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2483a54153f7fbd37acffa3c57e4e33d79c184a5	wikidoc	Diurnality	Diurnality # Overview In animal behavior, diurnality is an animal that is active during the daytime and rests during the night. Animals that are not diurnal are either nocturnal (active at night) or crepuscular (active primarily during twilight, i.e., at dusk and dawn). Many animal species are diurnal, including many mammals, insects and birds. The diurnal pattern is often controlled internally by the circadian rhythm (endogenous rhythm) of the animal. In some animals, especially insects, external patterns of the environment control the activity (exogenous rhythms). Some mainly nocturnal or crepuscular animals have been domesticated as pets and have changed into diurnal animals to coincide with the cycle of human life. Examples are pet dogs and cats, which are derived from the wolf and the wild cat. However these animals may exhibit their species' original behaviour when they are born feral. # Notes - ↑ Gullan, P.J. and P.S. Cranston, 1994. The Insects: An Outline of Entomology. Chapman and Hall London. pg. 115. - ↑ Gullan and Cranston. de:Temporale Spezialisten is:Dagdýr nl:Diurnaal	Diurnality # Overview In animal behavior, diurnality is an animal that is active during the daytime and rests during the night. Animals that are not diurnal are either nocturnal (active at night) or crepuscular (active primarily during twilight, i.e., at dusk and dawn). [1] Many animal species are diurnal, including many mammals, insects and birds. The diurnal pattern is often controlled internally by the circadian rhythm (endogenous rhythm) of the animal. In some animals, especially insects, external patterns of the environment control the activity (exogenous rhythms).[2] Some mainly nocturnal or crepuscular animals have been domesticated as pets and have changed into diurnal animals to coincide with the cycle of human life. Examples are pet dogs and cats, which are derived from the wolf and the wild cat.[citation needed] However these animals may exhibit their species' original behaviour when they are born feral. # Notes - ↑ Gullan, P.J. and P.S. Cranston, 1994. The Insects: An Outline of Entomology. Chapman and Hall London. pg. 115. - ↑ Gullan and Cranston. de:Temporale Spezialisten is:Dagdýr nl:Diurnaal Template:WH Template:WS	https://www.wikidoc.org/index.php/Diurnal_animal
018ac79c2dc61e11124f6d878b1c5627602547c0	wikidoc	Divalproex	Divalproex # 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 Divalproex is a histone deacetylase inhibitor that is FDA approved for the treatment of mania ,migraine and epilepsy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, diarrhea, indigestion, loss of appetite, nausea, vomiting, asthenia, dizziness, feeling nervous, headache, insomnia, somnolence, tremor, amblyopia, blurred vision, diplopia, infectious disease and influenza. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Mania - Dosing information - Recommended initial dose: 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. - There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. ### Migraine - Dosing information - Depakote is indicated for prophylaxis of migraine headaches in adults. - Depakote tablets are administered orally. Recommended starting dose: 250 mg PO bid. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. ### Epilepsy - Complex Partial Seizures - Monotherapy (Initial Therapy) - Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. - The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. - Conversion to Monotherapy - Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. - Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. - Adjunctive Therapy - Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. - In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed . However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy. - Simple and Complex Absence Seizures - Recommended initial dose : 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. - The maximum recommended dosage: 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. - A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations. - As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected . - Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. - In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. ### General Dosing Advice - Dosing in Elderly Patients - Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response. - Dose-Related Adverse Reactions - The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) . The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. - G.I. Irritation - Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Divalproex in adult patients. ### Non–Guideline-Supported Use ### Behavioral syndrome - Dementia - Dosing information - Not applied ### Bipolar I disorder - Dosing information - 15 to 20 mg/kg/day ### Bipolar II disorder - Dosing information - 20 mg/kg/day ### Chronic Headache disorder - Dosing information - Not applied # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Epilepsy - Dosing information in children 10 years of age or older. - Monotherapy (Initial Therapy) - Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. - The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. - Conversion to Monotherapy - Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. - Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. - Adjunctive Therapy - Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. - In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed . However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy. - Simple and Complex Absence Seizures - Recommended initial dose : 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. - The maximum recommended dosage: 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. - A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations. - As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected . - Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. - In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Divalproex in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Divalproex in pediatric patients. # Contraindications - Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction . - Depakote is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder . - Depakote is contraindicated in patients with known hypersensitivity to the drug - Depakote is contraindicated in patients with known urea cycle disorders . - Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women # Warnings ### Hepatotoxicity General Information on Hepatotoxicity - Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. - Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Patients with Known or Suspected Mitochondrial Disease - Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder . Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. - POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. - In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver test monitoring. - The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug. ### Birth Defects - Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. ### Decreased IQ Following in utero Exposure - Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 ) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 ), carbamazepine (105 ), and phenytoin (108 ). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. - Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children. - In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits. - Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. ### Use in Women of Childbearing Potential - Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients. - To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. - Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. ### Pancreatitis - Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated . ### Urea Cycle Disorders - Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders. ### Brain Atrophy - There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use of valproate products; in some cases, patients recovered with permanent sequelae. The motor and cognitive functions of patients on valproate should be routinely monitored and drug should be evaluated for continued use in the presence of suspected or apparent signs of brain atrophy. Reports of cerebral atrophy have also been reported in children who were exposed in utero to valproate products. ### Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including Depakote, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. - The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. - The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. - Table 1 shows absolute and relative risk by indication for all evaluated AEDs. - The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Depakote or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. - Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. ### Thrombocytopenia - The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. - Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. ### Hyperammonemia - Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. hyperammonemia should also be considered in patients who present with hypothermia . If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders . Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. ### Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use - Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia . In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. ### Hypothermia - Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate . Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. ### Multi-Organ hypersensitivity Reactions - Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. ### Interaction with Carbapenem Antibiotics - Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates. ### somnolence in the Elderly - In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. ### Monitoring: Drug Plasma Concentration - Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy . ### Effect on Ketone and Thyroid Function Tests - Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. - There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. ### Effect on HIV and CMV Viruses Replication - There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. ### Medication Residue in the Stool - There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the labeling: - Hepatic failure - Birth defects - Decreased IQ following in utero exposure - Pancreatitis - Thrombocytopenia - Hyperammonemic encephalopathy - Multi-organ hypersensitivity reactions - Somnolence in the elderly - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. ### Mania - The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. - The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: - Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. - Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. - Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. - Hemic and Lymphatic System: Ecchymosis. - Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. - Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. - Respiratory System: Dyspnea, rhinitis. - Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. - Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. - Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. ### Epilepsy - Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo-treated patients. - Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. - Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. - The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: - Body as a Whole: Back pain, chest pain, malaise. - Cardiovascular System: Tachycardia, hypertension, palpitation. - Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. - Hemic and Lymphatic System: Petechia. - Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. - Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. - Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. - Skin and Appendages: Rash, pruritus, dry skin. - Special Senses: Taste perversion, abnormal vision, deafness, otitis media. - Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. ### Migraine - Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). - Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. - The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: - Body as a Whole: Chest pain, chills, face edema, fever and malaise. - Cardiovascular System: Vasodilatation. - Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. - Hemic and Lymphatic System: Ecchymosis. - Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. - Musculoskeletal System: Leg cramps and myalgia. - Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. - Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. - Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of Depakote. 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. - Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome. - Psychiatric: Emotional upset, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. - Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness. - Hematologic: Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. - Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion. - Genitourinary: Enuresis and urinary tract infection. Special Senses: Hearing loss. - Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis. # Drug Interactions ### Effects of Co-Administered Drugs on Valproate Clearance - Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. - In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. - Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. - The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin - A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem Antibiotics - A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating Carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates . Felbamate - A study involving the co-administration of 1,200 mg/day of Felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the Felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when Felbamate therapy is initiated. Rifampin - A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. - Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids - A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine - A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol - A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine - Cimetidine and ranitidine do not affect the clearance of valproate. ### Effects of Valproate on Other Drugs - Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. - The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline - Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. - carbamazepine/carbamazepine-10,11-Epoxide - Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam - The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam - Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide - Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine - In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital - Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. - Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin - Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide - From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin - In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine - In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen - Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Clozapine - In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium - Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam - Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Olanzapine - No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine. Oral Contraceptive Steroids - Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. ### Topiramate - Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy . Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder. - Pregnancy Category X for prophylaxis of migraine headaches. Pregnancy Registry - To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, /. Fetal Risk Summary - All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies. - Exposure in utero to valproate products has been associated with cerebral atrophy . Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. - An observational study has suggested that exposure to valproate products during pregnancy may increase the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval : 1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5%-1.6%) in children not exposed to valproate products. Because the study was observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder cannot be considered definitive. In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits. Clinical Considerations - Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). - Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy. - Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: - Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). - Valproate is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. - Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. - To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. - Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. - Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. - Patients taking valproate may develop clotting abnormalities. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. - Patients taking valproate may develop hepatic failure . Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Data Human - There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. - In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 ) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 ), carbamazepine (105 ) and phenytoin (108 ). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. - Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. - There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal - In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Divalproex in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Divalproex during labor and delivery. ### Nursing Mothers - Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. ### Pediatric Use - Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions . When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. - Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. - The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. - Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. - The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). - In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults. Juvenile Animal Toxicology - In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. ### Geriatic Use - No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. - A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence. - There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. ### Gender There is no FDA guidance on the use of Divalproex with respect to specific gender populations. ### Race There is no FDA guidance on the use of Divalproex with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Divalproex in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Divalproex in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Divalproex in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Divalproex in patients who are immunocompromised. # Administration and Monitoring ### Administration - Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. - Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. - Depakote Sprinkle Capsules are administered orally. As Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected. ### Monitoring - Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy # IV Compatibility - There is limited information about the IV Compatibility. # Overdosage - Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. - In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. - Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. # Pharmacology There is limited information regarding Divalproex Pharmacology in the drug label. ## Mechanism of Action - Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). ## Structure - Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: - Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. ## Pharmacodynamics - The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. - For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy - The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania - In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL ## Pharmacokinetics Absorption/Bioavailability - Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. - However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). - While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. - Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy . Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Distribution Protein Binding - The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) for more detailed information on the pharmacokinetic interactions of valproate with other drugs. CNS Distribution - Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism - Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. - The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination - Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. - The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates - Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children - Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly - The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly. Effect of Sex - There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race - The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease - Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal. Renal Disease - A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis - Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis - Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility - Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. # Clinical Studies ## Mania - The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: - Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: - Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. ### Epilepsy - The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. - In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. - Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. - The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post-randomization assessment. - Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. ### Migraine - The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. - Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. - In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. - In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. - The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. - In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. - The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. - The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. # How Supplied - Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: - Bottles of 100………………………………………..(NDC 0074-6212-13) - Unit Dose Packages of 100.................………………(NDC 0074-6212-11) 250 mg peach-colored tablets: - Bottles of 100……………………………………….(NDC 0074-6214-13) - Bottles of 500……………………………………….(NDC 0074-6214-53) - Unit Dose Packages of 100................………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Unit Dose Packages of 100................……………...(NDC 0074-6215-11) ## Storage - Store tablets below 86°F (30°C). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol - Alcohol-Divalproex interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Depakote® - Depakote ER - Depakote Sprinkles - Depakote DR # Look-Alike Drug Names - FDA Package Insert for Divalproex contains no information regarding look alike drug names. # Drug Shortage Status # Price	Divalproex Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, 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 Divalproex is a histone deacetylase inhibitor that is FDA approved for the treatment of mania ,migraine and epilepsy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, diarrhea, indigestion, loss of appetite, nausea, vomiting, asthenia, dizziness, feeling nervous, headache, insomnia, somnolence, tremor, amblyopia, blurred vision, diplopia, infectious disease and influenza. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Mania - Dosing information - Recommended initial dose: 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day. - There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during Depakote treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of Depakote in such longer-term treatment. Although there are no efficacy data that specifically address longer-term antimanic treatment with Depakote, the safety of Depakote in long-term use is supported by data from record reviews involving approximately 360 patients treated with Depakote for greater than 3 months. ### Migraine - Dosing information - Depakote is indicated for prophylaxis of migraine headaches in adults. - Depakote tablets are administered orally. Recommended starting dose: 250 mg PO bid. Some patients may benefit from doses up to 1,000 mg/day. In the clinical trials, there was no evidence that higher doses led to greater efficacy. ### Epilepsy - Complex Partial Seizures - Monotherapy (Initial Therapy) - Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. - The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. - Conversion to Monotherapy - Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. - Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. - Adjunctive Therapy - Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. - In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed . However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy. - Simple and Complex Absence Seizures - Recommended initial dose : 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. - The maximum recommended dosage: 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. - A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations. - As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected . - Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. - In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. ### General Dosing Advice - Dosing in Elderly Patients - Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response. - Dose-Related Adverse Reactions - The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) . The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. - G.I. Irritation - Patients who experience G.I. irritation may benefit from administration of the drug with food or by slowly building up the dose from an initial low level. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Divalproex in adult patients. ### Non–Guideline-Supported Use ### Behavioral syndrome - Dementia - Dosing information - Not applied [1] ### Bipolar I disorder - Dosing information - 15 to 20 mg/kg/day [2] ### Bipolar II disorder - Dosing information - 20 mg/kg/day [2] ### Chronic Headache disorder - Dosing information - Not applied [3] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Epilepsy - Dosing information in children 10 years of age or older. - Monotherapy (Initial Therapy) - Depakote has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. - The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. - Conversion to Monotherapy - Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. - Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks. This reduction may be started at initiation of Depakote therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. - Adjunctive Therapy - Depakote may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. - In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed . However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy. - Simple and Complex Absence Seizures - Recommended initial dose : 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. - The maximum recommended dosage: 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in divided doses. - A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect. However, therapeutic valproate serum concentrations for most patients with absence seizures is considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher serum concentrations. - As the Depakote dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected . - Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. - In epileptic patients previously receiving Depakene (valproic acid) therapy, Depakote tablets should be initiated at the same daily dose and dosing schedule. After the patient is stabilized on Depakote tablets, a dosing schedule of two or three times a day may be elected in selected patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Divalproex in pediatric patients. ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Divalproex in pediatric patients. # Contraindications - Depakote should not be administered to patients with hepatic disease or significant hepatic dysfunction . - Depakote is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder . - Depakote is contraindicated in patients with known hypersensitivity to the drug * Depakote is contraindicated in patients with known urea cycle disorders . - Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women # Warnings ### Hepatotoxicity General Information on Hepatotoxicity - Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. - Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When Depakote is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Patients with Known or Suspected Mitochondrial Disease - Depakote is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder . Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in patients with these syndromes have been identified in children and adolescents. - POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders. - In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote for the development of acute liver injury with regular clinical assessments and serum liver test monitoring. - The drug should be discontinued immediately in the presence of significant hepatic dysfunction, suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of drug. ### Birth Defects - Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. ### Decreased IQ Following in utero Exposure - Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies1 is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]), and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. - Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children. - In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits. - Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. ### Use in Women of Childbearing Potential - Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients. - To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. - Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. ### Pancreatitis - Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, Depakote should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning]. ### Urea Cycle Disorders - Depakote is contraindicated in patients with known urea cycle disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders. ### Brain Atrophy - There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use of valproate products; in some cases, patients recovered with permanent sequelae. The motor and cognitive functions of patients on valproate should be routinely monitored and drug should be evaluated for continued use in the presence of suspected or apparent signs of brain atrophy. Reports of cerebral atrophy have also been reported in children who were exposed in utero to valproate products. ### Suicidal Behavior and Ideation - Antiepileptic drugs (AEDs), including Depakote, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. - Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. - The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. - The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. - Table 1 shows absolute and relative risk by indication for all evaluated AEDs. - The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Depakote or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. - Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. ### Thrombocytopenia - The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 109/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects. - Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. ### Hyperammonemia - Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.12)]. If ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and Precautions (5.6, 5.11)]. Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. ### Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use - Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia . In most cases, symptoms and signs abated with discontinuation of either drug. This adverse reaction is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. ### Hypothermia - Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. ### Multi-Organ hypersensitivity Reactions - Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility. ### Interaction with Carbapenem Antibiotics - Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates. ### somnolence in the Elderly - In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. ### Monitoring: Drug Plasma Concentration - Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy . ### Effect on Ketone and Thyroid Function Tests - Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test. - There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown. ### Effect on HIV and CMV Viruses Replication - There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. ### Medication Residue in the Stool - There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are discussed in greater detail in other sections of the labeling: - Hepatic failure - Birth defects - Decreased IQ following in utero exposure - Pancreatitis - Thrombocytopenia - Hyperammonemic encephalopathy - Multi-organ hypersensitivity reactions - Somnolence in the elderly - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. ### Mania - The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, Depakote, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, Depakote, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the Depakote-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving Depakote compared to placebo. - The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 Depakote-treated patients in controlled clinical trials: - Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity. - Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation. - Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess. - Hemic and Lymphatic System: Ecchymosis. - Metabolic and Nutritional Disorders: Edema, peripheral edema. Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching. - Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo. - Respiratory System: Dyspnea, rhinitis. - Skin and Appendages: Alopecia, discoid lupus erythematosus, dry skin, furunculosis, maculopapular rash, seborrhea. - Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus. - Urogenital System: Dysmenorrhea, dysuria, urinary incontinence. ### Epilepsy - Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo-treated patients. - Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs. - Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs. - The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures: - Body as a Whole: Back pain, chest pain, malaise. - Cardiovascular System: Tachycardia, hypertension, palpitation. - Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. - Hemic and Lymphatic System: Petechia. - Metabolic and Nutritional Disorders: SGOT increased, SGPT increased. Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia. - Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. - Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis. - Skin and Appendages: Rash, pruritus, dry skin. - Special Senses: Taste perversion, abnormal vision, deafness, otitis media. - Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency. ### Migraine - Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%). - Table 5 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the Depakote-treated group was greater than 5% and was greater than that for placebo patients. - The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 Depakote-treated patients in the controlled clinical trials: - Body as a Whole: Chest pain, chills, face edema, fever and malaise. - Cardiovascular System: Vasodilatation. - Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis. - Hemic and Lymphatic System: Ecchymosis. - Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase. - Musculoskeletal System: Leg cramps and myalgia. - Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo. Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis. - Skin and Appendages: Pruritus and rash. Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus. - Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of Depakote. 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. - Dermatologic: Photosensitivity, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome. - Psychiatric: Emotional upset, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. - Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness. - Hematologic: Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria. - Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion. - Genitourinary: Enuresis and urinary tract infection. Special Senses: Hearing loss. - Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis. # Drug Interactions ### Effects of Co-Administered Drugs on Valproate Clearance - Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. - In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. - Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. - The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin - A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem Antibiotics - A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating Carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates . Felbamate - A study involving the co-administration of 1,200 mg/day of Felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the Felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when Felbamate therapy is initiated. Rifampin - A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. - Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Antacids - A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate. Chlorpromazine - A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate. Haloperidol - A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels. Cimetidine and Ranitidine - Cimetidine and ranitidine do not affect the clearance of valproate. ### Effects of Valproate on Other Drugs - Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. - The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline - Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. - carbamazepine/carbamazepine-10,11-Epoxide - Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam - The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam - Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide - Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine - In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital - Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. - Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin - Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Tolbutamide - From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin - In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine - In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. Drugs for which either no interaction or a likely clinically unimportant interaction has been observed Acetaminophen - Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients. Clozapine - In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine. Lithium - Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium. Lorazepam - Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. Olanzapine - No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in Cmax and 35% reduction in AUC of olanzapine. Oral Contraceptive Steroids - Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction. ### Topiramate - Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy . Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder. - Pregnancy Category X for prophylaxis of migraine headaches. Pregnancy Registry - To collect information on the effects of in utero exposure to Depakote, physicians should encourage pregnant patients taking Depakote to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary - All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations). The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies. - Exposure in utero to valproate products has been associated with cerebral atrophy . Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. - An observational study has suggested that exposure to valproate products during pregnancy may increase the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5%-1.6%) in children not exposed to valproate products. Because the study was observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder cannot be considered definitive. In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits. Clinical Considerations - Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1-2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). - Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy. - Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: - Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). - Valproate is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. - Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. - To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient. - Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. - Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. - Patients taking valproate may develop clotting abnormalities. A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used in pregnancy, the clotting parameters should be monitored carefully. - Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also been reported following maternal use of valproate during pregnancy. Data Human - There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to be approximately 1 to 2%. - In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% (95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy (dose range 500-2,000 mg/day). The major malformation rate among the internal comparison group of 1,048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy was 2.9% (95% CI 2.0% to 4.1%). These data show a four-fold increased risk for any major malformation (Odds Ratio 4.0; 95% CI 2.1 to 7.4) following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy. Published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero. The largest of these studies is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I. 104–112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. - Although all of the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in utero and subsequent adverse effects on cognitive development. - There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy. Animal - In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following treatment of pregnant animals with valproate during organogenesis at clinically relevant doses (calculated on a body surface area basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Divalproex in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Divalproex during labor and delivery. ### Nursing Mothers - Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a nursing woman. ### Pediatric Use - Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning and Warnings and Precautions (5.1)]. When valproate is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. - Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. - The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials Depakote was studied in seven pediatric clinical trials. - Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash. - The remaining five trials were long term safety studies. Two six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years). - In these seven clinical trials, the safety and tolerability of Depakote in pediatric patients were shown to be comparable to those in adults. Juvenile Animal Toxicology - In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m2 basis. ### Geriatic Use - No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients. - A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence. - There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65. ### Gender There is no FDA guidance on the use of Divalproex with respect to specific gender populations. ### Race There is no FDA guidance on the use of Divalproex with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Divalproex in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Divalproex in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Divalproex in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Divalproex in patients who are immunocompromised. # Administration and Monitoring ### Administration - Depakote tablets are intended for oral administration. Depakote tablets should be swallowed whole and should not be crushed or chewed. - Patients should be informed to take Depakote every day as prescribed. If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. - Depakote Sprinkle Capsules are administered orally. As Depakote dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected. ### Monitoring - Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy # IV Compatibility - There is limited information about the IV Compatibility. # Overdosage - Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120 mcg/mL. - In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. - Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy. # Pharmacology There is limited information regarding Divalproex Pharmacology in the drug label. ## Mechanism of Action - Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA). ## Structure - Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: - Divalproex sodium occurs as a white powder with a characteristic odor. Depakote tablets are for oral administration. Depakote tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. ## Pharmacodynamics - The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. - For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. Epilepsy - The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations. Mania - In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 50 and 125 mcg/mL ## Pharmacokinetics Absorption/Bioavailability - Equivalent oral doses of Depakote (divalproex sodium) products and Depakene (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. - However, it is possible that differences among the various valproate products in Tmax and Cmax could be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tmax from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tmax from 3.3 to 4.8 hours). - While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. - Co-administration of oral valproate products with food and substitution among the various Depakote and Depakene formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2)]. Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. Distribution Protein Binding - The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) for more detailed information on the pharmacokinetic interactions of valproate with other drugs. CNS Distribution - Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration). Metabolism - Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. - The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear. Elimination - Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m2 and 11 L/1.73 m2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m2 and 92 L/1.73 m2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg. - The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn. Special Populations Effect of Age Neonates - Children within the first two months of life have a markedly decreased ability to eliminate valproate compared to older children and adults. This is a result of reduced clearance (perhaps due to delay in development of glucuronosyltransferase and other enzyme systems involved in valproate elimination) as well as increased volume of distribution (in part due to decreased plasma protein binding). For example, in one study, the half-life in children under 10 days ranged from 10 to 67 hours compared to a range of 7 to 13 hours in children greater than 2 months. Children - Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults. Elderly - The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly. Effect of Sex - There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 L/hr per 1.73 m2, respectively). Effect of Race - The effects of race on the kinetics of valproate have not been studied. Effect of Disease Liver Disease - Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal. Renal Disease - A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis - Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown. Mutagenesis - Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate, but this association was not observed in another study conducted in adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The biological significance of an increase in SCE frequency is not known. Fertility - Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m2 basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m2 basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m2 basis) for 60 days. The effect of valproate on testicular development and on sperm production and fertility in humans is unknown. # Clinical Studies ## Mania - The effectiveness of Depakote for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment. Depakote was initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. Mean Depakote doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: - Depakote was statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Depakote was initiated at a dose of 250 mg tid and adjusted within a dose range of 750-2,500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. Mean Depakote doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS). Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: - Depakote was statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1. ### Epilepsy - The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. - In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings. - Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo. - The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if 1) they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings for all patients randomized who had at least one post-randomization assessment. - Figure 3 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate. ### Migraine - The results of two multicenter, randomized, double-blind, placebo-controlled clinical trials established the effectiveness of Depakote in the prophylactic treatment of migraine headache. - Both studies employed essentially identical designs and recruited patients with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Patients with cluster headaches were excluded. Women of childbearing potential were excluded entirely from one study, but were permitted in the other if they were deemed to be practicing an effective method of contraception. - In each study following a 4-week single-blind placebo baseline period, patients were randomized, under double blind conditions, to Depakote or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period. Treatment outcome was assessed on the basis of 4-week migraine headache rates during the treatment phase. - In the first study, a total of 107 patients (24 M, 83 F), ranging in age from 26 to 73 were randomized 2:1, Depakote to placebo. Ninety patients completed the 8-week maintenance period. Drug dose titration, using 250 mg tablets, was individualized at the investigator's discretion. Adjustments were guided by actual/sham trough total serum valproate levels in order to maintain the study blind. In patients on Depakote doses ranged from 500 to 2,500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1,087 mg/day resulting in a mean trough total valproate level of 72.5 mcg/mL, with a range of 31 to 133 mcg/mL. - The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the Depakote group (see Figure 4). These rates were significantly different. - In the second study, a total of 176 patients (19 males and 157 females), ranging in age from 17 to 76 years, were randomized equally to one of three Depakote dose groups (500, 1,000, or 1,500 mg/day) or placebo. The treatments were given in two divided doses (BID). One hundred thirty-seven patients completed the 8-week maintenance period. Efficacy was to be determined by a comparison of the 4-week migraine headache rate in the combined 1,000/1,500 mg/day group and placebo group. - The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. The mean trough total valproate levels during the treatment phase were 39.6, 62.5, and 72.5 mcg/mL in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively. - The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the Depakote 500, 1,000, and 1,500 mg/day groups, respectively, based on intent-to-treat results (see Figure 4). migraine headache rates in the combined Depakote 1,000/1,500 mg group were significantly lower than in the placebo group. # How Supplied - Depakote tablets (divalproex sodium delayed-release tablets) are supplied as: 125 mg salmon pink-colored tablets: - Bottles of 100………………………………………..(NDC 0074-6212-13) - Unit Dose Packages of 100.................………………(NDC 0074-6212-11) 250 mg peach-colored tablets: - Bottles of 100……………………………………….(NDC 0074-6214-13) - Bottles of 500……………………………………….(NDC 0074-6214-53) - Unit Dose Packages of 100................………………(NDC 0074-6214-11) 500 mg lavender-colored tablets: Bottles of 100……………………………………….(NDC 0074-6215-13) Bottles of 500……………………………………….(NDC 0074-6215-53) Unit Dose Packages of 100................……………...(NDC 0074-6215-11) ## Storage - Store tablets below 86°F (30°C). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information # Precautions with Alcohol - Alcohol-Divalproex interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Depakote®[4] - Depakote ER - Depakote Sprinkles - Depakote DR # Look-Alike Drug Names - FDA Package Insert for Divalproex contains no information regarding look alike drug names. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Divalproex
81ca3a27c95586d0640b59ae0541fecc1ea8f49c	wikidoc	Dobutamine	Dobutamine - Inotropic support in the short-term treatment of adults with cardiac decompensation due to depressed contractility resulting either from organic heart disease or from cardiac surgical procedures - Dosing Information - Initial dose: 0.5 to 1 mcg/kg/min - Maintenance dose: 2 to 40 mcg/kg/min - Dosing Information - Initial dose: 0.5 to 1 mcg/kg/min - Maintenance dose: 2 to 40 mcg/kg/min - Dosing Information - Infusion 7.7 mcg/kg/minute - Dosing Information - 5-15 mcg/kg/m2 - Dosing Information - 10 mcg/kg/min IV 5 min prior to and during MRI. - Dosing Information - 5 mcg/kg/min - Dosing Information - 5-20 mcg/kg/min every 3 min - Dosing Information - 5 to 40 mcg/kg/min - Dosing Information - 8.3 mcg/kg/min - Dosing Information - 10 mcg/kg/min - Dosing Information - Dobutamine up to 40 mcg/kg/min in combination with atropine (1mg) - Dosing Information - Initial dose: 2.0 mcg/kg/min - Maintenance dose: increase 2.0 mcg/kg/min every 20 minutes - Dosing Information - 7.5 mcg/kg/min - Dosing Information - up to 30 mcg/kg/min - Patients who have shown previous manifestations of hypersensitivity to dobutamine. - Dobutamine hydrochloride may cause a marked increase in heart rate or blood pressure, especially systolic pressure. - Approximately 10% of patients in clinical studies have had rate increases of 30 beats/minute or more, and about 7.5% have had a 50 mm Hg or greater increase in systolic pressure. Usually, reduction of dosage promptly reverses these effects. - Because dobutamine hydrochloride facilitates atrioventricular conduction, patients with atrial fibrillation are at risk of developing rapid ventricular response. - Patients with pre-existing hypertension appear to face an increased risk of developing an exaggerated pressor response. # Ectopic Activity - Dobutamine hydrochloride may precipitate or exacerbate ventricular ectopic activity, but it rarely has caused ventricular tachycardia. # Hypersensitivity - Reactions suggestive of hypersensitivity associated with administration of Dobutamine Injection, USP, including skin rash, fever, eosinophilia, and bronchospasm, have been reported occasionally. - Dobutamine Injection, USP contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in certain susceptible people. - The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. - An increase in heart rate of 5 to 15 beats/minute has been noted in most patients. - The effect is dose related. - A 10- to 20-mm increase in systolic blood pressure has been noted in most patients. - The effect is dose related. - Approximately 5% of patients have had increased premature ventricular beats during infusions. - The effect is dose related. # Hypotension - Precipitous decreases in blood pressure have occasionally been described in association with dobutamine therapy. - Decreasing the dose or discontinuing the infusion typically results in rapid return of blood pressure to baseline values. - In rare cases, however, intervention may be required and reversibility may not be immediate. # Reactions at Sites of Intravenous Infusion - Phlebitis has occasionally been reported. - Local inflammatory changes have been described following inadvertent infiltration. - Isolated cases of cutaneous necrosis (destruction of skin tissue) have been reported. # Miscellaneous Uncommon Effects The following adverse effects have been reported in 1% to 3% of patients: - Nausea - Headache - Angina - Nonspecific chest pain - Palpitations - Shortness of breath - Isolated cases of thrombocytopenia have been reported. Administration of dobutamine, like other catecholamines, can produce a mild reduction in serum potassium concentration, rarely to hypokalemic levels. # Longer-Term Safety - Infusions of up to 72 hours have revealed no adverse effects other than those seen with shorter infusions - Preliminary studies indicate that the concomitant use of dobutamine and nitroprusside results in a higher cardiac output and, usually, a lower pulmonary wedge pressure than when either drug is used alone. - There was no evidence of drug interactions in clinical studies in which dobutamine was administered concurrently with other drugs, including digitalis preparations, furosemide, spironolactone, lidocaine, nitroglycerin, isosorbide dinitrate, morphine, atropine, heparin, protamine, potassium chloride, folic acid, and acetaminophen. - The rate of administration and the duration of therapy should be adjusted according to the patient's response as determined by heart rate, presence of ectopic activity, blood pressure, urine flow, and, whenever possible, measurement of central venous or pulmonary wedge pressure and cardiac output. - Concentrations of up to 5,000 mcg/mL have been administered to humans (250 mg/50 mL). The final volume administered should be determined by the fluid requirements of the patient. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - During the administration of dobutamine Injection, USP, as with any adrenergic agent, ECG and blood pressure should be continuously monitored. In addition, pulmonary wedge pressure and cardiac output should be monitored whenever possible to aid in the safe and effective infusion of dobutamine hydrochloride. - Hypovolemia should be corrected with suitable volume expanders before treatment with dobutamine hydrochloride is instituted. - No improvement may be observed in the presence of marked mechanical obstruction, such as severe valvular aortic stenosis. # Usage Following Acute Myocardial Infarction - Clinical experience with dobutamine hydrochloride following myocardial infarction has been insufficient to establish the safety of the drug for this use. - There is concern that any agent that increases contractile force and heart rate may increase the size of an infarction by intensifying ischemia, but it is not known whether dobutamine hydrochloride does so. # Laboratory Tests - Dobutamine, like other β2-agonists, can produce a mild reduction in serum potassium concentration, rarely to hypokalemic levels. - Accordingly, consideration should be given to monitoring serum potassium. - Intravenous solutions should be used within 24 hours. # Signs and Symptoms - Toxicity from dobutamine is usually due to excessive cardiac β-receptor stimulation. - The duration of action of dobutamine is generally short (T1/2 = 2 minutes) because it is rapidly metabolized by catechol-O-methyltransferase. - The symptoms of toxicity may include anorexia, nausea, vomiting, tremor, anxiety, palpitations, headache, shortness of breath, and anginal and nonspecific chest pain. - The positive inotropic and chronotropic effects of dobutamine on the myocardium may cause hypertension, tachyarrhythmias, myocardial ischemia, and ventricular fibrillation. - Hypotension may result from vasodilation. # Management - The initial actions to be taken in a dobutamine overdose are discontinuing administration, establishing an airway, and ensuring oxygenation and ventilation. - Resuscitative measures should be initiated promptly. Severe ventricular tachyarrhythmias may be successfully treated with propranolol or lidocaine. - Hypertension usually responds to a reduction in dose or discontinuation of therapy. - Protect the patient's airway and support ventilation and perfusion. - If needed, meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. If the product is ingested, unpredictable absorption may occur from the mouth and the gastrointestinal tract. - Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. - Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. - Safeguard the patient's airway when employing gastric emptying or charcoal. - Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemo-perfusion have not been established as beneficial for an overdose of dobutamine. In patients with depressed cardiac function, both dobutamine hydrochloride and isoproterenol increase the cardiac output to a similar degree. In the case of dobutamine hydrochloride, this increase is usually not accompanied by marked increases in heart rate (although tachycardia is occasionally observed), and the cardiac stroke volume is usually increased. In contrast, isoproterenol increases the cardiac index primarily by increasing the heart rate while stroke volume changes little or declines. Facilitation of atrioventricular conduction has been observed in human electrophysiologic studies and in patients with atrial fibrillation. Systemic vascular resistance is usually decreased with administration of dobutamine hydrochloride. Occasionally, minimum vasoconstriction has been observed. Most clinical experience with dobutamine hydrochloride is short-term − not more than several hours in duration. In the limited number of patients who were studied for 24, 48, and 72 hours, a persistent increase in cardiac output occurred in some, whereas output returned toward baseline values in others. - Dobutamine Hydrochloride, USP is chemically designated (±)-4-2-3-(ρ-hydroxyphenyl)-1-methylpropyl] amino]ethyl]-pyrocatechol hydrochloride. - It is a synthetic catecholamine. - Molecular Weight: 337.85 - Molecular Formula: C18H23NO3 - HCl The plasma half-life of dobutamine hydrochloride in humans is 2 minutes. The principal routes of metabolism are methylation of the catechol and conjugation. In human urine, the major excretion products are the conjugates of dobutamine and 3-O-methyl dobutamine. The 3-O-methyl derivative of dobutamine is inactive. Studies to evaluate the carcinogenic or mutagenic potential of dobutamine hydrochloride, or its potential to affect fertility, have not been conducted. - ↑ N. A. Awan, M. K. Evenson, K. E. Needham, J. M. Beattie & D. T. Mason (1983). "Effect of combined nitroglycerin and dobutamine infusion in left ventricular dysfunction". American heart journal. 106 (1 Pt 1): 35–40. PMID 6408917. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ A. Masoni, P. Alboni, C. Malacarne & L. Codeca (1979). "Effects of dobutamine on electrophysiological properties of the specialized conduction system in man". Journal of electrocardiology. 12 (4): 361–370. PMID 512532. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ F. M. Baer, P. Theissen, C. A. Schneider, E. Voth, U. Sechtem, H. Schicha & E. Erdmann (1998). "Dobutamine magnetic resonance imaging predicts contractile recovery of chronically dysfunctional myocardium after successful revascularization". Journal of the American College of Cardiology. 31 (5): 1040–1048. PMID 9562005. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ N. Takeyasu, S. Watanabe, R. Ajisaka, K. Eda, M. Toyama, K. Sakamoto, T. Saito, T. Yamanouchi, T. Masuoka, T. Takeda, Y. Itai, Y. Sugishita & I. Yamaguchi (2000). "Low-dose dobutamine radionuclide ventriculography for prediction of myocardial viability: quantitative analysis of regional left ventricular function". Clinical cardiology. 23 (6): 409–414. PMID 10875029. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ M. H. Hwang, I. Pacold, Z. E. Piao, R. Engelmeier, P. J. Scanlon & H. S. Loeb (1986). "The usefulness of dobutamine in the assessment of the severity of mitral stenosis". American heart journal. 111 (2): 312–316. PMID 3946174. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ S. Severi, R. Underwood, R. H. Mohiaddin, H. Boyd, M. Paterni & P. G. Camici (1995). "Dobutamine stress: effects on regional myocardial blood flow and wall motion". Journal of the American College of Cardiology. 26 (5): 1187–1195. doi:10.1016/0735-1097(95)00319-3. PMID 7594031. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ F. Jardin, B. Genevray, D. Brun-Ney & A. Margairaz (1985). "Dobutamine: a hemodynamic evaluation in pulmonary embolism shock". Critical care medicine. 13 (12): 1009–1012. PMID 4064710. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ J. Berre, D. De Backer, J. J. Moraine, C. Melot, R. J. Kahn & J. L. Vincent (1997). "Dobutamine increases cerebral blood flow velocity and jugular bulb hemoglobin saturation in septic patients". Critical care medicine. 25 (3): 392–398. PMID 9118652. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ A. Elhendy, F. B. Sozzi, R. Valkema, R. T. van Domburg, J. J. Bax & J. R. Roelandt (2000). "Dobutamine technetium-99m tetrofosmin SPECT imaging for the diagnosis of coronary artery disease in patients with limited exercise capacity". Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 7 (6): 649–654. doi:10.1067/mnc.2000.109660. PMID 11144480. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ C. J. Jr Fisher, Z. Horowitz & T. E. Albertson (1985). "Cardiorespiratory failure in toxic shock syndrome: effect of dobutamine". Critical care medicine. 13 (3): 160–165. PMID 3971725. Unknown parameter \|month= ignored (help) - ↑ R. M. Perkin, D. L. Levin, R. Webb, A. Aquino & J. Reedy (1982). "Dobutamine: a hemodynamic evaluation in children with shock". The Journal of pediatrics. 100 (6): 977–983. PMID 7086606. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ N. Noto, M. Ayusawa, K. Karasawa, H. Yamaguchi, N. Sumitomo, T. Okada & K. Harada (1996). "Dobutamine stress echocardiography for detection of coronary artery stenosis in children with Kawasaki disease". Journal of the American College of Cardiology. 27 (5): 1251–1256. doi:10.1016/0735-1097(95)00570-6. PMID 8609352. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link)	Dobutamine - Inotropic support in the short-term treatment of adults with cardiac decompensation due to depressed contractility resulting either from organic heart disease or from cardiac surgical procedures - Dosing Information - Initial dose: 0.5 to 1 mcg/kg/min - Maintenance dose: 2 to 40 mcg/kg/min - Dosing Information - Initial dose: 0.5 to 1 mcg/kg/min - Maintenance dose: 2 to 40 mcg/kg/min - Dosing Information - Infusion 7.7 mcg/kg/minute[1] - Dosing Information - 5-15 mcg/kg/m2[2] - Dosing Information - 10 mcg/kg/min IV 5 min prior to and during MRI. [3] - Dosing Information - 5 mcg/kg/min[4] - Dosing Information - 5-20 mcg/kg/min every 3 min [5] - Dosing Information - 5 to 40 mcg/kg/min[6] - Dosing Information - 8.3 mcg/kg/min[7] - Dosing Information - 10 mcg/kg/min [8] - Dosing Information - Dobutamine up to 40 mcg/kg/min in combination with atropine (1mg)[9] - Dosing Information [10] - Initial dose: 2.0 mcg/kg/min - Maintenance dose: increase 2.0 mcg/kg/min every 20 minutes - Dosing Information - 7.5 mcg/kg/min [11] - Dosing Information - up to 30 mcg/kg/min [12] - Patients who have shown previous manifestations of hypersensitivity to dobutamine. - Dobutamine hydrochloride may cause a marked increase in heart rate or blood pressure, especially systolic pressure. - Approximately 10% of patients in clinical studies have had rate increases of 30 beats/minute or more, and about 7.5% have had a 50 mm Hg or greater increase in systolic pressure. Usually, reduction of dosage promptly reverses these effects. - Because dobutamine hydrochloride facilitates atrioventricular conduction, patients with atrial fibrillation are at risk of developing rapid ventricular response. - Patients with pre-existing hypertension appear to face an increased risk of developing an exaggerated pressor response. ### Ectopic Activity - Dobutamine hydrochloride may precipitate or exacerbate ventricular ectopic activity, but it rarely has caused ventricular tachycardia. ### Hypersensitivity - Reactions suggestive of hypersensitivity associated with administration of Dobutamine Injection, USP, including skin rash, fever, eosinophilia, and bronchospasm, have been reported occasionally. - Dobutamine Injection, USP contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in certain susceptible people. - The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people. - An increase in heart rate of 5 to 15 beats/minute has been noted in most patients. - The effect is dose related. - A 10- to 20-mm increase in systolic blood pressure has been noted in most patients. - The effect is dose related. - Approximately 5% of patients have had increased premature ventricular beats during infusions. - The effect is dose related. ### Hypotension - Precipitous decreases in blood pressure have occasionally been described in association with dobutamine therapy. - Decreasing the dose or discontinuing the infusion typically results in rapid return of blood pressure to baseline values. - In rare cases, however, intervention may be required and reversibility may not be immediate. ### Reactions at Sites of Intravenous Infusion - Phlebitis has occasionally been reported. - Local inflammatory changes have been described following inadvertent infiltration. - Isolated cases of cutaneous necrosis (destruction of skin tissue) have been reported. ### Miscellaneous Uncommon Effects The following adverse effects have been reported in 1% to 3% of patients: - Nausea - Headache - Angina - Nonspecific chest pain - Palpitations - Shortness of breath - Isolated cases of thrombocytopenia have been reported. Administration of dobutamine, like other catecholamines, can produce a mild reduction in serum potassium concentration, rarely to hypokalemic levels. ### Longer-Term Safety - Infusions of up to 72 hours have revealed no adverse effects other than those seen with shorter infusions - Preliminary studies indicate that the concomitant use of dobutamine and nitroprusside results in a higher cardiac output and, usually, a lower pulmonary wedge pressure than when either drug is used alone. - There was no evidence of drug interactions in clinical studies in which dobutamine was administered concurrently with other drugs, including digitalis preparations, furosemide, spironolactone, lidocaine, nitroglycerin, isosorbide dinitrate, morphine, atropine, heparin, protamine, potassium chloride, folic acid, and acetaminophen. - The rate of administration and the duration of therapy should be adjusted according to the patient's response as determined by heart rate, presence of ectopic activity, blood pressure, urine flow, and, whenever possible, measurement of central venous or pulmonary wedge pressure and cardiac output. - Concentrations of up to 5,000 mcg/mL have been administered to humans (250 mg/50 mL). The final volume administered should be determined by the fluid requirements of the patient. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. - During the administration of dobutamine Injection, USP, as with any adrenergic agent, ECG and blood pressure should be continuously monitored. In addition, pulmonary wedge pressure and cardiac output should be monitored whenever possible to aid in the safe and effective infusion of dobutamine hydrochloride. - Hypovolemia should be corrected with suitable volume expanders before treatment with dobutamine hydrochloride is instituted. - No improvement may be observed in the presence of marked mechanical obstruction, such as severe valvular aortic stenosis. ### Usage Following Acute Myocardial Infarction - Clinical experience with dobutamine hydrochloride following myocardial infarction has been insufficient to establish the safety of the drug for this use. - There is concern that any agent that increases contractile force and heart rate may increase the size of an infarction by intensifying ischemia, but it is not known whether dobutamine hydrochloride does so. ### Laboratory Tests - Dobutamine, like other β2-agonists, can produce a mild reduction in serum potassium concentration, rarely to hypokalemic levels. - Accordingly, consideration should be given to monitoring serum potassium. - Intravenous solutions should be used within 24 hours. ### Signs and Symptoms - Toxicity from dobutamine is usually due to excessive cardiac β-receptor stimulation. - The duration of action of dobutamine is generally short (T1/2 = 2 minutes) because it is rapidly metabolized by catechol-O-methyltransferase. - The symptoms of toxicity may include anorexia, nausea, vomiting, tremor, anxiety, palpitations, headache, shortness of breath, and anginal and nonspecific chest pain. - The positive inotropic and chronotropic effects of dobutamine on the myocardium may cause hypertension, tachyarrhythmias, myocardial ischemia, and ventricular fibrillation. - Hypotension may result from vasodilation. ### Management - The initial actions to be taken in a dobutamine overdose are discontinuing administration, establishing an airway, and ensuring oxygenation and ventilation. - Resuscitative measures should be initiated promptly. Severe ventricular tachyarrhythmias may be successfully treated with propranolol or lidocaine. - Hypertension usually responds to a reduction in dose or discontinuation of therapy. - Protect the patient's airway and support ventilation and perfusion. - If needed, meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. If the product is ingested, unpredictable absorption may occur from the mouth and the gastrointestinal tract. - Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. - Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. - Safeguard the patient's airway when employing gastric emptying or charcoal. - Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemo-perfusion have not been established as beneficial for an overdose of dobutamine. In patients with depressed cardiac function, both dobutamine hydrochloride and isoproterenol increase the cardiac output to a similar degree. In the case of dobutamine hydrochloride, this increase is usually not accompanied by marked increases in heart rate (although tachycardia is occasionally observed), and the cardiac stroke volume is usually increased. In contrast, isoproterenol increases the cardiac index primarily by increasing the heart rate while stroke volume changes little or declines. Facilitation of atrioventricular conduction has been observed in human electrophysiologic studies and in patients with atrial fibrillation. Systemic vascular resistance is usually decreased with administration of dobutamine hydrochloride. Occasionally, minimum vasoconstriction has been observed. Most clinical experience with dobutamine hydrochloride is short-term − not more than several hours in duration. In the limited number of patients who were studied for 24, 48, and 72 hours, a persistent increase in cardiac output occurred in some, whereas output returned toward baseline values in others. - Dobutamine Hydrochloride, USP is chemically designated (±)-4-2-3-(ρ-hydroxyphenyl)-1-methylpropyl] amino]ethyl]-pyrocatechol hydrochloride. - It is a synthetic catecholamine. - Molecular Weight: 337.85 - Molecular Formula: C18H23NO3 • HCl The plasma half-life of dobutamine hydrochloride in humans is 2 minutes. The principal routes of metabolism are methylation of the catechol and conjugation. In human urine, the major excretion products are the conjugates of dobutamine and 3-O-methyl dobutamine. The 3-O-methyl derivative of dobutamine is inactive. Studies to evaluate the carcinogenic or mutagenic potential of dobutamine hydrochloride, or its potential to affect fertility, have not been conducted. - ↑ N. A. Awan, M. K. Evenson, K. E. Needham, J. M. Beattie & D. T. Mason (1983). "Effect of combined nitroglycerin and dobutamine infusion in left ventricular dysfunction". American heart journal. 106 (1 Pt 1): 35–40. PMID 6408917. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ A. Masoni, P. Alboni, C. Malacarne & L. Codeca (1979). "Effects of dobutamine on electrophysiological properties of the specialized conduction system in man". Journal of electrocardiology. 12 (4): 361–370. PMID 512532. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ F. M. Baer, P. Theissen, C. A. Schneider, E. Voth, U. Sechtem, H. Schicha & E. Erdmann (1998). "Dobutamine magnetic resonance imaging predicts contractile recovery of chronically dysfunctional myocardium after successful revascularization". Journal of the American College of Cardiology. 31 (5): 1040–1048. PMID 9562005. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ N. Takeyasu, S. Watanabe, R. Ajisaka, K. Eda, M. Toyama, K. Sakamoto, T. Saito, T. Yamanouchi, T. Masuoka, T. Takeda, Y. Itai, Y. Sugishita & I. Yamaguchi (2000). "Low-dose dobutamine radionuclide ventriculography for prediction of myocardial viability: quantitative analysis of regional left ventricular function". Clinical cardiology. 23 (6): 409–414. PMID 10875029. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ M. H. Hwang, I. Pacold, Z. E. Piao, R. Engelmeier, P. J. Scanlon & H. S. Loeb (1986). "The usefulness of dobutamine in the assessment of the severity of mitral stenosis". American heart journal. 111 (2): 312–316. PMID 3946174. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ S. Severi, R. Underwood, R. H. Mohiaddin, H. Boyd, M. Paterni & P. G. Camici (1995). "Dobutamine stress: effects on regional myocardial blood flow and wall motion". Journal of the American College of Cardiology. 26 (5): 1187–1195. doi:10.1016/0735-1097(95)00319-3. PMID 7594031. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ F. Jardin, B. Genevray, D. Brun-Ney & A. Margairaz (1985). "Dobutamine: a hemodynamic evaluation in pulmonary embolism shock". Critical care medicine. 13 (12): 1009–1012. PMID 4064710. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ J. Berre, D. De Backer, J. J. Moraine, C. Melot, R. J. Kahn & J. L. Vincent (1997). "Dobutamine increases cerebral blood flow velocity and jugular bulb hemoglobin saturation in septic patients". Critical care medicine. 25 (3): 392–398. PMID 9118652. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ A. Elhendy, F. B. Sozzi, R. Valkema, R. T. van Domburg, J. J. Bax & J. R. Roelandt (2000). "Dobutamine technetium-99m tetrofosmin SPECT imaging for the diagnosis of coronary artery disease in patients with limited exercise capacity". Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 7 (6): 649–654. doi:10.1067/mnc.2000.109660. PMID 11144480. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ C. J. Jr Fisher, Z. Horowitz & T. E. Albertson (1985). "Cardiorespiratory failure in toxic shock syndrome: effect of dobutamine". Critical care medicine. 13 (3): 160–165. PMID 3971725. Unknown parameter \|month= ignored (help) - ↑ R. M. Perkin, D. L. Levin, R. Webb, A. Aquino & J. Reedy (1982). "Dobutamine: a hemodynamic evaluation in children with shock". The Journal of pediatrics. 100 (6): 977–983. PMID 7086606. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link) - ↑ N. Noto, M. Ayusawa, K. Karasawa, H. Yamaguchi, N. Sumitomo, T. Okada & K. Harada (1996). "Dobutamine stress echocardiography for detection of coronary artery stenosis in children with Kawasaki disease". Journal of the American College of Cardiology. 27 (5): 1251–1256. doi:10.1016/0735-1097(95)00570-6. PMID 8609352. Unknown parameter \|month= ignored (help)CS1 maint: Multiple names: authors list (link)	https://www.wikidoc.org/index.php/Dobutamine
