal of anticancer drugs should be followed. Several guidelines on this subject have been published.2-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Spills and wastes should be treated with a 5% sodium hypochlorite solution prior to disposal.
- Protective clothing including polyethylene gloves must be worn.
- Transfer 5 mL of Sterile Water for Injection USP to the vial containing Pentostatin and mix thoroughly to obtain complete dissolution of a solution yielding 2 mg/mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
- Pentostatin may be given intravenously by bolus injection or diluted in a larger volume (25 to 50 mL) with 5% Dextrose Injection USP or 0.9% Sodium Chloride Injection USP. Dilution of the entire contents of a reconstituted vial with 25 mL or 50 mL provides a pentostatin concentration of 0.33 mg/mL or 0.18 mg/mL, respectively, for the diluted solutions.
- Pentostatin solution when diluted for infusion with 5% Dextrose Injection USP or 0.9% Sodium Chloride Injection USP does not interact with PVC infusion containers or administration sets at concentrations of 0.18 mg/mL to 0.33 mg/mL.
Stability
- Pentostatin vials are stable at refrigerated storage temperature 2° to 8° C (36° to 46°F) for the period stated on the package. Vials reconstituted or reconstituted and further diluted as directed may be stored at room temperature and ambient light but should be used within 8 hours because Pentostatin contains no preservatives.
# Overdosage
- No specific antidote for Pentostatin overdose is known. Pentostatin administered at higher doses (20- 50 mg/m2 in divided doses over 5 days) than recommended was associated with deaths due to severe renal, hepatic, pulmonary, and CNS toxicity. In case of overdose, management would include general supportive measures through any period of toxicity that occurs.
# Pharmacology
## Mechanism of Action
- Pentostatin is a potent transition state inhibitor of the enzyme adenosine deaminase (ADA). The greatest activity of ADA is found in cells of the lymphoid system with T-cells having higher activity than B-cells, and T-cell malignancies having higher ADA activity than B-cell malignancies. Pentostatin inhibition of ADA, particularly in the presence of adenosine or deoxyadenosine, leads to cytotoxicity, and this is believed to be due to elevated intracellular levels of dATP which can block DNA synthesis through inhibition of ribonucleotide reductase. Pentostatin can also inhibit RNA synthesis as well as cause increased DNA damage. In addition to elevated dATP, these mechanisms may also contribute to the overall cytotoxic effect of pentostatin. The precise mechanism of pentostatin’s antitumor effect, however, in hairy cell leukemia is not known.
## Structure
- Pentostatin® (pentostatin for injection) is supplied as a sterile, apyrogenic, lyophilized powder in single-dose vials for intravenous administration. Each vial contains 10 mg of pentostatin and 50 mg of Mannitol, USP. The pH of the final product is maintained between 7.0 and 8.5 by addition of sodium hydroxide or hydrochloric acid.
- Pentostatin, also known as 2’-deoxycoformycin (DCF), is a potent inhibitor of the enzyme adenosine deaminase and is isolated from fermentation cultures of Streptomyces antibioticus. Pentostatin is known chemically as (R)-3-(2-deoxy-ß-D-erythropentofuranosyl)3,6,7,8 tetrahydroimidazodiazepin-8-ol with a molecular formula of C11H16N4O4 and a molecular weight of 268.27. The molecular structure of pentostatin is:
- Pentostatin is a white to off-white solid, freely soluble in distilled water.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pentostatin in the drug label.
## Pharmacokinetics
- A tissue distribution and whole-body autoradiography study in the rat revealed that radioactivity concentrations were highest in the kidneys with very little central nervous system penetration.
- In man, following a single dose of 4 mg/m2 of pentostatin infused over 5 minutes, the distribution half-life was 11 minutes, the mean terminal half-life was 5.7 hours, the mean plasma clearance was 68 mL/min/m2, and approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity. The plasma protein binding of pentostatin is low, approximately 4%.
- A positive correlation was observed between pentostatin clearance and creatinine clearance (CrCl) in patients with creatinine clearance values ranging from 60 mL/min to 130 mL/min.1 Pentostatin half-life in patients with renal impairment (CrCl 60 mL/min, n=14), about 6 hours.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis:
- No animal carcinogenicity studies have been conducted with pentostatin.
Mutagenesis:
- Pentostatin was nonmutagenic when tested in Salmonella typhimurium strains TA-98, TA-1535, TA-1537, and TA-1538. When tested with strain TA-100, a repeatable statistically significant response trend was observed with and without metabolic activation. The response was 2.1 to 2.2 fold higher than the background at 10 mg/plate, the maximum possible drug concentration. Formulated pentostatin was clastogenic in the in vivo mouse bone marrow micronucleus assay at 20, 120, and 240 mg/kg. Pentostatin was not mutagenic to V79 Chinese hamster lung cells at the HGPRT locus exposed 3 hours to concentrations of 1 to 3 mg/mL, with or without metabolic activation. Pentostatin did not significantly increase chromosomal aberrations in V79 Chinese hamster lung cells exposed 3 hours to 1 to 3 mg/mL in the presence or absence of metabolic activation.
Impairment of Fertility:
- No fertility studies have been conducted in animals; however, in a 5-day intravenous toxicity study in dogs, mild seminiferous tubular degeneration was observed with doses of 1 and 4 mg/kg. The possible adverse effects on fertility in humans have not been determined.
# Clinical Studies
- The following table provides efficacy results for 4 groups (columns) of patients with hairy cell leukemia: patients who initially received Pentostatin, patients who initially received alpha-interferon (IFN), and 2 different groups of patients who received Pentostatin after proving to be refractory to, or intolerant of IFN therapy. The first 2 groups represent treatment results from the SWOG 8691 study, a large multicenter study comparing Pentostatin and IFN in untreated (frontline) patients with confirmed hairy cell leukemia. The third group represents evaluable patients from the SWOG study who crossed over to Pentostatin after initially receiving IFN. The fourth group, labeled NCI Phase 2 studies, displays pooled results of 2 noncomparative studies (MD Anderson and CALGB), in which Pentostatin was used to treat patients with confirmed IFN-refractory disease.
- In the SWOG 8691 study, Pentostatin was administered at a dose of 4 mg/m2 every 2 weeks. After 6 months of treatment, patients were evaluated for response. If a complete response was achieved, 2 additional doses of Pentostatin were administered and then discontinued. If a partial response was achieved, Pentostatin was continued for up to an additional 6 months. Pentostatin was discontinued for stable disease after 6 months or progressive disease after 2 months of therapy. IFN was administered 3 million units subcutaneously 3 times per week. Patients who achieved a complete or partial response after 6 months of treatment continued on IFN for another 6 months. IFN was discontinued if patients did not achieve a complete or partial response after 6 months of initial treatment or progressed after 2 months. This study allowed crossover of patients intolerant of, or refractory to, initial treatment.
- Interferon-refractory patients enrolled into the MD Anderson study received Pentostatin at a dose of 4 mg/m2 every other week for 3 months and responding patients received 3 additional months. CALGB patients received 4 mg/m2 of Pentostatin every other week for 3 months and responding patients were treated monthly for up to 9 additional months. Almost all patients had a PS of 0 to 2 in the Phase 2 and 3 studies.
- For each study, a complete response (CR) required clearing of the peripheral blood and bone marrow of all hairy cells, normalization of organomegaly and lymphadenopathy by physical examination, and recovery of hemoglobin to at least 12 g/dL, platelet count to at least 100,000/mm3, and granulocyte count to at least 1500/mm3. A partial response (PR) required that the percentage of hairy cells in the blood and bone marrow decrease by more than 50%, enlarged organs and lymph nodes decrease by more than 50% by physical examination, and hematologic parameters had to meet the same criteria as for complete response. The table below reports the response rate for 2 groups of patients: (1) Evaluable, ie, patients who could be evaluated for response and (2) Intent-to-Treat, ie, patients diagnosed with hairy cell leukemia.
- The results show that frontline patients treated with Pentostatin achieved a significantly higher rate of response than those treated with IFN. The time to recovery of neutrophil and platelet counts was shorter with Pentostatin treatment and the estimated duration of response was longer. The response rate in IFN-refractory patients treated with Pentostatin was similar to that in Pentostatin-treated frontline patients. At a median follow-up duration of 46 months, there was no statistically significant difference in survival between hairy cell leukemia patients initially treated with Pentostatin and those initially treated with IFN. However, no definite conclusions regarding survival can be made from these results because they are complicated by the fact that the majority of IFN patients crossed over to Pentostatin treatment.
- In the Phase 3 SWOG study, 25 patients with hairy cell leukemia died during treatment or follow-up: 18 patients had last received Pentostatin (3 of whom had crossed over from IFN), and 7 patients had last received IFN (1 of whom crossed over from Pentostatin). Eleven of the 25 deaths occurred within 60 days of the last dose of treatment. Of these, hairy cell leukemia was cited by the investigators as a contributory cause for 1 death in the Pentostatin group and 3 deaths in the IFN group. Additionally, infection contributed to the deaths of 3 patients in the Pentostatin group and 2 patients in the IFN group. Approximately 4% of hairy cell leukemia patients, in each arm, died more than 60 days after the last dose of either treatment and there was no outstanding cause of death among these patients.
# How Supplied
- Pentostatin (pentostatin for injection) is supplied as a sterile lyophilized white to off-white powder in single-dose vials containing 10 mg of pentostatin. The vials are packed in individual cartons. NDC 0409-0801-01.
## Storage
- Storage: Store Pentostatin vials under refrigerated storage conditions 2° to 8° C (36° to 46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Pentostatin in the drug label.
# Precautions with Alcohol
- Alcohol-Pentostatin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Nipent
# Look-Alike Drug Names
# Drug Shortage Status
# Price | Pentostatin
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.
# Black Box Warning
# Overview
Pentostatin is an antineoplastic agent that is FDA approved for the treatment of untreated or alpha-interferon-refractory hairy cell leukemia. There is a Black Box Warning for this drug as shown here. Common adverse reactions include disorder of skin, pruritus, abdominal pain, diarrhea, nausea, vomiting, anemia, leukopenia, thrombocytopenia, myalgia, headache, fever, fatigue.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Pentostatin is indicated as single-agent treatment for both untreated and alpha-interferon-refractory hairy cell leukemia patients with active disease as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms.
# Dosage
- It is recommended that patients receive hydration with 500 to 1,000 mL of 5% Dextrose in 0.5 Normal Saline or equivalent before Pentostatin administration. An additional 500 mL of 5% Dextrose or equivalent should be administered after Pentostatin is given.
- The recommended dosage of Pentostatin for the treatment of hairy cell leukemia is 4 mg/m2 every other week. Pentostatin may be administered intravenously by bolus injection or diluted in a larger volume and given over 20 to 30 minutes. (See Preparation of Intravenous Solution.)
- Higher doses are not recommended.
- No extravasation injuries were reported in clinical studies.
- The optimal duration of treatment has not been determined. In the absence of major toxicity and with observed continuing improvement, the patient should be treated until a complete response has been achieved. Although not established as required, the administration of two additional doses has been recommended following the achievement of a complete response.
- All patients receiving Pentostatin at 6 months should be assessed for response to treatment. If the patient has not achieved a complete or partial response, treatment with Pentostatin should be discontinued.
- If the patient has achieved a partial response, Pentostatin treatment should be continued in an effort to achieve a complete response. At any time thereafter that a complete response is achieved, two additional doses of Pentostatin are recommended. Pentostatin treatment should then be stopped. If the best response to treatment at the end of 12 months is a partial response, it is recommended that treatment with Pentostatin be stopped.
- Withholding or discontinuation of individual doses may be needed when severe adverse reactions occur. Drug treatment should be withheld in patients with severe rash, and withheld or discontinued in patients showing evidence of nervous system toxicity.
- Pentostatin treatment should be withheld in patients with active infection occurring during the treatment but may be resumed when the infection is controlled.
- Patients who have elevated serum creatinine should have their dose withheld and a creatinine clearance determined. There are insufficient data to recommend a starting or a subsequent dose for patients with impaired renal function (creatinine clearance <60 mL/min).
- Patients with impaired renal function should be treated only when the potential benefit justifies the potential risk. Two patients with impaired renal function (creatinine clearances 50 to 60 mL/min) achieved complete response without unusual adverse events when treated with 2 mg/m2.
- No dosage reduction is recommended at the start of therapy with Pentostatin in patients with anemia, neutropenia, or thrombocytopenia. In addition, dosage reductions are not recommended during treatment in patients with anemia and thrombocytopenia if patients can be otherwise supported hematologically. Pentostatin should be temporarily withheld if the absolute neutrophil count falls during treatment below 200 cells/mm3 in a patient who had an initial neutrophil count greater than 500 cells/mm3 and may be resumed when the count returns to predose levels.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pentostatin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pentostatin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Pentostatin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Pentostatin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Pentostatin in pediatric patients.
# Contraindications
- Pentostatin is contraindicated in patients who have demonstrated hypersensitivity to Pentostatin.
# Warnings
- Patients with hairy cell leukemia may experience myelosuppression primarily during the first few courses of treatment. Patients with infections prior to Pentostatin treatment have in some cases developed worsening of their condition leading to death, whereas others have achieved complete response. Patients with infection should be treated only when the potential benefit of treatment justifies the potential risk to the patient. Efforts should be made to control the infection before treatment is initiated or resumed.
- In patients with progressive hairy cell leukemia, the initial courses of Pentostatin treatment were associated with worsening of neutropenia. Therefore, frequent monitoring of complete blood counts during this time is necessary. If severe neutropenia continues beyond the initial cycles, patients should be evaluated for disease status, including a bone marrow examination.
- Elevations in liver function tests occurred during treatment with Pentostatin and were generally reversible.
- Renal toxicity was observed at higher doses in early studies; however, in patients treated at the recommended dose, elevations in serum creatinine were usually minor and reversible. There were some patients who began treatment with normal renal function who had evidence of mild to moderate toxicity at a final assessment.
- Rashes, occasionally severe, were commonly reported and may worsen with continued treatment. Withholding of treatment may be required.
- Acute pulmonary edema and hypotension, leading to death, have been reported in the literature in patients treated with pentostatin in combination with carmustine, etoposide and high dose cyclophosphamide as part of the ablative regimen for bone marrow transplant.
# Adverse Reactions
## Clinical Trials Experience
- Most patients treated for hairy cell leukemia in the five NCI-sponsored Phase 2 studies and the Phase 3 SWOG study experienced an adverse event. The following table lists the most frequently occurring adverse events in patients treated with Pentostatin (both frontline and IFN-refractory patients) compared with IFN (frontline only), regardless of drug association. The drug association of some adverse events is uncertain as they may be associated with the disease itself (eg, infection, hematologic suppression), but other events, such as the gastrointestinal symptoms, rashes, and abnormal liver function tests, can in many cases be attributed to the drug. Most adverse events that were assessed for severity were either mild or moderate, and diminished in frequency with continued therapy.
- The total incidence for all types of infections is considerably higher for both treatment groups in the SWOG 8691 study than is listed in the table above. An intent-to-treat analysis of infections found that 38% of patients treated with Pentostatin and 34% of patients treated with IFN averaged 2.4 and 1.9 documented infections during treatment, respectively. The following table lists the different types of infections that were reported as adverse events during the initial phase of the SWOG study. There were no apparent differences in the types of infection between the 2 treatment groups, with the possible exception of herpes zoster which was reported more frequently for Pentostatin (8%) than for IFN (1%).
- The drug relatedness of the adverse events listed below cannot be excluded. The following adverse events occurred in 3% to 10% of Pentostatin-treated patients in the initial phase of the SWOG study:
- Body as a Whole—Chest Pain, Death, Face edema, peripheral edema
- Cardiovascular System—Hemorrhage, Hypotension
- Digestive System—Dental Abnormalities, Dyspepsia, Flatulence, Gingivitis
- Hemic and Lymphatic System—Agranulocytosis
- Laboratory Deviations—Elevated Creatinine
- Musculoskeletal System—Arthralgia
- Nervous System—Confusion, Dizziness, Insomnia, Paresthesia, Somnolence
- Psychobiologic Function—Anxiety, Depression, Nervousness
- Respiratory System—Asthma
- Skin & Appendages—Skin Dry, Urticaria
- The remaining adverse events which occurred in less than 3% of Pentostatin-treated patients during the initial phase of the SWOG study:
- Body as a Whole—Flu-like Symptoms, Hangover Effect, Neoplasm
- Cardiovascular System—Angina Pectoris, Arrhythmia, A-V Block, Bradycardia, Extrasystoles Ventricular, Heart Arrest, Heart Failure, hypertension, pericardial effusion, phlebitis, pulmonary embolus, sinus arrest, tachycardia, thrombophlebitis Deep, vasculitis
- Digestive System—Constipation, Dysphagia, Glossitis, Ileus
- Hemic and Lymphatic System—Acute Leukemia, Anemia-Hemolytic, Aplastic Anemia
- Laboratory Deviations—Hypercalcemia, Hyponatremia
- Musculoskeletal System—arthritis, Gout
- Nervous System—Amnesia, Ataxia, Convulsions, Dreaming Abnormal, dysarthria, encephalitis, hyperkinesia, meningism, neuralgia, neuritis, neuropathy, paralysis, Syncope, twitching, Vertigo
- Psychobiologic Function—Decrease/Loss Libido, Emotional Lability, Hallucination, Hostility, Neurosis, Thinking Abnormal
- Respiratory System—Bronchospasm, Larynx Edema
- Skin and Appendages—Acne, Alopecia, Eczema, Petechial Rash, Photosensitivity Reaction
- Special Senses—Amblyopia, Deafness, Earache, Eyes Dry, Labyrinthitis, Lacrimation Disorder, Nonreactive Eye, Photophobia, Retinopathy, Tinnitus, Unusual Taste, Vision Abnormal, Watery Eyes
- Urogenital System—Amenorrhea, Breast Lump, Impotence, Kidney Function Abnormal, Nephropathy, Renal Failure, Renal Insufficiency, Renal Stone
- One patient with hairy cell leukemia treated with Pentostatin during another clinical study developed unilateral uveitis with vision loss.
- Nineteen (5%) patients withdrew from the Phase 3 SWOG 8691 study because of adverse events; 9 during initial Pentostatin treatment, 4 during Pentostatin crossover, 5 during initial IFN treatment, and 1 during both initial IFN treatment and Pentostatin crossover. In the Phase 2 studies in IFN-refractory hairy cell leukemia, 11% of patients withdrew from treatment with Pentostatin due to an adverse event.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Pentostatin in the drug label.
# Drug Interactions
- Allopurinol and Pentostatin are both associated with skin rashes. Based on clinical studies in 25 refractory patients who received both Pentostatin and allopurinol, the combined use of Pentostatin and allopurinol did not appear to produce a higher incidence of skin rashes than observed with Pentostatin alone. There has been a report of one patient who received both drugs and experienced a hypersensitivity vasculitis that resulted in death. It was unclear whether this adverse event and subsequent death resulted from the drug combination.
- Biochemical studies have demonstrated that pentostatin enhances the effects of vidarabine, a purine nucleoside with antiviral activity. The combined use of vidarabine and Pentostatin may result in an increase in adverse reactions associated with each drug. The therapeutic benefit of the drug combination has not been established.
- The combined use of Pentostatin and fludarabine phosphate is not recommended because it may be associated with an increased risk of fatal pulmonary toxicity (see WARNINGS).
- Acute pulmonary edema and hypotension, leading to death, have been reported in the literature in patients treated with pentostatin in combination with carmustine, etoposide and high dose cyclophosphamide as part of the ablative regimen for bone marrow transplant.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Pentostatin can cause fetal harm when administered to a pregnant woman. Pentostatin was administered intravenously at doses of 0, 0.01, 0.1, or 0.75 mg/kg/day (0, 0.06, 0.6, and 4.5 mg/m2) to pregnant rats on days 6 through 15 of gestation. Drug-related maternal toxicity occurred at doses of 0.1 and 0.75 mg/kg/day (0.6 and 4.5 mg/m2). Teratogenic effects were observed at 0.75 mg/kg/day (4.5 mg/m2) manifested by increased incidence of various skeletal malformations. In a dose range-finding study, pentostatin was administered intravenously to rats at doses of 0, 0.05, 0.1, 0.5, 0.75, or 1 mg/kg/day (0, 0.3, 0.6, 3, 4.5, 6 mg/m2), on days 6 through 15 of gestation. Fetal malformations that were observed were an omphalocele at 0.05 mg/kg (0.3 mg/m2), gastroschisis at 0.75 mg/kg and 1 mg/kg (4.5 and 6 mg/m2), and a flexure defect of the hindlimbs at 0.75 mg/kg (4.5 mg/m2). Pentostatin was also shown to be teratogenic in mice when administered as a single 2 mg/kg (6 mg/m2) intraperitoneal injection on day 7 of gestation. Pentostatin was not teratogenic in rabbits when administered intravenously on days 6 through 18 of gestation at doses of 0, 0.005, 0.01, or 0.02 mg/kg/day (0, 0.015, 0.03, or 0.06 mg/m2); however maternal toxicity, abortions, early deliveries, and deaths occurred in all drug-treated groups. There are no adequate and well-controlled studies in pregnant women. If Pentostatin is used during pregnancy, or if the patient becomes pregnant while taking (receiving) this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential receiving Pentostatin should be advised to avoid becoming pregnant.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pentostatin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Pentostatin during labor and delivery.
### Nursing Mothers
- It is not known whether Pentostatin 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 pentostatin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of Pentostatin to the mother.
### Pediatric Use
- Safety and effectiveness in children or adolescents have not been established.
### Geriatic Use
There is no FDA guidance on the use of Pentostatin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Pentostatin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Pentostatin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Pentostatin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Pentostatin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Pentostatin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Pentostatin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Pentostatin in the drug label.
# IV Compatibility
Preparation of Intravenous Solution
- Procedures for proper handling and disposal of anticancer drugs should be followed. Several guidelines on this subject have been published.2-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. Spills and wastes should be treated with a 5% sodium hypochlorite solution prior to disposal.
- Protective clothing including polyethylene gloves must be worn.
- Transfer 5 mL of Sterile Water for Injection USP to the vial containing Pentostatin and mix thoroughly to obtain complete dissolution of a solution yielding 2 mg/mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.
- Pentostatin may be given intravenously by bolus injection or diluted in a larger volume (25 to 50 mL) with 5% Dextrose Injection USP or 0.9% Sodium Chloride Injection USP. Dilution of the entire contents of a reconstituted vial with 25 mL or 50 mL provides a pentostatin concentration of 0.33 mg/mL or 0.18 mg/mL, respectively, for the diluted solutions.
- Pentostatin solution when diluted for infusion with 5% Dextrose Injection USP or 0.9% Sodium Chloride Injection USP does not interact with PVC infusion containers or administration sets at concentrations of 0.18 mg/mL to 0.33 mg/mL.
Stability
- Pentostatin vials are stable at refrigerated storage temperature 2° to 8° C (36° to 46°F) for the period stated on the package. Vials reconstituted or reconstituted and further diluted as directed may be stored at room temperature and ambient light but should be used within 8 hours because Pentostatin contains no preservatives.
# Overdosage
- No specific antidote for Pentostatin overdose is known. Pentostatin administered at higher doses (20- 50 mg/m2 in divided doses over 5 days) than recommended was associated with deaths due to severe renal, hepatic, pulmonary, and CNS toxicity. In case of overdose, management would include general supportive measures through any period of toxicity that occurs.
# Pharmacology
## Mechanism of Action
- Pentostatin is a potent transition state inhibitor of the enzyme adenosine deaminase (ADA). The greatest activity of ADA is found in cells of the lymphoid system with T-cells having higher activity than B-cells, and T-cell malignancies having higher ADA activity than B-cell malignancies. Pentostatin inhibition of ADA, particularly in the presence of adenosine or deoxyadenosine, leads to cytotoxicity, and this is believed to be due to elevated intracellular levels of dATP which can block DNA synthesis through inhibition of ribonucleotide reductase. Pentostatin can also inhibit RNA synthesis as well as cause increased DNA damage. In addition to elevated dATP, these mechanisms may also contribute to the overall cytotoxic effect of pentostatin. The precise mechanism of pentostatin’s antitumor effect, however, in hairy cell leukemia is not known.
## Structure
- Pentostatin® (pentostatin for injection) is supplied as a sterile, apyrogenic, lyophilized powder in single-dose vials for intravenous administration. Each vial contains 10 mg of pentostatin and 50 mg of Mannitol, USP. The pH of the final product is maintained between 7.0 and 8.5 by addition of sodium hydroxide or hydrochloric acid.
- Pentostatin, also known as 2’-deoxycoformycin (DCF), is a potent inhibitor of the enzyme adenosine deaminase and is isolated from fermentation cultures of Streptomyces antibioticus. Pentostatin is known chemically as (R)-3-(2-deoxy-ß-D-erythropentofuranosyl)3,6,7,8 tetrahydroimidazo[4,5d][1,3]diazepin-8-ol with a molecular formula of C11H16N4O4 and a molecular weight of 268.27. The molecular structure of pentostatin is:
- Pentostatin is a white to off-white solid, freely soluble in distilled water.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Pentostatin in the drug label.
## Pharmacokinetics
- A tissue distribution and whole-body autoradiography study in the rat revealed that radioactivity concentrations were highest in the kidneys with very little central nervous system penetration.
- In man, following a single dose of 4 mg/m2 of pentostatin infused over 5 minutes, the distribution half-life was 11 minutes, the mean terminal half-life was 5.7 hours, the mean plasma clearance was 68 mL/min/m2, and approximately 90% of the dose was excreted in the urine as unchanged pentostatin and/or metabolites as measured by adenosine deaminase inhibitory activity. The plasma protein binding of pentostatin is low, approximately 4%.
- A positive correlation was observed between pentostatin clearance and creatinine clearance (CrCl) in patients with creatinine clearance values ranging from 60 mL/min to 130 mL/min.1 Pentostatin half-life in patients with renal impairment (CrCl <50 mL/min, n=2) was 18 hours, which was much longer than that observed in patients with normal renal function (CrCl >60 mL/min, n=14), about 6 hours.
## Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis:
- No animal carcinogenicity studies have been conducted with pentostatin.
Mutagenesis:
- Pentostatin was nonmutagenic when tested in Salmonella typhimurium strains TA-98, TA-1535, TA-1537, and TA-1538. When tested with strain TA-100, a repeatable statistically significant response trend was observed with and without metabolic activation. The response was 2.1 to 2.2 fold higher than the background at 10 mg/plate, the maximum possible drug concentration. Formulated pentostatin was clastogenic in the in vivo mouse bone marrow micronucleus assay at 20, 120, and 240 mg/kg. Pentostatin was not mutagenic to V79 Chinese hamster lung cells at the HGPRT locus exposed 3 hours to concentrations of 1 to 3 mg/mL, with or without metabolic activation. Pentostatin did not significantly increase chromosomal aberrations in V79 Chinese hamster lung cells exposed 3 hours to 1 to 3 mg/mL in the presence or absence of metabolic activation.
Impairment of Fertility:
- No fertility studies have been conducted in animals; however, in a 5-day intravenous toxicity study in dogs, mild seminiferous tubular degeneration was observed with doses of 1 and 4 mg/kg. The possible adverse effects on fertility in humans have not been determined.
# Clinical Studies
- The following table provides efficacy results for 4 groups (columns) of patients with hairy cell leukemia: patients who initially received Pentostatin, patients who initially received alpha-interferon (IFN), and 2 different groups of patients who received Pentostatin after proving to be refractory to, or intolerant of IFN therapy. The first 2 groups represent treatment results from the SWOG 8691 study, a large multicenter study comparing Pentostatin and IFN in untreated (frontline) patients with confirmed hairy cell leukemia. The third group represents evaluable patients from the SWOG study who crossed over to Pentostatin after initially receiving IFN. The fourth group, labeled NCI Phase 2 studies, displays pooled results of 2 noncomparative studies (MD Anderson and CALGB), in which Pentostatin was used to treat patients with confirmed IFN-refractory disease.
- In the SWOG 8691 study, Pentostatin was administered at a dose of 4 mg/m2 every 2 weeks. After 6 months of treatment, patients were evaluated for response. If a complete response was achieved, 2 additional doses of Pentostatin were administered and then discontinued. If a partial response was achieved, Pentostatin was continued for up to an additional 6 months. Pentostatin was discontinued for stable disease after 6 months or progressive disease after 2 months of therapy. IFN was administered 3 million units subcutaneously 3 times per week. Patients who achieved a complete or partial response after 6 months of treatment continued on IFN for another 6 months. IFN was discontinued if patients did not achieve a complete or partial response after 6 months of initial treatment or progressed after 2 months. This study allowed crossover of patients intolerant of, or refractory to, initial treatment.
- Interferon-refractory patients enrolled into the MD Anderson study received Pentostatin at a dose of 4 mg/m2 every other week for 3 months and responding patients received 3 additional months. CALGB patients received 4 mg/m2 of Pentostatin every other week for 3 months and responding patients were treated monthly for up to 9 additional months. Almost all patients had a PS of 0 to 2 in the Phase 2 and 3 studies.
- For each study, a complete response (CR) required clearing of the peripheral blood and bone marrow of all hairy cells, normalization of organomegaly and lymphadenopathy by physical examination, and recovery of hemoglobin to at least 12 g/dL, platelet count to at least 100,000/mm3, and granulocyte count to at least 1500/mm3. A partial response (PR) required that the percentage of hairy cells in the blood and bone marrow decrease by more than 50%, enlarged organs and lymph nodes decrease by more than 50% by physical examination, and hematologic parameters had to meet the same criteria as for complete response. The table below reports the response rate for 2 groups of patients: (1) Evaluable, ie, patients who could be evaluated for response and (2) Intent-to-Treat, ie, patients diagnosed with hairy cell leukemia.
- The results show that frontline patients treated with Pentostatin achieved a significantly higher rate of response than those treated with IFN. The time to recovery of neutrophil and platelet counts was shorter with Pentostatin treatment and the estimated duration of response was longer. The response rate in IFN-refractory patients treated with Pentostatin was similar to that in Pentostatin-treated frontline patients. At a median follow-up duration of 46 months, there was no statistically significant difference in survival between hairy cell leukemia patients initially treated with Pentostatin and those initially treated with IFN. However, no definite conclusions regarding survival can be made from these results because they are complicated by the fact that the majority of IFN patients crossed over to Pentostatin treatment.
- In the Phase 3 SWOG study, 25 patients with hairy cell leukemia died during treatment or follow-up: 18 patients had last received Pentostatin (3 of whom had crossed over from IFN), and 7 patients had last received IFN (1 of whom crossed over from Pentostatin). Eleven of the 25 deaths occurred within 60 days of the last dose of treatment. Of these, hairy cell leukemia was cited by the investigators as a contributory cause for 1 death in the Pentostatin group and 3 deaths in the IFN group. Additionally, infection contributed to the deaths of 3 patients in the Pentostatin group and 2 patients in the IFN group. Approximately 4% of hairy cell leukemia patients, in each arm, died more than 60 days after the last dose of either treatment and there was no outstanding cause of death among these patients.
# How Supplied
- Pentostatin (pentostatin for injection) is supplied as a sterile lyophilized white to off-white powder in single-dose vials containing 10 mg of pentostatin. The vials are packed in individual cartons. NDC 0409-0801-01.
## Storage
- Storage: Store Pentostatin vials under refrigerated storage conditions 2° to 8° C (36° to 46°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Pentostatin in the drug label.
# Precautions with Alcohol
- Alcohol-Pentostatin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Nipent
# Look-Alike Drug Names
-
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nipent | |
bf04d8ad1df6c420d060ce3ef6afe124cfc0b034 | wikidoc | Nisoldipine | Nisoldipine
# 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
Nisoldipine is a calcium channel blocker, antianginal and antihypertensive agent that is FDA approved for the treatment of Hypertension. Common adverse reactions include palpitations，peripheral edema，vasodilatation，flushing，dizziness，headache, pharyngitis，sinusitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Hypertension
- Dosing information
- The dosage of Nisoldipine must be adjusted to each patient's needs.
- Initiate dosage: 17 mg PO qd then increased by 8.5 mg per week or longer intervals, to attain adequate control of blood pressure.
- Usual maintenance dosage: 17 to 34 mg PO qd‘’‘. Blood pressure response increases over the 8.5 - 34 mg daily dose range but adverse event rates also increase.
- Doses beyond ’‘’34 mg once daily‘’‘ are not recommended.
- Nisoldipine has been used safely with diuretics, ACE inhibitors, and beta-blocking agents.
- Patients over age 65, or patients with impaired liver function are expected to develop higher plasma concentrations of nisoldipine. Their blood pressure should be monitored closely during any dosage adjustment. A starting dose not exceeding 8.5 mg daily is recommended in these patient groups. Nisoldipine tablets should be administered orally once daily. Nisoldipine should be taken on an empty stomach (1 hour before or 2 hours after a meal).
- Grapefruit products should be avoided before and after dosing. Nisoldipine is an extended release dosage form and tablets should be swallowed whole, not bitten, divided or crushed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nisoldipine in adult patients.
### Non–Guideline-Supported Use
### Renovascular hypertension
- Dosing information
- 10 mg/day
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
FDA Package Insert for Nisoldipine contains no information regarding FDA-labeled indications and dosage information for children.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nisoldipine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nisoldipine in pediatric patients.
# Contraindications
Nisoldipine is contraindicated in patients with known hypersensitivity to dihydropyridine calcium channel blockers.
# Warnings
## Increased angina and/or Myocardial Infarction in patients with coronary artery disease
Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed increased frequency, duration and/or severity of angina, or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been established. In controlled studies of Nisoldipine in patients with angina this was seen about 1.5% of the time in patients given nisoldipine, compared with 0.9% in patients given placebo.
# PRECAUTIONS
## General
### Hypotension
Because nisoldipine, like other vasodilators, decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of Nisoldipine is recommended. Close observation is especially important for patients already taking medications that are known to lower blood pressure. Although in most patients the hypotensive effect of Nisoldipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment.
### Congestive Heart Failure
Although acute hemodynamic studies of nisoldipine in patients with NYHA Class II-IV heart failure have not demonstrated negative inotropic effects, safety of Nisoldipine in patients with heart failure has not been established. Caution therefore should be exercised when using Nisoldipine in patients with heart failure or compromised ventricular function, particularly in combination with a beta-blocker.
### Patients with Hepatic Impairment
Because nisoldipine is extensively metabolized by the liver and, in patients with cirrhosis, it reaches blood concentrations about 5 times those in normals, Nisoldipine should be administered cautiously in patients with severe hepatic dysfunction.
## Information for Patients
Nisoldipine is an extended release tablet and should be swallowed whole. Tablets should not be chewed, divided or crushed. Nisoldipine should be taken on an empty stomach (1 hour before or 2 hours after a meal). Grapefruit juice, which has been shown to increase significantly the bioavailability of nisoldipine and other dihydropyridine type calcium channel blockers, should not be taken with Nisoldipine.
This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
## Laboratory Tests
Nisoldipine is not known to interfere with the interpretation of laboratory tests.
## Drug Interactions
A 30 to 45% increase in AUC and Cmax of nisoldipine was observed with concomitant administration of cimetidine 400 mg twice daily. Ranitidine 150 mg twice daily did not interact significantly with nisoldipine (AUC was decreased by 15 - 20%). No pharmacodynamic effects of either histamine H2 receptor antagonist were observed.
### CYP3A4 inhibitors and inducers
Nisoldipine is substrate of CYP3A4 and coadministration of Nisoldipine with any known inducer or inhibitor of CYP3A4 should be avoided in general.
Coadministration of phenytoin with a dose bioequivalent to 34 mg Nisoldipine tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Coadministration of Nisoldipine with phenytoin should be avoided and alternative antihypertensive therapy should be considered. Pharmacokinetic interactions between nisoldipine and beta-blockers (atenolol, propranolol) were variable and not significant. Propranolol attenuated the heart rate increase following administration of immediate release nisoldipine. The blood pressure effect of Nisoldipine tended to be greater in patients on atenolol than in patients on no other antihypertensive therapy. Quinidine at 648 mg bid decreased the bioavailability (AUC) of nisoldipine by 26%, but not the peak concentration. Immediate release nisoldipine increased plasma quinidine concentrations by about 20%. This interaction was not accompanied by ECG changes and its clinical significance is not known. No significant interactions were found between nisoldipine and warfarin of digoxin.
## Carcinogenesis, Mutagenesis, Impairment of Fertility
Dietary administration of nisoldipine to male and female rats for up to 24 months (mean doses up to 82 and 111 mg/kg/day, 16 and 19 times the maximum recommended human dose on a mg/m2 basis, respectively and female mice for up to 21 months (mean doses of up to 217 mg/kg/day, 20 times the MRHD on a mg/m2 basis) revealed no evidence of tumorigenic effect of nisoldipine. In male mice receiving a mean dose of 163 mg nisoldipine/kg/day (16 times the MRHD of 60 mg/day on a mg/m2 basis), an increased frequency of stomach papilloma, but still within the historical range, was observed. No evidence of stomach neoplasia was observed at lower doses (up to 58 mg/kg/day). Nisoldipine was negative when tested in a battery of genotoxicity assays including the Ames test and the CHO/HGRPT assay for mutagenicity and the in vivo mouse micronucleus test and in vitro CHO cell test for clastogenicity.
When administered to male and female rats at doses of up to 30 mg/kg/day (about 5 times the MRHD on a mg/m2 basis) nisoldipine had no effect on fertility.
## Pregnancy Category C
Nisoldipine was neither teratogenic nor fetotoxic at doses that were not maternally toxic. Nisoldipine was fetotoxic but not teratogenic in rats and rabbits at doses resulting in maternal toxicity (reduced maternal body weight gain). In pregnant rats, increased fetal resorption (postimplantation loss) was observed at 100 mg/kg/day and decreased fetal weight was observed at both 30 and 100 mg/kg/day. These doses are, respectively, about 5 and 16 times the MRHD when compared on a mg/m2 basis. In pregnant rabbits, decreased fetal and placental weights were observed at a dose of 30 mg/kg/day, about 10 times the MRHD when compared on a mg/m2 basis. In a study in which pregnant monkeys (both treated and control) had high rates of abortion and mortality, the only surviving fetus from a group exposed to a maternal dose of 100 mg nisoldipine/kg/day (about 30 times the MRHD when compared on a mg/m2 basis) presented with forelimb and vertebral abnormalities not previously seen in control monkeys of the same strain. There are no adequate and well controlled studies in pregnant women. Nisoldipine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
### Nursing Mothers
It is not known whether nisoldipine is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made to discontinue nursing, or to discontinue Nisoldipine, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatric Use
Clinical studies of nisoldipine 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. Patients over 65 are expected to develop higher plasma concentrations of nisoldipine. 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.
# Adverse Reactions
## Clinical Trials Experience
More than 6000 patients world-wide have received nisoldipine in clinical trials for the treatment of hypertension, either as the immediate release or the Nisoldipine extended release formulation. Of about 1,500 patients who received Nisoldipine in hypertension studies, about 55% were exposed for at least 2 months and about one third were exposed for over 6 months, the great majority at doses equivalent to 17 mg and above.
Nisoldipine is generally well-tolerated. In the U.S. clinical trials of Nisoldipine in hypertension, 10.9% of the 921 Nisoldipine patients discontinued treatment due to adverse events compared with 2.9% of 280 placebo patients. The frequency of discontinuations due to adverse experiences was related to dose, with a 5.4% and 10.9% discontinuation rate at the lowest and highest daily dose, respectively.
The most frequently occurring adverse experiences with Nisoldipine are those related to its vasodilator properties; these are generally mild and only occasionally lead to patient withdrawal from treatment. The table below, from U.S. placebo-controlled parallel dose response trials of Nisoldipine using doses across the clinical dosage range in patients with hypertension, lists all of the adverse events, regardless of the causal relationship to Nisoldipine, for which the overall incidence on Nisoldipine was both >1% and greater with Nisoldipine than with placebo.
The common adverse events occurred at about the same rate in men as in women, and at a similar rate in patients over age 65 as in those under that age, except that headache was much less common in older patients. Except for peripheral edema and vasodilation, which were more common in whites, adverse event rates were similar in blacks and whites.
The following adverse events occurred in ≤1% of all patients treated for hypertension in U.S. and foreign clinical trials, or with unspecified incidence in other studies. Although a causal relationship of Nisoldipine to these events cannot be established, they are listed to alert the physician to a possible relationship with Nisoldipine treatment.
Body As A Whole: cellulitis, chills, facial edema, fever, flu syndrome, malaise
Cardiovascular: atrial fibrillation, cerebrovascular accident, congestive heart failure,first degree AV block, hypertension, hypotension, jugular venous distension, migraine, myocardial infarction, postural hypotension
Digestive: abnormal liver function tests, anorexia, colitis, diarrhea, dry mouth, dyspepsia, dysphagia, flatulence, gastritis, gastrointestinal hemorrhage, gingival hyperplasia,glossitis, hepatomegaly, increased appetite, melena, mouth ulceration
Endocrine: diabetes mellitus, thyroiditis
Hemic and Lymphatic:anemia, ecchymoses, leukopenia, petechiae
Metabolic and Nutritional: gout, hypokalemia, increased serum creatine kinase, increased nonprotein nitrogen, weight gain, weight loss
Musculoskeletal: arthralgia, arthritis, leg cramps, myalgia, myasthenia, myositis, tenosynovitis
Nervous: abnormal dreams, abnormal thinking and confusion, amnesia, anxiety, ataxia, cerebral ischemia, decreased libido, depression, hypesthesia, hypertonia, insomnia, nervousness, paresthesia, somnolence, tremor, vertigo
Respiratory: asthma, dyspnea, end inspiratory wheeze and fine rales, epistaxis, increased cough, laryngitis, pharyngitis, pleural effusion, rhinitis, sinusitis
Skin and Appendages: acne, alopecia, dry skin, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, maculopapular rash,pruritus, pustular rash, skin discoloration, skin ulcer, sweating, urticaria
Special Senses: abnormal vision, amblyopia, blepharitis, conjunctivitis, ear pain, glaucoma, itchy eyes, keratoconjunctivitis, otitis media, retinal detachment,tinnitus, watery eyes, taste disturbance, temporary unilateral loss of vision, vitreous floater
Urogenital: dysuria, hematuria, impotence, nocturia, urinary frequency, increased BUN and serum creatinine, vaginal hemorrhage, vaginitis
The following postmarketing event has been reported very rarely in patients receiving Nisoldipine: systemic hypersensitivity reaction which may include one or more of the following;angioedema, shortness of breath, tachycardia, chest tightness, hypotension, and rash. A definite causal relationship with Nisoldipine has not been established. An unusual event observed with immediate release nisoldipine but not observed with Nisoldipine was one case of photosensitivity. Gynecomastia has been associated with the use of calcium channel blockers.
## Postmarketing Experience
FDA Package Insert for Nisoldipine contains no information regarding postmarketing experience.
# Drug Interactions
A 30 to 45% increase in AUC and Cmax of nisoldipine was observed with concomitant administration of cimetidine 400 mg twice daily. Ranitidine 150 mg twice daily did not interact significantly with nisoldipine (AUC was decreased by 15 - 20%). No pharmacodynamic effects of either histamine H2 receptor antagonist were observed.
### CYP3A4 inhibitors and inducers
Nisoldipine is substrate of CYP3A4 and coadministration of Nisoldipine with any known inducer or inhibitor of CYP3A4 should be avoided in general.
Coadministration of phenytoin with a dose bioequivalent to 34 mg Nisoldipine tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Coadministration of Nisoldipine with phenytoin should be avoided and alternative antihypertensive therapy should be considered. Pharmacokinetic interactions between nisoldipine and beta-blockers (atenolol, propranolol) were variable and not significant. Propranolol attenuated the heart rate increase following administration of immediate release nisoldipine. The blood pressure effect of Nisoldipine tended to be greater in patients on atenolol than in patients on no other antihypertensive therapy. Quinidine at 648 mg bid decreased the bioavailability (AUC) of nisoldipine by 26%, but not the peak concentration. Immediate release nisoldipine increased plasma quinidine concentrations by about 20%. This interaction was not accompanied by ECG changes and its clinical significance is not known. No significant interactions were found between nisoldipine and warfarin of digoxin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
It is not known whether nisoldipine is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made to discontinue nursing, or to discontinue Nisoldipine, taking into account the importance of the drug to the mother.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nisoldipine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nisoldipine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Nisoldipine in women who are nursing.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Clinical studies of nisoldipine 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. Patients over 65 are expected to develop higher plasma concentrations of nisoldipine. 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 Nisoldipine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nisoldipine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nisoldipine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nisoldipine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nisoldipine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nisoldipine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA Package Insert for Nisoldipine contains no information regarding drug monitoring.
# IV Compatibility
FDA Package Insert for Nisoldipine contains no information regarding IV compatibility.
# Overdosage
There is no experience with nisoldipine overdosage. Generally, overdosage with other dihydropyridines leading to pronounced hypotension calls for active cardiovascular support including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents and fluids. Clearance of nisoldipine would be expected to be slowed in patients with impaired liver function. Since nisoldipine is highly protein bound, dialysis is not likely to be of any benefit; however, plasmapheresis may be beneficial.
# Pharmacology
## Mechanism of Action
Nisoldipine is a member of the dihydropyridine class of calcium channel antagonists (calcium ion antagonists or slow channel blockers) that inhibit the transmembrane influx of calcium into vascular smooth muscle and cardiac muscle. It reversibly competes with other dihydropyridines for binding to the calcium channel. Because the contractile process of vascular smooth muscle is dependent upon the movement of extracellular calcium into the muscle through specific ion channels, inhibition of the calcium channel results in dilation of the arterioles. In vitro studies show that the effects of nisoldipine on contractile processes are selective, with greater potency on vascular smooth muscle than on cardiac muscle. Although, like other dihydropyridine calcium channel blockers, nisoldipine has negative inotropic effects in vitro, studies conducted in intact anesthetized animals have shown that the vasodilating effect occurs at doses lower than those that affect cardiac contractility.
The effect of nisoldipine on blood pressure is principally a consequence of a dose-related decrease of peripheral vascular resistance. While nisoldipine, like other dihydropyridines, exhibits a mild diuretic effect, most of the antihypertensive activity is attributed to its effect on peripheral vascular resistance.
## Structure
Nisoldipine®(nisoldipine) is an extended release tablet dosage form of the dihydropyridine calcium channel blocker nisoldipine. Nisoldipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, methyl 2-methylpropyl ester, C20H24N2O6, and has the structural formula:
Nisoldipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 388.4.
## Pharmacodynamics
### Hemodynamic Effects
Administration of a single dose of nisoldipine leads to decreased systemic vascular resistance and blood pressure with a transient increase in heart rate. The change in heart rate is greater with immediate release nisoldipine preparations. The effect on blood pressure is directly related to the initial degree of elevation above normal. Chronic administration of nisoldipine results in a sustained decrease in vascular resistance and small increases in stroke index and left ventricular ejection fraction. A study of the immediate release formulation showed no effect of nisoldipine on the renin-angiotensin-aldosterone system or on plasma norepinephrine concentration in normals. Changes in blood pressure in hypertensive patients given Nisoldipine were dose related over the clinical dosage range.
Nisoldipine does not appear to have significant negative inotropic activity in intact animals or humans, and did not lead to worsening of clinical heart failure in three small studies of patients with asymptomatic and symptomatic left ventricular dysfunction. There is little information, however, in patients with severe congestive heart failure, and all calcium channel blockers should be used with caution in any patient with heart failure.
### Electrophysiologic Effects
Nisoldipine has no clinically important chronotropic effects. Except for mild shortening of sinus cycle, SA conduction time and AH intervals, single oral doses up to 20 mg of immediate release nisoldipine did not significantly change other conduction parameters. Similar electrophysiologic effects were seen with single IV doses, which could be blunted in patients pre-treated with beta-blockers. Dose and plasma level related flattening or inversion of T-waves have been observed in a few small studies. Such reports were concentrated in patients receiving rapidly increased high doses in one study; the phenomenon has not been a cause of safety concern in large clinical trials.
### Clinical Studies in Hypertension
The antihypertensive efficacy of Nisoldipine was studied in 5 double-blind, placebo-controlled, randomized studies, in which over 600 patients were treated with Nisoldipine as monotherapy and about 300 with placebo; 4 of the five studies compared 2 or 3 fixed doses while the fifth allowed titration from doses bioequivalent to 8.5 - 34 mg. Once daily administration of Nisoldipine produced sustained reductions in systolic and diastolic blood pressures over the 24 hour dosing interval in both supine and standing positions. The mean placebo-subtracted reductions in supine systolic and diastolic blood pressure at trough, 24 hours post-dose, in these studies, are shown below. Changes in standing blood pressure were similar:
MEAN SUPINE TROUGH SYSTOLIC AND DIASTOLIC BLOOD PRESSURE CHANGES (mm Hg)
In patients receiving atenolol, supine blood pressure reductions with Nisoldipine doses bioequivalent to 17 and 34 mg once daily were 12/6 and 19/8 mm Hg, respectively. The sustained antihypertensive effect of Nisoldipine was demonstrated by 24 hour blood pressure monitoring and examination of peak and trough effects. The trough/peak ratios ranged from 70 to 100% for diastolic and systolic blood pressure. The mean change in heart rate in these studies was less than one beat per minute. In 4 of the 5 studies, patients received intial doses bioequivalent to 17-25.5 mg Nisoldipine without incident (excessive effects on blood pressure or heart rate). The fifth study started patients on lower doses of Nisoldipine.
Patient race and gender did not influence the blood pressure lowering effect of Nisoldipine. Despite the higher plasma concentration of nisoldipine in the elderly, there was no consistent difference in their blood pressure response except that the lowest clinical dose was somewhat more effective than in non-elderly patients. No postural effect on blood pressure was apparent and there was no evidence of tolerance to the antihypertensive effect of Nisoldipine in patients treated for up to one year.
## Pharmacokinetics
Nisoldipine pharmacokinetics are independent of the dose across the clicinal dosage range of 17 to 51 mg, with plasma concentrations proportional to dose. Nisoldipine accumulation, during multiple dosing, is predictable from a single dose. Nisoldipine is relatively well absorbed into the systemic circulation with 87% of the radiolabeled drug recovered in urine and feces. The absolute bioavailability of nisoldipine is about 5%. Nisoldipine's low bioavailability is due, in part, to pre-systemic metabolism in the gut wall, and this metabolism decreases from the proximal to the distal parts of the intestine. A pronounced food-effect is observed when Nisoldipine is administered with a high-fat meal resulting in an increased peak concentration (Cmax) of up to 245%. Total exposure (AUC) is decreased by 25%. As a result, Nisoldipine should be taken on an empty stomach (1 hour before or 2 hours after a meal).
Maximal plasma concentrations of nisoldipine are reached at 9.2 ± 5.1 hours. The terminal elimination half-life (reflecting post absorption clearance of nisoldipine) ranges from 13.7 ± 4.3 hours. After oral administration, the concentration of (+)-nisoldipine, the active enantiomer, is about 6 times higher than the inactive (-) -nisoldipine enantiomer. The plasma protein binding of nisoldipine is very high, with less than 1% unbound over the plasma concentration range of 100 ng/mL to 10 mcg/mL.
Nisoldipine is highly metabolized; 5 major urinary metabolites have been identified. Although 60 - 80% of an oral dose undergoes urinary excretion, only traces of unchanged nisoldipine are found in urine. The major biotransformation pathway appears to be the hydroxylation of the isobutyl ester. A hydroxylated derivative of the side chain, present in plasma at concentrations approximately equal to the parent compound, appears to be the only active metabolite, and has about 10% of the activity of the parent compound. Cytochrome P450 enzymes are believed to play a major role in the metabolism of nisoldipine. The particular isoenzyme system responsible for its metabolism has not been identified, but other dihydropyridines are metabolized by cytochrome P450 IIIA4. Nisoldipine should not be administered with grapefruit juice, as this has been shown, in a study of 12 subjects, to interfere with nisoldipine metabolism, resulting in a mean increase in Cmax of about 3-fold (ranging up to about 7-fold) and AUC of almost 2-fold (ranging up to about 5-fold). A similar phenomenon has been seen with several other dihydropyridine calcium channel blockers.
## Special Populations
Renal Dysfunction
Because renal elimination is not an important pathway, bioavailability and pharmacokinetics of Nisoldipine were not significantly different in patients with various degrees of renal impairment. Dosing adjustments in patients with mild to moderate renal impairment are not necessary.
Geriatric
Elderly patients have been found to have 2 to 3 fold higher plasma concentrations (Cmax and AUC) than young subjects. This should be reflected in more cautious dosing (See DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency
In patients with liver cirrhosis given a dose bioequivalent to 8.5 mg Nisoldipine, plasma concentrations of the parent compound were 4 to 5 times higher than those in healthy young subjects. Lower starting and maintenance doses should be used in cirrhotic patients (See DOSAGE AND ADMINISTRATION).
Gender and Race
The effect of gender or race on the pharmacokinetics of nisoldipine has not been investigated.
Disease States
Hypertension does not significantly alter the pharmacokinetics of nisoldipine.
## Nonclinical Toxicology
Dietary administration of nisoldipine to male and female rats for up to 24 months (mean doses up to 82 and 111 mg/kg/day, 16 and 19 times the maximum recommended human dose on a mg/m2 basis, respectively and female mice for up to 21 months (mean doses of up to 217 mg/kg/day, 20 times the MRHD on a mg/m2 basis) revealed no evidence of tumorigenic effect of nisoldipine. In male mice receiving a mean dose of 163 mg nisoldipine/kg/day (16 times the MRHD of 60 mg/day on a mg/m2 basis), an increased frequency of stomach papilloma, but still within the historical range, was observed. No evidence of stomach neoplasia was observed at lower doses (up to 58 mg/kg/day). Nisoldipine was negative when tested in a battery of genotoxicity assays including the Ames test and the CHO/HGRPT assay for mutagenicity and the in vivo mouse micronucleus test and in vitro CHO cell test for clastogenicity.
When administered to male and female rats at doses of up to 30 mg/kg/day (about 5 times the MRHD on a mg/m2 basis) nisoldipine had no effect on fertility.
# Clinical Studies
The antihypertensive efficacy of Nisoldipine was studied in 5 double-blind, placebo-controlled, randomized studies, in which over 600 patients were treated with Nisoldipine as monotherapy and about 300 with placebo; 4 of the five studies compared 2 or 3 fixed doses while the fifth allowed titration from doses bioequivalent to 8.5 - 34 mg. Once daily administration of Nisoldipine produced sustained reductions in systolic and diastolic blood pressures over the 24 hour dosing interval in both supine and standing positions. The mean placebo-subtracted reductions in supine systolic and diastolic blood pressure at trough, 24 hours post-dose, in these studies, are shown below. Changes in standing blood pressure were similar:
In patients receiving atenolol, supine blood pressure reductions with Nisoldipine doses bioequivalent to 17 and 34 mg once daily were 12/6 and 19/8 mm Hg, respectively. The sustained antihypertensive effect of Nisoldipine was demonstrated by 24 hour blood pressure monitoring and examination of peak and trough effects. The trough/peak ratios ranged from 70 to 100% for diastolic and systolic blood pressure. The mean change in heart rate in these studies was less than one beat per minute. In 4 of the 5 studies, patients received initial doses bioequivalent to 17-25.5 mg Nisoldipine without incident (excessive effects on blood pressure or heart rate). The fifth study started patients on lower doses of Nisoldipine.
Patient race and gender did not influence the blood pressure lowering effect of Nisoldipine. Despite the higher plasma concentration of nisoldipine in the elderly, there was no consistent difference in their blood pressure response except that the lowest clinical dose was somewhat more effective than in non-elderly patients. No postural effect on blood pressure was apparent and there was no evidence of tolerance to the antihypertensive effect of Nisoldipine in patients treated for up to one year.
# How Supplied
Nisoldipine extended release tablets are supplied as 8.5 mg and 17 mg round film coated tablets and 25.5 mg and 34 mg elliptic film coated tablets. The different strengths can be identified as follows:
Nisoldipine Tablets are supplied in bottles of 100:
## Storage
Protect from light and moisture. Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) . Dispense in tight, light-resistant containers.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Nisoldipine is an extended release tablet and should be swallowed whole. Tablets should not be chewed, divided or crushed. Nisoldipine should be taken on an empty stomach (1 hour before or 2 hours after a meal). Grapefruit juice, which has been shown to increase significantly the bioavailability of nisoldipine and other dihydropyridine type calcium channel blockers, should not be taken with Nisoldipine.
This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
# Precautions with Alcohol
Alcohol-Nisoldipine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Sular
# Look-Alike Drug Names
There is limited information regarding Nisoldipine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Nisoldipine
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]
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# Overview
Nisoldipine is a calcium channel blocker, antianginal and antihypertensive agent that is FDA approved for the treatment of Hypertension. Common adverse reactions include palpitations，peripheral edema，vasodilatation，flushing，dizziness，headache, pharyngitis，sinusitis.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
### Hypertension
- Dosing information
- The dosage of Nisoldipine must be adjusted to each patient's needs.
- Initiate dosage: 17 mg PO qd then increased by 8.5 mg per week or longer intervals, to attain adequate control of blood pressure.
- Usual maintenance dosage: 17 to 34 mg PO qd‘’‘. Blood pressure response increases over the 8.5 - 34 mg daily dose range but adverse event rates also increase.
- Doses beyond ’‘’34 mg once daily‘’‘ are not recommended.
- Nisoldipine has been used safely with diuretics, ACE inhibitors, and beta-blocking agents.
- Patients over age 65, or patients with impaired liver function are expected to develop higher plasma concentrations of nisoldipine. Their blood pressure should be monitored closely during any dosage adjustment. A starting dose not exceeding 8.5 mg daily is recommended in these patient groups. Nisoldipine tablets should be administered orally once daily. Nisoldipine should be taken on an empty stomach (1 hour before or 2 hours after a meal).
- Grapefruit products should be avoided before and after dosing. Nisoldipine is an extended release dosage form and tablets should be swallowed whole, not bitten, divided or crushed.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nisoldipine in adult patients.
### Non–Guideline-Supported Use
### Renovascular hypertension
- Dosing information
- 10 mg/day[1]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
FDA Package Insert for Nisoldipine contains no information regarding FDA-labeled indications and dosage information for children.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Nisoldipine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Nisoldipine in pediatric patients.
# Contraindications
Nisoldipine is contraindicated in patients with known hypersensitivity to dihydropyridine calcium channel blockers.
# Warnings
## Increased angina and/or Myocardial Infarction in patients with coronary artery disease
Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed increased frequency, duration and/or severity of angina, or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been established. In controlled studies of Nisoldipine in patients with angina this was seen about 1.5% of the time in patients given nisoldipine, compared with 0.9% in patients given placebo.
# PRECAUTIONS
## General
### Hypotension
Because nisoldipine, like other vasodilators, decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of Nisoldipine is recommended. Close observation is especially important for patients already taking medications that are known to lower blood pressure. Although in most patients the hypotensive effect of Nisoldipine is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment.
### Congestive Heart Failure
Although acute hemodynamic studies of nisoldipine in patients with NYHA Class II-IV heart failure have not demonstrated negative inotropic effects, safety of Nisoldipine in patients with heart failure has not been established. Caution therefore should be exercised when using Nisoldipine in patients with heart failure or compromised ventricular function, particularly in combination with a beta-blocker.
### Patients with Hepatic Impairment
Because nisoldipine is extensively metabolized by the liver and, in patients with cirrhosis, it reaches blood concentrations about 5 times those in normals, Nisoldipine should be administered cautiously in patients with severe hepatic dysfunction.
## Information for Patients
Nisoldipine is an extended release tablet and should be swallowed whole. Tablets should not be chewed, divided or crushed. Nisoldipine should be taken on an empty stomach (1 hour before or 2 hours after a meal). Grapefruit juice, which has been shown to increase significantly the bioavailability of nisoldipine and other dihydropyridine type calcium channel blockers, should not be taken with Nisoldipine.