d14b36cd2fa4da1463658cdd224f55fa2f2edd9b	wikidoc	Docosanoid	Docosanoid In biochemistry, Docosanoids are signaling molecules made by oxygenation of twenty-two-carbon essential fatty acids, (EFAs), especially Docosahexaenoic acid (DHA). They include some resolvins and the docosatrienes. Docosatrienes contain conjugated triene structures generated from DHA as a defining feature. # Neuroprotectins The protectins comprise docosatrienes and resolvins of the D series that are both neuroprotective and anti-inflammatory. Neuroprotectin D1 is formed in retinal pigment epithelial cells when confronted with oxidative stress, in the brain during experimental stroke, and in the human brain from Alzheimer's disease patients as well as in human brain cells in culture. Neuroprotectin D1 displays potent anti-inflammatory and neuroprotective bioactivity. These substances are extremely potent. Neuroprotectin D1 and the 17S series resolvins are potent into the picomolar range. Neurofurans are docosanoids formed nonenzymatically by free radical mediated peroxidation of DHA. # Others Cyclooxygenase and Cytochrome P450 oxidase act upon adrenic acid to produce dihomoprostaglandins and dihomo-EETs, respectively.	Docosanoid In biochemistry, Docosanoids are signaling molecules made by oxygenation of twenty-two-carbon essential fatty acids, (EFAs), especially Docosahexaenoic acid (DHA). They include some resolvins and the docosatrienes. Docosatrienes contain conjugated triene structures generated from DHA as a defining feature.[1] # Neuroprotectins The protectins comprise docosatrienes and resolvins of the D series that are both neuroprotective and anti-inflammatory. [2] Neuroprotectin D1 is formed in retinal pigment epithelial cells when confronted with oxidative stress, in the brain during experimental stroke, and in the human brain from Alzheimer's disease patients as well as in human brain cells in culture. Neuroprotectin D1 displays potent anti-inflammatory and neuroprotective bioactivity.[3] These substances are extremely potent. Neuroprotectin D1 and the 17S series resolvins are potent into the picomolar range.[4] Neurofurans are docosanoids formed nonenzymatically by free radical mediated peroxidation of DHA. # Others Cyclooxygenase and Cytochrome P450 oxidase act upon adrenic acid to produce dihomoprostaglandins[5] and dihomo-EETs,[6] respectively.	https://www.wikidoc.org/index.php/Docosanoid
c76bfa410b115c956d9152f89df3434b683e2b33	wikidoc	Dofetilide	Dofetilide ## Maintenance of Normal Sinus Rhythm and Conversion of Atrial Fibrillation/Artrial Flutter - Dosing information - Usual recommended dosage: 500 mg PO bidas modified by the dosing algorithm described below. - Therapy with Tikosyn must be initiated (and, if necessary, re-initiated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Patients should continue to be monitored in this way for a minimum of three days. Additionally, patients should not be discharged within 12 hours of electrical or pharmacological conversion to normal sinus rhythm. - The dose of Tikosyn must be individualized according to calculated creatinine clearance and QTc. (QT interval should be used if the heart rate is <60 beats per minute. There are no data on use of Tikosyn when the heart rate is <50 beats per minute.) - Serum potassium should be maintained within the normal range before Tikosyn treatment is initiated and should be maintained within the normal range while the patient remains on Tikosyn therapy.Hypokalemia and Potassium-Depleting Diuretics). In clinical trials, potassium levels were generally maintained above 3.6–4.0 mEq/L. - Patients with atrial fibrillation should be anticoagulated according to usual medical practice prior to electrical or pharmacological cardioversion. Anticoagulant therapy may be continued after cardioversion according to usual medical practice for the treatment of people with AF. Hypokalemia should be corrected before initiation of Tikosyn therapy. - Patients to be discharged on Tikosyn therapy from an inpatient setting as described above must have an adequate supply of Tikosyn , at the patient's individualized dose, to allow uninterrupted dosing until the patient receives the first outpatient supply. - Tikosyn is distributed only to those hospitals and other appropriate institutions confirmed to have received applicable dosing and treatment initiation education programs. Inpatient and subsequent outpatient discharge and refill prescriptions are filled only upon confirmation that the prescribing physician has received applicable dosing and treatment initiation education programs. For this purpose, a list for use by pharmacists is maintained containing hospitals and physicians who have received one of the education programs. # Instructions for Individualized Dose Initiation - Step 1. Electrocardiographic assessment: Prior to administration of the first dose, the QTc must be determined using an average of 5–10 beats. If the QTc is greater than 440 msec (500 msec in patients with ventricular conduction abnormalities), Tikosyn is contraindicated. If heart rate is less than 60 beats per minute, QT interval should be used. Patients with heart rates <50 beats per minute have not been studied. - Step 2. Calculation of creatinine clearance: Prior to the administration of the first dose, the patient's creatinine clearance must be calculated using the following formula: - When serum creatinine is given in µmol/L, divide the value by 88.4 (1 mg/dL = 88.4 µmol/L). - Step 3. Starting Dose: The starting dose of Tikosyn is determined as follows: - Step 4. Administer the adjusted Tikosyn dose and begin continuous ECG monitoring. - Step 5. At 2–3 hours after administering the first dose of Tikosyn , determine the QTc. If the QTc has increased by greater than 15% compared to the baseline established in Step 1 OR if the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), subsequent dosing should be adjusted as follows: - Step 6. At 2–3 hours after each subsequent dose of Tikosyn , determine the QTc (for in-hospital doses 2–5). No further down titration of Tikosyn based on QTc is recommended. - NOTE: If at any time after the second dose of Tikosyn is given the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), Tikosyn should be discontinued. - Step 7. Patients are to be continuously monitored by ECG for a minimum of three days, or for a minimum of 12 hours after electrical or pharmacological conversion to normal sinus rhythm, whichever is greater. - The steps described above are summarized in the following diagram: - Renal function and QTc should be re-evaluated every three months or as medically warranted. If QTc exceeds 500 milliseconds (550 msec in patients with ventricular conduction abnormalities), Tikosyn therapy should be discontinued and patients should be carefully monitored until QTc returns to baseline levels. If renal function deteriorates, adjust dose as described in Initiation of Tikosyn Therapy, Step 3. # Special Considerations - Consideration of a Dose Lower than that Determined by the Algorithm - The dosing algorithm shown above should be used to determine the individualized dose of Tikosyn . In clinical trials, the highest dose of 500 mcg BID of Tikosyn as modified by the dosing algorithm led to greater effectiveness than lower doses of 125 or 250 mcg BID as modified by the dosing algorithm. The risk of Torsade de Pointes, however, is related to dose as well as to patient characteristics. Physicians, in consultation with their patients, may therefore in some cases choose doses lower than determined by the algorithm. It is critically important that if at any time this lower dose is increased, the patient needs to be rehospitalized for three days. Previous toleration of higher doses does not eliminate the need for rehospitalization. - The maximum recommended dose in patients with a calculated creatinine clearance greater than 60 mL/min is 500 mcg BID; doses greater than 500 mcg BID have been associated with an increased incidence of Torsade de Pointes. - A patient who misses a dose should NOT double the next dose. The next dose should be taken at the usual time. - If patients do not convert to normal sinus rhythm within 24 hours of initiation of Tikosyn therapy, electrical conversion should be considered. Patients continuing on Tikosyn after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of Tikosyn therapy, whichever is greater. Switch to Tikosyn from Class I or other Class III Antiarrhythmic Therapy' - Before initiating Tikosyn therapy, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of three (3) plasma half-lives. Because of the unpredictable pharmacokinetics of amiodarone, Tikosyn should not be initiated following amiodarone therapy until amiodarone plasma levels are below 0.3 mcg/mL or until amiodarone has been withdrawn for at least three months. Stopping Tikosyn Prior to Administration of Potentially Interacting Drugs - If Tikosyn needs to be discontinued to allow dosing of other potentially interacting drug(s), a washout period of at least two days should be followed before starting the other drug(s). ## Congestive heart failure - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) and Heart Rhythm Society (HRS) - Class of Recommendation: Not Applicable - Level of Evidence: Not Applicable - Dosing information - 500-1000 mg (adjust dose for renal function and QT-interval response during initiation phase) ## Coronary artery disease - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) and Heart Rhythm Society (HRS) - Class of Recommendation: Not Applicable - Level of Evidence: Not Applicable - Dosing information - 500-1000 mg (adjust dose for renal function and QT-interval response during initiation phase) - Dosing Information - 0.25-1 mg PO bid for 3-6 days - The concomitant use of verapamil or the cation transport system inhibitors cimetidine, trimethoprim (alone or in combination with sulfamethoxazole), or ketoconazole with Tikosyn is contraindicated, as each of these drugs cause a substantial increase in dofetilide plasma concentrations. In addition, other known inhibitors of the renal cation transport system such as prochlorperazine, dolutegravir and megestrol should not be used in patients on Tikosyn. - The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with Tikosyn is contraindicated because this has been shown to significantly increase dofetilide plasma concentrations and QT interval prolongation. - Tikosyn is also contraindicated in patients with a known hypersensitivity to the drug. - Tikosyn (dofetilide) can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to dofetilide plasma concentration. Factors such as reduced creatinine clearance or certain dofetilide drug interactions will increase dofetilide plasma concentration. The risk of TdP can be reduced by controlling the plasma concentration through adjustment of the initial dofetilide dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval. - Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance for all patients must precede administration of the first dose of dofetilide. For detailed instructions regarding dose selection. - The risk of dofetilide induced ventricular arrhythmia was assessed in three ways in clinical studies: 1) by description of the QT interval and its relation to the dose and plasma concentration of dofetilide; 2) by observing the frequency of TdP in Tikosyn -treated patients according to dose; 3) by observing the overall mortality rate in patients with atrial fibrillation and in patients with structural heart disease. - The QT interval increases linearly with increasing Tikosyn dose. - In the supraventricular arrhythmia population (patients with AF and other supraventricular arrhythmias), the overall incidence of Torsade de Pointes was 0.8%. The frequency of TdP by dose is shown in Table 4. There were no cases of TdP on placebo. - As shown in Table 5, the rate of TdP was reduced when patients were dosed according to their renal function. - The majority of the episodes of TdP occurred within the first three days of Tikosyn therapy (10/11 events in the studies of patients with supraventricular arrhythmias; 19/25 and 4/7 events in DIAMOND CHF and DIAMOND MI, respectively; 2/4 events in the DIAMOND AF subpopulation). - In a pooled survival analysis of patients in the supraventricular arrhythmia population (low prevalence of structural heart disease), deaths occurred in 0.9% (12/1346) of patients receiving Tikosyn and 0.4% (3/677) in the placebo group. Adjusted for duration of therapy, primary diagnosis, age, gender, and prevalence of structural heart disease, the point estimate of the hazard ratio for the pooled studies (Tikosyn /placebo) was 1.1 (95% CI: 0.3, 4.3). The DIAMOND CHF and MI trials examined mortality in patients with structural heart disease (ejection fraction ≤35%). In these large, double-blind studies, deaths occurred in 36% (541/1511) of Tikosyn patients and 37% (560/1517) of placebo patients. In an analysis of 506 DIAMOND patients with atrial fibrillation/flutter at baseline, one year mortality on Tikosyn was 31% vs. 32% on placebo. - Because of the small number of events, an excess mortality due to Tikosyn cannot be ruled out with confidence in the pooled survival analysis of placebo-controlled trials in patients with supraventricular arrhythmias. However, it is reassuring that in two large placebo-controlled mortality studies in patients with significant heart disease (DIAMOND CHF/MI), there were no more deaths in Tikosyn -treated patients than in patients given placebo. - Because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant drugs that interfere with the metabolism or renal elimination of dofetilide may increase the risk of arrhythmia(Torsade de Pointes). Tikosyn is metabolized to a small degree by the CYP3A4 isoenzyme of the cytochrome P450 system and an inhibitor of this system could increase systemic dofetilide exposure. More important, dofetilide is eliminated by cationic renal secretion, and three inhibitors of this process have been shown to increase systemic dofetilide exposure. The magnitude of the effect on renal elimination by cimetidine, trimethoprim, and ketoconazole (all contraindicated concomitant uses with dofetilide) suggests that all renal cation transport inhibitors should be contraindicated. - Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting diuretics, increasing the potential for Torsade de Pointes. Potassium levels should be within the normal range prior to administration of Tikosyn and maintained in the normal range during administration of Tikosyn. - The use of Tikosyn in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides, and certain fluoroquinolones. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with Tikosyn . In clinical trials, Tikosyn was administered to patients previously treated with oral amiodarone only if serum amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least three months. - In the following section, adverse reaction data for cardiac arrhythmias and non-cardiac adverse reactions are presented separately for patients included in the supraventricular arrhythmia development program and for patients included in the DIAMOND CHF and MI mortality trials , Safety in Patients with Structural Heart Disease, DIAMOND Studies, for a description of these trials). - In studies of patients with supraventricular arrhythmias, a total of 1,346 and 677 patients were exposed to Tikosyn and placebo for 551 and 207 patient years, respectively. A total of 8.7% of patients in the dofetilide groups were discontinued from clinical trials due to adverse events compared to 8.0% in the placebo groups. The most frequent reason for discontinuation (>1%) was ventricular tachycardia (2.0% on dofetilide vs. 1.3% on placebo). The most frequent adverse events were headache, chest pain, and dizziness - Torsade de Pointes is the only arrhythmia that showed a dose-response relationship to Tikosyn treatment. It did not occur in placebo treated patients. The incidence of Torsade de Pointes in patients with supraventricular arrhythmias was 0.8% (11/1346). The incidence of Torsade de Pointes in patients who were dosed according to the recommended dosing regimen was 0.8% (4/525). Table 6 shows the frequency by randomized dose of serious arrhythmias and conduction disturbances reported as adverse events in patients with supraventricular arrhythmias. - In the DIAMOND trials, a total of 1,511 patients were exposed to Tikosyn for 1757 patient years. The incidence of Torsade de Pointes was 3.3% in CHF patients and 0.9% in patients with a recent MI. - Table 7 shows the incidence of serious arrhythmias and conduction disturbances reported as adverse events in the DIAMOND subpopulation that had AF at entry to these trials. - Table 8 presents other adverse events reported with a frequency of >2% on Tikosyn and reported numerically more frequently on Tikosyn than on placebo in the studies of patients with supraventricular arrhythmias. - Adverse events reported at a rate >2% but no more frequently on Tikosyn than on placebo were: angina pectoris, anxiety, arthralgia, asthenia, atrial fibrillation, complications (application, injection, incision, insertion, or device), hypertension, pain, palpitation, peripheral edema, supraventricular tachycardia, sweating, urinary tract infection, ventricular tachycardia. - The following adverse events have been reported with a frequency of ≤2% and numerically more frequently with Tikosyn than placebo in patients with supraventricular arrhythmias: angioedema, bradycardia, cerebral ischemia, cerebrovascular accident, edema, facial paralysis, flaccid paralysis, heart arrest, increased cough, liver damage, migraine, myocardial infarct, paralysis, paresthesia, sudden death, and syncope. - The incidences of clinically significant laboratory test abnormalities in patients with supraventricular arrhythmias were similar for patients on Tikosyn and those on placebo. No clinically relevant effects were noted in serum alkaline phosphatase, serum GGT, LDH, AST, ALT, total bilirubin, total protein, blood urea nitrogen, creatinine, serum electrolytes (calcium, chloride, glucose, magnesium, potassium, sodium), or creatine kinase. Similarly, no clinically relevant effects were observed in hematologic parameters. - In the DIAMOND population, adverse events other than those related to the post-infarction and heart failure patient population were generally similar to those seen in the supraventricular arrhythmia groups. - Concomitant use of cimetidine is contraindicated. cimetidine at 400 mg BID (the usual prescription dose) co-administered with Tikosyn (500 mcg BID) for 7 days has been shown to increase dofetilide plasma levels by 58%. cimetidine at doses of 100 mg BID (OTC dose) resulted in a 13% increase in dofetilide plasma levels (500 mcg single dose). No studies have been conducted at intermediate doses of cimetidine. If a patient requires Tikosyn and anti-ulcer therapy, it is suggested that omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetic profile of Tikosyn . - Concomitant use of verapamil is contraindicated. Co-administration of Tikosyn with verapamil resulted in increases in dofetilide peak plasma levels of 42%, although overall exposure to dofetilide was not significantly increased. In an analysis of the supraventricular arrhythmia and DIAMOND patient populations, the concomitant administration of verapamil with dofetilide was associated with a higher occurrence of Torsade de Pointes. - Concomitant use of ketoconazoleis contraindicated. ketoconazoleat 400 mg daily (the maximum approved prescription dose) co-administered with Tikosyn (500 mcg BID) for 7 days has been shown to increase dofetilide Cmax by 53% in males and 97% in females, and AUC by 41% in males and 69% in females. - Concomitant use of trimethoprimalone or in combination with sulfamethoxazole is contraindicated. trimethoprim160 mg in combination with 800 mg sulfamethoxazole co-administered BID with Tikosyn (500 mcg BID) for 4 days has been shown to increase dofetilide AUC by 103% and Cmax by 93%. - Concomitant use of HCTZ alone or in combination with triamtereneis contraindicated. HCTZ 50 mg QD or HCTZ/triamterene50/100 mg QD was co-administered with Tikosyn (500 mcg BID) for 5 days (following 2 days of diuretic use at half dose). In patients receiving HCTZ alone, dofetilide AUC increased by 27% and Cmax by 21%. However, the pharmacodynamic effect increased by 197% (QTc increase over time) and by 95% (maximum QTc increase). In patients receiving HCTZ in combination with triamterene, dofetilide AUC increased by 30% and Cmax by 16%. However, the pharmacodynamic effect increased by 190% (QTc increase over time) and by 84% (maximum QTc increase). The pharmacodynamic effects can be explained by a combination of the increase in dofetilide exposure and the reductions in serum potassium. In the DIAMOND trials, 1252 patients were treated with Tikosyn and diuretics concomitantly, of whom 493 died compared to 508 deaths among the 1248 patients receiving placebo and diuretics. Of the 229 patients who had potassium depleting diuretics added to their concomitant medications in the DIAMOND trials, the patients on Tikosyn had a non-significantly reduced relative risk for death of 0.68 (95% CI: 0.376, 1.230). # Potential Drug Interactions - Dofetilide is eliminated in the kidney by cationic secretion. Inhibitors of renal cationic secretion are contraindicated with Tikosyn . In addition, drugs that are actively secreted via this route (e.g., triamterene, metformin, and amiloride) should be co-administered with care as they might increase dofetilide levels. - Dofetilide is metabolized to a small extent by the CYP3A4 isoenzyme of the cytochromeP450 system. Inhibitors of the CYP3A4 isoenzyme could increase systemic dofetilide exposure. Inhibitors of this isoenzyme (e.g., macrolide antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazadone, norfloxacin, quinine, zafirlukast) should be cautiously co-administered with Tikosyn as they can potentially increase dofetilide levels. Dofetilide is not an inhibitor of CYP3A4 nor of other cytochromeP450 isoenzymes (e.g., CYP2C9, CYP2D6) and is not expected to increase levels of drugs metabolized by CYP3A4. # Other Drug Interaction Information - Studies in healthy volunteers have shown that Tikosyn does not affect the pharmacokinetics of digoxin. In patients, the concomitant administration of digoxin with dofetilide was associated with a higher occurrence of Torsade de Pointes. It is not clear whether this represents an interaction with Tikosyn or the presence of more severe structural heart disease in patients on digoxin; structural heart disease is a known risk factor for arrhythmia. No increase in mortality was observed in patients taking digoxin as concomitant medication. - In healthy volunteers, amlodipine, phenytoin, glyburide, ranitidine, omeprazole, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone), antacid (aluminum and magnesium hydroxides), and theophylline did not affect the pharmacokinetics of Tikosyn . In addition, studies in healthy volunteers have shown that Tikosyn does not affect the pharmacokinetics or pharmacodynamics of warfarin, or the pharmacokinetics of propranolol (40 mg twice daily), phenytoin, theophylline, or oral contraceptives. - Population pharmacokinetic analyses were conducted on plasma concentration data from 1445 patients in clinical trials to examine the effects of concomitant medications on clearance or volume of distribution of dofetilide. Concomitant medications were grouped as ACE inhibitors, oral anticoagulants, calcium channel blockers, beta blockers, cardiac glycosides, inducers of CYP3A4, substrates and inhibitors of CYP3A4, substrates and inhibitors of P-glycoprotein, nitrates, sulphonylureas, loop diuretics, potassium sparing diuretics, thiazide diuretics, substrates and inhibitors of tubular organic cation transport, and QTc-prolonging drugs. Differences in clearance between patients on these medications (at any occasion in the study) and those off medications varied between -16% and +3%. The mean clearances of dofetilide were 16% and 15% lower in patients on thiazide diuretics and inhibitors of tubular organic cation transport, respectively. - There was no effect on mating or fertility when dofetilide was administered to male and female rats at doses as high as 1.0 mg/kg/day, a dose that would be expected to provide a mean dofetilide AUC(0–24hr) about 3 times the maximum likely human AUC. Increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight were, however, observed in other studies in rats. Reduced testicular weight and increased incidence of testicular atrophy were also consistent findings in dogs and mice. The no effect doses for these findings in chronic administration studies in these 3 species (3, 0.1, and 6 mg/kg/day) were associated with mean dofetilide AUCs that were about 4, 1.3, and 3 times the maximum likely human AUC, respectively. - Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. - The patient should be fully instructed on the need for compliance with the recommended dosing of Tikosyn and the potential for drug interactions, and the need for periodic monitoring of QTc and renal function to minimize the risk of serious abnormal rhythms. - In cases of overdose, cardiac monitoring should be initiated. Close medical monitoring and supervision should continue until the QT interval returns to normal levels. - Therapy with Tikosyn must be initiated (and, if necessary, re-initiated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Patients should continue to be monitored in this way for a minimum of three days. - If QTc exceeds 500 milliseconds (550 msec in patients with ventricular conduction abnormalities), Tikosyn therapy should be discontinued and patients should be carefully monitored until QTc returns to baseline levels. - Patients continuing on Tikosyn after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of Tikosyn therapy, whichever is greater - Before initiating Tikosyn therapy, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of three (3) plasma half-lives - In cases of overdose, cardiac monitoring should be initiated. Charcoal slurry may be given soon after overdosing but has been useful only when given within 15 minutes of Tikosyn administration. Treatment of Torsade de Pointes or overdose may include administration of isoproterenol infusion, with or without cardiac pacing. - Administration of intravenous magnesium sulfate may be effective in the management of Torsade de Pointes. Close medical monitoring and supervision should continue until the QT interval returns to normal levels. - Isoproterenol infusion into anesthetized dogs with cardiac pacing rapidly attenuates the dofetilide-induced prolongation of atrial and ventricular effective refractory periods in a dose-dependent manner. Magnesium sulfate, administered prophylactically either intravenously or orally in a dog model, was effective in the prevention of dofetilide-induced Torsade de Pointes ventricular tachycardia. Similarly, in man, intravenous magnesium sulfate may terminate Torsade de Pointes, irrespective of cause. - Tikosyn overdose was rare in clinical studies; there were two reported cases of Tikosyn overdose in the oral clinical program. One patient received very high multiples of the recommended dose (28 capsules), was treated with gastric aspiration 30 minutes later, and experienced no events. One patient inadvertently received two 500 mcg doses one hour apart and experienced ventricular fibrillation and cardiac arrest 2 hours after the second dose. In the supraventricular arrhythmia population, only 38 patients received doses greater than 500 mcg BID, all of whom received 750 mcg BID irrespective of creatinine clearance. In this very small patient population, the incidence of Torsade de Pointes was 10.5% (4/38 patients), and the incidence of new ventricular fibrillation was 2.6% (1/38 patients). - The chemical name for dofetilide is: - N-phenoxy]ethyl]amino]ethyl]phenyl]-methanesulfonamide. - Dofetilide is a white to off-white powder. It is very slightly soluble in water and propan-2-ol and is soluble in 0.1M aqueous sodium hydroxide, acetone, and aqueous 0.1M hydrochloric acid. - Tikosyn capsules contain the following inactive ingredients: microcrystalline cellulose, corn starch, colloidal silicon dioxide and magnesium stearate. Tikosyn is supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg) orange and white capsules, 250 mcg (0.25 mg) peach capsules, and 500 mcg (0.5 mg) peach and white capsules. - The oral bioavailability of dofetilide is >90%, with maximal plasma concentrations occurring at about 2–3 hours in the fasted state. Oral bioavailability is unaffected by food or antacid. The terminal half-life of Tikosyn is approximately 10 hours; steady state plasma concentrations are attained within 2–3 days, with an accumulation index of 1.5 to 2.0. Plasma concentrations are dose proportional. Plasma protein binding of dofetilide is 60–70%, is independent of plasma concentration, and is unaffected by renal impairment. Volume of distribution is 3 L/kg. - Approximately 80% of a single dose of dofetilide is excreted in urine, of which approximately 80% is excreted as unchanged dofetilide with the remaining 20% consisting of inactive or minimally active metabolites. Renal elimination involves both glomerular filtration and active tubular secretion (via the cation transport system, a process that can be inhibited by cimetidine, trimethoprim, prochlorperazine, megestrol, ketoconazole and dolutegravir). In vitro studies with human liver microsomes show that dofetilide can be metabolized by CYP3A4, but it has a low affinity for this isoenzyme. Metabolites are formed by N-dealkylation and N-oxidation. There are no quantifiable metabolites circulating in plasma, but 5 metabolites have been identified in urine. # Pharmacokinetics in Special Populations - In volunteers with varying degrees of renal impairment and patients with arrhythmias, the clearance of dofetilide decreases with decreasing creatinine clearance. As a result, and as seen in clinical studies, the half-life of dofetilide is longer in patients with lower creatinine clearances. Because increase in QT interval and the risk of ventricular arrhythmias are directly related to plasma concentrations of dofetilide, dosage adjustment based on calculated creatinine clearance is critically important. Patients with severe renal impairment (creatinine clearance <20 mL/min) were not included in clinical or pharmacokinetic studies. - There was no clinically significant alteration in the pharmacokinetics of dofetilide in volunteers with mild to moderate hepatic impairment (Child-Pugh Class A and B) compared to age- and weight-matched healthy volunteers. Patients with severe hepatic impairment were not studied. - Population pharmacokinetic analyses indicate that the plasma concentration of dofetilide in patients with supraventricular and ventricular arrhythmias, ischemic heart disease, or congestive heart failure are similar to those of healthy volunteers, after adjusting for renal function. - After correction for renal function, clearance of dofetilide is not related to age. - A population pharmacokinetic analysis showed that women have approximately 12–18% lower dofetilide oral clearances than men (14–22% greater plasma dofetilide levels), after correction for weight and creatinine clearance. In females, as in males, renal function was the single most important factor influencing dofetilide clearance. In normal female volunteers, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone) did not increase dofetilide exposure. - Increase in QT interval is directly related to dofetilide dose and plasma concentration. Figure 1 shows that the relationship in normal volunteers between dofetilide plasma concentrations and change in QTc is linear, with a positive slope of approximately 15–25 msec/(ng/mL) after the first dose and approximately 10–15 msec/(ng/mL) at Day 23 (reflecting a steady state of dosing). A linear relationship between mean QTc increase and dofetilide dose was also seen in patients with renal impairment, in patients with ischemic heart disease, and in patients with supraventricular and ventricular arrhythmias. - Note: The range of dofetilide plasma concentrations achieved with the 500 mcg BID dose adjusted for creatinine clearance is 1–3.5 ng/mL. - The relationship between dose, efficacy, and the increase in QTc from baseline at steady state for the two randomized, placebo-controlled studies (described further below) is shown in Figure 2. The studies examined the effectiveness of Tikosyn in conversion to sinus rhythm and maintenance of normal sinus rhythm after conversion in patients with atrial fibrillation/flutter of >1 week duration. As shown, both the probability of a patient's remaining in sinus rhythm at six months and the change in QTc from baseline at steady state of dosing increased in an approximately linear fashion with increasing dose of Tikosyn . Note that in these studies, doses were modified by results of creatinine clearance measurement and in-hospital QTc prolongation. - Figure 2: Relationship Between Tikosyn Dose, QTc Increase and Maintenance of NSR - There was no effect on mating or fertility when dofetilide was administered to male and female rats at doses as high as 1.0 mg/kg/day, a dose that would be expected to provide a mean dofetilide AUC(0–24hr) about 3 times the maximum likely human AUC. Increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight were, however, observed in other studies in rats. - Reduced testicular weight and increased incidence of testicular atrophy were also consistent findings in dogs and mice. The no effect doses for these findings in chronic administration studies in these 3 species (3, 0.1, and 6 mg/kg/day) were associated with mean dofetilide AUCs that were about 4, 1.3, and 3 times the maximum likely human AUC, respectively. - Two randomized, parallel, double-blind, placebo-controlled, dose-response trials evaluated the ability of Tikosyn 1) to convert patients with atrial fibrillation or atrial flutter (AF/AFl) of more than 1 week duration to normal sinus rhythm (NSR) and 2) to maintain NSR (delay time to recurrence of AF/AFl) after drug-induced or electrical cardioversion. A total of 996 patients with a one week to two year history of atrial fibrillation/atrial flutter were enrolled. Both studies randomized patients to placebo or to doses of Tikosyn 125 mcg, 250 mcg, 500 mcg, or in one study a comparator drug, given twice a day (these doses were lowered based on calculated creatinine clearance and, in one of the studies, for QT interval or QTc). All patients were started on therapy in a hospital where their ECG was monitored. - Patients were excluded from participation if they had had syncope within the past 6 months, AV block greater than first degree, MI or unstable angina within 1 month, cardiac surgery within 2 months, history of QT interval prolongation or polymorphic ventricular tachycardia associated with use of antiarrhythmic drugs, QT interval or QTc >440 msec, serum creatinine >2.5 mg/mL, significant diseases of other organ systems; used cimetidine; or used drugs known to prolong the QT interval. - Both studies enrolled mostly Caucasians (over 90%), males (over 70%), and patients ≥65 years of age (over 50%). Most (>90%) were NYHA Functional Class I or II. Approximately one-half had structural heart disease (including ischemic heart disease, cardiomyopathies, and valvular disease) and about one-half were hypertensive. A substantial proportion of patients were on concomitant therapy, including digoxin (over 60%), diuretics (over 20%), and ACE inhibitors (over 30%). About 90% were on anticoagulants. - Acute conversion rates are shown in Table 1 for randomized doses (doses were adjusted for calculated creatinine clearance and, in Study 1, for QT interval or QTc). Of patients who converted pharmacologically, approximately 70% converted within 24–36 hours. - Patients who did not convert to NSR with randomized therapy within 48–72 hours had electrical cardioversion. Those patients remaining in NSR after conversion in hospital were continued on randomized therapy as outpatients (maintenance period) for up to one year unless they experienced a recurrence of atrial fibrillation/atrial flutter or withdrew for other reasons. - Table 2 shows, by randomized dose, the percentage of patients at 6 and 12 months in both studies who remained on treatment in NSR and the percentage of patients who withdrew because of recurrence of AF/AFl or adverse events. - Table 3 and Figures 3 and 4 show, by randomized dose, the effectiveness of Tikosyn in maintaining NSR using Kaplan Meier analysis, which shows patients remaining on treatment. - The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 62% and 58%, respectively, for Tikosyn 500 mcg BID; 50% and 37%, respectively, for Tikosyn 250 mcg BID; and 37%, and 25%, respectively, for placebo. - The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 71% and 66%, respectively, for Tikosyn 500 mcg BID; 56% and 51%, respectively, for Tikosyn 250 mcg BID; and 26% and 21%, respectively, for placebo. - In both studies, Tikosyn resulted in a dose-related increase in the number of patients maintained in NSR at all time periods and delayed the time of recurrence of sustained AF. Data pooled from both studies show that there is a positive relationship between the probability