This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
## Laboratory Tests
Nisoldipine is not known to interfere with the interpretation of laboratory tests.
## Drug Interactions
A 30 to 45% increase in AUC and Cmax of nisoldipine was observed with concomitant administration of cimetidine 400 mg twice daily. Ranitidine 150 mg twice daily did not interact significantly with nisoldipine (AUC was decreased by 15 - 20%). No pharmacodynamic effects of either histamine H2 receptor antagonist were observed.
### CYP3A4 inhibitors and inducers
Nisoldipine is substrate of CYP3A4 and coadministration of Nisoldipine with any known inducer or inhibitor of CYP3A4 should be avoided in general.
Coadministration of phenytoin with a dose bioequivalent to 34 mg Nisoldipine tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Coadministration of Nisoldipine with phenytoin should be avoided and alternative antihypertensive therapy should be considered. Pharmacokinetic interactions between nisoldipine and beta-blockers (atenolol, propranolol) were variable and not significant. Propranolol attenuated the heart rate increase following administration of immediate release nisoldipine. The blood pressure effect of Nisoldipine tended to be greater in patients on atenolol than in patients on no other antihypertensive therapy. Quinidine at 648 mg bid decreased the bioavailability (AUC) of nisoldipine by 26%, but not the peak concentration. Immediate release nisoldipine increased plasma quinidine concentrations by about 20%. This interaction was not accompanied by ECG changes and its clinical significance is not known. No significant interactions were found between nisoldipine and warfarin of digoxin.
## Carcinogenesis, Mutagenesis, Impairment of Fertility
Dietary administration of nisoldipine to male and female rats for up to 24 months (mean doses up to 82 and 111 mg/kg/day, 16 and 19 times the maximum recommended human dose [MRHD] on a mg/m2 basis, respectively and female mice for up to 21 months (mean doses of up to 217 mg/kg/day, 20 times the MRHD on a mg/m2 basis) revealed no evidence of tumorigenic effect of nisoldipine. In male mice receiving a mean dose of 163 mg nisoldipine/kg/day (16 times the MRHD of 60 mg/day on a mg/m2 basis), an increased frequency of stomach papilloma, but still within the historical range, was observed. No evidence of stomach neoplasia was observed at lower doses (up to 58 mg/kg/day). Nisoldipine was negative when tested in a battery of genotoxicity assays including the Ames test and the CHO/HGRPT assay for mutagenicity and the in vivo mouse micronucleus test and in vitro CHO cell test for clastogenicity.
When administered to male and female rats at doses of up to 30 mg/kg/day (about 5 times the MRHD on a mg/m2 basis) nisoldipine had no effect on fertility.
## Pregnancy Category C
Nisoldipine was neither teratogenic nor fetotoxic at doses that were not maternally toxic. Nisoldipine was fetotoxic but not teratogenic in rats and rabbits at doses resulting in maternal toxicity (reduced maternal body weight gain). In pregnant rats, increased fetal resorption (postimplantation loss) was observed at 100 mg/kg/day and decreased fetal weight was observed at both 30 and 100 mg/kg/day. These doses are, respectively, about 5 and 16 times the MRHD when compared on a mg/m2 basis. In pregnant rabbits, decreased fetal and placental weights were observed at a dose of 30 mg/kg/day, about 10 times the MRHD when compared on a mg/m2 basis. In a study in which pregnant monkeys (both treated and control) had high rates of abortion and mortality, the only surviving fetus from a group exposed to a maternal dose of 100 mg nisoldipine/kg/day (about 30 times the MRHD when compared on a mg/m2 basis) presented with forelimb and vertebral abnormalities not previously seen in control monkeys of the same strain. There are no adequate and well controlled studies in pregnant women. Nisoldipine should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
### Nursing Mothers
It is not known whether nisoldipine is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made to discontinue nursing, or to discontinue Nisoldipine, taking into account the importance of the drug to the mother.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatric Use
Clinical studies of nisoldipine 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. Patients over 65 are expected to develop higher plasma concentrations of nisoldipine. 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.
# Adverse Reactions
## Clinical Trials Experience
More than 6000 patients world-wide have received nisoldipine in clinical trials for the treatment of hypertension, either as the immediate release or the Nisoldipine extended release formulation. Of about 1,500 patients who received Nisoldipine in hypertension studies, about 55% were exposed for at least 2 months and about one third were exposed for over 6 months, the great majority at doses equivalent to 17 mg and above.
Nisoldipine is generally well-tolerated. In the U.S. clinical trials of Nisoldipine in hypertension, 10.9% of the 921 Nisoldipine patients discontinued treatment due to adverse events compared with 2.9% of 280 placebo patients. The frequency of discontinuations due to adverse experiences was related to dose, with a 5.4% and 10.9% discontinuation rate at the lowest and highest daily dose, respectively.
The most frequently occurring adverse experiences with Nisoldipine are those related to its vasodilator properties; these are generally mild and only occasionally lead to patient withdrawal from treatment. The table below, from U.S. placebo-controlled parallel dose response trials of Nisoldipine using doses across the clinical dosage range in patients with hypertension, lists all of the adverse events, regardless of the causal relationship to Nisoldipine, for which the overall incidence on Nisoldipine was both >1% and greater with Nisoldipine than with placebo.
The common adverse events occurred at about the same rate in men as in women, and at a similar rate in patients over age 65 as in those under that age, except that headache was much less common in older patients. Except for peripheral edema and vasodilation, which were more common in whites, adverse event rates were similar in blacks and whites.
The following adverse events occurred in ≤1% of all patients treated for hypertension in U.S. and foreign clinical trials, or with unspecified incidence in other studies. Although a causal relationship of Nisoldipine to these events cannot be established, they are listed to alert the physician to a possible relationship with Nisoldipine treatment.
Body As A Whole: cellulitis, chills, facial edema, fever, flu syndrome, malaise
Cardiovascular: atrial fibrillation, cerebrovascular accident, congestive heart failure,first degree AV block, hypertension, hypotension, jugular venous distension, migraine, myocardial infarction, postural hypotension
Digestive: abnormal liver function tests, anorexia, colitis, diarrhea, dry mouth, dyspepsia, dysphagia, flatulence, gastritis, gastrointestinal hemorrhage, gingival hyperplasia,glossitis, hepatomegaly, increased appetite, melena, mouth ulceration
Endocrine: diabetes mellitus, thyroiditis
Hemic and Lymphatic:anemia, ecchymoses, leukopenia, petechiae
Metabolic and Nutritional: gout, hypokalemia, increased serum creatine kinase, increased nonprotein nitrogen, weight gain, weight loss
Musculoskeletal: arthralgia, arthritis, leg cramps, myalgia, myasthenia, myositis, tenosynovitis
Nervous: abnormal dreams, abnormal thinking and confusion, amnesia, anxiety, ataxia, cerebral ischemia, decreased libido, depression, hypesthesia, hypertonia, insomnia, nervousness, paresthesia, somnolence, tremor, vertigo
Respiratory: asthma, dyspnea, end inspiratory wheeze and fine rales, epistaxis, increased cough, laryngitis, pharyngitis, pleural effusion, rhinitis, sinusitis
Skin and Appendages: acne, alopecia, dry skin, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, maculopapular rash,pruritus, pustular rash, skin discoloration, skin ulcer, sweating, urticaria
Special Senses: abnormal vision, amblyopia, blepharitis, conjunctivitis, ear pain, glaucoma, itchy eyes, keratoconjunctivitis, otitis media, retinal detachment,tinnitus, watery eyes, taste disturbance, temporary unilateral loss of vision, vitreous floater
Urogenital: dysuria, hematuria, impotence, nocturia, urinary frequency, increased BUN and serum creatinine, vaginal hemorrhage, vaginitis
The following postmarketing event has been reported very rarely in patients receiving Nisoldipine: systemic hypersensitivity reaction which may include one or more of the following;angioedema, shortness of breath, tachycardia, chest tightness, hypotension, and rash. A definite causal relationship with Nisoldipine has not been established. An unusual event observed with immediate release nisoldipine but not observed with Nisoldipine was one case of photosensitivity. Gynecomastia has been associated with the use of calcium channel blockers.
## Postmarketing Experience
FDA Package Insert for Nisoldipine contains no information regarding postmarketing experience.
# Drug Interactions
A 30 to 45% increase in AUC and Cmax of nisoldipine was observed with concomitant administration of cimetidine 400 mg twice daily. Ranitidine 150 mg twice daily did not interact significantly with nisoldipine (AUC was decreased by 15 - 20%). No pharmacodynamic effects of either histamine H2 receptor antagonist were observed.
### CYP3A4 inhibitors and inducers
Nisoldipine is substrate of CYP3A4 and coadministration of Nisoldipine with any known inducer or inhibitor of CYP3A4 should be avoided in general.
Coadministration of phenytoin with a dose bioequivalent to 34 mg Nisoldipine tablets in epileptic patients lowered the nisoldipine plasma concentrations to undetectable levels. Coadministration of Nisoldipine with phenytoin should be avoided and alternative antihypertensive therapy should be considered. Pharmacokinetic interactions between nisoldipine and beta-blockers (atenolol, propranolol) were variable and not significant. Propranolol attenuated the heart rate increase following administration of immediate release nisoldipine. The blood pressure effect of Nisoldipine tended to be greater in patients on atenolol than in patients on no other antihypertensive therapy. Quinidine at 648 mg bid decreased the bioavailability (AUC) of nisoldipine by 26%, but not the peak concentration. Immediate release nisoldipine increased plasma quinidine concentrations by about 20%. This interaction was not accompanied by ECG changes and its clinical significance is not known. No significant interactions were found between nisoldipine and warfarin of digoxin.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
It is not known whether nisoldipine is excreted in human milk. Because many drugs are excreted in human milk, a decision should be made to discontinue nursing, or to discontinue Nisoldipine, taking into account the importance of the drug to the mother.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Nisoldipine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Nisoldipine during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Nisoldipine in women who are nursing.
### Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
### Geriatic Use
Clinical studies of nisoldipine 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. Patients over 65 are expected to develop higher plasma concentrations of nisoldipine. 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 Nisoldipine with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Nisoldipine with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Nisoldipine in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Nisoldipine in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Nisoldipine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Nisoldipine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Oral
### Monitoring
FDA Package Insert for Nisoldipine contains no information regarding drug monitoring.
# IV Compatibility
FDA Package Insert for Nisoldipine contains no information regarding IV compatibility.
# Overdosage
There is no experience with nisoldipine overdosage. Generally, overdosage with other dihydropyridines leading to pronounced hypotension calls for active cardiovascular support including monitoring of cardiovascular and respiratory function, elevation of extremities, judicious use of calcium infusion, pressor agents and fluids. Clearance of nisoldipine would be expected to be slowed in patients with impaired liver function. Since nisoldipine is highly protein bound, dialysis is not likely to be of any benefit; however, plasmapheresis may be beneficial.
# Pharmacology
## Mechanism of Action
Nisoldipine is a member of the dihydropyridine class of calcium channel antagonists (calcium ion antagonists or slow channel blockers) that inhibit the transmembrane influx of calcium into vascular smooth muscle and cardiac muscle. It reversibly competes with other dihydropyridines for binding to the calcium channel. Because the contractile process of vascular smooth muscle is dependent upon the movement of extracellular calcium into the muscle through specific ion channels, inhibition of the calcium channel results in dilation of the arterioles. In vitro studies show that the effects of nisoldipine on contractile processes are selective, with greater potency on vascular smooth muscle than on cardiac muscle. Although, like other dihydropyridine calcium channel blockers, nisoldipine has negative inotropic effects in vitro, studies conducted in intact anesthetized animals have shown that the vasodilating effect occurs at doses lower than those that affect cardiac contractility.
The effect of nisoldipine on blood pressure is principally a consequence of a dose-related decrease of peripheral vascular resistance. While nisoldipine, like other dihydropyridines, exhibits a mild diuretic effect, most of the antihypertensive activity is attributed to its effect on peripheral vascular resistance.
## Structure
Nisoldipine®(nisoldipine) is an extended release tablet dosage form of the dihydropyridine calcium channel blocker nisoldipine. Nisoldipine is 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-, methyl 2-methylpropyl ester, C20H24N2O6, and has the structural formula:
Nisoldipine is a yellow crystalline substance, practically insoluble in water but soluble in ethanol. It has a molecular weight of 388.4.
## Pharmacodynamics
### Hemodynamic Effects
Administration of a single dose of nisoldipine leads to decreased systemic vascular resistance and blood pressure with a transient increase in heart rate. The change in heart rate is greater with immediate release nisoldipine preparations. The effect on blood pressure is directly related to the initial degree of elevation above normal. Chronic administration of nisoldipine results in a sustained decrease in vascular resistance and small increases in stroke index and left ventricular ejection fraction. A study of the immediate release formulation showed no effect of nisoldipine on the renin-angiotensin-aldosterone system or on plasma norepinephrine concentration in normals. Changes in blood pressure in hypertensive patients given Nisoldipine were dose related over the clinical dosage range.
Nisoldipine does not appear to have significant negative inotropic activity in intact animals or humans, and did not lead to worsening of clinical heart failure in three small studies of patients with asymptomatic and symptomatic left ventricular dysfunction. There is little information, however, in patients with severe congestive heart failure, and all calcium channel blockers should be used with caution in any patient with heart failure.
### Electrophysiologic Effects
Nisoldipine has no clinically important chronotropic effects. Except for mild shortening of sinus cycle, SA conduction time and AH intervals, single oral doses up to 20 mg of immediate release nisoldipine did not significantly change other conduction parameters. Similar electrophysiologic effects were seen with single IV doses, which could be blunted in patients pre-treated with beta-blockers. Dose and plasma level related flattening or inversion of T-waves have been observed in a few small studies. Such reports were concentrated in patients receiving rapidly increased high doses in one study; the phenomenon has not been a cause of safety concern in large clinical trials.
### Clinical Studies in Hypertension
The antihypertensive efficacy of Nisoldipine was studied in 5 double-blind, placebo-controlled, randomized studies, in which over 600 patients were treated with Nisoldipine as monotherapy and about 300 with placebo; 4 of the five studies compared 2 or 3 fixed doses while the fifth allowed titration from doses bioequivalent to 8.5 - 34 mg. Once daily administration of Nisoldipine produced sustained reductions in systolic and diastolic blood pressures over the 24 hour dosing interval in both supine and standing positions. The mean placebo-subtracted reductions in supine systolic and diastolic blood pressure at trough, 24 hours post-dose, in these studies, are shown below. Changes in standing blood pressure were similar:
MEAN SUPINE TROUGH SYSTOLIC AND DIASTOLIC BLOOD PRESSURE CHANGES (mm Hg)
In patients receiving atenolol, supine blood pressure reductions with Nisoldipine doses bioequivalent to 17 and 34 mg once daily were 12/6 and 19/8 mm Hg, respectively. The sustained antihypertensive effect of Nisoldipine was demonstrated by 24 hour blood pressure monitoring and examination of peak and trough effects. The trough/peak ratios ranged from 70 to 100% for diastolic and systolic blood pressure. The mean change in heart rate in these studies was less than one beat per minute. In 4 of the 5 studies, patients received intial doses bioequivalent to 17-25.5 mg Nisoldipine without incident (excessive effects on blood pressure or heart rate). The fifth study started patients on lower doses of Nisoldipine.
Patient race and gender did not influence the blood pressure lowering effect of Nisoldipine. Despite the higher plasma concentration of nisoldipine in the elderly, there was no consistent difference in their blood pressure response except that the lowest clinical dose was somewhat more effective than in non-elderly patients. No postural effect on blood pressure was apparent and there was no evidence of tolerance to the antihypertensive effect of Nisoldipine in patients treated for up to one year.
## Pharmacokinetics
Nisoldipine pharmacokinetics are independent of the dose across the clicinal dosage range of 17 to 51 mg, with plasma concentrations proportional to dose. Nisoldipine accumulation, during multiple dosing, is predictable from a single dose. Nisoldipine is relatively well absorbed into the systemic circulation with 87% of the radiolabeled drug recovered in urine and feces. The absolute bioavailability of nisoldipine is about 5%. Nisoldipine's low bioavailability is due, in part, to pre-systemic metabolism in the gut wall, and this metabolism decreases from the proximal to the distal parts of the intestine. A pronounced food-effect is observed when Nisoldipine is administered with a high-fat meal resulting in an increased peak concentration (Cmax) of up to 245%. Total exposure (AUC) is decreased by 25%. As a result, Nisoldipine should be taken on an empty stomach (1 hour before or 2 hours after a meal).
Maximal plasma concentrations of nisoldipine are reached at 9.2 ± 5.1 hours. The terminal elimination half-life (reflecting post absorption clearance of nisoldipine) ranges from 13.7 ± 4.3 hours. After oral administration, the concentration of (+)-nisoldipine, the active enantiomer, is about 6 times higher than the inactive (-) -nisoldipine enantiomer. The plasma protein binding of nisoldipine is very high, with less than 1% unbound over the plasma concentration range of 100 ng/mL to 10 mcg/mL.
Nisoldipine is highly metabolized; 5 major urinary metabolites have been identified. Although 60 - 80% of an oral dose undergoes urinary excretion, only traces of unchanged nisoldipine are found in urine. The major biotransformation pathway appears to be the hydroxylation of the isobutyl ester. A hydroxylated derivative of the side chain, present in plasma at concentrations approximately equal to the parent compound, appears to be the only active metabolite, and has about 10% of the activity of the parent compound. Cytochrome P450 enzymes are believed to play a major role in the metabolism of nisoldipine. The particular isoenzyme system responsible for its metabolism has not been identified, but other dihydropyridines are metabolized by cytochrome P450 IIIA4. Nisoldipine should not be administered with grapefruit juice, as this has been shown, in a study of 12 subjects, to interfere with nisoldipine metabolism, resulting in a mean increase in Cmax of about 3-fold (ranging up to about 7-fold) and AUC of almost 2-fold (ranging up to about 5-fold). A similar phenomenon has been seen with several other dihydropyridine calcium channel blockers.
## Special Populations
Renal Dysfunction
Because renal elimination is not an important pathway, bioavailability and pharmacokinetics of Nisoldipine were not significantly different in patients with various degrees of renal impairment. Dosing adjustments in patients with mild to moderate renal impairment are not necessary.
Geriatric
Elderly patients have been found to have 2 to 3 fold higher plasma concentrations (Cmax and AUC) than young subjects. This should be reflected in more cautious dosing (See DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency
In patients with liver cirrhosis given a dose bioequivalent to 8.5 mg Nisoldipine, plasma concentrations of the parent compound were 4 to 5 times higher than those in healthy young subjects. Lower starting and maintenance doses should be used in cirrhotic patients (See DOSAGE AND ADMINISTRATION).
Gender and Race
The effect of gender or race on the pharmacokinetics of nisoldipine has not been investigated.
Disease States
Hypertension does not significantly alter the pharmacokinetics of nisoldipine.
## Nonclinical Toxicology
Dietary administration of nisoldipine to male and female rats for up to 24 months (mean doses up to 82 and 111 mg/kg/day, 16 and 19 times the maximum recommended human dose [MRHD] on a mg/m2 basis, respectively and female mice for up to 21 months (mean doses of up to 217 mg/kg/day, 20 times the MRHD on a mg/m2 basis) revealed no evidence of tumorigenic effect of nisoldipine. In male mice receiving a mean dose of 163 mg nisoldipine/kg/day (16 times the MRHD of 60 mg/day on a mg/m2 basis), an increased frequency of stomach papilloma, but still within the historical range, was observed. No evidence of stomach neoplasia was observed at lower doses (up to 58 mg/kg/day). Nisoldipine was negative when tested in a battery of genotoxicity assays including the Ames test and the CHO/HGRPT assay for mutagenicity and the in vivo mouse micronucleus test and in vitro CHO cell test for clastogenicity.
When administered to male and female rats at doses of up to 30 mg/kg/day (about 5 times the MRHD on a mg/m2 basis) nisoldipine had no effect on fertility.
# Clinical Studies
The antihypertensive efficacy of Nisoldipine was studied in 5 double-blind, placebo-controlled, randomized studies, in which over 600 patients were treated with Nisoldipine as monotherapy and about 300 with placebo; 4 of the five studies compared 2 or 3 fixed doses while the fifth allowed titration from doses bioequivalent to 8.5 - 34 mg. Once daily administration of Nisoldipine produced sustained reductions in systolic and diastolic blood pressures over the 24 hour dosing interval in both supine and standing positions. The mean placebo-subtracted reductions in supine systolic and diastolic blood pressure at trough, 24 hours post-dose, in these studies, are shown below. Changes in standing blood pressure were similar:
In patients receiving atenolol, supine blood pressure reductions with Nisoldipine doses bioequivalent to 17 and 34 mg once daily were 12/6 and 19/8 mm Hg, respectively. The sustained antihypertensive effect of Nisoldipine was demonstrated by 24 hour blood pressure monitoring and examination of peak and trough effects. The trough/peak ratios ranged from 70 to 100% for diastolic and systolic blood pressure. The mean change in heart rate in these studies was less than one beat per minute. In 4 of the 5 studies, patients received initial doses bioequivalent to 17-25.5 mg Nisoldipine without incident (excessive effects on blood pressure or heart rate). The fifth study started patients on lower doses of Nisoldipine.
Patient race and gender did not influence the blood pressure lowering effect of Nisoldipine. Despite the higher plasma concentration of nisoldipine in the elderly, there was no consistent difference in their blood pressure response except that the lowest clinical dose was somewhat more effective than in non-elderly patients. No postural effect on blood pressure was apparent and there was no evidence of tolerance to the antihypertensive effect of Nisoldipine in patients treated for up to one year.
# How Supplied
Nisoldipine extended release tablets are supplied as 8.5 mg and 17 mg round film coated tablets and 25.5 mg and 34 mg elliptic film coated tablets. The different strengths can be identified as follows:
Nisoldipine Tablets are supplied in bottles of 100:
## Storage
Protect from light and moisture. Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant containers.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Nisoldipine is an extended release tablet and should be swallowed whole. Tablets should not be chewed, divided or crushed. Nisoldipine should be taken on an empty stomach (1 hour before or 2 hours after a meal). Grapefruit juice, which has been shown to increase significantly the bioavailability of nisoldipine and other dihydropyridine type calcium channel blockers, should not be taken with Nisoldipine.
This product contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.
# Precautions with Alcohol
Alcohol-Nisoldipine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
Sular
# Look-Alike Drug Names
There is limited information regarding Nisoldipine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Nisoldipine | |
22c4a1fa7c07b8337e90e74430aaea02c3ea9f40 | wikidoc | Nitrosonium | Nitrosonium
The nitrosonium ion is NO+, the nitrogen atom is bonded to an oxygen atom with a bond order of 3, the overall diatomic species bearing a positive charge. This ion is usually obtained as the following salts: NOClO4, NOSO4H (nitrosyl sulfuric acid, more descriptively written ONSO2OH), and NOBF4. The ClO4− and BF4− salts are slightly soluble in CH3CN. NOBF4 can be purified by sublimation at 200–250 °C/0.01 mmHg.
For NOBF4:
Selected data: density = 2.185 g cm–3.3
MW =116.82
NO+ is isoelectronic with CO and N2. It arises via protonation of nitrous acid:
# Chemical Properties
## Hydrolysis
NO+ reacts readily with water to form nitrous acid:
For this reason, NOBF4 must be protected from water or even moist air. With base, the reaction generates nitrite:
## As a diazotizing agent
NO+ reacts with aryl amines, ArNH2, to give diazonium salt, ArN2+.
This is useful because N2+ is a more readily leaving group than NH2.
## As an oxidizing agent
NO+, e.g. as NOBF4, is a strong oxidizing agent:
- vs. ferrocene/ferrocenium, + in CH2Cl2 solution has a redox potential of 1.00 V (or 1.46-1.48 V vs SCE)
- vs. ferrocene/ferrocenium, + in CH3CN solution has a redox potential of 0.87 V vs. (or 1.27-1.25 V vs SCE)
NOBF4 is a convenient oxidant because the byproduct NO is a gas, which can be swept from the reaction using a stream of N2. Upon contact with air, NO forms NO2, which can cause secondary reactions if it is not removed. NO2 is readily detectable by its characteristic orange color.
## Nitrosylation of arenes
Electron-rich arenes are nitrosylated using NOBF4. The example involves anisole:
Nitrosonium, NO+, is sometimes confused with nitronium, NO2+, the active agent in nitrations. These species are quite different, however. Nitronium is a more potent electrophile than is nitrosonium, as anticipated by the fact that the former is derived from a strong acid (nitric acid) and the latter from a weak acid (nitrous acid).
## As a source of NO complexes
NOBF4 reacts with some metal carbonyl complexes to yield related metal nitrosyl complexes. One must be careful that + is transferred vs. electron transfer (see above). | Nitrosonium
The nitrosonium ion is NO+, the nitrogen atom is bonded to an oxygen atom with a bond order of 3, the overall diatomic species bearing a positive charge. This ion is usually obtained as the following salts: NOClO4, NOSO4H (nitrosyl sulfuric acid, more descriptively written ONSO2OH), and NOBF4. The ClO4− and BF4− salts are slightly soluble in CH3CN. NOBF4 can be purified by sublimation at 200–250 °C/0.01 mmHg.
For NOBF4:
Selected data: density = 2.185 g cm–3.3
MW =116.82
NO+ is isoelectronic with CO and N2. It arises via protonation of nitrous acid:
# Chemical Properties
## Hydrolysis
NO+ reacts readily with water to form nitrous acid:
For this reason, NOBF4 must be protected from water or even moist air. With base, the reaction generates nitrite:
## As a diazotizing agent
NO+ reacts with aryl amines, ArNH2, to give diazonium salt, ArN2+.
This is useful because N2+ is a more readily leaving group than NH2.
## As an oxidizing agent
NO+, e.g. as NOBF4, is a strong oxidizing agent:
- vs. ferrocene/ferrocenium, [NO]+ in CH2Cl2 solution has a redox potential of 1.00 V (or 1.46-1.48 V vs SCE)
- vs. ferrocene/ferrocenium, [NO]+ in CH3CN solution has a redox potential of 0.87 V vs. (or 1.27-1.25 V vs SCE)
NOBF4 is a convenient oxidant because the byproduct NO is a gas, which can be swept from the reaction using a stream of N2. Upon contact with air, NO forms NO2, which can cause secondary reactions if it is not removed. NO2 is readily detectable by its characteristic orange color.
## Nitrosylation of arenes
Electron-rich arenes are nitrosylated using NOBF4. The example involves anisole:
Nitrosonium, NO+, is sometimes confused with nitronium, NO2+, the active agent in nitrations. These species are quite different, however. Nitronium is a more potent electrophile than is nitrosonium, as anticipated by the fact that the former is derived from a strong acid (nitric acid) and the latter from a weak acid (nitrous acid).
## As a source of NO complexes
NOBF4 reacts with some metal carbonyl complexes to yield related metal nitrosyl complexes. One must be careful that [NO]+ is transferred vs. electron transfer (see above). | https://www.wikidoc.org/index.php/Nitrosonium | |
8e3fad5de74f89e16b2142e212633b86af469c9a | wikidoc | Nitroxoline | Nitroxoline
# Overview
Nitroxoline is an antibiotic that has been in use in Europe for about fifty years, and has proven to be very effective at combating biofilm infections. Nitroxoline was shown to cause a decrease in the biofilm density of P. aeruginosa infections, which would allow access to the infection by the immune system in vivo. It was shown that nitroxoline functions by chelating Fe2+ and Zn2+ ions from the biofilm matrix; when Fe2+ and Zn2+ were reintroduced into the system, biofilm formation was reconstituted. The activity of biofilm degradation is comparable to EDTA, but has a history of human use in clinical settings and therefore has a precedent with which to allow its use against “slimy” biofilm infections.
# Anticancer Activity
The chelating activities of nitroxoline have also been used in an anticancer setting. Nitroxoline has been shown to be more cytotoxic to HL60, DHL-4, Panc-1, and A2780 cells lines than clioquinol and other 8-hydroxyquinoline derivatives. It also demonstrated an increase in reactive oxygen species (ROS) production over controls, especially when Cu2+ was added. The ROS levels reached over 350% of the controls with addition of CuCl2. Interestingly, the cytotoxicity production was markedly decreased with addition of ZnCl2, indicating, based on this model, that nitroxoline is not a zinc chelator. Because the zinc chelating action of clioquinol has been associated with subacute myelo-optic neuropathy, the use of nitroxoline as a cytotoxic drug in the treatment of cancers should not exhibit neurotoxic effects in humans, and in vivo trials on tumor xenografts in mice have not yielded any negative neurodegenerative effects.
Nitroxoline has been shown to inhibit the enzymatic activity of cathepsin B. Cathepsin B degrades extra-cellular membrane proteins in tumor cells, allowing them to proliferate more freely, and metastasize throughout the body. Nitroxoline was shown to be a noncompetitive, reversible inhibitor of these actions in MCF-10A neoT cells. The Ki values it demonstrates are comparable to other reversible inhibitors of cathepsin B. This indicates that it may be a candidate for further trials as an anticancer drug, especially given its history as an antimicrobial agent and its well-known pharmacokinetic profile. The mechanism of action by which nitroxoline inhibits cathepsin B may also suggest that further research of noncovalent, noncompetitive inhibitors of cathepsin B could be warranted. In fact, it was recently shown that a balance exists between the potency and the kinetics of a molecule, reflected in the molecular weight, which must be optimized in order to create the best drug for inhibition of a target enzyme. For example, a certain inhibitor may have a high affinity for an enzyme, but it may prove impractical to use in a clinical setting for treatment because of its size.
Nitroxoline and its analogues have also been shown to have antiangiogenic properties. For example, nitroxoline inhibits MetAP2 activity, an enzyme associated with angiogenesis, and HUVEC proliferation. This is further evidence that nitroxoline would make an effective anticancer drug. With different derivatives of nitroxoline demonstrating various levels of inhibition, nitroxoline may also prove to be a novel starting point for future research into cancer treatment. | Nitroxoline
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nitroxoline is an antibiotic [1] that has been in use in Europe for about fifty years, and has proven to be very effective at combating biofilm infections. Nitroxoline was shown to cause a decrease in the biofilm density of P. aeruginosa infections, which would allow access to the infection by the immune system in vivo.[2] It was shown that nitroxoline functions by chelating Fe2+ and Zn2+ ions from the biofilm matrix; when Fe2+ and Zn2+ were reintroduced into the system, biofilm formation was reconstituted. The activity of biofilm degradation is comparable to EDTA, but has a history of human use in clinical settings and therefore has a precedent with which to allow its use against “slimy” biofilm infections.
# Anticancer Activity
The chelating activities of nitroxoline have also been used in an anticancer setting. Nitroxoline has been shown to be more cytotoxic to HL60, DHL-4, Panc-1, and A2780 cells lines than clioquinol and other 8-hydroxyquinoline derivatives. [3] It also demonstrated an increase in reactive oxygen species (ROS) production over controls, especially when Cu2+ was added. The ROS levels reached over 350% of the controls with addition of CuCl2. Interestingly, the cytotoxicity production was markedly decreased with addition of ZnCl2, indicating, based on this model, that nitroxoline is not a zinc chelator. Because the zinc chelating action of clioquinol has been associated with subacute myelo-optic neuropathy, the use of nitroxoline as a cytotoxic drug in the treatment of cancers should not exhibit neurotoxic effects in humans, and in vivo trials on tumor xenografts in mice have not yielded any negative neurodegenerative effects.
Nitroxoline has been shown to inhibit the enzymatic activity of cathepsin B. [4] Cathepsin B degrades extra-cellular membrane proteins in tumor cells, allowing them to proliferate more freely, and metastasize throughout the body. Nitroxoline was shown to be a noncompetitive, reversible inhibitor of these actions in MCF-10A neoT cells. The Ki[disambiguation needed] values it demonstrates are comparable to other reversible inhibitors of cathepsin B. This indicates that it may be a candidate for further trials as an anticancer drug, especially given its history as an antimicrobial agent and its well-known pharmacokinetic profile. The mechanism of action by which nitroxoline inhibits cathepsin B may also suggest that further research of noncovalent, noncompetitive inhibitors of cathepsin B could be warranted. In fact, it was recently shown that a balance exists between the potency and the kinetics of a molecule, reflected in the molecular weight, which must be optimized in order to create the best drug for inhibition of a target enzyme. [5] For example, a certain inhibitor may have a high affinity for an enzyme, but it may prove impractical to use in a clinical setting for treatment because of its size.
Nitroxoline and its analogues have also been shown to have antiangiogenic properties.[6] For example, nitroxoline inhibits MetAP2 activity, an enzyme associated with angiogenesis, and HUVEC proliferation.[7] This is further evidence that nitroxoline would make an effective anticancer drug. With different derivatives of nitroxoline demonstrating various levels of inhibition, nitroxoline may also prove to be a novel starting point for future research into cancer treatment. | https://www.wikidoc.org/index.php/Nitroxoline | |
d86ae50f951cec8aafd9e976ae28f0fd48b9bd0d | wikidoc | Nobel Prize | Nobel Prize
The Nobel Prize (Template:Lang-sv) was established in Alfred Nobel's will in 1895, and it was first awarded in Physics, Chemistry, Physiology or Medicine, Literature, and Peace in 1901. An associated prize, The Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel, was instituted by Sweden's central bank in 1968 and first awarded in 1969. The Nobel Prizes in the specific disciplines (Chemistry, Physics, Physiology or Medicine, and Literature) and the Prize in Economics, which is commonly "identified with" them, are widely regarded as the most prestigious award one can receive in those fields. The Nobel Peace Prize conveys social prestige, and that award also is often politically controversial. With the exception of the Nobel Peace Prize, the Nobel Prizes and the Prize in Economics are presented in Stockholm, Sweden, at the annual Prize Award Ceremony on December 10, the anniversary of Nobel's death. The Nobel Foundation refers to those six prizes awarded in Stockholm as the "Swedish Prizes." The Nobel Peace Prize and its recipients' lectures are presented at the annual Prize Award Ceremony in Oslo, Norway, also on December 10. The lectures by the recipients of the "Swedish Prizes" occur in the days prior to December 10. "Since the Nobel Prize is regarded by far as the most prestigious prize in the world, the Award Ceremonies as well as the Banquets in Stockholm and Oslo on 10 December have been transformed from local Swedish and Norwegian arrangements into major international events that receive worldwide coverage by the print media, radio and television."
# Alfred Nobel's will
The five Nobel Prizes were instituted by the final will of Alfred Nobel, a Swedish chemist and industrialist, who was the inventor of the highly explosive dynamite. Though Nobel wrote several wills during his lifetime, the last was written a little over a year before he died, and signed at the Swedish-Norwegian Club in Paris on November 27, 1895. Nobel bequeathed 94% of his total assets, 31 million Swedish Kronor, to establish and endow the five Nobel Prizes.
Although Nobel's will established the prizes, his plan was incomplete and, due to various other hurdles, it took five years before the Nobel Foundation could be established and the first prizes awarded on December 10, 1901. The nobel prize is often regarded as one of the most prostigious honors a person can recieve.
# Nomination and selection
Compared with some other prizes, the Prize nomination and selection process is long and rigorous. This is a key reason why the Prizes have grown in importance over the years to become the most important prizes in their field.
The Nobel Laureates are selected by their respective committees. For the Prizes in Chemistry, Physics and Economics, a committee consists of five members elected by The Royal Swedish Academy of Sciences; for the Prize in Literature, a committee of four to five members of the Swedish Academy; for the Prize in Physiology or Medicine, the committee consists of five members selected by The Nobel Assembly, which consists of 50 members elected by Karolinska Institutet; for the Peace Prize, the Norwegian Nobel Committee consists of five members elected by the Norwegian Storting (the Norwegian parliament). In its first stage, several thousand people are asked to nominate candidates. These names are scrutinized and discussed by experts in their specific disciplines until only the winners remain. This slow and thorough process, insisted upon by Alfred Nobel, is arguably what gives the prize its importance. Despite this, there have been questionable awards and questionable omissions over the prize's century-long history.
Forms, which amount to a personal and exclusive invitation, are sent to about three thousand selected individuals to invite them to submit nominations. For the peace prize, inquiries are sent to such people as governments of states, members of international courts, professors and rectors at university level, former Peace Prize laureates, current or former members of the Norwegian Nobel Committee, among others. The Norwegian Nobel Committee then bases its assessment on nominations sent in before 3 February. The submission deadline for nominations for Physics, Chemistry, Medicine, Literature and Economics is January 31. Self-nominations and nominations of deceased people are disqualified.
The names of the nominees are never publicly announced, and neither are they told that they have been considered for the Prize. Nomination records are sealed for fifty years. In practice some nominees do become known. It is also common for publicists to make such a claim, founded or not.
After the deadline has passed, the nominations are screened by committee, and a list is produced of approximately two hundred preliminary candidates. This list is forwarded to selected experts in the relevant field. They remove all but approximately fifteen names. The committee submits a report with recommendations to the appropriate institution. The Assembly for the Medicine Prize, for example, has fifty members. The institution members then select prize winners by vote.
The selection process varies slightly between the different disciplines. The Literature Prize is rarely awarded to more than one person per year, whereas other Prizes now often involve collaborators of two or three.
While posthumous nominations are not permitted, awards can occur if the individual died in the months between the nomination and the decision of the prize committee. The scenario has occurred twice: The 1931 Literature Prize of Erik Axel Karlfeldt, and the 1961 Peace Prize to UN Secretary General Dag Hammarskjöld. As of 1974, laureates must be alive at the time of the October announcement. There has been one laureate—William Vickrey (1996, Economics)—who died after the prize was announced but before it could be presented.
## Recognition time lag
The interval between the accomplishment of the achievement being recognized and the awarding of the Nobel Prize for it varies from discipline to discipline. Prizes in Literature are typically awarded to recognize a cumulative lifetime body of work rather than a single achievement. In this case the notion of "lag" does not directly apply. Prizes in Peace, on the other hand, are often awarded within a few years of the events they recognize. For instance, Kofi Annan was awarded the 2001 Peace Prize just four years after becoming the Secretary-General of the UN.
Awards in the scientific disciplines of physics and chemistry require that the significance of achievements being recognized is "tested by time." In practice it means that the lag between the discovery and the award is typically on the order of 20 years and can be much longer. For example, Subrahmanyan Chandrasekhar shared the 1983 Nobel Prize in Physics for his work on stellar structure and evolution from the 1930s. Unfortunately, not all scientists live long enough for their work to be recognized. Some important scientific discoveries are never considered for a Prize if the discoverers have died by the time the impact of their work is realized.
# Award ceremonies
The committees and institutions serving as the selection boards for the Nobel Prizes typically announce the names of the laureates in October, with the Prizes awarded at formal ceremonies held annually on December 10, the anniversary of Alfred Nobel's death. In 2005 and 2006, these Prize ceremonies were held at the Stockholm Concert Hall, with the Nobel Banquet following immediately in the Blue Hall of Stockholm City Hall. Previously, the Nobel Prizes ceremony was held in a ballroom in Stockholm's Grand Hotel.
The Nobel Peace Prize ceremony has been held at the Norwegian Nobel Institute (1905-1946); at the Aula of the University of Oslo (1947-1990); and most recently at the Oslo City Hall.
A maximum of three laureates and two different works may be selected per award. Each award can be given to a maximum of three recipients per year. Each "Nobel Prize Award" consists of a gold medal, a diploma, and a monetary grant:
The highlight of the Nobel Prize Award Ceremony in Stockholm is when each Nobel Laureate steps forward to receive the prize from the hands of His Majesty the King of Sweden. In Oslo, the Chairman of the Norwegian Nobel Committee presents the Nobel Peace Prize in the presence of the King of Norway. Under the eyes of a watching world, the Nobel Laureate receives three things: a diploma, a medal and a document confirming the prize amount.
The grant is currently 10 million SEK, slightly more than €1 million (US$1.5 million).
If there are two winners in a particular category, the award grant is divided equally amongst the recipients. If there are three, the awarding committee has the option of dividing the grant equally, or awarding one-half to one recipient, and one-quarter to each of the others. It is not uncommon for recipients to donate prize money to benefit scientific, cultural or humanitarian causes.
Since 1902, the King of Sweden has, with the exception of the Peace Prize, presented all the prizes in Stockholm. At first King Oscar II did not approve of awarding grand prizes to foreigners, but is said to have changed his mind once his attention had been drawn to the publicity value of the prizes for Sweden.
Until the Norwegian Nobel Committee was established in 1904, the President of Norwegian Parliament made the formal presentation of the Nobel Peace Prize. The Committee's five members are entrusted with researching and adjudicating the Prize as well as awarding it. Although appointed by the Norwegian Parliament (Stortinget), they are independent and answer to no legislative authority. Members of the Norwegian government are not permitted to sit on the Committee.
# The Nobel Prize medals
The Nobel Prize medals, which have been minted by Myntverket in Sweden and the Mint of Norway since 1902, are registered trademarks of the Nobel Foundation. Their engraved designs are internationally-recognized symbols of the prestige of the Nobel Prize. All of these medal designs feature an image of Alfred Nobel in left profile on their front sides (the "face" of the medal). Four of the five Nobel Prize medals (Physics, Chemistry, Physiology or Medicine, and Literature) feature the same design on their faces (front sides). The reverse sides of the Nobel Prize medals for Chemistry and Physics share a design. Both sides of the Nobel Peace Prize Medal and the Medal for The Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel are unique designs.
The Nobel Prize medals in Physics, Chemistry, Physiology or Medicine and Literature are identical on the face: it shows the image of Alfred Nobel and the years of his birth and death (1833-1896). Nobel's portrait also appears on the Nobel Peace Prize Medal and the Medal for the Prize in Economics, but with a slightly different design. The image on the reverse varies according to the institution awarding the prize. All medals made before 1980 were struck in 23 carat gold. Today, they are made from 18 carat green gold plated with 24 carat gold.
# Controversies and criticisms
Alfred Nobel became increasingly uneasy with the military use of the explosives which he had created in the course of his jobs; his discomfort increased apparently after he read his own premature obituary, published in error by a French newspaper on the occasion of the death of Nobel's brother Ludvig, which condemned Alfred as a "merchant of death."
Since the first Nobel Prize was awarded in 1901, the proceedings, nominations, awards and exclusions have generated criticism and engendered much controversy.
## Overlooked achievements
Mahatma Gandhi was nominated for the Nobel Peace Prize five times between 1937 and 1948 but never received the prize before being assassinated on 30 January 1948, two days before the closing date for the 1948 Peace Prize nominations. The Norwegian Nobel Committee had very likely planned to give him the Peace Prize in 1948 as they considered a posthumous award, but ultimately decided against it and instead chose not to award the prize that year.
The strict rules against a prize being awarded to more than three people at once is also a cause for controversy. Where a prize is awarded to recognise an achievement by a team of more than three collaborators, inevitably one or more will miss out. For example, in 2002, a Prize was awarded to Koichi Tanaka and John Fenn for the development of mass spectrometry in protein chemistry, an award that failed to recognise the achievements of Franz Hillenkamp and Michael Karas of the Institute for Physical and Theoretical Chemistry at the University of Frankfurt.
Similarly, the prohibition of posthumous awards fails to recognise achievements by a collaborator who happens to die before the prize is awarded. Rosalind Franklin, who was key in the discovery of the structure of DNA in 1953, died of ovarian cancer in 1958, four years before Francis Crick, James D. Watson and Maurice Wilkins (one of Franklin's collaborators) were awarded the Prize for Medicine or Physiology in 1962. Franklin's significant and relevant contribution was only briefly mentioned in Crick and Watson's Nobel Prize-winning paper: "We have also been stimulated by a knowledge of the general nature of the unpublished experimental results and ideas of Dr. M.H.F. Wilkins, Dr. R.E. Franklin, and co-workers...."
In some cases, awards have arguably omitted similar discoveries made earlier. For example, the 2000 Nobel Prize in Chemistry for "the discovery and development of conductive organic polymers" (1977) ignored the much earlier discovery of highly-conductive charge transfer complex polymers: the 1963 series of papers by Weiss, et al. reported even higher conductivity in similarly iodine-doped oxidized polypyrrole.
## Lack of a Nobel Prize in Mathematics
Although there is no Nobel Prize in Mathematics, leading to considerable speculation about why Alfred Nobel omitted it, some mathematicians have won the Nobel Prize in other fields: Bertrand Russell for literature (1950); Max Born and Walther Bothe for physics (1954); Andrew Fire for physiology or medicine (2006). Other mathematicians have won the Bank of Sweden Prize in Economic Sciences in Memory of Alfred Nobel: Kenneth Arrow (1972), Leonid Kantorovich (1975), John Forbes Nash (1994), Clive W. J. Granger (2003), Robert J. Aumann and Thomas C. Schelling (2005), and Roger Myerson (2007).
Several prizes in mathematics have some similarities to the Nobel Prize. The Fields Medal is often described as the "Nobel Prize of mathematics", but it differs in being awarded only once every four years to people younger than forty years old. Other prestigious prizes in mathematics are the Crafoord Prize, awarded by the Royal Swedish Academy of Sciences since 1982; the Abel Prize, awarded by the Norwegian government beginning in 2001; the Shaw Prize in mathematical sciences awarded since 2004; and the Gauss Prize, granted jointly by the International Mathematical Union and the German Mathematical Society for "outstanding mathematical contributions that have found significant applications outside of mathematics," and introduced at the International Congress of Mathematicians in 2006. The Clay Mathematics Institute has devised seven "Millennium Problems," whose solution results in a significant cash award: since it has a clear, predetermined objective for its award and since it can be awarded whenever a problem is solved, this prize also differs from the Nobel Prizes.
# Uniquely distinguished laureates
## Multiple laureates
Since the establishment of the Nobel Prize, four people have received two Nobel Prizes:
- Maria Skłodowska-Curie: in Physics 1903, for the discovery of radioactivity; and in Chemistry 1911, for the isolation of pure radium
- Linus Pauling: in Chemistry 1954, for the hybridized orbital theory; and Peace 1962, for nuclear test-ban treaty activism; he "remains the only person to have won two unshared Nobel Prizes."
- John Bardeen: in Physics 1956, for the invention of the transistor; and Physics 1972, for the theory of superconductivity; and
- Frederick Sanger: in Chemistry 1958, for structure of the insulin molecule; and in Chemistry 1980, for virus nucleotide sequencing.
Although Otto Heinrich Warburg was nominated for a second Nobel Prize for Physiology or Medicine in 1944, he was not selected that time.
As a group, the International Committee of the Red Cross (ICRC) has received the Nobel Peace Prize three times: in 1917, 1944, and 1963. The first two prizes were specifically in recognition of the group's work during the world wars.
The United Nations High Commissioner for Refugees (UNHCR) has won the Peace Prize twice: in 1954 and 1981.
## Family laureates
A number of families have included multiple laureates. The Curie family claim the most Nobel Prizes, with five:
- Maria Skłodowska-Curie, Physics 1903 and Chemistry 1911
- Her husband Pierre Curie, Physics 1903
- Their daughter Irène Joliot-Curie, Chemistry 1935
- Their son-in-law Frederic Joliot-Curie, Chemistry 1935
In addition, Henry Labouisse, the husband of the Curies' second daughter Ève, was the director of UNICEF when it won the Nobel Peace Prize in 1965.
- C.V Raman won the Nobel prize in Physics in 1930, he was the uncle of S. Chandrashekar who won the Nobel prize in Physics in 1983.
- Manne Siegbahn won the Nobel prize in Physics in 1924, he was the father of Kai Siegbahn who shared the Nobel prize in Physics in 1981.
- William Henry Bragg shared the Nobel prize in Physics in 1915 with his son, William Lawrence Bragg.
- Arthur Kornberg shared with Severo Ochoa the 1959 Nobel prize in Physiology or Medicine for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid. Kornberg's son Roger won the 2006 Nobel prize in Chemistry for his studies of the molecular basis of eukaryotic transcription.
- J. J. Thomson, awarded the Noble prize for Physics in 1906, was the father of George Paget Thomson who was awarded the Nobel prize for Physics in 1937.
## Age extremes
William Lawrence Bragg, who was only 25 when he shared the 1915 Nobel Prize in Physics with his father William Henry Bragg, is the youngest person ever to win a Nobel Prize. Leonid Hurwicz, 90, is the oldest Nobel Laureate at the time of the award in the 2007 Prize in Economics. | Nobel Prize
Template:Infobox award
The Nobel Prize (Template:Lang-sv) was established in Alfred Nobel's will in 1895, and it was first awarded in Physics, Chemistry, Physiology or Medicine, Literature, and Peace in 1901. An associated prize, The Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel, was instituted by Sweden's central bank in 1968 and first awarded in 1969.[1] The Nobel Prizes in the specific disciplines (Chemistry, Physics, Physiology or Medicine, and Literature) and the Prize in Economics, which is commonly "identified with" them, are widely regarded as the most prestigious award one can receive in those fields.[1] The Nobel Peace Prize conveys social prestige, and that award also is often politically controversial. With the exception of the Nobel Peace Prize, the Nobel Prizes and the Prize in Economics are presented in Stockholm, Sweden, at the annual Prize Award Ceremony on December 10, the anniversary of Nobel's death. The Nobel Foundation refers to those six prizes awarded in Stockholm as the "Swedish Prizes."[2] The Nobel Peace Prize and its recipients' lectures are presented at the annual Prize Award Ceremony in Oslo, Norway, also on December 10.[3][4] The lectures by the recipients of the "Swedish Prizes" occur in the days prior to December 10.[5] "Since the Nobel Prize is regarded by far as the most prestigious prize in the world, the Award Ceremonies as well as the Banquets in Stockholm and Oslo on 10 December have been transformed from local Swedish and Norwegian arrangements into major international events that receive worldwide coverage by the print media, radio and television."[5]
# Alfred Nobel's will
The five Nobel Prizes were instituted by the final will of Alfred Nobel, a Swedish chemist and industrialist, who was the inventor of the highly explosive dynamite. Though Nobel wrote several wills during his lifetime, the last was written a little over a year before he died, and signed at the Swedish-Norwegian Club in Paris on November 27, 1895. Nobel bequeathed 94% of his total assets, 31 million Swedish Kronor, to establish and endow the five Nobel Prizes.[6]
Although Nobel's will established the prizes, his plan was incomplete and, due to various other hurdles, it took five years before the Nobel Foundation could be established and the first prizes awarded on December 10, 1901.[8] The nobel prize is often regarded as one of the most prostigious honors a person can recieve.
# Nomination and selection
Compared with some other prizes, the Prize nomination and selection process is long and rigorous. This is a key reason why the Prizes have grown in importance over the years to become the most important prizes in their field.[9]
The Nobel Laureates are selected by their respective committees. For the Prizes in Chemistry, Physics and Economics, a committee consists of five members elected by The Royal Swedish Academy of Sciences; for the Prize in Literature, a committee of four to five members of the Swedish Academy; for the Prize in Physiology or Medicine, the committee consists of five members selected by The Nobel Assembly, which consists of 50 members elected by Karolinska Institutet; for the Peace Prize, the Norwegian Nobel Committee consists of five members elected by the Norwegian Storting (the Norwegian parliament).[10] In its first stage, several thousand people are asked to nominate candidates. These names are scrutinized and discussed by experts in their specific disciplines until only the winners remain. This slow and thorough process, insisted upon by Alfred Nobel, is arguably what gives the prize its importance. Despite this, there have been questionable awards and questionable omissions over the prize's century-long history.
Forms, which amount to a personal and exclusive invitation, are sent to about three thousand selected individuals to invite them to submit nominations. For the peace prize, inquiries are sent to such people as governments of states, members of international courts, professors and rectors at university level, former Peace Prize laureates, current or former members of the Norwegian Nobel Committee, among others. The Norwegian Nobel Committee then bases its assessment on nominations sent in before 3 February.[11] The submission deadline for nominations for Physics, Chemistry, Medicine, Literature and Economics is January 31.[12] Self-nominations and nominations of deceased people are disqualified.
The names of the nominees are never publicly announced, and neither are they told that they have been considered for the Prize. Nomination records are sealed for fifty years. In practice some nominees do become known. It is also common for publicists to make such a claim, founded or not.
After the deadline has passed, the nominations are screened by committee, and a list is produced of approximately two hundred preliminary candidates. This list is forwarded to selected experts in the relevant field. They remove all but approximately fifteen names. The committee submits a report with recommendations to the appropriate institution. The Assembly for the Medicine Prize, for example, has fifty members. The institution members then select prize winners by vote.
The selection process varies slightly between the different disciplines. The Literature Prize is rarely awarded to more than one person per year, whereas other Prizes now often involve collaborators of two or three.
While posthumous nominations are not permitted, awards can occur if the individual died in the months between the nomination and the decision of the prize committee. The scenario has occurred twice: The 1931 Literature Prize of Erik Axel Karlfeldt, and the 1961 Peace Prize to UN Secretary General Dag Hammarskjöld. As of 1974, laureates must be alive at the time of the October announcement. There has been one laureate—William Vickrey (1996, Economics)—who died after the prize was announced but before it could be presented.
## Recognition time lag
The interval between the accomplishment of the achievement being recognized and the awarding of the Nobel Prize for it varies from discipline to discipline. Prizes in Literature are typically awarded to recognize a cumulative lifetime body of work rather than a single achievement. In this case the notion of "lag" does not directly apply. Prizes in Peace, on the other hand, are often awarded within a few years of the events they recognize. For instance, Kofi Annan was awarded the 2001 Peace Prize just four years after becoming the Secretary-General of the UN.
Awards in the scientific disciplines of physics and chemistry require that the significance of achievements being recognized is "tested by time." In practice it means that the lag between the discovery and the award is typically on the order of 20 years and can be much longer. For example, Subrahmanyan Chandrasekhar shared the 1983 Nobel Prize in Physics for his work on stellar structure and evolution from the 1930s. Unfortunately, not all scientists live long enough for their work to be recognized. Some important scientific discoveries are never considered for a Prize if the discoverers have died by the time the impact of their work is realized.
# Award ceremonies
The committees and institutions serving as the selection boards for the Nobel Prizes typically announce the names of the laureates in October, with the Prizes awarded at formal ceremonies held annually on December 10, the anniversary of Alfred Nobel's death.[5] In 2005 and 2006, these Prize ceremonies were held at the Stockholm Concert Hall, with the Nobel Banquet following immediately in the Blue Hall of Stockholm City Hall. Previously, the Nobel Prizes ceremony was held in a ballroom in Stockholm's Grand Hotel.[5]
The Nobel Peace Prize ceremony has been held at the Norwegian Nobel Institute (1905-1946); at the Aula of the University of Oslo (1947-1990); and most recently at the Oslo City Hall.[5]
A maximum of three laureates and two different works may be selected per award. Each award can be given to a maximum of three recipients per year. Each "Nobel Prize Award" consists of a gold medal, a diploma, and a monetary grant:
The highlight of the Nobel Prize Award Ceremony in Stockholm is when each Nobel Laureate steps forward to receive the prize from the hands of His Majesty the King of Sweden. In Oslo, the Chairman of the Norwegian Nobel Committee presents the Nobel Peace Prize in the presence of the King of Norway. Under the eyes of a watching world, the Nobel Laureate receives three things: a diploma, a medal and a document confirming the prize amount.[13]
The grant is currently 10 million SEK, slightly more than €1 million (US$1.5 million).[14]
If there are two winners in a particular category, the award grant is divided equally amongst the recipients. If there are three, the awarding committee has the option of dividing the grant equally, or awarding one-half to one recipient, and one-quarter to each of the others. It is not uncommon for recipients to donate prize money to benefit scientific, cultural or humanitarian causes.
Since 1902, the King of Sweden has, with the exception of the Peace Prize, presented all the prizes in Stockholm. At first King Oscar II did not approve of awarding grand prizes to foreigners, but is said to have changed his mind once his attention had been drawn to the publicity value of the prizes for Sweden.
Until the Norwegian Nobel Committee was established in 1904, the President of Norwegian Parliament made the formal presentation of the Nobel Peace Prize. The Committee's five members are entrusted with researching and adjudicating the Prize as well as awarding it. Although appointed by the Norwegian Parliament (Stortinget), they are independent and answer to no legislative authority. Members of the Norwegian government are not permitted to sit on the Committee.
# The Nobel Prize medals
The Nobel Prize medals, which have been minted by Myntverket[15] in Sweden and the Mint of Norway since 1902, are registered trademarks of the Nobel Foundation. Their engraved designs are internationally-recognized symbols of the prestige of the Nobel Prize. All of these medal designs feature an image of Alfred Nobel in left profile on their front sides (the "face" of the medal). Four of the five Nobel Prize medals (Physics, Chemistry, Physiology or Medicine, and Literature) feature the same design on their faces (front sides). The reverse sides of the Nobel Prize medals for Chemistry and Physics share a design.[2][13][16] Both sides of the Nobel Peace Prize Medal[17] and the Medal for The Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel are unique designs.[2][13]
The Nobel Prize medals in Physics, Chemistry, Physiology or Medicine and Literature are identical on the face: it shows the image of Alfred Nobel and the years of his birth and death (1833-1896). Nobel's portrait also appears on the Nobel Peace Prize Medal and the Medal for the Prize in Economics, but with a slightly different design. The image on the reverse varies according to the institution awarding the prize. All medals made before 1980 were struck in 23 carat gold. Today, they are made from 18 carat green gold plated with 24 carat gold.[2][13]
# Controversies and criticisms
Alfred Nobel became increasingly uneasy with the military use of the explosives which he had created in the course of his jobs; his discomfort increased apparently after he read his own premature obituary, published in error by a French newspaper on the occasion of the death of Nobel's brother Ludvig, which condemned Alfred as a "merchant of death."[18]
Since the first Nobel Prize was awarded in 1901, the proceedings, nominations, awards and exclusions have generated criticism and engendered much controversy.
## Overlooked achievements
Mahatma Gandhi was nominated for the Nobel Peace Prize five times between 1937 and 1948 but never received the prize before being assassinated on 30 January 1948, two days before the closing date for the 1948 Peace Prize nominations. The Norwegian Nobel Committee had very likely planned to give him the Peace Prize in 1948 as they considered a posthumous award, but ultimately decided against it and instead chose not to award the prize that year.[19]
The strict rules against a prize being awarded to more than three people at once is also a cause for controversy. Where a prize is awarded to recognise an achievement by a team of more than three collaborators, inevitably one or more will miss out. For example, in 2002, a Prize was awarded to Koichi Tanaka and John Fenn for the development of mass spectrometry in protein chemistry, an award that failed to recognise the achievements of Franz Hillenkamp and Michael Karas of the Institute for Physical and Theoretical Chemistry at the University of Frankfurt.[20]
Similarly, the prohibition of posthumous awards fails to recognise achievements by a collaborator who happens to die before the prize is awarded. Rosalind Franklin, who was key in the discovery of the structure of DNA in 1953, died of ovarian cancer in 1958, four years before Francis Crick, James D. Watson and Maurice Wilkins (one of Franklin's collaborators) were awarded the Prize for Medicine or Physiology in 1962.[21] Franklin's significant and relevant contribution was only briefly mentioned in Crick and Watson's Nobel Prize-winning paper: "We have also been stimulated by a knowledge of the general nature of the unpublished experimental results and ideas of Dr. M.H.F. Wilkins, Dr. R.E. Franklin, and co-workers...."[22]
In some cases, awards have arguably omitted similar discoveries made earlier. For example, the 2000 Nobel Prize in Chemistry for "the discovery and development of conductive organic polymers" (1977) ignored the much earlier discovery of highly-conductive charge transfer complex polymers: the 1963 series of papers by Weiss, et al. reported even higher conductivity in similarly iodine-doped oxidized polypyrrole.[23][24]
## Lack of a Nobel Prize in Mathematics
Although there is no Nobel Prize in Mathematics, leading to considerable speculation about why Alfred Nobel omitted it,[25][26] some mathematicians have won the Nobel Prize in other fields: Bertrand Russell for literature (1950); Max Born and Walther Bothe for physics (1954); Andrew Fire for physiology or medicine (2006). Other mathematicians have won the Bank of Sweden Prize in Economic Sciences in Memory of Alfred Nobel: Kenneth Arrow (1972), Leonid Kantorovich (1975), John Forbes Nash (1994), Clive W. J. Granger (2003), Robert J. Aumann and Thomas C. Schelling (2005), and Roger Myerson (2007).