of staying in NSR, Tikosyn dose, and increase in QTc. - Analysis of pooled data for patients randomized to a Tikosyn dose of 500 mcg twice daily showed that maintenance of NSR was similar in both males and females, in both patients aged <65 years and patients ≥65 years of age, and in both patients with atrial flutter as a primary diagnosis and those with a primary diagnosis of atrial fibrillation. - During the period of in-hospital initiation of dosing, 23% of patients in Studies 1 and 2 had their dose adjusted downward on the basis of their calculated creatinine clearance, and 3% had their dose down-titrated due to increased QT interval or QTc. Increased QT interval or QTc led to discontinuation of therapy in 3% of patients. Safety in Patients with Structural Heart Disease: DIAMOND Studies (The Danish Investigations of Arrhythmia and Mortality on Dofetilide) - The two DIAMOND studies were 3-year trials comparing the effects of Tikosyn and placebo on mortality and morbidity in patients with impaired left ventricular function (ejection fraction ≤35%). Patients were treated for at least one year. One study was in patients with moderate to severe (60% NYHA Class III or IV) congestive heart failure (DIAMOND CHF) and the other was in patients with recent myocardial infarction (DIAMOND MI) (of whom 40% had NYHA Class III or IV heart failure). Both groups were at relatively high risk of sudden death. The DIAMOND trials were intended to determine whether Tikosyn could reduce that risk. The trials did not demonstrate a reduction in mortality; however, they provide reassurance that, when initiated carefully, in a hospital or equivalent setting, Tikosyn did not increase mortality in patients with structural heart disease, an important finding because other antiarrhythmics have increased mortality in post-infarction populations. The DIAMOND trials therefore provide evidence of a method of safe use of Tikosyn in a population susceptible to ventricular arrhythmias. In addition, the subset of patients with AF in the DIAMOND trials provide further evidence of safety in a population of patients with structural heart disease accompanying the AF. Note, however, that this AF population was given a lower (250 mcg BID) dose, DIAMOND Patients with Atrial Fibrillation). - In both DIAMOND studies, patients were randomized to 500 mcg BID of Tikosyn , but this was reduced to 250 mcg BID if calculated creatinine clearance was 40–60 mL/min, if patients had AF, or if QT interval prolongation (>550 msec or >20% increase from baseline) occurred after dosing. Dose reductions for reduced calculated creatinine clearance occurred in 47% and 45% of DIAMOND CHF and MI patients, respectively. Dose reductions for increased QT interval or QTc occurred in 5% and 7% of DIAMOND CHF and MI patients, respectively. Increased QT interval or QTc (>550 msec or >20% increase from baseline) resulted in discontinuation of 1.8% of patients in DIAMOND CHF and 2.5% of patients in DIAMOND MI. - In the DIAMOND studies, all patients were hospitalized for at least 3 days after treatment was initiated and monitored by telemetry. Patients with QTc greater than 460 msec, second or third degree AV block (unless with pacemaker), resting heart rate <50 bpm, or prior history of polymorphic ventricular tachycardia were excluded. - DIAMOND CHF studied 1518 patients hospitalized with severe CHF who had confirmed impaired left ventricular function (ejection fraction ≤35%). Patients received a median duration of therapy of greater than one year. There were 311 deaths from all causes in patients randomized to Tikosyn (n=762) and 317 deaths in patients randomized to placebo (n=756). The probability of survival at one year was 73% (95% CI: 70% – 76%) in the Tikosyn group and 72% (95% CI: 69% – 75%) in the placebo group. Similar results were seen for cardiac deaths and arrhythmic deaths. Torsade de Pointes occurred in 25/762 patients (3.3%) receiving Tikosyn . The majority of cases (76%) occurred within the first 3 days of dosing. In all, 437/762 (57%) of patients on Tikosyn and 459/756 (61%) on placebo required hospitalization. Of these, 229/762 (30%) of patients on Tikosyn and 290/756 (38%) on placebo required hospitalization because of worsening heart failure. - DIAMOND MI studied 1510 patients hospitalized with recent myocardial infarction (2–7 days) who had confirmed impaired left ventricular function (ejection fraction ≤35%). Patients received a median duration of therapy of greater than one year. There were 230 deaths in patients randomized to Tikosyn (n=749) and 243 deaths in patients randomized to placebo (n=761). The probability of survival at one year was 79% (95% CI: 76% – 82%) in the Tikosyn group and 77% (95% CI: 74% – 80%) in the placebo group. Cardiac and arrhythmic mortality showed a similar result. Torsade de Pointes occurred in 7/749 patients (0.9%) receiving Tikosyn . Of these, 4 cases occurred within the first 3 days of dosing and 3 cases occurred between Day 4 and the conclusion of the study. In all, 371/749 (50%) of patients on Tikosyn and 419/761 (55%) on placebo required hospitalization. Of these, 200/749 (27%) of patients on Tikosyn and 205/761 (27%) on placebo required hospitalization because of worsening heart failure. - DIAMOND Patients with Atrial Fibrillation (the DIAMOND AF subpopulation). There were 506 patients in the two DIAMOND studies who had atrial fibrillation (AF) at entry to the studies (249 randomized to Tikosyn and 257 randomized to placebo). DIAMOND AF patients randomized to Tikosyn received 250 mcg BID; 65% of these patients had impaired renal function, so that 250 mcg BID represents the dose they would have received in the AF trials, which would give drug exposure similar to a person with normal renal function given 500 mcg BID. In the DIAMOND AF subpopulation, there were 111 deaths (45%) in the 249 patients in the Tikosyn group and 116 deaths (45%) in the 257 patients in the placebo group. Hospital readmission rates for any reason were 125/249 or 50% on Tikosyn and 156/257 or 61% for placebo. Of these, readmission rates for worsening heart failure were 73/249 or 29% on Tikosyn and 102/257 or 40% for placebo. - Of the 506 patients in the DIAMOND studies who had atrial fibrillation or flutter at baseline, 12% of patients in the Tikosyn group and 2% of patients in the placebo group had converted to normal sinus rhythm after one month. In those patients converted to normal sinus rhythm, 79% of the Tikosyn group and 42% of the placebo group remained in normal sinus rhythm for one year. - In the DIAMOND studies, although Torsade de Pointes occurred more frequently in the Tikosyn -treated patients, Tikosyn , given with an initial 3-day hospitalization and with dose modified for reduced creatinine clearance and increased QT interval, was not associated with an excess risk of mortality in these populations with structural heart disease in the individual studies or in an analysis of the combined studies. The presence of atrial fibrillation did not affect outcome. - Tikosyn 250 mcg (0.25 mg) capsules are supplied as No. 4 capsules, peach cap and body, printed with TKN 250 PFIZER, and are available in: - Tikosyn 500 mcg (0.5 mg) capsules are supplied as No. 2 capsules, peach cap and white body, printed with TKN 500 PFIZER, and are available in: - Tikosyn can cause serious side effects, including a type of abnormal heartbeat called Torsade de Pointes, which can lead to death. - To establish the right dose of Tikosyn , treatment with Tikosyn must be started in a hospital where your heart rate and kidney function will be checked for the first 3 days of treatment. It is important that when you go home, you take the exact dose of Tikosyn that your doctor prescribed for you. - While you take Tikosyn , always watch for signs of abnormal heartbeat. Call your doctor and go to the hospital right away if you: - Feel faint - Become dizzy, or - Have a fast heartbeat # What is Tikosyn ? - Tikosyn is a prescription medicine that is used to treat an irregular heartbeat (atrial fibrillation or atrial flutter). - It is not known if Tikosyn is safe and effective in children under 18 years of age. # Who should not take Tikosyn ? - Do not take Tikosyn if you: - Have an irregular heartbeat called long QT syndrome - Have kidney problems or are on kidney dialysis - Take any of these medicines: - Cimetidine (TAGAMET, TAGAMET HB)1 - Verapamil (CALAN, CALAN SR, COVERA-HS, ISOPTIN, ISOPTIN SR, VERELAN, VERELAN PM, TARKA)1 - Ketoconazole (NIZORAL, XOLEGEL, EXTINA)1 - Trimethoprim alone (PROLOPRIM, TRIMPEX)1 or the combination of trimethoprim and sulfamethoxazole (BACTRIM, SEPTRA SULFATRIM)1 prochlorperazine (COMPAZINE, COMPO)1 - Megestrol (MEGACE)1 - Dolutegravir (TIVICAY) - Hydrochlorothiazide alone or in combination with other medicines (such as ESIDRIX, EZIDE, HYDRODIURIL, HYDRO-PAR, MICROZIDE, or ORETIC)1 - Ask your doctor if you are not sure if any of your medicines are the kind listed above. - Are allergic to dofetilide in Tikosyn . See the end of this leaflet for a complete list of ingredients in Tikosyn . # What should I tell my doctor before taking Tikosyn ? - Before taking Tikosyn , tell your doctor about all of your medical conditions including if you: - Have heart problems - Have kidney or liver problems - Are pregnant or plan to become pregnant. It is not known if Tikosyn will harm your unborn baby. - Are breast-feeding or plan to breast-feed. It is not known if Tikosyn passes into your breast milk. You and your doctor should decide if you will :* :- take Tikosyn or breast-feed. You should not do both. Especially tell your doctor if you take medicines to treat: - Heart problems - High blood pressure - Depression or other mental problems - Asthma - Allergies, or hay fever - Skin problems - Infections - Ask your doctor if you are not sure about the medicines you take. Tell your doctor about all prescription and non-prescription medicines, vitamins, dietary supplements, and any natural or herbal remedies. Tikosyn and other medicines may affect each other, causing serious side effects. If you take Tikosyn with certain medicines, you will be more likely to have a different type of abnormal heartbeat. Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. # How should I take Tikosyn ? - Take Tikosyn exactly as your doctor tells you. - Do not change your Tikosyn dose unless your doctor tells you to. - Your doctor will do tests before you start and while you take Tikosyn . - Do not stop taking Tikosyn until your doctor tells you to stop. If you miss a dose, just take the next dose at your regular time. Do not take 2 doses of Tikosyn at the same time. - Tikosyn can be taken with or without food. - If you take too much Tikosyn , call your doctor or go to the nearest hospital emergency room right away. Take your Tikosyn capsules with you to show to the doctor. # What are the possible side effects of Tikosyn ? - Tikosyn can cause serious side effects, including a type of abnormal heartbeat called Torsade de Pointes, which can lead to death. See What is the most important information I should know about Tikosyn ?The most common side effects of Tikosyn include: - Headache - Chest pain - dizziness - Call your doctor right away if you have signs of electrolyte imbalance: - Severe diarrhea - Unusual sweating - Vomiting - Not hungry (loss of appetite) - Increased thirst (drinking more than normal) - Tell your doctor if you have any side effects that bother you or do not go away. These are not all the possible side effects of Tikosyn . For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. # How should I store Tikosyn ? - Store Tikosyn between 59° to 86°F (15° to 30°C). - Keep Tikosyn away from moisture and humidity. - Keep Tikosyn in a tightly closed container. - Keep Tikosyn and all medicines out of the reach of children. # General information about Tikosyn - Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Tikosyn for a condition for which it was not prescribed. Do not give Tikosyn to other people, even if they have the same symptoms you have. It may harm them. - This Medication Guide summarizes the most important information about Tikosyn . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Tikosyn that is written for health professionals. For more about Tikosyn , go to www.Tikosyn .com or call 1-877-Tikosyn (1-877-845-6796). # What are the ingredients in Tikosyn ? Active ingredient: dofetilide Inactive ingredients: - Capsule fill: microcrystalline cellulose, corn starch, colloidal silicon dioxide, and magnesium stearate - Capsule shell: gelatin, titanium dioxide, and FD&C Yellow 6 - Imprinting ink: iron oxide black, shellac, n-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide	Dofetilide ### Maintenance of Normal Sinus Rhythm and Conversion of Atrial Fibrillation/Artrial Flutter - Dosing information - Usual recommended dosage: 500 mg PO bidas modified by the dosing algorithm described below. - Therapy with Tikosyn must be initiated (and, if necessary, re-initiated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Patients should continue to be monitored in this way for a minimum of three days. Additionally, patients should not be discharged within 12 hours of electrical or pharmacological conversion to normal sinus rhythm. - The dose of Tikosyn must be individualized according to calculated creatinine clearance and QTc. (QT interval should be used if the heart rate is <60 beats per minute. There are no data on use of Tikosyn when the heart rate is <50 beats per minute.) - Serum potassium should be maintained within the normal range before Tikosyn treatment is initiated and should be maintained within the normal range while the patient remains on Tikosyn therapy.Hypokalemia and Potassium-Depleting Diuretics). In clinical trials, potassium levels were generally maintained above 3.6–4.0 mEq/L. - Patients with atrial fibrillation should be anticoagulated according to usual medical practice prior to electrical or pharmacological cardioversion. Anticoagulant therapy may be continued after cardioversion according to usual medical practice for the treatment of people with AF. Hypokalemia should be corrected before initiation of Tikosyn therapy. - Patients to be discharged on Tikosyn therapy from an inpatient setting as described above must have an adequate supply of Tikosyn , at the patient's individualized dose, to allow uninterrupted dosing until the patient receives the first outpatient supply. - Tikosyn is distributed only to those hospitals and other appropriate institutions confirmed to have received applicable dosing and treatment initiation education programs. Inpatient and subsequent outpatient discharge and refill prescriptions are filled only upon confirmation that the prescribing physician has received applicable dosing and treatment initiation education programs. For this purpose, a list for use by pharmacists is maintained containing hospitals and physicians who have received one of the education programs. ## Instructions for Individualized Dose Initiation - Step 1. Electrocardiographic assessment: Prior to administration of the first dose, the QTc must be determined using an average of 5–10 beats. If the QTc is greater than 440 msec (500 msec in patients with ventricular conduction abnormalities), Tikosyn is contraindicated. If heart rate is less than 60 beats per minute, QT interval should be used. Patients with heart rates <50 beats per minute have not been studied. - Step 2. Calculation of creatinine clearance: Prior to the administration of the first dose, the patient's creatinine clearance must be calculated using the following formula: - When serum creatinine is given in µmol/L, divide the value by 88.4 (1 mg/dL = 88.4 µmol/L). - Step 3. Starting Dose: The starting dose of Tikosyn is determined as follows: - Step 4. Administer the adjusted Tikosyn dose and begin continuous ECG monitoring. - Step 5. At 2–3 hours after administering the first dose of Tikosyn , determine the QTc. If the QTc has increased by greater than 15% compared to the baseline established in Step 1 OR if the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), subsequent dosing should be adjusted as follows: - Step 6. At 2–3 hours after each subsequent dose of Tikosyn , determine the QTc (for in-hospital doses 2–5). No further down titration of Tikosyn based on QTc is recommended. - NOTE: If at any time after the second dose of Tikosyn is given the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), Tikosyn should be discontinued. - Step 7. Patients are to be continuously monitored by ECG for a minimum of three days, or for a minimum of 12 hours after electrical or pharmacological conversion to normal sinus rhythm, whichever is greater. - The steps described above are summarized in the following diagram: - Renal function and QTc should be re-evaluated every three months or as medically warranted. If QTc exceeds 500 milliseconds (550 msec in patients with ventricular conduction abnormalities), Tikosyn therapy should be discontinued and patients should be carefully monitored until QTc returns to baseline levels. If renal function deteriorates, adjust dose as described in Initiation of Tikosyn Therapy, Step 3. ## Special Considerations - Consideration of a Dose Lower than that Determined by the Algorithm - The dosing algorithm shown above should be used to determine the individualized dose of Tikosyn . In clinical trials, the highest dose of 500 mcg BID of Tikosyn as modified by the dosing algorithm led to greater effectiveness than lower doses of 125 or 250 mcg BID as modified by the dosing algorithm. The risk of Torsade de Pointes, however, is related to dose as well as to patient characteristics. Physicians, in consultation with their patients, may therefore in some cases choose doses lower than determined by the algorithm. It is critically important that if at any time this lower dose is increased, the patient needs to be rehospitalized for three days. Previous toleration of higher doses does not eliminate the need for rehospitalization. - The maximum recommended dose in patients with a calculated creatinine clearance greater than 60 mL/min is 500 mcg BID; doses greater than 500 mcg BID have been associated with an increased incidence of Torsade de Pointes. - A patient who misses a dose should NOT double the next dose. The next dose should be taken at the usual time. - If patients do not convert to normal sinus rhythm within 24 hours of initiation of Tikosyn therapy, electrical conversion should be considered. Patients continuing on Tikosyn after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of Tikosyn therapy, whichever is greater. Switch to Tikosyn from Class I or other Class III Antiarrhythmic Therapy' - Before initiating Tikosyn therapy, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of three (3) plasma half-lives. Because of the unpredictable pharmacokinetics of amiodarone, Tikosyn should not be initiated following amiodarone therapy until amiodarone plasma levels are below 0.3 mcg/mL or until amiodarone has been withdrawn for at least three months. Stopping Tikosyn Prior to Administration of Potentially Interacting Drugs - If Tikosyn needs to be discontinued to allow dosing of other potentially interacting drug(s), a washout period of at least two days should be followed before starting the other drug(s). ### Congestive heart failure - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) and Heart Rhythm Society (HRS) - Class of Recommendation: Not Applicable - Level of Evidence: Not Applicable - Dosing information - 500-1000 mg (adjust dose for renal function and QT-interval response during initiation phase) ### Coronary artery disease - Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) and Heart Rhythm Society (HRS) - Class of Recommendation: Not Applicable - Level of Evidence: Not Applicable - Dosing information - 500-1000 mg (adjust dose for renal function and QT-interval response during initiation phase) - Dosing Information - 0.25-1 mg PO bid for 3-6 days - The concomitant use of verapamil or the cation transport system inhibitors cimetidine, trimethoprim (alone or in combination with sulfamethoxazole), or ketoconazole with Tikosyn is contraindicated, as each of these drugs cause a substantial increase in dofetilide plasma concentrations. In addition, other known inhibitors of the renal cation transport system such as prochlorperazine, dolutegravir and megestrol should not be used in patients on Tikosyn. - The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with Tikosyn is contraindicated because this has been shown to significantly increase dofetilide plasma concentrations and QT interval prolongation. - Tikosyn is also contraindicated in patients with a known hypersensitivity to the drug. - Tikosyn (dofetilide) can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to dofetilide plasma concentration. Factors such as reduced creatinine clearance or certain dofetilide drug interactions will increase dofetilide plasma concentration. The risk of TdP can be reduced by controlling the plasma concentration through adjustment of the initial dofetilide dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval. - Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance for all patients must precede administration of the first dose of dofetilide. For detailed instructions regarding dose selection. - The risk of dofetilide induced ventricular arrhythmia was assessed in three ways in clinical studies: 1) by description of the QT interval and its relation to the dose and plasma concentration of dofetilide; 2) by observing the frequency of TdP in Tikosyn -treated patients according to dose; 3) by observing the overall mortality rate in patients with atrial fibrillation and in patients with structural heart disease. - The QT interval increases linearly with increasing Tikosyn dose. - In the supraventricular arrhythmia population (patients with AF and other supraventricular arrhythmias), the overall incidence of Torsade de Pointes was 0.8%. The frequency of TdP by dose is shown in Table 4. There were no cases of TdP on placebo. - As shown in Table 5, the rate of TdP was reduced when patients were dosed according to their renal function. - The majority of the episodes of TdP occurred within the first three days of Tikosyn therapy (10/11 events in the studies of patients with supraventricular arrhythmias; 19/25 and 4/7 events in DIAMOND CHF and DIAMOND MI, respectively; 2/4 events in the DIAMOND AF subpopulation). - In a pooled survival analysis of patients in the supraventricular arrhythmia population (low prevalence of structural heart disease), deaths occurred in 0.9% (12/1346) of patients receiving Tikosyn and 0.4% (3/677) in the placebo group. Adjusted for duration of therapy, primary diagnosis, age, gender, and prevalence of structural heart disease, the point estimate of the hazard ratio for the pooled studies (Tikosyn /placebo) was 1.1 (95% CI: 0.3, 4.3). The DIAMOND CHF and MI trials examined mortality in patients with structural heart disease (ejection fraction ≤35%). In these large, double-blind studies, deaths occurred in 36% (541/1511) of Tikosyn patients and 37% (560/1517) of placebo patients. In an analysis of 506 DIAMOND patients with atrial fibrillation/flutter at baseline, one year mortality on Tikosyn was 31% vs. 32% on placebo. - Because of the small number of events, an excess mortality due to Tikosyn cannot be ruled out with confidence in the pooled survival analysis of placebo-controlled trials in patients with supraventricular arrhythmias. However, it is reassuring that in two large placebo-controlled mortality studies in patients with significant heart disease (DIAMOND CHF/MI), there were no more deaths in Tikosyn -treated patients than in patients given placebo. - Because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant drugs that interfere with the metabolism or renal elimination of dofetilide may increase the risk of arrhythmia(Torsade de Pointes). Tikosyn is metabolized to a small degree by the CYP3A4 isoenzyme of the cytochrome P450 system and an inhibitor of this system could increase systemic dofetilide exposure. More important, dofetilide is eliminated by cationic renal secretion, and three inhibitors of this process have been shown to increase systemic dofetilide exposure. The magnitude of the effect on renal elimination by cimetidine, trimethoprim, and ketoconazole (all contraindicated concomitant uses with dofetilide) suggests that all renal cation transport inhibitors should be contraindicated. - Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting diuretics, increasing the potential for Torsade de Pointes. Potassium levels should be within the normal range prior to administration of Tikosyn and maintained in the normal range during administration of Tikosyn. - The use of Tikosyn in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides, and certain fluoroquinolones. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with Tikosyn . In clinical trials, Tikosyn was administered to patients previously treated with oral amiodarone only if serum amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least three months. - In the following section, adverse reaction data for cardiac arrhythmias and non-cardiac adverse reactions are presented separately for patients included in the supraventricular arrhythmia development program and for patients included in the DIAMOND CHF and MI mortality trials , Safety in Patients with Structural Heart Disease, DIAMOND Studies, for a description of these trials). - In studies of patients with supraventricular arrhythmias, a total of 1,346 and 677 patients were exposed to Tikosyn and placebo for 551 and 207 patient years, respectively. A total of 8.7% of patients in the dofetilide groups were discontinued from clinical trials due to adverse events compared to 8.0% in the placebo groups. The most frequent reason for discontinuation (>1%) was ventricular tachycardia (2.0% on dofetilide vs. 1.3% on placebo). The most frequent adverse events were headache, chest pain, and dizziness . - Torsade de Pointes is the only arrhythmia that showed a dose-response relationship to Tikosyn treatment. It did not occur in placebo treated patients. The incidence of Torsade de Pointes in patients with supraventricular arrhythmias was 0.8% (11/1346). The incidence of Torsade de Pointes in patients who were dosed according to the recommended dosing regimen was 0.8% (4/525). Table 6 shows the frequency by randomized dose of serious arrhythmias and conduction disturbances reported as adverse events in patients with supraventricular arrhythmias. - In the DIAMOND trials, a total of 1,511 patients were exposed to Tikosyn for 1757 patient years. The incidence of Torsade de Pointes was 3.3% in CHF patients and 0.9% in patients with a recent MI. - Table 7 shows the incidence of serious arrhythmias and conduction disturbances reported as adverse events in the DIAMOND subpopulation that had AF at entry to these trials. - Table 8 presents other adverse events reported with a frequency of >2% on Tikosyn and reported numerically more frequently on Tikosyn than on placebo in the studies of patients with supraventricular arrhythmias. - Adverse events reported at a rate >2% but no more frequently on Tikosyn than on placebo were: angina pectoris, anxiety, arthralgia, asthenia, atrial fibrillation, complications (application, injection, incision, insertion, or device), hypertension, pain, palpitation, peripheral edema, supraventricular tachycardia, sweating, urinary tract infection, ventricular tachycardia. - The following adverse events have been reported with a frequency of ≤2% and numerically more frequently with Tikosyn than placebo in patients with supraventricular arrhythmias: angioedema, bradycardia, cerebral ischemia, cerebrovascular accident, edema, facial paralysis, flaccid paralysis, heart arrest, increased cough, liver damage, migraine, myocardial infarct, paralysis, paresthesia, sudden death, and syncope. - The incidences of clinically significant laboratory test abnormalities in patients with supraventricular arrhythmias were similar for patients on Tikosyn and those on placebo. No clinically relevant effects were noted in serum alkaline phosphatase, serum GGT, LDH, AST, ALT, total bilirubin, total protein, blood urea nitrogen, creatinine, serum electrolytes (calcium, chloride, glucose, magnesium, potassium, sodium), or creatine kinase. Similarly, no clinically relevant effects were observed in hematologic parameters. - In the DIAMOND population, adverse events other than those related to the post-infarction and heart failure patient population were generally similar to those seen in the supraventricular arrhythmia groups. - Concomitant use of cimetidine is contraindicated. cimetidine at 400 mg BID (the usual prescription dose) co-administered with Tikosyn (500 mcg BID) for 7 days has been shown to increase dofetilide plasma levels by 58%. cimetidine at doses of 100 mg BID (OTC dose) resulted in a 13% increase in dofetilide plasma levels (500 mcg single dose). No studies have been conducted at intermediate doses of cimetidine. If a patient requires Tikosyn and anti-ulcer therapy, it is suggested that omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetic profile of Tikosyn . - Concomitant use of verapamil is contraindicated. Co-administration of Tikosyn with verapamil resulted in increases in dofetilide peak plasma levels of 42%, although overall exposure to dofetilide was not significantly increased. In an analysis of the supraventricular arrhythmia and DIAMOND patient populations, the concomitant administration of verapamil with dofetilide was associated with a higher occurrence of Torsade de Pointes. - Concomitant use of ketoconazoleis contraindicated. ketoconazoleat 400 mg daily (the maximum approved prescription dose) co-administered with Tikosyn (500 mcg BID) for 7 days has been shown to increase dofetilide Cmax by 53% in males and 97% in females, and AUC by 41% in males and 69% in females. - Concomitant use of trimethoprimalone or in combination with sulfamethoxazole is contraindicated. trimethoprim160 mg in combination with 800 mg sulfamethoxazole co-administered BID with Tikosyn (500 mcg BID) for 4 days has been shown to increase dofetilide AUC by 103% and Cmax by 93%. - Concomitant use of HCTZ alone or in combination with triamtereneis contraindicated. HCTZ 50 mg QD or HCTZ/triamterene50/100 mg QD was co-administered with Tikosyn (500 mcg BID) for 5 days (following 2 days of diuretic use at half dose). In patients receiving HCTZ alone, dofetilide AUC increased by 27% and Cmax by 21%. However, the pharmacodynamic effect increased by 197% (QTc increase over time) and by 95% (maximum QTc increase). In patients receiving HCTZ in combination with triamterene, dofetilide AUC increased by 30% and Cmax by 16%. However, the pharmacodynamic effect increased by 190% (QTc increase over time) and by 84% (maximum QTc increase). The pharmacodynamic effects can be explained by a combination of the increase in dofetilide exposure and the reductions in serum potassium. In the DIAMOND trials, 1252 patients were treated with Tikosyn and diuretics concomitantly, of whom 493 died compared to 508 deaths among the 1248 patients receiving placebo and diuretics. Of the 229 patients who had potassium depleting diuretics added to their concomitant medications in the DIAMOND trials, the patients on Tikosyn had a non-significantly reduced relative risk for death of 0.68 (95% CI: 0.376, 1.230). ## Potential Drug Interactions - Dofetilide is eliminated in the kidney by cationic secretion. Inhibitors of renal cationic secretion are contraindicated with Tikosyn . In addition, drugs that are actively secreted via this route (e.g., triamterene, metformin, and amiloride) should be co-administered with care as they might increase dofetilide levels. - Dofetilide is metabolized to a small extent by the CYP3A4 isoenzyme of the cytochromeP450 system. Inhibitors of the CYP3A4 isoenzyme could increase systemic dofetilide exposure. Inhibitors of this isoenzyme (e.g., macrolide antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazadone, norfloxacin, quinine, zafirlukast) should be cautiously co-administered with Tikosyn as they can potentially increase dofetilide levels. Dofetilide is not an inhibitor of CYP3A4 nor of other cytochromeP450 isoenzymes (e.g., CYP2C9, CYP2D6) and is not expected to increase levels of drugs metabolized by CYP3A4. ## Other Drug Interaction Information - Studies in healthy volunteers have shown that Tikosyn does not affect the pharmacokinetics of digoxin. In patients, the concomitant administration of digoxin with dofetilide was associated with a higher occurrence of Torsade de Pointes. It is not clear whether this represents an interaction with Tikosyn or the presence of more severe structural heart disease in patients on digoxin; structural heart disease is a known risk factor for arrhythmia. No increase in mortality was observed in patients taking digoxin as concomitant medication. - In healthy volunteers, amlodipine, phenytoin, glyburide, ranitidine, omeprazole, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone), antacid (aluminum and magnesium hydroxides), and theophylline did not affect the pharmacokinetics of Tikosyn . In addition, studies in healthy volunteers have shown that Tikosyn does not affect the pharmacokinetics or pharmacodynamics of warfarin, or the pharmacokinetics of propranolol (40 mg twice daily), phenytoin, theophylline, or oral contraceptives. - Population pharmacokinetic analyses were conducted on plasma concentration data from 1445 patients in clinical trials to examine the effects of concomitant medications on clearance or volume of distribution of dofetilide. Concomitant medications were grouped as ACE inhibitors, oral anticoagulants, calcium channel blockers, beta blockers, cardiac glycosides, inducers of CYP3A4, substrates and inhibitors of CYP3A4, substrates and inhibitors of P-glycoprotein, nitrates, sulphonylureas, loop diuretics, potassium sparing diuretics, thiazide diuretics, substrates and inhibitors of tubular organic cation transport, and QTc-prolonging drugs. Differences in clearance between patients on these medications (at any occasion in the study) and those off medications varied between -16% and +3%. The mean clearances of dofetilide were 16% and 15% lower in patients on thiazide diuretics and inhibitors of tubular organic cation transport, respectively. - There was no effect on mating or fertility when dofetilide was administered to male and female rats at doses as high as 1.0 mg/kg/day, a dose that would be expected to provide a mean dofetilide AUC(0–24hr) about 3 times the maximum likely human AUC. Increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight were, however, observed in other studies in rats. Reduced testicular weight and increased incidence of testicular atrophy were also consistent findings in dogs and mice. The no effect doses for these findings in chronic administration studies in these 3 species (3, 0.1, and 6 mg/kg/day) were associated with mean dofetilide AUCs that were about 4, 1.3, and 3 times the maximum likely human AUC, respectively. - Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. - The patient should be fully instructed on the need for compliance with the recommended dosing of Tikosyn and the potential for drug interactions, and the need for periodic monitoring of QTc and renal function to minimize the risk of serious abnormal rhythms. - In cases of overdose, cardiac monitoring should be initiated. Close medical monitoring and supervision should continue until the QT interval returns to normal levels. - Therapy with Tikosyn must be initiated (and, if necessary, re-initiated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Patients should continue to be monitored in this way for a minimum of three days. - If QTc exceeds 500 milliseconds (550 msec in patients with ventricular conduction abnormalities), Tikosyn therapy should be discontinued and patients should be carefully monitored until QTc returns to baseline levels. - Patients continuing on Tikosyn after successful electrical cardioversion should continue to be monitored by electrocardiography for 12 hours post cardioversion, or a minimum of 3 days after initiation of Tikosyn therapy, whichever is greater - Before initiating Tikosyn therapy, previous antiarrhythmic therapy should be withdrawn under careful monitoring for a minimum of three (3) plasma half-lives - In cases of overdose, cardiac monitoring should be initiated. Charcoal slurry may be given soon after overdosing but has been useful only when given within 15 minutes of Tikosyn administration. Treatment of Torsade de Pointes or overdose may include administration of isoproterenol infusion, with or without cardiac pacing. - Administration of intravenous magnesium sulfate may be effective in the management of Torsade de Pointes. Close medical monitoring and supervision should continue until the QT interval returns to normal levels. - Isoproterenol infusion into anesthetized dogs with cardiac pacing rapidly attenuates the dofetilide-induced prolongation of atrial and ventricular effective refractory periods in a dose-dependent manner. Magnesium sulfate, administered prophylactically either intravenously or orally in a dog model, was effective in the prevention of dofetilide-induced Torsade de Pointes ventricular tachycardia. Similarly, in man, intravenous magnesium sulfate may terminate Torsade de Pointes, irrespective of cause. - Tikosyn overdose was rare in clinical studies; there were two reported cases of Tikosyn overdose in the oral clinical program. One patient received very high multiples of the recommended dose (28 capsules), was treated with gastric aspiration 30 minutes later, and experienced no events. One patient inadvertently received two 500 mcg doses one hour apart and experienced ventricular fibrillation and cardiac arrest 2 hours after the second dose. In the supraventricular arrhythmia population, only 38 patients received doses greater than 500 mcg BID, all of whom received 750 mcg BID irrespective of creatinine clearance. In this very small patient population, the incidence of Torsade de Pointes was 10.5% (4/38 patients), and the incidence of new ventricular fibrillation was 2.6% (1/38 patients). - The chemical name for dofetilide is: - N-[4-[2-[methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl]-methanesulfonamide. - Dofetilide is a white to off-white powder. It is very slightly soluble in water and propan-2-ol and is soluble in 0.1M aqueous sodium hydroxide, acetone, and aqueous 0.1M hydrochloric acid. - Tikosyn capsules contain the following inactive ingredients: microcrystalline cellulose, corn starch, colloidal silicon dioxide and magnesium stearate. Tikosyn is supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg) orange and white capsules, 250 mcg (0.25 mg) peach capsules, and 500 mcg (0.5 mg) peach and white capsules. - The oral bioavailability of dofetilide is >90%, with maximal plasma concentrations occurring at about 2–3 hours in the fasted state. Oral bioavailability is unaffected by food or antacid. The terminal half-life of Tikosyn is approximately 10 hours; steady state plasma concentrations are attained within 2–3 days, with an accumulation index of 1.5 to 2.0. Plasma concentrations are dose proportional. Plasma protein binding of dofetilide is 60–70%, is independent of plasma concentration, and is unaffected by renal impairment. Volume of distribution is 3 L/kg. - Approximately 80% of a single dose of dofetilide is excreted in