Several prizes in mathematics have some similarities to the Nobel Prize. The Fields Medal is often described as the "Nobel Prize of mathematics", but it differs in being awarded only once every four years to people younger than forty years old. Other prestigious prizes in mathematics are the Crafoord Prize, awarded by the Royal Swedish Academy of Sciences since 1982; the Abel Prize, awarded by the Norwegian government beginning in 2001; the Shaw Prize in mathematical sciences awarded since 2004; and the Gauss Prize, granted jointly by the International Mathematical Union and the German Mathematical Society for "outstanding mathematical contributions that have found significant applications outside of mathematics," and introduced at the International Congress of Mathematicians in 2006. The Clay Mathematics Institute has devised seven "Millennium Problems," whose solution results in a significant cash award:[27] since it has a clear, predetermined objective for its award and since it can be awarded whenever a problem is solved, this prize also differs from the Nobel Prizes.
# Uniquely distinguished laureates
## Multiple laureates
Since the establishment of the Nobel Prize, four people have received two Nobel Prizes:[28]
- Maria Skłodowska-Curie: in Physics 1903, for the discovery of radioactivity; and in Chemistry 1911, for the isolation of pure radium
- Linus Pauling: in Chemistry 1954, for the hybridized orbital theory; and Peace 1962, for nuclear test-ban treaty activism; he "remains the only person to have won two unshared Nobel Prizes."[29]
- John Bardeen: in Physics 1956, for the invention of the transistor; and Physics 1972, for the theory of superconductivity; and
- Frederick Sanger: in Chemistry 1958, for structure of the insulin molecule; and in Chemistry 1980, for virus nucleotide sequencing.
Although Otto Heinrich Warburg was nominated for a second Nobel Prize for Physiology or Medicine in 1944, he was not selected that time.[30]
As a group, the International Committee of the Red Cross (ICRC) has received the Nobel Peace Prize three times: in 1917, 1944, and 1963. The first two prizes were specifically in recognition of the group's work during the world wars.
The United Nations High Commissioner for Refugees (UNHCR) has won the Peace Prize twice: in 1954 and 1981.
## Family laureates
A number of families have included multiple laureates.[28] The Curie family claim the most Nobel Prizes, with five:
- Maria Skłodowska-Curie, Physics 1903 and Chemistry 1911
- Her husband Pierre Curie, Physics 1903
- Their daughter Irène Joliot-Curie, Chemistry 1935
- Their son-in-law Frederic Joliot-Curie, Chemistry 1935
In addition, Henry Labouisse, the husband of the Curies' second daughter Ève, was the director of UNICEF when it won the Nobel Peace Prize in 1965.
- C.V Raman won the Nobel prize in Physics in 1930, he was the uncle of S. Chandrashekar who won the Nobel prize in Physics in 1983.
- Manne Siegbahn won the Nobel prize in Physics in 1924, he was the father of Kai Siegbahn who shared the Nobel prize in Physics in 1981.
- William Henry Bragg shared the Nobel prize in Physics in 1915 with his son, William Lawrence Bragg.
- Arthur Kornberg shared with Severo Ochoa the 1959 Nobel prize in Physiology or Medicine for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid.[31] Kornberg's son Roger won the 2006 Nobel prize in Chemistry for his studies of the molecular basis of eukaryotic transcription.[32]
- J. J. Thomson, awarded the Noble prize for Physics in 1906, was the father of George Paget Thomson who was awarded the Nobel prize for Physics in 1937.
## Age extremes
William Lawrence Bragg, who was only 25 when he shared the 1915 Nobel Prize in Physics with his father William Henry Bragg, is the youngest person ever to win a Nobel Prize.[33] Leonid Hurwicz, 90, is the oldest Nobel Laureate at the time of the award in the 2007 Prize in Economics.[34] | https://www.wikidoc.org/index.php/Nobel_Prize | |
0d229e9d162761df11a1094b3f3bbd997ea69c46 | wikidoc | Noble metal | Noble metal
Noble metals are metals that are resistant to corrosion or oxidation, unlike most base metals. They tend to be precious metals, often due to rarity in the crust of the Earth. Examples include gold, silver, tantalum, platinum, palladium and rhodium.
Some of the noble metals can be dissolved in aqua regia, a highly concentrated mixture of acids.
The term can also be used in a relative sense. A "Galvanic series" is a hierarchy of metals (or other electrically conductive materials, including composites and semimetals) that runs from noble to active, and allows designers to see at a glance how materials will interact in the environment used to generate the series. In this sense of the word, graphite is more noble than silver (even though it is alchemically more base) and the relative nobility of many materials is highly dependent upon context, as for aluminium and stainless steel in conditions of varying pH.
In physics the definition of a noble metal is even more strict. It is required that the d-bands of the electronic structure are filled. Taking this into account, only copper, silver and gold are noble metals, as all d-like band are filled and don't cross the Fermi level. For platinum two d-bands cross the Fermi level, changing its chemical behaviour; it is used (in contrast to gold, for example) as a catalyst. The different reactivity can easily be seen while preparing clean metal surfaces in ultra high vacuum; surfaces of noble metals (e.g., gold) are easy to clean and stay clean for a long time, while those of platinum or palladium, for example, are covered by carbon monoxide very quickly. | Noble metal
Noble metals are metals that are resistant to corrosion or oxidation, unlike most base metals. They tend to be precious metals, often due to rarity in the crust of the Earth. Examples include gold, silver, tantalum, platinum, palladium and rhodium.
Some of the noble metals can be dissolved in aqua regia, a highly concentrated mixture of acids.
The term can also be used in a relative sense. A "Galvanic series" is a hierarchy of metals (or other electrically conductive materials, including composites and semimetals) that runs from noble to active, and allows designers to see at a glance how materials will interact in the environment used to generate the series. In this sense of the word, graphite is more noble than silver (even though it is alchemically more base) and the relative nobility of many materials is highly dependent upon context, as for aluminium and stainless steel in conditions of varying pH.
In physics the definition of a noble metal is even more strict. It is required that the d-bands of the electronic structure are filled. Taking this into account, only copper, silver and gold are noble metals, as all d-like band are filled and don't cross the Fermi level. For platinum two d-bands cross the Fermi level, changing its chemical behaviour; it is used (in contrast to gold, for example) as a catalyst. The different reactivity can easily be seen while preparing clean metal surfaces in ultra high vacuum; surfaces of noble metals (e.g., gold) are easy to clean and stay clean for a long time, while those of platinum or palladium, for example, are covered by carbon monoxide very quickly.
# External links
- To see which bands cross the Fermi level, the Fermi surfaces of almost all the metals can be found at the Fermi Surface Database
- The following article might also clarify the correlation between band structure and the term noble metal E. Hüger and K. Osuch, Making a noble Metal of Pd, Europhys. Lett., 71 (2005) 276 | https://www.wikidoc.org/index.php/Noble_metal | |
4fc7e48d21c89a08daa8eb310fe7cf0780309c61 | wikidoc | Nomifensine | Nomifensine
# Overview
Nomifensine (Merital, Alival) is a norepinephrine-dopamine reuptake inhibitor developed by a team at Hoechst AG in the 1960s. The drug was test marketed in the United States by Hoechst AG (now Sanofi-Aventis), i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters. This is a mechanism of action shared by some recreational drugs like cocaine and the medication Tametraline (see DRI). Research showed that the (S) isomer is responsible for activity.
The drug was an effective antidepressant, without sedative effects. Nomifensine did not interact significantly with alcohol and lacked anticholinergic effects. No withdrawal symptoms were seen after 6 months treatment. The drug was however considered not suitable for agitated patients as it presumably made agitation worse.
In January 1986 the drug was withdraw by its manufacturers for safety reasons.
Some case reports in the 1980s suggested that there was potential for psychological dependence on nomifensine, typically in patients with a history of stimulant addiction, or when the drug was used in very high doses (400–600 mg per day).
In a 1989 study it has been investigated for use in treating adult ADHD and proven successful. In a 1977 study it has not proven of benefit in advanced parkinsonism, except for depression associated with the parkinsonism.
# Clinical uses
Nomifensine was investigated for use as an antidepressant in the 1970s, and was found to be a useful antidepressant at doses of 50–225 mg per day, both motivating and anxiolytic.
# Side effects
During treatment with nomifensine there were relatively few adverse effects mainly renal failure, paranoid symptoms, drowsiness or insomnia, headache, and dry mouth.
Side effects affecting the cardiovascular system included tachycardia and palpitations, but nomifensine was significantly less cardiotoxic than the standard triciclyc antidepressants.
Due to the risk of a risk of haemolytic anaemia, the U.S. Food and Drug Administration (FDA) withdrew approval for nomifensine on March 20, 1992. Nomifensine has subsequently been withdrawn from the Canadian and UK markets as well.
Some deaths were linked to immunohaemolytic anemia caused by this compound although the mechanism remained unclear.
In 2012 structure–affinity relationship data (compare SAR) were published.
# Synthesis | Nomifensine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Nomifensine (Merital, Alival) is a norepinephrine-dopamine reuptake inhibitor developed by a team at Hoechst AG in the 1960s.[2] The drug was test marketed in the United States by Hoechst AG (now Sanofi-Aventis), i.e. a drug that increases the amount of synaptic norepinephrine and dopamine available to receptors by blocking the dopamine and norepinephrine reuptake transporters.[3] This is a mechanism of action shared by some recreational drugs like cocaine and the medication Tametraline (see DRI). Research showed that the (S) isomer is responsible for activity.[4]
The drug was an effective antidepressant, without sedative effects. Nomifensine did not interact significantly with alcohol and lacked anticholinergic effects. No withdrawal symptoms were seen after 6 months treatment. The drug was however considered not suitable for agitated patients as it presumably made agitation worse.[5][6]
In January 1986 the drug was withdraw by its manufacturers for safety reasons.[7]
Some case reports in the 1980s suggested that there was potential for psychological dependence on nomifensine, typically in patients with a history of stimulant addiction, or when the drug was used in very high doses (400–600 mg per day).[8]
In a 1989 study it has been investigated for use in treating adult ADHD and proven successful.[9] In a 1977 study it has not proven of benefit in advanced parkinsonism, except for depression associated with the parkinsonism.[10]
# Clinical uses
Nomifensine was investigated for use as an antidepressant in the 1970s, and was found to be a useful antidepressant at doses of 50–225 mg per day, both motivating and anxiolytic.
# Side effects
During treatment with nomifensine there were relatively few adverse effects mainly renal failure, paranoid symptoms, drowsiness or insomnia, headache, and dry mouth.
Side effects affecting the cardiovascular system included tachycardia and palpitations, but nomifensine was significantly less cardiotoxic than the standard triciclyc antidepressants.[11]
Due to the risk of a risk of haemolytic anaemia, the U.S. Food and Drug Administration (FDA) withdrew approval for nomifensine on March 20, 1992. Nomifensine has subsequently been withdrawn from the Canadian and UK markets as well.[12]
Some deaths were linked to immunohaemolytic anemia caused by this compound although the mechanism remained unclear.[13]
In 2012 structure–affinity relationship data (compare SAR) were published.[14]
# Synthesis | https://www.wikidoc.org/index.php/Nomifensine | |
efb6c23a77aaf804bc15dc3b6d93ab0820d0c1dc | wikidoc | Noncovalent | Noncovalent
A noncovalent bond is a type of chemical bond, typically between macromolecules, that does not involve the sharing of pairs of electrons, but rather involves more dispersed variations of electromagnetic interactions. The noncovalent bond is the dominant type of bond between supermolecules in supermolecular chemistry. Noncovalent bonds are critical in maintaining the three-dimensional structure of large molecules, such as proteins and nucleic acids, and are involved in many biological processes in which large molecules bind specifically but transiently to one another. The energy released in the formation of noncovalent bonds is on the order of 1-5 kcal per mol. There are four main types of non-covalent bonds: hydrogen bonding, ionic interactions, Van der Waals interactions, and hydrophobic bonds. Examples of noncovalent bonds include: those binding interactions which hold the two strands DNA in the DNA double helix together, those which fold polypeptides into such secondary structures as the alpha helix and the beta conformation, those which enable enzymes to bind to their substrate, and those which enable antibodies to bind to their antigen.
# Overview
In general, noncovalent bonding refers to a variety of interactions that are not covalent in nature between molecules or parts of molecules that provide force to hold the molecules or parts of molecules together, usually in a specific orientation or conformation. Noncovalent bonding is the dominant type of bonding in supramolecular chemistry. These noncovalent interactions include: ionic bonds, hydrophobic interactions, hydrogen bonds, Van der Waals forces, i.e. "London dispersion forces", and Dipole-dipole bonds.
The terms "noncovalent bonding," "noncovalent interactions," and "noncovalent forces" all refer to these forces as a whole without specifying or distinguishing which specific forces are involved: noncovalent interactions often involve several of these forces working in concert. Noncovalent bonds are weak by nature and must therefore work together to have a significant effect. In addition, the combined bond strength is greater than the sum of the individual bonds. This is because the free energy of multiple bonds between two molecules is greater than the sum of the enthalpies of each bond due to entropic effects.
# Examples
## Protein structure
Main article: Protein structure
Intramolecular noncovalent interactions are largely responsible for the secondary and tertiary structure of proteins and therefore the protein's function in the mechanisms of life. Intermolecular noncovalent interactions are responsible for protein complexes (quaternary structure) where two or more proteins function in a coherent mechanism.
## Pharmaceuticals
Most drugs work by noncovalently interacting with biomolecules such as proteins or RNA. Relatively few drugs actually form covalent bonds with the biomolecules they interact with; instead, they interfere with or activate some biological mechanism through noncovalently interacting in very specific locations on specific biomolecules which present the perfect combination of noncovalent binding partners in just the right geometry. | Noncovalent
A noncovalent bond is a type of chemical bond, typically between macromolecules, that does not involve the sharing of pairs of electrons, but rather involves more dispersed variations of electromagnetic interactions. The noncovalent bond is the dominant type of bond between supermolecules in supermolecular chemistry.[1] Noncovalent bonds are critical in maintaining the three-dimensional structure of large molecules, such as proteins and nucleic acids, and are involved in many biological processes in which large molecules bind specifically but transiently to one another. The energy released in the formation of noncovalent bonds is on the order of 1-5 kcal per mol.[2] There are four main types of non-covalent bonds: hydrogen bonding, ionic interactions, Van der Waals interactions, and hydrophobic bonds.[2] Examples of noncovalent bonds include: those binding interactions which hold the two strands DNA in the DNA double helix together, those which fold polypeptides into such secondary structures as the alpha helix and the beta conformation, those which enable enzymes to bind to their substrate, and those which enable antibodies to bind to their antigen.[3]
# Overview
In general, noncovalent bonding refers to a variety of interactions that are not covalent in nature between molecules or parts of molecules that provide force to hold the molecules or parts of molecules together, usually in a specific orientation or conformation. Noncovalent bonding is the dominant type of bonding in supramolecular chemistry. These noncovalent interactions include: ionic bonds, hydrophobic interactions, hydrogen bonds, Van der Waals forces, i.e. "London dispersion forces", and Dipole-dipole bonds.
The terms "noncovalent bonding," "noncovalent interactions," and "noncovalent forces" all refer to these forces as a whole without specifying or distinguishing which specific forces are involved: noncovalent interactions often involve several of these forces working in concert. Noncovalent bonds are weak by nature and must therefore work together to have a significant effect. In addition, the combined bond strength is greater than the sum of the individual bonds. This is because the free energy of multiple bonds between two molecules is greater than the sum of the enthalpies of each bond due to entropic effects.
# Examples
## Protein structure
Main article: Protein structure
Intramolecular noncovalent interactions are largely responsible for the secondary and tertiary structure of proteins and therefore the protein's function in the mechanisms of life. Intermolecular noncovalent interactions are responsible for protein complexes (quaternary structure) where two or more proteins function in a coherent mechanism.
## Pharmaceuticals
Most drugs work by noncovalently interacting with biomolecules such as proteins or RNA. Relatively few drugs actually form covalent bonds with the biomolecules they interact with; instead, they interfere with or activate some biological mechanism through noncovalently interacting in very specific locations on specific biomolecules which present the perfect combination of noncovalent binding partners in just the right geometry. | https://www.wikidoc.org/index.php/Noncovalent | |
fdcb7626822bab5a4f1ee2b93f37007aee0112eb | wikidoc | Nonoxynol-9 | Nonoxynol-9
Nonoxynol-9, sometimes abbreviated as N-9, is a non-ionic nonoxynol surfactant that is used as an ingredient in various cleaning and cosmetic products, but is also widely used in contraceptives for its spermicidal properties.
Although it was at one time widely promoted as a protection against sexually transmitted infections including HIV, subsequent studies have shown that it can in fact increase the risk of infection by damaging the physical barriers of the rectum or vagina.
# Uses
## Spermicide
As a spermicide, it attacks the acrosomal membranes of the sperm causing the sperm to be immobilized.
Nonoxynol-9 is the active ingredient in most spermicidal creams, jellies, foams, gel, film, and suppositories.
A 2004 study found that over a six-month period, the typical-use failure rates for five nonoxynol-9 vaginal contraceptives (film, suppository, and gels at three different concentrations) ranged from 10% to 20%.
## Condoms
Many models of condoms are lubricated with solutions containing nonoxynol-9. In this role, it has been promoted as a backup method for pregnancy and STI prevention in the event of condom failure.
However, the 2001 WHO/CONRAD Technical Consultation on Nonoxynol-9 concluded that:
There is no published scientific evidence that N-9-lubricated condoms provide any additional protection against pregnancy or STIs compared with condoms lubricated with other products. Since adverse effects due to the addition of N-9 to condoms cannot be excluded, such condoms should no longer be promoted. However, it is better to use N-9-lubricated condoms than no condoms.
Additionally, the WHO statement suggests that N-9 should not be used rectally under any circumstances.
## Cervical barriers
Almost all brands of diaphragm jelly contain nonoxynol-9 as the active ingredient. This jelly may also be used for cervical caps and Lea's shields.
Most contraceptive sponges contain nonoxynol-9 as an active ingredient.
## Shaving Cream
Nonoxynol-9 is sometimes included in shaving creams for its properties as a nonionic surfactant; it helps break down skin oils that normally protect hair from moisture, so that they become wet and, hence, softer and easier to shave. Gillette formerly used nonoxynol-9 for this purpose in its Foamy products, but has discontinued the practice.
## Sports Cream
Nonoxynol-9 is also found in Bengay Vanishing Scent as an inactive ingredient.
# Side effects
Nonoxynol-9's ability to kill microbes in vitro was initially taken as evidence that it might be effective at preventing STI transmission. However, more recent findings indicate that it may actually increase a person's risk of contracting STIs, especially if used frequently. This is because the chemical causes tiny abrasions inside the sensitive vaginal and anal walls. These abrasions may make transmission more likely especially if condoms are not used.
From 1996 to 2000, a UN-sponsored study carried out in several locations in Africa followed nearly 1000 sex workers who used nonoxynol-9 gels or a placebo. The HIV infection rate among those using nonoxynol-9 was about 50% higher than those who used the placebo; those using nonoxynol-9 also had a higher incidence of vaginal lesions, which may have contributed to this increased risk. Regular use of nonoxynol-9 likely increases the risk of infection with sexually transmitted human papillomaviruses (HPVs) that can cause cervical cancer. While these results may not be directly applicable to lower-frequency use, these findings combined with lack of any demonstrated HIV-prevention benefit from nonoxynol-9 use have led most major health agencies to recommend that it no longer be used by women at high risk of HIV infection. The WHO further notes that "Nonoxynol-9 offers no protection against sexually transmitted infections such as gonorrhoea, chlamydia."
Nonoxynol-9 based products (including condoms containing the spermicide) should not be used for prevention of HIV or STDs or for contraception between non-monogamous partners because of the increased risk of infection by HIV or sexually transmitted infections. However, non-spermicide condoms are available and are still highly successful at preventing both pregnancy and STD transmission.
Frequent use of nonoxynol-9 is linked to higher risk of urinary tract infections (UTIs).
Some people have reported allergic reactions to Nonoxynol-9; however, it is possible to test it oneself on the lymph nodes on the upper thigh by the groin to see if one is hypersensitive. If so, the skin usually turns red and causes a burning sensation. Recovery from an allergic reaction usually takes about 6-8 hours.
# Alternatives
Chemically speaking, there are two alternatives to nonoxynol-9 spermicide:
- Menfegol: Available as a foaming tablet in Europe.
- Benzalkonium chloride: Stand-alone benzalkonium chloride spermicide is only available in Canada and Europe (Hungary) and limited to pessary form. Benzalkonium chloride is also the active ingredient in one brand of contraceptive sponge, available only in France.
For use with a cervical barrier such as a diaphragm, a jelly containing lactic acid may work as a substitute.
Lactic acid is known to immobilize sperm, also. But in contrast with nonoxynol-9, this immobilization seems to be reversible and is for that reason less reliable. | Nonoxynol-9
Nonoxynol-9, sometimes abbreviated as N-9, is a non-ionic nonoxynol surfactant that is used as an ingredient in various cleaning and cosmetic products, but is also widely used in contraceptives for its spermicidal properties.
Although it was at one time widely promoted as a protection against sexually transmitted infections including HIV, subsequent studies have shown that it can in fact increase the risk of infection by damaging the physical barriers of the rectum or vagina.[1]
# Uses
## Spermicide
As a spermicide, it attacks the acrosomal membranes of the sperm causing the sperm to be immobilized.
Nonoxynol-9 is the active ingredient in most spermicidal creams, jellies, foams, gel, film, and suppositories.
A 2004 study found that over a six-month period, the typical-use failure rates for five nonoxynol-9 vaginal contraceptives (film, suppository, and gels at three different concentrations) ranged from 10% to 20%.[2]
## Condoms
Many models of condoms are lubricated with solutions containing nonoxynol-9. In this role, it has been promoted as a backup method for pregnancy and STI prevention in the event of condom failure.
However, the 2001 WHO/CONRAD Technical Consultation on Nonoxynol-9 concluded that:
There is no published scientific evidence that N-9-lubricated condoms provide any additional protection against pregnancy or STIs compared with condoms lubricated with other products. Since adverse effects due to the addition of N-9 to condoms cannot be excluded, such condoms should no longer be promoted. However, it is better to use N-9-lubricated condoms than no condoms.
Additionally, the WHO statement suggests that N-9 should not be used rectally under any circumstances.
## Cervical barriers
Almost all brands of diaphragm jelly contain nonoxynol-9 as the active ingredient. This jelly may also be used for cervical caps and Lea's shields.
Most contraceptive sponges contain nonoxynol-9 as an active ingredient.
## Shaving Cream
Nonoxynol-9 is sometimes included in shaving creams for its properties as a nonionic surfactant; it helps break down skin oils that normally protect hair from moisture, so that they become wet and, hence, softer and easier to shave. Gillette formerly used nonoxynol-9 for this purpose in its Foamy products, but has discontinued the practice.[3]
## Sports Cream
Nonoxynol-9 is also found in Bengay Vanishing Scent as an inactive ingredient.
# Side effects
Nonoxynol-9's ability to kill microbes in vitro was initially taken as evidence that it might be effective at preventing STI transmission. However, more recent findings indicate that it may actually increase a person's risk of contracting STIs, especially if used frequently. This is because the chemical causes tiny abrasions inside the sensitive vaginal and anal walls. These abrasions may make transmission more likely especially if condoms are not used.
From 1996 to 2000, a UN-sponsored study carried out in several locations in Africa followed nearly 1000 sex workers who used nonoxynol-9 gels or a placebo. The HIV infection rate among those using nonoxynol-9 was about 50% higher than those who used the placebo; those using nonoxynol-9 also had a higher incidence of vaginal lesions, which may have contributed to this increased risk. Regular use of nonoxynol-9 likely increases the risk of infection with sexually transmitted human papillomaviruses (HPVs) that can cause cervical cancer.[4][5] While these results may not be directly applicable to lower-frequency use, these findings combined with lack of any demonstrated HIV-prevention benefit from nonoxynol-9 use have led most major health agencies to recommend that it no longer be used by women at high risk of HIV infection. The WHO further notes that "Nonoxynol-9 offers no protection against sexually transmitted infections such as gonorrhoea, chlamydia."[1]
Nonoxynol-9 based products (including condoms containing the spermicide) should not be used for prevention of HIV or STDs or for contraception between non-monogamous partners because of the increased risk of infection by HIV or sexually transmitted infections. However, non-spermicide condoms are available and are still highly successful at preventing both pregnancy and STD transmission.
Frequent use of nonoxynol-9 is linked to higher risk of urinary tract infections (UTIs).
Some people have reported allergic reactions to Nonoxynol-9; however, it is possible to test it oneself on the lymph nodes on the upper thigh by the groin to see if one is hypersensitive. If so, the skin usually turns red and causes a burning sensation. Recovery from an allergic reaction usually takes about 6-8 hours.
# Alternatives
Chemically speaking, there are two alternatives to nonoxynol-9 spermicide:
- Menfegol: Available as a foaming tablet in Europe.
- Benzalkonium chloride: Stand-alone benzalkonium chloride spermicide is only available in Canada and Europe (Hungary) and limited to pessary form.[citation needed] Benzalkonium chloride is also the active ingredient in one brand of contraceptive sponge, available only in France.
For use with a cervical barrier such as a diaphragm, a jelly containing lactic acid may work as a substitute.
Lactic acid is known to immobilize sperm, also. But in contrast with nonoxynol-9, this immobilization seems to be reversible and is for that reason less reliable. | https://www.wikidoc.org/index.php/Nonoxynol-9 | |
377213d43108a8e2e8a8f0621becc230cee53f6f | wikidoc | Norfloxacin | Norfloxacin
# 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
Norfloxacin is an fluoroquinolone antibiotic that is FDA approved for the treatment of urinary tract infections (UTI), prostatitis and sexually transmited diseases (STD). Common adverse reactions include nausea, stomach cramps, dizziness and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Proteus vulgaris, Staphylococcus aureus, or Streptococcus agalactiae.
- Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae.
- Prostatitis due to Escherichia coli.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Norfloxacin in adult patients.
### Non–Guideline-Supported Use
- Dosage: 400 q12h
- Dosage: 400 mg q12h for 3 days
- Dosage: 400 mg q12h for 7 days
- Dosage: 400 q12h for 5 days
- Dosage: 400 mg q12h for 3 days
- Dosage: 200 mg PO q24h before bedtime
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Norfloxacin 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 Norfloxacin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Norfloxacin in pediatric patients.
# Contraindications
- Norfloxacin is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents.
# Warnings
- Fluoroquinolones, including Norfloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Norfloxacin should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.
- Fluoroquinolones, including Norfloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid Norfloxacin in patients with known history of myasthenia gravis.
### Safety in Children, Adolescents, Nursing mothers, and during Pregnancy
- The safety and efficacy of oral norfloxacin in pediatric patients, adolescents (under the age of 18), pregnant women, and nursing mothers have not been established. The oral administration of single doses of norfloxacin, 6 times the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species.
- Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures.
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including Norfloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal edema or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including Norfloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:
- Fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome);
- Vasculitis; arthralgia; myalgia; serum sickness;
- Allergic pneumonitis;
- Interstitial nephritis; acute renal insufficiency or failure;
- Hepatitis; jaundice; acute hepatic necrosis or failure;
- Anemia, including hemolytic anemia and aplastic anemia; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be instituted
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Norfloxacin 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.
- Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including norfloxacin. Symptoms may occur soon after initiation of norfloxacin and may be irreversible. Norfloxacin should be discontinued immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation.
- Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months.
# Adverse Reactions
## Clinical Trials Experience
In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship.
- The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%).
- Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting.
- Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%).
In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship.
- The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%).
- Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting.
- Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria.
- Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria.
## Postmarketing Experience
The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with Norfloxacin. Visual disturbances have been reported with drugs in this class.
The following additional adverse reactions have been reported since the drug was marketed:
Hypersensitivity Reactions
- Anaphylactoid reactions
- Angioedema Dyspnea
- Vasculitis
- Urticaria
- Arthritis
- Arthralgia
- Myalgia
- Toxic epidermal necrolysis
- Stevens-Johnson syndrome
- Erythema multiforme
- Exfoliative dermatitis
- Photosensitivity/phototoxicity reactions
- Leukocytoclastic vasculitis
- Drug rash with eosinophilia and systemic symptoms (DRESS syndrome).
- Pseudomembranous colitis
- Hepatitis
- Jaundice
- Elevated liver function tests
- Pancreatitis (rare)
- Stomatitis
- Hepatic failure
- Prolonged QTc interval and ventricular arrhythmia including torsades de pointes.
- Interstitial nephritis
- Renal failure
- Peripheral neuropathy
- Guillain-Barré syndrome
- Ataxia
- Paresthesia
- Hypoesthesia
- Psychic disturbances
- Tendinitis
- Tendon rupture
- Exacerbation of myasthenia gravis
- Elevated creatine kinase (CK)
- Muscle spasms
- Neutropenia
- Leukopenia
- Agranulocytosis
- Hemolytic anemia
- Thrombocytopenia
- Hearing loss
- Tinnitus
- Diplopia
- Dysgeusia
Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis.
# Drug Interactions
- Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored.
- Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required.
- Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly.
- Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored.
- The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered.
- Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin.
- The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract.
Multivitamins, or other products containing iron or zinc, antacids or sucralfate, should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin.
Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin.
Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin.
The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times2 the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times2 the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin 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 Norfloxacin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Norfloxacin during labor and delivery.
### Nursing Mothers
- It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species.
### Geriatic Use
- Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as Norfloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing Norfloxacin to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue Norfloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur.
Of the 340 subjects in one large clinical study of Norfloxacin for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids. In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out.
- This drug 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. A pharmacokinetic study of Norfloxacin in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out.
- In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using Norfloxacin concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QTc prolongation, uncorrected hypokalemia).
### Gender
There is no FDA guidance on the use of Norfloxacin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Norfloxacin with respect to specific racial populations.
### Renal Impairment
- Norfloxacin may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2.
When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.
### Hepatic Impairment
There is no FDA guidance on the use of Norfloxacin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Norfloxacin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Norfloxacin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Tablet, film coated
### Monitoring
- The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered.
- Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required.
# IV Compatibility
There is limited information regarding the compatibility of Norfloxacin and IV administrations.
# Overdosage
No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained.
# Pharmacology
## Mechanism of Action
Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells:
- Inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase.
- Inhibition of the relaxation of supercoiled DNA.
- Promotion of double-stranded DNA breakage.
The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity.
## Structure
Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is:
## Pharmacodynamics
There is limited information regarding Norfloxacin Pharmacodynamics in the drug label.
## Pharmacokinetics
- In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing.
In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) μghr/mL and 2.02 (0.77) μg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 μghr/mL and Cmax 1.5 μg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours.
There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment.
The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary. Drug absorption appears unaffected by decreasing renal function.
Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 μg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min.
Two to three hours after a single 400-mg dose, urinary concentrations of 200 μg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 μg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%.
The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated:
## Nonclinical Toxicology
There is limited information regarding Norfloxacin Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Norfloxacin Clinical Studies in the drug label.
# How Supplied
- Tablets Norfloxacin 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-20 unit of use bottles of 20.
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Norfloxacin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Norfloxacin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Noroxin
# Look-Alike Drug Names
There is limited information regarding Norfloxacin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Norfloxacin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alberto Plate [2]
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# Overview
Norfloxacin is an fluoroquinolone antibiotic that is FDA approved for the treatment of urinary tract infections (UTI), prostatitis and sexually transmited diseases (STD). Common adverse reactions include nausea, stomach cramps, dizziness and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus saprophyticus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter cloacae, Proteus vulgaris, Staphylococcus aureus, or Streptococcus agalactiae.
- Uncomplicated urethral and cervical gonorrhea due to Neisseria gonorrhoeae.
- Prostatitis due to Escherichia coli.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Norfloxacin in adult patients.
### Non–Guideline-Supported Use
- Dosage: 400 q12h [2]
- Dosage: 400 mg q12h for 3 days [3]
- Dosage: 400 mg q12h for 7 days [4]
- Dosage: 400 q12h for 5 days[5]
- Dosage: 400 mg q12h for 3 days[6]
- Dosage: 200 mg PO q24h before bedtime[7]
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Norfloxacin 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 Norfloxacin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Norfloxacin in pediatric patients.
# Contraindications
- Norfloxacin is contraindicated in persons with a history of hypersensitivity, tendinitis, or tendon rupture associated with the use of norfloxacin or any member of the quinolone group of antimicrobial agents.
# Warnings
- Fluoroquinolones, including Norfloxacin, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Tendon rupture can occur during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Norfloxacin should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.
- Fluoroquinolones, including Norfloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Post-marketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid Norfloxacin in patients with known history of myasthenia gravis.
### Safety in Children, Adolescents, Nursing mothers, and during Pregnancy
- The safety and efficacy of oral norfloxacin in pediatric patients, adolescents (under the age of 18), pregnant women, and nursing mothers have not been established. The oral administration of single doses of norfloxacin, 6 times the recommended human clinical dose (on a mg/kg basis), caused lameness in immature dogs. Histologic examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Other quinolones also produced erosions of the cartilage in weight-bearing joints and other signs of arthropathy in immature animals of various species.
- Convulsions have been reported in patients receiving norfloxacin. Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychoses have been reported in patients receiving drugs in this class. Quinolones may also cause central nervous system (CNS) stimulation which may lead to tremors, restlessness, lightheadedness, confusion, and hallucinations. If these reactions occur in patients receiving norfloxacin, the drug should be discontinued and appropriate measures instituted. The effects of norfloxacin on brain function or on the electrical activity of the brain have not been tested. Therefore, until more information becomes available, norfloxacin, like all other quinolones, should be used with caution in patients with known or suspected CNS disorders, such as severe cerebral arteriosclerosis, epilepsy, and other factors which predispose to seizures.
- Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including Norfloxacin. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal edema or facial edema, dyspnea, urticaria and itching. Only a few patients had a history of hypersensitivity reactions. If an allergic reaction to norfloxacin occurs, discontinue the drug. Serious acute hypersensitivity reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous fluids, antihistamines, corticosteroids, pressor amines, and airway management, including intubation, should be administered as indicated.
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including Norfloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:
- Fever, rash or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome);
- Vasculitis; arthralgia; myalgia; serum sickness;
- Allergic pneumonitis;
- Interstitial nephritis; acute renal insufficiency or failure;
- Hepatitis; jaundice; acute hepatic necrosis or failure;
- Anemia, including hemolytic anemia and aplastic anemia; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity, and supportive measures should be instituted
- Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Norfloxacin 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.
- Cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving fluoroquinolones, including norfloxacin. Symptoms may occur soon after initiation of norfloxacin and may be irreversible. Norfloxacin should be discontinued immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation.
- Norfloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with norfloxacin should have a follow-up serologic test for syphilis after three months.
# Adverse Reactions
## Clinical Trials Experience
In clinical trials involving 82 healthy subjects and 228 patients with gonorrhea, treated with a single dose of norfloxacin, 6.5% reported drug-related adverse experiences. However, the following incidence figures were calculated without reference to drug relationship.
- The most common adverse experiences (>1.0%) were: dizziness (2.6%), nausea (2.6%), headache (2.0%), and abdominal cramping (1.6%).
- Additional reactions (0.3%-1.0%) were: anorexia, diarrhea, hyperhidrosis, asthenia, anal/rectal pain, constipation, dyspepsia, flatulence, tingling of the fingers, and vomiting.
- Laboratory adverse changes considered drug-related were reported in 4.5% of patients/subjects. These laboratory changes were: increased AST (SGOT) (1.6%), decreased WBC (1.3%), decreased platelet count (1.0%), increased urine protein (1.0%), decreased hematocrit and hemoglobin (0.6%), and increased eosinophils (0.6%).
In clinical trials involving 52 healthy subjects and 1980 patients with urinary tract infections or prostatitis treated with multiple doses of norfloxacin, 3.6% reported drug-related adverse experiences. However, the incidence figures below were calculated without reference to drug relationship.
- The most common adverse experiences (>1.0%) were: nausea (4.2%), headache (2.8%), dizziness (1.7%), and asthenia (1.3%).
- Additional reactions (0.3%-1.0%) were: abdominal pain, back pain, constipation, diarrhea, dry mouth, dyspepsia/heartburn, fever, flatulence, hyperhidrosis, loose stools, pruritus, rash, somnolence, and vomiting.
- Less frequent reactions (0.1%-0.2%) included: abdominal swelling, allergies, anorexia, anxiety, bitter taste, blurred vision, bursitis, chest pain, chills, depression, dysmenorrhea, edema, erythema, foot or hand swelling, insomnia, mouth ulcer, myocardial infarction, palpitation, pruritus ani, renal colic, sleep disturbances, and urticaria.
- Abnormal laboratory values observed in these patients/subjects were: eosinophilia (1.5%), elevation of ALT (SGPT) (1.4%), decreased WBC and/or neutrophil count (1.4%), elevation of AST (SGOT) (1.4%), and increased alkaline phosphatase (1.1%). Those occurring less frequently included increased BUN, increased LDH, increased serum creatinine, decreased hematocrit, and glycosuria.
## Postmarketing Experience
The most frequently reported adverse reaction in post-marketing experience is rash. CNS effects characterized as generalized seizures, myoclonus and tremors have been reported with Norfloxacin. Visual disturbances have been reported with drugs in this class.
The following additional adverse reactions have been reported since the drug was marketed:
Hypersensitivity Reactions
- Anaphylactoid reactions
- Angioedema Dyspnea
- Vasculitis
- Urticaria
- Arthritis
- Arthralgia
- Myalgia
- Toxic epidermal necrolysis
- Stevens-Johnson syndrome
- Erythema multiforme
- Exfoliative dermatitis
- Photosensitivity/phototoxicity reactions
- Leukocytoclastic vasculitis
- Drug rash with eosinophilia and systemic symptoms (DRESS syndrome).
- Pseudomembranous colitis
- Hepatitis
- Jaundice
- Elevated liver function tests
- Pancreatitis (rare)
- Stomatitis
- Hepatic failure
- Prolonged QTc interval and ventricular arrhythmia including torsades de pointes.
- Interstitial nephritis
- Renal failure
- Peripheral neuropathy
- Guillain-Barré syndrome
- Ataxia
- Paresthesia
- Hypoesthesia
- Psychic disturbances
- Tendinitis
- Tendon rupture
- Exacerbation of myasthenia gravis
- Elevated creatine kinase (CK)
- Muscle spasms
- Neutropenia
- Leukopenia
- Agranulocytosis
- Hemolytic anemia
- Thrombocytopenia
- Hearing loss
- Tinnitus
- Diplopia
- Dysgeusia
Other adverse events reported with quinolones include: agranulocytosis, albuminuria, candiduria, crystalluria, cylindruria, dysphagia, elevation of blood glucose, elevation of serum cholesterol, elevation of serum potassium, elevation of serum triglycerides, hematuria, hepatic necrosis, symptomatic hypoglycemia, nystagmus, postural hypotension, prolongation of prothrombin time, and vaginal candidiasis.
# Drug Interactions
- Quinolones, including norfloxacin, have been shown in vitro to inhibit CYP1A2. Concomitant use with drugs metabolized by CYP1A2 (e.g., caffeine, clozapine, ropinirole, tacrine, theophylline, tizanidine) may result in increased substrate drug concentrations when given in usual doses. Patients taking any of these drugs concomitantly with norfloxacin should be carefully monitored.
- Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required.
- Elevated serum levels of cyclosporine have been reported with concomitant use of cyclosporine with norfloxacin. Therefore, cyclosporine serum levels should be monitored and appropriate cyclosporine dosage adjustments made when these drugs are used concomitantly.
- Quinolones, including norfloxacin, may enhance the effects of oral anticoagulants, including warfarin or its derivatives or similar agents. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored.
- The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered.
- Diminished urinary excretion of norfloxacin has been reported during the concomitant administration of probenecid and norfloxacin.
- The concomitant use of nitrofurantoin is not recommended since nitrofurantoin may antagonize the antibacterial effect of NOROXIN in the urinary tract.
Multivitamins, or other products containing iron or zinc, antacids or sucralfate, should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because they may interfere with absorption resulting in lower serum and urine levels of norfloxacin.
Videx® (Didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be administered concomitantly with, or within 2 hours of, the administration of norfloxacin, because these products may interfere with absorption resulting in lower serum and urine levels of norfloxacin.
Some quinolones have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of the plasma half-life that may lead to accumulation of caffeine in plasma when products containing caffeine are consumed while taking norfloxacin.
The concomitant administration of a non-steroidal anti-inflammatory drug (NSAID) with a quinolone, including norfloxacin, may increase the risk of CNS stimulation and convulsive seizures. Therefore, NOROXIN should be used with caution in individuals receiving NSAIDS concomitantly.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Norfloxacin has been shown to produce embryonic loss in monkeys when given in doses 10 times2 the maximum daily total human dose (on a mg/kg basis). At this dose, peak plasma levels obtained in monkeys were approximately 2 times those obtained in humans. There has been no evidence of a teratogenic effect in any of the animal species tested (rat, rabbit, mouse, monkey) at 6-50 times2 the maximum daily human dose (on a mg/kg basis). There are, however, no adequate and well-controlled studies in pregnant women. Norfloxacin 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 Norfloxacin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Norfloxacin during labor and delivery.
### Nursing Mothers
- It is not known whether norfloxacin is excreted in human milk. When a 200-mg dose of NOROXIN was administered to nursing mothers, norfloxacin was not detected in human milk. However, because the dose studied was low, because other drugs in this class are secreted in human milk, and because of the potential for serious adverse reactions from norfloxacin in nursing infants, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
### Pediatric Use
- The safety and effectiveness of oral norfloxacin in pediatric patients and adolescents below the age of 18 years have not been established. Norfloxacin causes arthropathy in juvenile animals of several animal species.
### Geriatic Use
- Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as Norfloxacin. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing Norfloxacin to elderly patients, especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue Norfloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur.
Of the 340 subjects in one large clinical study of Norfloxacin for treatment of urinary tract infections, 103 patients were 65 and older, 77 of whom were 70 and older; no overall differences in safety and effectiveness were evident between these subjects and younger subjects. In clinical practice, no difference in the type of reported adverse experiences have been observed between the elderly and younger patients except for a possible increased risk of tendon rupture in elderly patients receiving concomitant corticosteroids. In addition, increased risk for other adverse experiences in some older individuals cannot be ruled out.
- This drug 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. A pharmacokinetic study of Norfloxacin in elderly volunteers (65 to 75 years of age with normal renal function for their age) was carried out.
- In general, elderly patients may be more susceptible to drug-associated effects of the QTc interval. Therefore, precaution should be taken when using Norfloxacin concomitantly with drugs that can result in prolongation of the QTc interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsades de pointes (e.g., known QTc prolongation, uncorrected hypokalemia).
### Gender
There is no FDA guidance on the use of Norfloxacin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Norfloxacin with respect to specific racial populations.
### Renal Impairment
- Norfloxacin may be used for the treatment of urinary tract infections in patients with renal insufficiency. In patients with a creatinine clearance rate of 30 mL/min/1.73 m2 or less, the recommended dosage is one 400-mg tablet once daily for the duration given above. At this dosage, the urinary concentration exceeds the MICs for most urinary pathogens susceptible to norfloxacin, even when the creatinine clearance is less than 10 mL/min/1.73 m2.
When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.
### Hepatic Impairment
There is no FDA guidance on the use of Norfloxacin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Norfloxacin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Norfloxacin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Tablet, film coated
### Monitoring
- The concomitant administration of quinolones including norfloxacin with glyburide (a sulfonylurea agent) has, on rare occasions, resulted in severe hypoglycemia. Therefore, monitoring of blood glucose is recommended when these agents are co-administered.
- Elevated plasma levels of theophylline have been reported with concomitant quinolone use. There have been reports of theophylline-related side effects in patients on concomitant therapy with norfloxacin and theophylline. Therefore, monitoring of theophylline plasma levels should be considered and dosage of theophylline adjusted as required.
# IV Compatibility
There is limited information regarding the compatibility of Norfloxacin and IV administrations.
# Overdosage
No significant lethality was observed in male and female mice and rats at single oral doses up to 4 g/kg. In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Adequate hydration must be maintained.
# Pharmacology
## Mechanism of Action
Norfloxacin inhibits bacterial deoxyribonucleic acid synthesis and is bactericidal. At the molecular level, three specific events are attributed to norfloxacin in E. coli cells:
- Inhibition of the ATP-dependent DNA supercoiling reaction catalyzed by DNA gyrase.
- Inhibition of the relaxation of supercoiled DNA.
- Promotion of double-stranded DNA breakage.
The fluorine atom at the 6 position provides increased potency against gram-negative organisms, and the piperazine moiety at the 7 position is responsible for antipseudomonal activity.
## Structure
Norfloxacin, a fluoroquinolone, is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C16H18FN3O3 and the structural formula is:
## Pharmacodynamics
There is limited information regarding Norfloxacin Pharmacodynamics in the drug label.
## Pharmacokinetics
- In fasting healthy volunteers, at least 30-40% of an oral dose of NOROXIN is absorbed. Absorption is rapid following single doses of 200 mg, 400 mg and 800 mg. At the respective doses, mean peak serum and plasma concentrations of 0.8, 1.5 and 2.4 μg/mL are attained approximately one hour after dosing. The presence of food and/or dairy products may decrease absorption. The effective half-life of norfloxacin in serum and plasma is 3-4 hours. Steady-state concentrations of norfloxacin will be attained within two days of dosing.
In healthy elderly volunteers (65-75 years of age with normal renal function for their age), norfloxacin is eliminated more slowly because of their slightly decreased renal function. Following a single 400-mg dose of norfloxacin, the mean (± SD) AUC and Cmax of 9.8 (2.83) μg•hr/mL and 2.02 (0.77) μg/mL, respectively, were observed in healthy elderly volunteers. The extent of systemic exposure was slightly higher than that seen in younger adults (AUC 6.4 μg•hr/mL and Cmax 1.5 μg/mL). Drug absorption appears unaffected. However, the effective half-life of norfloxacin in these elderly subjects is 4 hours.
There is no information on accumulation of norfloxacin with repeated administration in elderly patients. However, no dosage adjustment is required based on age alone. In elderly patients with reduced renal function, the dosage should be adjusted as for other patients with renal impairment.
The disposition of norfloxacin in patients with creatinine clearance rates greater than 30 mL/min/1.73 m2 is similar to that in healthy volunteers. In patients with creatinine clearance rates equal to or less than 30 mL/min/1.73 m2, the renal elimination of norfloxacin decreases so that the effective serum half-life is 6.5 hours. In these patients, alteration of dosage is necessary. Drug absorption appears unaffected by decreasing renal function.
Norfloxacin is eliminated through metabolism, biliary excretion, and renal excretion. After a single 400-mg dose of NOROXIN, mean antimicrobial activities equivalent to 278, 773, and 82 μg of norfloxacin/g of feces were obtained at 12, 24, and 48 hours, respectively. Renal excretion occurs by both glomerular filtration and tubular secretion as evidenced by the high rate of renal clearance (approximately 275 mL/min). Within 24 hours of drug administration, 26 to 32% of the administered dose is recovered in the urine as norfloxacin with an additional 5-8% being recovered in the urine as six active metabolites of lesser antimicrobial potency. Only a small percentage (less than 1%) of the dose is recovered thereafter. Fecal recovery accounts for another 30% of the administered dose. In elderly subjects (average creatinine clearance 91 mL/min/1.73 m2) approximately 22% of the administered dose was recovered in urine and renal clearance averaged 154 mL/min.
Two to three hours after a single 400-mg dose, urinary concentrations of 200 μg/mL or more are attained in the urine. In healthy volunteers, mean urinary concentrations of norfloxacin remain above 30 μg/mL for at least 12 hours following a 400-mg dose. The urinary pH may affect the solubility of norfloxacin. Norfloxacin is least soluble at urinary pH of 7.5 with greater solubility occurring at pHs above and below this value. The serum protein binding of norfloxacin is between 10 and 15%.
The following are mean concentrations of norfloxacin in various fluids and tissues measured 1 to 4 hours post-dose after two 400-mg doses, unless otherwise indicated:
## Nonclinical Toxicology
There is limited information regarding Norfloxacin Nonclinical Toxicology in the drug label.
# Clinical Studies
There is limited information regarding Norfloxacin Clinical Studies in the drug label.
# How Supplied
- Tablets Norfloxacin 400 mg are white to off-white, oval shaped, film-coated tablets, coded 705 on one side and plain on the other. They are supplied as follows: NDC 0006-0705-20 unit of use bottles of 20.
## Storage
- Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Norfloxacin Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Norfloxacin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Noroxin
# Look-Alike Drug Names
There is limited information regarding Norfloxacin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Norfloxacin | |
522b1762511fdc3395975217be6b2cc640243376 | wikidoc | Rhinoplasty | Rhinoplasty
# Overview
Rhinoplasty (Template:Lang-el, "Nose" + error: {{lang}}: text has italic markup (help), "to shape") is a surgical procedure which is usually performed by either an Plastic Surgeon, otolaryngologist-head and neck surgeon, or maxillofacial surgeon, or in order to improve the function (reconstructive surgery) and/or the appearance (cosmetic surgery) of a human nose. Rhinoplasty is also commonly called a "nose reshaping" or "nose job". Rhinoplasty can be performed to meet aesthetic goals or for reconstructive purposes to correct trauma, birth defects or breathing problems. It can be combined with other surgical procedures such as chin augmentation to enhance the aesthetic results.
# History
Rhinoplasty was first developed by Sushruta, an important physician (often regarded as the "father of plastic surgery") who lived in ancient India circa 500 BC, which he first described in his text Sushruta Samhita. He and his later students and disciples used rhinoplasty to reconstruct noses that were amputated as a punishment for crimes. The techniques of forehead flap rhinoplasty he developed are practiced almost unchanged to this day. This knowledge of plastic surgery existed in India up to the late 18th century as can be seen from the reports published in Gentleman's Magazine (October, 1794).
The first intranasal rhinoplasty in the West was performed by John Orlando Roe in 1887. It was later used for cosmetic purposes by Jacques Joseph (b. Jakob Lewin Joseph) in 1898 to help a patient who felt that the shape or size of his nose caused embarrassment and social discomfort. Joseph's first rhinoplasty patient was a young man whose large nose caused him such embarrassment that he felt unable to appear in public. He approached Joseph because he had heard of a previous successful otoplasty, or "ear reshaping," which the surgeon had performed.
Rhinoplasty can be performed under a general anesthetic, sedation, or with local anesthetic. Initially, local anesthesia which is a mixture of lidocaine and epinephrine is injected to numb the area, and temporarily reduce vascularity. There are two possible approaches to the nose: closed approach and open approach. In closed rhinoplasty, incisions are made inside the nostrils. In open rhynoplasty, an additional inconspicuous incision is made across the columella, the bit of skin that separates the nostrils. The surgeon first separates the skin and soft tissues of the nose from the underlying structures. Reshapes the cartilage and bone, and then sutures the incisions closed. Some surgeons use a stent or packin inside the nose, followed by tape or stent on the outside.
The patient returns home after the surgery. Most surgeons recommend antibiotics, pain medications, and steroid medication after surgery. Most people choose to remain home for a week, although it is safe to be outdoors. If there are external sutures, they are usually removed 4 to 5 days after surgery. The external cast is removed at one week. If there are internal stents, they are usually removed at four days to two weeks. The periorbital bruising usually lasts two weeks. Due to wound healing, there is moderate shifting and settling of the nose over the first year.
In some cases, the surgeon may shape a small piece of the patient's own cartilage or bone, as a graft, to strengthen or change the shape of the nose. Usually the cartilage is harvested from the septum If there isn't enough septum cartilage, which can occur in revision rhinoplasty, cartilage can be harvested from the concha of the ear or the ribs. In the rare case where bone is required, it is harvested from the cranium, the hip, or the ribs. Sometimes a synthetic implant may be used to augment the bridge of the nose.
To improve nasal breathing function, a septoplasty may also be performed. If there is turbinate hypertrophy, an inferior turbinectomy can be done.
Although rhinoplasty is usually considered to be safe and successful, several complications can arise. Post operative bleeding is uncommon and often resolves without needing treatment. Infection is rare and can occasionally progress to an abscess that requires surgical drainage under general anesthetic. Adhesions, which are scars that form to bridge across the nasal cavity from the septum to the turbinates, are also rare but cause nasal obstruction to breathing and usually need to be cut away. A hole can be inadvertently made at the time of surgery in the septum, called a septal perforation. This can cause chronic nose bleeding, crusting, difficult breathing and whistling with breathing.
If too much of the underlying structure of the nose (cartilage and/or bone) is removed, this can cause the overlying nasal skin to have little shape resulting in a "polly beak" deformity. Likewise if the septum is not supported, the bridge of the nose can sink resulting in a "saddle nose" deformity. The tip of the nose can be over-rotated causing the nostrils to be too visible and creating a pig-like look. If the cartilages of the tip of the nose are over-resected, this can cause a pinched look to the tip. If an incision is made across the collumella (open approach rhinoplasty) there can be variable degree of numbness to the nose that may take months to resolve.
The cost of rhinoplasty varies regionally and between surgeons. If it is for functional reasons, like breathing correction, it can be covered by many health plans. For example in 2006 in Ontario, Canada the provincial health insurance carrier paid $480, while the cost for cosmetic rhinoplasty varied between $1,000 and $10,000.
# Ethnic rhinoplasty
Although techniques and methods employed during rhinoplasty surgeries are the same regardless of race, there are some trends that apply to patients of certain ethnic backgrounds, due to their similar anatomic features.
East Asian patients often want their noses to appear narrower and their bridges higher. If very little elevation of the bridge is desired, the nasal bones can be cut and moved towards the midline. This technique will narrow the brige and also cause a slight elevation in the dorsum. East Asian patients who seek greater augmentation of the bridge of their nose require implants. A variety of alloplastic implants including Gore-Tex, Med-Por, or silicone can be used. Tissues from the patient's own body (autologous) can be used for augmentation, in order to reduce the risk of complications such as infection or extrusion. Septum cartilage, rib cartilage (costal cartilage), ear cartilage (auricular cartilage), and fascia are being often used. In non surgical rhinoplasty, filler materials such as hyaluronic acid or calcium based microspheres can be injected under the skin, in the bridge of the nose. These injections however, are non permanent lasting between six months to a year.
Patients of African descent commonly seek narrowing of wide nostrils in a procedure known as alar base reduction. This procedure may include removing sections of the base of the nostrils or sections of the nose where it meets the face. Risk of keloid scar formation is very low, if the patient has had not had keloids in the past. The tip of the nose can be restructured by removing tiny sections of cartilage to give the nose more definition, or adding cartilage grafts to provide additional structure to the nasal tip.
# Revision rhinoplasty
Revision rhinoplasty is a nose operation carried out to correct or revise an unsatisfactory outcome from a previous rhinoplasty. It is also known as secondary rhinoplasty. Occasionally there can be a third rhinoplasty or in some instaces even more surgeries may be required. An unsatisfactory outcome occurs in 5 to 20% of rhinoplasties. There are two main reasons for performing secondary rhinoplasty. The first is purely cosmetic. A patient may be unsatisfied with all or part of a previous "nose reshaping”. A nasal fracture may not have been reduced enough, or too much. A prominent or bulbous nasal tip may have not been addressed appropriately, or over-aggressively. The nose may looked pinched, it may look like a parrot’s beak, or like a boxer’s nose. In all cases of surgery there is scarring and in some individuals the scarring can be unpredictable. There are many scenarios in which previous nose surgery may have left a nose aesthetically unappealing to a patient. The second reason for revision rhinoplasty is functional. The original nasal surgery may have been carried out to help with difficulties in breathing, and the outcome may have been unsatisfactory. Alternatively, the original surgery may have been performed for cosmetic reasons, but may have disrupted a normal physiologic mechanism involving the inspiration or expiration of air, making it difficult to breathe exposing a previously undiagnosed problem. Secondary rhinoplasty, and especially tertiary rhinoplasty, are extremely complicated procedures. This is self-evident because it is clear that even when the patient was operated upon for the first time, even when the tissues were “virginal,” and untouched the desired result were not obtained.
# Reconstructive rhinoplasty
Reconstructive rhinoplasty refers to restoring the normal shape and function of the nose following damage from: traumatic accident, autoimmune disorder, intra-nasal drug abuse, previous injudicious cosmetic surgery, cancer involvement, or congenital abnormality. Rhinoplasty can restore skin coverage; recreate normal contours, and re-establish nasal airflow.
Rhinoplasty for traumatic deformity:
Traumatic accidents are the commonest cause of nasal deformity. Typically the nasal bones are broken and displaced. Occasionally, the nasal cartilages are disrupted or displaced, and in the worst cases the nasal dorsum is collapsed. Rhinoplasty allows shaving of the displaced bony humps, and re-alignment of the nasal bones after they are cut. When cartilage is disrupted, stitching of the cartilage for re-suspension, or use of cartilage grafts to camouflage depressions allows re-establishment of normal nasal contour. When the dorsum is collapsed, grafts of rib cartilage, ear cartilage, or cranial bone can be used to restore continuity to the dorsum. Although synthetic implants are also available for augmenting the nasal dorsum, cartilage or bone graft from the patient’s own body poses fewer risks of infection or rejection.
Rhinoplasty for collapsed nose due to septum perforation:
Autoimmune problems such as Wegener’s Granulomatosis, Sarcoidosis, Churg-Strauss Syndrome, and Relapsing Polychondritis can lead to creation of a hole in the nasal septum, and loss of support in the dorsum leading to a saddle nose deformity. Intra nasal use of drugs such as cocaine, or extreme abuse of nasal decongestant sprays can similarly cause septum perforation and nasal dorsum collapse. Dorsum reconstruction is accomplished through the use of rib cartilage or bone grafts.
Rhinoplasty to correct nasal obstruction following injudicious cosmetic surgery:
Reconstructive rhinoplasty after injudicious cosmetic surgery allows the restoration of normal breathing. When nasal cartilages are over-aggressively trimmed during rhinoplasty, the nose can appear pinched and nasal potency compromised. Patients complain of nasal blockage that is worsened by attempts at deep inspiration. Internal cartilage grafts to support the nasal tip (batton grafts) or widen the middle vault of the nose (spreader grafts) can be quite effective in restoring normal breathing. These grafting techniques will increase the size of the nasal tip and widen the dorsum. Khosh et al.
Rhinoplasty for skin cancer excision:
Excision of skin cancers from the nose can lead to loss of internal support as well as external skin coverage. Skin cancer excision in the nose is commonly accomplished via the Mohs’ technique. Once the cancer is removed, reconstructive rhinoplasty aims to provide skin coverage utilizing techniques such as skin graft, local skin flaps, or pedicle flaps. If cancer resection leads to loss of tissue in the area of the nasal tip, cartilage grafts are utilized to maintain support and prevent long-term distortion, by the force of scar contracture.
Rhinoplasty for Rhinophyma:
Rhinophyma is the late stage manifestation of a skin condition known as Rosacea, where the skin is infected with acne roseacea. The skin in the area of the nasal tip becomes red, thickened, and enlarged as exemplified by W C Fields. Although known acne treatments such as antibiotics and Acutane can halt the progression of this disease, thickening of the skin and obscuring of the nasal tip landmarks can only be remedied by surgical correction. Currently, laser excision of thickened abnormal skin represents the best option in rhinoplasty for Rhinophyma. The CO2 laser and the Erbium YAG laser are the most effective types of laser for this disorder.