urine, of which approximately 80% is excreted as unchanged dofetilide with the remaining 20% consisting of inactive or minimally active metabolites. Renal elimination involves both glomerular filtration and active tubular secretion (via the cation transport system, a process that can be inhibited by cimetidine, trimethoprim, prochlorperazine, megestrol, ketoconazole and dolutegravir). In vitro studies with human liver microsomes show that dofetilide can be metabolized by CYP3A4, but it has a low affinity for this isoenzyme. Metabolites are formed by N-dealkylation and N-oxidation. There are no quantifiable metabolites circulating in plasma, but 5 metabolites have been identified in urine. ## Pharmacokinetics in Special Populations - In volunteers with varying degrees of renal impairment and patients with arrhythmias, the clearance of dofetilide decreases with decreasing creatinine clearance. As a result, and as seen in clinical studies, the half-life of dofetilide is longer in patients with lower creatinine clearances. Because increase in QT interval and the risk of ventricular arrhythmias are directly related to plasma concentrations of dofetilide, dosage adjustment based on calculated creatinine clearance is critically important. Patients with severe renal impairment (creatinine clearance <20 mL/min) were not included in clinical or pharmacokinetic studies. - There was no clinically significant alteration in the pharmacokinetics of dofetilide in volunteers with mild to moderate hepatic impairment (Child-Pugh Class A and B) compared to age- and weight-matched healthy volunteers. Patients with severe hepatic impairment were not studied. - Population pharmacokinetic analyses indicate that the plasma concentration of dofetilide in patients with supraventricular and ventricular arrhythmias, ischemic heart disease, or congestive heart failure are similar to those of healthy volunteers, after adjusting for renal function. - After correction for renal function, clearance of dofetilide is not related to age. - A population pharmacokinetic analysis showed that women have approximately 12–18% lower dofetilide oral clearances than men (14–22% greater plasma dofetilide levels), after correction for weight and creatinine clearance. In females, as in males, renal function was the single most important factor influencing dofetilide clearance. In normal female volunteers, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone) did not increase dofetilide exposure. - Increase in QT interval is directly related to dofetilide dose and plasma concentration. Figure 1 shows that the relationship in normal volunteers between dofetilide plasma concentrations and change in QTc is linear, with a positive slope of approximately 15–25 msec/(ng/mL) after the first dose and approximately 10–15 msec/(ng/mL) at Day 23 (reflecting a steady state of dosing). A linear relationship between mean QTc increase and dofetilide dose was also seen in patients with renal impairment, in patients with ischemic heart disease, and in patients with supraventricular and ventricular arrhythmias. - Note: The range of dofetilide plasma concentrations achieved with the 500 mcg BID dose adjusted for creatinine clearance is 1–3.5 ng/mL. - The relationship between dose, efficacy, and the increase in QTc from baseline at steady state for the two randomized, placebo-controlled studies (described further below) is shown in Figure 2. The studies examined the effectiveness of Tikosyn in conversion to sinus rhythm and maintenance of normal sinus rhythm after conversion in patients with atrial fibrillation/flutter of >1 week duration. As shown, both the probability of a patient's remaining in sinus rhythm at six months and the change in QTc from baseline at steady state of dosing increased in an approximately linear fashion with increasing dose of Tikosyn . Note that in these studies, doses were modified by results of creatinine clearance measurement and in-hospital QTc prolongation. - Figure 2: Relationship Between Tikosyn Dose, QTc Increase and Maintenance of NSR - There was no effect on mating or fertility when dofetilide was administered to male and female rats at doses as high as 1.0 mg/kg/day, a dose that would be expected to provide a mean dofetilide AUC(0–24hr) about 3 times the maximum likely human AUC. Increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight were, however, observed in other studies in rats. - Reduced testicular weight and increased incidence of testicular atrophy were also consistent findings in dogs and mice. The no effect doses for these findings in chronic administration studies in these 3 species (3, 0.1, and 6 mg/kg/day) were associated with mean dofetilide AUCs that were about 4, 1.3, and 3 times the maximum likely human AUC, respectively. - Two randomized, parallel, double-blind, placebo-controlled, dose-response trials evaluated the ability of Tikosyn 1) to convert patients with atrial fibrillation or atrial flutter (AF/AFl) of more than 1 week duration to normal sinus rhythm (NSR) and 2) to maintain NSR (delay time to recurrence of AF/AFl) after drug-induced or electrical cardioversion. A total of 996 patients with a one week to two year history of atrial fibrillation/atrial flutter were enrolled. Both studies randomized patients to placebo or to doses of Tikosyn 125 mcg, 250 mcg, 500 mcg, or in one study a comparator drug, given twice a day (these doses were lowered based on calculated creatinine clearance and, in one of the studies, for QT interval or QTc). All patients were started on therapy in a hospital where their ECG was monitored. - Patients were excluded from participation if they had had syncope within the past 6 months, AV block greater than first degree, MI or unstable angina within 1 month, cardiac surgery within 2 months, history of QT interval prolongation or polymorphic ventricular tachycardia associated with use of antiarrhythmic drugs, QT interval or QTc >440 msec, serum creatinine >2.5 mg/mL, significant diseases of other organ systems; used cimetidine; or used drugs known to prolong the QT interval. - Both studies enrolled mostly Caucasians (over 90%), males (over 70%), and patients ≥65 years of age (over 50%). Most (>90%) were NYHA Functional Class I or II. Approximately one-half had structural heart disease (including ischemic heart disease, cardiomyopathies, and valvular disease) and about one-half were hypertensive. A substantial proportion of patients were on concomitant therapy, including digoxin (over 60%), diuretics (over 20%), and ACE inhibitors (over 30%). About 90% were on anticoagulants. - Acute conversion rates are shown in Table 1 for randomized doses (doses were adjusted for calculated creatinine clearance and, in Study 1, for QT interval or QTc). Of patients who converted pharmacologically, approximately 70% converted within 24–36 hours. - Patients who did not convert to NSR with randomized therapy within 48–72 hours had electrical cardioversion. Those patients remaining in NSR after conversion in hospital were continued on randomized therapy as outpatients (maintenance period) for up to one year unless they experienced a recurrence of atrial fibrillation/atrial flutter or withdrew for other reasons. - Table 2 shows, by randomized dose, the percentage of patients at 6 and 12 months in both studies who remained on treatment in NSR and the percentage of patients who withdrew because of recurrence of AF/AFl or adverse events. - Table 3 and Figures 3 and 4 show, by randomized dose, the effectiveness of Tikosyn in maintaining NSR using Kaplan Meier analysis, which shows patients remaining on treatment. - The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 62% and 58%, respectively, for Tikosyn 500 mcg BID; 50% and 37%, respectively, for Tikosyn 250 mcg BID; and 37%, and 25%, respectively, for placebo. - The point estimates of the probabilities of remaining in NSR at 6 and 12 months were 71% and 66%, respectively, for Tikosyn 500 mcg BID; 56% and 51%, respectively, for Tikosyn 250 mcg BID; and 26% and 21%, respectively, for placebo. - In both studies, Tikosyn resulted in a dose-related increase in the number of patients maintained in NSR at all time periods and delayed the time of recurrence of sustained AF. Data pooled from both studies show that there is a positive relationship between the probability of staying in NSR, Tikosyn dose, and increase in QTc. - Analysis of pooled data for patients randomized to a Tikosyn dose of 500 mcg twice daily showed that maintenance of NSR was similar in both males and females, in both patients aged <65 years and patients ≥65 years of age, and in both patients with atrial flutter as a primary diagnosis and those with a primary diagnosis of atrial fibrillation. - During the period of in-hospital initiation of dosing, 23% of patients in Studies 1 and 2 had their dose adjusted downward on the basis of their calculated creatinine clearance, and 3% had their dose down-titrated due to increased QT interval or QTc. Increased QT interval or QTc led to discontinuation of therapy in 3% of patients. Safety in Patients with Structural Heart Disease: DIAMOND Studies (The Danish Investigations of Arrhythmia and Mortality on Dofetilide) - The two DIAMOND studies were 3-year trials comparing the effects of Tikosyn and placebo on mortality and morbidity in patients with impaired left ventricular function (ejection fraction ≤35%). Patients were treated for at least one year. One study was in patients with moderate to severe (60% NYHA Class III or IV) congestive heart failure (DIAMOND CHF) and the other was in patients with recent myocardial infarction (DIAMOND MI) (of whom 40% had NYHA Class III or IV heart failure). Both groups were at relatively high risk of sudden death. The DIAMOND trials were intended to determine whether Tikosyn could reduce that risk. The trials did not demonstrate a reduction in mortality; however, they provide reassurance that, when initiated carefully, in a hospital or equivalent setting, Tikosyn did not increase mortality in patients with structural heart disease, an important finding because other antiarrhythmics [notably the Class IC antiarrhythmics studied in the Cardiac Arrhythmia Suppression Trial (CAST) and a pure Class III antiarrhythmic, d-sotalol (SWORD)] have increased mortality in post-infarction populations. The DIAMOND trials therefore provide evidence of a method of safe use of Tikosyn in a population susceptible to ventricular arrhythmias. In addition, the subset of patients with AF in the DIAMOND trials provide further evidence of safety in a population of patients with structural heart disease accompanying the AF. Note, however, that this AF population was given a lower (250 mcg BID) dose, DIAMOND Patients with Atrial Fibrillation). - In both DIAMOND studies, patients were randomized to 500 mcg BID of Tikosyn , but this was reduced to 250 mcg BID if calculated creatinine clearance was 40–60 mL/min, if patients had AF, or if QT interval prolongation (>550 msec or >20% increase from baseline) occurred after dosing. Dose reductions for reduced calculated creatinine clearance occurred in 47% and 45% of DIAMOND CHF and MI patients, respectively. Dose reductions for increased QT interval or QTc occurred in 5% and 7% of DIAMOND CHF and MI patients, respectively. Increased QT interval or QTc (>550 msec or >20% increase from baseline) resulted in discontinuation of 1.8% of patients in DIAMOND CHF and 2.5% of patients in DIAMOND MI. - In the DIAMOND studies, all patients were hospitalized for at least 3 days after treatment was initiated and monitored by telemetry. Patients with QTc greater than 460 msec, second or third degree AV block (unless with pacemaker), resting heart rate <50 bpm, or prior history of polymorphic ventricular tachycardia were excluded. - DIAMOND CHF studied 1518 patients hospitalized with severe CHF who had confirmed impaired left ventricular function (ejection fraction ≤35%). Patients received a median duration of therapy of greater than one year. There were 311 deaths from all causes in patients randomized to Tikosyn (n=762) and 317 deaths in patients randomized to placebo (n=756). The probability of survival at one year was 73% (95% CI: 70% – 76%) in the Tikosyn group and 72% (95% CI: 69% – 75%) in the placebo group. Similar results were seen for cardiac deaths and arrhythmic deaths. Torsade de Pointes occurred in 25/762 patients (3.3%) receiving Tikosyn . The majority of cases (76%) occurred within the first 3 days of dosing. In all, 437/762 (57%) of patients on Tikosyn and 459/756 (61%) on placebo required hospitalization. Of these, 229/762 (30%) of patients on Tikosyn and 290/756 (38%) on placebo required hospitalization because of worsening heart failure. - DIAMOND MI studied 1510 patients hospitalized with recent myocardial infarction (2–7 days) who had confirmed impaired left ventricular function (ejection fraction ≤35%). Patients received a median duration of therapy of greater than one year. There were 230 deaths in patients randomized to Tikosyn (n=749) and 243 deaths in patients randomized to placebo (n=761). The probability of survival at one year was 79% (95% CI: 76% – 82%) in the Tikosyn group and 77% (95% CI: 74% – 80%) in the placebo group. Cardiac and arrhythmic mortality showed a similar result. Torsade de Pointes occurred in 7/749 patients (0.9%) receiving Tikosyn . Of these, 4 cases occurred within the first 3 days of dosing and 3 cases occurred between Day 4 and the conclusion of the study. In all, 371/749 (50%) of patients on Tikosyn and 419/761 (55%) on placebo required hospitalization. Of these, 200/749 (27%) of patients on Tikosyn and 205/761 (27%) on placebo required hospitalization because of worsening heart failure. - DIAMOND Patients with Atrial Fibrillation (the DIAMOND AF subpopulation). There were 506 patients in the two DIAMOND studies who had atrial fibrillation (AF) at entry to the studies (249 randomized to Tikosyn and 257 randomized to placebo). DIAMOND AF patients randomized to Tikosyn received 250 mcg BID; 65% of these patients had impaired renal function, so that 250 mcg BID represents the dose they would have received in the AF trials, which would give drug exposure similar to a person with normal renal function given 500 mcg BID. In the DIAMOND AF subpopulation, there were 111 deaths (45%) in the 249 patients in the Tikosyn group and 116 deaths (45%) in the 257 patients in the placebo group. Hospital readmission rates for any reason were 125/249 or 50% on Tikosyn and 156/257 or 61% for placebo. Of these, readmission rates for worsening heart failure were 73/249 or 29% on Tikosyn and 102/257 or 40% for placebo. - Of the 506 patients in the DIAMOND studies who had atrial fibrillation or flutter at baseline, 12% of patients in the Tikosyn group and 2% of patients in the placebo group had converted to normal sinus rhythm after one month. In those patients converted to normal sinus rhythm, 79% of the Tikosyn group and 42% of the placebo group remained in normal sinus rhythm for one year. - In the DIAMOND studies, although Torsade de Pointes occurred more frequently in the Tikosyn -treated patients, Tikosyn , given with an initial 3-day hospitalization and with dose modified for reduced creatinine clearance and increased QT interval, was not associated with an excess risk of mortality in these populations with structural heart disease in the individual studies or in an analysis of the combined studies. The presence of atrial fibrillation did not affect outcome. - Tikosyn 250 mcg (0.25 mg) capsules are supplied as No. 4 capsules, peach cap and body, printed with TKN 250 PFIZER, and are available in: - Tikosyn 500 mcg (0.5 mg) capsules are supplied as No. 2 capsules, peach cap and white body, printed with TKN 500 PFIZER, and are available in: - Tikosyn can cause serious side effects, including a type of abnormal heartbeat called Torsade de Pointes, which can lead to death. - To establish the right dose of Tikosyn , treatment with Tikosyn must be started in a hospital where your heart rate and kidney function will be checked for the first 3 days of treatment. It is important that when you go home, you take the exact dose of Tikosyn that your doctor prescribed for you. - While you take Tikosyn , always watch for signs of abnormal heartbeat. Call your doctor and go to the hospital right away if you: - Feel faint - Become dizzy, or - Have a fast heartbeat ## What is Tikosyn ? - Tikosyn is a prescription medicine that is used to treat an irregular heartbeat (atrial fibrillation or atrial flutter). - It is not known if Tikosyn is safe and effective in children under 18 years of age. ## Who should not take Tikosyn ? - Do not take Tikosyn if you: - Have an irregular heartbeat called long QT syndrome - Have kidney problems or are on kidney dialysis - Take any of these medicines: - Cimetidine (TAGAMET, TAGAMET HB)1 - Verapamil (CALAN, CALAN SR, COVERA-HS, ISOPTIN, ISOPTIN SR, VERELAN, VERELAN PM, TARKA)1 - Ketoconazole (NIZORAL, XOLEGEL, EXTINA)1 - Trimethoprim alone (PROLOPRIM, TRIMPEX)1 or the combination of trimethoprim and sulfamethoxazole (BACTRIM, SEPTRA SULFATRIM)1 prochlorperazine (COMPAZINE, COMPO)1 - Megestrol (MEGACE)1 - Dolutegravir (TIVICAY) - Hydrochlorothiazide alone or in combination with other medicines (such as ESIDRIX, EZIDE, HYDRODIURIL, HYDRO-PAR, MICROZIDE, or ORETIC)1 - Ask your doctor if you are not sure if any of your medicines are the kind listed above. - Are allergic to dofetilide in Tikosyn . See the end of this leaflet for a complete list of ingredients in Tikosyn . ## What should I tell my doctor before taking Tikosyn ? - Before taking Tikosyn , tell your doctor about all of your medical conditions including if you: - Have heart problems - Have kidney or liver problems - Are pregnant or plan to become pregnant. It is not known if Tikosyn will harm your unborn baby. - Are breast-feeding or plan to breast-feed. It is not known if Tikosyn passes into your breast milk. You and your doctor should decide if you will :* :* take Tikosyn or breast-feed. You should not do both. Especially tell your doctor if you take medicines to treat: - Heart problems - High blood pressure - Depression or other mental problems - Asthma - Allergies, or hay fever - Skin problems - Infections - Ask your doctor if you are not sure about the medicines you take. Tell your doctor about all prescription and non-prescription medicines, vitamins, dietary supplements, and any natural or herbal remedies. Tikosyn and other medicines may affect each other, causing serious side effects. If you take Tikosyn with certain medicines, you will be more likely to have a different type of abnormal heartbeat. Know the medicines you take. Keep a list of your medicines and show it to your doctor and pharmacist when you get a new medicine. ## How should I take Tikosyn ? - Take Tikosyn exactly as your doctor tells you. - Do not change your Tikosyn dose unless your doctor tells you to. - Your doctor will do tests before you start and while you take Tikosyn . - Do not stop taking Tikosyn until your doctor tells you to stop. If you miss a dose, just take the next dose at your regular time. Do not take 2 doses of Tikosyn at the same time. - Tikosyn can be taken with or without food. - If you take too much Tikosyn , call your doctor or go to the nearest hospital emergency room right away. Take your Tikosyn capsules with you to show to the doctor. ## What are the possible side effects of Tikosyn ? - Tikosyn can cause serious side effects, including a type of abnormal heartbeat called Torsade de Pointes, which can lead to death. See What is the most important information I should know about Tikosyn ?The most common side effects of Tikosyn include: - Headache - Chest pain - dizziness - Call your doctor right away if you have signs of electrolyte imbalance: - Severe diarrhea - Unusual sweating - Vomiting - Not hungry (loss of appetite) - Increased thirst (drinking more than normal) - Tell your doctor if you have any side effects that bother you or do not go away. These are not all the possible side effects of Tikosyn . For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. ## How should I store Tikosyn ? - Store Tikosyn between 59° to 86°F (15° to 30°C). - Keep Tikosyn away from moisture and humidity. - Keep Tikosyn in a tightly closed container. - Keep Tikosyn and all medicines out of the reach of children. ## General information about Tikosyn - Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Tikosyn for a condition for which it was not prescribed. Do not give Tikosyn to other people, even if they have the same symptoms you have. It may harm them. - This Medication Guide summarizes the most important information about Tikosyn . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Tikosyn that is written for health professionals. For more about Tikosyn , go to www.Tikosyn .com or call 1-877-Tikosyn (1-877-845-6796). ## What are the ingredients in Tikosyn ? Active ingredient: dofetilide Inactive ingredients: - Capsule fill: microcrystalline cellulose, corn starch, colloidal silicon dioxide, and magnesium stearate - Capsule shell: gelatin, titanium dioxide, and FD&C Yellow 6 - Imprinting ink: iron oxide black, shellac, n-butyl alcohol, isopropyl alcohol, propylene glycol, and ammonium hydroxide	https://www.wikidoc.org/index.php/Dofetilide
02c949c50daceb6dc711f20a6d36d68be06e793c	wikidoc	Donna Eden	Donna Eden Donna Eden is an author, lecturer, and teacher of energy medicine. In her work, she often collaborates with her husband, David Feinstein, PhD, a former faculty member of The Johns Hopkins University School of Medicine Donna and David co-wrote the bestseller book, Energy Medicine. They also co-authored Six Pillars of Energy Medicine: Clinical Strengths of a Complementary Paradigm, which was published in a peered-reviewed journal, Alternative Therapies in Health and Medicine. Donna serves on the faculty of the Energy Medicine University. She conceived and trademarked the term "Energy Kinesiology" to describe a process of using muscle testing for detecting and correcting imbalances in the body; in May 2002 she granted unrestricted rights to use the term to the Energy Kinesiology Association. Donna also co-founded the nonprofit Energy Medicine Institute in Ashland, Oregon. The Eden Energy Medicine Certification Program is based on her work. # Ideas and Theories Eden's practice has centered on "energy healing" and she has shared her ideas on energy medicine throughout the United States. These fields may be considered part of alternative medicine. She claims she has the ability to see the body's energies, and can use that ability to accurately determine the causes of physical and psychological problems based on the state of those energies, and to devise highly effective treatments. # Bibliography - Energy Medicine (paperback, with David Feinstein); Jeremy P. Tarcher/Putnam 1998 ISBN 978-1585420216 - The Energy Medicine Kit Sounds True kit edition 2005 (paperback); ISBN 978-1591792086 - The Promise of Energy Psychology: Revolutionary Tools for Dramatic Personal Change (paperback, with David Feinstein and Gary Craig); Jeremy P. Tarcher/Penguin 2005 ISBN 978-1585424429 - Energy Medicine for Women: Aligning Your Body's Energies to Boost Your Health and Vitality (paperback); Penguin Group (USA) Inc. 2008 ISBN 978-1585426478 # Notes - ↑ Ranked #3 on Amazon bestsellers for the category of Health, Mind & Body > Alternative Medicine > Energy Healing accessed 1/27/08 - ↑ Alternative Therapies in Health and Medicine 2008, 14(1), 44-54 accessed 1/27/08; also pdf version of the article - ↑ Energy Medicine University - Faculty Bios - ↑ Energy Kinesiology Association News June 2003; also Alan Smith: Unbreak Your Health: The Complete Guide to Complementary & Alternative Therapies, Loving Healing Press 2007 ISBN 1932690360 - ↑ Kripalu - Center for Yoga and Health; accessed 1/27/08 - ↑ Amazon editorial review for her DVD "The Energies of Love" accessed 1/27/08. - ↑ The Handbook of Humanistic Psychology By Kirk J. Schneider, James F. T. Bugental, J. Fraser Pierson, Sage Publications 2001, pg 193, ISBN 0761927824; also Essentials of Managing Stress By Brian Luke Seaward, Jones & Bartlett Publishers. pg 42 ISBN 0763708577; also The Great Rethinking conference: Just For The Health Of It!, November 3-6, 2006; accessed 1/27/08	Donna Eden Donna Eden is an author, lecturer, and teacher of energy medicine. In her work, she often collaborates with her husband, David Feinstein, PhD, a former faculty member of The Johns Hopkins University School of Medicine Donna and David co-wrote the bestseller [1] book, Energy Medicine. They also co-authored Six Pillars of Energy Medicine: Clinical Strengths of a Complementary Paradigm, which was published in a peered-reviewed journal, Alternative Therapies in Health and Medicine. [2] Donna serves on the faculty of the Energy Medicine University[3]. She conceived and trademarked the term "Energy Kinesiology" to describe a process of using muscle testing for detecting and correcting imbalances in the body; in May 2002 she granted unrestricted rights to use the term to the Energy Kinesiology Association.[4] Donna also co-founded the nonprofit Energy Medicine Institute in Ashland, Oregon. The Eden Energy Medicine Certification Program is based on her work. # Ideas and Theories Eden's practice has centered on "energy healing"[5] and she has shared her ideas on energy medicine throughout the United States.[6] These fields may be considered part of alternative medicine. She claims she has the ability to see the body's energies[7], and can use that ability to accurately determine the causes of physical and psychological problems based on the state of those energies, and to devise highly effective treatments. # Bibliography - Energy Medicine (paperback, with David Feinstein); Jeremy P. Tarcher/Putnam 1998 ISBN 978-1585420216 - The Energy Medicine Kit Sounds True kit edition 2005 (paperback); ISBN 978-1591792086 - The Promise of Energy Psychology: Revolutionary Tools for Dramatic Personal Change (paperback, with David Feinstein and Gary Craig); Jeremy P. Tarcher/Penguin 2005 ISBN 978-1585424429 - Energy Medicine for Women: Aligning Your Body's Energies to Boost Your Health and Vitality (paperback); Penguin Group (USA) Inc. 2008 ISBN 978-1585426478 # Notes - ↑ Ranked #3 on Amazon bestsellers for the category of Health, Mind & Body > Alternative Medicine > Energy Healing accessed 1/27/08 - ↑ Alternative Therapies in Health and Medicine 2008, 14(1), 44-54 accessed 1/27/08; also pdf version of the article - ↑ Energy Medicine University - Faculty Bios - ↑ Energy Kinesiology Association News June 2003; also Alan Smith: Unbreak Your Health: The Complete Guide to Complementary & Alternative Therapies, Loving Healing Press 2007 ISBN 1932690360 - ↑ Kripalu - Center for Yoga and Health; accessed 1/27/08 - ↑ Amazon editorial review for her DVD "The Energies of Love" accessed 1/27/08. - ↑ The Handbook of Humanistic Psychology By Kirk J. Schneider, James F. T. Bugental, J. Fraser Pierson, Sage Publications 2001, pg 193, ISBN 0761927824; also Essentials of Managing Stress By Brian Luke Seaward, Jones & Bartlett Publishers. pg 42 ISBN 0763708577; also The Great Rethinking conference: Just For The Health Of It!, November 3-6, 2006; accessed 1/27/08	https://www.wikidoc.org/index.php/Donna_Eden
b75986fe694fd9db95409627f2cb6e4d127521c6	wikidoc	Doravirine	Doravirine # 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 Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is FDA approved for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history, in combination with other antiretroviral agents. Common adverse reactions include nausea, dizziness, headache, fatigue, diarrhea, abdominal pain, and abnormal dreams. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Doravirine is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history. Dosage - One tablet taken orally once daily with or without food in adult patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding doravirine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding doravirine Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and efficacy of doravirine have not been established in pediatric patients less than 18 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding doravirine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding doravirine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Doravirine is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of doravirine. These drugs include, but are not limited to, the following: the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin the androgen receptor inhibitor enzalutamide the antimycobacterials rifampin, rifapentine the cytotoxic agent mitotane St. John's wort (Hypericum perforatum) - the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin - the androgen receptor inhibitor enzalutamide - the antimycobacterials rifampin, rifapentine - the cytotoxic agent mitotane - St. John's wort (Hypericum perforatum) # Warnings - The concomitant use of doravirine and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of doravirine and possible development of resistance. - See TABLE 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during doravirine therapy, review concomitant medications during doravirine therapy, and monitor for adverse reactions. - Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. - Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of 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. - The safety assessment of doravirine used in combination with other antiretroviral agents is based on Week 48 data from two Phase 3, randomized, international, multicenter, double-blind, active-controlled trials (DRIVE-FORWARD (Protocol 018) and DRIVE-AHEAD (Protocol 021)). - In DRIVE-FORWARD, 766 adult subjects received either doravirine 100 mg (n=383) or darunavir 800 mg + ritonavir 100 mg (DRV+r) (n=383) once daily, each in combination with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC). By Week 48, 2% in the doravirine group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication. - In DRIVE-AHEAD, 728 adult subjects received either DELSTRIGO (n=364) or efavirenz (EFV)/FTC/TDF once daily (n=364). By Week 48, 3% in the DELSTRIGO group and 6% in the EFV/FTC/TDF group had adverse events leading to discontinuation of study medication. - Adverse reactions reported in greater than or equal to 5% of subjects in any treatment group in DRIVE-FORWARD and DRIVE-AHEAD are presented in Table 1. - The majority (72%) of adverse reactions associated with doravirine occurred at severity Grade 1 (mild). - For DRIVE-AHEAD, the analysis of subjects with neuropsychiatric adverse events by Week 48 is presented in Table 2. The proportion of subjects who reported one or more neuropsychiatric adverse events was 24% and 57% in the DELSTRIGO and EFV/FTC/TDF groups, respectively. - A statistically significantly lower proportion of DELSTRIGO-treated subjects compared to EFV/FTC/TDF-treated subjects reported neuropsychiatric adverse events by Week 48 in the three pre-specified categories of dizziness, sleep disorders and disturbances, and altered sensorium. - Neuropsychiatric adverse events in the pre-defined category of depression and suicide/self-injury were reported in 4% and 7% of subjects, in the DELSTRIGO and EFV/FTC/TDF groups, respectively. - In DRIVE-AHEAD through 48 weeks of treatment, the majority of subjects who reported neuropsychiatric adverse events reported events that were mild to moderate in severity (97% and 96% , in the DELSTRIGO and EFV/FTC/TDF groups, respectively) and the majority of subjects reported these events in the first 4 weeks of treatment (72% in the DELSTRIGO group and 86% in the EFV/FTC/TDF group). - Neuropsychiatric adverse events led to treatment discontinuation in 1% (2/364) and 1% (5/364) of subjects in the DELSTRIGO and EFV/FTC/TDF groups, respectively. The proportion of subjects who reported neuropsychiatric adverse events through Week 4 was 17% (62/364) in the DELSTRIGO group and 49% (177/364) in the EFV/FTC/TDF group. At Week 48, the prevalence of neuropsychiatric adverse events was 12% (44/364) in the DELSTRIGO group and 22% (81/364) in the EFV/FTC/TDF group. - The percentages of subjects with selected laboratory abnormalities (that represent a worsening from baseline) who were treated with doravirine or DRV+r in DRIVE-FORWARD, or DELSTRIGO or EFV/FTC/TDF in DRIVE-AHEAD are presented in Table 3. - For DRIVE-FORWARD and DRIVE-AHEAD, changes from baseline at Week 48 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol are shown in Table 4. - The LDL and non-HDL comparisons were pre-specified and are summarized in Table 4. The differences were statistically significant, showing superiority for doravirine for both parameters. The clinical benefit of these findings has not been demonstrated. ## Postmarketing Experience There is limited information regarding Doravirine Postmarketing Experience in the drug label. # Drug Interactions - Co-administration of doravirine with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce doravirine efficacy. Co-administration of doravirine and drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. - Table 5 shows significant drug interactions with doravirine. - No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, and methadone. - No clinically significant changes in concentration were observed for the following agents when co-administered with doravirine: dolutegravir, lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Exposure Registry - There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to doravirine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary - No adequate human data are available to establish whether or not doravirine poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when doravirine was administered at exposures ≥8 times the exposure in humans at the recommended human dose (RHD) of doravirine. - The background rate of major birth defects is 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates individuals and infants from the limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation. Animal Data - Doravirine was administered orally to pregnant rabbits (up to 300 mg/kg/day on gestation days (GD) 7 to 20) and rats (up to 450 mg/kg/day on GD 6 to 20 and separately from GD 6 to lactation/postpartum day 20). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at exposures (AUC) approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the RHD. Doravirine was transferred to the fetus through the placenta in embryo-fetal studies, with fetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on gestation day 20. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Doravirine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Doravirine during labor and delivery. ### Nursing Mothers Risk Summary - The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking potential transmission of HIV-1 infection. - It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant. Doravirine is present in the milk of lactating rats (see DATA). Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving doravirine. Data - Doravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed 2 hours post dose on lactation day 14. ### Pediatric Use - Safety and efficacy of doravirine have not been established in pediatric patients less than 18 years of age. ### Geriatic Use - Clinical trials of doravirine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of doravirine in elderly patients, 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 Doravirine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Doravirine with respect to specific racial populations. ### Renal Impairment - No dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. Doravirine has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients. ### Hepatic Impairment - No dosage adjustment of doravirine is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Doravirine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Doravirine in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended dosage regimen of doravirine in adults is one 100 mg tablet taken orally once daily with or without food. - If doravirine is co-administered with rifabutin, increase doravirine dosage to one tablet twice daily (approximately 12 hours apart) for the duration of rifabutin co-administration. ### Monitoring There is limited information regarding Doravirine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Doravirine and IV administrations. # Overdosage There is limited information regarding Doravirine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Doravirine is an antiretroviral drug. ## Structure - Doravirine has a molecular formula of C17H11ClF3N5O3 and a molecular weight of 425.75. - It has the following structural formula: ## Pharmacodynamics - In a Phase 2 trial evaluating doravirine over a dose range of 0.25 to 2 times the recommended dose of doravirine, (in combination with FTC/TDF) in HIV-1 infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine. Cardiac Electrophysiology - At a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose of doravirine, doravirine does not prolong the QT interval to any clinically relevant extent. ## Pharmacokinetics - Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Doravirine pharmacokinetics are provided in Table 6. Specific Populations - No clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, severe hepatic impairment (Child-Pugh C), or <18 years of age is unknown. Patients with Renal Impairment - In a study comparing 8 subjects with severe renal impairment to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal impairment. In a population pharmacokinetic analysis, renal function did not have a clinically relevant effect on doravirine pharmacokinetics. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis. Patients with Hepatic Impairment - No clinically significant difference in the pharmacokinetics of doravirine was observed in subjects with moderate hepatic impairment (Child-Pugh score B) compared to subjects without hepatic impairment. Doravirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C). Drug Interaction Studies - Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine. Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine. - Doravirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Doravirine did not inhibit major drug metabolizing enzymes in vitro, including CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and UGT1A1 and is not likely to be an inducer of CYP1A2, 2B6, or 3A4. Based on in vitro assays, doravirine is not likely to be an inhibitor of OATP1B1, OATP1B3, P-glycoprotein, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2K. Drug interaction studies were performed with doravirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration with other drugs on the exposure (Cmax, AUC, and C24) of doravirine are summarized in Table 7. A single doravirine 100 mg dose was administered in these studies unless otherwise noted. - Based on drug interaction studies conducted with doravirine, no clinically significant drug interactions have been observed following the co-administration of doravirine and the following drugs: dolutegravir, ritonavir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam. ## Microbiology Mechanism of Action - Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Doravirine does not inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ. Antiviral Activity in Cell Culture - Doravirine exhibited an EC50 value of 12.0±4.4 nM against wild-type laboratory strains of HIV-1 when tested in the presence of 100% normal human serum (NHS) using MT4-GFP reporter cells. Doravirine demonstrated antiviral activity against a broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC50 values ranging from 0.6 nM to 10.0 nM. Antiviral Activity in Combination with other HIV Antiviral Agents - The antiviral activity of doravirine in cell culture was not antagonistic when combined with the NNRTIs delavirdine, efavirenz, etravirine, nevirapine, or rilpivirine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, or zidovudine; the PIs darunavir or indinavir; the gp41 fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir. Resistance In Cell Culture - Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in RT included: V106A, V106M, V106I, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F. In Clinical Trials - In the doravirine treatment arms of the DRIVE-FORWARD and DRIVE-AHEAD trials (n=747), 11 subjects showed the emergence of doravirine-associated resistance substitutions in their HIV among 28 (39%) subjects in the resistance analysis subset (subjects with HIV-1 RNA greater than 400 copies per mL at virologic failure or early study discontinuation and having resistance data). Emergent doravirine resistance-associated substitutions in RT included one or more of the following: A98G, V106I, V106A, V106M/T, V108I, E138G/K, Y188L, H221Y, P225H, F227C, F227C/R, and Y318Y/F. Seven of 11 (64%) subjects with emergent doravirine-associated resistance substitutions showed doravirine phenotypic resistance and all of them had at least a 100-fold reduction in doravirine susceptibility (range >97- to >211–fold reduction in doravirine susceptibility). The other 4 virologic failures who had only amino acid mixtures of NNRTI resistance substitutions showed doravirine phenotypic fold-changes of less than 2-fold. Of the 28 subjects in the resistance analysis subset, 8 subjects (29%) developed genotypic and/or phenotypic resistance to the other drugs (abacavir, lamivudine, emtricitabine, or TDF) in the regimens of the DRIVE-FORWARD and DRIVE-AHEAD trials. The resistance-associated substitutions that emerged were RT M41L (n=1), A62V (n=1), K65R (n=2), T69T/A (n=1), and M184V (n=5). - In the DRV+r treatment arm of the DRIVE-FORWARD trial (n=383), no subjects showed the emergence of darunavir-associated resistance substitutions among 9 subjects with resistance data and none of the subjects had emergent resistance to lamivudine or TDF. In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364), 12 subjects showed the emergence of efavirenz-associated resistance substitutions among 20 (60%) subjects in the resistance analysis subset and genotypic resistance to emtricitabine or tenofovir developed in 5 evaluable subjects; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), and M184V/I (n=5). Cross-Resistance - A panel of 96 diverse clinical isolates containing NNRTI-associated substitutions was evaluated for susceptibility to doravirine. Clinical isolates containing the Y188L substitution alone or in combination with K103N or V106I, V106A in combination with G190A and F227L, or E138K in combination with Y181C and M230L showed greater than 100-fold reduced susceptibility to doravirine. - Cross-resistance has been observed among NNRTIs. Treatment-emergent doravirine resistance-associated substitutions can confer cross resistance to efavirenz, etravirine, nevirapine, and rilpivirine. Of the 7 virologic failures who developed doravirine phenotypic resistance, all had phenotypic resistance to nevirapine, 6 had phenotypic resistance to efavirenz, 4 had phenotypic resistance to rilpivirine, and 3 had partial resistance to etravirine based on the Monogram PhenoSense assay. ## Nonclinical Toxicology Carcinogenesis - Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to 6 and 7 times, respectively, the human exposures at the RHD. A statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls. Mutagenesis - Doravirine was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays. Impairment of fertility - There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at systemic exposures (AUC) approximately 7 times the exposure in humans at the RHD. # Clinical Studies - The efficacy of doravirine is based on the analyses of 48-week data from two randomized, multicenter, double-blind, active controlled Phase 3 trials (DRIVE-FORWARD, NCT02275780 and DRIVE-AHEAD, NCT02403674) in HIV-1 infected subjects with no antiretroviral treatment history (n=1494). - In DRIVE-FORWARD, 766 subjects were randomized and received at least 1 dose of either doravirine once daily or darunavir 800 mg + ritonavir 100 mg (DRV+r) once daily each in combination with emtricitabine/tenofovir DF (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator. At baseline, the median age of subjects was 33 years, 16% were female, 27% were non-white, 4% had hepatitis B and/or C virus co-infection, 10% had a history of AIDS, 20% had HIV-1 RNA greater than 100,000 copies/mL, 86% had CD4+ T-cell count greater than 200 cells/mm3, 13% received ABC/3TC, and 87% received FTC/TDF; these characteristics were similar between treatment groups. - In DRIVE-AHEAD, 728 subjects were randomized and received at least 1 dose of either DELSTRIGO (DOR/3TC/TDF) or EFV 600 mg/FTC 200 mg/TDF 300 mg once daily. At baseline, the median age of subjects was 31 years, 15% were female, 52% were non-white, 3% had hepatitis B or C co-infection, 14% had a history of AIDS, 21% had HIV-1 RNA greater than 100,000 copies/mL, and 88% had CD4+ T-cell count greater than 200 cells/mm3; these characteristics were similar between treatment groups. - Week 48 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 8. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. - In DRIVE-FORWARD, the mean CD4+ T-cell counts in the doravirine and DRV+r groups increased from baseline by 193 and 186 cells/mm3, respectively. - In DRIVE-AHEAD, the mean CD4+ T-cell counts in the DELSTRIGO and EFV/FTC/TDF groups increased from baseline by 198 and 188 cells/mm3, respectively. # How Supplied - Each doravirine tablet contains 100 mg of doravirine, is white, oval-shaped and film-coated, and is debossed with the corporate logo and 700 on one side and plain on the other side. Each bottle contains 30 tablets (NDC 0006-3069-01) with silica gel desiccant and is closed with a child-resistant closure. ## Storage - Store doravirine in the original bottle. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccant. - Store doravirine 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 Drug Interactions - Inform patients that doravirine may interact with certain other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort. - For patients concomitantly receiving rifabutin, take one tablet of doravirine twice daily (approximately 12 hours apart). Immune Reconstitution Syndrome - Inform patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection. Dosing Instructions - Advise patients to take doravirine every day at a regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses as it can result in development of resistance. If a patient forgets to take doravirine, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time. Pregnancy Registry - Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in pregnant individuals exposed to doravirine. Lactation - Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk. # Precautions with Alcohol Alcohol-Doravirine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Pifeltro # Look-Alike Drug Names There is limited information regarding Doravirine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Doravirine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Zach Leibowitz [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Doravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that is FDA approved for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history, in combination with other antiretroviral agents. Common adverse reactions include nausea, dizziness, headache, fatigue, diarrhea, abdominal pain, and abnormal dreams. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Indication - Doravirine is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment history. Dosage - One tablet taken orally once daily with or without food in adult patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding doravirine Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding doravirine Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and efficacy of doravirine have not been established in pediatric patients less than 18 years of age. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding doravirine Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding doravirine Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - Doravirine is contraindicated when co-administered with drugs that are strong cytochrome P450 (CYP)3A enzyme inducers as significant decreases in doravirine plasma concentrations may occur, which may decrease the effectiveness of doravirine. These drugs include, but are not limited to, the following: the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin the androgen receptor inhibitor enzalutamide the antimycobacterials rifampin, rifapentine the cytotoxic agent mitotane St. John's wort (Hypericum perforatum) - the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin - the androgen receptor inhibitor enzalutamide - the antimycobacterials rifampin, rifapentine - the cytotoxic agent mitotane - St. John's wort (Hypericum perforatum) # Warnings - The concomitant use of doravirine and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect of doravirine and possible development of resistance. - See TABLE 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during doravirine therapy, review concomitant medications during doravirine therapy, and monitor for adverse reactions. - Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment. - Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of 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. - The safety assessment of doravirine used in combination with other antiretroviral agents is based on Week 48 data from two Phase 3, randomized, international, multicenter, double-blind, active-controlled trials (DRIVE-FORWARD (Protocol 018) and DRIVE-AHEAD (Protocol 021)). - In DRIVE-FORWARD, 766 adult subjects received either doravirine 100 mg (n=383) or darunavir 800 mg + ritonavir 100 mg (DRV+r) (n=383) once daily, each in combination with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or abacavir/lamivudine (ABC/3TC). By Week 48, 2% in the doravirine group and 3% in the DRV+r group had adverse events leading to discontinuation of study medication. - In DRIVE-AHEAD, 728 adult subjects received either DELSTRIGO [doravirine (DOR)/3TC/TDF] (n=364) or efavirenz (EFV)/FTC/TDF once daily (n=364). By Week 48, 3% in the DELSTRIGO group and 6% in the EFV/FTC/TDF group had adverse events leading to discontinuation of study medication. - Adverse reactions reported in greater than or equal to 5% of subjects in any treatment group in DRIVE-FORWARD and DRIVE-AHEAD are presented in Table 1. - The majority (72%) of adverse reactions associated with doravirine occurred at severity Grade 1 (mild). - For DRIVE-AHEAD, the analysis of subjects with neuropsychiatric adverse events by Week 48 is presented in Table 2. The proportion of subjects who reported one or more neuropsychiatric adverse events was 24% and 57% in the DELSTRIGO and EFV/FTC/TDF groups, respectively. - A statistically significantly lower proportion of DELSTRIGO-treated subjects compared to EFV/FTC/TDF-treated subjects reported neuropsychiatric adverse events by Week 48 in the three pre-specified categories of dizziness, sleep disorders and disturbances, and altered sensorium. - Neuropsychiatric adverse events in the pre-defined category of depression and suicide/self-injury were reported in 4% and 7% of subjects, in the DELSTRIGO and EFV/FTC/TDF groups, respectively. - In DRIVE-AHEAD through 48 weeks of treatment, the majority of subjects who reported neuropsychiatric adverse events reported events that were mild to moderate in severity (97% [83/86] and 96% [198/207], in the DELSTRIGO and EFV/FTC/TDF groups, respectively) and the majority of subjects reported these events in the first 4 weeks of treatment (72% [62/86] in the DELSTRIGO group and 86% [177/207] in the EFV/FTC/TDF group). - Neuropsychiatric adverse events led to treatment discontinuation in 1% (2/364) and 1% (5/364) of subjects in the DELSTRIGO and EFV/FTC/TDF groups, respectively. The proportion of subjects who reported neuropsychiatric adverse events through Week 4 was 17% (62/364) in the DELSTRIGO group and 49% (177/364) in the EFV/FTC/TDF group. At Week 48, the prevalence of neuropsychiatric adverse events was 12% (44/364) in the DELSTRIGO group and 22% (81/364) in the EFV/FTC/TDF group. - The percentages of subjects with selected laboratory abnormalities (that represent a worsening from baseline) who were treated with doravirine or DRV+r in DRIVE-FORWARD, or DELSTRIGO or EFV/FTC/TDF in DRIVE-AHEAD are presented in Table 3. - For DRIVE-FORWARD and DRIVE-AHEAD, changes from baseline at Week 48 in LDL-cholesterol, non-HDL-cholesterol, total cholesterol, triglycerides, and HDL-cholesterol are shown in Table 4. - The LDL and non-HDL comparisons were pre-specified and are summarized in Table 4. The differences were statistically significant, showing superiority for doravirine for both parameters. The clinical benefit of these findings has not been demonstrated. ## Postmarketing Experience There is limited information regarding Doravirine Postmarketing Experience in the drug label. # Drug Interactions - Co-administration of doravirine with a CYP3A inducer decreases doravirine plasma concentrations, which may reduce doravirine efficacy. Co-administration of doravirine and drugs that are inhibitors of CYP3A may result in increased plasma concentrations of doravirine. - Table 5 shows significant drug interactions with doravirine. - No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, and methadone. - No clinically significant changes in concentration were observed for the following agents when co-administered with doravirine: dolutegravir, lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Exposure Registry - There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to doravirine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary - No adequate human data are available to establish whether or not doravirine poses a risk to pregnancy outcomes. In animal reproduction studies, no adverse developmental effects were observed when doravirine was administered at exposures ≥8 times the exposure in humans at the recommended human dose (RHD) of doravirine. - The background rate of major birth defects is 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates individuals and infants from the limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation. Animal Data - Doravirine was administered orally to pregnant rabbits (up to 300 mg/kg/day on gestation days (GD) 7 to 20) and rats (up to 450 mg/kg/day on GD 6 to 20 and separately from GD 6 to lactation/postpartum day 20). No significant toxicological effects on embryo-fetal (rats and rabbits) or pre/post-natal (rats) development were observed at exposures (AUC) approximately 9 times (rats) and 8 times (rabbits) the exposure in humans at the RHD. Doravirine was transferred to the fetus through the placenta in embryo-fetal studies, with fetal plasma concentrations of up to 40% (rabbits) and 52% (rats) that of maternal concentrations observed on gestation day 20. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Doravirine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Doravirine during labor and delivery. ### Nursing Mothers Risk Summary - The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking potential transmission of HIV-1 infection. - It is unknown whether doravirine is present in human milk, affects human milk production, or has effects on the breastfed infant. Doravirine is present in the milk of lactating rats (see DATA). Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving doravirine. Data - Doravirine was excreted into the milk of lactating rats following oral administration (450 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations approximately 1.5 times that of maternal plasma concentrations observed 2 hours post dose on lactation day 14. ### Pediatric Use - Safety and efficacy of doravirine have not been established in pediatric patients less than 18 years of age. ### Geriatic Use - Clinical trials of doravirine did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of doravirine in elderly patients, 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 Doravirine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Doravirine with respect to specific racial populations. ### Renal Impairment - No dosage adjustment of doravirine is required in patients with mild, moderate, or severe renal impairment. Doravirine has not been adequately studied in patients with end-stage renal disease and has not been studied in dialysis patients. ### Hepatic Impairment - No dosage adjustment of doravirine is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Doravirine has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Doravirine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Doravirine in patients who are immunocompromised. # Administration and Monitoring ### Administration - The recommended dosage regimen of doravirine in adults is one 100 mg tablet taken orally once daily with or without food. - If doravirine is co-administered with rifabutin, increase doravirine dosage to one tablet twice daily (approximately 12 hours apart) for the duration of rifabutin co-administration. ### Monitoring There is limited information regarding Doravirine Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Doravirine and IV administrations. # Overdosage There is limited information regarding Doravirine overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Doravirine is an antiretroviral drug. ## Structure - Doravirine has a molecular formula of C17H11ClF3N5O3 and a molecular weight of 425.75. - It has the following structural formula: ## Pharmacodynamics - In a Phase 2 trial evaluating doravirine over a dose range of 0.25 to 2 times the recommended dose of doravirine, (in combination with FTC/TDF) in HIV-1 infected subjects with no antiretroviral treatment history, no exposure-response relationship for efficacy was identified for doravirine. Cardiac Electrophysiology - At a doravirine dose of 1200 mg, which provides approximately 4 times the peak concentration observed following the recommended dose of doravirine, doravirine does not prolong the QT interval to any clinically relevant extent. ## Pharmacokinetics - Doravirine pharmacokinetics are similar in healthy subjects and HIV-1-infected subjects. Doravirine pharmacokinetics are provided in Table 6. Specific Populations - No clinically significant difference on the pharmacokinetics of doravirine were observed based on age (18 to 78 years of age), sex, and race/ethnicity, mild to severe renal impairment (creatinine clearance (CLcr) >15 mL/min, estimated by Cockcroft-Gault), or moderate hepatic impairment (Child-Pugh B). The pharmacokinetics of doravirine in patients with end-stage renal disease or undergoing dialysis, severe hepatic impairment (Child-Pugh C), or <18 years of age is unknown. Patients with Renal Impairment - In a study comparing 8 subjects with severe renal impairment to 8 subjects without renal impairment, the single dose exposure of doravirine was 43% higher in subjects with severe renal impairment. In a population pharmacokinetic analysis, renal function did not have a clinically relevant effect on doravirine pharmacokinetics. Doravirine has not been studied in patients with end-stage renal disease or in patients undergoing dialysis. Patients with Hepatic Impairment - No clinically significant difference in the pharmacokinetics of doravirine was observed in subjects with moderate hepatic impairment (Child-Pugh score B) compared to subjects without hepatic impairment. Doravirine has not been studied in subjects with severe hepatic impairment (Child-Pugh score C). Drug Interaction Studies - Doravirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of doravirine. Co-administration of doravirine and drugs that induce CYP3A may result in decreased plasma concentrations of doravirine. Co-administration of doravirine and drugs that inhibit CYP3A may result in increased plasma concentrations of doravirine. - Doravirine is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes. Doravirine did not inhibit major drug metabolizing enzymes in vitro, including CYPs 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4, and UGT1A1 and is not likely to be an inducer of CYP1A2, 2B6, or 3A4. Based on in vitro assays, doravirine is not likely to be an inhibitor of OATP1B1, OATP1B3, P-glycoprotein, BSEP, OAT1, OAT3, OCT2, MATE1, and MATE2K. Drug interaction studies were performed with doravirine and other drugs likely to be co-administered or commonly used as probes for pharmacokinetic interactions. The effects of co-administration with other drugs on the exposure (Cmax, AUC, and C24) of doravirine are summarized in Table 7. A single doravirine 100 mg dose was administered in these studies unless otherwise noted. - Based on drug interaction studies conducted with doravirine, no clinically significant drug interactions have been observed following the co-administration of doravirine and the following drugs: dolutegravir, ritonavir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam. ## Microbiology Mechanism of Action - Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Doravirine does not inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA polymerase γ. Antiviral Activity in Cell Culture - Doravirine exhibited an EC50 value of 12.0±4.4 nM against wild-type laboratory strains of HIV-1 when tested in the presence of 100% normal human serum (NHS) using MT4-GFP reporter cells. Doravirine demonstrated antiviral activity against a broad panel of primary HIV-1 isolates (A, A1, AE, AG, B, BF, C, D, G, H) with EC50 values ranging from 0.6 nM to 10.0 nM. Antiviral Activity in Combination with other HIV Antiviral Agents - The antiviral activity of doravirine in cell culture was not antagonistic when combined with the NNRTIs delavirdine, efavirenz, etravirine, nevirapine, or rilpivirine; the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, or zidovudine; the PIs darunavir or indinavir; the gp41 fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir. Resistance In Cell Culture - Doravirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and subtypes, as well as NNRTI-resistant HIV-1. Observed emergent amino acid substitutions in RT included: V106A, V106M, V106I, V108I, H221Y, F227C, F227I, F227L, F227V, M230I, L234I, P236L, and Y318F. In Clinical Trials - In the doravirine treatment arms of the DRIVE-FORWARD and DRIVE-AHEAD trials (n=747), 11 subjects showed the emergence of doravirine-associated resistance substitutions in their HIV among 28 (39%) subjects in the resistance analysis subset (subjects with HIV-1 RNA greater than 400 copies per mL at virologic failure or early study discontinuation and having resistance data). Emergent doravirine resistance-associated substitutions in RT included one or more of the following: A98G, V106I, V106A, V106M/T, V108I, E138G/K, Y188L, H221Y, P225H, F227C, F227C/R, and Y318Y/F. Seven of 11 (64%) subjects with emergent doravirine-associated resistance substitutions showed doravirine phenotypic resistance and all of them had at least a 100-fold reduction in doravirine susceptibility (range >97- to >211–fold reduction in doravirine susceptibility). The other 4 virologic failures who had only amino acid mixtures of NNRTI resistance substitutions showed doravirine phenotypic fold-changes of less than 2-fold. Of the 28 subjects in the resistance analysis subset, 8 subjects (29%) developed genotypic and/or phenotypic resistance to the other drugs (abacavir, lamivudine, emtricitabine, or TDF) in the regimens of the DRIVE-FORWARD and DRIVE-AHEAD trials. The resistance-associated substitutions that emerged were RT M41L (n=1), A62V (n=1), K65R (n=2), T69T/A (n=1), and M184V (n=5). - In the DRV+r treatment arm of the DRIVE-FORWARD trial (n=383), no subjects showed the emergence of darunavir-associated resistance substitutions among 9 subjects with resistance data and none of the subjects had emergent resistance to lamivudine or TDF. In the EFV/FTC/TDF treatment arm of the DRIVE-AHEAD trial (n=364), 12 subjects showed the emergence of efavirenz-associated resistance substitutions among 20 (60%) subjects in the resistance analysis subset and genotypic resistance to emtricitabine or tenofovir developed in 5 evaluable subjects; emergent resistance-associated substitutions were RT K65R (n=1), D67G/K70E (n=1), L74V/V75M/V118I (n=1), and M184V/I (n=5). Cross-Resistance - A panel of 96 diverse clinical isolates containing NNRTI-associated substitutions was evaluated for susceptibility to doravirine. Clinical isolates containing the Y188L substitution alone or in combination with K103N or V106I, V106A in combination with G190A and F227L, or E138K in combination with Y181C and M230L showed greater than 100-fold reduced susceptibility to doravirine. - Cross-resistance has been observed among NNRTIs. Treatment-emergent doravirine resistance-associated substitutions can confer cross resistance to efavirenz, etravirine, nevirapine, and rilpivirine. Of the 7 virologic failures who developed doravirine phenotypic resistance, all had phenotypic resistance to nevirapine, 6 had phenotypic resistance to efavirenz, 4 had phenotypic resistance to rilpivirine, and 3 had partial resistance to etravirine based on the Monogram PhenoSense assay. ## Nonclinical Toxicology Carcinogenesis - Doravirine was not carcinogenic in long-term oral carcinogenicity studies in mice and rats at exposures up to 6 and 7 times, respectively, the human exposures at the RHD. A statistically significant incidence of thyroid parafollicular cell adenoma and carcinoma seen only in female rats at the high dose was within the range observed in historical controls. Mutagenesis - Doravirine was not genotoxic in a battery of in vitro or in vivo assays, including microbial mutagenesis, chromosomal aberration in Chinese hamster ovary cells, and in in vivo rat micronucleus assays. Impairment of fertility - There were no effects on fertility, mating performance or early embryonic development when doravirine was administered to rats at systemic exposures (AUC) approximately 7 times the exposure in humans at the RHD. # Clinical Studies - The efficacy of doravirine is based on the analyses of 48-week data from two randomized, multicenter, double-blind, active controlled Phase 3 trials (DRIVE-FORWARD, NCT02275780 and DRIVE-AHEAD, NCT02403674) in HIV-1 infected subjects with no antiretroviral treatment history (n=1494). - In DRIVE-FORWARD, 766 subjects were randomized and received at least 1 dose of either doravirine once daily or darunavir 800 mg + ritonavir 100 mg (DRV+r) once daily each in combination with emtricitabine/tenofovir DF (FTC/TDF) or abacavir/lamivudine (ABC/3TC) selected by the investigator. At baseline, the median age of subjects was 33 years, 16% were female, 27% were non-white, 4% had hepatitis B and/or C virus co-infection, 10% had a history of AIDS, 20% had HIV-1 RNA greater than 100,000 copies/mL, 86% had CD4+ T-cell count greater than 200 cells/mm3, 13% received ABC/3TC, and 87% received FTC/TDF; these characteristics were similar between treatment groups. - In DRIVE-AHEAD, 728 subjects were randomized and received at least 1 dose of either DELSTRIGO (DOR/3TC/TDF) or EFV 600 mg/FTC 200 mg/TDF 300 mg once daily. At baseline, the median age of subjects was 31 years, 15% were female, 52% were non-white, 3% had hepatitis B or C co-infection, 14% had a history of AIDS, 21% had HIV-1 RNA greater than 100,000 copies/mL, and 88% had CD4+ T-cell count greater than 200 cells/mm3; these characteristics were similar between treatment groups. - Week 48 outcomes for DRIVE-FORWARD and DRIVE-AHEAD are provided in Table 8. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs. - In DRIVE-FORWARD, the mean CD4+ T-cell counts in the doravirine and DRV+r groups increased from baseline by 193 and 186 cells/mm3, respectively. - In DRIVE-AHEAD, the mean CD4+ T-cell counts in the DELSTRIGO and EFV/FTC/TDF groups increased from baseline by 198 and 188 cells/mm3, respectively. # How Supplied - Each doravirine tablet contains 100 mg of doravirine, is white, oval-shaped and film-coated, and is debossed with the corporate logo and 700 on one side and plain on the other side. Each bottle contains 30 tablets (NDC 0006-3069-01) with silica gel desiccant and is closed with a child-resistant closure. ## Storage - Store doravirine in the original bottle. Keep the bottle tightly closed to protect from moisture. Do not remove the desiccant. - Store doravirine 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 Drug Interactions - Inform patients that doravirine may interact with certain other drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort. - For patients concomitantly receiving rifabutin, take one tablet of doravirine twice daily (approximately 12 hours apart). Immune Reconstitution Syndrome - Inform patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection. Dosing Instructions - Advise patients to take doravirine every day at a regularly scheduled time with or without food. Inform patients that it is important not to miss or skip doses as it can result in development of resistance. If a patient forgets to take doravirine, tell the patient to take the missed dose right away, unless it is almost time for the next dose. Advise the patient not to take 2 doses at one time and to take the next dose at the regularly scheduled time. Pregnancy Registry - Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in pregnant individuals exposed to doravirine. Lactation - Instruct mothers with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk. # Precautions with Alcohol Alcohol-Doravirine interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names Pifeltro # Look-Alike Drug Names There is limited information regarding Doravirine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Doravirine
93544723ab617cf73045b54018e21e9de2ac41d3	wikidoc	Dorsal fin	Dorsal fin A dorsal fin is a fin located on the backs of some fishes, whales, dolphins, and porpoises, as well as the (extinct) ichthyosaurs. Its main purpose is to stabilize the animal against rolling and assist in sudden turns. Some animals have developed dorsal fins with protective functions, such as spines or venom. Many catfish can lock the leading ray of the dorsal fin in an extended position to discourage predation or to wedge themselves into a crevice. Dorsal fins come in a variety of shapes and sizes. They are infamous for being the sign of an approaching shark. # Whales, dolphins, and porpoises In relation to the size of the creature, the dorsal fin of the male orca is quite large, as much as 1.8 m high. (The female orca has a shorter dorsal fin that is more curved.) Many (30-100%) captive male killer whales (orcas) experience collapse of the dorsal fin, possibly because lack of exercise through turning leads to diminished muscle tone, other possible factors include change in diet, sex drive and pressure in the pool due to counter-clockwise swimming, this reacts with the sodium nitrate in the whale's pituitary gland and leads to the loss of connective tissue in the dorsal area (Only about 1% of wild orcas have collapsed dorsal fins.) The dorsal fins of most other whales are relatively small. The bowhead whale has no dorsal fin at all, as an evolutionary adaptation to its life spent cruising under icepack. The dorsal fins of whales develop distinctive nicks and wear patterns with time, and this fact is used by wildlife biologists to identify individuals in the field. ar:زعنفة ظهرية de:Finne (Flosse) id:Sirip punggung no:Ryggfinne uk:Спинний плавець	Dorsal fin A dorsal fin is a fin located on the backs of some fishes, whales, dolphins, and porpoises, as well as the (extinct) ichthyosaurs. Its main purpose is to stabilize the animal against rolling and assist in sudden turns. Some animals have developed dorsal fins with protective functions, such as spines or venom. Many catfish can lock the leading ray of the dorsal fin in an extended position to discourage predation or to wedge themselves into a crevice. Dorsal fins come in a variety of shapes and sizes. They are infamous for being the sign of an approaching shark. # Whales, dolphins, and porpoises In relation to the size of the creature, the dorsal fin of the male orca is quite large, as much as 1.8 m high. (The female orca has a shorter dorsal fin that is more curved.) Many (30-100%)[citation needed] captive male killer whales (orcas) experience collapse of the dorsal fin, possibly because lack of exercise through turning leads to diminished muscle tone, other possible factors include change in diet, sex drive and pressure in the pool due to counter-clockwise swimming, this reacts with the sodium nitrate in the whale's pituitary gland and leads to the loss of connective tissue in the dorsal area (Only about 1% of wild orcas have collapsed dorsal fins.) The dorsal fins of most other whales are relatively small. The bowhead whale has no dorsal fin at all, as an evolutionary adaptation to its life spent cruising under icepack. The dorsal fins of whales develop distinctive nicks and wear patterns with time, and this fact is used by wildlife biologists to identify individuals in the field. ar:زعنفة ظهرية de:Finne (Flosse) id:Sirip punggung no:Ryggfinne uk:Спинний плавець Template:WS	https://www.wikidoc.org/index.php/Dorsal_fin
eccc31894a26b06f09a5430b40f5336576906696	wikidoc	Doug Sharp	Doug Sharp Doug Sharp (born November 27, 1969) is an American bobsledder who has competed from the late 1990s to the early 2000s. He won the bronze medal in the four-man event at the 2002 Winter Olympics in Salt Lake City. Prior to his involvement in bobsleigh, Sharp was also involved in Athletics (track and field) in the pole vault, barely missing the cut-off qualification for the United States Olympic trials for the 1996 Summer Olympics in Atlanta. He also played American football and ice hockey. At the time of the 2002 Winter Olympics, he also served as an assistant athletics coach for the University of Louisville in Kentucky. Sharp also is a licensed chiropractor and serves in the United States Army in artillery. He graduated from Purdue University in 1993.	Doug Sharp Template:MedalSport Template:MedalBronze Template:MedalBottom Doug Sharp (born November 27, 1969) is an American bobsledder who has competed from the late 1990s to the early 2000s. He won the bronze medal in the four-man event at the 2002 Winter Olympics in Salt Lake City. Prior to his involvement in bobsleigh, Sharp was also involved in Athletics (track and field) in the pole vault, barely missing the cut-off qualification for the United States Olympic trials for the 1996 Summer Olympics in Atlanta. He also played American football and ice hockey. At the time of the 2002 Winter Olympics, he also served as an assistant athletics coach for the University of Louisville in Kentucky. Sharp also is a licensed chiropractor and serves in the United States Army in artillery. He graduated from Purdue University in 1993.	https://www.wikidoc.org/index.php/Doug_Sharp
4f3e22ec07be4df24423b25c7d04cd4488492b5f	wikidoc	Downs cell	Downs cell The Downs process is a method for the commercial preparation of metallic sodium, in which molten NaCl is electrolyzed in a special apparatus called the Downs cell. # How it works The Downs cell uses a carbon anode and iron cathode. The electrolyte is sodium chloride that has been fused to a liquid by heating. Although crystaline sodium chloride is a poor conductor of electricity, fusing it mobilizes the sodium and chloride ions, which become charge carriers and allow conduction of electric current. Some calcium chloride and/or sodium carbonate is added to the electrolyte to reduce the temperature required to keep the electrolyte liquid. Sodium chloride normally melts at 804 °C, but the mixture can be kept liquid at temperatures around 600 °C. The anode reaction is: The cathode reaction is: for an overall reaction of The calcium does not enter into the reaction because its reduction potential of 2.87 volts is higher than that of sodium. Hence the sodium ions are reduced to metallic form in preference to those of calcium. If the electrolyte contained only calcium ion and no sodium, it would be calcium metal produced as the cathode product (which indeed is how metallic calcium is produced). Both the products of the electrolysis, sodium metal and chlorine gas, are less dense than the electrolyte and therefore float to the surface. Perforated iron baffles are arranged in the cell (see the diagram to the right) to direct the products into separate chambers without their ever coming into contact with each other. Although theory predicts that a potential of a little over 4 volts should be sufficient to cause the reaction to go foward, in practice potentials of up to 8 volts are used. This is done in order to achieve useful current densities in the electrolyte despite its inherent electrical resistance. The overvoltage and consequent resistive heating contributes to the heat required to keep the electrolyte in a liquid state. The Downs process also produces chlorine as a byproduct, although chlorine produced this way accounts for only a small fraction of chlorine produced industrially by other methods.	Downs cell The Downs process is a method for the commercial preparation of metallic sodium, in which molten NaCl is electrolyzed in a special apparatus called the Downs cell. # How it works The Downs cell uses a carbon anode and iron cathode. The electrolyte is sodium chloride that has been fused to a liquid by heating. Although crystaline sodium chloride is a poor conductor of electricity, fusing it mobilizes the sodium and chloride ions, which become charge carriers and allow conduction of electric current. Some calcium chloride and/or sodium carbonate is added to the electrolyte to reduce the temperature required to keep the electrolyte liquid. Sodium chloride normally melts at 804 °C, but the mixture can be kept liquid at temperatures around 600 °C. The anode reaction is: The cathode reaction is: for an overall reaction of The calcium does not enter into the reaction because its reduction potential of 2.87 volts is higher than that of sodium. Hence the sodium ions are reduced to metallic form in preference to those of calcium.[1] If the electrolyte contained only calcium ion and no sodium, it would be calcium metal produced as the cathode product (which indeed is how metallic calcium is produced). Both the products of the electrolysis, sodium metal and chlorine gas, are less dense than the electrolyte and therefore float to the surface. Perforated iron baffles are arranged in the cell (see the diagram to the right) to direct the products into separate chambers without their ever coming into contact with each other.[2] Although theory predicts that a potential of a little over 4 volts should be sufficient to cause the reaction to go foward, in practice potentials of up to 8 volts are used. This is done in order to achieve useful current densities in the electrolyte despite its inherent electrical resistance. The overvoltage and consequent resistive heating contributes to the heat required to keep the electrolyte in a liquid state. The Downs process also produces chlorine as a byproduct, although chlorine produced this way accounts for only a small fraction of chlorine produced industrially by other methods.[2]	https://www.wikidoc.org/index.php/Downs_Cell