Rhinoplasty for congenital nasal deformity:
Vascular malformations and cleft lip anomalies are relatively common causes of congenital nasal deformities. In vascular malformations, the disease process can cause distortions of the skin and underlying structure of the nose. In cleft palate abnormalities, the size, position, and orientation of the nasal tip cartilages may be distorted. Rhinoplasty for reconstruction of vascular malformations can involve laser treatment of the skin and possible surgical excision. When the underlying cartilage structure is disturbed, cartilage grafts and stitching of the native nasal cartilages can help improve nasal appearance. In cleft lip patients, reconstructive rhinoplasty allows re-orientation of the nasal tip cartilages. Additional refinements with cartilage grafts to the tip are also frequently employed.
Source*
# Side Effects of Rhinoplasty
Following your procedure, you will experience side effects commonly associated with rhinoplasty. These side effects are considered normal and are usually temporary.
Swelling: Expect swelling of your nose and the surrounding tissues to peak approximately thirty-six to forty-eight hours after surgery. You can expect more pronounced swelling if osteotomies (cuts or fractures to the nasal bones) were made during your procedure. Swelling is usually greatest when you rise in the morning. This side effect begins to subside within the first two weeks but will take at least a year to disappear completely.
Bruising: Bruising may occur between the eyes and on the cheeks, especially if you've had osteotomies performed. Bruising peaks approximately two days after surgery and then disappears, usually within two weeks.
Pain: The pain associated with rhinoplasty is usually mild. Most of the pain will probably disappear by the second or third day after surgery.
Nasal blockage: Congestion is to be expected following nasal surgery and may feel similar to the effects of a head cold. Cold-like symptoms are common for about six weeks after surgery.
Drainage: Following surgery, you can expect some nasal drainage to be tinged with blood, especially during the first day or two. You may notice an increase in nasal drainage when you rise to an upright position after being in a reclining position. This is normal and is not a cause for concern.
Stiffness in upper lip: Your upper lip may feel stiff, making it more difficult to smile. This feeling will usually dissipate within a few weeks.
Numbness of tip: The tip of your nose may feel numb, but the numbness usually disappears within a few months.
Depression: Don't be surprised if you discover that you feel a little blue in the days following your surgery. This is a common occurrence following surgery, when bruising and swelling are at their worst. This emotional letdown may be due to the fact that your face temporarily looks worse than it did prior to surgery, but it may also be attributable to stress, fatigue, or metabolic changes in your body. Rest assured that these feelings usually disappear within a few days.
Source*Paul S. Nassif, M.D., F.A.C.S.
# In the Operating Room
This section gives a small introduction to the surgical techniques used during a rhinoplasty.
Much more detail about performing the rhinoplasty operation can be found at this online Rhinoplasty Tutorial.
The incisions for a rhinoplasty are hidden inside the nose which is refered to as the closed rhinoplasty technique. Some surgeons may combine the intranasal incisions with a small incision across the base of the nose depicted by the dotted line,this is refered to as the open rhinoplasty technique. Surgeon preference and/or patient anatomy may dictate the type of approach ,open versus closed,used in a apticular patient.
The incisions allow the surgeon to see the size and shape of the cartilages and bones on the inside of the nose, so that they can be altered.
Here, the scissors are pointing out the lower lateral cartilage (in blue), which is one of the cartilages that gives the tip of the nose its shape. The red line shows the location of the planned incision across the bottom of the nose.
Once the skin has been lifted from the bone and cartilage framework of the nose, often the first task is to remove a hump, if one is present. Part of the hump is made of bone, and part of the hump is cartilage.
In the photograph, the black line shows the desired profile. The nose is made of bone above the scalloped grey line and cartilage below that line. The part of the hump made of bone is shaded red, and the part of the hump made of cartilage is shaded blue.
The soft cartilage of the hump is removed with a scalpel, and the bony hump is often removed with a chisel, shown at the top of this photograph. "Osteotome" is the medical term for a chisel. This photograph also shows the copper hammer that is used with the osteotome.
After the main part of the hump is removed with an osteotome, files are used to smooth out the remaining bone. The files are also called rasps, and they come in different shapes, orientations, and grades.
Some surgeons use rasps to remove the entire hump, foregoing use of the osteotome.
A common complaint is that the tip of the nose is too wide. Many surgical techniques are available to narrow the tip of the nose, depending on what is causing the excess width.
In this photo, a suture is being placed to narrow the tip of the nose. The red line outlines the edge of the tip cartilage, which is narrowed when the suture tightens the fold of the cartilage at its apex. The suture is in light blue, ending in the needle, which appears white in the photograph. The cartilage is being held in place with tweezers, which are shaded green.
If the position of the nasal bones gives excess width to the upper part of the nose, the bones are moved inward, to a more narrow position. This skull shows in blue the position of the bones in the nose. For orientation, the eye sockets are outlined in red.
To narrow a nasal bone, two cuts are made in the bone with a tiny chisel: one cut starting at the yellow dot and extending up along the green arrow, and another cut starting at the blue dot and extending out along the black arrow. The piece of bone thus loosened from the skull is pushed inward, narrowing the nose.
These chisel cuts are made from underneath the skin, so there is no scar in the area after healing.
At the end of the procedure, after the incisions are closed, the nose is dressed, to hold it securely in place as it heals.
This photo shows the nose just before the dressing and splint are placed. The purple marks on the nose guided the surgeon in making accurate cuts in the bone during surgery.
Preparing for the metal splint: the nose is first covered with paper tape in a manner to help maintain the nose's new shape.
After taping, the metal splint is designed and cut and shaped, and it is placed on the nose.
The metal splint is then covered with the tape, to hold it in place. The operation is now completed. The dressing will be removed in one week.
# Non-surgical rhinoplasty
Non-surgical rhinoplasty refers to a procedure in which fillers are used to alter and shape a person's nose without invasive surgery. This procedure has been performed by doctors since 2003. By filling in depressed areas, lifting the angle of the tip or smoothing the appearance of bumps on the bridge of the nose, it can create a symmetrical nose that goes in harmony with the rest of a person's face, creating a better balance, and give the appearance of a smaller nose.
Although the procedure is usually performed for aesthetic purposes, it can also be used to correct some birth defects. Because the procedure is not invasive, the bruising and swelling are minimal. Duration of results depends on the type of filler used. Radiesse (calcium hydroxyapatite) lasts for 8 to 12 months and this is the filler that is ideal. Hyaluronic acid fillers usually last for 5-6 months. Artefill, a permanent filler was recently approved by the FDA.
source*
Source* | Rhinoplasty
Editors-In-Chief: Martin I. Newman, M.D., FACS, Cleveland Clinic Florida [1]; Michel C. Samson, M.D., FRCSC, FACS [2]; Jay Pensler, M.D., Northwestern University Feinberg School of Medicine [3]
# Overview
Rhinoplasty (Template:Lang-el, "Nose" + [Plassein] error: {{lang}}: text has italic markup (help), "to shape") is a surgical procedure which is usually performed by either an Plastic Surgeon, otolaryngologist-head and neck surgeon, or maxillofacial surgeon, or in order to improve the function (reconstructive surgery) and/or the appearance (cosmetic surgery) of a human nose. Rhinoplasty is also commonly called a "nose reshaping" or "nose job". Rhinoplasty can be performed to meet aesthetic goals or for reconstructive purposes to correct trauma, birth defects or breathing problems. It can be combined with other surgical procedures such as chin augmentation to enhance the aesthetic results.
# History
Rhinoplasty was first developed by Sushruta, an important physician (often regarded as the "father of plastic surgery") who lived in ancient India circa 500 BC, which he first described in his text Sushruta Samhita. He and his later students and disciples used rhinoplasty to reconstruct noses that were amputated as a punishment for crimes. The techniques of forehead flap rhinoplasty he developed are practiced almost unchanged to this day. This knowledge of plastic surgery existed in India up to the late 18th century as can be seen from the reports published in Gentleman's Magazine (October, 1794).
The first intranasal rhinoplasty in the West was performed by John Orlando Roe in 1887. It was later used for cosmetic purposes by Jacques Joseph (b. Jakob Lewin Joseph) in 1898 to help a patient who felt that the shape or size of his nose caused embarrassment and social discomfort. Joseph's first rhinoplasty patient was a young man whose large nose caused him such embarrassment that he felt unable to appear in public. He approached Joseph because he had heard of a previous successful otoplasty, or "ear reshaping," which the surgeon had performed.
Rhinoplasty can be performed under a general anesthetic, sedation, or with local anesthetic. Initially, local anesthesia which is a mixture of lidocaine and epinephrine is injected to numb the area, and temporarily reduce vascularity. There are two possible approaches to the nose: closed approach and open approach. In closed rhinoplasty, incisions are made inside the nostrils. In open rhynoplasty, an additional inconspicuous incision is made across the columella, the bit of skin that separates the nostrils. The surgeon first separates the skin and soft tissues of the nose from the underlying structures. Reshapes the cartilage and bone, and then sutures the incisions closed. Some surgeons use a stent or packin inside the nose, followed by tape or stent on the outside.
The patient returns home after the surgery. Most surgeons recommend antibiotics, pain medications, and steroid medication after surgery. Most people choose to remain home for a week, although it is safe to be outdoors. If there are external sutures, they are usually removed 4 to 5 days after surgery. The external cast is removed at one week. If there are internal stents, they are usually removed at four days to two weeks. The periorbital bruising usually lasts two weeks. Due to wound healing, there is moderate shifting and settling of the nose over the first year.
In some cases, the surgeon may shape a small piece of the patient's own cartilage or bone, as a graft, to strengthen or change the shape of the nose. Usually the cartilage is harvested from the septum If there isn't enough septum cartilage, which can occur in revision rhinoplasty, cartilage can be harvested from the concha of the ear or the ribs. In the rare case where bone is required, it is harvested from the cranium, the hip, or the ribs. Sometimes a synthetic implant may be used to augment the bridge of the nose.
To improve nasal breathing function, a septoplasty may also be performed. If there is turbinate hypertrophy, an inferior turbinectomy can be done.
Although rhinoplasty is usually considered to be safe and successful, several complications can arise. Post operative bleeding is uncommon and often resolves without needing treatment. Infection is rare and can occasionally progress to an abscess that requires surgical drainage under general anesthetic. Adhesions, which are scars that form to bridge across the nasal cavity from the septum to the turbinates, are also rare but cause nasal obstruction to breathing and usually need to be cut away. A hole can be inadvertently made at the time of surgery in the septum, called a septal perforation. This can cause chronic nose bleeding, crusting, difficult breathing and whistling with breathing.
If too much of the underlying structure of the nose (cartilage and/or bone) is removed, this can cause the overlying nasal skin to have little shape resulting in a "polly beak" deformity. Likewise if the septum is not supported, the bridge of the nose can sink resulting in a "saddle nose" deformity. The tip of the nose can be over-rotated causing the nostrils to be too visible and creating a pig-like look. If the cartilages of the tip of the nose are over-resected, this can cause a pinched look to the tip. If an incision is made across the collumella (open approach rhinoplasty) there can be variable degree of numbness to the nose that may take months to resolve.
The cost of rhinoplasty varies regionally and between surgeons. If it is for functional reasons, like breathing correction, it can be covered by many health plans. For example in 2006 in Ontario, Canada the provincial health insurance carrier paid $480, while the cost for cosmetic rhinoplasty varied between $1,000 and $10,000.
# Ethnic rhinoplasty
Although techniques and methods employed during rhinoplasty surgeries are the same regardless of race, there are some trends that apply to patients of certain ethnic backgrounds, due to their similar anatomic features.
East Asian patients often want their noses to appear narrower and their bridges higher. If very little elevation of the bridge is desired, the nasal bones can be cut and moved towards the midline. This technique will narrow the brige and also cause a slight elevation in the dorsum. East Asian patients who seek greater augmentation of the bridge of their nose require implants. A variety of alloplastic implants including Gore-Tex, Med-Por, or silicone can be used. Tissues from the patient's own body (autologous) can be used for augmentation, in order to reduce the risk of complications such as infection or extrusion. Septum cartilage, rib cartilage (costal cartilage), ear cartilage (auricular cartilage), and fascia are being often used. In non surgical rhinoplasty, filler materials such as hyaluronic acid or calcium based microspheres can be injected under the skin, in the bridge of the nose. These injections however, are non permanent lasting between six months to a year.
Patients of African descent commonly seek narrowing of wide nostrils in a procedure known as alar base reduction. This procedure may include removing sections of the base of the nostrils or sections of the nose where it meets the face. Risk of keloid scar formation is very low, if the patient has had not had keloids in the past. The tip of the nose can be restructured by removing tiny sections of cartilage to give the nose more definition, or adding cartilage grafts to provide additional structure to the nasal tip.
# Revision rhinoplasty
Revision rhinoplasty is a nose operation carried out to correct or revise an unsatisfactory outcome from a previous rhinoplasty. It is also known as secondary rhinoplasty. Occasionally there can be a third rhinoplasty or in some instaces even more surgeries may be required. An unsatisfactory outcome occurs in 5 to 20% of rhinoplasties. There are two main reasons for performing secondary rhinoplasty. The first is purely cosmetic. A patient may be unsatisfied with all or part of a previous "nose reshaping”. A nasal fracture may not have been reduced enough, or too much. A prominent or bulbous nasal tip may have not been addressed appropriately, or over-aggressively. The nose may looked pinched, it may look like a parrot’s beak, or like a boxer’s nose. In all cases of surgery there is scarring and in some individuals the scarring can be unpredictable. There are many scenarios in which previous nose surgery may have left a nose aesthetically unappealing to a patient. The second reason for revision rhinoplasty is functional. The original nasal surgery may have been carried out to help with difficulties in breathing, and the outcome may have been unsatisfactory. Alternatively, the original surgery may have been performed for cosmetic reasons, but may have disrupted a normal physiologic mechanism involving the inspiration or expiration of air, making it difficult to breathe exposing a previously undiagnosed problem. Secondary rhinoplasty, and especially tertiary rhinoplasty, are extremely complicated procedures. This is self-evident because it is clear that even when the patient was operated upon for the first time, even when the tissues were “virginal,” and untouched the desired result were not obtained.
# Reconstructive rhinoplasty
Reconstructive rhinoplasty refers to restoring the normal shape and function of the nose following damage from: traumatic accident, autoimmune disorder, intra-nasal drug abuse, previous injudicious cosmetic surgery, cancer involvement, or congenital abnormality. Rhinoplasty can restore skin coverage; recreate normal contours, and re-establish nasal airflow.
Rhinoplasty for traumatic deformity:
Traumatic accidents are the commonest cause of nasal deformity. Typically the nasal bones are broken and displaced. Occasionally, the nasal cartilages are disrupted or displaced, and in the worst cases the nasal dorsum is collapsed. Rhinoplasty allows shaving of the displaced bony humps, and re-alignment of the nasal bones after they are cut. When cartilage is disrupted, stitching of the cartilage for re-suspension, or use of cartilage grafts to camouflage depressions allows re-establishment of normal nasal contour. When the dorsum is collapsed, grafts of rib cartilage, ear cartilage, or cranial bone can be used to restore continuity to the dorsum. Although synthetic implants are also available for augmenting the nasal dorsum, cartilage or bone graft from the patient’s own body poses fewer risks of infection or rejection.
Rhinoplasty for collapsed nose due to septum perforation:
Autoimmune problems such as Wegener’s Granulomatosis, Sarcoidosis, Churg-Strauss Syndrome, and Relapsing Polychondritis can lead to creation of a hole in the nasal septum, and loss of support in the dorsum leading to a saddle nose deformity. Intra nasal use of drugs such as cocaine, or extreme abuse of nasal decongestant sprays can similarly cause septum perforation and nasal dorsum collapse. Dorsum reconstruction is accomplished through the use of rib cartilage or bone grafts.
Rhinoplasty to correct nasal obstruction following injudicious cosmetic surgery:
Reconstructive rhinoplasty after injudicious cosmetic surgery allows the restoration of normal breathing. When nasal cartilages are over-aggressively trimmed during rhinoplasty, the nose can appear pinched and nasal potency compromised. Patients complain of nasal blockage that is worsened by attempts at deep inspiration. Internal cartilage grafts to support the nasal tip (batton grafts) or widen the middle vault of the nose (spreader grafts) can be quite effective in restoring normal breathing. These grafting techniques will increase the size of the nasal tip and widen the dorsum.[1] Khosh et al.
Rhinoplasty for skin cancer excision:
Excision of skin cancers from the nose can lead to loss of internal support as well as external skin coverage. Skin cancer excision in the nose is commonly accomplished via the Mohs’ technique. Once the cancer is removed, reconstructive rhinoplasty aims to provide skin coverage utilizing techniques such as skin graft, local skin flaps, or pedicle flaps. If cancer resection leads to loss of tissue in the area of the nasal tip, cartilage grafts are utilized to maintain support and prevent long-term distortion, by the force of scar contracture.
Rhinoplasty for Rhinophyma:
Rhinophyma is the late stage manifestation of a skin condition known as Rosacea, where the skin is infected with acne roseacea. The skin in the area of the nasal tip becomes red, thickened, and enlarged as exemplified by W C Fields. Although known acne treatments such as antibiotics and Acutane can halt the progression of this disease, thickening of the skin and obscuring of the nasal tip landmarks can only be remedied by surgical correction. Currently, laser excision of thickened abnormal skin represents the best option in rhinoplasty for Rhinophyma. The CO2 laser and the Erbium YAG laser are the most effective types of laser for this disorder.[2]
Rhinoplasty for congenital nasal deformity:
Vascular malformations and cleft lip anomalies are relatively common causes of congenital nasal deformities. In vascular malformations, the disease process can cause distortions of the skin and underlying structure of the nose. In cleft palate abnormalities, the size, position, and orientation of the nasal tip cartilages may be distorted. Rhinoplasty for reconstruction of vascular malformations can involve laser treatment of the skin and possible surgical excision. When the underlying cartilage structure is disturbed, cartilage grafts and stitching of the native nasal cartilages can help improve nasal appearance. In cleft lip patients, reconstructive rhinoplasty allows re-orientation of the nasal tip cartilages. Additional refinements with cartilage grafts to the tip are also frequently employed.[3]
Source*[4]
# Side Effects of Rhinoplasty
Following your procedure, you will experience side effects commonly associated with rhinoplasty. These side effects are considered normal and are usually temporary.
Swelling: Expect swelling of your nose and the surrounding tissues to peak approximately thirty-six to forty-eight hours after surgery. You can expect more pronounced swelling if osteotomies (cuts or fractures to the nasal bones) were made during your procedure. Swelling is usually greatest when you rise in the morning. This side effect begins to subside within the first two weeks but will take at least a year to disappear completely.
Bruising: Bruising may occur between the eyes and on the cheeks, especially if you've had osteotomies performed. Bruising peaks approximately two days after surgery and then disappears, usually within two weeks.
Pain: The pain associated with rhinoplasty is usually mild. Most of the pain will probably disappear by the second or third day after surgery.
Nasal blockage: Congestion is to be expected following nasal surgery and may feel similar to the effects of a head cold. Cold-like symptoms are common for about six weeks after surgery.
Drainage: Following surgery, you can expect some nasal drainage to be tinged with blood, especially during the first day or two. You may notice an increase in nasal drainage when you rise to an upright position after being in a reclining position. This is normal and is not a cause for concern.
Stiffness in upper lip: Your upper lip may feel stiff, making it more difficult to smile. This feeling will usually dissipate within a few weeks.
Numbness of tip: The tip of your nose may feel numb, but the numbness usually disappears within a few months.
Depression: Don't be surprised if you discover that you feel a little blue in the days following your surgery. This is a common occurrence following surgery, when bruising and swelling are at their worst. This emotional letdown may be due to the fact that your face temporarily looks worse than it did prior to surgery, but it may also be attributable to stress, fatigue, or metabolic changes in your body. Rest assured that these feelings usually disappear within a few days.
Source*Paul S. Nassif, M.D., F.A.C.S.
# In the Operating Room
This section gives a small introduction to the surgical techniques used during a rhinoplasty.
Much more detail about performing the rhinoplasty operation can be found at this online Rhinoplasty Tutorial.
The incisions for a rhinoplasty are hidden inside the nose which is refered to as the closed rhinoplasty technique. Some surgeons may combine the intranasal incisions with a small incision across the base of the nose depicted by the dotted line,this is refered to as the open rhinoplasty technique. Surgeon preference and/or patient anatomy may dictate the type of approach ,open versus closed,used in a apticular patient.
The incisions allow the surgeon to see the size and shape of the cartilages and bones on the inside of the nose, so that they can be altered.
Here, the scissors are pointing out the lower lateral cartilage (in blue), which is one of the cartilages that gives the tip of the nose its shape. The red line shows the location of the planned incision across the bottom of the nose.
Once the skin has been lifted from the bone and cartilage framework of the nose, often the first task is to remove a hump, if one is present. Part of the hump is made of bone, and part of the hump is cartilage.
In the photograph, the black line shows the desired profile. The nose is made of bone above the scalloped grey line and cartilage below that line. The part of the hump made of bone is shaded red, and the part of the hump made of cartilage is shaded blue.
The soft cartilage of the hump is removed with a scalpel, and the bony hump is often removed with a chisel, shown at the top of this photograph. "Osteotome" is the medical term for a chisel. This photograph also shows the copper hammer that is used with the osteotome.
After the main part of the hump is removed with an osteotome, files are used to smooth out the remaining bone. The files are also called rasps, and they come in different shapes, orientations, and grades.
Some surgeons use rasps to remove the entire hump, foregoing use of the osteotome.
A common complaint is that the tip of the nose is too wide. Many surgical techniques are available to narrow the tip of the nose, depending on what is causing the excess width.
In this photo, a suture is being placed to narrow the tip of the nose. The red line outlines the edge of the tip cartilage, which is narrowed when the suture tightens the fold of the cartilage at its apex. The suture is in light blue, ending in the needle, which appears white in the photograph. The cartilage is being held in place with tweezers, which are shaded green.
If the position of the nasal bones gives excess width to the upper part of the nose, the bones are moved inward, to a more narrow position. This skull shows in blue the position of the bones in the nose. For orientation, the eye sockets are outlined in red.
To narrow a nasal bone, two cuts are made in the bone with a tiny chisel: one cut starting at the yellow dot and extending up along the green arrow, and another cut starting at the blue dot and extending out along the black arrow. The piece of bone thus loosened from the skull is pushed inward, narrowing the nose.
These chisel cuts are made from underneath the skin, so there is no scar in the area after healing.
At the end of the procedure, after the incisions are closed, the nose is dressed, to hold it securely in place as it heals.
This photo shows the nose just before the dressing and splint are placed. The purple marks on the nose guided the surgeon in making accurate cuts in the bone during surgery.
Preparing for the metal splint: the nose is first covered with paper tape in a manner to help maintain the nose's new shape.
After taping, the metal splint is designed and cut and shaped, and it is placed on the nose.
The metal splint is then covered with the tape, to hold it in place. The operation is now completed. The dressing will be removed in one week.
# Non-surgical rhinoplasty
Non-surgical rhinoplasty refers to a procedure in which fillers are used to alter and shape a person's nose without invasive surgery.[4] This procedure has been performed by doctors since 2003.[5] By filling in depressed areas, lifting the angle of the tip or smoothing the appearance of bumps on the bridge of the nose,[6] it can create a symmetrical nose that goes in harmony with the rest of a person's face, creating a better balance, and give the appearance of a smaller nose.
Although the procedure is usually performed for aesthetic purposes, it can also be used to correct some birth defects. Because the procedure is not invasive, the bruising and swelling are minimal. Duration of results depends on the type of filler used. Radiesse (calcium hydroxyapatite) lasts for 8 to 12 months and this is the filler that is ideal. Hyaluronic acid fillers usually last for 5-6 months. Artefill, a permanent filler was recently approved by the FDA.
source*[5]
Source*[6] | https://www.wikidoc.org/index.php/Nose_job | |
9caeccb08aa36a4863d7c787bedc90519bbccfb8 | wikidoc | Nuchal cord | Nuchal cord
A nuchal cord occurs when the umbilical cord becomes wrapped around the fetal neck 360 degrees.
# Classification
- A "Type A" nuchal cord is wrapped around the neck.
- A "Type B" nuchal cord is a hitch and is not wrapped. In the Type B case, a caesarian section delivery may be recommended but is not necessary.
# Diagnosis
Doppler ultrasound has been successfully used to identify a Nuchal cord, and also to determine the orientation of the loop.
# Prognosis and treatment
Nuchal cord can be managed by home fetal monitoring. Nuchal cord can be a cause of stillbirth but can also be prevented.
Cutting the umbilical cord should not be done until it has stopped pulsating (upwards of 20 minutes after birth). In the case of a nuchal cord the child is still receiving blood and oxygen to the brain. As always the umbilical cord should not be cut until it ceases to pulsate (after all the blood from the placenta has been sent to the child.) | Nuchal cord
A nuchal cord occurs when the umbilical cord becomes wrapped around the fetal neck 360 degrees.
# Classification
- A "Type A" nuchal cord is wrapped around the neck.
- A "Type B" nuchal cord is a hitch and is not wrapped. In the Type B case, a caesarian section delivery may be recommended but is not necessary.
# Diagnosis
Doppler ultrasound has been successfully used to identify a Nuchal cord, and also to determine the orientation of the loop.
# Prognosis and treatment
Nuchal cord can be managed by home fetal monitoring. Nuchal cord can be a cause of stillbirth but can also be prevented.
Cutting the umbilical cord should not be done until it has stopped pulsating (upwards of 20 minutes after birth). In the case of a nuchal cord the child is still receiving blood and oxygen to the brain. As always the umbilical cord should not be cut until it ceases to pulsate (after all the blood from the placenta has been sent to the child.)[1] | https://www.wikidoc.org/index.php/Nuchal_cord | |
1bd03d95cb0dded26e1b9b13df463fbea30536df | wikidoc | Nuchal scan | Nuchal scan
# Overview
A nuchal scan is a sonographic prenatal screening scan (ultrasound) to help identify higher risks of Down syndrome in developing babies, particularly for older mothers who have higher risks of such pregnancies. The scan is carried out at 11-13 weeks pregnancy and assesses the amount of fluid behind the neck of the fetus - also known as 'the nuchal translucency'. Babies at risk of Down tend to have a higher amount of fluid around the neck. The scan may also help confirm both the accuracy of the pregnancy dates and the foetal viability. Its high definition imaging may also detect other less common chromosomal abnormalities.
# Indication
All women, whatever their age, have a small risk of delivering a baby with a physical and/or mental handicap. The most common genetic disorder is Down syndrome with the risk rising with maternal age from 1 in 1530 pregnancies at age 20, to 1 in 30 at age 44.
Whilst the only way to know for sure whether or not the fetus has a chromosomal abnormality is by having an invasive test such as an amniocentesis or chorionic villus sampling, such tests carry a risk of causing a miscarriage variously estimated at between 1% and 0.06%, whether or not the fetus is normal or affected with Down. Most women, especially those with a low risk of having a Down-affected fetus, may wish to avoid the risk to the fetus and the discomfort of invasive testing.
The aim of the nuchal scan is to estimate the risk of the fetus having Down syndrome more accurately than calculating based on maternal age alone. Only those women with significantly higher risks than that predicted for their age group, or those with an estimated risk above that of the fetal loss rate associated with amniocentesis are advised to proceed to invasive testing.
# Procedure
Nuchal scan is performed between the 11th and 13th week of gestation, because the accuracy is best in this period. The scan is obtained with the fetus in sagittal section and a neutral position of the fetal head (neither hyperflexed nor extended, either of which can influence the nuchal translucency thickness). The fetal image is enlarged to fill 75% of the screen, and the maximum thickness is measured, from leading edge to leading edge. It is important to distinguish the nuchal lucency from the underlying amnionic membrane.
Normal thickness depends on the crown-rump length (CRL) of the fetus. Among those fetuses whose nuchal translucency exceeds the normal values, there is a relatively high risk of significant abnormality.
# Accuracy
Between 65 and 85% of trisomic fetuses will have a large nuchal thickness. Further, other, non-trisomic abnormalities may also demonstrate an enlarged nuchal transparency. This leaves the measurement of nuchal transparency as a potentially useful 1st trimester screening tool. Abnormal findings allow for early careful evaluation of chromosomes and possible structural defects on a targeted basis.
At 12 weeks of gestational age, an "average" nuchal thickness of 2.18mm has been observed, however, up to 13% of chromosomally normal fetuses present with a nuchal luncency of greater than 2.5mm, and thus for even greater accuracy of predicting risks, the outcome of the nuchal scan may be combined with the results of simultaneous maternal blood tests. The blood test is used to measure the levels of hormones - primarily hCG and PAPP-A. In pregnancies affected by Down syndrome there is a tendency for the levels of human chorionic gonadotropin (hCG) to be increased and pregnancy-associated plasma protein A (PAPP-A) to be decreased.
The advantage of Nuchal scanning over the previous use of just biochemical blood profiling, is mainly the reduction in false positive rates.
Nuchal scanning alone detects 62% of all Downs Syndrome with a false positive rate of 5.0%, the combination with blood testing gives corresponding values of 73% and 4.7%.
In another study values of 79.6% and 2.7% for the combined screening were then improved with the addition of second trimester ultrasound scanning to 89.7% and 4.2% respectively.
A further study reported detection of 88% for trisomy 21 (Downs syndrome) and 75% for trisomy 18 (Edwards syndrome), with a 3.3% false-positive rate.. Finally, using the additional ultrasound feature of an absent nasal bone can further increase detection rates for Downs syndrome to more than 95%..
When screening is positive, amniocentesis testing is required to confirm the presence of a genetic abnormality. However this proceedure carries a 1% risk of miscarriage so prior screening with low false negative rates are needed to minimise the chance of miscarrying what is later proved to have been a genetically normal fetus.
# Development of nuchal translucency
The translucent area measured (the nuchal translucency) is only usable to measure between 10 and 13 weeks’ gestation, when the fetal lymphatic system is developing and the peripheral resistance of the placenta is high. After 14 weeks the lymphatic system is likely to have developed sufficiently to drain away any excess fluid, and changes to the placental circulation will result in a drop in peripheral resistance. So after this time any abnormalities causing fluid accumulation may seem to correct themselves and can thus go undetected by nuchal scanning. | Nuchal scan
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
A nuchal scan is a sonographic prenatal screening scan (ultrasound) to help identify higher risks of Down syndrome in developing babies, particularly for older mothers who have higher risks of such pregnancies. The scan is carried out at 11-13 weeks pregnancy and assesses the amount of fluid behind the neck of the fetus - also known as 'the nuchal translucency'. Babies at risk of Down tend to have a higher amount of fluid around the neck. The scan may also help confirm both the accuracy of the pregnancy dates and the foetal viability. Its high definition imaging may also detect other less common chromosomal abnormalities.[citation needed]
# Indication
All women, whatever their age, have a small risk of delivering a baby with a physical and/or mental handicap. The most common genetic disorder is Down syndrome with the risk rising with maternal age from 1 in 1530 pregnancies at age 20, to 1 in 30 at age 44.[1]
Whilst the only way to know for sure whether or not the fetus has a chromosomal abnormality is by having an invasive test such as an amniocentesis or chorionic villus sampling, such tests carry a risk of causing a miscarriage variously estimated at between 1%[citation needed] and 0.06%[2], whether or not the fetus is normal or affected with Down. Most women, especially those with a low risk of having a Down-affected fetus, may wish to avoid the risk to the fetus and the discomfort of invasive testing[citation needed].
The aim of the nuchal scan is to estimate the risk of the fetus having Down syndrome more accurately than calculating based on maternal age alone. Only those women with significantly higher risks than that predicted for their age group, or those with an estimated risk above that of the fetal loss rate associated with amniocentesis are advised to proceed to invasive testing.
# Procedure
Nuchal scan is performed between the 11th and 13th week of gestation, because the accuracy is best in this period. The scan is obtained with the fetus in sagittal section and a neutral position of the fetal head (neither hyperflexed nor extended, either of which can influence the nuchal translucency thickness). The fetal image is enlarged to fill 75% of the screen, and the maximum thickness is measured, from leading edge to leading edge. It is important to distinguish the nuchal lucency from the underlying amnionic membrane.
Normal thickness depends on the crown-rump length (CRL) of the fetus. Among those fetuses whose nuchal translucency exceeds the normal values, there is a relatively high risk of significant abnormality.
# Accuracy
Between 65 and 85% of trisomic fetuses will have a large nuchal thickness. Further, other, non-trisomic abnormalities may also demonstrate an enlarged nuchal transparency. This leaves the measurement of nuchal transparency as a potentially useful 1st trimester screening tool. Abnormal findings allow for early careful evaluation of chromosomes and possible structural defects on a targeted basis.
At 12 weeks of gestational age, an "average" nuchal thickness of 2.18mm has been observed, however, up to 13% of chromosomally normal fetuses present with a nuchal luncency of greater than 2.5mm, and thus for even greater accuracy of predicting risks, the outcome of the nuchal scan may be combined with the results of simultaneous maternal blood tests. The blood test is used to measure the levels of hormones - primarily hCG and PAPP-A. In pregnancies affected by Down syndrome there is a tendency for the levels of human chorionic gonadotropin (hCG) to be increased and pregnancy-associated plasma protein A (PAPP-A) to be decreased.
The advantage of Nuchal scanning over the previous use of just biochemical blood profiling, is mainly the reduction in false positive rates.[3]
Nuchal scanning alone detects 62% of all Downs Syndrome with a false positive rate of 5.0%, the combination with blood testing gives corresponding values of 73% and 4.7%.[4]
In another study values of 79.6% and 2.7% for the combined screening were then improved with the addition of second trimester ultrasound scanning to 89.7% and 4.2% respectively.[5]
A further study reported detection of 88% for trisomy 21 (Downs syndrome) and 75% for trisomy 18 (Edwards syndrome), with a 3.3% false-positive rate.[6]. Finally, using the additional ultrasound feature of an absent nasal bone can further increase detection rates for Downs syndrome to more than 95%.[7].
When screening is positive, amniocentesis testing is required to confirm the presence of a genetic abnormality. However this proceedure carries a 1% risk of miscarriage so prior screening with low false negative rates are needed to minimise the chance of miscarrying what is later proved to have been a genetically normal fetus.
# Development of nuchal translucency
The translucent area measured (the nuchal translucency) is only usable to measure between 10 and 13 weeks’ gestation, when the fetal lymphatic system is developing and the peripheral resistance of the placenta is high. After 14 weeks the lymphatic system is likely to have developed sufficiently to drain away any excess fluid, and changes to the placental circulation will result in a drop in peripheral resistance. So after this time any abnormalities causing fluid accumulation may seem to correct themselves and can thus go undetected by nuchal scanning. | https://www.wikidoc.org/index.php/Nuchal_scan | |
96cf58d49ffc9655ed7bb1b7a29baca8ae3c8c58 | wikidoc | Nut (fruit) | Nut (fruit)
A nut can be either a seed or a fruit.
# Botanical definitions
A nut in botany is a simple dry fruit with one seed (rarely two) in which the ovary wall becomes very hard (stony or woody) at maturity, and where the seed remains unattached or unfused with the ovary wall. Most nuts come from pistils with inferior ovaries (see flower) and all are indehiscent (not opening at maturity). True nuts are produced, for example, by some plants — families of the order Fagales.
- Family Juglandaceae
Walnut—esp. Persian Walnut (Juglans regia)
Butternut (Juglans)
Hickory, Pecan (Carya)
Wingnut (Pterocarya)
- Walnut—esp. Persian Walnut (Juglans regia)
- Butternut (Juglans)
- Hickory, Pecan (Carya)
- Wingnut (Pterocarya)
- Family Fagaceae
Chestnut (Castanea)
Beech (Fagus)
Oak (Quercus)
Stone-oak, Tanoak (Lithocarpus)
- Chestnut (Castanea)
- Beech (Fagus)
- Oak (Quercus)
- Stone-oak, Tanoak (Lithocarpus)
- Family Betulaceae
Alder (Alnus)
Birch (Betula)
Hazel, Filbert (Corylus)
Hornbeam
- Alder (Alnus)
- Birch (Betula)
- Hazel, Filbert (Corylus)
- Hornbeam
# Culinary definition and uses
A nut in cuisine is a much less restrictive category than a nut in botany, as the term is applied (or misapplied, depending upon the viewpoint) to many seeds that are not true nuts. Any large, oily kernel found within a shell and used in food may be regarded as a nut. Because nuts generally have a high oil content, they are a highly prized food and energy source. A large number of seeds are edible by humans and used in cooking, eaten raw, sprouted, or roasted as a snack food, or pressed for oil that is used in cookery and cosmetics. Nuts (or seeds generally) are also a significant source of nutrition for wildlife. This is particularly true in temperate climates where animals such as jays and squirrels store acorns and other nuts during the autumn to keep them from starving during the winter and early spring.
Nuts, including both tree nuts and peanuts, are among the most common food allergens.
Some fruits and seeds that are nuts in the culinary sense but not in the botanical sense:
- Almond is the edible seed of a drupe — the leathery "flesh" is removed at harvest.
- Brazil nut is the seed from a capsule.
- Candlenut (used for oil) is a seed.
- Cashew nut is a seed.
- Coconut is a dry, fibrous drupe.
- Horse-chestnut is an inedible capsule.
- Macadamia nut is a creamy white kernel (Macadamia integrifolia).
- Mongongo
- Peanut is a legume and a seed.
- Pine nut is the seed of several species of pine (coniferous trees).
- Pistachio nut is the seed of a thin-shelled drupe.
See also: List of edible seeds
# Nutritional benefits
Several epidemiological studies have revealed that people who consume nuts regularly are less likely to suffer from coronary heart disease. Recent clinical trials have found that consumption of various nuts such as almonds and walnuts can lower serum LDL cholesterol concentrations. Although nuts contain various substances thought to possess cardioprotective effects, scientists believe that their fatty acid profile is at least in part responsible for the hypolipidemic response observed in clinical trials.
In addition to possessing cardioprotective effects, nuts generally have a very low glycemic index (GI). Consequently, dietitians frequently recommend nuts be included in diets prescribed for patients with insulin resistance problems such as diabetes mellitus type 2.
One study found that people who eat nuts live two to three years longer than those who do not. However, this may be because people who eat nuts tend to eat less junk food.
# Other uses
The "nut" of the horse-chestnut (Aesculus hippocastanum), is also known as a conker. Conkers are inedible, due to the presence of the toxic glucoside aesculin, but are collected and used in an old children's game, also known as conkers, in which a nut is threaded onto a strong cord and then each child attempts to break their opponent's conker by hitting it with their own. A related species, Aesculus californica, was formerly eaten by the Native Americans of California in times of famine. It must be leached to remove the toxic constituents before eating. | Nut (fruit)
A nut can be either a seed or a fruit.
# Botanical definitions
A nut in botany is a simple dry fruit with one seed (rarely two) in which the ovary wall becomes very hard (stony or woody) at maturity, and where the seed remains unattached or unfused with the ovary wall. Most nuts come from pistils with inferior ovaries (see flower) and all are indehiscent (not opening at maturity). True nuts are produced, for example, by some plants — families of the order Fagales.
- Family Juglandaceae
Walnut—esp. Persian Walnut (Juglans regia)
Butternut (Juglans)
Hickory, Pecan (Carya)
Wingnut (Pterocarya)
- Walnut—esp. Persian Walnut (Juglans regia)
- Butternut (Juglans)
- Hickory, Pecan (Carya)
- Wingnut (Pterocarya)
- Family Fagaceae
Chestnut (Castanea)
Beech (Fagus)
Oak (Quercus)
Stone-oak, Tanoak (Lithocarpus)
- Chestnut (Castanea)
- Beech (Fagus)
- Oak (Quercus)
- Stone-oak, Tanoak (Lithocarpus)
- Family Betulaceae
Alder (Alnus)
Birch (Betula)
Hazel, Filbert (Corylus)
Hornbeam
- Alder (Alnus)
- Birch (Betula)
- Hazel, Filbert (Corylus)
- Hornbeam
# Culinary definition and uses
A nut in cuisine is a much less restrictive category than a nut in botany, as the term is applied (or misapplied, depending upon the viewpoint) to many seeds that are not true nuts. Any large, oily kernel found within a shell and used in food may be regarded as a nut. Because nuts generally have a high oil content, they are a highly prized food and energy source. A large number of seeds are edible by humans and used in cooking, eaten raw, sprouted, or roasted as a snack food, or pressed for oil that is used in cookery and cosmetics. Nuts (or seeds generally) are also a significant source of nutrition for wildlife. This is particularly true in temperate climates where animals such as jays and squirrels store acorns and other nuts during the autumn to keep them from starving during the winter and early spring.
Nuts, including both tree nuts and peanuts, are among the most common food allergens.[1]
Some fruits and seeds that are nuts in the culinary sense but not in the botanical sense:
- Almond is the edible seed of a drupe — the leathery "flesh" is removed at harvest.
- Brazil nut is the seed from a capsule.
- Candlenut (used for oil) is a seed.
- Cashew nut is a seed.
- Coconut is a dry, fibrous drupe.
- Horse-chestnut is an inedible capsule.
- Macadamia nut is a creamy white kernel (Macadamia integrifolia).
- Mongongo
- Peanut is a legume and a seed.
- Pine nut is the seed of several species of pine (coniferous trees).
- Pistachio nut is the seed of a thin-shelled drupe.
See also: List of edible seeds
# Nutritional benefits
Several epidemiological studies have revealed that people who consume nuts regularly are less likely to suffer from coronary heart disease. Recent clinical trials have found that consumption of various nuts such as almonds and walnuts can lower serum LDL cholesterol concentrations. Although nuts contain various substances thought to possess cardioprotective effects, scientists believe that their fatty acid profile is at least in part responsible for the hypolipidemic response observed in clinical trials.
In addition to possessing cardioprotective effects, nuts generally have a very low glycemic index (GI). Consequently, dietitians frequently recommend nuts be included in diets prescribed for patients with insulin resistance problems such as diabetes mellitus type 2.
One study found that people who eat nuts live two to three years longer than those who do not. However, this may be because people who eat nuts tend to eat less junk food. [2]
# Other uses
The "nut" of the horse-chestnut (Aesculus hippocastanum), is also known as a conker. Conkers are inedible, due to the presence of the toxic glucoside aesculin, but are collected and used in an old children's game, also known as conkers, in which a nut is threaded onto a strong cord and then each child attempts to break their opponent's conker by hitting it with their own. A related species, Aesculus californica, was formerly eaten by the Native Americans of California in times of famine. It must be leached to remove the toxic constituents before eating. | https://www.wikidoc.org/index.php/Nut_(fruit) | |
d7baa3c8840b119e58969079ae2b088dadaf08b2 | wikidoc | Ocrelizumab | Ocrelizumab
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# Overview
Ocrelizumab is a CD20-directed cytolytic antibody that is FDA approved for the treatment of relapsing or primary progressive forms of multiple sclerosis. Common adverse reactions include upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ocrelizumab is indicated for the treatment of adult patients with relapsing or primary progressive forms of multiple sclerosis.
- Administer Ocrelizumab under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions such as serious infusion reactions.
- Initial dose: 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion.
- Subsequent doses: single 600 mg intravenous infusion every 6 months.
- Observe the patient for at least one hour after the completion of the infusion.
- If a planned infusion of Ocrelizumab is missed, administer Ocrelizumab as soon as possible; do not wait until the next scheduled dose. Reset the dose schedule to administer the next sequential dose 6 months after the missed dose is administered. Doses of Ocrelizumab must be separated by at least 5 months.
- Dose modifications in response to infusion reactions depends on the severity.
Life-threatening Infusion Reactions
- Immediately stop and permanently discontinue Ocrelizumab if there are signs of a life-threatening or disabling infusion reaction. Provide appropriate supportive treatment.
Severe Infusion Reactions
- Immediately interrupt the infusion and administer appropriate supportive treatment, as necessary. Restart the infusion only after all symptoms have resolved. When restarting, begin at half of the infusion rate at the time of onset of the infusion reaction. If this rate is tolerated, increase the rate as described in TABLE 1. This change in rate will increase the total duration of the infusion but not the total dose.
Mild to Moderate Infusion Reactions
- Reduce the infusion rate to half the rate at the onset of the infusion reaction and maintain the reduced rate for at least 30 minutes. If this rate is tolerated, increase the rate as described in TABLE 1. This change in rate will increase the total duration of the infusion but not the total dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Ocrelizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ocrelizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ocrelizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Ocrelizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ocrelizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Ocrelizumab is contraindicated in patients with:
- Active HBV infection.
- A history of life-threatening infusion reaction to Ocrelizumab.
# Warnings
- Ocrelizumab can cause infusion reactions, which can include pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, and tachycardia. In multiple sclerosis (MS) clinical trials, the incidence of infusion reactions in Ocrelizumab-treated patients was 34 to 40%, with the highest incidence with the first infusion. There were no fatal infusion reactions, but 0.3% of Ocrelizumab-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization.
- Observe patients treated with Ocrelizumab for infusion reactions during the infusion and for at least one hour after completion of the infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion.
Reducing the Risk of Infusion Reactions and Managing Infusion Reactions
- Administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered.
- Management recommendations for infusion reactions depend on the type and severity of the reaction. For life-threatening infusion reactions, immediately and permanently stop Ocrelizumab and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.
- A higher proportion of Ocrelizumab-treated patients experienced infections compared to patients taking REBIF or placebo. In RMS trials, 58% of Ocrelizumab-treated patients experienced one or more infections compared to 52% of REBIF-treated patients. In the PPMS trial, 70% of Ocrelizumab-treated patients experienced one or more infections compared to 68% of patients on placebo. Ocrelizumab increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections. Ocrelizumab was not associated with an increased risk of serious infections in MS patients. Delay Ocrelizumab administration in patients with an active infection until the infection is resolved.
Respiratory Tract Infections
- A higher proportion of Ocrelizumab-treated patients experienced respiratory tract infections compared to patients taking REBIF or placebo. In RMS trials, 40% of Ocrelizumab-treated patients experienced upper respiratory tract infections compared to 33% of REBIF-treated patients, and 8% of Ocrelizumab-treated patients experienced lower respiratory tract infections compared to 5% of REBIF-treated patients. In the PPMS trial, 49% of Ocrelizumab-treated patients experienced upper respiratory tract infections compared to 43% of patients on placebo and 10% of Ocrelizumab-treated patients experienced lower respiratory tract infections compared to 9% of patients on placebo. The infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections and bronchitis.
Herpes
- In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in Ocrelizumab-treated patients than in REBIF-treated patients, including herpes zoster (2.1% vs. 1.0%), herpes simplex (0.7% vs. 0.1%), oral herpes (3.0% vs. 2.2%), genital herpes (0.1% vs. 0%), and herpes virus infection (0.1% vs. 0%). Infections were predominantly mild to moderate in severity. There were no reports of disseminated herpes.
- In the placebo-controlled (PPMS) clinical trial, oral herpes was reported more frequently in the Ocrelizumab-treated patients than in the patients on placebo (2.7% vs 0.8%).
Progressive Multifocal Leukoencephalopathy (PML)
- PML is an opportunistic viral infection of the brain caused by the John Cunningham (JC) virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no cases of PML were identified in Ocrelizumab clinical trials, JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). At the first sign or symptom suggestive of PML, withhold Ocrelizumab and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
Hepatitis B Virus (HBV) Reactivation
- There were no reports of hepatitis B reactivation in MS patients treated with Ocrelizumab. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with other anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with Ocrelizumab. Do not administer Ocrelizumab to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for surface antigen and positive for HB core antibody or are carriers of HBV , consult liver disease experts before starting and during treatment.
Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants
- When initiating Ocrelizumab after an immunosuppressive therapy or initiating an immunosuppressive therapy after Ocrelizumab, consider the potential for increased immunosuppressive effects. Ocrelizumab has not been studied in combination with other MS therapies.
Vaccinations
- Administer all immunizations according to immunization guidelines at least 6 weeks prior to initiation of Ocrelizumab.
- The safety of immunization with live or live-attenuated vaccines following Ocrelizumab therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.
- No data are available on the effects of live or non-live vaccination in patients receiving Ocrelizumab.
- An increased risk of malignancy with Ocrelizumab may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in Ocrelizumab-treated patients. Breast cancer occurred in 6 of 781 females treated with Ocrelizumab and none of 668 females treated with REBIF or placebo. Patients should follow standard breast cancer screening guidelines.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reactions 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.
- The safety of Ocrelizumab has been evaluated in 1311 patients across MS clinical studies, which included 825 patients in active-controlled clinical trials in patients with relapsing forms of MS (RMS) and 486 patients in a placebo-controlled study in patients with primary progressive MS (PPMS).
Adverse Reactions in Patients with Relapsing Forms of MS
- In active-controlled clinical trials (Study 1 and Study 2), 825 patients with RMS received Ocrelizumab 600 mg intravenously every 24 weeks (initial treatment was given as two separate 300 mg infusions at Weeks 0 and 2). The overall exposure in the 96-week controlled treatment periods was 1448 patient-years.
- The most common adverse reactions in RMS trials (incidence ≥ 10%) were upper respiratory tract infections and infusion reactions. TABLE 2 summarizes the adverse reactions that occurred in RMS trials (Study 1 and Study 2).
Adverse Reactions in Patients with Primary Progressive MS
- In a placebo-controlled clinical trial (Study 3), a total of 486 patients with PPMS received one course of Ocrelizumab (600 mg of Ocrelizumab administered as two 300 mg infusions two weeks apart) given intravenously every 24 weeks and 239 patients received placebo intravenously. The overall exposure in the controlled treatment period was 1416 patient-years, with median treatment duration of 3 years.
- The most common adverse reactions in the PPMS trial (incidence ≥ 10%) were upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections. TABLE 3 summarizes the adverse reactions that occurred in the PPMS trial (Study 3).
Laboratory Abnormalities
Decreased Immunoglobulins
- Ocrelizumab decreased total immunoglobulins with the greatest decline seen in IgM levels. In MS clinical trials, there was no apparent association between immunoglobulin decrease and risk for serious infections.
- In the active-controlled (RMS) trials (Study 1 and Study 2), the proportion of patients at baseline reporting IgG, IgA, and IgM below the lower limit of normal (LLN) in Ocrelizumab-treated patients was 0.5%, 1.5%, and 0.1%, respectively. Following treatment, the proportion of Ocrelizumab-treated patients reporting IgG, IgA, and IgM below the LLN at 96 weeks was 1.5%, 2.4%, and 16.5%, respectively.
- In the placebo-controlled (PPMS) trial (Study 3), the proportion of patients at baseline reporting IgG, IgA, and IgM below the LLN in Ocrelizumab-treated patients was 0.0%, 0.2%, and 0.2%, respectively. Following treatment, the proportion of Ocrelizumab-treated patients reporting IgG, IgA, and IgM below the LLN at 120 weeks was 1.1%, 0.5%, and 15.5%, respectively.
Decreased Neutrophil Levels
- In the PPMS clinical trial (Study 3), decreased neutrophil counts occurred in 13% of Ocrelizumab-treated patients compared to 10% in placebo patients. The majority of the decreased neutrophil counts were only observed once for a given patient treated with Ocrelizumab and were between LLN - 1.5 × 109/L and 1.0 × 109/L. Overall, 1% of the patients in the Ocrelizumab group had neutrophil counts less than 1.0 × 109/L and these were not associated with an infection.
- As with all therapeutic proteins, there is potential for immunogenicity. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to Ocrelizumab with the incidence of antibodies to other products may be misleading.
- Patients in MS trials (Study 1, Study 2, and Study 3) were tested at multiple time points (baseline and every 6 months post-treatment for the duration of the trial) for anti-drug antibodies (ADAs). Out of 1311 patients treated with Ocrelizumab, 12 (~1%) tested positive for ADAs, of which 2 patients tested positive for neutralizing antibodies. These data are not adequate to assess the impact of ADAs on the safety and efficacy of Ocrelizumab.
## Postmarketing Experience
There is limited information regarding Ocrelizumab Postmarketing Experience in the drug label.
# Drug Interactions
- Immunosuppressive or Immune-Modulating Therapies
- The concomitant use of Ocrelizumab and other immune-modulating or immunosuppressive therapies, including immunosuppressant doses of corticosteroids, is expected to increase the risk of immunosuppression. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with Ocrelizumab. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, consider the duration and mode of action of these drugs because of additive immunosuppressive effects when initiating Ocrelizumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no adequate data on the developmental risk associated with use of Ocrelizumab in pregnant women. There are no data on B-cell levels in human neonates following maternal exposure to Ocrelizumab. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. Ocrelizumab is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier. Following administration of Ocrelizumab to pregnant monkeys at doses similar to or greater than those used clinically, increased perinatal mortality, depletion of B-cell populations, renal, bone marrow, and testicular toxicity were observed in the offspring in the absence of maternal toxicity.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data (Animal)
- Following intravenous administration of Ocrelizumab to monkeys during organogenesis (loading doses of 15 or 75 mg/kg on gestation days 20, 21, and 22, followed by weekly doses of 20 or 100 mg/kg), depletion of B-lymphocytes in lymphoid tissue (spleen and lymph nodes) was observed in fetuses at both doses.
- Intravenous administration of Ocrelizumab (three daily loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) to pregnant monkeys throughout the period of organogenesis and continuing through the neonatal period resulted in perinatal deaths (some associated with bacterial infections), renal toxicity (glomerulopathy and inflammation), lymphoid follicle formation in the bone marrow, and severe decreases in circulating B-lymphocytes in neonates. The cause of the neonatal deaths is uncertain; however, both affected neonates were found to have bacterial infections. Reduced testicular weight was observed in neonates at the high dose.
- A no-effect dose for adverse developmental effects was not identified; the doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ocrelizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ocrelizumab during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of Ocrelizumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Ocrelizumab was excreted in the milk of Ocrelizumab-treated monkeys. Human IgG is excreted in human milk, and the potential for absorption of Ocrelizumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ocrelizumab and any potential adverse effects on the breastfed infant from Ocrelizumab or from the underlying maternal condition.
### Pediatric Use
- Safety and effectiveness of Ocrelizumab in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of Ocrelizumab 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 Ocrelizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ocrelizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ocrelizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ocrelizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Contraception
- Women of childbearing potential should use contraception while receiving Ocrelizumab and for 6 months after the last infusion of Ocrelizumab.
### Immunocompromised Patients
There is no FDA guidance one the use of Ocrelizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Solution in vial is clear or slightly opalescent, and colorless to pale brown; do not use if discolored.
- Do not shake vial.
- 300 mg dose: Withdraw 10 mL from vial and further dilute in 250 mL of NS to final concentration of about 1.2 mg/mL.
- 600 mg dose: Withdraw 20 mL from 2 vials and further dilute in 500 mL of NS to final concentration of about 1.2 mg/mL.
- Only dilute in NS; do not dilute with any other diluent.
- May use polyvinyl chloride (PCV) or polyolefin (PO) infusion bags and IV administration sets.
- Diluted solution should be used immediately or stored for up to 8 hours at a room temperature not exceeding 25 degrees C (77 degrees F) or for up to 24 hours if stored in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). Storage time includes infusion time.
- Prior to administration, bring infusion bag to room temperature.
- Administer diluted solution via a dedicated line with a 0.2 or 0.22 micron in-line filter.
- 300 mg dose: Begin infusion rate at 30 mL/hr and increase by 30 mL/hr every 30 minutes, as tolerated, to MAX 180 mL/hr for a duration of 2.5 hours or longer. Observe patient for at least 1 hour after infusion completion.
- 600 mg dose: Begin infusion rate at 40 mL/hr and increase by 40 mL/hr every 30 minutes, as tolerated, to MAX 200 mL/hr for a duration of 3.5 hours or longer. Observe patient for at least 1 hour after infusion completion.
- If infusion cannot be completed the same day, discard remaining solution.
- Missed dose: Give as soon as possible; do not wait until the next scheduled dose. Reset the dose schedule to administer the next sequential dose 6 months after the missed dose; doses must be separated by at least 5 months.
### Monitoring
- Reductions in the rates of relapse and disability progression are indicative of efficacy.
- Hepatitis B virus screening: Prior to initiation.
- Signs and symptoms of active infection: Prior to every infusion.
- Signs and symptoms of infusion reactions: During infusion and for at least 1 hour after completion.
# IV Compatibility
There is limited information regarding the compatibility of Ocrelizumab and IV administrations.
# Overdosage
There is limited information regarding Ocrelizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which Ocrelizumab exerts its therapeutic effects in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, Ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.
## Structure
There is limited information regarding Ocrelizumab Structure in the drug label.
## Pharmacodynamics
- For B-cell counts, assays for CD19+ B-cells are used because the presence of Ocrelizumab interferes with the CD20 assay. Treatment with Ocrelizumab reduces CD19+ B-cell counts in blood by 14 days after infusion. In clinical studies, B-cell counts rose to above the lower limit of normal (LLN) or above baseline counts between infusions of Ocrelizumab at least one time in 0.3% to 4.1% of patients. In a clinical study of 51 patients, the median time for B-cell counts to return to either baseline or LLN was 72 weeks (range 27-175 weeks) after the last Ocrelizumab infusion. Within 2.5 years after the last infusion, B-cell counts rose to either baseline or LLN in 90% of patients.
## Pharmacokinetics
- Pharmacokinetics (PK) of Ocrelizumab in MS clinical studies fit a two compartment model with time-dependent clearance. The overall exposure at the steady-state (AUC over the 24 week dosing intervals) of Ocrelizumab was 3,510 mcg/mL per day. In clinical studies in MS patients, maintenance doses of Ocrelizumab were either 600 mg every 6 months (RMS patients) or two 300 mg infusions separated by 14 days every 6 months (PPMS patients). The mean maximum concentration was 212 mcg/mL in patients with RMS (600 mg infusion) and 141 mcg/mL in patients with PPMS (two 300 mg infusions administered within two weeks). The pharmacokinetics of Ocrelizumab was essentially linear and dose proportional between 400 mg and 2000 mg.
Distribution
- The population PK estimate of the central volume of distribution was 2.78 L. Peripheral volume and inter-compartment clearance were estimated at 2.68 L and 0.29 L/day, respectively.
Elimination
- Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.05 L/day, which declined with a half-life of 33 weeks. The terminal elimination half-life was 26 days.
Metabolism
- The metabolism of Ocrelizumab has not been directly studied because antibodies are cleared principally by catabolism.
Specific Populations
Renal impairment
- Patients with mild renal impairment were included in clinical trials. No significant change in the pharmacokinetics of Ocrelizumab was observed in those patients.
Hepatic impairment
- Patients with mild hepatic impairment were included in clinical trials. No significant change in the pharmacokinetics of Ocrelizumab was observed in those patients.
## Nonclinical Toxicology
- No carcinogenicity studies have been performed to assess the carcinogenic potential of Ocrelizumab.
- No studies have been performed to assess the mutagenic potential of Ocrelizumab. As an antibody, Ocrelizumab is not expected to interact directly with DNA.
- No effects on reproductive organs were observed in male monkeys administered Ocrelizumab by intravenous injection (three loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) for 8 weeks. There were also no effects on estrus cycle in female monkeys administered Ocrelizumab over three menstrual cycles using the same dosing regimen. The doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis.
# Clinical Studies
- The efficacy of Ocrelizumab was demonstrated in two randomized, double-blind, double-dummy, active comparator-controlled clinical trials of identical design, in patients with RMS treated for 96 weeks (Study1 and Study 2). The dose of Ocrelizumab was 600 mg every 24 weeks (initial treatment was given as two 300 mg IV infusions administered 2 weeks apart, and subsequent doses were administered as a single 600 mg IV infusion) and placebo subcutaneous injections were given 3 times per week. The dose of REBIF, the active comparator, was 44 mcg given as subcutaneous injections 3 times per week and placebo IV infusions were given every 24 weeks. Both studies included patients who had experienced at least one relapse within the prior year, or two relapses within the prior two years, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.5. Patients with primary progressive forms of multiple sclerosis (MS) were excluded. Neurological evaluations were performed every 12 weeks and at the time of a suspected relapse. Brain MRIs were performed at baseline and at Weeks 24, 48, and 96.
- The primary outcome of both Study 1 and Study 2 was the annualized relapse rate (ARR). Additional outcome measures included the proportion of patients with confirmed disability progression, the mean number of MRI T1 gadolinium (Gd)-enhancing lesions at Weeks 24, 48, and 96, and new or enlarging MRI T2 hyperintense lesions. Progression of disability was defined as an increase of 1 point or more from the baseline EDSS score attributable to MS when the baseline EDSS score was 5.5 or less, or 0.5 points or more when the baseline EDSS score was above 5.5. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit 12 weeks after the initial documentation of neurological worsening. The primary population for analysis of confirmed disability progression was the pooled population from Studies 1 and 2.
- In Study 1, 410 patients were randomized to Ocrelizumab and 411 to REBIF; 11% of Ocrelizumab-treated and 17% of REBIF-treated patients did not complete the 96-week double-blind treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 37 years; 66% were female. The mean time from MS diagnosis to randomization was 3.8 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8; 74% of patients had not been treated with a non-steroid therapy for MS in the 2 years prior to the study. At baseline, 40% of patients had one or more T1 Gd-enhancing lesions (mean 1.8).
- In Study 2, 417 patients were randomized to Ocrelizumab and 418 to REBIF; 14% of Ocrelizumab-treated and 23% of REBIF-treated patients did not complete the 96-week double-blind treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 37 years; 66% were female. The mean time from MS diagnosis to randomization was 4.1 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8; 74% of patients had not been treated with a non-steroid therapy for MS in the 2 years prior to the study. At baseline, 40% of Ocrelizumab-treated patients had one or more T1 Gd-enhancing lesions (mean 1.9).
- In Study 1 and Study 2, Ocrelizumab significantly lowered the annualized relapse rate and the proportion of patients with disability progression confirmed at 12 weeks after onset compared to REBIF. Results for Study 1 and Study 2 are presented in TABLE 4 and FIGURE 1.
- In exploratory subgroup analyses of Study 1 and Study 2, the effect of Ocrelizumab on annualized relapse rate and disability progression was similar in male and female patients.
- Study 3 was a randomized, double-blind, placebo-controlled clinical trial in patients with PPMS. Patients were randomized 2:1 to receive either Ocrelizumab 600 mg or placebo as two 300 mg intravenous infusions 2 weeks apart every 24 weeks for at least 120 weeks. Selection criteria required a baseline EDSS of 3 to 6.5 and a score of 2 or greater for the EDSS pyramidal functional system due to lower extremity findings. Neurological assessments were conducted every 12 weeks. An MRI scan was obtained at baseline and at Weeks 24, 48, and 120.
- In Study 3, the primary outcome was the time to onset of disability progression attributable to MS confirmed to be present at the next neurological assessment at least 12 weeks later. Disability progression occurred when the EDSS score increased by 1 point or more from the baseline EDSS if the baseline EDSS was 5.5 points or less, or by 0.5 points or more if the baseline EDSS was more than 5.5 points. In Study 3, confirmed disability progression also was deemed to have occurred if patients who had onset of disability progression discontinued participation in the study before the next assessment. Additional outcome measures included timed 25-foot walk, and percentage change in T2 hyperintense lesion volume.
- Study 3 randomized 488 patients to Ocrelizumab and 244 to placebo; 21% of Ocrelizumab-treated patients and 34% of placebo-treated patients did not complete the trial. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 45; 49% were female. The mean time since symptom onset was 6.7 years, the mean EDSS score was 4.7, and 26% had one or more T1 Gd-enhancing lesions at baseline; 88% of patients had not been treated previously with a non-steroid treatment for MS. The time to onset of disability progression confirmed at 12 weeks after onset was significantly longer for Ocrelizumab-treated patients than for placebo-treated patients (see FIGURE 2). Results for Study 3 are presented in TABLE 5 and FIGURE 2.
- In the overall population in Study 3, the proportion of patients with 20 percent worsening of the timed 25-foot walk confirmed at 12 weeks was 49% in Ocrelizumab-treated patients compared to 59% in placebo-treated patients (25% risk reduction).
- In exploratory subgroup analyses of Study 3, the proportion of female patients with disability progression confirmed at 12 weeks after onset was similar in Ocrelizumab-treated patients and placebo-treated patients (approximately 36% in each group). In male patients, the proportion of patients with disability progression confirmed at 12 weeks after onset was approximately 30% in Ocrelizumab-treated patients and 43% in placebo-treated patients. Clinical and MRI endpoints that generally favored Ocrelizumab numerically in the overall population, and that showed similar trends in both male and female patients, included annualized relapse rate, change in T2 lesion volume, and number of new or enlarging T2 lesions.
# How Supplied
- Ocrelizumab injection is a preservative-free, sterile, clear or slightly opalescent, and colorless to pale brown solution supplied as a carton containing one 300 mg/10 mL (30 mg/mL) single-dose vial (NDC 50242-150-01).
## Storage
- Store Ocrelizumab vials at 2°C–8°C (36°F–46°F) in the outer carton to protect from light. Do not freeze or shake.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Infusion Reactions
- Inform patients about the signs and symptoms of infusion reactions, and that infusion reactions can occur up to 24 hours after infusion. Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions.
Infection
- Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose. Signs include fever, chills, constant cough, or signs of herpes such as cold sore, shingles, or genital sores.
- Advise patients that PML has happened with drugs that are similar to Ocrelizumab and may happen with Ocrelizumab. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
- Advise patients that Ocrelizumab may cause reactivation of hepatitis B infection and that monitoring will be required if they are at risk.
Vaccination
- Advise patients to complete any required vaccinations at least 6 weeks prior to initiation of Ocrelizumab. Administration of live-attenuated or live vaccines is not recommended during Ocrelizumab treatment and until B-cell recovery.
Malignancies
- Advise patients that an increased risk of malignancy, including breast cancer, may exist with Ocrelizumab. Advise patients that they should follow standard breast cancer screening guidelines.
Pregnancy
- Instruct patients that if they are pregnant or plan to become pregnant while taking Ocrelizumab they should inform their healthcare provider.
# Precautions with Alcohol
Alcohol-Ocrelizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Ocrevus
# Look-Alike Drug Names
There is limited information regarding Ocrelizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | Ocrelizumab
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2];
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# Overview
Ocrelizumab is a CD20-directed cytolytic antibody that is FDA approved for the treatment of relapsing or primary progressive forms of multiple sclerosis. Common adverse reactions include upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ocrelizumab is indicated for the treatment of adult patients with relapsing or primary progressive forms of multiple sclerosis.
- Administer Ocrelizumab under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions such as serious infusion reactions.
- Initial dose: 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion.
- Subsequent doses: single 600 mg intravenous infusion every 6 months.
- Observe the patient for at least one hour after the completion of the infusion.
- If a planned infusion of Ocrelizumab is missed, administer Ocrelizumab as soon as possible; do not wait until the next scheduled dose. Reset the dose schedule to administer the next sequential dose 6 months after the missed dose is administered. Doses of Ocrelizumab must be separated by at least 5 months.
- Dose modifications in response to infusion reactions depends on the severity.
Life-threatening Infusion Reactions
- Immediately stop and permanently discontinue Ocrelizumab if there are signs of a life-threatening or disabling infusion reaction. Provide appropriate supportive treatment.
Severe Infusion Reactions
- Immediately interrupt the infusion and administer appropriate supportive treatment, as necessary. Restart the infusion only after all symptoms have resolved. When restarting, begin at half of the infusion rate at the time of onset of the infusion reaction. If this rate is tolerated, increase the rate as described in TABLE 1. This change in rate will increase the total duration of the infusion but not the total dose.
Mild to Moderate Infusion Reactions
- Reduce the infusion rate to half the rate at the onset of the infusion reaction and maintain the reduced rate for at least 30 minutes. If this rate is tolerated, increase the rate as described in TABLE 1. This change in rate will increase the total duration of the infusion but not the total dose.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Ocrelizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ocrelizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ocrelizumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Ocrelizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.
### Non–Guideline-Supported Use
There is limited information regarding Ocrelizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.
# Contraindications
- Ocrelizumab is contraindicated in patients with:
- Active HBV infection.
- A history of life-threatening infusion reaction to Ocrelizumab.
# Warnings
- Ocrelizumab can cause infusion reactions, which can include pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, and tachycardia. In multiple sclerosis (MS) clinical trials, the incidence of infusion reactions in Ocrelizumab-treated patients [who received methylprednisolone (or an equivalent steroid) and possibly other pre-medication to reduce the risk of infusion reactions prior to each infusion] was 34 to 40%, with the highest incidence with the first infusion. There were no fatal infusion reactions, but 0.3% of Ocrelizumab-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization.
- Observe patients treated with Ocrelizumab for infusion reactions during the infusion and for at least one hour after completion of the infusion. Inform patients that infusion reactions can occur up to 24 hours after the infusion.
Reducing the Risk of Infusion Reactions and Managing Infusion Reactions
- Administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered.
- Management recommendations for infusion reactions depend on the type and severity of the reaction. For life-threatening infusion reactions, immediately and permanently stop Ocrelizumab and administer appropriate supportive treatment. For less severe infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.
- A higher proportion of Ocrelizumab-treated patients experienced infections compared to patients taking REBIF or placebo. In RMS trials, 58% of Ocrelizumab-treated patients experienced one or more infections compared to 52% of REBIF-treated patients. In the PPMS trial, 70% of Ocrelizumab-treated patients experienced one or more infections compared to 68% of patients on placebo. Ocrelizumab increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections. Ocrelizumab was not associated with an increased risk of serious infections in MS patients. Delay Ocrelizumab administration in patients with an active infection until the infection is resolved.
Respiratory Tract Infections
- A higher proportion of Ocrelizumab-treated patients experienced respiratory tract infections compared to patients taking REBIF or placebo. In RMS trials, 40% of Ocrelizumab-treated patients experienced upper respiratory tract infections compared to 33% of REBIF-treated patients, and 8% of Ocrelizumab-treated patients experienced lower respiratory tract infections compared to 5% of REBIF-treated patients. In the PPMS trial, 49% of Ocrelizumab-treated patients experienced upper respiratory tract infections compared to 43% of patients on placebo and 10% of Ocrelizumab-treated patients experienced lower respiratory tract infections compared to 9% of patients on placebo. The infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections and bronchitis.
Herpes
- In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in Ocrelizumab-treated patients than in REBIF-treated patients, including herpes zoster (2.1% vs. 1.0%), herpes simplex (0.7% vs. 0.1%), oral herpes (3.0% vs. 2.2%), genital herpes (0.1% vs. 0%), and herpes virus infection (0.1% vs. 0%). Infections were predominantly mild to moderate in severity. There were no reports of disseminated herpes.
- In the placebo-controlled (PPMS) clinical trial, oral herpes was reported more frequently in the Ocrelizumab-treated patients than in the patients on placebo (2.7% vs 0.8%).
Progressive Multifocal Leukoencephalopathy (PML)
- PML is an opportunistic viral infection of the brain caused by the John Cunningham (JC) virus that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Although no cases of PML were identified in Ocrelizumab clinical trials, JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies and other MS therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants). At the first sign or symptom suggestive of PML, withhold Ocrelizumab and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
Hepatitis B Virus (HBV) Reactivation
- There were no reports of hepatitis B reactivation in MS patients treated with Ocrelizumab. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with other anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with Ocrelizumab. Do not administer Ocrelizumab to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment.
Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants
- When initiating Ocrelizumab after an immunosuppressive therapy or initiating an immunosuppressive therapy after Ocrelizumab, consider the potential for increased immunosuppressive effects. Ocrelizumab has not been studied in combination with other MS therapies.
Vaccinations
- Administer all immunizations according to immunization guidelines at least 6 weeks prior to initiation of Ocrelizumab.
- The safety of immunization with live or live-attenuated vaccines following Ocrelizumab therapy has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.
- No data are available on the effects of live or non-live vaccination in patients receiving Ocrelizumab.
- An increased risk of malignancy with Ocrelizumab may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in Ocrelizumab-treated patients. Breast cancer occurred in 6 of 781 females treated with Ocrelizumab and none of 668 females treated with REBIF or placebo. Patients should follow standard breast cancer screening guidelines.
# Adverse Reactions
## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reactions 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.
- The safety of Ocrelizumab has been evaluated in 1311 patients across MS clinical studies, which included 825 patients in active-controlled clinical trials in patients with relapsing forms of MS (RMS) and 486 patients in a placebo-controlled study in patients with primary progressive MS (PPMS).
Adverse Reactions in Patients with Relapsing Forms of MS
- In active-controlled clinical trials (Study 1 and Study 2), 825 patients with RMS received Ocrelizumab 600 mg intravenously every 24 weeks (initial treatment was given as two separate 300 mg infusions at Weeks 0 and 2). The overall exposure in the 96-week controlled treatment periods was 1448 patient-years.
- The most common adverse reactions in RMS trials (incidence ≥ 10%) were upper respiratory tract infections and infusion reactions. TABLE 2 summarizes the adverse reactions that occurred in RMS trials (Study 1 and Study 2).
Adverse Reactions in Patients with Primary Progressive MS
- In a placebo-controlled clinical trial (Study 3), a total of 486 patients with PPMS received one course of Ocrelizumab (600 mg of Ocrelizumab administered as two 300 mg infusions two weeks apart) given intravenously every 24 weeks and 239 patients received placebo intravenously. The overall exposure in the controlled treatment period was 1416 patient-years, with median treatment duration of 3 years.
- The most common adverse reactions in the PPMS trial (incidence ≥ 10%) were upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections. TABLE 3 summarizes the adverse reactions that occurred in the PPMS trial (Study 3).
Laboratory Abnormalities
Decreased Immunoglobulins
- Ocrelizumab decreased total immunoglobulins with the greatest decline seen in IgM levels. In MS clinical trials, there was no apparent association between immunoglobulin decrease and risk for serious infections.
- In the active-controlled (RMS) trials (Study 1 and Study 2), the proportion of patients at baseline reporting IgG, IgA, and IgM below the lower limit of normal (LLN) in Ocrelizumab-treated patients was 0.5%, 1.5%, and 0.1%, respectively. Following treatment, the proportion of Ocrelizumab-treated patients reporting IgG, IgA, and IgM below the LLN at 96 weeks was 1.5%, 2.4%, and 16.5%, respectively.
- In the placebo-controlled (PPMS) trial (Study 3), the proportion of patients at baseline reporting IgG, IgA, and IgM below the LLN in Ocrelizumab-treated patients was 0.0%, 0.2%, and 0.2%, respectively. Following treatment, the proportion of Ocrelizumab-treated patients reporting IgG, IgA, and IgM below the LLN at 120 weeks was 1.1%, 0.5%, and 15.5%, respectively.
Decreased Neutrophil Levels
- In the PPMS clinical trial (Study 3), decreased neutrophil counts occurred in 13% of Ocrelizumab-treated patients compared to 10% in placebo patients. The majority of the decreased neutrophil counts were only observed once for a given patient treated with Ocrelizumab and were between LLN - 1.5 × 109/L and 1.0 × 109/L. Overall, 1% of the patients in the Ocrelizumab group had neutrophil counts less than 1.0 × 109/L and these were not associated with an infection.
- As with all therapeutic proteins, there is potential for immunogenicity. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. Therefore, comparison of the incidence of antibodies to Ocrelizumab with the incidence of antibodies to other products may be misleading.
- Patients in MS trials (Study 1, Study 2, and Study 3) were tested at multiple time points (baseline and every 6 months post-treatment for the duration of the trial) for anti-drug antibodies (ADAs). Out of 1311 patients treated with Ocrelizumab, 12 (~1%) tested positive for ADAs, of which 2 patients tested positive for neutralizing antibodies. These data are not adequate to assess the impact of ADAs on the safety and efficacy of Ocrelizumab.
## Postmarketing Experience
There is limited information regarding Ocrelizumab Postmarketing Experience in the drug label.
# Drug Interactions
- Immunosuppressive or Immune-Modulating Therapies
- The concomitant use of Ocrelizumab and other immune-modulating or immunosuppressive therapies, including immunosuppressant doses of corticosteroids, is expected to increase the risk of immunosuppression. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with Ocrelizumab. When switching from drugs with prolonged immune effects, such as daclizumab, fingolimod, natalizumab, teriflunomide, or mitoxantrone, consider the duration and mode of action of these drugs because of additive immunosuppressive effects when initiating Ocrelizumab.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Risk Summary
- There are no adequate data on the developmental risk associated with use of Ocrelizumab in pregnant women. There are no data on B-cell levels in human neonates following maternal exposure to Ocrelizumab. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. Ocrelizumab is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier. Following administration of Ocrelizumab to pregnant monkeys at doses similar to or greater than those used clinically, increased perinatal mortality, depletion of B-cell populations, renal, bone marrow, and testicular toxicity were observed in the offspring in the absence of maternal toxicity.
- In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
Data (Animal)
- Following intravenous administration of Ocrelizumab to monkeys during organogenesis (loading doses of 15 or 75 mg/kg on gestation days 20, 21, and 22, followed by weekly doses of 20 or 100 mg/kg), depletion of B-lymphocytes in lymphoid tissue (spleen and lymph nodes) was observed in fetuses at both doses.
- Intravenous administration of Ocrelizumab (three daily loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) to pregnant monkeys throughout the period of organogenesis and continuing through the neonatal period resulted in perinatal deaths (some associated with bacterial infections), renal toxicity (glomerulopathy and inflammation), lymphoid follicle formation in the bone marrow, and severe decreases in circulating B-lymphocytes in neonates. The cause of the neonatal deaths is uncertain; however, both affected neonates were found to have bacterial infections. Reduced testicular weight was observed in neonates at the high dose.
- A no-effect dose for adverse developmental effects was not identified; the doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ocrelizumab in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ocrelizumab during labor and delivery.
### Nursing Mothers
Risk Summary
- There are no data on the presence of Ocrelizumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Ocrelizumab was excreted in the milk of Ocrelizumab-treated monkeys. Human IgG is excreted in human milk, and the potential for absorption of Ocrelizumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Ocrelizumab and any potential adverse effects on the breastfed infant from Ocrelizumab or from the underlying maternal condition.
### Pediatric Use
- Safety and effectiveness of Ocrelizumab in pediatric patients have not been established.
### Geriatic Use
- Clinical studies of Ocrelizumab 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 Ocrelizumab with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ocrelizumab with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ocrelizumab in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ocrelizumab in patients with hepatic impairment.
### Females of Reproductive Potential and Males
Contraception
- Women of childbearing potential should use contraception while receiving Ocrelizumab and for 6 months after the last infusion of Ocrelizumab.
### Immunocompromised Patients
There is no FDA guidance one the use of Ocrelizumab in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Solution in vial is clear or slightly opalescent, and colorless to pale brown; do not use if discolored.
- Do not shake vial.
- 300 mg dose: Withdraw 10 mL from vial and further dilute in 250 mL of NS to final concentration of about 1.2 mg/mL.
- 600 mg dose: Withdraw 20 mL from 2 vials and further dilute in 500 mL of NS to final concentration of about 1.2 mg/mL.
- Only dilute in NS; do not dilute with any other diluent.
- May use polyvinyl chloride (PCV) or polyolefin (PO) infusion bags and IV administration sets.
- Diluted solution should be used immediately or stored for up to 8 hours at a room temperature not exceeding 25 degrees C (77 degrees F) or for up to 24 hours if stored in the refrigerator at 2 to 8 degrees C (36 to 46 degrees F). Storage time includes infusion time.
- Prior to administration, bring infusion bag to room temperature.
- Administer diluted solution via a dedicated line with a 0.2 or 0.22 micron in-line filter.
- 300 mg dose: Begin infusion rate at 30 mL/hr and increase by 30 mL/hr every 30 minutes, as tolerated, to MAX 180 mL/hr for a duration of 2.5 hours or longer. Observe patient for at least 1 hour after infusion completion.
- 600 mg dose: Begin infusion rate at 40 mL/hr and increase by 40 mL/hr every 30 minutes, as tolerated, to MAX 200 mL/hr for a duration of 3.5 hours or longer. Observe patient for at least 1 hour after infusion completion.
- If infusion cannot be completed the same day, discard remaining solution.
- Missed dose: Give as soon as possible; do not wait until the next scheduled dose. Reset the dose schedule to administer the next sequential dose 6 months after the missed dose; doses must be separated by at least 5 months.
### Monitoring
- Reductions in the rates of relapse and disability progression are indicative of efficacy.
- Hepatitis B virus screening: Prior to initiation.
- Signs and symptoms of active infection: Prior to every infusion.
- Signs and symptoms of infusion reactions: During infusion and for at least 1 hour after completion.
# IV Compatibility
There is limited information regarding the compatibility of Ocrelizumab and IV administrations.
# Overdosage
There is limited information regarding Ocrelizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
# Pharmacology
## Mechanism of Action
- The precise mechanism by which Ocrelizumab exerts its therapeutic effects in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, Ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.
## Structure
There is limited information regarding Ocrelizumab Structure in the drug label.
## Pharmacodynamics
- For B-cell counts, assays for CD19+ B-cells are used because the presence of Ocrelizumab interferes with the CD20 assay. Treatment with Ocrelizumab reduces CD19+ B-cell counts in blood by 14 days after infusion. In clinical studies, B-cell counts rose to above the lower limit of normal (LLN) or above baseline counts between infusions of Ocrelizumab at least one time in 0.3% to 4.1% of patients. In a clinical study of 51 patients, the median time for B-cell counts to return to either baseline or LLN was 72 weeks (range 27-175 weeks) after the last Ocrelizumab infusion. Within 2.5 years after the last infusion, B-cell counts rose to either baseline or LLN in 90% of patients.
## Pharmacokinetics
- Pharmacokinetics (PK) of Ocrelizumab in MS clinical studies fit a two compartment model with time-dependent clearance. The overall exposure at the steady-state (AUC over the 24 week dosing intervals) of Ocrelizumab was 3,510 mcg/mL per day. In clinical studies in MS patients, maintenance doses of Ocrelizumab were either 600 mg every 6 months (RMS patients) or two 300 mg infusions separated by 14 days every 6 months (PPMS patients). The mean maximum concentration was 212 mcg/mL in patients with RMS (600 mg infusion) and 141 mcg/mL in patients with PPMS (two 300 mg infusions administered within two weeks). The pharmacokinetics of Ocrelizumab was essentially linear and dose proportional between 400 mg and 2000 mg.
Distribution
- The population PK estimate of the central volume of distribution was 2.78 L. Peripheral volume and inter-compartment clearance were estimated at 2.68 L and 0.29 L/day, respectively.
Elimination
- Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.05 L/day, which declined with a half-life of 33 weeks. The terminal elimination half-life was 26 days.
Metabolism
- The metabolism of Ocrelizumab has not been directly studied because antibodies are cleared principally by catabolism.
Specific Populations
Renal impairment
- Patients with mild renal impairment were included in clinical trials. No significant change in the pharmacokinetics of Ocrelizumab was observed in those patients.
Hepatic impairment
- Patients with mild hepatic impairment were included in clinical trials. No significant change in the pharmacokinetics of Ocrelizumab was observed in those patients.
## Nonclinical Toxicology
- No carcinogenicity studies have been performed to assess the carcinogenic potential of Ocrelizumab.
- No studies have been performed to assess the mutagenic potential of Ocrelizumab. As an antibody, Ocrelizumab is not expected to interact directly with DNA.
- No effects on reproductive organs were observed in male monkeys administered Ocrelizumab by intravenous injection (three loading doses of 15 or 75 mg/kg, followed by weekly doses of 20 or 100 mg/kg) for 8 weeks. There were also no effects on estrus cycle in female monkeys administered Ocrelizumab over three menstrual cycles using the same dosing regimen. The doses tested in monkey are 2 and 10 times the recommended human dose of 600 mg, on a mg/kg basis.
# Clinical Studies
- The efficacy of Ocrelizumab was demonstrated in two randomized, double-blind, double-dummy, active comparator-controlled clinical trials of identical design, in patients with RMS treated for 96 weeks (Study1 and Study 2). The dose of Ocrelizumab was 600 mg every 24 weeks (initial treatment was given as two 300 mg IV infusions administered 2 weeks apart, and subsequent doses were administered as a single 600 mg IV infusion) and placebo subcutaneous injections were given 3 times per week. The dose of REBIF, the active comparator, was 44 mcg given as subcutaneous injections 3 times per week and placebo IV infusions were given every 24 weeks. Both studies included patients who had experienced at least one relapse within the prior year, or two relapses within the prior two years, and had an Expanded Disability Status Scale (EDSS) score from 0 to 5.5. Patients with primary progressive forms of multiple sclerosis (MS) were excluded. Neurological evaluations were performed every 12 weeks and at the time of a suspected relapse. Brain MRIs were performed at baseline and at Weeks 24, 48, and 96.
- The primary outcome of both Study 1 and Study 2 was the annualized relapse rate (ARR). Additional outcome measures included the proportion of patients with confirmed disability progression, the mean number of MRI T1 gadolinium (Gd)-enhancing lesions at Weeks 24, 48, and 96, and new or enlarging MRI T2 hyperintense lesions. Progression of disability was defined as an increase of 1 point or more from the baseline EDSS score attributable to MS when the baseline EDSS score was 5.5 or less, or 0.5 points or more when the baseline EDSS score was above 5.5. Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit 12 weeks after the initial documentation of neurological worsening. The primary population for analysis of confirmed disability progression was the pooled population from Studies 1 and 2.
- In Study 1, 410 patients were randomized to Ocrelizumab and 411 to REBIF; 11% of Ocrelizumab-treated and 17% of REBIF-treated patients did not complete the 96-week double-blind treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 37 years; 66% were female. The mean time from MS diagnosis to randomization was 3.8 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8; 74% of patients had not been treated with a non-steroid therapy for MS in the 2 years prior to the study. At baseline, 40% of patients had one or more T1 Gd-enhancing lesions (mean 1.8).
- In Study 2, 417 patients were randomized to Ocrelizumab and 418 to REBIF; 14% of Ocrelizumab-treated and 23% of REBIF-treated patients did not complete the 96-week double-blind treatment period. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 37 years; 66% were female. The mean time from MS diagnosis to randomization was 4.1 years, the mean number of relapses in the previous year was 1.3, and the mean EDSS score was 2.8; 74% of patients had not been treated with a non-steroid therapy for MS in the 2 years prior to the study. At baseline, 40% of Ocrelizumab-treated patients had one or more T1 Gd-enhancing lesions (mean 1.9).
- In Study 1 and Study 2, Ocrelizumab significantly lowered the annualized relapse rate and the proportion of patients with disability progression confirmed at 12 weeks after onset compared to REBIF. Results for Study 1 and Study 2 are presented in TABLE 4 and FIGURE 1.
- In exploratory subgroup analyses of Study 1 and Study 2, the effect of Ocrelizumab on annualized relapse rate and disability progression was similar in male and female patients.
- Study 3 was a randomized, double-blind, placebo-controlled clinical trial in patients with PPMS. Patients were randomized 2:1 to receive either Ocrelizumab 600 mg or placebo as two 300 mg intravenous infusions 2 weeks apart every 24 weeks for at least 120 weeks. Selection criteria required a baseline EDSS of 3 to 6.5 and a score of 2 or greater for the EDSS pyramidal functional system due to lower extremity findings. Neurological assessments were conducted every 12 weeks. An MRI scan was obtained at baseline and at Weeks 24, 48, and 120.
- In Study 3, the primary outcome was the time to onset of disability progression attributable to MS confirmed to be present at the next neurological assessment at least 12 weeks later. Disability progression occurred when the EDSS score increased by 1 point or more from the baseline EDSS if the baseline EDSS was 5.5 points or less, or by 0.5 points or more if the baseline EDSS was more than 5.5 points. In Study 3, confirmed disability progression also was deemed to have occurred if patients who had onset of disability progression discontinued participation in the study before the next assessment. Additional outcome measures included timed 25-foot walk, and percentage change in T2 hyperintense lesion volume.
- Study 3 randomized 488 patients to Ocrelizumab and 244 to placebo; 21% of Ocrelizumab-treated patients and 34% of placebo-treated patients did not complete the trial. The baseline demographic and disease characteristics were balanced between the two treatment groups. At baseline, the mean age of patients was 45; 49% were female. The mean time since symptom onset was 6.7 years, the mean EDSS score was 4.7, and 26% had one or more T1 Gd-enhancing lesions at baseline; 88% of patients had not been treated previously with a non-steroid treatment for MS. The time to onset of disability progression confirmed at 12 weeks after onset was significantly longer for Ocrelizumab-treated patients than for placebo-treated patients (see FIGURE 2). Results for Study 3 are presented in TABLE 5 and FIGURE 2.
- In the overall population in Study 3, the proportion of patients with 20 percent worsening of the timed 25-foot walk confirmed at 12 weeks was 49% in Ocrelizumab-treated patients compared to 59% in placebo-treated patients (25% risk reduction).
- In exploratory subgroup analyses of Study 3, the proportion of female patients with disability progression confirmed at 12 weeks after onset was similar in Ocrelizumab-treated patients and placebo-treated patients (approximately 36% in each group). In male patients, the proportion of patients with disability progression confirmed at 12 weeks after onset was approximately 30% in Ocrelizumab-treated patients and 43% in placebo-treated patients. Clinical and MRI endpoints that generally favored Ocrelizumab numerically in the overall population, and that showed similar trends in both male and female patients, included annualized relapse rate, change in T2 lesion volume, and number of new or enlarging T2 lesions.
# How Supplied
- Ocrelizumab injection is a preservative-free, sterile, clear or slightly opalescent, and colorless to pale brown solution supplied as a carton containing one 300 mg/10 mL (30 mg/mL) single-dose vial (NDC 50242-150-01).
## Storage
- Store Ocrelizumab vials at 2°C–8°C (36°F–46°F) in the outer carton to protect from light. Do not freeze or shake.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Infusion Reactions
- Inform patients about the signs and symptoms of infusion reactions, and that infusion reactions can occur up to 24 hours after infusion. Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion reactions.
Infection
- Advise patients to contact their healthcare provider for any signs of infection during treatment or after the last dose. Signs include fever, chills, constant cough, or signs of herpes such as cold sore, shingles, or genital sores.
- Advise patients that PML has happened with drugs that are similar to Ocrelizumab and may happen with Ocrelizumab. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
- Advise patients that Ocrelizumab may cause reactivation of hepatitis B infection and that monitoring will be required if they are at risk.
Vaccination
- Advise patients to complete any required vaccinations at least 6 weeks prior to initiation of Ocrelizumab. Administration of live-attenuated or live vaccines is not recommended during Ocrelizumab treatment and until B-cell recovery.
Malignancies
- Advise patients that an increased risk of malignancy, including breast cancer, may exist with Ocrelizumab. Advise patients that they should follow standard breast cancer screening guidelines.
Pregnancy
- Instruct patients that if they are pregnant or plan to become pregnant while taking Ocrelizumab they should inform their healthcare provider.
# Precautions with Alcohol
Alcohol-Ocrelizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.
# Brand Names
- Ocrevus
# Look-Alike Drug Names
There is limited information regarding Ocrelizumab Look-Alike Drug Names in the drug label.
# Drug Shortage Status
Drug Shortage
# Price | https://www.wikidoc.org/index.php/Ocrelizumab | |
075fa8dd54c30d71f81e828817c8b6e4985c6014 | wikidoc | Ocriplasmin | Ocriplasmin
# 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
Ocriplasmin is a proteolytic enzyme that is FDA approved for the treatment of symptomatic vitreomacular adhesion. Common adverse reactions include blurred vision, conjunctival hemorrhage, macular hole, pain in eye, photopsia, retinal edema, uveitis, visual impairment, vitreous floaters.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ocriplasmin® is a proteolytic enzyme indicated for the treatment of symptomatic vitreomacular adhesion.
- Must be diluted before use. For single-use ophthalmic intravitreal injection only. Ocriplasmin must only be administered by a qualified physician.
- The recommended dose is 0.125 mg (0.1 mL of the diluted solution) administered by intravitreal injection to the affected eye once as a single dose.
- The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad spectrum microbiocide should be administered according to standard medical practice.
- The injection needle should be inserted 3.5-4.0 mm posterior to the limbus aiming towards the center of the vitreous cavity, avoiding the horizontal meridian. The injection volume of 0.1 mL is then delivered into the mid-vitreous.
- Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available.
- Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurred or decreased vision) without delay.
- Each vial should only be used to provide a single injection for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, and injection needles should be changed before Ocriplasmin is administered to the other eye, however, treatment with Ocriplasmin in the other eye is not recommended within 7 days of the initial injection in order to monitor the post-injection course including the potential for decreased vision in the injected eye.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ocriplasmin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ocriplasmin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ocriplasmin 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 Ocriplasmin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ocriplasmin in pediatric patients.
# Contraindications
None
# Warnings
- A decrease of ≥ 3 line of best corrected visual acuity (BCVA) was experienced by 5.6% of patients treated with Ocriplasmin and 3.2% of patients treated with vehicle in the controlled trials.
- The majority of these decreases in vision were due to progression of the condition with traction and many required surgical intervention. Patients should be monitored appropriately.
- Intravitreal injections are associated with intraocular inflammation / infection, intraocular hemorrhage and increased intraocular pressure (IOP). In the controlled trials, intraocular inflammation occurred in 7.1% of patients injected with Ocriplasmin vs. 3.7% of patients injected with vehicle. Most of the post-injection intraocular inflammation events were mild and transient. Intraocular hemorrhage occurred in 2.4% vs. 3.7% of patients injected with Ocriplasmin vs. vehicle, respectively. Increased intraocular pressure occurred in 4.1% vs. 5.3% of patients injected with Ocriplasmin vs. vehicle, respectively.
- One case of lens subluxation was reported in a premature infant who received an intravitreal injection of 0.175 mg (1.4 times higher than the recommended dose). Lens subluxation was observed in three animal species (monkey, rabbit, minipig) following a single intravitreal injection that achieved vitreous concentrations of ocriplasmin 1.4 times higher than achieved with the recommended treatment dose. Administration of a second intravitreal dose in monkeys, 28 days apart, produced lens subluxation in 100% of the treated eyes.
- In the controlled trials, the incidence of retinal detachment was 0.9% in the Ocriplasmin group and 1.6% in the vehicle group, while the incidence of retinal tear (without detachment) was 1.1% in the Ocriplasmin group and 2.7% in the vehicle group. Most of these events occurred during or after vitrectomy in both groups. The incidence of retinal detachment that occurred pre-vitrectomy was 0.4% in the Ocriplasmin group and none in the vehicle group, while the incidence of retinal tear (without detachment) that occurred pre-vitrectomy was none in the Ocriplasmin group and 0.5% in the vehicle group.
- Dyschromatopsia (generally described as yellowish vision) was reported in 2% of all patients injected with Ocriplasmin. In approximately half of these dyschromatopsia cases there were also electroretinographic (ERG) changes reported (a- and b-wave amplitude decrease).
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are described below and elsewhere in the labeling:
- Decreased Vision.
- Intravitreal Injection Procedure Associated Effects.
- Potential for Lens Subluxation.
- Retinal Breaks.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice.
- Approximately 800 patients have been treated with an intravitreal injection of Ocriplasmin. Of these, 465 patients received an intravitreal injection of ocriplasmin 0.125 mg (187 patients received vehicle) in the 2 vehicle-controlled studies (Study 1 and Study 2).
- The most common adverse reactions (incidence 5% - 20% listed in descending order of frequency) in the vehicle-controlled clinical studies were: vitreous floaters, conjunctival hemorrhage, eye pain, photopsia, blurred vision, macular hole, reduced visual acuity, visual impairment, and retinal edema.
- Less common adverse reactions observed in the studies at a frequency of 2% - < 5% in patients treated with Ocriplasmin included macular edema, increased intraocular pressure, anterior chamber cell, photophobia, vitreous detachment, ocular discomfort, iritis, cataract, dry eye, metamorphopsia, conjunctival hyperemia, and retinal degeneration.
- Dyschromatopsia was reported in 2% of patients injected with Ocriplasmin, with the majority of cases reported from two uncontrolled clinical studies. In approximately half of these dyschromatopsia cases there were also electroretinographic (ERG) changes reported (a- and b-wave amplitude decrease).
- As with all therapeutic proteins, there is potential for immunogenicity. Immunogenicity for this product has not been evaluated.
## Postmarketing Experience
There is limited information regarding Ocriplasmin Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ocriplasmin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with ocriplasmin. There are no adequate and well-controlled studies of ocriplasmin in pregnant women.
- It is not known whether ocriplasmin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The systemic exposure to ocriplasmin is expected to be low after intravitreal injection of a single 0.125 mg dose. Assuming 100% systemic absorption (and a plasma volume of 2700 mL), the estimated plasma concentration is 46 ng/mL. Ocriplasmin should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ocriplasmin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ocriplasmin during labor and delivery.
### Nursing Mothers
- It is not known whether ocriplasmin is excreted in human milk. Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when Ocriplasmin is administered to a nursing woman.
### Pediatric Use
- The use of Ocriplasmin in pediatric patients is not recommended. A single center, randomized, placebo controlled, double masked clinical study to investigate the safety and efficacy of a single intravitreal injection of 0.175 mg ocriplasmin in pediatric subjects as an adjunct to vitrectomy was conducted in 24 eyes of 22 patients. There were no statistical or clinical differences between groups for the induction of total macular PVD, any of the secondary endpoints or adverse events.
### Geriatic Use
- In the clinical studies, 384 and 145 patients were ≥ 65 years and of these 192 and 73 patients were ≥ 75 years in the Ocriplasmin and vehicle groups respectively. No significant differences in efficacy or safety were seen with increasing age in these studies.
### Gender
There is no FDA guidance on the use of Ocriplasmin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ocriplasmin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ocriplasmin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ocriplasmin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ocriplasmin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ocriplasmin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravitreal injection
### Monitoring
- Patients should be monitored and instructed to report any symptoms without delay.
- Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure.
# IV Compatibility
There is limited information regarding the compatibility of Ocriplasmin and IV administrations.
# Overdosage
- The clinical data on the effects of Ocriplasmin overdose are limited. One case of accidental overdose of 0.250 mg ocriplasmin (twice the recommended dose) was reported to be associated with inflammation and a decrease in visual acuity.
# Pharmacology
## Mechanism of Action
- Ocriplasmin has proteolytic activity against protein components of the vitreous body and the vitreoretinal interface (VRI) (e.g. laminin, fibronectin and collagen), thereby dissolving the protein matrix responsible for the vitreomacular adhesion (VMA).
## Structure
- Ocriplasmin is a recombinant truncated form of human plasmin with a molecular weight of 27.2 kDa produced by recombinant DNA technology in a Pichia pastoris expression system.
- JETREA is a sterile, clear and colorless solution with no preservatives in a single-use glass vial containing 0.5 mg ocriplasmin in 0.2 mL solution for intravitreal injection after dilution.
- Each vial contains 0.5 mg ocriplasmin (active) and 0.21 mg citric acid, 0.75 mg mannitol, sodium hydroxide (for pH adjustment) and water for injection. The pH of the solution is 3.1.
## Pharmacodynamics
There is limited information regarding Ocriplasmin Pharmacodynamics in the drug label.
## Pharmacokinetics
- The intravitreal pharmacokinetics of ocriplasmin were determined in a clinical study in patients scheduled for vitrectomy where 0.125 mg ocriplasmin (corresponding to an average concentration of 29 mcg ocriplasmin per mL vitreous volume ) was administered as a single intravitreal dose at different time points prior to vitrectomy. The mean ocriplasmin activity levels decreased with time from injection to time of sampling as illustrated in Table 1, according to a second order kinetic process. At 24 hours post injection the levels in the vitreous were below 3% of the theoretical concentration reached immediately after injection.
- Because of the small dose administered (0.125 mg), detectable levels of ocriplasmin in systemic circulation are not expected after intravitreal injection.
## Nonclinical Toxicology
- No carcinogenicity, mutagenicity or reproductive and developmental toxicity studies were conducted with ocriplasmin.
- The ocular toxicity of ocriplasmin after a single intravitreal dose has been evaluated in rabbits, monkeys and minipigs. Ocriplasmin induced an inflammatory response and transient ERG changes in rabbits and monkeys, which tended to resolve over time. Lens subluxation was observed in the 3 species at ocriplasmin concentrations in the vitreous at or above 41 mcg/mL, a concentration 1.4-fold above the intended clinical concentration in the vitreous of 29 mcg/mL. Intraocular hemorrhage was observed in rabbits and monkeys.
- A second intravitreal administration of ocriplasmin (28 days apart) in monkeys at doses of 75 mcg/eye (41 mcg/mL vitreous) or 125 mcg/eye (68 mcg/mL vitreous) was associated with lens subluxation in all ocriplasmin treated eyes. Sustained increases in IOP occurred in two animals with lens subluxation. Microscopic findings in the eye included vitreous liquefaction, degeneration/disruption of the hyaloideocapsular ligament (with loss of ciliary zonular fibers), lens degeneration, mononuclear cell infiltration of the vitreous, and vacuolation of the retinal inner nuclear cell layer. These doses are 1.4-fold and 2.3-fold the intended clinical concentration in the vitreous of 29 mcg/mL, respectively.
# Clinical Studies
- The efficacy and safety of JETREA was demonstrated in two multicenter, randomized, double masked, vehicle-controlled, 6 month studies in patients with symptomatic vitreomacular adhesion (VMA). A total of 652 patients (JETREA 464, vehicle 188) were randomized in these 2 studies. Randomization was 2:1 (JETREA:vehicle) in Study 1 and 3:1 in Study 2.
- Patients were treated with a single injection of JETREA or vehicle. In both of the studies, the proportion of patients who achieved VMA resolution at Day 28 (i.e., achieved success on the primary endpoint) was significantly higher in the ocriplasmin group compared with the vehicle group through Month 6 (Table 2 and Figure 7).
# How Supplied
- Each vial of JETREA contains 0.5 mg ocriplasmin in 0.2 mL citric-buffered solution (2.5 mg/mL). JETREA is supplied in a 2 mL glass vial with a latex free rubber stopper. Vials are for single use only.
- NDC 24856-001-00
## Storage
- Store frozen at or below -4°F (-20°C). Protect the vials from light by storing in the original package until time of use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- In the days following JETREA administration, patients are at risk of developing intraocular inflammation/infection. Advise patients to seek immediate care from an ophthalmologist if the eye becomes red, sensitive to light, painful, or develops a change in vision.- Patients may experience temporary visual impairment after receiving an intravitreal injection of JETREA . Advise patients to not drive or operate heavy machinery until this visual impairment has resolved. If visual impairment persists or decreases further, advise patients to seek care from an ophthalmologist.
# Precautions with Alcohol
Alcohol-Ocriplasmin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- JETREA®
# Look-Alike Drug Names
There is limited information regarding Ocriplasmin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Ocriplasmin
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
Ocriplasmin is a proteolytic enzyme that is FDA approved for the treatment of symptomatic vitreomacular adhesion. Common adverse reactions include blurred vision, conjunctival hemorrhage, macular hole, pain in eye, photopsia, retinal edema, uveitis, visual impairment, vitreous floaters.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Ocriplasmin® is a proteolytic enzyme indicated for the treatment of symptomatic vitreomacular adhesion.
- Must be diluted before use. For single-use ophthalmic intravitreal injection only. Ocriplasmin must only be administered by a qualified physician.
- The recommended dose is 0.125 mg (0.1 mL of the diluted solution) administered by intravitreal injection to the affected eye once as a single dose.
- The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include the use of sterile gloves, a sterile drape and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad spectrum microbiocide should be administered according to standard medical practice.
- The injection needle should be inserted 3.5-4.0 mm posterior to the limbus aiming towards the center of the vitreous cavity, avoiding the horizontal meridian. The injection volume of 0.1 mL is then delivered into the mid-vitreous.
- Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available.
- Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurred or decreased vision) without delay.
- Each vial should only be used to provide a single injection for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, and injection needles should be changed before Ocriplasmin is administered to the other eye, however, treatment with Ocriplasmin in the other eye is not recommended within 7 days of the initial injection in order to monitor the post-injection course including the potential for decreased vision in the injected eye.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ocriplasmin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ocriplasmin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Ocriplasmin 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 Ocriplasmin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ocriplasmin in pediatric patients.
# Contraindications
None
# Warnings
- A decrease of ≥ 3 line of best corrected visual acuity (BCVA) was experienced by 5.6% of patients treated with Ocriplasmin and 3.2% of patients treated with vehicle in the controlled trials.
- The majority of these decreases in vision were due to progression of the condition with traction and many required surgical intervention. Patients should be monitored appropriately.
- Intravitreal injections are associated with intraocular inflammation / infection, intraocular hemorrhage and increased intraocular pressure (IOP). In the controlled trials, intraocular inflammation occurred in 7.1% of patients injected with Ocriplasmin vs. 3.7% of patients injected with vehicle. Most of the post-injection intraocular inflammation events were mild and transient. Intraocular hemorrhage occurred in 2.4% vs. 3.7% of patients injected with Ocriplasmin vs. vehicle, respectively. Increased intraocular pressure occurred in 4.1% vs. 5.3% of patients injected with Ocriplasmin vs. vehicle, respectively.
- One case of lens subluxation was reported in a premature infant who received an intravitreal injection of 0.175 mg (1.4 times higher than the recommended dose). Lens subluxation was observed in three animal species (monkey, rabbit, minipig) following a single intravitreal injection that achieved vitreous concentrations of ocriplasmin 1.4 times higher than achieved with the recommended treatment dose. Administration of a second intravitreal dose in monkeys, 28 days apart, produced lens subluxation in 100% of the treated eyes.
- In the controlled trials, the incidence of retinal detachment was 0.9% in the Ocriplasmin group and 1.6% in the vehicle group, while the incidence of retinal tear (without detachment) was 1.1% in the Ocriplasmin group and 2.7% in the vehicle group. Most of these events occurred during or after vitrectomy in both groups. The incidence of retinal detachment that occurred pre-vitrectomy was 0.4% in the Ocriplasmin group and none in the vehicle group, while the incidence of retinal tear (without detachment) that occurred pre-vitrectomy was none in the Ocriplasmin group and 0.5% in the vehicle group.
- Dyschromatopsia (generally described as yellowish vision) was reported in 2% of all patients injected with Ocriplasmin. In approximately half of these dyschromatopsia cases there were also electroretinographic (ERG) changes reported (a- and b-wave amplitude decrease).
# Adverse Reactions
## Clinical Trials Experience
The following adverse reactions are described below and elsewhere in the labeling:
- Decreased Vision.
- Intravitreal Injection Procedure Associated Effects.
- Potential for Lens Subluxation.
- Retinal Breaks.
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates in one clinical trial of a drug cannot be directly compared with rates in the clinical trials of the same or another drug and may not reflect the rates observed in practice.
- Approximately 800 patients have been treated with an intravitreal injection of Ocriplasmin. Of these, 465 patients received an intravitreal injection of ocriplasmin 0.125 mg (187 patients received vehicle) in the 2 vehicle-controlled studies (Study 1 and Study 2).
- The most common adverse reactions (incidence 5% - 20% listed in descending order of frequency) in the vehicle-controlled clinical studies were: vitreous floaters, conjunctival hemorrhage, eye pain, photopsia, blurred vision, macular hole, reduced visual acuity, visual impairment, and retinal edema.
- Less common adverse reactions observed in the studies at a frequency of 2% - < 5% in patients treated with Ocriplasmin included macular edema, increased intraocular pressure, anterior chamber cell, photophobia, vitreous detachment, ocular discomfort, iritis, cataract, dry eye, metamorphopsia, conjunctival hyperemia, and retinal degeneration.
- Dyschromatopsia was reported in 2% of patients injected with Ocriplasmin, with the majority of cases reported from two uncontrolled clinical studies. In approximately half of these dyschromatopsia cases there were also electroretinographic (ERG) changes reported (a- and b-wave amplitude decrease).
- As with all therapeutic proteins, there is potential for immunogenicity. Immunogenicity for this product has not been evaluated.
## Postmarketing Experience
There is limited information regarding Ocriplasmin Postmarketing Experience in the drug label.
# Drug Interactions
There is limited information regarding Ocriplasmin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
- Animal reproduction studies have not been conducted with ocriplasmin. There are no adequate and well-controlled studies of ocriplasmin in pregnant women.
- It is not known whether ocriplasmin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. The systemic exposure to ocriplasmin is expected to be low after intravitreal injection of a single 0.125 mg dose. Assuming 100% systemic absorption (and a plasma volume of 2700 mL), the estimated plasma concentration is 46 ng/mL. Ocriplasmin should be given to a pregnant woman only if clearly needed.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ocriplasmin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Ocriplasmin during labor and delivery.
### Nursing Mothers
- It is not known whether ocriplasmin is excreted in human milk. Because many drugs are excreted in human milk, and because the potential for absorption and harm to infant growth and development exists, caution should be exercised when Ocriplasmin is administered to a nursing woman.
### Pediatric Use
- The use of Ocriplasmin in pediatric patients is not recommended. A single center, randomized, placebo controlled, double masked clinical study to investigate the safety and efficacy of a single intravitreal injection of 0.175 mg ocriplasmin in pediatric subjects as an adjunct to vitrectomy was conducted in 24 eyes of 22 patients. There were no statistical or clinical differences between groups for the induction of total macular PVD, any of the secondary endpoints or adverse events.
### Geriatic Use
- In the clinical studies, 384 and 145 patients were ≥ 65 years and of these 192 and 73 patients were ≥ 75 years in the Ocriplasmin and vehicle groups respectively. No significant differences in efficacy or safety were seen with increasing age in these studies.
### Gender
There is no FDA guidance on the use of Ocriplasmin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Ocriplasmin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Ocriplasmin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Ocriplasmin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ocriplasmin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Ocriplasmin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Intravitreal injection
### Monitoring
- Patients should be monitored and instructed to report any symptoms without delay.
- Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure.
# IV Compatibility
There is limited information regarding the compatibility of Ocriplasmin and IV administrations.
# Overdosage
- The clinical data on the effects of Ocriplasmin overdose are limited. One case of accidental overdose of 0.250 mg ocriplasmin (twice the recommended dose) was reported to be associated with inflammation and a decrease in visual acuity.
# Pharmacology
## Mechanism of Action
- Ocriplasmin has proteolytic activity against protein components of the vitreous body and the vitreoretinal interface (VRI) (e.g. laminin, fibronectin and collagen), thereby dissolving the protein matrix responsible for the vitreomacular adhesion (VMA).
## Structure
- Ocriplasmin is a recombinant truncated form of human plasmin with a molecular weight of 27.2 kDa produced by recombinant DNA technology in a Pichia pastoris expression system.
- JETREA is a sterile, clear and colorless solution with no preservatives in a single-use glass vial containing 0.5 mg ocriplasmin in 0.2 mL solution for intravitreal injection after dilution.
- Each vial contains 0.5 mg ocriplasmin (active) and 0.21 mg citric acid, 0.75 mg mannitol, sodium hydroxide (for pH adjustment) and water for injection. The pH of the solution is 3.1.
## Pharmacodynamics
There is limited information regarding Ocriplasmin Pharmacodynamics in the drug label.
## Pharmacokinetics
- The intravitreal pharmacokinetics of ocriplasmin were determined in a clinical study in patients scheduled for vitrectomy where 0.125 mg ocriplasmin (corresponding to an average concentration of 29 mcg ocriplasmin per mL vitreous volume [approximately 4.3 mL/eye]) was administered as a single intravitreal dose at different time points prior to vitrectomy. The mean ocriplasmin activity levels decreased with time from injection to time of sampling as illustrated in Table 1, according to a second order kinetic process. At 24 hours post injection the levels in the vitreous were below 3% of the theoretical concentration reached immediately after injection.
- Because of the small dose administered (0.125 mg), detectable levels of ocriplasmin in systemic circulation are not expected after intravitreal injection.
## Nonclinical Toxicology
- No carcinogenicity, mutagenicity or reproductive and developmental toxicity studies were conducted with ocriplasmin.
- The ocular toxicity of ocriplasmin after a single intravitreal dose has been evaluated in rabbits, monkeys and minipigs. Ocriplasmin induced an inflammatory response and transient ERG changes in rabbits and monkeys, which tended to resolve over time. Lens subluxation was observed in the 3 species at ocriplasmin concentrations in the vitreous at or above 41 mcg/mL, a concentration 1.4-fold above the intended clinical concentration in the vitreous of 29 mcg/mL. Intraocular hemorrhage was observed in rabbits and monkeys.
- A second intravitreal administration of ocriplasmin (28 days apart) in monkeys at doses of 75 mcg/eye (41 mcg/mL vitreous) or 125 mcg/eye (68 mcg/mL vitreous) was associated with lens subluxation in all ocriplasmin treated eyes. Sustained increases in IOP occurred in two animals with lens subluxation. Microscopic findings in the eye included vitreous liquefaction, degeneration/disruption of the hyaloideocapsular ligament (with loss of ciliary zonular fibers), lens degeneration, mononuclear cell infiltration of the vitreous, and vacuolation of the retinal inner nuclear cell layer. These doses are 1.4-fold and 2.3-fold the intended clinical concentration in the vitreous of 29 mcg/mL, respectively.
# Clinical Studies
- The efficacy and safety of JETREA was demonstrated in two multicenter, randomized, double masked, vehicle-controlled, 6 month studies in patients with symptomatic vitreomacular adhesion (VMA). A total of 652 patients (JETREA 464, vehicle 188) were randomized in these 2 studies. Randomization was 2:1 (JETREA:vehicle) in Study 1 and 3:1 in Study 2.
- Patients were treated with a single injection of JETREA or vehicle. In both of the studies, the proportion of patients who achieved VMA resolution at Day 28 (i.e., achieved success on the primary endpoint) was significantly higher in the ocriplasmin group compared with the vehicle group through Month 6 (Table 2 and Figure 7).
# How Supplied
- Each vial of JETREA contains 0.5 mg ocriplasmin in 0.2 mL citric-buffered solution (2.5 mg/mL). JETREA is supplied in a 2 mL glass vial with a latex free rubber stopper. Vials are for single use only.
- NDC 24856-001-00
## Storage
- Store frozen at or below -4°F (-20°C). Protect the vials from light by storing in the original package until time of use.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- In the days following JETREA administration, patients are at risk of developing intraocular inflammation/infection. Advise patients to seek immediate care from an ophthalmologist if the eye becomes red, sensitive to light, painful, or develops a change in vision.* Patients may experience temporary visual impairment after receiving an intravitreal injection of JETREA . Advise patients to not drive or operate heavy machinery until this visual impairment has resolved. If visual impairment persists or decreases further, advise patients to seek care from an ophthalmologist.
# Precautions with Alcohol
Alcohol-Ocriplasmin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- JETREA®[1]
# Look-Alike Drug Names
There is limited information regarding Ocriplasmin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Ocriplasmin | |
00faf84b2b25208703e05390eec3f3585e72c1ca | wikidoc | Omacetaxine | Omacetaxine
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# Overview
Omacetaxine is an antineoplastic agent that is FDA approved for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI). Common adverse reactions include pancytopenia, thrombocytopenia, increased alanine aminotransferase, myelosuppression, bleeding and hyperglycemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Omacetaxine is indicated for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI).
### Dosing Information
- The recommended starting schedule for induction is 1.25 mg/m2 administered subcutaneously twice daily at approximately 12 hour intervals for 14 consecutive days every 28 days, over a 28-day cycle. Cycles should be repeated every 28 days until patients achieve a hematologic response.
- The recommended maintenance schedule is 1.25 mg/m2 administered subcutaneously twice daily approximately 12 hour intervals for 7 consecutive days every 28 days, over a 28-day cycle.
- Treatment should continue as long as patients are clinically benefiting from therapy.
- Omacetaxine treatment cycles may be delayed and/or the number of days of dosing during the cycle reduced for hematologic toxicities (e.g. neutropenia, thrombocytopenia) .
- Complete blood counts (CBCs) should be performed weekly during induction and initial maintenance cycles. After initial maintenance cycles, monitor CBCs every two weeks or as clinically indicated. If a patient experiences Grade 4 neutropenia (absolute neutrophil count (ANC) less than 0.5 x 109/L) or Grade 3 thrombocytopenia (platelet counts less than 50 x 109/L) during a cycle, delay starting the next cycle until ANC is greater than or equal to 1.0 x 109/L and platelet count is greater than or equal to 50 x 109/L. Also, for the next cycle, reduce the number of dosing days by 2 days (e.g. to 12 or 5 days).
- Manage other clinically significant non-hematologic toxicity symptomatically. Interrupt and/or delay Omacetaxine until toxicity is resolved.
- Omacetaxine should be prepared in a healthcare facility and must be reconstituted by a healthcare professional.
- Reconstitute Omacetaxine with one mL of 0.9% Sodium Chloride Injection, USP, prior to subcutaneous injection. After addition of the diluent, gently swirl until a clear solution is obtained. The lyophilized powder should be completely dissolved in less than one minute. The resulting solution is clear and colorless and contains 3.5 mg/mL Omacetaxine . Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
- Omacetaxine does not contain antimicrobial preservatives. Therefore care must be taken to ensure that the solution for injection is not contaminated during preparation.
- Omacetaxine is a cytotoxic drug. Follow special handling and disposal procedures. Wear protective eyewear and gloves during handling and administration of the product. Proper aseptic technique should be used. Avoid skin and eye contact. If Omacetaxine comes into contact with skin, immediately and thoroughly wash affected area with soap and water. If contact with the eyes occurs, thoroughly flush the eyes with water.
- If Omacetaxine is not used immediately after reconstitution, follow in-use storage conditions and allowable storage times prior to use as instructed in Table 1. *Do not administer Omacetaxine outside of the storage conditions and timeframes listed in TABLE 1.
- Before a decision is made to allow Omacetaxine to be administered by someone other than a healthcare professional, ensure that the patient is an appropriate candidate for self-administration or for administration by a caregiver. Provide training on proper handling, storage conditions, administration, disposal, and clean-up of accidental spillage of the product. Ensure that patients receive the necessary supplies for home administration. At minimum these should include:
- Reconstituted Omacetaxine in syringe with a capped needle for subcutaneous injection. Syringe(s) should be filled to the patient-specific dose.
Protective eyewear
- Gloves
- An appropriate biohazard container
- Absorbent pad(s) for placement of administration materials and for accidental spillage
- Alcohol swabs
- Gauze pads
- Ice packs or cooler for transportation of reconstituted Omacetaxine syringes
- If a patient or caregiver cannot be trained for any reason, then in such patients, Omacetaxine should be administered by a healthcare professional.
- After administration, any unused solution should be discarded properly. Instruct patients planning home administration on the following: do not recap or clip the used needle, and do not place used needles, syringes, vials, and other used supplies in a household trash or recycling bin. Used needles, syringes, vials, and other used supplies should be disposed of in an appropriate biohazard container.
- If accidental spillage occurs, continue to use protective eyewear and gloves, wipe the spilled liquid with the absorbent pad, and wash the area with water and soap. Then, place the pad and gloves into the biohazard container and wash hands thoroughly. Return the biohazard container to the clinic or pharmacy for final disposal.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Omacetaxine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Omacetaxine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Omacetaxine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Omacetaxine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Omacetaxine in pediatric patients.
# Contraindications
- None.
# Warnings
- In uncontrolled trials with Omacetaxine , patients with chronic phase and accelerated phase CML experienced NCI CTC (version 3.0) Grade 3 or 4 thrombocytopenia (85%, 88%), neutropenia (81%, 71%), and anemia (62%, 80%), respectively. Fatalities related to myelosuppression occurred in 3% of patients in the safety population (N=163). Patients with neutropenia are at increased risk for infections, and should be monitored frequently and advised to contact a physician if they have symptoms of infection or fever.