ed7f61bad1ed39eb691390656684bbb0af5dd29f	wikidoc	Dronabinol	Dronabinol # 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 Dronabinol is a cannabinoid that is FDA approved for the treatment of anorexia associated with weight loss in patients with AIDS, and for the prophylaxis of nausea and vomiting associated with cancer chemotherapy. Common adverse reactions include asthenia,abdominal pain, nausea, vomiting, palpitations, tachycardia, vasodilation,diarrhea, fecal incontinence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications Dronabinol Capsules is indicated for the treatment of: - Anorexia associated with weight loss in patients with AIDS; and - Nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. # Dosage Appetite Stimulation - Initially, 2.5 mg dronabinol capsules should be administered orally twice daily (b.i.d.), before lunch and supper. For patients unable to tolerate this 5 mg/day dosage of dronabinol capsules, the dosage can be reduced to 2.5 mg/day, administered as a single dose in the evening or at bedtime. If clinically indicated and in the absence of significant adverse effects, the dosage may be gradually increased to a maximum of 20 mg/day dronabinol capsules, administered in divided oral doses. Caution should be exercised in escalating the dosage of dronabinol capsules because of the increased frequency of dose-related adverse experiences at higher dosages. Antiemetic - Dronabinol Capsules are best administered at an initial dose of 5 mg/m2, given 1 to 3 hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given, for a total of 4 to 6 doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in the absence of significant side effects, the dose may be escalated by 2.5 mg/m2 increments to a maximum of 15 mg/m2 per dose. Caution should be exercised in dose escalation, however, as the incidence of disturbing psychiatric symptoms increases significantly at maximum dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dronabinol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dronabinol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Dronabinol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dronabinol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dronabinol in pediatric patients. # Contraindications - Dronabinol Capsules is contraindicated in any patient who has a known sensitivity to Dronabinol Capsules or any of its ingredients. It contains cannabinoid and sesame oil and should never be used by patients allergic to these substances. # Warnings - Patients receiving treatment with Dronabinol Capsules should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely. ## Precautions General - The risk/benefit ratio of Dronabinol Capsules use should be carefully evaluated in patients with the following medical conditions because of individual variation in response and tolerance to the effects of Dronabinol Capsules. - Seizure and seizure-like activity have been reported in patients receiving dronabinol capsules during marketed use of the drug and in clinical trials. Dronabinol capsules should be used with caution in patients with a history of seizure disorder because dronabinol capsules may lower the seizure threshold. A causal relationship between dronabinol capsules and these events has not been established. Dronabinol capsules should be discontinued immediately in patients who develop seizures and medical attention should be sought immediately. - Dronabinol Capsules should be used with caution in patients with cardiac disorders because of occasional hypotension, possible hypertension, syncope, or tachycardia. - Dronabinol capsules should be used with caution in patients with a history of substance abuse, including alcohol abuse or dependence, because they may be more prone to abuse dronabinol capsules as well. Multiple substance abuse is common and marijuana, which contains the same active compound, is a frequently abused substance. - Dronabinol capsules should be used with caution and careful psychiatric monitoring in patients with mania, depression, or schizophrenia because Dronabinol Capsules may exacerbate these illnesses. - Dronabinol Capsules should be used with caution in patients receiving concomitant therapy with sedatives, hypnotics or other psychoactive drugs because of the potential for additive or synergistic CNS effects. - Dronabinol capsules should be used with caution in elderly patients because they may be more sensitive to the neurological, psychoactive, and postural hypotensive effects of the drug. - Dronabinol capsules should be used with caution in pregnant patients, nursing mothers, or pediatric patients because it has not been studied in these patient populations. # Adverse Reactions ## Clinical Trials Experience - Adverse experiences information summarized in the tables below was derived from well-controlled clinical trials conducted in the U.S. and U.S. territories involving 474 patients exposed to Dronabinol Capsules. Studies of AIDS-related weight loss included 157 patients receiving dronabinol at a dose of 2.5 mg twice daily and 67 receiving placebo. Studies of different durations were combined by considering the first occurrence of events during the first 28 days. Studies of nausea and vomiting related to cancer chemotherapy included 317 patients receiving dronabinol and 68 receiving placebo. - A cannabinoid dose-related "high" (easy laughing, elation and heightened awareness) has been reported by patients receiving dronabinol capsules in the antiemetic (24%) and the lower dose appetite stimulant clinical trials (8%). - The most frequently reported adverse experiences in patients with AIDS during placebo-controlled clinical trials involved the CNS and were reported by 33% of patients receiving dronabinol capsules. About 25% of patients reported a minor CNS adverse event during the first 2 weeks and about 4% reported such an event each week for the next 6 weeks thereafter. PROBABLY CAUSALLY RELATED Incidence greater than 1% Rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea (N=317). Rates were generally higher in the anti-emetic use (given in parentheses). PROBABLY CAUSALLY RELATED Incidence greater than 1% Rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea (N=317). Rates were generally higher in the anti-emetic use (given in parentheses). CAUSAL RELATIONSHIP UNKNOWN Incidence less than 1% The clinical significance of the association of these events with dronabinol capsules treatment is unknown, but they are reported as alerting information for the clinician. ## Postmarketing Experience - Seizure and seizure-like activity have been reported in patients receiving dronabinol capsules during marketed use of the drug and in clinical trials.Reports of fatigue have also been received. A causal relationship between dronabinol capsules and these events has not been established. # Drug Interactions - In studies involving patients with AIDS and/or cancer, dronabinol capsules has been co-administered with a variety of medications (e.g., cytotoxic agents, anti-infective agents, sedatives, or opioid analgesics) without resulting in any clinically significant drug/drug interactions. Although no drug/drug interactions were discovered during the clinical trials of dronabinol capsules, cannabinoids may interact with other medications through both metabolic and pharmacodynamic mechanisms. Dronabinol is highly protein bound to plasma proteins, and therefore, might displace other protein-bound drugs. Although this displacement has not been confirmed in vivo, practitioners should monitor patients for a change in dosage requirements when administering dronabinol to patients receiving other highly protein-bound drugs. Published reports of drug/drug interactions involving cannabinoids are summarized in the following table. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C - Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m2, equivalent to 0.2 to 5 times maximum recommended human dose (MRHD) of 90 mg/m2/day in cancer patients or 1 to 30 times MRHD of 15 mg/m2/day in AIDS patients, and in rats at 74 to 295 mg/m2 (equivalent to 0.8 to 3 times MRHD of 90 mg/m2 in cancer patients or 5 to 20 times MRHD of 15 mg/ m2/day in AIDS patients). These studies have revealed no evidence of teratogenicity due to dronabinol. At these dosages in mice and rats, dronabinol decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions. Such effects were dose dependent and less apparent at lower doses which produced less maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Dronabinol should be used only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dronabinol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dronabinol during labor and delivery. ### Nursing Mothers - Use of dronabinol capsules is not recommended in nursing mothers since, in addition to the secretion of HIV virus in breast milk, dronabinol is concentrated in and secreted in human breast milk and is absorbed by the nursing baby. ### Pediatric Use There is no FDA guidance on the use of Dronabinol with respect to pediatric patients. ### Geriatic Use - Clinical studies of dronabinol capsules in AIDS and cancer patients did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of falls, decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Dronabinol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dronabinol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Dronabinol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Dronabinol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dronabinol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dronabinol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Dronabinol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Dronabinol in the drug label. # Overdosage - Signs and symptoms following mild dronabinol capsules intoxication include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and tachycardia; following moderate intoxication include memory impairment, depersonalization, mood alteration, urinary retention, and reduced bowel motility; and following severe intoxication include decreased motor coordination, lethargy, slurred speech, and postural hypotension. Apprehensive patients may experience panic reactions and seizures may occur in patients with existing seizure disorders. - The estimated lethal human dose of intravenous dronabinol is 30 mg/kg (2100 mg/ 70 kg). Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules. Management - A potentially serious oral ingestion, if recent, should be managed with gut decontamination. In unconscious patients with a secure airway, instill activated charcoal (30 to 100 g in adults, 1 to 2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal. Patients experiencing depressive, hallucinatory or psychotic reactions should be placed in a quiet area and offered reassurance. Benzodiazepines (5 to 10 mg diazepam po) may be used for treatment of extreme agitation. Hypotension usually responds to Trendelenburg position and IV fluids. Pressors are rarely required. # Pharmacology There is limited information regarding Dronabinol Pharmacology in the drug label. ## Mechanism of Action There is limited information regarding Dronabinol Mechanism of Action in the drug label. ## Structure - Dronabinol is a cannabinoid designated chemically as (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzopyran-1-ol. Dronabinol has the following empirical and structural formulas: - Dronabinol, the active ingredient in dronabinol capsules, is synthetic delta-9-tetrahydrocannabinol (delta-9-THC). Delta-9-tetrahydrocannabinol is also a naturally occurring component of Cannabis sativa L. (Marijuana). - Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7. - Capsules for oral administration: Dronabinol Capsules are supplied as oval, soft gelatin capsules containing either 2.5 mg, 5 mg, or 10 mg dronabinol. Each dronabinol capsule strength is formulated with the following inactive ingredients: 2.5 mg capsule contains gelatin, glycerin, sesame oil, titanium dioxide, SDA 35A alcohol, propylene glycol, black iron oxide, polyvinyl acetate phthalate, purified water, isopropyl alcohol, polyethylene glycol, and ammonium hydroxide; 5 mg capsule contains iron oxide red, iron oxide black, gelatin, glycerin, sesame oil, titanium dioxide, SDA 35A alcohol, propylene glycol, polyvinyl acetate phthalate, purified water, isopropyl alcohol, polyethylene glycol, and ammonium hydroxide; 10 mg capsule contains iron oxide red, iron oxide yellow, gelatin, glycerin, sesame oil, titanium dioxide, SDA 35A alcohol, propylene glycol, black iron oxide, polyvinyl acetate phthalate, purified water, isopropyl alcohol, polyethylene glycol, and ammonium hydroxide. ## Pharmacodynamics - Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but occasional subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing. - Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great interpatient variability. - After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration. - Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol and other cannabinoids with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male volunteers (N = 12) received 210 mg/day dronabinol, administered orally in divided doses, for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These volunteers developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation. - Tachyphylaxis and tolerance do not, however, appear to develop to the appetite stimulant effect of dronabinol capsules. In studies involving patients with Acquired Immune Deficiency Syndrome (AIDS), the appetite stimulant effect of Dronabinol capsules has been sustained for up to five months in clinical trials, at dosages ranging from 2.5 mg/day to 20 mg/day. ## Pharmacokinetics Absorption and Distribution - Dronabinol capsules is almost completely absorbed (90 to 95%) after single oral doses. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97%. - The elimination phase of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. Because of its large volume of distribution, dronabinol and its metabolites may be excreted at low levels for prolonged periods of time. - The pharmacokinetics of dronabinol after single doses (2.5, 5, and 10 mg) and multiple doses (2.5, 5, and 10 mg given twice a day; BID) have been studied in healthy women and men. - A slight increase in dose proportionality on mean Cmax and AUC(0 to 12) of dronabinol was observed with increasing dose over the dose range studied. Metabolism - Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by microsomal hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral dosing and decline over several days. Values for clearance average about 0.2 L/kg-hr, but are highly variable due to the complexity of cannabinoid distribution. Elimination - Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces. - Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces. - In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol. Special Populations - The pharmacokinetic profile of dronabinol capsules has not been investigated in either pediatric or geriatric patients. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies in mice and rats have been conducted under the U.S. National Toxicology Program (NTP). In the 2-year carcinogenicity study in rats, there was no evidence of carcinogenicity at doses up to 50 mg/kg/day, about 20 times the maximum recommended human dose on a body surface area basis. In the 2-year carcinogenicity study in mice, treatment with dronabinol at 125 mg/kg/day, about 25 times the maximum recommended human dose on a body surface area basis, produced thyroid follicular cell adenoma in both male and female mice but not at 250 or 500 mg/kg/day. - Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary cells, and the in vivo mouse micronucleus test. It, however, produced a weak positive response in a sister chromatid exchange test in Chinese hamster ovary cells. - In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m2, equivalent to 0.3 to 1.5 times maximum recommended human dose (MRHD) of 90 mg/m2/day in cancer patients or 2 to 10 times MRHD of 15 mg/m2/day in AIDS patients, reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also observed. However, sperm count, mating success and testosterone levels were not affected. The significance of these animal findings in humans is not known. # Clinical Studies Appetite Stimulation - The appetite stimulant effect of Dronabinol Capsules in the treatment of AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind, placebo-controlled study involving 139 patients. The initial dosage of dronabinol capsules in all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before supper. In pilot studies, early morning administration of dronabinol capsules appeared to have been associated with an increased frequency of adverse experiences, as compared to dosing later in the day. The effect of dronabinolc capsules on appetite, weight, mood, and nausea was measured at scheduled intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion, somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to 2.5 mg/day, administered as a single dose at supper or bedtime. - Of the 112 patients that completed at least 2 visits in the randomized, double-blind, placebo-controlled study, 99 patients had appetite data at 4-weeks (50 received dronabinol capsules and 49 received placebo) and 91 patients had appetite data at 6-weeks (46 received dronabinol capsules and 45 received placebo). A statistically significant difference between dronabinol capsules and placebo was seen in appetite as measured by the visual analog scale at weeks 4 and 6. Trends toward improved body weight and mood, and decreases in nausea were also seen. - After completing the 6-week study, patients were allowed to continue treatment with dronabinol capsules in an open-label study, in which there was a sustained improvement in appetite. Antiemetic - Dronabinol capsules treatment of chemotherapy-induced emesis was evaluated in 454 patients with cancer, who received a total of 750 courses of treatment of various malignancies. The antiemetic efficacy of Dronabinol Capsules was greatest in patients receiving cytotoxic therapy with MOPP for Hodgkin's and non-Hodgkin's lymphomas. Dronabinol Capsule dosages ranged from 2.5 mg/day to 40 mg/day, administered in equally divided doses every four to six hours (four times daily). As indicated in the following table, escalating the Dronabinol Capsules dose above 7 mg/m2 increased the frequency of adverse experiences, with no additional antiemetic benefit. - Combination antiemetic therapy with Dronabinol Capsules and a phenothiazine (prochlorperazine) may result in synergistic or additive antiemetic effects and attenuate the toxicities associated with each of the agents. # How Supplied - Dronabinol Capsules are available containing 2.5 mg, 5 mg or 10 mg of dronabinol. - The 2.5 mg capsule is an opaque off-white soft gelatin capsule printed with INS in black ink. They are available as follows: NDC 0378-8170-91 bottles of 60 capsules - The 5 mg capsule is an opaque maroon or brown soft gelatin capsule printed with INS in white ink. They are available as follows: NDC 0378-8171-91 bottles of 60 capsules - The 10 mg capsule is an opaque tan to tan-orange soft gelatin capsule printed with INS in black ink. They are available as follows: NDC 0378-8172-91 bottles of 60 capsules ## Storage - Dronabinol Capsules should be packaged in a well-closed container and stored in a refrigerator between 2° and 8°C (36° and 46°F). Protect from freezing and light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients receiving treatment with dronabinol capsules should be alerted to the potential for additive central nervous system depression if dronabinol capsules is used concomitantly with alcohol or other CNS depressants such as benzodiazepines and barbiturates. - Patients receiving treatment with dronabinol capsules should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely. - Patients using dronabinol Capsules should be advised of possible changes in mood and other adverse behavioral effects of the drug so as to avoid panic in the event of such manifestations. Patients should remain under the supervision of a responsible adult during initial use of dronabinol capsules and following dosage adjustments. # Precautions with Alcohol - Alcohol-Dronabinol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - DRONABINOL # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Dronabinol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Dronabinol is a cannabinoid that is FDA approved for the treatment of anorexia associated with weight loss in patients with AIDS, and for the prophylaxis of nausea and vomiting associated with cancer chemotherapy. Common adverse reactions include asthenia,abdominal pain, nausea, vomiting, palpitations, tachycardia, vasodilation,diarrhea, fecal incontinence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications Dronabinol Capsules is indicated for the treatment of: - Anorexia associated with weight loss in patients with AIDS; and - Nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments. # Dosage Appetite Stimulation - Initially, 2.5 mg dronabinol capsules should be administered orally twice daily (b.i.d.), before lunch and supper. For patients unable to tolerate this 5 mg/day dosage of dronabinol capsules, the dosage can be reduced to 2.5 mg/day, administered as a single dose in the evening or at bedtime. If clinically indicated and in the absence of significant adverse effects, the dosage may be gradually increased to a maximum of 20 mg/day dronabinol capsules, administered in divided oral doses. Caution should be exercised in escalating the dosage of dronabinol capsules because of the increased frequency of dose-related adverse experiences at higher dosages. Antiemetic - Dronabinol Capsules are best administered at an initial dose of 5 mg/m2, given 1 to 3 hours prior to the administration of chemotherapy, then every 2 to 4 hours after chemotherapy is given, for a total of 4 to 6 doses/day. Should the 5 mg/m2 dose prove to be ineffective, and in the absence of significant side effects, the dose may be escalated by 2.5 mg/m2 increments to a maximum of 15 mg/m2 per dose. Caution should be exercised in dose escalation, however, as the incidence of disturbing psychiatric symptoms increases significantly at maximum dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dronabinol in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dronabinol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Dronabinol in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Dronabinol in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Dronabinol in pediatric patients. # Contraindications - Dronabinol Capsules is contraindicated in any patient who has a known sensitivity to Dronabinol Capsules or any of its ingredients. It contains cannabinoid and sesame oil and should never be used by patients allergic to these substances. # Warnings - Patients receiving treatment with Dronabinol Capsules should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely. ## Precautions General - The risk/benefit ratio of Dronabinol Capsules use should be carefully evaluated in patients with the following medical conditions because of individual variation in response and tolerance to the effects of Dronabinol Capsules. - Seizure and seizure-like activity have been reported in patients receiving dronabinol capsules during marketed use of the drug and in clinical trials. Dronabinol capsules should be used with caution in patients with a history of seizure disorder because dronabinol capsules may lower the seizure threshold. A causal relationship between dronabinol capsules and these events has not been established. Dronabinol capsules should be discontinued immediately in patients who develop seizures and medical attention should be sought immediately. - Dronabinol Capsules should be used with caution in patients with cardiac disorders because of occasional hypotension, possible hypertension, syncope, or tachycardia. - Dronabinol capsules should be used with caution in patients with a history of substance abuse, including alcohol abuse or dependence, because they may be more prone to abuse dronabinol capsules as well. Multiple substance abuse is common and marijuana, which contains the same active compound, is a frequently abused substance. - Dronabinol capsules should be used with caution and careful psychiatric monitoring in patients with mania, depression, or schizophrenia because Dronabinol Capsules may exacerbate these illnesses. - Dronabinol Capsules should be used with caution in patients receiving concomitant therapy with sedatives, hypnotics or other psychoactive drugs because of the potential for additive or synergistic CNS effects. - Dronabinol capsules should be used with caution in elderly patients because they may be more sensitive to the neurological, psychoactive, and postural hypotensive effects of the drug. - Dronabinol capsules should be used with caution in pregnant patients, nursing mothers, or pediatric patients because it has not been studied in these patient populations. # Adverse Reactions ## Clinical Trials Experience - Adverse experiences information summarized in the tables below was derived from well-controlled clinical trials conducted in the U.S. and U.S. territories involving 474 patients exposed to Dronabinol Capsules. Studies of AIDS-related weight loss included 157 patients receiving dronabinol at a dose of 2.5 mg twice daily and 67 receiving placebo. Studies of different durations were combined by considering the first occurrence of events during the first 28 days. Studies of nausea and vomiting related to cancer chemotherapy included 317 patients receiving dronabinol and 68 receiving placebo. - A cannabinoid dose-related "high" (easy laughing, elation and heightened awareness) has been reported by patients receiving dronabinol capsules in the antiemetic (24%) and the lower dose appetite stimulant clinical trials (8%). - The most frequently reported adverse experiences in patients with AIDS during placebo-controlled clinical trials involved the CNS and were reported by 33% of patients receiving dronabinol capsules. About 25% of patients reported a minor CNS adverse event during the first 2 weeks and about 4% reported such an event each week for the next 6 weeks thereafter. PROBABLY CAUSALLY RELATED Incidence greater than 1% Rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea (N=317). Rates were generally higher in the anti-emetic use (given in parentheses). PROBABLY CAUSALLY RELATED Incidence greater than 1% Rates derived from clinical trials in AIDS-related anorexia (N=157) and chemotherapy-related nausea (N=317). Rates were generally higher in the anti-emetic use (given in parentheses). CAUSAL RELATIONSHIP UNKNOWN Incidence less than 1% The clinical significance of the association of these events with dronabinol capsules treatment is unknown, but they are reported as alerting information for the clinician. ## Postmarketing Experience - Seizure and seizure-like activity have been reported in patients receiving dronabinol capsules during marketed use of the drug and in clinical trials.Reports of fatigue have also been received. A causal relationship between dronabinol capsules and these events has not been established. # Drug Interactions - In studies involving patients with AIDS and/or cancer, dronabinol capsules has been co-administered with a variety of medications (e.g., cytotoxic agents, anti-infective agents, sedatives, or opioid analgesics) without resulting in any clinically significant drug/drug interactions. Although no drug/drug interactions were discovered during the clinical trials of dronabinol capsules, cannabinoids may interact with other medications through both metabolic and pharmacodynamic mechanisms. Dronabinol is highly protein bound to plasma proteins, and therefore, might displace other protein-bound drugs. Although this displacement has not been confirmed in vivo, practitioners should monitor patients for a change in dosage requirements when administering dronabinol to patients receiving other highly protein-bound drugs. Published reports of drug/drug interactions involving cannabinoids are summarized in the following table. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category C - Reproduction studies with dronabinol have been performed in mice at 15 to 450 mg/m2, equivalent to 0.2 to 5 times maximum recommended human dose (MRHD) of 90 mg/m2/day in cancer patients or 1 to 30 times MRHD of 15 mg/m2/day in AIDS patients, and in rats at 74 to 295 mg/m2 (equivalent to 0.8 to 3 times MRHD of 90 mg/m2 in cancer patients or 5 to 20 times MRHD of 15 mg/ m2/day in AIDS patients). These studies have revealed no evidence of teratogenicity due to dronabinol. At these dosages in mice and rats, dronabinol decreased maternal weight gain and number of viable pups and increased fetal mortality and early resorptions. Such effects were dose dependent and less apparent at lower doses which produced less maternal toxicity. There are no adequate and well-controlled studies in pregnant women. Dronabinol should be used only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dronabinol in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Dronabinol during labor and delivery. ### Nursing Mothers - Use of dronabinol capsules is not recommended in nursing mothers since, in addition to the secretion of HIV virus in breast milk, dronabinol is concentrated in and secreted in human breast milk and is absorbed by the nursing baby. ### Pediatric Use There is no FDA guidance on the use of Dronabinol with respect to pediatric patients. ### Geriatic Use - Clinical studies of dronabinol capsules in AIDS and cancer patients did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious usually starting at the low end of the dosing range, reflecting the greater frequency of falls, decreased hepatic, renal, or cardiac function, increased sensitivity to psychoactive effects and of concomitant disease or other drug therapy. ### Gender There is no FDA guidance on the use of Dronabinol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Dronabinol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Dronabinol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Dronabinol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Dronabinol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Dronabinol in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Dronabinol in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Dronabinol in the drug label. # Overdosage - Signs and symptoms following mild dronabinol capsules intoxication include drowsiness, euphoria, heightened sensory awareness, altered time perception, reddened conjunctiva, dry mouth and tachycardia; following moderate intoxication include memory impairment, depersonalization, mood alteration, urinary retention, and reduced bowel motility; and following severe intoxication include decreased motor coordination, lethargy, slurred speech, and postural hypotension. Apprehensive patients may experience panic reactions and seizures may occur in patients with existing seizure disorders. - The estimated lethal human dose of intravenous dronabinol is 30 mg/kg (2100 mg/ 70 kg). Significant CNS symptoms in antiemetic studies followed oral doses of 0.4 mg/kg (28 mg/70 kg) of dronabinol capsules. Management - A potentially serious oral ingestion, if recent, should be managed with gut decontamination. In unconscious patients with a secure airway, instill activated charcoal (30 to 100 g in adults, 1 to 2 g/kg in infants) via a nasogastric tube. A saline cathartic or sorbitol may be added to the first dose of activated charcoal. Patients experiencing depressive, hallucinatory or psychotic reactions should be placed in a quiet area and offered reassurance. Benzodiazepines (5 to 10 mg diazepam po) may be used for treatment of extreme agitation. Hypotension usually responds to Trendelenburg position and IV fluids. Pressors are rarely required. # Pharmacology There is limited information regarding Dronabinol Pharmacology in the drug label. ## Mechanism of Action There is limited information regarding Dronabinol Mechanism of Action in the drug label. ## Structure - Dronabinol is a cannabinoid designated chemically as (6aR-trans)-6a,7,8,10a-tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. Dronabinol has the following empirical and structural formulas: - Dronabinol, the active ingredient in dronabinol capsules, is synthetic delta-9-tetrahydrocannabinol (delta-9-THC). Delta-9-tetrahydrocannabinol is also a naturally occurring component of Cannabis sativa L. (Marijuana). - Dronabinol is a light yellow resinous oil that is sticky at room temperature and hardens upon refrigeration. Dronabinol is insoluble in water and is formulated in sesame oil. It has a pKa of 10.6 and an octanol-water partition coefficient: 6,000:1 at pH 7. - Capsules for oral administration: Dronabinol Capsules are supplied as oval, soft gelatin capsules containing either 2.5 mg, 5 mg, or 10 mg dronabinol. Each dronabinol capsule strength is formulated with the following inactive ingredients: 2.5 mg capsule contains gelatin, glycerin, sesame oil, titanium dioxide, SDA 35A alcohol, propylene glycol, black iron oxide, polyvinyl acetate phthalate, purified water, isopropyl alcohol, polyethylene glycol, and ammonium hydroxide; 5 mg capsule contains iron oxide red, iron oxide black, gelatin, glycerin, sesame oil, titanium dioxide, SDA 35A alcohol, propylene glycol, polyvinyl acetate phthalate, purified water, isopropyl alcohol, polyethylene glycol, and ammonium hydroxide; 10 mg capsule contains iron oxide red, iron oxide yellow, gelatin, glycerin, sesame oil, titanium dioxide, SDA 35A alcohol, propylene glycol, black iron oxide, polyvinyl acetate phthalate, purified water, isopropyl alcohol, polyethylene glycol, and ammonium hydroxide. ## Pharmacodynamics - Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but occasional subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing. - Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great interpatient variability. - After oral administration, dronabinol has an onset of action of approximately 0.5 to 1 hours and peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration. - Tachyphylaxis and tolerance develop to some of the pharmacologic effects of dronabinol and other cannabinoids with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male volunteers (N = 12) received 210 mg/day dronabinol, administered orally in divided doses, for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These volunteers developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation. - Tachyphylaxis and tolerance do not, however, appear to develop to the appetite stimulant effect of dronabinol capsules. In studies involving patients with Acquired Immune Deficiency Syndrome (AIDS), the appetite stimulant effect of Dronabinol capsules has been sustained for up to five months in clinical trials, at dosages ranging from 2.5 mg/day to 20 mg/day. ## Pharmacokinetics Absorption and Distribution - Dronabinol capsules is almost completely absorbed (90 to 95%) after single oral doses. Due to the combined effects of first pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches the systemic circulation. Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility. The plasma protein binding of dronabinol and its metabolites is approximately 97%. - The elimination phase of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours. Because of its large volume of distribution, dronabinol and its metabolites may be excreted at low levels for prolonged periods of time. - The pharmacokinetics of dronabinol after single doses (2.5, 5, and 10 mg) and multiple doses (2.5, 5, and 10 mg given twice a day; BID) have been studied in healthy women and men. - A slight increase in dose proportionality on mean Cmax and AUC(0 to 12) of dronabinol was observed with increasing dose over the dose range studied. Metabolism - Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by microsomal hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral dosing and decline over several days. Values for clearance average about 0.2 L/kg-hr, but are highly variable due to the complexity of cannabinoid distribution. Elimination - Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of elimination with about half of a radio-labeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces. - Following single dose administration, low levels of dronabinol metabolites have been detected for more than 5 weeks in the urine and feces. - In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six week period. The urinary cannabinoid/creatinine ratio was closely correlated with dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol. Special Populations - The pharmacokinetic profile of dronabinol capsules has not been investigated in either pediatric or geriatric patients. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility - Carcinogenicity studies in mice and rats have been conducted under the U.S. National Toxicology Program (NTP). In the 2-year carcinogenicity study in rats, there was no evidence of carcinogenicity at doses up to 50 mg/kg/day, about 20 times the maximum recommended human dose on a body surface area basis. In the 2-year carcinogenicity study in mice, treatment with dronabinol at 125 mg/kg/day, about 25 times the maximum recommended human dose on a body surface area basis, produced thyroid follicular cell adenoma in both male and female mice but not at 250 or 500 mg/kg/day. - Dronabinol was not genotoxic in the Ames tests, the in vitro chromosomal aberration test in Chinese hamster ovary cells, and the in vivo mouse micronucleus test. It, however, produced a weak positive response in a sister chromatid exchange test in Chinese hamster ovary cells. - In a long-term study (77 days) in rats, oral administration of dronabinol at doses of 30 to 150 mg/m2, equivalent to 0.3 to 1.5 times maximum recommended human dose (MRHD) of 90 mg/m2/day in cancer patients or 2 to 10 times MRHD of 15 mg/m2/day in AIDS patients, reduced ventral prostate, seminal vesicle and epididymal weights and caused a decrease in seminal fluid volume. Decreases in spermatogenesis, number of developing germ cells, and number of Leydig cells in the testis were also observed. However, sperm count, mating success and testosterone levels were not affected. The significance of these animal findings in humans is not known. # Clinical Studies Appetite Stimulation - The appetite stimulant effect of Dronabinol Capsules in the treatment of AIDS-related anorexia associated with weight loss was studied in a randomized, double-blind, placebo-controlled study involving 139 patients. The initial dosage of dronabinol capsules in all patients was 5 mg/day, administered in doses of 2.5 mg one hour before lunch and one hour before supper. In pilot studies, early morning administration of dronabinol capsules appeared to have been associated with an increased frequency of adverse experiences, as compared to dosing later in the day. The effect of dronabinolc capsules on appetite, weight, mood, and nausea was measured at scheduled intervals during the six-week treatment period. Side effects (feeling high, dizziness, confusion, somnolence) occurred in 13 of 72 patients (18%) at this dosage level and the dosage was reduced to 2.5 mg/day, administered as a single dose at supper or bedtime. - Of the 112 patients that completed at least 2 visits in the randomized, double-blind, placebo-controlled study, 99 patients had appetite data at 4-weeks (50 received dronabinol capsules and 49 received placebo) and 91 patients had appetite data at 6-weeks (46 received dronabinol capsules and 45 received placebo). A statistically significant difference between dronabinol capsules and placebo was seen in appetite as measured by the visual analog scale at weeks 4 and 6. Trends toward improved body weight and mood, and decreases in nausea were also seen. - After completing the 6-week study, patients were allowed to continue treatment with dronabinol capsules in an open-label study, in which there was a sustained improvement in appetite. Antiemetic - Dronabinol capsules treatment of chemotherapy-induced emesis was evaluated in 454 patients with cancer, who received a total of 750 courses of treatment of various malignancies. The antiemetic efficacy of Dronabinol Capsules was greatest in patients receiving cytotoxic therapy with MOPP for Hodgkin's and non-Hodgkin's lymphomas. Dronabinol Capsule dosages ranged from 2.5 mg/day to 40 mg/day, administered in equally divided doses every four to six hours (four times daily). As indicated in the following table, escalating the Dronabinol Capsules dose above 7 mg/m2 increased the frequency of adverse experiences, with no additional antiemetic benefit. - Combination antiemetic therapy with Dronabinol Capsules and a phenothiazine (prochlorperazine) may result in synergistic or additive antiemetic effects and attenuate the toxicities associated with each of the agents. # How Supplied - Dronabinol Capsules are available containing 2.5 mg, 5 mg or 10 mg of dronabinol. - The 2.5 mg capsule is an opaque off-white soft gelatin capsule printed with INS in black ink. They are available as follows: NDC 0378-8170-91 bottles of 60 capsules - The 5 mg capsule is an opaque maroon or brown soft gelatin capsule printed with INS in white ink. They are available as follows: NDC 0378-8171-91 bottles of 60 capsules - The 10 mg capsule is an opaque tan to tan-orange soft gelatin capsule printed with INS in black ink. They are available as follows: NDC 0378-8172-91 bottles of 60 capsules ## Storage - Dronabinol Capsules should be packaged in a well-closed container and stored in a refrigerator between 2° and 8°C (36° and 46°F). Protect from freezing and light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients receiving treatment with dronabinol capsules should be alerted to the potential for additive central nervous system depression if dronabinol capsules is used concomitantly with alcohol or other CNS depressants such as benzodiazepines and barbiturates. - Patients receiving treatment with dronabinol capsules should be specifically warned not to drive, operate machinery, or engage in any hazardous activity until it is established that they are able to tolerate the drug and to perform such tasks safely. - Patients using dronabinol Capsules should be advised of possible changes in mood and other adverse behavioral effects of the drug so as to avoid panic in the event of such manifestations. Patients should remain under the supervision of a responsible adult during initial use of dronabinol capsules and following dosage adjustments. # Precautions with Alcohol - Alcohol-Dronabinol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - DRONABINOL # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Dronabinol