- Monitor complete blood counts weekly during induction and initial maintenance cycles and every two weeks during later maintenance cycles, as clinically indicated. In clinical trials myelosuppression was generally reversible and usually managed by delaying next cycle and/or reducing days of treatment with Omacetaxine .
- Omacetaxine causes severe thrombocytopenia which increases the risk of hemorrhage. In clinical trials with CP and AP CML patients, a high incidence of Grade 3 and 4 thrombocytopenia (85% and 88%, respectively) was observed. Fatalities from cerebral hemorrhage occurred in 2% of patients treated with Omacetaxine in the safety population. Severe, non-fatal, gastrointestinal hemorrhages occurred in 2% of patients in the same population. Most bleeding events were associated with severe thrombocytopenia.
- Monitor platelet counts as part of the CBC monitoring as recommended . Avoid anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) when the platelet count is less than 50,000/µL as they may increase the risk of bleeding.
- Omacetaxine can induce glucose intolerance. Grade 3 or 4 hyperglycemia was reported in 11% of patients in the safety population. Hyperosmolar non-ketotic hyperglycemia occurred in 1 patient treated with Omacetaxine in the safety population. Monitor blood glucose levels frequently, especially in patients with diabetes or risk factors for diabetes. Avoid Omacetaxine in patients with poorly controlled diabetes mellitus until good glycemic control has been established.
- Omacetaxine can cause fetal harm when administered to a pregnant woman. Omacetaxine mepesuccinate caused embryo-fetal death in animals. Females of reproductive potential should avoid becoming pregnant while being treated with Omacetaxine . There are no adequate and well-controlled studies of Omacetaxine in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions have been associated with Omacetaxine in clinical trials and are discussed in greater detail in other sections of the label.
- Myelosuppression
- Bleeding
- Hyperglycemia
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety data for Omacetaxine are from 3 clinical trials which enrolled a total of 163 adult patients with TKI resistant and/or intolerant chronic phase (N=108) and accelerated phase (N=55) CML. All patients were treated with initial induction therapy consisting of a dose of 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and a twice daily schedule for 7 consecutive days every 28 days (maintenance cycle).
- The median duration of exposure for the 108 patients with chronic phase CML was 7.4 months (range 0 to 43 months). The median total cycles of exposure was 6 (range 1 to 41), and the median total dose delivered during the trials was 131 mg/m2 (range 1.2 to 678). Among the patients with chronic phase CML, 87% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 42% and 16% respectively. Of the 91 patients who received at least 2 cycles of treatment, 79 (87%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 2 (17 days) and cycle 3 (25 days) when more patients were receiving induction cycles.
- Adverse reactions were reported for 99% of the patients with chronic phase CML. A total of 18% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to discontinuation were pancytopenia, thrombocytopenia, and increased alanine aminotransferase (each 2%). A total of 87% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reaction (TABLE 2).There is limited information regarding Clinical Trial Experience of Omacetaxine in the drug label.
- Serious adverse reactions were reported for 51% of patients. Serious adverse reactions reported for at least 5% of patients were bone marrow failure and thrombocytopenia (each 10%), and febrile neutropenia (6%). Serious adverse reactions of infections were reported for 8% of patients.
- Deaths occurred while on study in five (5%) patients with CP CML. Two patients died due to cerebral hemorrhage, one due to multi-organ failure, one due to progression of disease, and one from unknown causes.
- Median total cycles of exposure was 2 (range 1 to 29), and the median total dose delivered during the trials was 70 mg/m2. The median duration of exposure for the 55 patients with accelerated phase CML was 1.9 months (range 0 to 30 months). Of the patients with accelerated phase CML, 86% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 55% and 44% respectively. Of the 40 patients who received at least 2 cycles of treatment, 27 (68%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 3 (31 days) and cycle 8 (36 days).
- Adverse reactions regardless of investigator attribution were reported for 100% patients with accelerated phase CML. A total of 33% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to withdrawal were leukocytosis (6%), and thrombocytopenia (4%). A total of 84% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reaction.
- Serious adverse reactions were reported for 60% of patients. Serious adverse reactions reported for at least 5% of patients were febrile neutropenia (18%), thrombocytopenia (9%), anemia (7%), and diarrhea (6%). Serious adverse reactions of infections were reported for 11% of patients.
- Death occurred while on study in 5 (9%) patients with AP CML. Two patients died due to cerebral hemorrhage and three due to progression of disease.
- Grade 3/4 laboratory abnormalities reported in patients with chronic and accelerated phase CML are described in TABLE 4. Myelosuppression occurred in all patients treated with Omacetaxine . Five patients with chronic phase CML and 4 patients with accelerated phase CML permanently discontinued Omacetaxine due to pancytopenia, thrombocytopenia, febrile neutropenia, or bone marrow necrosis. An event of hyperosmolar non-ketotic hyperglycemia was reported in one patient in the safety population and a similar case has been reported in the literature. Two patients with chronic phase CML permanently discontinued Omacetaxine due to elevated transaminases.
- The following adverse reactions were reported in patients in the Omacetaxine clinical studies of patients with chronic phase and accelerated phase CML at a frequency of 1% to less than 10%. Within each category, adverse reactions are ranked on the basis of frequency.
- Cardiac Disorders: tachycardia, palpitations, acute coronary syndrome, angina pectoris, arrhythmia, bradycardia, ventricular extrasystoles.
- Ear and Labyrinth Disorders: ear pain, ear hemorrhage, tinnitus.
- Eye Disorders: cataract, vision blurred, conjunctival hemorrhage, dry eye, lacrimation increased, conjunctivitis, diplopia, eye pain, eyelid edema.
- Gastrointestinal Disorders: stomatitis, mouth ulceration, abdominal distension, dyspepsia, gastroesophageal reflux disease, gingival bleeding, aphthous stomatitis, dry mouth, hemorrhoids, gastritis, gastrointestinal hemorrhage, melena, mouth hemorrhage, oral pain, anal fissure, dysphagia, gingival pain, gingivitis.
- General Disorders and Administration Site Conditions: mucosal inflammation, pain, chest pain, hyperthermia, influenza-like illness, catheter site pain, general edema, malaise.
- Immune System Disorders: hypersensitivity.
- Injury, Poisoning and Procedural Complications: contusion, transfusion reaction.
- Metabolism and Nutrition Disorders: decreased appetite, diabetes mellitus, gout, dehydration.
- Musculoskeletal and Connective Tissue Disorders: bone pain, myalgia, muscular weakness, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, musculoskeletal discomfort.
- Nervous System Disorders: dizziness, cerebral hemorrhage, paresthesia, convulsion, hypoesthesia, lethargy, sciatica, burning sensation, dysgeusia, tremor.
- Psychiatric Disorders: anxiety, depression, agitation, confusional state, mental status change.
- Renal and Urinary Disorders: dysuria.
- Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain, nasal congestion, dysphonia, productive cough, rales, rhinorrhea, hemoptysis, sinus congestion.
- Skin and Subcutaneous Tissue Disorders: erythema, pruritus, dry skin, petechiae, hyperhidrosis, night sweats, ecchymosis, purpura, skin lesion, skin ulcer, rash erythematous, rash papular, skin exfoliation, skin hyperpigmentation.
- Vascular Disorders: hematoma, hypertension, hot flush, hypotension.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Omacetaxine in the drug label.
# Drug Interactions
- Based on the findings from in vitro drug interaction studies with Omacetaxine , no clinical drug interaction trials were warranted
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on its mechanism of action and findings from animal studies, Omacetaxine can cause fetal harm when administered to pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- In an embryo-fetal development study, pregnant mice were administered omacetaxine mepesuccinate subcutaneously during the period of organogenesis at doses of 0.21 or 0.41 mg/kg/day. Drug-related adverse effects included embryonic death, an increase in unossified bones/reduced bone ossification and decreased fetal body weights. Fetal toxicity occurred at doses of 0.41 mg/kg (1.23 mg/m2) which is approximately half the recommended daily human dose on a body surface area basis.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Omacetaxine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Omacetaxine during labor and delivery.
### Nursing Mothers
- It is not known whether omacetaxine mepesuccinate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reaction in nursing infants, 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
- The safety and effectiveness of Omacetaxine in pediatric patients have not been established
### Geriatic Use
- In the chronic and accelerated phase CML efficacy populations 23 (30%) and 16 (46%) patients were ≥65 years of age. For the age subgroups of <65 years of age and ≥65 years of age, there were differences between the subgroups, with higher rates of major cytogenetic responses (MCyRs) in younger patients with CP CML compared with older patients (23% vs. 9%, respectively) and higher rates of major hematologic responses (MaHRs) in older patients with AP CML compared with younger patients (31% vs. 0%, respectively). Patients ≥65 years of age were more likely to experience toxicity, most notably hematologic toxicity.
### Gender
- Of the 76 patients included in the chronic phase CML population efficacy analysis, 47 (62%) of the patients were men and 29 (38%) were women. For patients with chronic phase CML, the MCyR rate in men was higher than in women (21% vs. 14%, respectively). There were differences noted in the safety profile of omacetaxine mepesuccinate in men and women with chronic phase CML although the small number of patients in each group prevents a definitive assessment. There were inadequate patient numbers in the accelerated phase subset to draw conclusions regarding a gender effect on efficacy.
### Race
There is no FDA guidance on the use of Omacetaxine with respect to specific racial populations.
### Renal Impairment
- No formal studies assessing the impact of renal impairment on the pharmacokinetics of omacetaxine mepesuccinate have been conducted.
### Hepatic Impairment
- No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of omacetaxine mepesuccinate have been conducted.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Omacetaxine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Omacetaxine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Omacetaxine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Omacetaxine in the drug label.
# Overdosage
- A patient in the clinical expanded access program received an overdose of 2.5 mg/m2 twice daily for 5 days in the 16th cycle. The patient presented with gastrointestinal disorders, gingival hemorrhage, alopecia, and Grade 4 thrombocytopenia and neutropenia. When Omacetaxine treatment was temporarily interrupted the gastrointestinal disorders and hemorrhagic syndrome resolved, and neutrophil values returned to within normal range. The alopecia and thrombocytopenia (Grade 1) improved, and Omacetaxine was restarted.
- No specific antidote for Omacetaxine overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters.
There is limited information regarding Chronic Overdose of Omacetaxine in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of omacetaxine mepesuccinate has not been fully elucidated but includes inhibition of protein synthesis and is independent of direct Bcr-Abl binding. Omacetaxine mepesuccinate binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaeabacteria. In vitro, omacetaxine mepesuccinate reduced protein levels of the Bcr-Abl oncoprotein and Mcl-1, an anti-apoptotic Bcl-2 family member. Omacetaxine mepesuccinate showed activity in mouse models of wild-type and T315I mutated Bcr-Abl CML.
## Structure
- Omacetaxine contains the active ingredient omacetaxine mepesuccinate, a cephalotaxine ester. It is a protein synthesis inhibitor. Omacetaxine mepesuccinate is prepared by a semi-synthetic process from cephalotaxine, an extract from the leaves of Cephalotaxus sp. The chemical name of omacetaxine mepesuccinate is cephalotaxine, 4-methyl (2R)-hydroxyl-2-(4-hydroxyl-4-methylpentyl) butanedioate (ester).
Omacetaxine mepesuccinate has the following chemical structure:
- The molecular formula is C29H39NO9 with a molecular weight of 545.6 g/mol. Omacetaxine for Injection is a sterile, preservative-free, white to off-white, lyophilized powder in a single-use vial. Each vial contains 3.5 mg omacetaxine mepesuccinate and mannitol.
- Omacetaxine is intended for subcutaneous administration after reconstitution with 1.0 mL of 0.9% Sodium Chloride Injection, USP. The pH of the reconstituted solution is between 5.5 and 7.0.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Omacetaxine in the drug label.
## Pharmacokinetics
- The dose proportionality of omacetaxine mepesuccinate is unknown. A 90% increase in systemic exposure to omacetaxine mepesuccinate was observed between the first dose and steady state.
- The absolute bioavailability of omacetaxine mepesuccinate has not been determined. Omacetaxine mepesuccinate is absorbed following subcutaneous administration, and maximum concentrations are achieved after approximately 30 minutes.
- The steady-state (mean ± SD) volume of distribution of omacetaxine mepesuccinate is approximately 141 ± 93.4 L following subcutaneous administration of 1.25 mg/m2 twice daily for 11 days . *The plasma protein binding of omacetaxine mepesuccinate is less than or equal to 50%.
- Omacetaxine mepesuccinate is primarily hydrolyzed to 4′-DMHHT via plasma esterases with little hepatic microsomal oxidative and/or esterase-mediated metabolism in vitro.
- The major elimination route of omacetaxine mepesuccinate is unknown. The mean percentage of omacetaxine mepesuccinate excreted unchanged in the urine is less than 15%. The mean half-life of omacetaxine mepesuccinate following subcutaneous administration is approximately 6 hours.
- Cytochrome P450 Enzymes (CYPs): Omacetaxine mepesuccinate is not a substrate of CYP450 enzymes in vitro. Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit major CYPs in vitro at concentrations that can be expected clinically. The potential for omacetaxine mepesuccinate or 4′-DMHHT to induce CYP450 enzymes has not been determined.
- Transporter Systems: Omacetaxine mepesuccinate is a P-glycoprotein (P-gp) substrate in vitro. Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit P-gp mediated efflux of loperamide in vitro at concentrations that can be expected clinically.
- In an uncontrolled pharmacokinetic study there were no reports of QTcF > 480 ms or ΔQTcF > 60 ms in 21 treated patients who received omacetaxine mepesuccinate 1.25 mg/m2 BID for 14 consecutive days. There was no evidence for concentration-dependent increases in QTc for omacetaxine mepesuccinate or 4’-DMHHT. Although the mean effect on QTc was 4.2 ms (upper 95% CI: 9.5 ms), QTc effects less than 10 ms cannot be verified due to the absence of a placebo and positive controls.
## Nonclinical Toxicology
- No carcinogenicity studies have been conducted with omacetaxine mepesuccinate.
- Omacetaxine mepesuccinate was genotoxic in an in vitro chromosomal aberration test system in Chinese hamster ovary (CHO) cells, but was not mutagenic when tested in an in vitro bacterial cell assay (Ames test), and it did not induce genetic damage using an in vivo mouse micronucleus assay.
- Omacetaxine may impair male fertility. Studies in mice demonstrated adverse effects on male reproductive organs. Bilateral degeneration of the seminiferous tubular epithelium in testes and hypospermia/aspermia in the epididymides were reported in the highest dose group (2.33 mg/kg/day reduced to 1.67 mg/kg/day; 7 to 5 mg/m2/day) following subcutaneous injection of omacetaxine mepesuccinate for six cycles over six months. The doses used in the mice were approximately two to three times the clinical dose (2.5 mg/m2/day) based on body surface area.
# Clinical Studies
- The efficacy of Omacetaxine was evaluated using a combined cohort of adult patients with CML from two trials. The combined cohort consisted of patients who had received 2 or more approved TKIs and had, at a minimum, documented evidence of resistance or intolerance to dasatinib and/or nilotinib. Resistance was defined as one of the following: no complete hematologic response (CHR) by 12 weeks (whether lost or never achieved); or no cytogenetic response by 24 weeks (i.e., 100% Ph positive ) (whether lost or never achieved); or no major cytogenetic response (MCyR) by 52 weeks (i.e., ≥35% Ph+) (whether lost or never achieved); or progressive leukocytosis. Intolerance was defined as one of the following: 1) Grade 3-4 non-hematologic toxicity that does not resolve with adequate intervention; or 2) Grade 4 hematologic toxicity lasting more than 7 days; or 3) any Grade ≥ 2 toxicity that is unacceptable to the patient. Patients with NYHA class III or IV heart disease, active ischemia or other uncontrolled cardiac conditions were excluded.
- Patients were treated with omacetaxine mepesuccinate at a dose of 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and twice daily schedule for 7 consecutive days every 28 days (maintenance cycle). Patients were allowed to continue to receive maintenance treatment for up to 24 months. Responses were adjudicated by an independent Data Monitoring Committee (DMC).
- A total of 76 patients with chronic phase CML were included in the efficacy analysis. The demographics were: median age 59 years, 62% were male, 30% were 65 years of age or older, 80% were Caucasian, 5% were African-American, 4% were Asian and 4% were Hispanic. Thirty-six (47%) patients had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (54%), interferon (30%), and/or cytarabine (29%). The efficacy endpoint was based on MCyR (adjudicated by a DMC).
- The mean time to MCyR onset in the 14 patients was 3.5 months. The median duration of MCyR for the 14 patients was 12.5 months (Kaplan-Meier estimate).
- A total of 35 patients with accelerated phase CML were included in the efficacy analysis. The demographics were: median age was 63 years, 57% were male, 46% were 65 years of age or older, 68% were Caucasian, 23% were African-American, 3% were Asian and 3% were Hispanic. Twenty-two (63%) of 35 patients with accelerated phase had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (43%), interferon (31%), and/or cytarabine (29%). The efficacy endpoint was assessed based on MCyR and MaHR (complete hematologic response or no evidence of leukemia ). The efficacy results for the patients with accelerated phase as adjudicated by the DMC
- The mean time to response onset in the 5 patients was 2.3 months. The median duration of MaHR for the 5 patients was 4.7 months (Kaplan-Meier estimate).
# How Supplied
- Omacetaxine (omacetaxine mepesuccinate) for Injection is supplied in 8 mL clear glass single-use vial in individual cartons. Each vial contains 3.5 mg of Omacetaxine (omacetaxine mepesuccinate) for Injection (NDC 63459-177-14).
## Storage
- Store unopened vials at 20oC to 25ºC (68o F to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF) . Prior to re-constitution, keep product in carton to protect from light.Omacetaxine mepesuccinate is a cytotoxic drug. Follow special handling and disposal procedures1.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Assist patients and caregivers in understanding their contents and give them the opportunity to discuss the contents of the Medication Guide and Instructions for Use and to obtain answers to any questions they may have prior to initiating therapy. The complete text of the Medication Guide and Instructions for Use are attached to the prescribing information.
- Once it is determined that a patient is an appropriate candidate for self-administration or administration by a caregiver, ensure that patients receive the necessary supplies for home administration of Omacetaxine and train them on the following.
- How to transport reconstituted Omacetaxine in a secure container or packaging and under recommended temperature conditions
- Acceptable storage conditions and use times for reconstituted Omacetaxine
When stored in a refrigerator (2°C to 8°C ), use within 6 days (144 hours)
When stored at room temperature (not to exceed 25°C ), use within 12 hours
- When stored in a refrigerator (2°C to 8°C ), use within 6 days (144 hours)
- When stored at room temperature (not to exceed 25°C ), use within 12 hours
- If stored in a refrigerator, keep Omacetaxine from coming into contact with food or drink.
- To wear disposable gloves and protective eyewear when handling Omacetaxine .
- To wash hands before putting on gloves and after removing gloves.
- Not to eat or drink while handling Omacetaxine . To administer Omacetaxine in an area away from food or food preparation areas.
- To administer Omacetaxine in a location away from children and pregnant women.
- Proper subcutaneous injection technique including acceptable sites.
- The importance of body site selection for administering the injection, as well as the importance of alternating the injection sites. Advise patients to not inject Omacetaxine into areas of the skin that are tender, red, bruised, hard, or that have scars or stretch marks.
- In the case of a missed dose: If a patient misses an injection, skip the missed dose and the patient should give the next scheduled injection at the next scheduled time. Inform patients NOT to give two injections to make up for a missed injection.
- In the case that Omacetaxine comes into contact with a patient’s skin or eyes: Advise patients to wash exposed skin with soap and water and in the case of eye exposure, thoroughly flush the eye with water. After washing or flushing, advise patients to call their healthcare provider immediately.
- In the case that too much Omacetaxine is injected or that Omacetaxine is accidentally swallowed: Instruct patients to contact their healthcare provider immediately if they have injected too much Omacetaxine , or if someone has swallowed Omacetaxine .
- Disposal procedures, including use of an appropriate biohazard container and return of the container to the clinic or pharmacy for final disposal. Inform patients NOT to recap or clip the used needle and not to place used needles, syringes, vials, and other used supplies in a household trash or recycle container.
- Accidental spillage procedures, including wiping the spilled liquid with the absorbent pad (using protective eyewear and gloves), washing the area with water and soap, and proper disposal of materials.
- Advise patients of the possibility of serious bleeding due to low platelet counts. Instruct patients to report immediately any signs or symptoms suggestive of hemorrhage (unusual bleeding, easy bruising or blood in urine or stool; confusion, slurred speech, or altered vision). Instruct patients to report in advance if they plan to have any dental or surgical procedures.
- Advise patients of the likelihood that Omacetaxine will cause a decrease in white blood cells, platelets, and red blood cells and that monitoring of these parameters will be needed. Instruct patients to contact a health care professional if they develop a fever, or other signs/symptoms of infection; shortness of breath, significant fatigue, or bleeding.
- Advise patients with diabetes of the possibility of hyperglycemia and the need for careful monitoring of blood glucose levels. Patients with poorly controlled diabetes mellitus should not be treated with omacetaxine mepesuccinate until good glycemic control has been established.
- Advise patients that omacetaxine mepesuccinate can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential hazard to the fetus and to avoid becoming pregnant. Advise females to avoid nursing while receiving Omacetaxine .
- Advise patients that they may experience nausea, diarrhea, abdominal pain, constipation, and vomiting. If these symptoms persist, they should seek medical attention.
- Advise patients that Omacetaxine may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect.
- Advise patients that they may experience skin rash. Advise patients to immediately report severe or worsening rash or itching.
- Advise patients that they may experience hair loss
# Precautions with Alcohol
- Alcohol-Omacetaxine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SYNRIBO®
# Look-Alike Drug Names
There is limited information regarding Omacetaxine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Omacetaxine
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
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# Overview
Omacetaxine is an antineoplastic agent that is FDA approved for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI). Common adverse reactions include pancytopenia, thrombocytopenia, increased alanine aminotransferase, myelosuppression, bleeding and hyperglycemia.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Omacetaxine is indicated for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI).
### Dosing Information
- The recommended starting schedule for induction is 1.25 mg/m2 administered subcutaneously twice daily at approximately 12 hour intervals for 14 consecutive days every 28 days, over a 28-day cycle. Cycles should be repeated every 28 days until patients achieve a hematologic response.
- The recommended maintenance schedule is 1.25 mg/m2 administered subcutaneously twice daily approximately 12 hour intervals for 7 consecutive days every 28 days, over a 28-day cycle.
- Treatment should continue as long as patients are clinically benefiting from therapy.
- Omacetaxine treatment cycles may be delayed and/or the number of days of dosing during the cycle reduced for hematologic toxicities (e.g. neutropenia, thrombocytopenia) .
- Complete blood counts (CBCs) should be performed weekly during induction and initial maintenance cycles. After initial maintenance cycles, monitor CBCs every two weeks or as clinically indicated. If a patient experiences Grade 4 neutropenia (absolute neutrophil count (ANC) less than 0.5 x 109/L) or Grade 3 thrombocytopenia (platelet counts less than 50 x 109/L) during a cycle, delay starting the next cycle until ANC is greater than or equal to 1.0 x 109/L and platelet count is greater than or equal to 50 x 109/L. Also, for the next cycle, reduce the number of dosing days by 2 days (e.g. to 12 or 5 days).
- Manage other clinically significant non-hematologic toxicity symptomatically. Interrupt and/or delay Omacetaxine until toxicity is resolved.
- Omacetaxine should be prepared in a healthcare facility and must be reconstituted by a healthcare professional.
- Reconstitute Omacetaxine with one mL of 0.9% Sodium Chloride Injection, USP, prior to subcutaneous injection. After addition of the diluent, gently swirl until a clear solution is obtained. The lyophilized powder should be completely dissolved in less than one minute. The resulting solution is clear and colorless and contains 3.5 mg/mL Omacetaxine . Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.
- Omacetaxine does not contain antimicrobial preservatives. Therefore care must be taken to ensure that the solution for injection is not contaminated during preparation.
- Omacetaxine is a cytotoxic drug. Follow special handling and disposal procedures. Wear protective eyewear and gloves during handling and administration of the product. Proper aseptic technique should be used. Avoid skin and eye contact. If Omacetaxine comes into contact with skin, immediately and thoroughly wash affected area with soap and water. If contact with the eyes occurs, thoroughly flush the eyes with water.
- If Omacetaxine is not used immediately after reconstitution, follow in-use storage conditions and allowable storage times prior to use as instructed in Table 1. *Do not administer Omacetaxine outside of the storage conditions and timeframes listed in TABLE 1.
- Before a decision is made to allow Omacetaxine to be administered by someone other than a healthcare professional, ensure that the patient is an appropriate candidate for self-administration or for administration by a caregiver. Provide training on proper handling, storage conditions, administration, disposal, and clean-up of accidental spillage of the product. Ensure that patients receive the necessary supplies for home administration. At minimum these should include:
- Reconstituted Omacetaxine in syringe with a capped needle for subcutaneous injection. Syringe(s) should be filled to the patient-specific dose.
Protective eyewear
- Gloves
- An appropriate biohazard container
- Absorbent pad(s) for placement of administration materials and for accidental spillage
- Alcohol swabs
- Gauze pads
- Ice packs or cooler for transportation of reconstituted Omacetaxine syringes
- If a patient or caregiver cannot be trained for any reason, then in such patients, Omacetaxine should be administered by a healthcare professional.
- After administration, any unused solution should be discarded properly. Instruct patients planning home administration on the following: do not recap or clip the used needle, and do not place used needles, syringes, vials, and other used supplies in a household trash or recycling bin. Used needles, syringes, vials, and other used supplies should be disposed of in an appropriate biohazard container.
- If accidental spillage occurs, continue to use protective eyewear and gloves, wipe the spilled liquid with the absorbent pad, and wash the area with water and soap. Then, place the pad and gloves into the biohazard container and wash hands thoroughly. Return the biohazard container to the clinic or pharmacy for final disposal.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Omacetaxine in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Omacetaxine in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Omacetaxine in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Omacetaxine in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Omacetaxine in pediatric patients.
# Contraindications
- None.
# Warnings
- In uncontrolled trials with Omacetaxine , patients with chronic phase and accelerated phase CML experienced NCI CTC (version 3.0) Grade 3 or 4 thrombocytopenia (85%, 88%), neutropenia (81%, 71%), and anemia (62%, 80%), respectively. Fatalities related to myelosuppression occurred in 3% of patients in the safety population (N=163). Patients with neutropenia are at increased risk for infections, and should be monitored frequently and advised to contact a physician if they have symptoms of infection or fever.
- Monitor complete blood counts weekly during induction and initial maintenance cycles and every two weeks during later maintenance cycles, as clinically indicated. In clinical trials myelosuppression was generally reversible and usually managed by delaying next cycle and/or reducing days of treatment with Omacetaxine .
- Omacetaxine causes severe thrombocytopenia which increases the risk of hemorrhage. In clinical trials with CP and AP CML patients, a high incidence of Grade 3 and 4 thrombocytopenia (85% and 88%, respectively) was observed. Fatalities from cerebral hemorrhage occurred in 2% of patients treated with Omacetaxine in the safety population. Severe, non-fatal, gastrointestinal hemorrhages occurred in 2% of patients in the same population. Most bleeding events were associated with severe thrombocytopenia.
- Monitor platelet counts as part of the CBC monitoring as recommended . Avoid anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) when the platelet count is less than 50,000/µL as they may increase the risk of bleeding.
- Omacetaxine can induce glucose intolerance. Grade 3 or 4 hyperglycemia was reported in 11% of patients in the safety population. Hyperosmolar non-ketotic hyperglycemia occurred in 1 patient treated with Omacetaxine in the safety population. Monitor blood glucose levels frequently, especially in patients with diabetes or risk factors for diabetes. Avoid Omacetaxine in patients with poorly controlled diabetes mellitus until good glycemic control has been established.
- Omacetaxine can cause fetal harm when administered to a pregnant woman. Omacetaxine mepesuccinate caused embryo-fetal death in animals. Females of reproductive potential should avoid becoming pregnant while being treated with Omacetaxine . There are no adequate and well-controlled studies of Omacetaxine in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus
# Adverse Reactions
## Clinical Trials Experience
- The following serious adverse reactions have been associated with Omacetaxine in clinical trials and are discussed in greater detail in other sections of the label.
- Myelosuppression
- Bleeding
- Hyperglycemia
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
- The safety data for Omacetaxine are from 3 clinical trials which enrolled a total of 163 adult patients with TKI resistant and/or intolerant chronic phase (N=108) and accelerated phase (N=55) CML. All patients were treated with initial induction therapy consisting of a dose of 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and a twice daily schedule for 7 consecutive days every 28 days (maintenance cycle).
- The median duration of exposure for the 108 patients with chronic phase CML was 7.4 months (range 0 to 43 months). The median total cycles of exposure was 6 (range 1 to 41), and the median total dose delivered during the trials was 131 mg/m2 (range 1.2 to 678). Among the patients with chronic phase CML, 87% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 42% and 16% respectively. Of the 91 patients who received at least 2 cycles of treatment, 79 (87%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 2 (17 days) and cycle 3 (25 days) when more patients were receiving induction cycles.
- Adverse reactions were reported for 99% of the patients with chronic phase CML. A total of 18% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to discontinuation were pancytopenia, thrombocytopenia, and increased alanine aminotransferase (each 2%). A total of 87% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reaction (TABLE 2).There is limited information regarding Clinical Trial Experience of Omacetaxine in the drug label.
- Serious adverse reactions were reported for 51% of patients. Serious adverse reactions reported for at least 5% of patients were bone marrow failure and thrombocytopenia (each 10%), and febrile neutropenia (6%). Serious adverse reactions of infections were reported for 8% of patients.
- Deaths occurred while on study in five (5%) patients with CP CML. Two patients died due to cerebral hemorrhage, one due to multi-organ failure, one due to progression of disease, and one from unknown causes.
- Median total cycles of exposure was 2 (range 1 to 29), and the median total dose delivered during the trials was 70 mg/m2. The median duration of exposure for the 55 patients with accelerated phase CML was 1.9 months (range 0 to 30 months). Of the patients with accelerated phase CML, 86% received 14 days of treatment during cycle 1. By cycles 2 and 3, the percentage of patients receiving 14 days of treatment decreased to 55% and 44% respectively. Of the 40 patients who received at least 2 cycles of treatment, 27 (68%) had at least 1 cycle delay during the trials. The median number of days of cycle delays was greatest for cycle 3 (31 days) and cycle 8 (36 days).
- Adverse reactions regardless of investigator attribution were reported for 100% patients with accelerated phase CML. A total of 33% of patients had adverse reactions leading to withdrawal. The most frequently occurring adverse reactions leading to withdrawal were leukocytosis (6%), and thrombocytopenia (4%). A total of 84% of patients reported at least 1 Grade 3 or Grade 4 treatment emergent adverse reaction.
- Serious adverse reactions were reported for 60% of patients. Serious adverse reactions reported for at least 5% of patients were febrile neutropenia (18%), thrombocytopenia (9%), anemia (7%), and diarrhea (6%). Serious adverse reactions of infections were reported for 11% of patients.
- Death occurred while on study in 5 (9%) patients with AP CML. Two patients died due to cerebral hemorrhage and three due to progression of disease.
- Grade 3/4 laboratory abnormalities reported in patients with chronic and accelerated phase CML are described in TABLE 4. Myelosuppression occurred in all patients treated with Omacetaxine . Five patients with chronic phase CML and 4 patients with accelerated phase CML permanently discontinued Omacetaxine due to pancytopenia, thrombocytopenia, febrile neutropenia, or bone marrow necrosis. An event of hyperosmolar non-ketotic hyperglycemia was reported in one patient in the safety population and a similar case has been reported in the literature. Two patients with chronic phase CML permanently discontinued Omacetaxine due to elevated transaminases.
- The following adverse reactions were reported in patients in the Omacetaxine clinical studies of patients with chronic phase and accelerated phase CML at a frequency of 1% to less than 10%. Within each category, adverse reactions are ranked on the basis of frequency.
- Cardiac Disorders: tachycardia, palpitations, acute coronary syndrome, angina pectoris, arrhythmia, bradycardia, ventricular extrasystoles.
- Ear and Labyrinth Disorders: ear pain, ear hemorrhage, tinnitus.
- Eye Disorders: cataract, vision blurred, conjunctival hemorrhage, dry eye, lacrimation increased, conjunctivitis, diplopia, eye pain, eyelid edema.
- Gastrointestinal Disorders: stomatitis, mouth ulceration, abdominal distension, dyspepsia, gastroesophageal reflux disease, gingival bleeding, aphthous stomatitis, dry mouth, hemorrhoids, gastritis, gastrointestinal hemorrhage, melena, mouth hemorrhage, oral pain, anal fissure, dysphagia, gingival pain, gingivitis.
- General Disorders and Administration Site Conditions: mucosal inflammation, pain, chest pain, hyperthermia, influenza-like illness, catheter site pain, general edema, malaise.
- Immune System Disorders: hypersensitivity.
- Injury, Poisoning and Procedural Complications: contusion, transfusion reaction.
- Metabolism and Nutrition Disorders: decreased appetite, diabetes mellitus, gout, dehydration.
- Musculoskeletal and Connective Tissue Disorders: bone pain, myalgia, muscular weakness, muscle spasms, musculoskeletal chest pain, musculoskeletal pain, musculoskeletal stiffness, musculoskeletal discomfort.
- Nervous System Disorders: dizziness, cerebral hemorrhage, paresthesia, convulsion, hypoesthesia, lethargy, sciatica, burning sensation, dysgeusia, tremor.
- Psychiatric Disorders: anxiety, depression, agitation, confusional state, mental status change.
- Renal and Urinary Disorders: dysuria.
- Respiratory, Thoracic and Mediastinal Disorders: pharyngolaryngeal pain, nasal congestion, dysphonia, productive cough, rales, rhinorrhea, hemoptysis, sinus congestion.
- Skin and Subcutaneous Tissue Disorders: erythema, pruritus, dry skin, petechiae, hyperhidrosis, night sweats, ecchymosis, purpura, skin lesion, skin ulcer, rash erythematous, rash papular, skin exfoliation, skin hyperpigmentation.
- Vascular Disorders: hematoma, hypertension, hot flush, hypotension.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Omacetaxine in the drug label.
# Drug Interactions
- Based on the findings from in vitro drug interaction studies with Omacetaxine , no clinical drug interaction trials were warranted
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): D
- Based on its mechanism of action and findings from animal studies, Omacetaxine can cause fetal harm when administered to pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.
- In an embryo-fetal development study, pregnant mice were administered omacetaxine mepesuccinate subcutaneously during the period of organogenesis at doses of 0.21 or 0.41 mg/kg/day. Drug-related adverse effects included embryonic death, an increase in unossified bones/reduced bone ossification and decreased fetal body weights. Fetal toxicity occurred at doses of 0.41 mg/kg (1.23 mg/m2) which is approximately half the recommended daily human dose on a body surface area basis.
Pregnancy Category (AUS):
- There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Omacetaxine in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Omacetaxine during labor and delivery.
### Nursing Mothers
- It is not known whether omacetaxine mepesuccinate is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reaction in nursing infants, 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
- The safety and effectiveness of Omacetaxine in pediatric patients have not been established
### Geriatic Use
- In the chronic and accelerated phase CML efficacy populations 23 (30%) and 16 (46%) patients were ≥65 years of age. For the age subgroups of <65 years of age and ≥65 years of age, there were differences between the subgroups, with higher rates of major cytogenetic responses (MCyRs) in younger patients with CP CML compared with older patients (23% vs. 9%, respectively) and higher rates of major hematologic responses (MaHRs) in older patients with AP CML compared with younger patients (31% vs. 0%, respectively). Patients ≥65 years of age were more likely to experience toxicity, most notably hematologic toxicity.
### Gender
- Of the 76 patients included in the chronic phase CML population efficacy analysis, 47 (62%) of the patients were men and 29 (38%) were women. For patients with chronic phase CML, the MCyR rate in men was higher than in women (21% vs. 14%, respectively). There were differences noted in the safety profile of omacetaxine mepesuccinate in men and women with chronic phase CML although the small number of patients in each group prevents a definitive assessment. There were inadequate patient numbers in the accelerated phase subset to draw conclusions regarding a gender effect on efficacy.
### Race
There is no FDA guidance on the use of Omacetaxine with respect to specific racial populations.
### Renal Impairment
- No formal studies assessing the impact of renal impairment on the pharmacokinetics of omacetaxine mepesuccinate have been conducted.
### Hepatic Impairment
- No formal studies assessing the impact of hepatic impairment on the pharmacokinetics of omacetaxine mepesuccinate have been conducted.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Omacetaxine in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Omacetaxine in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Subcutaneous
### Monitoring
There is limited information regarding Monitoring of Omacetaxine in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Omacetaxine in the drug label.
# Overdosage
- A patient in the clinical expanded access program received an overdose of 2.5 mg/m2 twice daily for 5 days in the 16th cycle. The patient presented with gastrointestinal disorders, gingival hemorrhage, alopecia, and Grade 4 thrombocytopenia and neutropenia. When Omacetaxine treatment was temporarily interrupted the gastrointestinal disorders and hemorrhagic syndrome resolved, and neutrophil values returned to within normal range. The alopecia and thrombocytopenia (Grade 1) improved, and Omacetaxine was restarted.
- No specific antidote for Omacetaxine overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters.
There is limited information regarding Chronic Overdose of Omacetaxine in the drug label.
# Pharmacology
## Mechanism of Action
- The mechanism of action of omacetaxine mepesuccinate has not been fully elucidated but includes inhibition of protein synthesis and is independent of direct Bcr-Abl binding. Omacetaxine mepesuccinate binds to the A-site cleft in the peptidyl-transferase center of the large ribosomal subunit from a strain of archaeabacteria. In vitro, omacetaxine mepesuccinate reduced protein levels of the Bcr-Abl oncoprotein and Mcl-1, an anti-apoptotic Bcl-2 family member. Omacetaxine mepesuccinate showed activity in mouse models of wild-type and T315I mutated Bcr-Abl CML.
## Structure
- Omacetaxine contains the active ingredient omacetaxine mepesuccinate, a cephalotaxine ester. It is a protein synthesis inhibitor. Omacetaxine mepesuccinate is prepared by a semi-synthetic process from cephalotaxine, an extract from the leaves of Cephalotaxus sp. The chemical name of omacetaxine mepesuccinate is cephalotaxine, 4-methyl (2R)-hydroxyl-2-(4-hydroxyl-4-methylpentyl) butanedioate (ester).
Omacetaxine mepesuccinate has the following chemical structure:
- The molecular formula is C29H39NO9 with a molecular weight of 545.6 g/mol. Omacetaxine for Injection is a sterile, preservative-free, white to off-white, lyophilized powder in a single-use vial. Each vial contains 3.5 mg omacetaxine mepesuccinate and mannitol.
- Omacetaxine is intended for subcutaneous administration after reconstitution with 1.0 mL of 0.9% Sodium Chloride Injection, USP. The pH of the reconstituted solution is between 5.5 and 7.0.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Omacetaxine in the drug label.
## Pharmacokinetics
- The dose proportionality of omacetaxine mepesuccinate is unknown. A 90% increase in systemic exposure to omacetaxine mepesuccinate was observed between the first dose and steady state.
- The absolute bioavailability of omacetaxine mepesuccinate has not been determined. Omacetaxine mepesuccinate is absorbed following subcutaneous administration, and maximum concentrations are achieved after approximately 30 minutes.
- The steady-state (mean ± SD) volume of distribution of omacetaxine mepesuccinate is approximately 141 ± 93.4 L following subcutaneous administration of 1.25 mg/m2 twice daily for 11 days . *The plasma protein binding of omacetaxine mepesuccinate is less than or equal to 50%.
- Omacetaxine mepesuccinate is primarily hydrolyzed to 4′-DMHHT via plasma esterases with little hepatic microsomal oxidative and/or esterase-mediated metabolism in vitro.
- The major elimination route of omacetaxine mepesuccinate is unknown. The mean percentage of omacetaxine mepesuccinate excreted unchanged in the urine is less than 15%. The mean half-life of omacetaxine mepesuccinate following subcutaneous administration is approximately 6 hours.
- Cytochrome P450 Enzymes (CYPs): Omacetaxine mepesuccinate is not a substrate of CYP450 enzymes in vitro. Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit major CYPs in vitro at concentrations that can be expected clinically. The potential for omacetaxine mepesuccinate or 4′-DMHHT to induce CYP450 enzymes has not been determined.
- Transporter Systems: Omacetaxine mepesuccinate is a P-glycoprotein (P-gp) substrate in vitro. Omacetaxine mepesuccinate and 4′-DMHHT do not inhibit P-gp mediated efflux of loperamide in vitro at concentrations that can be expected clinically.
- In an uncontrolled pharmacokinetic study there were no reports of QTcF > 480 ms or ΔQTcF > 60 ms in 21 treated patients who received omacetaxine mepesuccinate 1.25 mg/m2 BID for 14 consecutive days. There was no evidence for concentration-dependent increases in QTc for omacetaxine mepesuccinate or 4’-DMHHT. Although the mean effect on QTc was 4.2 ms (upper 95% CI: 9.5 ms), QTc effects less than 10 ms cannot be verified due to the absence of a placebo and positive controls.
## Nonclinical Toxicology
- No carcinogenicity studies have been conducted with omacetaxine mepesuccinate.
- Omacetaxine mepesuccinate was genotoxic in an in vitro chromosomal aberration test system in Chinese hamster ovary (CHO) cells, but was not mutagenic when tested in an in vitro bacterial cell assay (Ames test), and it did not induce genetic damage using an in vivo mouse micronucleus assay.
- Omacetaxine may impair male fertility. Studies in mice demonstrated adverse effects on male reproductive organs. Bilateral degeneration of the seminiferous tubular epithelium in testes and hypospermia/aspermia in the epididymides were reported in the highest dose group (2.33 mg/kg/day reduced to 1.67 mg/kg/day; 7 to 5 mg/m2/day) following subcutaneous injection of omacetaxine mepesuccinate for six cycles over six months. The doses used in the mice were approximately two to three times the clinical dose (2.5 mg/m2/day) based on body surface area.
# Clinical Studies
- The efficacy of Omacetaxine was evaluated using a combined cohort of adult patients with CML from two trials. The combined cohort consisted of patients who had received 2 or more approved TKIs and had, at a minimum, documented evidence of resistance or intolerance to dasatinib and/or nilotinib. Resistance was defined as one of the following: no complete hematologic response (CHR) by 12 weeks (whether lost or never achieved); or no cytogenetic response by 24 weeks (i.e., 100% Ph positive [Ph+]) (whether lost or never achieved); or no major cytogenetic response (MCyR) by 52 weeks (i.e., ≥35% Ph+) (whether lost or never achieved); or progressive leukocytosis. Intolerance was defined as one of the following: 1) Grade 3-4 non-hematologic toxicity that does not resolve with adequate intervention; or 2) Grade 4 hematologic toxicity lasting more than 7 days; or 3) any Grade ≥ 2 toxicity that is unacceptable to the patient. Patients with NYHA class III or IV heart disease, active ischemia or other uncontrolled cardiac conditions were excluded.
- Patients were treated with omacetaxine mepesuccinate at a dose of 1.25 mg/m2 administered subcutaneously twice daily for 14 consecutive days every 28 days (induction cycle). Responding patients were then treated with the same dose and twice daily schedule for 7 consecutive days every 28 days (maintenance cycle). Patients were allowed to continue to receive maintenance treatment for up to 24 months. Responses were adjudicated by an independent Data Monitoring Committee (DMC).
- A total of 76 patients with chronic phase CML were included in the efficacy analysis. The demographics were: median age 59 years, 62% were male, 30% were 65 years of age or older, 80% were Caucasian, 5% were African-American, 4% were Asian and 4% were Hispanic. Thirty-six (47%) patients had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (54%), interferon (30%), and/or cytarabine (29%). The efficacy endpoint was based on MCyR (adjudicated by a DMC).
- The mean time to MCyR onset in the 14 patients was 3.5 months. The median duration of MCyR for the 14 patients was 12.5 months (Kaplan-Meier estimate).
- A total of 35 patients with accelerated phase CML were included in the efficacy analysis. The demographics were: median age was 63 years, 57% were male, 46% were 65 years of age or older, 68% were Caucasian, 23% were African-American, 3% were Asian and 3% were Hispanic. Twenty-two (63%) of 35 patients with accelerated phase had failed treatment with imatinib, dasatinib, and nilotinib. Most patients had also received prior non-TKI treatments, most commonly hydroxyurea (43%), interferon (31%), and/or cytarabine (29%). The efficacy endpoint was assessed based on MCyR and MaHR (complete hematologic response [CHR] or no evidence of leukemia [NEL]). The efficacy results for the patients with accelerated phase as adjudicated by the DMC
- The mean time to response onset in the 5 patients was 2.3 months. The median duration of MaHR for the 5 patients was 4.7 months (Kaplan-Meier estimate).
# How Supplied
- Omacetaxine (omacetaxine mepesuccinate) for Injection is supplied in 8 mL clear glass single-use vial in individual cartons. Each vial contains 3.5 mg of Omacetaxine (omacetaxine mepesuccinate) for Injection (NDC 63459-177-14).
## Storage
- Store unopened vials at 20oC to 25ºC (68o F to 77ºF); excursions permitted from 15ºC to 30ºC (59ºF to 86ºF) [see USP Controlled Room Temperature]. Prior to re-constitution, keep product in carton to protect from light.Omacetaxine mepesuccinate is a cytotoxic drug. Follow special handling and disposal procedures1.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
- Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide and Instructions for Use). Assist patients and caregivers in understanding their contents and give them the opportunity to discuss the contents of the Medication Guide and Instructions for Use and to obtain answers to any questions they may have prior to initiating therapy. The complete text of the Medication Guide and Instructions for Use are attached to the prescribing information.
- Once it is determined that a patient is an appropriate candidate for self-administration or administration by a caregiver, ensure that patients receive the necessary supplies for home administration of Omacetaxine and train them on the following.
- How to transport reconstituted Omacetaxine in a secure container or packaging and under recommended temperature conditions
- Acceptable storage conditions and use times for reconstituted Omacetaxine
When stored in a refrigerator (2°C to 8°C [36°F to 46°F]), use within 6 days (144 hours)
When stored at room temperature (not to exceed 25°C [77°F]), use within 12 hours
- When stored in a refrigerator (2°C to 8°C [36°F to 46°F]), use within 6 days (144 hours)
- When stored at room temperature (not to exceed 25°C [77°F]), use within 12 hours
- If stored in a refrigerator, keep Omacetaxine from coming into contact with food or drink.
- To wear disposable gloves and protective eyewear when handling Omacetaxine .
- To wash hands before putting on gloves and after removing gloves.
- Not to eat or drink while handling Omacetaxine . To administer Omacetaxine in an area away from food or food preparation areas.
- To administer Omacetaxine in a location away from children and pregnant women.
- Proper subcutaneous injection technique including acceptable sites.
- The importance of body site selection for administering the injection, as well as the importance of alternating the injection sites. Advise patients to not inject Omacetaxine into areas of the skin that are tender, red, bruised, hard, or that have scars or stretch marks.
- In the case of a missed dose: If a patient misses an injection, skip the missed dose and the patient should give the next scheduled injection at the next scheduled time. Inform patients NOT to give two injections to make up for a missed injection.
- In the case that Omacetaxine comes into contact with a patient’s skin or eyes: Advise patients to wash exposed skin with soap and water and in the case of eye exposure, thoroughly flush the eye with water. After washing or flushing, advise patients to call their healthcare provider immediately.
- In the case that too much Omacetaxine is injected or that Omacetaxine is accidentally swallowed: Instruct patients to contact their healthcare provider immediately if they have injected too much Omacetaxine , or if someone has swallowed Omacetaxine .
- Disposal procedures, including use of an appropriate biohazard container and return of the container to the clinic or pharmacy for final disposal. Inform patients NOT to recap or clip the used needle and not to place used needles, syringes, vials, and other used supplies in a household trash or recycle container.
- Accidental spillage procedures, including wiping the spilled liquid with the absorbent pad (using protective eyewear and gloves), washing the area with water and soap, and proper disposal of materials.
- Advise patients of the possibility of serious bleeding due to low platelet counts. Instruct patients to report immediately any signs or symptoms suggestive of hemorrhage (unusual bleeding, easy bruising or blood in urine or stool; confusion, slurred speech, or altered vision). Instruct patients to report in advance if they plan to have any dental or surgical procedures.
- Advise patients of the likelihood that Omacetaxine will cause a decrease in white blood cells, platelets, and red blood cells and that monitoring of these parameters will be needed. Instruct patients to contact a health care professional if they develop a fever, or other signs/symptoms of infection; shortness of breath, significant fatigue, or bleeding.
- Advise patients with diabetes of the possibility of hyperglycemia and the need for careful monitoring of blood glucose levels. Patients with poorly controlled diabetes mellitus should not be treated with omacetaxine mepesuccinate until good glycemic control has been established.
- Advise patients that omacetaxine mepesuccinate can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential hazard to the fetus and to avoid becoming pregnant. Advise females to avoid nursing while receiving Omacetaxine .
- Advise patients that they may experience nausea, diarrhea, abdominal pain, constipation, and vomiting. If these symptoms persist, they should seek medical attention.
- Advise patients that Omacetaxine may cause tiredness and to avoid driving any vehicle or operating any dangerous tools or machinery if they experience this side effect.
- Advise patients that they may experience skin rash. Advise patients to immediately report severe or worsening rash or itching.
- Advise patients that they may experience hair loss
# Precautions with Alcohol
- Alcohol-Omacetaxine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- SYNRIBO®
# Look-Alike Drug Names
There is limited information regarding Omacetaxine Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Omacetaxine | |
e6b65228754a2571c55bc9bc87d7edb0b34e9083 | wikidoc | Papaveretum | Papaveretum
# Overview
Papaveretum (BAN) is a preparation containing a mixture of hydrochloride salts of opium alkaloids. Since 1993, papaveretum has been defined in the British Pharmacopoeia (BP) as a mixture of 253 parts morphine hydrochloride, 23 parts papaverine hydrochloride, and 20 parts codeine hydrochloride. It is commonly marketed to medical agencies under the trade name Omnopon.
Although the use of papaveretum is now relatively uncommon following the wide availability of single-component opiates and synthetic opioids (e.g. pethidine) it is still used to relieve moderate to severe pain and for pre-operative sedation. In clinical settings, papaveretum is usually administered to patients via subcutaneous, intramuscular or intravenous routes. Additionally, the morphine syrettes found in combat medical kits issued to military personnel actually contain omnopon.
Prior to 1993, papaveretum also contained noscapine, though this component was removed from the BP formulation due to the genotoxic potential of noscapine. | Papaveretum
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Papaveretum (BAN) is a preparation containing a mixture of hydrochloride salts of opium alkaloids. Since 1993, papaveretum has been defined in the British Pharmacopoeia (BP) as a mixture of 253 parts morphine hydrochloride, 23 parts papaverine hydrochloride, and 20 parts codeine hydrochloride.[1] It is commonly marketed to medical agencies under the trade name Omnopon.
Although the use of papaveretum is now relatively uncommon following the wide availability of single-component opiates and synthetic opioids (e.g. pethidine) it is still used to relieve moderate to severe pain and for pre-operative sedation. In clinical settings, papaveretum is usually administered to patients via subcutaneous, intramuscular or intravenous routes. Additionally, the morphine syrettes found in combat medical kits issued to military personnel actually contain omnopon.
Prior to 1993, papaveretum also contained noscapine, though this component was removed from the BP formulation due to the genotoxic potential of noscapine. | https://www.wikidoc.org/index.php/Omnopon | |
ea62ae51cac2ab9b067db1037e62a422508194c9 | wikidoc | Oncomelania | Oncomelania
Oncomelania is a genus of very small tropical freshwater snails, aquatic gastropod mollusks in the family Pomatiopsidae.
Various Oncomelania species are significant medically, because they can serve as vectors for two serious human diseases: they can carry the schistosomiasis blood fluke parasite, and the paragonimus lung fluke parasites.
These Oncomelania snails are distantly related to the marine periwinkle, and more closely related to the small marine snails of the family Rissoidae.
# Species in the genus Oncomelania
- Oncomelania hupensis
- Oncomelania nosophora | Oncomelania
Oncomelania is a genus of very small tropical freshwater snails, aquatic gastropod mollusks in the family Pomatiopsidae.
Various Oncomelania species are significant medically, because they can serve as vectors for two serious human diseases: they can carry the schistosomiasis blood fluke parasite, and the paragonimus lung fluke parasites.
These Oncomelania snails are distantly related to the marine periwinkle, and more closely related to the small marine snails of the family Rissoidae.
# Species in the genus Oncomelania
- Oncomelania hupensis
- Oncomelania nosophora | https://www.wikidoc.org/index.php/Oncomelania | |
3236dc3155b590a45e617b48c76b2f272e0ba36a | wikidoc | Onycholysis | Onycholysis
# Overview
Onycholysis is a loosening of the exposed portion of the nail from the nail bed, usually beginning at the free edge and continuing to the lunula. It is frequently associated with an internal disorder, trauma, infection, nail fungi, allergy to nail enhancement products, or side effects of drugs.
# Pathophysiology
## Gross Pathology
Image shown below is courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
# Causes
## Common Causes
- Trauma: such as excessive manicuring.
- Infection: especially fungal.
- Skin disease: such as psoriasis and dermatitis.
- Impaired peripheral circulation such as in Raynaud's disease.
- Systemic disease: such as hyperthyroidism, hypothyroidism, reactive arthritis, porphyria cutanea tarda.
- Reactions to some detergents such as washing dishes with bare hands and using detergent-based shampoos or soaps.
- Treatment with docetaxel.
- Occurring spontaneously with an unknown cause.
## Causes in Alphabetical Order
- Alopecia areata
- Atopic dermatitis
- Benoxaprofen
- Circulatory system diseases
- Dermatitis
- Diabetes Insipidus
- Diabetes Mellitus
- Doxorubicin Hydrochloride
- Drugs
- Eczema
- Hemangioma under the nail
- Hyperthyroidism
- Hypothyroidism
- Infections
- Onychomycosis
- Porphyria Cutanea Tarda
- Psoriasis
- Raynaud's disease
- Reactive Arthritis
- Reiter's Disease
- Thyroid Disease
- Tinea unguium
- Trauma
- Tumor
- Yellow nail syndrome | Onycholysis
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Onycholysis is a loosening of the exposed portion of the nail from the nail bed, usually beginning at the free edge and continuing to the lunula. It is frequently associated with an internal disorder, trauma, infection, nail fungi, allergy to nail enhancement products, or side effects of drugs.
# Pathophysiology
## Gross Pathology
Image shown below is courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology
# Causes
## Common Causes
- Trauma: such as excessive manicuring.
- Infection: especially fungal.
- Skin disease: such as psoriasis and dermatitis.
- Impaired peripheral circulation such as in Raynaud's disease.
- Systemic disease: such as hyperthyroidism, hypothyroidism, reactive arthritis, porphyria cutanea tarda.
- Reactions to some detergents such as washing dishes with bare hands and using detergent-based shampoos or soaps.
- Treatment with docetaxel.
- Occurring spontaneously with an unknown cause.
## Causes in Alphabetical Order
- Alopecia areata
- Atopic dermatitis
- Benoxaprofen
- Circulatory system diseases
- Dermatitis
- Diabetes Insipidus
- Diabetes Mellitus
- Doxorubicin Hydrochloride
- Drugs
- Eczema
- Hemangioma under the nail
- Hyperthyroidism
- Hypothyroidism
- Infections
- Onychomycosis
- Porphyria Cutanea Tarda
- Psoriasis
- Raynaud's disease
- Reactive Arthritis
- Reiter's Disease
- Thyroid Disease
- Tinea unguium
- Trauma
- Tumor
- Yellow nail syndrome | https://www.wikidoc.org/index.php/Onycholysis | |
647f75026f17659b11f395907c80741059188385 | wikidoc | Open source | Open source
Open source is a development methodology, which offers practical accessibility to a product's source (goods and knowledge). Some consider open source as one of various possible design approaches, while others consider it a critical strategic element of their operations. Before open source became widely adopted, developers and producers used a variety of phrases to describe the concept; the term open source gained popularity with the rise of the Internet, which provided access to diverse production models, communication paths, and interactive communities.
The open source model of operation and decision making allows concurrent input of different agendas, approaches and priorities, and differs from the more closed, centralized models of development. The principles and practices are commonly applied to the development of source code for software that is made available for public collaboration, and it is usually released as open-source software.
# Society and culture
Open source culture is the creative practice of appropriation and free sharing of found and created content. Examples include collage, found footage film, music, and appropriation art. Open source culture is one in which fixations, works entitled to copyright protection, are made generally available. Participants in the culture can modify those products and redistribute them back into the community or other organizations.
The rise of open-source culture in the 20th century resulted from a growing tension between creative practices that involve appropriation, and therefore require access to content that is often copyrighted, and increasingly restrictive intellectual property laws and policies governing access to copyrighted content. The two main ways in which intellectual property laws became more restrictive in the 20th century were extensions to the term of copyright (particularly in the United States) and penalties, such as those articulated in the Digital Millennium Copyright Act (DMCA), placed on attempts to circumvent anti-piracy technologies.
Although artistic appropriation is often permitted under fair use doctrines, the complexity and ambiguity of these doctrines creates an atmosphere of uncertainty among cultural practitioners. Also, the protective actions of copyright owners create what some call a "chilling effect" among cultural practitioners.
In the late 20th century, cultural practitioners began to adopt the intellectual property licensing techniques of free software and open-source software to make their work more freely available to others, including the Creative Commons.
The idea of an "open source" culture runs parallel to "Free Culture," but is substantively different. Free culture is a term derived from the free software movement, and in contrast to that vision of culture, proponents of OSC maintain that some intellectual property law needs to exist to protect cultural producers. Yet they propose a more nuanced position than corporations have traditionally sought. Instead of seeing intellectual property law as an expression of instrumental rules intended to uphold either natural rights or desirable outcomes, an argument for OSC takes into account diverse goods (as in "the Good life") and ends.
One way of achieving the goal of making the fixations of cultural work generally available is to maximally utilize technology and digital media. As predicted by Moore's law, the cost of digital media and storage plummeted in the late 20th Century. Consequently, the marginal cost of digitally duplicating anything capable of being transmitted via digital media dropped to near zero. Combined with an explosive growth in personal computer and technology ownership, the result is an increase in general population's access to digital media. This phenomenon facilitated growth in open source culture because it allowed for rapid and inexpensive duplication and distribution of culture. Where the access to the majority of culture produced prior to the advent of digital media was limited by other constraints of proprietary and potentially "open" mediums, digital media is the latest technology with the potential to increase access to cultural products. Artists and users who choose to distribute their work digitally face none of the physical limitations that traditional cultural producers have been typically faced with. Accordingly, the audience of an open source culture faces little physical cost in acquiring digital media.
Open source culture precedes Richard Stallman's codification of the concept with the creation of the Free Software Foundation. As the public began to communicate through Bulletin Board Systems (BBS) like FidoNet, places like Sourcery Systems BBS were dedicated to providing source code to Public Domain, Shareware and Freeware programs.
Essentially born out of a desire for increased general access to digital media, the Internet is open source culture's most valuable asset. It is questionable whether the goals of an open source culture could be achieved without the Internet. The global network not only fosters an environment where culture can be generally accessible, but also allows for easy and inexpensive redistribution of culture back into various communities. Some reasons for this are as follows.
First, the Internet allows even greater access to inexpensive digital media and storage. Instead of users being limited to their own facilities and resources, they are granted access to a vast network of facilities and resources, some for free. Sites such as Archive.org offer up free web space for anyone willing to license their work under a Creative Commons license. The resulting cultural product is then available to download for free (generally accessible) to anyone with an Internet connection.
Second, users are granted unprecedented access to each other. Older analog technologies such as the telephone or television have limitations on the kind of interaction users can have. In the case of television there is little, if any interaction between users participating on the network. And in the case of the telephone, users rarely interact with any more than a couple of their known peers. On the Internet, however, users have the potential to access and meet millions of their peers. This aspect of the Internet facilitates the modification of culture as users are able to collaborate and communicate with each other across international and cultural boundaries. The speed in which digital media travels on the Internet in turn facilitates the redistribution of culture.
Through various technologies such as peer-to-peer networks and blogs, cultural producers can take advantage of vast social networks in order to distribute their products. As opposed to traditional media distribution, redistributing digital media on the Internet can be virtually costless. Technologies such as BitTorrent and Gnutella take advantage of various characteristics of the Internet protocol (TCP/IP) in an attempt to totally decentralize file distribution.
## Government
- Open source government — primarily refers to use of open source software technologies in traditional government organizations and government operations such as voting.
- Open politics (sometimes known as Open source politics) — is a term used to describe a political process that uses Internet technologies such as blogs, email and polling to provide for a rapid feedback mechanism between political organizations and their supporters. There is also an alternative conception of the term Open source politics which relates to the development of public policy under a set of rules and processes similar to the Open Source Software movement.
- Open source governance — is similar to open source politics, but it applies more to the democratic process and promotes the freedom of information.
## Ethics
Open Source ethics is split into two strands:
- Open Source Ethics as an Ethical School - Charles Ess and David Berry are researching whether ethics can learn anything from an open source approach. Ess famously even defined the AoIR Research Guidelines as an example of open source ethics.
- Open Source Ethics as a Professional Body of Rules - This is based principally on the computer ethics school, studying the questions of ethics and professionalism in the computer industry in general and software development in particular.
## Media
Open source journalism — referred to the standard journalistic techniques of news gathering and fact checking, and reflected a similar term that was in use from 1992 in military intelligence circles, open source intelligence. It is now commonly used to describe forms of innovative publishing of online journalism, rather than the sourcing of news stories by a professional journalist. In the Dec 25, 2006 issue of TIME magazine this is referred to as user created content and listed alongside more traditional open source projects such as OpenSolaris and Linux.
Weblogs, or blogs, are another significant platform for open source culture. Blogs consist of periodic, reverse chronologically ordered posts, using a technology that makes webpages easily updatable with no understanding of design, code, or file transfer required. While corporations, political campaigns and other formal institutions have begun using these tools to distribute information, many blogs are used by individuals for personal expression, political organizing, and socializing. Some, such as LiveJournal or WordPress, utilize open source software that is open to the public and can be modified by users to fit their own tastes. Whether the code is open or not, this format represents a nimble tool for people to borrow and re-present culture; whereas traditional websites made the illegal reproduction of culture difficult to regulate, the mutability of blogs makes "open sourcing" even more uncontrollable since it allows a larger portion of the population to replicate material more quickly in the public sphere.
Messageboards are another platform for open source culture. Messageboards (also known as discussion boards or forums), are places online where people with similar interests can congregate and post messages for the community to read and respond to. Messageboards sometimes have moderators who enforce community standards of etiquette such as banning users who are spammers. Other common board features are private messages (where users can send messages to one another) as well as chat (a way to have a real time conversation online) and image uploading. Some messageboards use phpBB, which is a free open source package. Where blogs are more about individual expression and tend to revolve around their authors, messageboards are about creating a conversation amongst its users where information can be shared freely and quickly. Messageboards are a way to remove intermediaries from everyday life - for instance, instead of relying on commercials and other forms of advertising, one can ask other users for frank reviews of a product, movie or CD. By removing the cultural middlemen, messageboards help speed the flow of information and exchange of ideas.
OpenDocument is an open document file format for saving and exchanging editable office documents such as text documents (including memos, reports, and books), spreadsheets, charts, and presentations. Organizations and individuals that store their data in an open format such as OpenDocument avoid being locked in to a single software vendor, leaving them free to switch software if their current vendor goes out of business, raises their prices, changes their software, or changes their licensing terms to something less favorable.
Open source movie production is either an open call system in which a changing crew and cast collaborate in movie production, a system in which the end result is made available for re-use by others or in which exclusively open source products are used in the production. The 2006 movie Elephants Dream is said to be the "world's first open movie", created entirely using open source technology.
An open source documentary film has a production process allowing the open contributions of archival material, footage, and other filmic elements, both in unedited and edited form. By doing so, on-line contributors become part of the process of creating the film, helping to influence the editorial and visual material to be used in the documentary, as well as its thematic development. The first open source documentary film to go into production "The American Revolution" ," which will examine the role that WBCN-FM in Boston played in the cultural, social and political changes locally and nationally from 1968 to 1974, is being produced by Lichtenstein Creative Media and the non-profit The Fund for Independent Media. Open Source Cinema is a website to create Basement Tapes, a feature documentary about copyright in the digital age, co-produced by the National Film Board of Canada.
Open Source Filmmaking refers to a form of filmmaking that takes a method of idea formation from open source software, but in this case the 'source' for a film maker is raw unedited footage rather than programming code. It can also refer to a method of filmmaking where the process of creation is 'open' i.e. a disparate group of contributors, at different times contribute to the final piece.
Open-IPTV is IPTV that is not limited to one recording studio, production studio, or cast. Open-IPTV uses the Internet or other means to pool efforts and resources together to create an online community that all contributes to a show.
## Education
Within the academic community, there is discussion about expanding what could be called the "intellectual commons" (analogous to the Creative Commons). Proponents of this view have hailed the Connexions Project at Rice University, OpenCourseWare project at MIT, Eugene Thacker's article on "Open Source DNA", the "Open Source Cultural Database", openwebschool, and Wikipedia as examples of applying open source outside the realm of computer software.
Open source curricula are instructional resources whose digital source can be freely used, distributed and modified.
Another strand to the academic community is in the area of research. Many funded research projects produce software as part of their work. There is an increasing interest in making the outputs of such projects available under an open source license. In the UK the Joint Information Systems Committee (JISC) has developed a policy on open source software. JISC also funds a development service called OSS Watch which acts as an advisory service for higher and further education institutions wishing to use, contribute to and develop open source software.
## Fitness
CrossFit is an open source strength and conditioning fitness movement. Its founder freely shares his methodology and publishes a website with gigabytes of data, information and interactive forums. CrossFit athletes and instructors share their modifications, adaptations and enhancements. The result has been new CrossFit "flavors" including: CrossFit for Kids, CrossFit for Seniors, CrossFit in the Park, and CrossFit for Combat Athletes. Web posts and CrossFit Journal articles often focus on how to modify the program for specific groups who have only limited access to equipment. Examples include high school track athletes and soldiers in Iraq. CrossFit athletes also post YouTube videos and invite critiques of their form.
## Innovation communities
The principle of sharing predates the open source movement; for example, the free sharing of information has been institutionalized in the scientific enterprise since at least the 19th century. Open source principles have always been part of the scientific community. The sociologist Robert K. Merton described the four basic elements of the community - universalism (an international perspective), communism (sharing information), disinterestedness (removing one's personal views from the scientific inquiry) and organized skepticism (requirements of proof and review) that accurately describe the scientific community today. These principles are, in part, complemented by US law's focus on protecting expression and method but not the ideas themselves. There is also a tradition of publishing research results to the scientific community instead of keeping all such knowledge proprietary. One of the recent initiatives in scientific publishing has been open access - the idea that research should be published in such a way that it is free and available to the public. There are currently many open access journals where the information is available for free online, however most journals do charge a fee (either to users or libraries for access). The Budapest Open Access Initiative is an international effort with the goal of making all research articles available for free on the Internet. The National Institutes of Health has recently proposed a policy on "Enhanced Public Access to NIH Research Information." This policy would provide a free, searchable resource of NIH-funded results to the public and with other international repositories six months after its initial publication. The NIH's move is an important one because there is significant amount of public funding in scientific research. Many of the questions have yet to be answered - the balancing of profit vs. public access, and ensuring that desirable standards and incentives do not diminish with a shift to open access.
Farmavita.Net - Community of Pharmaceuticals Executives have recently proposed new business model of Open Source Pharmaceuticals . The project is targeted to development and sharing of know-how for manufacture of essential and life saving medicines. It is mainly dedicated to the countries with less developed economies where local pharmaceutical research and development resources are insufficient for national needs. It will be limited to generic medicines with established use. By the definition, medicinal product have a “well-established use” if is used for at least 15 years, with recognized efficacy and an acceptable level of safety. In that event, the expensive clinical test and trial results could be replaced by appropriate scientific literature.
Benjamin Franklin was an early contributor eventually donating all his inventions including the Franklin stove, bifocals and the lightning rod to the public domain after successfully profiting off their sales and patents.
New NGO communities are starting to use the open source technology as a tool. One example is the Open Source Youth Network started in 2007 in Lisboa by ISCA members.
Open innovation is also a new emerging concept which advocate putting R&D in a common pool, the Eclipse platform is openly presenting itself as an Open innovation network
## Arts and recreation
Copyright protection is used in the performing arts and even in athletic activities. Some groups have attempted to remove copyright from such practices.
# The Open Source Definition
The Open Source Definition is used by the Open Source Initiative to determine whether or not a software license can be considered open source. The definition was based on the Debian Free Software Guidelines, written and adapted primarily by Bruce Perens.
# Proliferation of the term
While the term applied originally only to the source code of software, it is now being applied to many other areas such as open source ecology, a movement to decentralize technologies so that any human can use them. However, it is often misapplied to other areas which have different and competing principles, which overlap only partially.
Opponents of the spread of the label “open source,” including Richard Stallman, argue that the requirements and restrictions ensure the continuation of the effort, and resist attempts to redefine the labels. He argues also that most supporters of open source are actually supporters of much more equitable agreements and support re-integration of derived works and that most contributors do not intend to release their work to others who can extend it, hide the extensions, patent those very extensions, and demand royalties or restrict the use of all other users—all while not violating the open source principles with respect to the initial code they acquired.
# Perens' principles
See The Open Source Definition for the exact operational definition and examples of licenses that satisfy, and do not satisfy, those principles.
Under Perens' definition, open source describes a broad general type of software license that makes source code available to the general public with relaxed or non-existent copyright restrictions. The principles, as stated, say absolutely nothing about trademark or patent use and require absolutely no cooperation to ensure that any common audit or release regime applies to any derived works. It is an explicit “feature” of open source that it may put no restrictions on the use or distribution by any organization or user.
It forbids this, in principle, to guarantee continued access to derived works even by the major original contributors. In contrast to free software or open content licenses, which are often confused with open source but have much more rigorous rules and conventions, open source deliberately errs in favor of allowing any use by any party whatsoever, and offers few or no means or recourses to prevent a free rider problem or deal with proliferation of bad copies that mislead end users.
Perhaps because of this flexibility, which facilitates large commercial users and vendors, the most successful applications of open source have been in consortium. These use other means such as trademarks to control bad copies and require specific performance guarantees from consortium members to assure re-integration of improvements. Accordingly they do not need potentially conflicting clauses in licenses.
The loose definition has led to a proliferation of licenses that can claim to be open source but which would not satisfy the share alike provision that free software and open content licenses require. A very common license, the Creative Commons CC-by-nc-sa, requires a commercial user to acquire a separate license for-profit use. This is explicitly against the open source principles, as it discriminates against a type of use or user. However, the requirement imposed by free software to reliably redistribute derived works, does not violate these principles. Accordingly, free software and consortium licenses are a type of open source, but open content isn't insofar as it allows such restrictions.
# Non-software use
The principles of open source have been adapted for many other forms of user generated content and technology, including open source hardware.
Supporters of the open content movement advocate some restrictions of use, requirements to share changes, and attribution to other authors of the work.
This “culture” or ideology takes the view that the principles apply more generally to facilitate concurrent input of different agendas, approaches and priorities, in contrast with more centralized models of development such as those typically used in commercial companies.
Advocates of the open source principles often point to Wikipedia as an example, but Wikipedia has in fact often restricted certain types of use or user, and the GFDL license it uses makes specific requirements of all users that technically violate the open source principles.
# History
Very similar to open standards, researchers with access to the Advanced Research Projects Agency Network (ARPANET) used a process called Request for Comments to develop telecommunication network protocols. Characterized by contemporary open source work, this 1960's collaborative process led to the birth of the Internet in 1969. There are earlier instances of open source movements and free software such as IBM's source releases of its operating systems in the 1960s and the SHARE user group that formed to facilitate the exchange of such software.
The decision by some people in the free software movement to use the label “open source” came out of a strategy session held at Palo Alto, California, in reaction to Netscape's January 1998 announcement of a source code release for Navigator. The group of individuals at the session included Christine Peterson who suggested “open source”, Todd Anderson, Larry Augustin, Jon Hall, Sam Ockman, Michael Tiemann and Eric S. Raymond. They used the opportunity before the release of Navigator's source code to free themselves of the ideological and confrontational connotations of the term free software. Netscape licensed and released its code as open source under the Netscape Public License and subsequently under the Mozilla Public License.
The term was given a big boost at an event organized in April 1998 by technology publisher Tim O'Reilly. Originally titled the “Freeware Summit” and later known as the “Open Source Summit”, the event brought together the leaders of many of the most important free and open source projects, including Linus Torvalds, Larry Wall, Brian Behlendorf, Eric Allman, Guido van Rossum, Michael Tiemann, Paul Vixie, Jamie Zawinski of Netscape, and Eric Raymond. At that meeting, the confusion caused by the name “free software” was brought up. Tiemann argued for “sourceware” as a new term, while Raymond argued for “open source.” The assembled developers took a vote, and the winner was announced at a press conference that evening. Five days later, Raymond made the first public call to the free software community to adopt the new term. The Open Source Initiative was formed shortly thereafter.
The Open Source Initiative (OSI) formed in February 1998 by Raymond and Perens. With about 20 years of evidence from case histories of closed and open development already provided by the Internet, the OSI continued to present the 'open source' case to commercial businesses. They sought to bring a higher profile to the practical benefits of freely available source code, and wanted to bring major software businesses and other high-tech industries into open source. Perens adapted Debian's Free Software Guidelines to make the The Open Source Definition.
# Widely-used open source products
Open source software (OSS) projects are built and maintained by network of volunteer programmers. Prime examples of open source products are the Apache HTTP Server, the internet address system Internet Protocol, and the internet browser Mozilla Firefox. Yet, one of the most successful programs is the Linux operating system, an open source Unix-like operating system.
# Criticism
The criticisms of the specific Open_Source_Initiative (OSI) principles are dealt with above as part of the definition and differentiation from other terms. The open content movement does not recognize nor endorse the OSI principles and embraces instead mutual share-alike agreements that require derived works to be re-integrated and treated equitably, e.g. not patented or trademarked to the detriment of the individual contributors/creators.
Another criticism of the Open Source movement is that these projects may not be really as self-organizing as their proponents claim. This argument holds that successful Open Source projects frequently have a strong central manager, even if that manager is a volunteer. The article Open Source Projects Manage Themselves? Dream On. by Chuck Connell explains this viewpoint. However this is a criticism of the development model, not of the Open Source itself. Also, the author does not state that self organization surely does not work, just points to the cases when the central management was likely involved.
The legal and cultural criticisms are both addressed as part of a common set of objections and criticisms by those who prefer share-alike as an organizing principle. This includes Creative Commons which simply ignores the OSI principles and endorses licenses that clearly violate them such as CC-by-nc-sa or; Creative Commons, Attribute, Non-Commercial, Share-Alike.
Of the vocal critics Richard Stallman of the Free Software Foundation (FSF)—whose GFDL license is used by Wikipedia itself, flatly opposes the term “Open Source” being applied to what they refer to as “free software”. Although it's clear that legally free software does qualify as open source, he considers that the category is abusive. They also oppose the professed pragmatism of the Open Source Initiative, as they fear that the free software ideals of freedom and community are threatened by compromising on the FSF's idealistic standards for software freedom.
# Business models
There are a number of commonly recognized barriers to the adoption of open source software by enterprises. These barriers include the perception that open source licenses are viral, lack of formal support and training, the velocity of change, and a lack of a long term roadmap. The majority of these barriers are risk-related. From the other side, not all proprietary projects disclose exact future plans, not all open source licenses are equally viral and many serious OSS projects (especially operating systems) actually make money from paid support and documentation.
Many business models exist around open source software to provide a 'whole product' to help reduce these risks. The 'whole product' typically includes support, commercial licenses, professional services, training, certification, partner programs, references and use cases. These business models range from 'services only' organizations that do not participate in the development of the software to models where the majority of the software is created by full-time committers that are employed by a central organization. These business models have come into existence recently and their operation is not commonly understood. One model that has been developed to explain this is the Bee Keeper Model
A commonly employed Business Strategy of Commercial Open Source Software Firms is the Dual-License Strategy, as demonstrated by MySQL, Alfresco, and others. | Open source
Open source is a development methodology,[1] which offers practical accessibility to a product's source (goods and knowledge). Some consider open source as one of various possible design approaches, while others consider it a critical strategic element of their operations. Before open source became widely adopted, developers and producers used a variety of phrases to describe the concept; the term open source gained popularity with the rise of the Internet, which provided access to diverse production models, communication paths, and interactive communities.
The open source model of operation and decision making allows concurrent input of different agendas, approaches and priorities, and differs from the more closed, centralized models of development.[2] The principles and practices are commonly applied to the development of source code for software that is made available for public collaboration, and it is usually released as open-source software.
# Society and culture
Open source culture is the creative practice of appropriation and free sharing of found and created content. Examples include collage, found footage film, music, and appropriation art. Open source culture is one in which fixations, works entitled to copyright protection, are made generally available. Participants in the culture can modify those products and redistribute them back into the community or other organizations.
The rise of open-source culture in the 20th century resulted from a growing tension between creative practices that involve appropriation, and therefore require access to content that is often copyrighted, and increasingly restrictive intellectual property laws and policies governing access to copyrighted content. The two main ways in which intellectual property laws became more restrictive in the 20th century were extensions to the term of copyright (particularly in the United States) and penalties, such as those articulated in the Digital Millennium Copyright Act (DMCA), placed on attempts to circumvent anti-piracy technologies.
Although artistic appropriation is often permitted under fair use doctrines, the complexity and ambiguity of these doctrines creates an atmosphere of uncertainty among cultural practitioners. Also, the protective actions of copyright owners create what some call a "chilling effect" among cultural practitioners.
In the late 20th century, cultural practitioners began to adopt the intellectual property licensing techniques of free software and open-source software to make their work more freely available to others, including the Creative Commons.
The idea of an "open source" culture runs parallel to "Free Culture," but is substantively different. Free culture is a term derived from the free software movement, and in contrast to that vision of culture, proponents of OSC maintain that some intellectual property law needs to exist to protect cultural producers. Yet they propose a more nuanced position than corporations have traditionally sought. Instead of seeing intellectual property law as an expression of instrumental rules intended to uphold either natural rights or desirable outcomes, an argument for OSC takes into account diverse goods (as in "the Good life") and ends.
One way of achieving the goal of making the fixations of cultural work generally available is to maximally utilize technology and digital media. As predicted by Moore's law, the cost of digital media and storage plummeted in the late 20th Century. Consequently, the marginal cost of digitally duplicating anything capable of being transmitted via digital media dropped to near zero. Combined with an explosive growth in personal computer and technology ownership, the result is an increase in general population's access to digital media. This phenomenon facilitated growth in open source culture because it allowed for rapid and inexpensive duplication and distribution of culture. Where the access to the majority of culture produced prior to the advent of digital media was limited by other constraints of proprietary and potentially "open" mediums, digital media is the latest technology with the potential to increase access to cultural products. Artists and users who choose to distribute their work digitally face none of the physical limitations that traditional cultural producers have been typically faced with. Accordingly, the audience of an open source culture faces little physical cost in acquiring digital media.
Open source culture precedes Richard Stallman's codification of the concept with the creation of the Free Software Foundation. As the public began to communicate through Bulletin Board Systems (BBS) like FidoNet, places like Sourcery Systems BBS were dedicated to providing source code to Public Domain, Shareware and Freeware programs.
Essentially born out of a desire for increased general access to digital media, the Internet is open source culture's most valuable asset. It is questionable whether the goals of an open source culture could be achieved without the Internet. The global network not only fosters an environment where culture can be generally accessible, but also allows for easy and inexpensive redistribution of culture back into various communities. Some reasons for this are as follows.
First, the Internet allows even greater access to inexpensive digital media and storage. Instead of users being limited to their own facilities and resources, they are granted access to a vast network of facilities and resources, some for free. Sites such as Archive.org offer up free web space for anyone willing to license their work under a Creative Commons license. The resulting cultural product is then available to download for free (generally accessible) to anyone with an Internet connection.
Second, users are granted unprecedented access to each other. Older analog technologies such as the telephone or television have limitations on the kind of interaction users can have. In the case of television there is little, if any interaction between users participating on the network. And in the case of the telephone, users rarely interact with any more than a couple of their known peers. On the Internet, however, users have the potential to access and meet millions of their peers. This aspect of the Internet facilitates the modification of culture as users are able to collaborate and communicate with each other across international and cultural boundaries. The speed in which digital media travels on the Internet in turn facilitates the redistribution of culture.
Through various technologies such as peer-to-peer networks and blogs, cultural producers can take advantage of vast social networks in order to distribute their products. As opposed to traditional media distribution, redistributing digital media on the Internet can be virtually costless. Technologies such as BitTorrent and Gnutella take advantage of various characteristics of the Internet protocol (TCP/IP) in an attempt to totally decentralize file distribution.
## Government
- Open source government — primarily refers to use of open source software technologies in traditional government organizations and government operations such as voting.
- Open politics (sometimes known as Open source politics) — is a term used to describe a political process that uses Internet technologies such as blogs, email and polling to provide for a rapid feedback mechanism between political organizations and their supporters. There is also an alternative conception of the term Open source politics which relates to the development of public policy under a set of rules and processes similar to the Open Source Software movement.
- Open source governance — is similar to open source politics, but it applies more to the democratic process and promotes the freedom of information.
## Ethics
Open Source ethics is split into two strands:
- Open Source Ethics as an Ethical School - Charles Ess and David Berry are researching whether ethics can learn anything from an open source approach. Ess famously even defined the AoIR Research Guidelines as an example of open source ethics.[3]
- Open Source Ethics as a Professional Body of Rules - This is based principally on the computer ethics school, studying the questions of ethics and professionalism in the computer industry in general and software development in particular.[4]
## Media
Open source journalism — referred to the standard journalistic techniques of news gathering and fact checking, and reflected a similar term that was in use from 1992 in military intelligence circles, open source intelligence. It is now commonly used to describe forms of innovative publishing of online journalism, rather than the sourcing of news stories by a professional journalist. In the Dec 25, 2006 issue of TIME magazine this is referred to as user created content and listed alongside more traditional open source projects such as OpenSolaris and Linux.
Weblogs, or blogs, are another significant platform for open source culture. Blogs consist of periodic, reverse chronologically ordered posts, using a technology that makes webpages easily updatable with no understanding of design, code, or file transfer required. While corporations, political campaigns and other formal institutions have begun using these tools to distribute information, many blogs are used by individuals for personal expression, political organizing, and socializing. Some, such as LiveJournal or WordPress, utilize open source software that is open to the public and can be modified by users to fit their own tastes. Whether the code is open or not, this format represents a nimble tool for people to borrow and re-present culture; whereas traditional websites made the illegal reproduction of culture difficult to regulate, the mutability of blogs makes "open sourcing" even more uncontrollable since it allows a larger portion of the population to replicate material more quickly in the public sphere.
Messageboards are another platform for open source culture. Messageboards (also known as discussion boards or forums), are places online where people with similar interests can congregate and post messages for the community to read and respond to. Messageboards sometimes have moderators who enforce community standards of etiquette such as banning users who are spammers. Other common board features are private messages (where users can send messages to one another) as well as chat (a way to have a real time conversation online) and image uploading. Some messageboards use phpBB, which is a free open source package. Where blogs are more about individual expression and tend to revolve around their authors, messageboards are about creating a conversation amongst its users where information can be shared freely and quickly. Messageboards are a way to remove intermediaries from everyday life - for instance, instead of relying on commercials and other forms of advertising, one can ask other users for frank reviews of a product, movie or CD. By removing the cultural middlemen, messageboards help speed the flow of information and exchange of ideas.
OpenDocument is an open document file format for saving and exchanging editable office documents such as text documents (including memos, reports, and books), spreadsheets, charts, and presentations. Organizations and individuals that store their data in an open format such as OpenDocument avoid being locked in to a single software vendor, leaving them free to switch software if their current vendor goes out of business, raises their prices, changes their software, or changes their licensing terms to something less favorable.
Open source movie production is either an open call system in which a changing crew and cast collaborate in movie production, a system in which the end result is made available for re-use by others or in which exclusively open source products are used in the production. The 2006 movie Elephants Dream is said to be the "world's first open movie"[5], created entirely using open source technology.
An open source documentary film has a production process allowing the open contributions of archival material, footage, and other filmic elements, both in unedited and edited form. By doing so, on-line contributors become part of the process of creating the film, helping to influence the editorial and visual material to be used in the documentary, as well as its thematic development. The first open source documentary film to go into production "The American Revolution" [6]," which will examine the role that WBCN-FM in Boston played in the cultural, social and political changes locally and nationally from 1968 to 1974, is being produced by Lichtenstein Creative Media and the non-profit The Fund for Independent Media. Open Source Cinema is a website to create Basement Tapes, a feature documentary about copyright in the digital age, co-produced by the National Film Board of Canada.
Open Source Filmmaking refers to a form of filmmaking that takes a method of idea formation from open source software, but in this case the 'source' for a film maker is raw unedited footage rather than programming code. It can also refer to a method of filmmaking where the process of creation is 'open' i.e. a disparate group of contributors, at different times contribute to the final piece.
Open-IPTV is IPTV that is not limited to one recording studio, production studio, or cast. Open-IPTV uses the Internet or other means to pool efforts and resources together to create an online community that all contributes to a show.
## Education
Within the academic community, there is discussion about expanding what could be called the "intellectual commons" (analogous to the Creative Commons). Proponents of this view have hailed the Connexions Project at Rice University, OpenCourseWare project at MIT, Eugene Thacker's article on "Open Source DNA", the "Open Source Cultural Database", openwebschool, and Wikipedia as examples of applying open source outside the realm of computer software.
Open source curricula are instructional resources whose digital source can be freely used, distributed and modified.
Another strand to the academic community is in the area of research. Many funded research projects produce software as part of their work. There is an increasing interest in making the outputs of such projects available under an open source license. In the UK the Joint Information Systems Committee (JISC) has developed a policy on open source software. JISC also funds a development service called OSS Watch which acts as an advisory service for higher and further education institutions wishing to use, contribute to and develop open source software.
## Fitness
CrossFit is an open source strength and conditioning fitness movement. Its founder freely shares his methodology and publishes a website with gigabytes of data, information and interactive forums. CrossFit athletes and instructors share their modifications, adaptations and enhancements. The result has been new CrossFit "flavors" including: CrossFit for Kids, CrossFit for Seniors, CrossFit in the Park, and CrossFit for Combat Athletes. Web posts and CrossFit Journal articles often focus on how to modify the program for specific groups who have only limited access to equipment. Examples include high school track athletes and soldiers in Iraq. CrossFit athletes also post YouTube videos and invite critiques of their form. [7]
## Innovation communities
The principle of sharing predates the open source movement; for example, the free sharing of information has been institutionalized in the scientific enterprise since at least the 19th century. Open source principles have always been part of the scientific community. The sociologist Robert K. Merton described the four basic elements of the community - universalism (an international perspective), communism (sharing information), disinterestedness (removing one's personal views from the scientific inquiry) and organized skepticism (requirements of proof and review) that accurately describe the scientific community today. These principles are, in part, complemented by US law's focus on protecting expression and method but not the ideas themselves. There is also a tradition of publishing research results to the scientific community instead of keeping all such knowledge proprietary. One of the recent initiatives in scientific publishing has been open access - the idea that research should be published in such a way that it is free and available to the public. There are currently many open access journals where the information is available for free online, however most journals do charge a fee (either to users or libraries for access). The Budapest Open Access Initiative is an international effort with the goal of making all research articles available for free on the Internet. The National Institutes of Health has recently proposed a policy on "Enhanced Public Access to NIH Research Information." This policy would provide a free, searchable resource of NIH-funded results to the public and with other international repositories six months after its initial publication. The NIH's move is an important one because there is significant amount of public funding in scientific research. Many of the questions have yet to be answered - the balancing of profit vs. public access, and ensuring that desirable standards and incentives do not diminish with a shift to open access.
Farmavita.Net - Community of Pharmaceuticals Executives have recently proposed new business model of Open Source Pharmaceuticals [8]. The project is targeted to development and sharing of know-how for manufacture of essential and life saving medicines. It is mainly dedicated to the countries with less developed economies where local pharmaceutical research and development resources are insufficient for national needs. It will be limited to generic medicines with established use. By the definition, medicinal product have a “well-established use” if is used for at least 15 years, with recognized efficacy and an acceptable level of safety. In that event, the expensive clinical test and trial results could be replaced by appropriate scientific literature.
Benjamin Franklin was an early contributor eventually donating all his inventions including the Franklin stove, bifocals and the lightning rod to the public domain after successfully profiting off their sales and patents.
New NGO communities are starting to use the open source technology as a tool. One example is the Open Source Youth Network started in 2007 in Lisboa by ISCA members[9].
Open innovation is also a new emerging concept which advocate putting R&D in a common pool, the Eclipse platform is openly presenting itself as an Open innovation network [10]
## Arts and recreation
Copyright protection is used in the performing arts and even in athletic activities. Some groups have attempted to remove copyright from such practices.[11]
# The Open Source Definition
The Open Source Definition is used by the Open Source Initiative to determine whether or not a software license can be considered open source. The definition was based on the Debian Free Software Guidelines, written and adapted primarily by Bruce Perens.[12]
# Proliferation of the term
While the term applied originally only to the source code of software,[13] it is now being applied to many other areas such as open source ecology, a movement to decentralize technologies so that any human can use them. However, it is often misapplied to other areas which have different and competing principles, which overlap only partially.
Opponents of the spread of the label “open source,” including Richard Stallman, argue that the requirements and restrictions ensure the continuation of the effort, and resist attempts to redefine the labels. He argues also that most supporters of open source are actually supporters of much more equitable agreements and support re-integration of derived works and that most contributors do not intend to release their work to others who can extend it, hide the extensions, patent those very extensions, and demand royalties or restrict the use of all other users—all while not violating the open source principles with respect to the initial code they acquired.
# Perens' principles
See The Open Source Definition for the exact operational definition and examples of licenses that satisfy, and do not satisfy, those principles.
Under Perens' definition, open source describes a broad general type of software license that makes source code available to the general public with relaxed or non-existent copyright restrictions. The principles, as stated, say absolutely nothing about trademark or patent use and require absolutely no cooperation to ensure that any common audit or release regime applies to any derived works. It is an explicit “feature” of open source that it may put no restrictions on the use or distribution by any organization or user.
It forbids this, in principle, to guarantee continued access to derived works even by the major original contributors. In contrast to free software or open content licenses, which are often confused with open source but have much more rigorous rules and conventions, open source deliberately errs in favor of allowing any use by any party whatsoever, and offers few or no means or recourses to prevent a free rider problem or deal with proliferation of bad copies that mislead end users.
Perhaps because of this flexibility, which facilitates large commercial users and vendors, the most successful applications of open source have been in consortium. These use other means such as trademarks to control bad copies and require specific performance guarantees from consortium members to assure re-integration of improvements. Accordingly they do not need potentially conflicting clauses in licenses.
The loose definition has led to a proliferation of licenses that can claim to be open source but which would not satisfy the share alike provision that free software and open content licenses require. A very common license, the Creative Commons CC-by-nc-sa, requires a commercial user to acquire a separate license for-profit use. This is explicitly against the open source principles, as it discriminates against a type of use or user. However, the requirement imposed by free software to reliably redistribute derived works, does not violate these principles. Accordingly, free software and consortium licenses are a type of open source, but open content isn't insofar as it allows such restrictions.
# Non-software use
The principles of open source have been adapted for many other forms of user generated content and technology, including open source hardware.
Supporters of the open content movement advocate some restrictions of use, requirements to share changes, and attribution to other authors of the work.
This “culture” or ideology takes the view that the principles apply more generally to facilitate concurrent input of different agendas, approaches and priorities, in contrast with more centralized models of development such as those typically used in commercial companies.[14]
Advocates of the open source principles often point to Wikipedia as an example, but Wikipedia has in fact often restricted certain types of use or user, and the GFDL license it uses makes specific requirements of all users that technically violate the open source principles.
# History
Very similar to open standards, researchers with access to the Advanced Research Projects Agency Network (ARPANET) used a process called Request for Comments to develop telecommunication network protocols. Characterized by contemporary open source work, this 1960's collaborative process led to the birth of the Internet in 1969. There are earlier instances of open source movements and free software such as IBM's source releases of its operating systems in the 1960s and the SHARE user group that formed to facilitate the exchange of such software.
The decision by some people in the free software movement to use the label “open source” came out of a strategy session[15] held at Palo Alto, California, in reaction to Netscape's January 1998 announcement of a source code release for Navigator. The group of individuals at the session included Christine Peterson who suggested “open source”, Todd Anderson, Larry Augustin, Jon Hall, Sam Ockman, Michael Tiemann and Eric S. Raymond. They used the opportunity before the release of Navigator's source code to free themselves of the ideological and confrontational connotations of the term free software. Netscape licensed and released its code as open source under the Netscape Public License and subsequently under the Mozilla Public License.[16]
The term was given a big boost at an event organized in April 1998 by technology publisher Tim O'Reilly. Originally titled the “Freeware Summit” and later known as the “Open Source Summit”,[17] the event brought together the leaders of many of the most important free and open source projects, including Linus Torvalds, Larry Wall, Brian Behlendorf, Eric Allman, Guido van Rossum, Michael Tiemann, Paul Vixie, Jamie Zawinski of Netscape, and Eric Raymond. At that meeting, the confusion caused by the name “free software” was brought up. Tiemann argued for “sourceware” as a new term, while Raymond argued for “open source.” The assembled developers took a vote, and the winner was announced at a press conference that evening. Five days later, Raymond made the first public call to the free software community to adopt the new term.[18] The Open Source Initiative was formed shortly thereafter.[19]
The Open Source Initiative (OSI) formed in February 1998 by Raymond and Perens. With about 20 years of evidence from case histories of closed and open development already provided by the Internet, the OSI continued to present the 'open source' case to commercial businesses. They sought to bring a higher profile to the practical benefits of freely available source code, and wanted to bring major software businesses and other high-tech industries into open source. Perens adapted Debian's Free Software Guidelines to make the The Open Source Definition.[20]
# Widely-used open source products
Open source software (OSS) projects are built and maintained by network of volunteer programmers. Prime examples of open source products are the Apache HTTP Server, the internet address system Internet Protocol, and the internet browser Mozilla Firefox. Yet, one of the most successful programs is the Linux operating system, an open source Unix-like operating system.[21][22]
# Criticism
Template:Refimprovesect
The criticisms of the specific Open_Source_Initiative (OSI) principles are dealt with above as part of the definition and differentiation from other terms. The open content movement does not recognize nor endorse the OSI principles and embraces instead mutual share-alike agreements that require derived works to be re-integrated and treated equitably, e.g. not patented or trademarked to the detriment of the individual contributors/creators.
Another criticism of the Open Source movement is that these projects may not be really as self-organizing as their proponents claim. This argument holds that successful Open Source projects frequently have a strong central manager, even if that manager is a volunteer. The article Open Source Projects Manage Themselves? Dream On. by Chuck Connell explains this viewpoint. However this is a criticism of the development model, not of the Open Source itself. Also, the author does not state that self organization surely does not work, just points to the cases when the central management was likely involved.
The legal and cultural criticisms are both addressed as part of a common set of objections and criticisms by those who prefer share-alike as an organizing principle. This includes Creative Commons which simply ignores the OSI principles and endorses licenses that clearly violate them such as CC-by-nc-sa or; Creative Commons, Attribute, Non-Commercial, Share-Alike.
Of the vocal critics Richard Stallman of the Free Software Foundation (FSF)—whose GFDL license is used by Wikipedia itself, flatly opposes the term “Open Source” being applied to what they refer to as “free software”. Although it's clear that legally free software does qualify as open source, he considers that the category is abusive. [23] They also oppose the professed pragmatism of the Open Source Initiative, as they fear that the free software ideals of freedom and community are threatened by compromising on the FSF's idealistic standards for software freedom.[24][25]
# Business models
There are a number of commonly recognized barriers to the adoption of open source software by enterprises. These barriers include the perception that open source licenses are viral, lack of formal support and training, the velocity of change, and a lack of a long term roadmap. The majority of these barriers are risk-related. From the other side, not all proprietary projects disclose exact future plans, not all open source licenses are equally viral and many serious OSS projects (especially operating systems) actually make money from paid support and documentation.
Many business models exist around open source software to provide a 'whole product' to help reduce these risks. The 'whole product' typically includes support, commercial licenses, professional services, training, certification, partner programs, references and use cases. These business models range from 'services only' organizations that do not participate in the development of the software to models where the majority of the software is created by full-time committers that are employed by a central organization. These business models have come into existence recently and their operation is not commonly understood. One model that has been developed to explain this is the Bee Keeper Model
A commonly employed Business Strategy of Commercial Open Source Software Firms is the Dual-License Strategy, as demonstrated by MySQL, Alfresco, and others. | https://www.wikidoc.org/index.php/Open_source | |
942fff3028f55a1930e053f867c1617860a1f50d | wikidoc | Opium poppy | Opium poppy
# Overview
The opium poppy, Papaver somniferum, is the type of poppy from which opium and many refined opiates such as morphine, thebaine, codeine, papaverine, and noscapine are extracted. The binomial name means, loosely, the "sleep-bringing poppy", referring to its narcotic properties. The seeds are important food items, and contain healthy oils used in salads worldwide. The plant itself is valuable for ornamental purposes.
# Varieties
Papaver somniferum is a species of plant with many sub-groups or varieties. Colors of the flower vary widely, as do other physical characteristics such as number and shape of petals, number of pods, production of morphine, etc.
Papaver somniferum Paeoniflorum Group (sometimes called Papaver paeoniflorum) is a sub-type of opium poppy whose flowers are highly double, and are grown in many colors. Papaver somniferum Laciniatum Group (sometimes called Papaver laciniatum) is a sub-type of opium poppy whose flowers are highly double and deeply lobed, to the point of looking like a ruffly pompon.
A few of the varieties, notably the "Norman" and "Przemko" varieties, have "low morphine" content (less than one percent), making them markedly less useful for drug production. Most varieties, however, including those most popular for ornamental use or seed production, have a higher morphine content.
# Legality
In the United States, opium is listed as a Schedule II controlled substance by the Drug Enforcement Administration. In addition, "Opium poppy and poppy straw" are also prohibited. However, this is not typically enforced for poppies grown or sold for ornamental or food purposes.
Opium poppy cultivation in the United Kingdom does not need a license, however, a license is required for those wishing to extract opium for medicinal products.
# Use as food
The seeds of the poppy are widely used as the popular "poppy seed" found in and on many food items such as bagels, bialys, muffins and cakes. The seeds can be pressed to form poppyseed oil, which can be used in cooking, or as a carrier for oil-based paints. The primary flavor compound is 2-pentylfuran.
Although the amount of opiates in poppy seeds is not enough to produce a narcotic effect in cooking or consumption, the television show MythBusters demonstrated that one could test positive for narcotics after consuming 4 poppy seed bagels. The show Brainiac: Science Abuse had subjects that tested positive with only 2 poppy seed bagels. This situation was parodied on the show Seinfeld.
In India, Iran and Turkey opium poppy is known as Khaskhas or Haşhaş (pronounced: "Hashhash" or in Persian: "Khash Khaash") and is considered a highly nutritious food item, mostly added in dough while baking bread, highly recommended for pregnant women and new mothers.
In Lithuania and Eastern Slovakia a traditional meal is prepared for the Kūčios (Christmas Eve) dinner from the poppy seeds. They are ground and mixed with water; round yeast biscuits (kūčiukai) (slovak - Bobalky) are soaked in the resulting poppy seed 'milk' and served cold.
In Hungary poppy strudel and traditional bejgli is very popular in winter, especially during Christmas.
# Poppies as medicine
In both India and Turkey, opium production is used for medicinal purposes, making poppy-based drugs, such as morphine or codeine, for domestic use or exporting raw poppy materials to other countries. The United States buys 80 percent of its medicinal opium from these two countries. However, there is an acute global shortage of opium poppy-based medicines some of which (morphine) are on the World Health Organisation's list of essential drugs as they are the most effective way of relieving severe pain. A recent initiative to extend opium production for medicinal purposes called Poppy for Medicine was launched by The Senlis Council which thinks that Afghanistan could produce medicinal opium under a scheme similar to that operating in Turkey and India (see the Council's recent report "Poppy for Medicine" ). The Council proposes licensing poppy production in Afghanistan, within an integrated control system supported by the Afghan government and its international allies, in order to promote economic growth in the country, create vital drugs and combat poverty and the diversion of illegal opium to drug traffickers and terrorist elements. With poppy for medicine projects, opium poppy can be used as a valuable resource.
The British] government has given the go ahead to the pharmaceutical company Macfarlan Smith (a Johnson Matthey company) to cultivate opium poppies in England for medicinal reasons. This move is well received by British farmers, with a major opium poppy field based in Didcot, England.
# Ornamental cultivation
Many seed companies and nurseries grow and sell live plants and seeds in many highly beautiful variations. They are also sold dried for dried flower arrangements. This is technically illegal in the United States, but this is not generally enforced unless the plants are being sold for drug production.
Many countries grow the plants; some of which rely heavily on the commercial production of the drug as a major source of income. As an additional source of profit, the same seeds are sold in the culinary trade shortly thereafter, making cultivation of the plant a significant source of income. This international trade in seeds of Papaver somniferum was addressed by a UN resolution "to fight the international trade in illicit opium poppy seeds" on July 28, 1998.
# History
Use of the opium poppy predates written history. Images of opium poppies have been found in ancient Sumerian artifacts (ca. 4000 BC)(southwest of modern Iran). The opium poppy was also known to the ancient Greeks, from whom it gained its modern name of Opium. In historic contexts from Greece remains have been discovered in proto-geometric contexts at sites such as kalapodi and Kastanas.
Opium was used for treating asthma, stomach illnesses, and bad eye sight. The Opium Wars between China and the British Empire took place in the late 1830s when the Chinese attempted to stop the sale of opium by Britain, in China.
Many modern writers, particularly in the nineteenth century, have written on the opium poppy and its effects, notably L. Frank Baum with The Wonderful Wizard of Oz, and Thomas de Quincey's Confessions of an English Opium Eater
The French Romantic composer Hector Berlioz used an opium hallucination for the program of his Symphonie Fantastique. In this work, a young artist overdoses on opium and experiences a series of visions of his unrequited love.
# Sources and notes
## Inline citations
- ↑ Jump up to: 1.0 1.1 1.2 "Poppy law" on Erowid.org
- ↑ How potent are the major culinary (spicerack) varieties such as McCormick? from poppies.org
- ↑ dea.gov
- ↑ Making opium tea
- ↑ Poppy tea information on Erowid.org
- ↑ The painkilling fields: England's opium poppies that tackle the NHS morphine crisis, Press release, 2007-15-09.
- ↑ Yiu H. Hui, Handbook of Food Science, Technology, and Engineering. CRC Press 2006. ISBN 0849398487
- ↑ Review of undertakings by Macfarlan Smith Limited
- ↑ Jump up to: 9.0 9.1 History at Poppies International
## General references
- The Heroin Harvest
- Comprehensive profile for Papaver somniferum from MaltaWildPlants.com
- Opium FAQ v1.0 from Opioids.com
- Opium Poppy Cultivation and Heroin Processing in Southeast Asia from the School of Pacific and Asian Studies DEAD LINK
## Photos
- The Papaver somniferum Photo Gallery
- Photos of opium poppies on www.geopium.org
- Opium Poppy fields of North Tasmania | Opium poppy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The opium poppy, Papaver somniferum, is the type of poppy from which opium and many refined opiates such as morphine, thebaine, codeine, papaverine, and noscapine are extracted. The binomial name means, loosely, the "sleep-bringing poppy", referring to its narcotic properties. The seeds are important food items, and contain healthy oils used in salads worldwide. The plant itself is valuable for ornamental purposes.
# Varieties
Papaver somniferum is a species of plant with many sub-groups or varieties. Colors of the flower vary widely, as do other physical characteristics such as number and shape of petals, number of pods, production of morphine, etc.
Papaver somniferum Paeoniflorum Group (sometimes called Papaver paeoniflorum) is a sub-type of opium poppy whose flowers are highly double, and are grown in many colors. Papaver somniferum Laciniatum Group (sometimes called Papaver laciniatum) is a sub-type of opium poppy whose flowers are highly double and deeply lobed, to the point of looking like a ruffly pompon.
A few of the varieties, notably the "Norman" and "Przemko" varieties, have "low morphine" content (less than one percent), making them markedly less useful for drug production. Most varieties, however, including those most popular for ornamental use or seed production, have a higher morphine content.[1][2]
# Legality
In the United States, opium is listed as a Schedule II controlled substance by the Drug Enforcement Administration. In addition, "Opium poppy and poppy straw" are also prohibited.[3] However, this is not typically enforced for poppies grown or sold for ornamental or food purposes.[4][5]
Opium poppy cultivation in the United Kingdom does not need a license, however, a license is required for those wishing to extract opium for medicinal products.[6]
# Use as food
The seeds of the poppy are widely used as the popular "poppy seed" found in and on many food items such as bagels, bialys, muffins and cakes. The seeds can be pressed to form poppyseed oil, which can be used in cooking, or as a carrier for oil-based paints. The primary flavor compound is 2-pentylfuran.[7]
Although the amount of opiates in poppy seeds is not enough to produce a narcotic effect in cooking or consumption,[1] the television show MythBusters demonstrated that one could test positive for narcotics after consuming 4 poppy seed bagels. The show Brainiac: Science Abuse had subjects that tested positive with only 2 poppy seed bagels. This situation was parodied on the show Seinfeld.
In India, Iran and Turkey opium poppy is known as Khaskhas or Haşhaş (pronounced: "Hashhash" or in Persian: "Khash Khaash") and is considered a highly nutritious food item, mostly added in dough while baking bread, highly recommended for pregnant women and new mothers.
In Lithuania and Eastern Slovakia a traditional meal is prepared for the Kūčios (Christmas Eve) dinner from the poppy seeds. They are ground and mixed with water; round yeast biscuits (kūčiukai) (slovak - Bobalky) are soaked in the resulting poppy seed 'milk' and served cold.
In Hungary poppy strudel and traditional bejgli is very popular in winter, especially during Christmas.
# Poppies as medicine
In both India and Turkey, opium production is used for medicinal purposes, making poppy-based drugs, such as morphine or codeine, for domestic use or exporting raw poppy materials to other countries. The United States buys 80 percent of its medicinal opium from these two countries. However, there is an acute global shortage of opium poppy-based medicines some of which (morphine) are on the World Health Organisation's list of essential drugs as they are the most effective way of relieving severe pain. A recent initiative to extend opium production for medicinal purposes called Poppy for Medicine was launched by The Senlis Council which thinks that Afghanistan could produce medicinal opium under a scheme similar to that operating in Turkey and India (see the Council's recent report "Poppy for Medicine" [2]). The Council proposes licensing poppy production in Afghanistan, within an integrated control system supported by the Afghan government and its international allies, in order to promote economic growth in the country, create vital drugs and combat poverty and the diversion of illegal opium to drug traffickers and terrorist elements. With poppy for medicine projects, opium poppy can be used as a valuable resource.
The British] government has given the go ahead to the pharmaceutical company Macfarlan Smith (a Johnson Matthey company) to cultivate opium poppies in England for medicinal reasons. This move is well received by British farmers, with a major opium poppy field based in Didcot, England. [8]
# Ornamental cultivation
Many seed companies and nurseries grow and sell live plants and seeds in many highly beautiful variations. They are also sold dried for dried flower arrangements. This is technically illegal in the United States, but this is not generally enforced unless the plants are being sold for drug production.[1]
Many countries grow the plants; some of which rely heavily on the commercial production of the drug as a major source of income. As an additional source of profit, the same seeds are sold in the culinary trade shortly thereafter, making cultivation of the plant a significant source of income. This international trade in seeds of Papaver somniferum was addressed by a UN resolution "to fight the international trade in illicit opium poppy seeds" on July 28, 1998.
# History
Use of the opium poppy predates written history. Images of opium poppies have been found in ancient Sumerian artifacts (ca. 4000 BC)(southwest of modern Iran). The opium poppy was also known to the ancient Greeks, from whom it gained its modern name of Opium. In historic contexts from Greece remains have been discovered in proto-geometric contexts at sites such as kalapodi and Kastanas.[9]
Opium was used for treating asthma, stomach illnesses, and bad eye sight. The Opium Wars between China and the British Empire took place in the late 1830s when the Chinese attempted to stop the sale of opium by Britain, in China.[9]
Many modern writers, particularly in the nineteenth century, have written on the opium poppy and its effects, notably L. Frank Baum with The Wonderful Wizard of Oz, and Thomas de Quincey's Confessions of an English Opium Eater
The French Romantic composer Hector Berlioz used an opium hallucination for the program of his Symphonie Fantastique. In this work, a young artist overdoses on opium and experiences a series of visions of his unrequited love.
# Sources and notes
## Inline citations
- ↑ Jump up to: 1.0 1.1 1.2 "Poppy law" on Erowid.org
- ↑ How potent are the major culinary (spicerack) varieties such as McCormick? from poppies.org
- ↑ dea.gov
- ↑ Making opium tea
- ↑ Poppy tea information on Erowid.org
- ↑ The painkilling fields: England's opium poppies that tackle the NHS morphine crisis, Press release, 2007-15-09.
- ↑ Yiu H. Hui, Handbook of Food Science, Technology, and Engineering. CRC Press 2006. ISBN 0849398487
- ↑ Review of undertakings by Macfarlan Smith Limited
- ↑ Jump up to: 9.0 9.1 History at Poppies International
## General references
- The Heroin Harvest
- Comprehensive profile for Papaver somniferum from MaltaWildPlants.com
- Opium FAQ v1.0 from Opioids.com
- Opium Poppy Cultivation and Heroin Processing in Southeast Asia from the School of Pacific and Asian Studies DEAD LINK
## Photos
- The Papaver somniferum Photo Gallery
- Photos of opium poppies on www.geopium.org
- Opium Poppy fields of North Tasmania
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Opium_poppy | |
6857d574b716ed47bd9de6a2e52049aabe79ff23 | wikidoc | Optic tract | Optic tract
# Overview
The optic tract is a part of the visual system in the brain.
It is a continuation of the optic nerve and runs from the optic chiasm (where half of the information from each eye crosses sides, and half stays on the same side) to the lateral geniculate nucleus.
# Right vs. left
The relationships of the retinal fibers to the optic tracts are as follows:
# Pathology
A lesion in the left optic tract will cause right-sided homonomous hemianopsia.
# Additional images
- Diagram of hippocampus
- Schematic diagram of the primate lateral geniculate nucleus.
- Superficial dissection of brain-stem. Ventral view.
- Coronal section of brain through intermediate mass of third ventricle.
- Hind- and mid-brains; postero-lateral view.
- Scheme showing central connections of the optic nerves and optic tracts.
- Base of brain.
- Section of brain showing upper surface of temporal lobe.
- Dissection showing the course of the cerebrospinal fibers.
it:Tratto ottico | Optic tract
Template:Infobox Brain
# Overview
The optic tract is a part of the visual system in the brain.
It is a continuation of the optic nerve and runs from the optic chiasm (where half of the information from each eye crosses sides, and half stays on the same side) to the lateral geniculate nucleus.
# Right vs. left
The relationships of the retinal fibers to the optic tracts are as follows:
# Pathology
A lesion in the left optic tract will cause right-sided homonomous hemianopsia.
# Additional images
- Diagram of hippocampus
- Schematic diagram of the primate lateral geniculate nucleus.
- Superficial dissection of brain-stem. Ventral view.
- Coronal section of brain through intermediate mass of third ventricle.
- Hind- and mid-brains; postero-lateral view.
- Scheme showing central connections of the optic nerves and optic tracts.
- Base of brain.
- Section of brain showing upper surface of temporal lobe.
- Dissection showing the course of the cerebrospinal fibers.
Template:Visual system
Template:Sensory system
Template:Neuroscience-stub
it:Tratto ottico
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Optic_tract | |
415d6d3b6a723e5a69be3f15f46ed139b5306a53 | wikidoc | Oral mucosa | Oral mucosa
# Overview
The oral mucosa is the mucous membrane epithelium of the mouth. It can be divided into three categories.
- Masticatory mucosa - keratinized stratified squamous epithelium, found on the dorsum of the tongue, hard palate and attached gingiva.
- Lining mucosa - non-keratinized stratified squamous epithelium, found almost everywhere else in the oral cavity.
- Specialized mucosa - specifically in the regions of the taste buds on the dorsum of the tongue. | Oral mucosa
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
Template:Infobox Anatomy
The oral mucosa is the mucous membrane epithelium of the mouth. It can be divided into three categories.
- Masticatory mucosa - keratinized stratified squamous epithelium, found on the dorsum of the tongue, hard palate and attached gingiva.
- Lining mucosa - non-keratinized stratified squamous epithelium, found almost everywhere else in the oral cavity.
- Specialized mucosa - specifically in the regions of the taste buds on the dorsum of the tongue.
# External links
- Histology image: 09601loa – Histology Learning System at Boston University - "Digestive System: Oral Cavity and Teeth - lip, oral mucosa"
- Template:OklahomaHistology - "Lip"
- Template:OklahomaHistology - "Lip"
Template:Oral pathology
Template:WH
Template:WikiDoc Sources | https://www.wikidoc.org/index.php/Oral_mucosa | |
30be153e56d9b74e78b84671bcf5ed726a56123c | wikidoc | Organ trade | Organ trade
Organ trade is the trade involving human organs for transplantation. It is a business driven by the simple market calculus of supply and demand. General belief is that there is a worldwide shortage of organs available for transplantion. However, considering the predictions of economic theory and analysis of empirical data, the shortages are believed to be the result of government restrictions upon organ trade.
# Legal organ trade
In the 1970s pharmaceuticals that prevent organ rejection were introduced. This along with a lack of medical regulation helped foster the organ market. Living donor procedures include kidney, liver, cornea and lung transplants. Most organ trade involves kidney or liver transplants.
Before legislation passed in 1994, India had a successful legal market in organ trading. Low cost and availability brought in business from around the globe and transformed India into one of the largest kidney transplant centers in the world. Several problems began surfacing during the period of legal organ trade in India. In some cases patients were unaware a kidney transplant procedure even took place. Other problems included patients being promised an amount much higher than what was actually paid out. Ethical issues surrounding contribution donating pushed the Indian government to pass legislation banning the sale of organs.
In China, organs are often procured from executed prisoners. Nicholas Bequelin, a researcher for Human Rights Watch, estimated that 90 percent of organs from China are from deceased prisoners. China still suffers a shortage of organs for transplant even with more lax regulation.The Chinese government, after receiving severe scrutiny from the rest of the world, has passed legislation ending the legal sale of organs. However, no legislation currently prohibits the collection of organs from deceased inmates who sign agreements before execution.
In Iran the practice of selling one's kidney for profit is legal. Iran currently has no wait lists for Kidney transplantation. Kidney sales are legal and regulated. The Charity Association for the Support of Kidney Patients (CASKP) and the Charity Foundation for Special Diseases (CFSD) control the trade of organs with the support of the government. The organizations match donors to recipients, setting up tests to ensure compatibility. The amounts paid to the donor vary in Iran but the average figures are $5000-$6000 for kidney donation. Employment opportunities are also offered in some cases. This legal trade has not been complication free but it has eliminated the waiting list for kidneys in Iran.
# Illegal organ trade
Poverty and loopholes in legislation contribute to the illegal trade of organs. Poverty is seen in all countries with a large black market for organs. This, however, is not the only factor affecting the flourishing illegal markets. Some of the poorest countries in the world do not have organ trade. Legislation is another contributing factor in the organ black market. In Jordan, organ trade is illegal but in many cases organ donors are brought into Iran from Jordan to perform procedures. India’s Transplantation of Human Organs Act (THOA) requires that an organ donor must be a relative, spouse, or donating for reasons of “affection”. No monetary transactions for organs are legal in India currently but there are no laws concerning funds given to a spouse. The spousal inclusion provides a loophole for illegal trade; in some cases contribution donors simply marry the recipient to avoid legal penalty.
Illegal goods are often high priced and unstable in the black market. The amount a donor would receive for a kidney ranges from $800 to $10,000 or more. Liver donors see similar returns. Many economists encourage the creation of legal framework to allow organ trade not only to eliminate the organ shortage but also to help dissolve the corrupt illegal market.
# Economics
The illegal status of organ trade creates a price ceiling for organs at zero dollars. This price ceiling affects supply and demand creating a shortage.
In theory the elimination of the price ceiling would eliminate the shortage. It is estimated that in America, if 0.06% of individuals aged 18-65 donated a kidney that the waiting list for organs would be fulfilled. Currently with little incentives to donate an organ approximately 6,000 people die yearly waiting for a transplant organ. For every individual taken off the waiting list two more are added. The regulation of organ trade could solve the organ shortage and create safer and fair practices for donors. | Organ trade
Organ trade is the trade involving human organs for transplantation. It is a business driven by the simple market calculus of supply and demand. General belief is that there is a worldwide shortage of organs available for transplantion.[1] However, considering the predictions of economic theory and analysis of empirical data, the shortages are believed to be the result of government restrictions upon organ trade.[2]
# Legal organ trade
In the 1970s pharmaceuticals that prevent organ rejection were introduced. This along with a lack of medical regulation helped foster the organ market. Living donor procedures include kidney, liver, cornea and lung transplants. Most organ trade involves kidney or liver transplants.
Before legislation passed in 1994, India had a successful legal market in organ trading. Low cost and availability brought in business from around the globe and transformed India into one of the largest kidney transplant centers in the world.[3] Several problems began surfacing during the period of legal organ trade in India. In some cases patients were unaware a kidney transplant procedure even took place.[4] Other problems included patients being promised an amount much higher than what was actually paid out.[5] Ethical issues surrounding contribution donating pushed the Indian government to pass legislation banning the sale of organs.[6]
In China, organs are often procured from executed prisoners. Nicholas Bequelin, a researcher for Human Rights Watch, estimated that 90 percent of organs from China are from deceased prisoners.[7] China still suffers a shortage of organs for transplant even with more lax regulation.The Chinese government, after receiving severe scrutiny from the rest of the world, has passed legislation ending the legal sale of organs. However, no legislation currently prohibits the collection of organs from deceased inmates who sign agreements before execution.
In Iran the practice of selling one's kidney for profit is legal. Iran currently has no wait lists for Kidney transplantation.[8] Kidney sales are legal and regulated. The Charity Association for the Support of Kidney Patients (CASKP) and the Charity Foundation for Special Diseases (CFSD) control the trade of organs with the support of the government. The organizations match donors to recipients, setting up tests to ensure compatibility. The amounts paid to the donor vary in Iran but the average figures are $5000-$6000 for kidney donation. Employment opportunities are also offered in some cases. This legal trade has not been complication free but it has eliminated the waiting list for kidneys in Iran.
# Illegal organ trade
Poverty and loopholes in legislation contribute to the illegal trade of organs.[9] Poverty is seen in all countries with a large black market for organs. This, however, is not the only factor affecting the flourishing illegal markets. Some of the poorest countries in the world do not have organ trade. Legislation is another contributing factor in the organ black market. In Jordan, organ trade is illegal but in many cases organ donors are brought into Iran from Jordan to perform procedures.[10] India’s Transplantation of Human Organs Act (THOA) requires that an organ donor must be a relative, spouse, or donating for reasons of “affection”. No monetary transactions for organs are legal in India currently but there are no laws concerning funds given to a spouse. The spousal inclusion provides a loophole for illegal trade; in some cases contribution donors simply marry the recipient to avoid legal penalty.[11]
Illegal goods are often high priced and unstable in the black market.[12] The amount a donor would receive for a kidney ranges from $800 to $10,000 or more.[13] Liver donors see similar returns. Many economists encourage the creation of legal framework to allow organ trade not only to eliminate the organ shortage but also to help dissolve the corrupt illegal market.
# Economics
The illegal status of organ trade creates a price ceiling for organs at zero dollars. This price ceiling affects supply and demand creating a shortage.[14]
In theory the elimination of the price ceiling would eliminate the shortage. It is estimated that in America, if 0.06% of individuals aged 18-65 donated a kidney that the waiting list for organs would be fulfilled.[15] Currently with little incentives to donate an organ approximately 6,000 people die yearly waiting for a transplant organ. For every individual taken off the waiting list two more are added.[16] The regulation of organ trade could solve the organ shortage and create safer and fair practices for donors.[17] | https://www.wikidoc.org/index.php/Organ_trade | |
75e2e74106f7d9fcf3bba22b116c3d2fb9d81792 | wikidoc | Tolbutamide | Tolbutamide
# 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
Tolbutamide is a sulfonylurea and hypoglicemic agent that is FDA approved for the treatment of hyperglicemia in patients with non-insulin-dependent diabetes mellitus (type II) whose hyperglycemia cannot be controlled by diet alone. Common adverse reactions include hypoglycemia, epigastric fullness, heartburn, nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Tolbutamide tablets are indicated as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus (type II) whose hyperglycemia cannot be controlled by diet alone.
- In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible.
- If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of tolbutamide tablets must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of tolbutamide tablets.
- During maintenance programs, tolbutamide tablets should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations.
- In considering the use of tolbutamide tablets in asymptomatic patients, it should be recognized that controlling the blood glucose in non-insulin dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.
# Dosage
- There is no fixed dosage regimen for the management of diabetes mellitus with tolbutamide tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy.
- Short-term administration of tolbutamide tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet.
Usual Starting Dose
The usual starting dose is 1 to 2 grams daily. This may be increased or decreased, depending on individual patient response. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary regimens are more prone to exhibit unsatisfactory response to drug therapy.
Transfer from Other Hypoglycemic Therapy
Patients Receiving Other Antidiabetic Therapy
Transfer of patients from other oral antidiabetes regimens to tolbutamide tablets should be done conservatively. When transferring patients from oral hypoglycemic agents other than chlorpropamide to tolbutamide, no transition period and no initial or priming doses are necessary. When transferring patients from chlorpropamide, however, particular care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide, in the body and the possibility that subsequent overlapping drug effects might provoke hypoglycemia.
Patients Receiving Insulin
Patients requiring 20 units or less of insulin daily may be placed directly on tolbutamide tablets and insulin abruptly discontinued. Patients whose insulin requirement is between 20 and 40 units daily may be started on therapy with tolbutamide tablets with a concurrent 30% to 50% reduction in insulin dose, with further daily reduction of the insulin when response to tolbutamide tablets is observed. In patients requiring more than 40 units of insulin daily, therapy with tolbutamide tablets may be initiated in conjunction with a 20% reduction in insulin dose the first day, with further careful reduction of insulin as response is observed. Occasionally, conversion to tolbutamide tablets in the hospital may be advisable in candidates who require more than 40 units of insulin daily. During this conversion period when both insulin and tolbutamide tablets are being used hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least 3 times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is type I diabetic who requires insulin therapy.
Maximum Dose
Daily doses of greater than 3 grams are not recommended.
Usual Maintenance Dose
The maintenance dose is in the range of 0.25 to 3 grams daily. Maintenance doses above 2 grams are seldom required.
Dosage Interval
The total daily dose may be taken either in the morning or in divided doses through the day. While either schedule is usually effective, the divided dose system is preferred by some clinicians from the standpoint of digestive tolerance.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
# Indications and Dosing
- Conversion from an oral hypoglycemic to tolbuamide: other oral hypoglycemic except chlorpropamide, transition period or priming doses not necessary; chlorpropamide, use extreme caution during the first 2 weeks.
- Conversion from insulin to tolbutamide: insulin dose of 20 units/day or less, no adjustment; between 20 and 40 units/day, reduce insulin by 30% to 50%; more than 40 units/day, reduce insulin by 20% on day 1; monitor blood or urine glucose during conversion.
- Type 2 diabetes mellitus: initial, 1 to 2 g orally once daily in the morning or in divided doses.
- Type 2 diabetes mellitus: maintenance, usual range 0.25 to 3 g orally daily; MAX 3 g daily.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolbutamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tolbutamide FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Safety and effectiveness not established in pediatric patients
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolbutamide in pediatric patients.
# Contraindications
Tolbutamide tablets are contraindicated in patients with:
- Known hypersensitivity or allergy to the drug.
- Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
- Type I diabetes, as sole therapy.
# Warnings
## SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY
- The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups.
- UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of tolbutamide and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
# Adverse Reactions
## Clinical Trials Experience
## Hypoglycemia
## Gastrointestinal Reactions
Cholestatic jaundice may occur rarely; tolbutamide should be discontinued if this occurs. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and occur in 1.4% of patients treated during clinical trial. They tend to be dose related and may disappear when dosage is reduced.
## Dermatologic Reactions
- Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.1% of patients treated during clinical trials. These may be transient and may disappear despite continued use of tolbutamide; if skin reactions persist, the drug should be discontinued.
- Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.
## Hematologic Reactions
Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.
## Metabolic Reactions
Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas.
## Endocrine Reactions
Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with this and other sulfonylureas.
## Miscellaneous Reactions
- Headache and taste alterations have occasionally been reported with tolbutamide administration.
## Postmarketing Experience
There is limited information regarding Tolbutamide Postmarketing Experience in the drug label.
# Drug Interactions
- The hypoglycemia action of sulfonylurea may be potentiated by certain drugs including non-steroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving tolbutamide, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving tolbutamide, the patient should be observed closely for loss of control.
- Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving tolbutamide, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving tolbutamide, the patient should be observed closely for hypoglycemia.
- A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Teratogenic Effects: Pregnancy Category C
- Tolbutamide has been shown to be teratogenic in rats when given in doses 25 to 100 times the human dose. In some studies, pregnant rats given high doses of tolbutamide have shown ocular and bony abnormalities and increased mortality in offspring. Repeat studies in other species (rabbits) have not demonstrated a teratogenic effect. There are no adequate and well controlled studies in pregnant women. Tolbutamide is not recommended for the treatment of pregnant diabetic patients.
- Serious consideration should also be given to the possible hazards of the use of tolbutamide in women of childbearing age and in those who might become pregnant while using the drug.
Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Nonteratogenic Effects
- Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If tolbutamide is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolbutamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tolbutamide during labor and delivery.
### Nursing Mothers
Although it is not known whether tolbutamide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, 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. If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
### Pediatric Use
Safety and effectiveness in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Tolbutamide in geriatric settings.
### Gender
There is no FDA guidance on the use of Tolbutamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tolbutamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tolbutamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tolbutamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tolbutamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tolbutamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
ORAL
### Monitoring
There is limited information regarding Tolbutamide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tolbutamide and IV administrations.
# Overdosage
Overdosage of sulfonylureas including tolbutamide can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) dextrose injection. This should be followed by a continuous infusion of a more dilute (10%) dextrose injection at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.
# Pharmacology
## Mechanism of Action
- Tolbutamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolbutamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood-glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.
- Some patients who are initially responsive to oral hypoglycemic drugs, including tolbutamide, may become unresponsive or poorly responsive over time. Alternatively, tolbutamide may be effective in some patients who have become unresponsive to one or more of the other sulfonylurea drugs.
## Structure
- Tolbutamide is an oral blood-glucose-lowering drug of the sulfonylurea class. Tolbutamide is a pure, white, crystalline compound which is practically insoluble in water. The chemical name is benzenesulfonamide, N--4-methyl-. Its structure can be represented as follows:
- Tolbutamide is supplied as compressed tablets containing 500 mg of tolbutamide, USP.
Each tablet for oral administration contains 500 mg of tolbutamide and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate.
## Pharmacodynamics
There is limited information regarding Tolbutamide Pharmacodynamics in the drug label.
## Pharmacokinetics
- When administered orally, tolbutamide is readily absorbed from the gastrointestinal tract. Absorption is not impaired and glucose lowering and insulin releasing effects are not altered if the drug is taken with food. Detectable levels are present in the plasma within 20 minutes after oral ingestion of a 500 mg tolbutamide tablet, with peak levels occurring at 3 to 4 hours and only small amounts detectable at 24 hours. The half-life of tolbutamide is 4.5 to 6.5 hours. As tolbutamide has no p-amino group, it cannot be acetylated, which is one of the common modes of metabolic degradation for the antibacterial sulfonamides. However, the presence of the p-methyl group renders tolbutamide susceptible to oxidation, and this appears to be the principal manner of its metabolic degradation in man. The p-methyl group is oxidized to form a carboxyl group, converting tolbutamide into the totally inactive metabolite 1-butyl-3-p-carboxy-phenylsulfonylurea, which can be recovered in the urine within 24 hours in amounts accounting for up to 75% of the administered dose.
- The major tolbutamide metabolite has been found to have no hypoglycemic or other action when administered orally and IV to both normal and diabetic subjects. This tolbutamide metabolite is highly soluble over the critical acid range of urinary pH values, and its solubility increases with increase in pH. Because of the marked solubility of the tolbutamide metabolite, crystalluria does not occur. A second metabolite, 1-butyl-3-(p-hydroxymethyl) phenyl sulfonylurea also occurs to a limited extent. It is an inactive metabolite.
- The administration of 3 grams of tolbutamide to either nondiabetic or tolbutamide-responsive diabetic subjects will, in both instances, occasion a gradual lowering of blood glucose. Increasing the dose to 6 grams does not usually cause a response which is significantly different from that produced by the 3 gram dose. Following the administration of a 3 gram dose of tolbutamide solution, non-diabetic fasting adults exhibit a 30% or greater reduction in blood glucose within one hour, following which the blood glucose gradually returns to the fasting level over 6 to 12 hours. Following the administration of a 3 gram dose of tolbutamide solution, tolbutamide responsive diabetic patients show a gradually progressive blood glucose lowering effect, the maximal response being reached between 5 to 8 hours after ingestion of a single 3 gram dose. The blood glucose then rises gradually and by the 24th hour has usually returned to pretest levels. The magnitude of the reduction, when expressed in terms of percent of the pretest blood glucose, tends to be similar to the response seen in the nondiabetic subject.
## Nonclinical Toxicology
## Carcinogenicity and Mutagenicity
- Bioassay for carcinogenicity was performed in both sexes of rats and mice following ingestion of tolbutamide for 78 weeks. No evidence of carcinogenicity was found.
- Tolbutamide has also been demonstrated to be non mutagenic in the Ames salmonella/mammalian microsome mutagenicity test.
# Clinical Studies
There is limited information regarding Tolbutamide Clinical Studies in the drug label.
# How Supplied
- Tolbutamide Tablets, USP are available containing 500 mg of tolbutamide, USP. The tablets are white to off-white round, scored tablets debossed with M to the left of the score and 13 to the right of the score on one side of the tablet and blank on the other side. They are available as follows:
- NDC 0378-0215-01
- NDC 0378-0215-05
## Storage
Store at 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Tolbutamide Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Tolbutamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
TOLBUTAMIDE
# Look-Alike Drug Names
There is limited information regarding Tolbutamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Tolbutamide
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]
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# Overview
Tolbutamide is a sulfonylurea and hypoglicemic agent that is FDA approved for the treatment of hyperglicemia in patients with non-insulin-dependent diabetes mellitus (type II) whose hyperglycemia cannot be controlled by diet alone. Common adverse reactions include hypoglycemia, epigastric fullness, heartburn, nausea.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
# Indications
- Tolbutamide tablets are indicated as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus (type II) whose hyperglycemia cannot be controlled by diet alone.
- In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible.
- If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of tolbutamide tablets must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of tolbutamide tablets.
- During maintenance programs, tolbutamide tablets should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations.
- In considering the use of tolbutamide tablets in asymptomatic patients, it should be recognized that controlling the blood glucose in non-insulin dependent diabetes has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.
# Dosage
- There is no fixed dosage regimen for the management of diabetes mellitus with tolbutamide tablets or any other hypoglycemic agent. In addition to the usual monitoring of urinary glucose, the patient's blood glucose must also be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy.
- Short-term administration of tolbutamide tablets may be sufficient during periods of transient loss of control in patients usually controlled well on diet.
Usual Starting Dose
The usual starting dose is 1 to 2 grams daily. This may be increased or decreased, depending on individual patient response. Failure to follow an appropriate dosage regimen may precipitate hypoglycemia. Patients who do not adhere to their prescribed dietary regimens are more prone to exhibit unsatisfactory response to drug therapy.
Transfer from Other Hypoglycemic Therapy
Patients Receiving Other Antidiabetic Therapy
Transfer of patients from other oral antidiabetes regimens to tolbutamide tablets should be done conservatively. When transferring patients from oral hypoglycemic agents other than chlorpropamide to tolbutamide, no transition period and no initial or priming doses are necessary. When transferring patients from chlorpropamide, however, particular care should be exercised during the first 2 weeks because of the prolonged retention of chlorpropamide, in the body and the possibility that subsequent overlapping drug effects might provoke hypoglycemia.
Patients Receiving Insulin
Patients requiring 20 units or less of insulin daily may be placed directly on tolbutamide tablets and insulin abruptly discontinued. Patients whose insulin requirement is between 20 and 40 units daily may be started on therapy with tolbutamide tablets with a concurrent 30% to 50% reduction in insulin dose, with further daily reduction of the insulin when response to tolbutamide tablets is observed. In patients requiring more than 40 units of insulin daily, therapy with tolbutamide tablets may be initiated in conjunction with a 20% reduction in insulin dose the first day, with further careful reduction of insulin as response is observed. Occasionally, conversion to tolbutamide tablets in the hospital may be advisable in candidates who require more than 40 units of insulin daily. During this conversion period when both insulin and tolbutamide tablets are being used hypoglycemia may rarely occur. During insulin withdrawal, patients should test their urine for glucose and acetone at least 3 times daily and report results to their physician. The appearance of persistent acetonuria with glycosuria indicates that the patient is type I diabetic who requires insulin therapy.
Maximum Dose
Daily doses of greater than 3 grams are not recommended.
Usual Maintenance Dose
The maintenance dose is in the range of 0.25 to 3 grams daily. Maintenance doses above 2 grams are seldom required.
Dosage Interval
The total daily dose may be taken either in the morning or in divided doses through the day. While either schedule is usually effective, the divided dose system is preferred by some clinicians from the standpoint of digestive tolerance.
In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS).
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
# Indications and Dosing
- Conversion from an oral hypoglycemic to tolbuamide: other oral hypoglycemic except chlorpropamide, transition period or priming doses not necessary; chlorpropamide, use extreme caution during the first 2 weeks.
- Conversion from insulin to tolbutamide: insulin dose of 20 units/day or less, no adjustment; between 20 and 40 units/day, reduce insulin by 30% to 50%; more than 40 units/day, reduce insulin by 20% on day 1; monitor blood or urine glucose during conversion.
- Type 2 diabetes mellitus: initial, 1 to 2 g orally once daily in the morning or in divided doses.
- Type 2 diabetes mellitus: maintenance, usual range 0.25 to 3 g orally daily; MAX 3 g daily.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolbutamide in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Tolbutamide FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
- Safety and effectiveness not established in pediatric patients
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Tolbutamide in pediatric patients.
# Contraindications
Tolbutamide tablets are contraindicated in patients with:
- Known hypersensitivity or allergy to the drug.
- Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
- Type I diabetes, as sole therapy.
# Warnings
## SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY
- The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups.
- UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of tolbutamide and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.
# Adverse Reactions
## Clinical Trials Experience
## Hypoglycemia
## Gastrointestinal Reactions
Cholestatic jaundice may occur rarely; tolbutamide should be discontinued if this occurs. Gastrointestinal disturbances, e.g., nausea, epigastric fullness, and heartburn, are the most common reactions and occur in 1.4% of patients treated during clinical trial. They tend to be dose related and may disappear when dosage is reduced.
## Dermatologic Reactions
- Allergic skin reactions, e.g., pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occur in 1.1% of patients treated during clinical trials. These may be transient and may disappear despite continued use of tolbutamide; if skin reactions persist, the drug should be discontinued.
- Porphyria cutanea tarda and photosensitivity reactions have been reported with sulfonylureas.
## Hematologic Reactions
Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, and pancytopenia have been reported with sulfonylureas.
## Metabolic Reactions
Hepatic porphyria and disulfiram-like reactions have been reported with sulfonylureas.
## Endocrine Reactions
Cases of hyponatremia and the syndrome of inappropriate antidiuretic hormone (SIADH) secretion have been reported with this and other sulfonylureas.
## Miscellaneous Reactions
- Headache and taste alterations have occasionally been reported with tolbutamide administration.
## Postmarketing Experience
There is limited information regarding Tolbutamide Postmarketing Experience in the drug label.
# Drug Interactions
- The hypoglycemia action of sulfonylurea may be potentiated by certain drugs including non-steroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta-adrenergic blocking agents. When such drugs are administered to a patient receiving tolbutamide, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving tolbutamide, the patient should be observed closely for loss of control.
- Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. When such drugs are administered to a patient receiving tolbutamide, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving tolbutamide, the patient should be observed closely for hypoglycemia.
- A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with the intravenous, topical or vaginal preparations of miconazole is not known.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
Teratogenic Effects: Pregnancy Category C
- Tolbutamide has been shown to be teratogenic in rats when given in doses 25 to 100 times the human dose. In some studies, pregnant rats given high doses of tolbutamide have shown ocular and bony abnormalities and increased mortality in offspring. Repeat studies in other species (rabbits) have not demonstrated a teratogenic effect. There are no adequate and well controlled studies in pregnant women. Tolbutamide is not recommended for the treatment of pregnant diabetic patients.
- Serious consideration should also be given to the possible hazards of the use of tolbutamide in women of childbearing age and in those who might become pregnant while using the drug.
Because recent information suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.
Nonteratogenic Effects
- Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If tolbutamide is used during pregnancy, it should be discontinued at least 2 weeks before the expected delivery date.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tolbutamide in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Tolbutamide during labor and delivery.
### Nursing Mothers
Although it is not known whether tolbutamide is excreted in human milk, some sulfonylurea drugs are known to be excreted in human milk. Because the potential for hypoglycemia in nursing infants may exist, 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. If the drug is discontinued and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
### Pediatric Use
Safety and effectiveness in children have not been established.
### Geriatic Use
There is no FDA guidance on the use of Tolbutamide in geriatric settings.
### Gender
There is no FDA guidance on the use of Tolbutamide with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Tolbutamide with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Tolbutamide in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Tolbutamide in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Tolbutamide in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Tolbutamide in patients who are immunocompromised.
# Administration and Monitoring
### Administration
ORAL
### Monitoring
There is limited information regarding Tolbutamide Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Tolbutamide and IV administrations.
# Overdosage
Overdosage of sulfonylureas including tolbutamide can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) dextrose injection. This should be followed by a continuous infusion of a more dilute (10%) dextrose injection at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.
# Pharmacology
## Mechanism of Action
- Tolbutamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolbutamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood-glucose-lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs.
- Some patients who are initially responsive to oral hypoglycemic drugs, including tolbutamide, may become unresponsive or poorly responsive over time. Alternatively, tolbutamide may be effective in some patients who have become unresponsive to one or more of the other sulfonylurea drugs.
## Structure
- Tolbutamide is an oral blood-glucose-lowering drug of the sulfonylurea class. Tolbutamide is a pure, white, crystalline compound which is practically insoluble in water. The chemical name is benzenesulfonamide, N-[(butylamino)-carbonyl]-4-methyl-. Its structure can be represented as follows:
- Tolbutamide is supplied as compressed tablets containing 500 mg of tolbutamide, USP.
Each tablet for oral administration contains 500 mg of tolbutamide and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate.
## Pharmacodynamics
There is limited information regarding Tolbutamide Pharmacodynamics in the drug label.
## Pharmacokinetics
- When administered orally, tolbutamide is readily absorbed from the gastrointestinal tract. Absorption is not impaired and glucose lowering and insulin releasing effects are not altered if the drug is taken with food. Detectable levels are present in the plasma within 20 minutes after oral ingestion of a 500 mg tolbutamide tablet, with peak levels occurring at 3 to 4 hours and only small amounts detectable at 24 hours. The half-life of tolbutamide is 4.5 to 6.5 hours. As tolbutamide has no p-amino group, it cannot be acetylated, which is one of the common modes of metabolic degradation for the antibacterial sulfonamides. However, the presence of the p-methyl group renders tolbutamide susceptible to oxidation, and this appears to be the principal manner of its metabolic degradation in man. The p-methyl group is oxidized to form a carboxyl group, converting tolbutamide into the totally inactive metabolite 1-butyl-3-p-carboxy-phenylsulfonylurea, which can be recovered in the urine within 24 hours in amounts accounting for up to 75% of the administered dose.
- The major tolbutamide metabolite has been found to have no hypoglycemic or other action when administered orally and IV to both normal and diabetic subjects. This tolbutamide metabolite is highly soluble over the critical acid range of urinary pH values, and its solubility increases with increase in pH. Because of the marked solubility of the tolbutamide metabolite, crystalluria does not occur. A second metabolite, 1-butyl-3-(p-hydroxymethyl) phenyl sulfonylurea also occurs to a limited extent. It is an inactive metabolite.
- The administration of 3 grams of tolbutamide to either nondiabetic or tolbutamide-responsive diabetic subjects will, in both instances, occasion a gradual lowering of blood glucose. Increasing the dose to 6 grams does not usually cause a response which is significantly different from that produced by the 3 gram dose. Following the administration of a 3 gram dose of tolbutamide solution, non-diabetic fasting adults exhibit a 30% or greater reduction in blood glucose within one hour, following which the blood glucose gradually returns to the fasting level over 6 to 12 hours. Following the administration of a 3 gram dose of tolbutamide solution, tolbutamide responsive diabetic patients show a gradually progressive blood glucose lowering effect, the maximal response being reached between 5 to 8 hours after ingestion of a single 3 gram dose. The blood glucose then rises gradually and by the 24th hour has usually returned to pretest levels. The magnitude of the reduction, when expressed in terms of percent of the pretest blood glucose, tends to be similar to the response seen in the nondiabetic subject.
## Nonclinical Toxicology
## Carcinogenicity and Mutagenicity
- Bioassay for carcinogenicity was performed in both sexes of rats and mice following ingestion of tolbutamide for 78 weeks. No evidence of carcinogenicity was found.
- Tolbutamide has also been demonstrated to be non mutagenic in the Ames salmonella/mammalian microsome mutagenicity test.
# Clinical Studies
There is limited information regarding Tolbutamide Clinical Studies in the drug label.
# How Supplied
- Tolbutamide Tablets, USP are available containing 500 mg of tolbutamide, USP. The tablets are white to off-white round, scored tablets debossed with M to the left of the score and 13 to the right of the score on one side of the tablet and blank on the other side. They are available as follows:
- NDC 0378-0215-01
- NDC 0378-0215-05
## Storage
Store at 20° to 25°C (68° to 77°F).
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Tolbutamide Patient Counseling Information in the drug label.
# Precautions with Alcohol
Alcohol-Tolbutamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
TOLBUTAMIDE
# Look-Alike Drug Names
There is limited information regarding Tolbutamide Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Orinase | |
f4db438abcf3e77bdbaeae12ab69441fbae7a24a | wikidoc | Oritavancin | Oritavancin
# 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
Oritavancin is an antibiotic that is FDA approved for the treatment of acute bacterial skin and skin structure infections caused by Gram-positive microorganisms. Common adverse reactions include nausea, vomiting and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Oritavancin is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms:
- Staphylococcus aureus (including methicillin-susceptible and methicillin–resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), and Enterococcus faecalis (vancomycin-susceptible isolates only).
- Dosage: a single 1200 mg dose administered by intravenous infusion over 3 hours
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oritavancin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oritavancin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy are not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oritavancin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oritavancin in pediatric patients.
# Contraindications
Use of intravenous unfractionated heparin sodium is contraindicated for 48 hours after oritavancin administration because the activated partial thromboplastin time (aPTT) test results are expected to remain falsely elevated for approximately 48 hours after oritavancin administration.
Oritavancin is contraindicated in patients with known hypersensitivity to oritavancin.
# Warnings
Co-administration of oritavancin and warfarin may result in higher exposure of warfarin, which may increase the risk of bleeding. Use oritavancin in patients on chronic warfarin therapy only when the benefits can be expected to outweigh the risk of bleeding. Frequently monitor for signs of bleeding.
-ritavancin has been shown to artificially prolong PT and INR for up to 24 hours, making the monitoring of the anticoagulation effect of warfarin unreliable up to 24 hours after an oritavancin dose.
-ritavancin has been shown to artificially prolong aPTT for 48 hours and the PT and INR for 24 hours by binding to and preventing action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests.
For patients who require aPTT monitoring within 48 hours of oritavancin dosing, a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered.
Effects by oritavancin on activated clotting time (ACT) are expected since the phospholipid reagents are also utilized in this coagulation test. oritavancin has no effect on the coagulation system.
Serious hypersensitivity reactions have been reported with the use of oritavancin. If an acute hypersensitivity reaction occurs during oritavancin infusion, discontinue oritavancin immediately and institute appropriate supportive care. Before using oritavancin, inquire carefully about previous hypersensitivity reactions to glycopeptides. Due to the possibility of cross-sensitivity, carefully monitor for signs of hypersensitivity during oritavancin infusion in patients with a history of glycopeptide allergy. In the Phase 3 ABSSSI clinical trials, the median onset of hypersensitivity reactions in oritavancin-treated patients was 1.2 days and the median duration of these reactions was 2.4 days.
Infusion related reactions have been reported with oritavancin including pruritus, urticaria or flushing. If reactions do occur, consider slowing or interrupting oritavancin infusion.
Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including oritavancin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
In Phase 3 ABSSSI clinical trials, more cases of osteomyelitis were reported in the oritavancin treated arm than in the vancomycin-treated arm. Monitor patients for signs and symptoms of osteomyelitis. If osteomyelitis is suspected or diagnosed, institute appropriate alternate antibacterial therapy}.
Prescribing oritavancin 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 oritavancin cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
-ritavancin has been evaluated in two, double-blind, controlled ABSSSI clinical trials, which included 976 adult patients treated with a single 1200 mg intravenous dose of oritavancin and 983 patients treated with intravenous vancomycin for 7 to 10 days. The median age of patients treated with oritavancin was 45.6 years, ranging between 18 and 89 years of age with 8.8% ≥65 years of age. Patients treated with oritavancin were predominantly male (65.4%), 64.4% were Caucasian, 5.8% were African American, and 28.1% were Asian. Safety was evaluated for up to 60 days after dosing.
In the pooled ABSSSI clinical trials, serious adverse reactions were reported in 57/976 (5.8%) patients treated with oritavancin and 58/983 (5.9%) treated with vancomycin. The most commonly reported serious adverse reaction was cellulitis in both treatment groups: 11/976 (1.1%) in oritavancin and 12/983 (1.2%) in the vancomycin arms, respectively.
The most commonly reported adverse reactions (≥3%) in patients receiving a single 1200 mg dose of oritavancin in the pooled ABSSSI clinical trials were: headache, nausea, vomiting, limb and subcutaneous abscesses, and diarrhea.
In the pooled ABSSSI clinical trials, oritavancin was discontinued due to adverse reactions in 36/976 (3.7%) of patients; the most common reported reactions leading to discontinuation were cellulitis (4/976, 0.4%) and osteomyelitis (3/976, 0.3%).
TABLE 1 provides selected adverse reactions occurring in ≥ 1.5% of patients receiving oritavancin in the pooled ABSSSI clinical trials. There were 540 (55.3%) patients in the oritavancin arm and 559 (56.9%) patients in the vancomycin arm, who reported ≥1 adverse reaction.
The following selected adverse reactions were reported in oritavancin-treated patients at a rate of less than 1.5%:
- Blood and lymphatic system disorders: anemia, eosinophilia
- General Disorders and administration site conditions: infusion site erythema, extravasation, induration, pruritis, rash, edema peripheral
- Immune system disorders: hypersensitivity
- Infections and infestations: osteomyelitis
- Investigations: total bilirubin increased, hyperuricemia
- Metabolism and nutrition disorders: hypoglycemia
- Musculoskeletal and connective tissue disorders: tenosynovitis, myalgia
- Respiratory, thoracic and mediastinal disorders: bronchospasm, wheezing
- Skin and Subcutaneous Tissue Disorders: urticaria, angioedema, erythema multiforme, pruritis, leucocytoclastic vasculitis, rash.
## Postmarketing Experience
There is limited information regarding Oritavancin Postmarketing Experience in the drug label.
# Drug Interactions
A cocktail drug-drug interaction study was conducted in healthy volunteers (n=16) evaluating the concomitant administration of a single 1200 mg dose of oritavancin with probe substrates for several CYP450 enzymes. oritavancin was found to be a nonspecific, weak inhibitor (CYP2C9 and CYP2C19) or inducer (CYP3A4 and CYP2D6) of several CYP isoforms.
Caution should be used when administering oritavancin concomitantly with drugs with a narrow therapeutic window that are predominantly metabolized by one of the affected CYP450 enzymes (e.g., warfarin), as co-administration may increase (e.g. for CYP2C9 substrates) or decrease (e.g. for CYP2D6 substrates) concentrations of the narrow therapeutic range drug. Patients should be closely monitored for signs of toxicity or lack of efficacy if they have been given oritavancin while on a potentially affected compound (e.g. patients should be monitored for bleeding if concomitantly receiving oritavancin and warfarin).
-ritavancin has been shown to artificially prolong aPTT for 48 hours and PT and INR for up to 24 hours by binding to and preventing action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests. Effects by oritavancin on ACT are expected since the phospholipid reagents are also utilized in this coagulation test. oritavancin has no effect on the coagulation system.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to oritavancin at the highest concentrations administered, 30 mg/kg/day and 15 mg/kg/day, respectively. Those daily doses would be equivalent to a human dose of 300 mg, or 25% of the single clinical dose of 1200 mg. Higher doses were not evaluated in nonclinical developmental and reproductive toxicology studies.
There are no adequate and well-controlled trials in pregnant women. Oritavancin 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 Oritavancin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Oritavancin during labor and delivery.
### Nursing Mothers
It is unknown whether oritavancin is excreted in human milk. Following a single intravenous infusion in lactating rats, radio-labeled -oritavancin was excreted in milk and absorbed by nursing pups. Caution should be exercised when oritavancin is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness of oritavancin in pediatric patients (younger than 18 years of age) has not been studied.
### Geriatic Use
The pooled Phase 3 ABSSSI clinical trials of oritavancin did not include sufficient numbers of subjects aged 65 and older 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, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
Population pharmacokinetic analysis from the Phase 3 ABSSSI trials in patients indicated that gender had no clinically relevant effect on the exposure of oritavancin. No dosage adjustment is warranted in these subpopulations.
### Race
Population pharmacokinetic analysis from the Phase 3 ABSSSI trials in patients indicated that race had no clinically relevant effect on the exposure of oritavancin. No dosage adjustment is warranted in these subpopulations.
### Renal Impairment
No dosage adjustment of oritavancin is needed in patients with mild or moderate renal impairment. The pharmacokinetics of oritavancin in severe renal impairment have not been evaluated. Oritavancin is not removed from blood by hemodialysis.
### Hepatic Impairment
No dosage adjustment of oritavancin is needed in patients with mild or moderate hepatic impairment. The pharmacokinetics of oritavancin in patients with severe hepatic insufficiency has not been studied.
### Females of Reproductive Potential and Males
Oritavancin did not affect the fertility or reproductive performance of male rats (exposed to daily doses up to 30 mg/kg for at least 4 weeks) and female rats (exposed to daily doses up to 30 mg/kg for at least 2 weeks prior to mating). Those daily doses would be equivalent to a human dose of 300 mg, or 25% of clinical dose. Higher doses were not evaluated in nonclinical fertility studies.
### Immunocompromised Patients
There is no FDA guidance one the use of Oritavancin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Oritavancin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Oritavancin and IV administrations.
# Overdosage
In the oritavancin clinical program there was no incidence of accidental overdose of oritavancin.
Based on an in vitro hemodialysis study, oritavancin is unlikely to be removed from blood by hemodialysis. In the event of overdose, supportive measures should be taken.
# Pharmacology
## Mechanism of Action
Oritavancin has three mechanisms of action: (i) inhibition of the transglycosylation (polymerization) step of cell wall biosynthesis by binding to the stem peptide of peptidoglycan precursors; (ii) inhibition of the transpeptidation (crosslinking) step of cell wall biosynthesis by binding to the peptide bridging segments of the cell wall; and (iii) disruption of bacterial membrane integrity, leading to depolarization, permeabilization, and cell death. These multiple mechanisms contribute to the concentration-dependent bactericidal activity of oritavancin.
## Structure
The chemical structure is represented below:
## Pharmacodynamics
The antimicrobial activity of oritavancin appears to correlate with the ratio of area under the concentration-time curve to minimal inhibitory concentration (AUC/MIC) based on animal models of infection.
Exposure-response analyses from both preclinical and clinical studies support the treatment of clinically relevant Gram-positive microorganisms (e.g. S. aureus and S. pyogenes) causative of ABSSSI with a single 1200 mg dose of oritavancin.
In a thorough QTc study of 135 healthy subjects at a dose 1.3 times the 1200 mg recommended dose, oritavancin did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
The population PK analysis was derived using data from the two Phase 3 ABSSSI clinical trials in 297 patients. The mean pharmacokinetic parameters of oritavancin in patients following a single 1200 mg dose are presented in TABLE 2.
Oritavancin exhibits linear pharmacokinetics at a dose up to 1200 mg. The mean, population-predicted oritavancin concentration-time profile displays a multi-exponential decline with a long terminal plasma half-life as shown in FIGURE 1.
Oritavancin is approximately 85% bound to human plasma proteins.
Based on population PK analysis, the population mean total volume of distribution is estimated to be approximately 87.6 L, indicating oritavancin is extensively distributed into the tissues.
Exposures of oritavancin in skin blister fluid were approximately 20% of those in plasma (AUC0-24) after single 800 mg dose in healthy subjects.
Non-clinical studies including in vitro human liver microsome studies indicated that oritavancin is not metabolized. No mass balance study has been conducted in humans. In humans, oritavancin is slowly excreted unchanged in feces and urine with less than 1% and 5% of the dose recovered in feces and urine, respectively, after 2 weeks of collection.
Oritavancin has a terminal half-life of approximately 245 hours and a clearance of 0.445 L/h based on population pharmacokinetic analyses.
## Nonclinical Toxicology
In serial passage studies, resistance to oritavancin was observed in isolates of S. aureus and E. faecalis. Resistance to oritavancin was not observed in clinical studies.
In in vitro studies, oritavancin exhibits synergistic bactericidal activity in combination with gentamicin, moxifloxacin or rifampicin against isolates of methicillin-susceptible S. aureus (MSSA), with gentamicin or linezolid against isolates of heterogeneous vancomycin-intermediate S. aureus (hVISA), VISA, and vancomycin-resistant S. aureus (VRSA), and with rifampin against isolates of VRSA. In vitro studies demonstrated no antagonism between oritavancin and gentamicin, moxifloxacin, linezolid or rifampin.
Oritavancin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the Indications and Usage section.
- Staphylococcus aureus (including methicillin-resistant isolates)
- Streptococcus agalactiae
- Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)
- Streptococcus dysgalactiae
- Streptococcus pyogenes
- Enterococcus faecalis (vancomycin-susceptible isolates only)
The following in vitro data are available but their clinical significance has not been established. At least 90% of isolates of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to 0.12 mcg/mL for oritavancin. However, the safety and effectiveness of oritavancin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.
- Enterococcus faecium (vancomycin-susceptible isolates only)
Long term studies in animals have not been conducted to determine the carcinogenic potential of oritavancin.
No mutagenic or clastogenic potential of oritavancin was found in a battery of tests, including an Ames assay, in vitro chromosome aberration assay in Chinese hamster ovary cells, in vitro forward mutation assay in mouse lymphoma cells and an in vivo mouse micronucleus assay.
# Clinical Studies
A total of 1987 adults with clinically documented ABSSSI suspected or proven to be due to Gram-positive pathogens were randomized into two identically designed, randomized, double-blind, multi-center, multinational, non-inferiority trials (Trial 1 and Trial 2) comparing a single 1200 mg intravenous dose of oritavancin to intravenous vancomycin (1 g or 15 mg/kg every 12 hours) for 7 to 10 days. The primary analysis population (modified intent to treat, mITT) included all randomized patients who received any study drug. Patients could receive concomitant aztreonam or metronidazole for suspected Gram-negative and anaerobic infection, respectively. Patient demographic and baseline characteristics were balanced between treatment groups. Approximately 64% of patients were Caucasian and 65% were males. The mean age was 45 years and the mean body mass index was 27 kg/m2. Across both trials, approximately 60% of patients were enrolled from the United States and 27% of patients from Asia. A history of diabetes was present in 14% of patients. The types of ABSSSI across both trials included cellulitis/erysipelas (40%), wound infection (29%), and major cutaneous abscesses (31%). Median infection area at baseline across both trials was 266.6 cm2.
The primary endpoint in both trials was early clinical response (responder), defined as cessation of spread or reduction in size of baseline lesion, absence of fever, and no rescue antibacterial drug at 48 to 72 hours after initiation of therapy.
TABLE 5 provides the efficacy results for the primary endpoint in Trial 1 and Trial 2 in the primary analysis population.
A key secondary endpoint in these two ABSSSI trials evaluated the percentage of patients achieving a 20% or greater reduction in lesion area from baseline at 48-72 hours after initiation of therapy. TABLE 6 summarizes the findings for this endpoint in the two ABSSSI trials.
Another secondary efficacy endpoint in the two trials was investigator-assessed clinical success at post therapy evaluation at day 14 to 24 (7 to 14 days from end of blinded therapy). A patient was categorized as a clinical success if the patient experienced a complete or nearly complete resolution of baseline signs and symptoms related to primary ABSSSI site (erythema, induration/edema, purulent drainage, fluctuance, pain, tenderness, local increase in heat/warmth) such that no further treatment with antibacterial drugs was needed.
TABLE 7 summarizes the findings for this endpoint in the mITT and clinically evaluable population in these two ABSSSI trials. Note that there are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at the post therapy visits. Therefore, comparisons of oritavancin to vancomycin based on clinical success rates at these visits cannot be utilized to establish non-inferiority conclusions.
Outcomes by Baseline Pathogen: TABLE 8 shows outcomes in patients with an identified baseline pathogen in the microbiological Intent-to-Treat (microITT) population in a pooled analysis of Trial 1 and Trial 2. The outcomes shown in the table are clinical response rates at 48 to 72 hours and clinical success rates at follow-up study day14 to 24.
# How Supplied
- Single use 50 mL capacity glass vials containing sterile lyophilized powder equivalent to 400 mg of oritavancin (NDC 65293-015-01).
## Storage
Stored at 20°C to 25°C (68°F to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. They should inform their healthcare provider about any previous hypersensitivity reactions to oritavancin, other glycopeptides (vancomycin, telavancin, or dalbavancin) or other allergens.
Patients should be advised that diarrhea is a common problem caused by antibacterial drugs including oritavancin, which usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider.
# Precautions with Alcohol
Alcohol-Oritavancin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Orbactiv
# Look-Alike Drug Names
There is limited information regarding Oritavancin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Oritavancin
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
Oritavancin is an antibiotic that is FDA approved for the treatment of acute bacterial skin and skin structure infections caused by Gram-positive microorganisms. Common adverse reactions include nausea, vomiting and headache.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- Oritavancin is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive microorganisms:
- Staphylococcus aureus (including methicillin-susceptible and methicillin–resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), and Enterococcus faecalis (vancomycin-susceptible isolates only).
- Dosage: a single 1200 mg dose administered by intravenous infusion over 3 hours
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oritavancin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oritavancin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
Safety and efficacy are not established in pediatric patients
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Oritavancin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Oritavancin in pediatric patients.
# Contraindications
Use of intravenous unfractionated heparin sodium is contraindicated for 48 hours after oritavancin administration because the activated partial thromboplastin time (aPTT) test results are expected to remain falsely elevated for approximately 48 hours after oritavancin administration.
Oritavancin is contraindicated in patients with known hypersensitivity to oritavancin.
# Warnings
Co-administration of oritavancin and warfarin may result in higher exposure of warfarin, which may increase the risk of bleeding. Use oritavancin in patients on chronic warfarin therapy only when the benefits can be expected to outweigh the risk of bleeding. Frequently monitor for signs of bleeding.
oritavancin has been shown to artificially prolong PT and INR for up to 24 hours, making the monitoring of the anticoagulation effect of warfarin unreliable up to 24 hours after an oritavancin dose.
oritavancin has been shown to artificially prolong aPTT for 48 hours and the PT and INR for 24 hours by binding to and preventing action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests.
For patients who require aPTT monitoring within 48 hours of oritavancin dosing, a non-phospholipid dependent coagulation test such as a Factor Xa (chromogenic) assay or an alternative anticoagulant not requiring aPTT monitoring may be considered.
Effects by oritavancin on activated clotting time (ACT) are expected since the phospholipid reagents are also utilized in this coagulation test. oritavancin has no effect on the coagulation system.
Serious hypersensitivity reactions have been reported with the use of oritavancin. If an acute hypersensitivity reaction occurs during oritavancin infusion, discontinue oritavancin immediately and institute appropriate supportive care. Before using oritavancin, inquire carefully about previous hypersensitivity reactions to glycopeptides. Due to the possibility of cross-sensitivity, carefully monitor for signs of hypersensitivity during oritavancin infusion in patients with a history of glycopeptide allergy. In the Phase 3 ABSSSI clinical trials, the median onset of hypersensitivity reactions in oritavancin-treated patients was 1.2 days and the median duration of these reactions was 2.4 days.
Infusion related reactions have been reported with oritavancin including pruritus, urticaria or flushing. If reactions do occur, consider slowing or interrupting oritavancin infusion.
Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including oritavancin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
In Phase 3 ABSSSI clinical trials, more cases of osteomyelitis were reported in the oritavancin treated arm than in the vancomycin-treated arm. Monitor patients for signs and symptoms of osteomyelitis. If osteomyelitis is suspected or diagnosed, institute appropriate alternate antibacterial therapy}.
Prescribing oritavancin 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 oritavancin cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
oritavancin has been evaluated in two, double-blind, controlled ABSSSI clinical trials, which included 976 adult patients treated with a single 1200 mg intravenous dose of oritavancin and 983 patients treated with intravenous vancomycin for 7 to 10 days. The median age of patients treated with oritavancin was 45.6 years, ranging between 18 and 89 years of age with 8.8% ≥65 years of age. Patients treated with oritavancin were predominantly male (65.4%), 64.4% were Caucasian, 5.8% were African American, and 28.1% were Asian. Safety was evaluated for up to 60 days after dosing.
In the pooled ABSSSI clinical trials, serious adverse reactions were reported in 57/976 (5.8%) patients treated with oritavancin and 58/983 (5.9%) treated with vancomycin. The most commonly reported serious adverse reaction was cellulitis in both treatment groups: 11/976 (1.1%) in oritavancin and 12/983 (1.2%) in the vancomycin arms, respectively.
The most commonly reported adverse reactions (≥3%) in patients receiving a single 1200 mg dose of oritavancin in the pooled ABSSSI clinical trials were: headache, nausea, vomiting, limb and subcutaneous abscesses, and diarrhea.
In the pooled ABSSSI clinical trials, oritavancin was discontinued due to adverse reactions in 36/976 (3.7%) of patients; the most common reported reactions leading to discontinuation were cellulitis (4/976, 0.4%) and osteomyelitis (3/976, 0.3%).
TABLE 1 provides selected adverse reactions occurring in ≥ 1.5% of patients receiving oritavancin in the pooled ABSSSI clinical trials. There were 540 (55.3%) patients in the oritavancin arm and 559 (56.9%) patients in the vancomycin arm, who reported ≥1 adverse reaction.
The following selected adverse reactions were reported in oritavancin-treated patients at a rate of less than 1.5%:
- Blood and lymphatic system disorders: anemia, eosinophilia
- General Disorders and administration site conditions: infusion site erythema, extravasation, induration, pruritis, rash, edema peripheral
- Immune system disorders: hypersensitivity
- Infections and infestations: osteomyelitis
- Investigations: total bilirubin increased, hyperuricemia
- Metabolism and nutrition disorders: hypoglycemia
- Musculoskeletal and connective tissue disorders: tenosynovitis, myalgia
- Respiratory, thoracic and mediastinal disorders: bronchospasm, wheezing
- Skin and Subcutaneous Tissue Disorders: urticaria, angioedema, erythema multiforme, pruritis, leucocytoclastic vasculitis, rash.
## Postmarketing Experience
There is limited information regarding Oritavancin Postmarketing Experience in the drug label.
# Drug Interactions
A cocktail drug-drug interaction study was conducted in healthy volunteers (n=16) evaluating the concomitant administration of a single 1200 mg dose of oritavancin with probe substrates for several CYP450 enzymes. oritavancin was found to be a nonspecific, weak inhibitor (CYP2C9 and CYP2C19) or inducer (CYP3A4 and CYP2D6) of several CYP isoforms.
Caution should be used when administering oritavancin concomitantly with drugs with a narrow therapeutic window that are predominantly metabolized by one of the affected CYP450 enzymes (e.g., warfarin), as co-administration may increase (e.g. for CYP2C9 substrates) or decrease (e.g. for CYP2D6 substrates) concentrations of the narrow therapeutic range drug. Patients should be closely monitored for signs of toxicity or lack of efficacy if they have been given oritavancin while on a potentially affected compound (e.g. patients should be monitored for bleeding if concomitantly receiving oritavancin and warfarin).
oritavancin has been shown to artificially prolong aPTT for 48 hours and PT and INR for up to 24 hours by binding to and preventing action of the phospholipid reagents which activate coagulation in commonly used laboratory coagulation tests. Effects by oritavancin on ACT are expected since the phospholipid reagents are also utilized in this coagulation test. oritavancin has no effect on the coagulation system.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA): C
Reproduction studies performed in rats and rabbits have revealed no evidence of harm to the fetus due to oritavancin at the highest concentrations administered, 30 mg/kg/day and 15 mg/kg/day, respectively. Those daily doses would be equivalent to a human dose of 300 mg, or 25% of the single clinical dose of 1200 mg. Higher doses were not evaluated in nonclinical developmental and reproductive toxicology studies.
There are no adequate and well-controlled trials in pregnant women. Oritavancin 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 Oritavancin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Oritavancin during labor and delivery.
### Nursing Mothers
It is unknown whether oritavancin is excreted in human milk. Following a single intravenous infusion in lactating rats, radio-labeled [14C]-oritavancin was excreted in milk and absorbed by nursing pups. Caution should be exercised when oritavancin is administered to a nursing woman.
### Pediatric Use
Safety and effectiveness of oritavancin in pediatric patients (younger than 18 years of age) has not been studied.
### Geriatic Use
The pooled Phase 3 ABSSSI clinical trials of oritavancin did not include sufficient numbers of subjects aged 65 and older 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, but greater sensitivity of some older individuals cannot be ruled out.
### Gender
Population pharmacokinetic analysis from the Phase 3 ABSSSI trials in patients indicated that gender had no clinically relevant effect on the exposure of oritavancin. No dosage adjustment is warranted in these subpopulations.
### Race
Population pharmacokinetic analysis from the Phase 3 ABSSSI trials in patients indicated that race had no clinically relevant effect on the exposure of oritavancin. No dosage adjustment is warranted in these subpopulations.
### Renal Impairment
No dosage adjustment of oritavancin is needed in patients with mild or moderate renal impairment. The pharmacokinetics of oritavancin in severe renal impairment have not been evaluated. Oritavancin is not removed from blood by hemodialysis.
### Hepatic Impairment
No dosage adjustment of oritavancin is needed in patients with mild or moderate hepatic impairment. The pharmacokinetics of oritavancin in patients with severe hepatic insufficiency has not been studied.
### Females of Reproductive Potential and Males
Oritavancin did not affect the fertility or reproductive performance of male rats (exposed to daily doses up to 30 mg/kg for at least 4 weeks) and female rats (exposed to daily doses up to 30 mg/kg for at least 2 weeks prior to mating). Those daily doses would be equivalent to a human dose of 300 mg, or 25% of clinical dose. Higher doses were not evaluated in nonclinical fertility studies.
### Immunocompromised Patients
There is no FDA guidance one the use of Oritavancin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
Intravenous
### Monitoring
There is limited information regarding Oritavancin Monitoring in the drug label.
# IV Compatibility
There is limited information regarding the compatibility of Oritavancin and IV administrations.
# Overdosage
In the oritavancin clinical program there was no incidence of accidental overdose of oritavancin.
Based on an in vitro hemodialysis study, oritavancin is unlikely to be removed from blood by hemodialysis. In the event of overdose, supportive measures should be taken.
# Pharmacology
## Mechanism of Action
Oritavancin has three mechanisms of action: (i) inhibition of the transglycosylation (polymerization) step of cell wall biosynthesis by binding to the stem peptide of peptidoglycan precursors; (ii) inhibition of the transpeptidation (crosslinking) step of cell wall biosynthesis by binding to the peptide bridging segments of the cell wall; and (iii) disruption of bacterial membrane integrity, leading to depolarization, permeabilization, and cell death. These multiple mechanisms contribute to the concentration-dependent bactericidal activity of oritavancin.
## Structure
The chemical structure is represented below:
## Pharmacodynamics
The antimicrobial activity of oritavancin appears to correlate with the ratio of area under the concentration-time curve to minimal inhibitory concentration (AUC/MIC) based on animal models of infection.
Exposure-response analyses from both preclinical and clinical studies support the treatment of clinically relevant Gram-positive microorganisms (e.g. S. aureus and S. pyogenes) causative of ABSSSI with a single 1200 mg dose of oritavancin.
In a thorough QTc study of 135 healthy subjects at a dose 1.3 times the 1200 mg recommended dose, oritavancin did not prolong the QTc interval to any clinically relevant extent.
## Pharmacokinetics
The population PK analysis was derived using data from the two Phase 3 ABSSSI clinical trials in 297 patients. The mean pharmacokinetic parameters of oritavancin in patients following a single 1200 mg dose are presented in TABLE 2.
Oritavancin exhibits linear pharmacokinetics at a dose up to 1200 mg. The mean, population-predicted oritavancin concentration-time profile displays a multi-exponential decline with a long terminal plasma half-life as shown in FIGURE 1.
Oritavancin is approximately 85% bound to human plasma proteins.
Based on population PK analysis, the population mean total volume of distribution is estimated to be approximately 87.6 L, indicating oritavancin is extensively distributed into the tissues.
Exposures of oritavancin in skin blister fluid were approximately 20% of those in plasma (AUC0-24) after single 800 mg dose in healthy subjects.
Non-clinical studies including in vitro human liver microsome studies indicated that oritavancin is not metabolized. No mass balance study has been conducted in humans. In humans, oritavancin is slowly excreted unchanged in feces and urine with less than 1% and 5% of the dose recovered in feces and urine, respectively, after 2 weeks of collection.
Oritavancin has a terminal half-life of approximately 245 hours and a clearance of 0.445 L/h based on population pharmacokinetic analyses.
## Nonclinical Toxicology
In serial passage studies, resistance to oritavancin was observed in isolates of S. aureus and E. faecalis. Resistance to oritavancin was not observed in clinical studies.
In in vitro studies, oritavancin exhibits synergistic bactericidal activity in combination with gentamicin, moxifloxacin or rifampicin against isolates of methicillin-susceptible S. aureus (MSSA), with gentamicin or linezolid against isolates of heterogeneous vancomycin-intermediate S. aureus (hVISA), VISA, and vancomycin-resistant S. aureus (VRSA), and with rifampin against isolates of VRSA. In vitro studies demonstrated no antagonism between oritavancin and gentamicin, moxifloxacin, linezolid or rifampin.
Oritavancin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the Indications and Usage section.
- Staphylococcus aureus (including methicillin-resistant isolates)
- Streptococcus agalactiae
- Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus)
- Streptococcus dysgalactiae
- Streptococcus pyogenes
- Enterococcus faecalis (vancomycin-susceptible isolates only)
The following in vitro data are available but their clinical significance has not been established. At least 90% of isolates of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to 0.12 mcg/mL for oritavancin. However, the safety and effectiveness of oritavancin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.
- Enterococcus faecium (vancomycin-susceptible isolates only)
Long term studies in animals have not been conducted to determine the carcinogenic potential of oritavancin.
No mutagenic or clastogenic potential of oritavancin was found in a battery of tests, including an Ames assay, in vitro chromosome aberration assay in Chinese hamster ovary cells, in vitro forward mutation assay in mouse lymphoma cells and an in vivo mouse micronucleus assay.
# Clinical Studies
A total of 1987 adults with clinically documented ABSSSI suspected or proven to be due to Gram-positive pathogens were randomized into two identically designed, randomized, double-blind, multi-center, multinational, non-inferiority trials (Trial 1 and Trial 2) comparing a single 1200 mg intravenous dose of oritavancin to intravenous vancomycin (1 g or 15 mg/kg every 12 hours) for 7 to 10 days. The primary analysis population (modified intent to treat, mITT) included all randomized patients who received any study drug. Patients could receive concomitant aztreonam or metronidazole for suspected Gram-negative and anaerobic infection, respectively. Patient demographic and baseline characteristics were balanced between treatment groups. Approximately 64% of patients were Caucasian and 65% were males. The mean age was 45 years and the mean body mass index was 27 kg/m2. Across both trials, approximately 60% of patients were enrolled from the United States and 27% of patients from Asia. A history of diabetes was present in 14% of patients. The types of ABSSSI across both trials included cellulitis/erysipelas (40%), wound infection (29%), and major cutaneous abscesses (31%). Median infection area at baseline across both trials was 266.6 cm2.
The primary endpoint in both trials was early clinical response (responder), defined as cessation of spread or reduction in size of baseline lesion, absence of fever, and no rescue antibacterial drug at 48 to 72 hours after initiation of therapy.
TABLE 5 provides the efficacy results for the primary endpoint in Trial 1 and Trial 2 in the primary analysis population.
A key secondary endpoint in these two ABSSSI trials evaluated the percentage of patients achieving a 20% or greater reduction in lesion area from baseline at 48-72 hours after initiation of therapy. TABLE 6 summarizes the findings for this endpoint in the two ABSSSI trials.
Another secondary efficacy endpoint in the two trials was investigator-assessed clinical success at post therapy evaluation at day 14 to 24 (7 to 14 days from end of blinded therapy). A patient was categorized as a clinical success if the patient experienced a complete or nearly complete resolution of baseline signs and symptoms related to primary ABSSSI site (erythema, induration/edema, purulent drainage, fluctuance, pain, tenderness, local increase in heat/warmth) such that no further treatment with antibacterial drugs was needed.
TABLE 7 summarizes the findings for this endpoint in the mITT and clinically evaluable population in these two ABSSSI trials. Note that there are insufficient historical data to establish the magnitude of drug effect for antibacterial drugs compared with placebo at the post therapy visits. Therefore, comparisons of oritavancin to vancomycin based on clinical success rates at these visits cannot be utilized to establish non-inferiority conclusions.
Outcomes by Baseline Pathogen: TABLE 8 shows outcomes in patients with an identified baseline pathogen in the microbiological Intent-to-Treat (microITT) population in a pooled analysis of Trial 1 and Trial 2. The outcomes shown in the table are clinical response rates at 48 to 72 hours and clinical success rates at follow-up study day14 to 24.
# How Supplied
- Single use 50 mL capacity glass vials containing sterile lyophilized powder equivalent to 400 mg of oritavancin (NDC 65293-015-01).
## Storage
Stored at 20°C to 25°C (68°F to 77°F)
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment. They should inform their healthcare provider about any previous hypersensitivity reactions to oritavancin, other glycopeptides (vancomycin, telavancin, or dalbavancin) or other allergens.
Patients should be advised that diarrhea is a common problem caused by antibacterial drugs including oritavancin, which usually resolves when the drug is discontinued. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, patients should contact their healthcare provider.
# Precautions with Alcohol
Alcohol-Oritavancin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
- Orbactiv [1]
# Look-Alike Drug Names
There is limited information regarding Oritavancin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Oritavancin | |
6c07f8e1018f6d6f2f243ad0d39cbd90ccd3a201 | wikidoc | Orosomucoid | Orosomucoid
Orosomucoid (ORM) or alpha-1-acid glycoprotein (α1AGp, AGP or AAG) is an acute phase (acute phase protein) plasma alpha-globulin glycoprotein and is modulated by two polymorphic genes. It is synthesized primarily in hepatocytes and has a normal plasma concentration between 0.6-1.2 mg/mL (1-3% plasma protein). Plasma levels are affected by pregnancy, burns, certain drugs, and certain diseases, particularly HIV.
The only established function of ORM is to act as a carrier of basic and neutrally charged lipophilic compounds. In medicine, it is known as the primary carrier of basic (positively charged) drugs (whereas albumin carries acidic (negatively charged) and neutral drugs), steroids, and protease inhibitors. Aging causes a small decrease in plasma albumin levels; if anything, there is a small increase in alpha-1-acid glycoprotein. The effect of these changes on drug protein binding and drug delivery, however, appear to be minimal. AGP shows a complex interaction with thyroid homeostasis: ORM in low concentrations was observed to stimulate the thyrotropin (TSH) receptor and intracellular accumulation of cyclic AMP. High AGP concentrations, however, inhibited TSH signalling.
Alpha-1-acid glycoprotein has been identified as one of four potentially useful circulating biomarkers for estimating the five-year risk of all-cause mortality (the other three are albumin, very low-density lipoprotein particle size, and citrate).
Orosomucoid increases in amount in obstructive jaundices while diminishes in hepatocellular jaundice and in intestinal infections. | Orosomucoid
Orosomucoid (ORM) or alpha-1-acid glycoprotein (α1AGp,[1] AGP or AAG) is an acute phase (acute phase protein) plasma alpha-globulin glycoprotein and is modulated by two polymorphic genes. It is synthesized primarily in hepatocytes and has a normal plasma concentration between 0.6-1.2 mg/mL (1-3% plasma protein).[2] Plasma levels are affected by pregnancy, burns, certain drugs, and certain diseases, particularly HIV.[2]
The only established function of ORM is to act as a carrier of basic and neutrally charged lipophilic compounds. In medicine, it is known as the primary carrier of basic (positively charged) drugs (whereas albumin carries acidic (negatively charged) and neutral drugs), steroids, and protease inhibitors.[2][3] Aging causes a small decrease in plasma albumin levels; if anything, there is a small increase in alpha-1-acid glycoprotein. The effect of these changes on drug protein binding and drug delivery, however, appear to be minimal.[4] AGP shows a complex interaction with thyroid homeostasis: ORM in low concentrations was observed to stimulate the thyrotropin (TSH) receptor and intracellular accumulation of cyclic AMP. High AGP concentrations, however, inhibited TSH signalling.[5][6]
Alpha-1-acid glycoprotein has been identified as one of four potentially useful circulating biomarkers for estimating the five-year risk of all-cause mortality (the other three are albumin, very low-density lipoprotein particle size, and citrate).[7]
Orosomucoid increases in amount in obstructive jaundices while diminishes in hepatocellular jaundice and in intestinal infections. | https://www.wikidoc.org/index.php/Orosomucoid |
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