ddeadf1387ccc3ef3ad656decfbfa9197fd7b925	wikidoc	Droperidol	Droperidol # 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 Droperidol is a general anesthetic that is FDA approved for the {{{indicationType}}} of prophylaxis use in nausea and vomiting, associated with surgical or diagnostic procedures;. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cardiovascular: hypotension, tachycardia, neurologic: somnolence, postoperative, psychiatric: anxiety, dysphoric mood, hyperactive behavior, restlessness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Chemotherapy-induced nausea and vomiting; prophylaxis: optimal dosing and timing not yet defined - Nausea and vomiting, associated with surgical or diagnostic procedures; prophylaxis: initial maximum dose 2.5 mg IM/IV, may repeat 1.25 mg dose based on patient response, caution is advise ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Agitation - Psychotic disorder. - Chemotherapy-induced nausea and vomiting; Prophylaxis. - Headache, Benign. - Migraine. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Droperidol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Nausea and vomiting, associated with surgical or diagnostic procedures; Prophylaxis: (2 to 12 years) initial maximum dose 0.1 mg/kg slow IV/IM, may repeat 0.1 mg/kg dose based on patient response, caution is advised ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Droperidol in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Droperidol in pediatric patients. # Contraindications - Droperidol is contraindicated in patients with known or suspected QT prolongation (i.e., QTc interval greater than 440 msec for males or 450 msec for females). This would include patients with congenital long QT syndrome. - Droperidol (droperidol) is contraindicated in patients with known hypersensitivity to the drug. - Droperidol is not recommended for any use other than for the treatment of perioperative nausea and vomiting in patients for whom other treatments are ineffective or inappropriate (see Warnings). # Warnings - Droperidol should be administered with extreme caution in the presence of risk factors for development of prolonged QT syndrome, such as: - A dose-dependent prolongation of the QT interval was observed within 10 minutes of droperidol administration in a study of 40 patients without known cardiac disease who underwent extracranial head and neck surgery. Significant QT prolongation was observed at all three dose levels evaluated, with 0.1, 0.175, and 0.25 mg/kg associated with prolongation of median QTc by 37, 44, and 59 msec, respectively. - Cases of QT prolongation and serious arrhythmias (e.g. torsade de pointes, ventricular arrythmias, cardiac arrest, and death) have been observed during post-marketing treatment with Droperidol. Some cases have occurred in patients with no known risk factors and at doses at or below recommended doses. There has been at least one case of nonfatal torsade de pointes confirmed by rechallenge. - Based on these reports, all patients should undergo a 12-lead ECG prior to administration of Droperidol to determine if a prolonged QT interval (i.e., QTc greater than 440 msec for males or 450 msec for females) is present. If there is a prolonged QT interval, Droperidol should NOT be administered. For patients in whom the potential benefit of Droperidol treatment is felt to outweigh the risks of potentially serious arrhythmias, ECG monitoring should be performed prior to treatment and continued for 2 to 3 hours after completing treatment to monitor for arrhythmias. - Fluids And Other Countermeasures To Manage Hypotension Should Be Readily Available. - As with other CNS depressant drugs, patients who have received Droperidol (droperidol) should have appropriate surveillance. - It is recommended that opioids, when required, initially be used in reduced doses. - As with other neuroleptic agents, very rare reports of neuroleptic malignant syndrome (altered consciousness, muscle rigidity and autonomic instability) have occurred in patients who have received Droperidol (droperidol). Since it may be difficult to distinguish neuroleptic malignant syndrome from malignant hyperpyrexia in the perioperative period, prompt treatment with dantrolene should be considered if increases in temperature, heart rate or carbon dioxide production occur. # Adverse Reactions ## Clinical Trials Experience QT interval prolongation, torsade de pointes, cardiac arrest, and ventricular tachycardia have been reported in patients treated with Droperidol. Some of these cases were associated with death. Some cases occurred in patients with no known risk factors, and some were associated with droperidol doses at or below recommended doses. - Physicians should be alert to palpitations, syncope, or other symptoms suggestive of episodes of irregular cardiac rhythm in patients taking Droperidol and promptly evaluate such cases (see Warnings, Effects on Cardiac Conduction). - The most common somatic adverse reactions reported to occur with Droperidol (droperidol) are mild to moderate hypotension and tachycardia, but these effects usually subside without treatment. If hypotension occurs and is severe or persists, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy. - The most common behavioral adverse effects of Droperidol (droperidol) include dysphoria, postoperative drowsiness, restlessness, hyperactivity and anxiety, which can either be the result of an inadequate dosage (lack of adequate treatment effect) or of an adverse drug reaction (part of the symptom complex of akathisia). - Care should be taken to search for extrapyramidal signs and symptoms (dystonia, akathisia, oculogyric crisis) to differentiate these different clinical conditions. When extrapyramidal symptoms are the cause, they can usually be controlled with anticholinergic agents. - Postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression) have also been reported. - Other less common reported adverse reactions include anaphylaxis, dizziness, chills and/or shivering, laryn-gospasm, and bronchospasm. - Elevated blood pressure, with or without pre-existing hypertension, has been reported following administration of Droperidol combined with Sublimaze (fentanyl citrate) or other parenteral analgesics. This might be due to unexplained alterations in sympathetic activity following large doses: however, it is also frequently attributed to anesthetic or surgical stimulation during light anesthesia. ## Postmarketing Experience There is limited information regarding Droperidol Postmarketing Experience in the drug label. # Drug Interactions Potentially Arrhythmogenic Agents: Any drug known to have the potential to prolong the QT interval should not be used together with Droperidol. Possible pharmacodynamic interactions can occur between Droperidol and potentially arrhythmogenic agents such as class I or III antiarrhythmics, antihistamines that prolong the QT interval, antimalarials, calcium channel blockers, neuroleptics that prolong the QT interval, and antidepressants. - Caution should be used when patients are taking concomitant drugs known to induce hypokalemia or Hypomagnesemia as they may precipitate QT prolongation and interact with Droperidol. These would include diuretics, laxatives and supraphysiological use of steroid hormones with mineralocorticoid potential. - CNS Depressant Drugs: Other CNS depressant drugs (e.g., barbiturates, tranquilizers, opioids and general anesthetics) have additive or potentiating effects with Droperidol. Following the administration of Droperidol, the dose of other CNS depressant drugs should be reduced. - No carcinogenicity studies have been carried out with Droperidol. The micronucleus test in female rats revealed no mutagenic effects in single oral doses as high as 160 mg/kg. An oral study in rats (Segment I) revealed no impairment of fertility in either male or females at 0.63. 2.5 and 10 mg/kg doses (approximately 2.9 and 36 times maximum recommended human iv/im dosage). - Droperidol administered intravenously has been shown to cause a slight increase in mortality of the newborn rat at 4.4 times the upper human dose. At 44 times the upper human dose, mortality rate was comparable to that for control animals. Following intramuscular administration, increased mortality of the offspring at 1.8 times the upper human dose is attributed to CNS depression in the dams who neglected to remove placentae from their offspring. Droperidol has not been shown to be teratogenic in animals. There are no adequate and well-controlled studies in pregnant women. Droperidol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - There are insufficient data to support the use of Droperidol in labor and delivery. Therefore, such use is not recommended. - It is not known whether Droperidol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Droperidol is administered to a nursing mother. - The safety of Droperidol in children younger than two years of age has not been established. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Droperidol administered intravenously has been shown to cause a slight increase in mortality of the newborn rat at 4.4 times the upper human dose. At 44 times the upper human dose, mortality rate was comparable to that for control animals. Following intramuscular administration, increased mortality of the offspring at 1.8 times the upper human dose is attributed to CNS depression in the dams who neglected to remove placentae from their offspring. Droperidol has not been shown to be teratogenic in animals. There are no adequate and well-controlled studies in pregnant women. Droperidol 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 Droperidol in women who are pregnant. ### Labor and Delivery - There are insufficient data to support the use of Droperidol in labor and delivery. Therefore, such use is not recommended. ### Nursing Mothers - It is not known whether Droperidol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Droperidol is administered to a nursing mother. ### Pediatric Use - The safety of Droperidol in children younger than two years of age has not been established. ### Geriatic Use There is no FDA guidance on the use of Droperidol in geriatric settings. ### Gender There is no FDA guidance on the use of Droperidol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Droperidol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Droperidol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Droperidol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Droperidol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Droperidol in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Droperidol Administration in the drug label. ### Monitoring There is limited information regarding Droperidol Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Droperidol and IV administrations. # Overdosage - The manifestations of Droperidol (droperidol) overdosage are an extension of its pharmacologic actions and may include QT prolongation and serious arrhythmias (e.g., torsade de pointes) (see Box Warning, Warnings, and Precautions). - In the presence of hypoventilation or apnea, oxygen should be administered and respiration should be assisted or controlled as indicated. A patent airway must be maintained; an oropharyngeal airway or endotracheal tube might be indicated. The patient should be carefully observed for 24 hours; body warmth and adequate fluid intake should be maintained. If hypotension occurs and is severe or persists, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy (see Precautions). - If significant extrapyramidal reactions occur in the context of an overdose, an anticholinergic should be administered. - The intravenous Median Lethal Dose of Droperidol is 20 to 43 mg/kg in mice; 30 mg/kg in rats; 25 mg/kg in dogs and 11 to 13 mg/kg in rabbits. The intramuscular Median Lethal Dose of Droperidol is 195 mg/kg in mice; 104 to 110 mg/kg in rats; 97 mg/kg in rabbits and 200 mg/kg in guinea pigs. # Pharmacology ## Mechanism of Action - Droperidol (droperidol) produces marked tranquilization and sedation. It allays apprehension and provides a state of mental detachment and indifference while maintaining a state of reflex alertness. - Droperidol produces an antiemetic effect as evidenced by the antagonism of apomorphine in dogs. It lowers the incidence of nausea and vomiting during surgical procedures and provides antiemetic protection in the postoperative period. - Droperidol potentiates other CNS depressants. It produces mild alpha-adrenergic blockade, peripheral vascular dilatation and reduction of the pressor effect of epinephrine. It can produce hypotension and decreased peripheral vascular resistance and may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may reduce the incidence of epinephrine-induced arrhythmias, but it does not prevent other cardiac arrhythmias. - The onset of action of single intramuscular and intravenous doses is from three to ten minutes following administration, although the peak effect may not be apparent for up to thirty minutes. The duration of the tranquilizing and sedative effects generally is two to four hours, although alteration of alertness may persist for as long as twelve hours. ## Structure Droperidol contains droperidol, a neuroleptic (tranquilizer) agent. Droperidol® (droperidol) Injection is available in ampules and vials. Each milliliter contains 2.5 mg of droperidol in an aqueous solution adjusted to pH 3.4 ± 0.4 with lactic acid. Droperidol is chemically identified as l-(l--l,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone with a molecular weight of 379.43. The structural formula of droperidol is: - Molecular formula: C22H22FN3O2, partition coefficient in n-octanol: water: 3.46, pKa: 7.46 - INAPSINE is a sterile, non-pyrogenic, aqueous solution for intravenous or intramuscular injection. ## Pharmacodynamics There is limited information regarding Droperidol Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Droperidol Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Droperidol Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Droperidol Clinical Studies in the drug label. # How Supplied There is limited information regarding Droperidol How Supplied in the drug label. ## Storage There is limited information regarding Droperidol Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Droperidol Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Droperidol 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 Droperidol Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Droperidol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Droperidol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Droperidol is a general anesthetic that is FDA approved for the {{{indicationType}}} of prophylaxis use in nausea and vomiting, associated with surgical or diagnostic procedures;. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cardiovascular: hypotension, tachycardia, neurologic: somnolence, postoperative, psychiatric: anxiety, dysphoric mood, hyperactive behavior, restlessness. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Chemotherapy-induced nausea and vomiting; prophylaxis: optimal dosing and timing not yet defined - Nausea and vomiting, associated with surgical or diagnostic procedures; prophylaxis: initial maximum dose 2.5 mg IM/IV, may repeat 1.25 mg dose based on patient response, caution is advise ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Agitation - Psychotic disorder. - Chemotherapy-induced nausea and vomiting; Prophylaxis. - Headache, Benign. - Migraine. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Droperidol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Nausea and vomiting, associated with surgical or diagnostic procedures; Prophylaxis: (2 to 12 years) initial maximum dose 0.1 mg/kg slow IV/IM, may repeat 0.1 mg/kg dose based on patient response, caution is advised ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Droperidol in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Droperidol in pediatric patients. # Contraindications - Droperidol is contraindicated in patients with known or suspected QT prolongation (i.e., QTc interval greater than 440 msec for males or 450 msec for females). This would include patients with congenital long QT syndrome. - Droperidol (droperidol) is contraindicated in patients with known hypersensitivity to the drug. - Droperidol is not recommended for any use other than for the treatment of perioperative nausea and vomiting in patients for whom other treatments are ineffective or inappropriate (see Warnings). # Warnings - Droperidol should be administered with extreme caution in the presence of risk factors for development of prolonged QT syndrome, such as: - A dose-dependent prolongation of the QT interval was observed within 10 minutes of droperidol administration in a study of 40 patients without known cardiac disease who underwent extracranial head and neck surgery. Significant QT prolongation was observed at all three dose levels evaluated, with 0.1, 0.175, and 0.25 mg/kg associated with prolongation of median QTc by 37, 44, and 59 msec, respectively. - Cases of QT prolongation and serious arrhythmias (e.g. torsade de pointes, ventricular arrythmias, cardiac arrest, and death) have been observed during post-marketing treatment with Droperidol. Some cases have occurred in patients with no known risk factors and at doses at or below recommended doses. There has been at least one case of nonfatal torsade de pointes confirmed by rechallenge. - Based on these reports, all patients should undergo a 12-lead ECG prior to administration of Droperidol to determine if a prolonged QT interval (i.e., QTc greater than 440 msec for males or 450 msec for females) is present. If there is a prolonged QT interval, Droperidol should NOT be administered. For patients in whom the potential benefit of Droperidol treatment is felt to outweigh the risks of potentially serious arrhythmias, ECG monitoring should be performed prior to treatment and continued for 2 to 3 hours after completing treatment to monitor for arrhythmias. - Fluids And Other Countermeasures To Manage Hypotension Should Be Readily Available. - As with other CNS depressant drugs, patients who have received Droperidol (droperidol) should have appropriate surveillance. - It is recommended that opioids, when required, initially be used in reduced doses. - As with other neuroleptic agents, very rare reports of neuroleptic malignant syndrome (altered consciousness, muscle rigidity and autonomic instability) have occurred in patients who have received Droperidol (droperidol). Since it may be difficult to distinguish neuroleptic malignant syndrome from malignant hyperpyrexia in the perioperative period, prompt treatment with dantrolene should be considered if increases in temperature, heart rate or carbon dioxide production occur. # Adverse Reactions ## Clinical Trials Experience QT interval prolongation, torsade de pointes, cardiac arrest, and ventricular tachycardia have been reported in patients treated with Droperidol. Some of these cases were associated with death. Some cases occurred in patients with no known risk factors, and some were associated with droperidol doses at or below recommended doses. - Physicians should be alert to palpitations, syncope, or other symptoms suggestive of episodes of irregular cardiac rhythm in patients taking Droperidol and promptly evaluate such cases (see Warnings, Effects on Cardiac Conduction). - The most common somatic adverse reactions reported to occur with Droperidol (droperidol) are mild to moderate hypotension and tachycardia, but these effects usually subside without treatment. If hypotension occurs and is severe or persists, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy. - The most common behavioral adverse effects of Droperidol (droperidol) include dysphoria, postoperative drowsiness, restlessness, hyperactivity and anxiety, which can either be the result of an inadequate dosage (lack of adequate treatment effect) or of an adverse drug reaction (part of the symptom complex of akathisia). - Care should be taken to search for extrapyramidal signs and symptoms (dystonia, akathisia, oculogyric crisis) to differentiate these different clinical conditions. When extrapyramidal symptoms are the cause, they can usually be controlled with anticholinergic agents. - Postoperative hallucinatory episodes (sometimes associated with transient periods of mental depression) have also been reported. - Other less common reported adverse reactions include anaphylaxis, dizziness, chills and/or shivering, laryn-gospasm, and bronchospasm. - Elevated blood pressure, with or without pre-existing hypertension, has been reported following administration of Droperidol combined with Sublimaze (fentanyl citrate) or other parenteral analgesics. This might be due to unexplained alterations in sympathetic activity following large doses: however, it is also frequently attributed to anesthetic or surgical stimulation during light anesthesia. ## Postmarketing Experience There is limited information regarding Droperidol Postmarketing Experience in the drug label. # Drug Interactions Potentially Arrhythmogenic Agents: Any drug known to have the potential to prolong the QT interval should not be used together with Droperidol. Possible pharmacodynamic interactions can occur between Droperidol and potentially arrhythmogenic agents such as class I or III antiarrhythmics, antihistamines that prolong the QT interval, antimalarials, calcium channel blockers, neuroleptics that prolong the QT interval, and antidepressants. - Caution should be used when patients are taking concomitant drugs known to induce hypokalemia or Hypomagnesemia as they may precipitate QT prolongation and interact with Droperidol. These would include diuretics, laxatives and supraphysiological use of steroid hormones with mineralocorticoid potential. - CNS Depressant Drugs: Other CNS depressant drugs (e.g., barbiturates, tranquilizers, opioids and general anesthetics) have additive or potentiating effects with Droperidol. Following the administration of Droperidol, the dose of other CNS depressant drugs should be reduced. - No carcinogenicity studies have been carried out with Droperidol. The micronucleus test in female rats revealed no mutagenic effects in single oral doses as high as 160 mg/kg. An oral study in rats (Segment I) revealed no impairment of fertility in either male or females at 0.63. 2.5 and 10 mg/kg doses (approximately 2.9 and 36 times maximum recommended human iv/im dosage). - Droperidol administered intravenously has been shown to cause a slight increase in mortality of the newborn rat at 4.4 times the upper human dose. At 44 times the upper human dose, mortality rate was comparable to that for control animals. Following intramuscular administration, increased mortality of the offspring at 1.8 times the upper human dose is attributed to CNS depression in the dams who neglected to remove placentae from their offspring. Droperidol has not been shown to be teratogenic in animals. There are no adequate and well-controlled studies in pregnant women. Droperidol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - There are insufficient data to support the use of Droperidol in labor and delivery. Therefore, such use is not recommended. - It is not known whether Droperidol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Droperidol is administered to a nursing mother. - The safety of Droperidol in children younger than two years of age has not been established. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Droperidol administered intravenously has been shown to cause a slight increase in mortality of the newborn rat at 4.4 times the upper human dose. At 44 times the upper human dose, mortality rate was comparable to that for control animals. Following intramuscular administration, increased mortality of the offspring at 1.8 times the upper human dose is attributed to CNS depression in the dams who neglected to remove placentae from their offspring. Droperidol has not been shown to be teratogenic in animals. There are no adequate and well-controlled studies in pregnant women. Droperidol 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 Droperidol in women who are pregnant. ### Labor and Delivery - There are insufficient data to support the use of Droperidol in labor and delivery. Therefore, such use is not recommended. ### Nursing Mothers - It is not known whether Droperidol is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Droperidol is administered to a nursing mother. ### Pediatric Use - The safety of Droperidol in children younger than two years of age has not been established. ### Geriatic Use There is no FDA guidance on the use of Droperidol in geriatric settings. ### Gender There is no FDA guidance on the use of Droperidol with respect to specific gender populations. ### Race There is no FDA guidance on the use of Droperidol with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Droperidol in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Droperidol in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Droperidol in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Droperidol in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Droperidol Administration in the drug label. ### Monitoring There is limited information regarding Droperidol Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Droperidol and IV administrations. # Overdosage - The manifestations of Droperidol (droperidol) overdosage are an extension of its pharmacologic actions and may include QT prolongation and serious arrhythmias (e.g., torsade de pointes) (see Box Warning, Warnings, and Precautions). - In the presence of hypoventilation or apnea, oxygen should be administered and respiration should be assisted or controlled as indicated. A patent airway must be maintained; an oropharyngeal airway or endotracheal tube might be indicated. The patient should be carefully observed for 24 hours; body warmth and adequate fluid intake should be maintained. If hypotension occurs and is severe or persists, the possibility of hypovolemia should be considered and managed with appropriate parenteral fluid therapy (see Precautions). - If significant extrapyramidal reactions occur in the context of an overdose, an anticholinergic should be administered. - The intravenous Median Lethal Dose of Droperidol is 20 to 43 mg/kg in mice; 30 mg/kg in rats; 25 mg/kg in dogs and 11 to 13 mg/kg in rabbits. The intramuscular Median Lethal Dose of Droperidol is 195 mg/kg in mice; 104 to 110 mg/kg in rats; 97 mg/kg in rabbits and 200 mg/kg in guinea pigs. # Pharmacology ## Mechanism of Action - Droperidol (droperidol) produces marked tranquilization and sedation. It allays apprehension and provides a state of mental detachment and indifference while maintaining a state of reflex alertness. - Droperidol produces an antiemetic effect as evidenced by the antagonism of apomorphine in dogs. It lowers the incidence of nausea and vomiting during surgical procedures and provides antiemetic protection in the postoperative period. - Droperidol potentiates other CNS depressants. It produces mild alpha-adrenergic blockade, peripheral vascular dilatation and reduction of the pressor effect of epinephrine. It can produce hypotension and decreased peripheral vascular resistance and may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may reduce the incidence of epinephrine-induced arrhythmias, but it does not prevent other cardiac arrhythmias. - The onset of action of single intramuscular and intravenous doses is from three to ten minutes following administration, although the peak effect may not be apparent for up to thirty minutes. The duration of the tranquilizing and sedative effects generally is two to four hours, although alteration of alertness may persist for as long as twelve hours. ## Structure Droperidol contains droperidol, a neuroleptic (tranquilizer) agent. Droperidol® (droperidol) Injection is available in ampules and vials. Each milliliter contains 2.5 mg of droperidol in an aqueous solution adjusted to pH 3.4 ± 0.4 with lactic acid. Droperidol is chemically identified as l-(l-[3-(p-fluorobenzoyl) propyl]-l,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone with a molecular weight of 379.43. The structural formula of droperidol is: - Molecular formula: C22H22FN3O2, partition coefficient in n-octanol: water: 3.46, pKa: 7.46 - INAPSINE is a sterile, non-pyrogenic, aqueous solution for intravenous or intramuscular injection. ## Pharmacodynamics There is limited information regarding Droperidol Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Droperidol Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Droperidol Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Droperidol Clinical Studies in the drug label. # How Supplied There is limited information regarding Droperidol How Supplied in the drug label. ## Storage There is limited information regarding Droperidol Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Droperidol Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Droperidol 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 Droperidol Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Droperidol Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Droperidol
0a3a9d19174fbd77deca7cdf43edf73ff48c85ef	wikidoc	Drosophila	Drosophila Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately vinegar flies, wine flies, pomace flies, grape flies, and picked fruit-flies, a reference to the characteristic of many species to linger around overripe or rotting fruit. A second, related fly family, the Tephritidae, are also called fruit flies; these feed primarily on unripe or ripe fruit, with many species being regarded as destructive agricultural pests, especially the Mediterranean fruit fly. One species of Drosophila in particular, D. melanogaster, has been heavily used in research in genetics and is a common model organism in developmental biology. Indeed, the terms "fruit fly" and "Drosophila" are often used synonymously with D. melanogaster in modern biological literature. The entire genus, however, contains about 1,500 species and is very diverse in appearance, behavior, and breeding habitat. Scientists who research Drosophila are often called Drosophilists. # Name The term "Drosophila", meaning "dew-loving", is a modern scientific Latin adaptation from Greek words δρόσος, drósos, "dew", and φίλος, phílos, "loving" with the Latin feminine suffix -a. # Morphology Drosophila are small flies, typically pale yellow to reddish brown to black, with red eyes. Many species, including the noted Hawaiian picture-wings, have distinct black patterns on the wings. The plumose (feathery) arista, bristling of the head and thorax, and wing venation are characters used to diagnose the family. Most are small, about 2–4 millimetres long, but some, especially many of the Hawaiian species, are larger than a house fly. # Life cycle and ecology ## Habitat Drosophila are found all around the world, with more species in the tropical regions. They can be found in deserts, tropical rainforest, cities, swamps, and alpine zones. Some northern species hibernate. Most species breed in various kinds of decaying plant and fungal material, including fruit, bark, slime fluxes, flowers, and mushrooms. A few species have switched to being parasites or predators. Many species can be attracted to baits of fermented bananas or mushrooms, but others are not attracted to any kind of baits. Males may congregate at patches of suitable breeding substrate to compete for the females, or form leks, conducting courtship in an area separate from breeding sites. Several Drosophila species, including D. melanogaster, D. immigrans, and D. simulans, are closely associated with humans, and are often referred to as domestic species. These and other species (D. subobscura, Zaprionus indianus) have been accidentally introduced around the world by human activities such as fruit transports. ## Reproduction Males of this genus are known to have the longest sperm cells of any organism on Earth, including one species, Drosophila bifurca, that have sperm that are 5.8 centimetres long. The cells are mostly tail, and are delivered to the females in tangled coils. The other members of the genus Drosophila also make relatively few giant sperm cells, with D. bifurca's being the longest. D. melanogaster sperm cells are a more modest 1.8 millimetres long, although this is still about 300 times as long as a human sperm. Drosophila vary widely in their reproductive capacity. Those such as D. melanogaster that breed in large, relatively rare resources have ovaries that mature 10–20 eggs at a time, so that they can be laid together on one site. Others that breed in more-abundant but less nutritious substrates, such as leaves, may only lay one egg per day. The eggs have one or more respiratory filaments near the anterior end; the tips of these extend above the surface and allow oxygen to reach the embryo. Larvae feed not on the vegetable matter itself but on the yeasts and microorganisms present on the decaying breeding substrate. Development time varies widely between species (between 7 and more than 60 days) and depends on the environmental factors such as temperature, breeding substrate, and crowding. ## Laboratory–cultured animals Drosophila melanogaster is a popular experimental animal because it is easily cultured in mass out of the wild, has a short generation time, and mutant animals are readily obtainable. In 1906 Thomas Hunt Morgan began his work on D. melanogaster and reported his first finding of a white (eyed) mutant in 1910 to the academic community. He was in search of a model organism to study genetic heredity and required a species that could randomly acquire genetic mutation that would visibly manifest as morphological changes in the adult animal. His work on Drosophila earned him the 1933 Nobel Prize in Medicine for identifying chromosomes as the vector of inheritance for genes. However, some species of Drosophila are difficult to culture in the laboratory, often because they breed on a single specific host in the wild. For some it can be done with particular recipes for rearing media, or by introducing chemicals such as sterols that are found in the natural host; for others it is (so far) impossible. In some cases, the larvae can develop on normal Drosophila lab medium but the female will not lay eggs; for these it is often simply a matter of putting in a small piece of the natural host to receive the eggs. The Drosophila Stock Center in Tucson maintains cultures of hundreds of species for researchers. ## Predators Drosophila are prey for many generalist predators such as robber flies. In Hawaii, the introduction of yellowjackets from the mainland United States has led to the decline of many of the large species. The larvae are preyed on by other fly larvae, staphylinid beetles, and ants. # Systematics The genus Drosophila as currently defined is paraphyletic (see below) and contains 1450 described species, while the estimated total number of species is estimated at thousands. The majority of the species are members of two subgenera: Drosophila (~1,100 species) and Sophophora (including D. (S.) melanogaster; ~330 species). The Hawaiian species of Drosophila (estimated to be more than 500, with ~380 species described) are sometimes recognized as a separate genus or subgenus, Idiomyia, but this is not widely accepted. About 250 species are part of the genus Scaptomyza, which arose from the Hawaiian Drosophila and later re-colonized continental areas. Evidence from phylogenetic studies suggests that the following genera arose from within the genus Drosophila: - Hirtodrosophila Duda, 1923 - Mycodrosophila Oldenburg, 1914 - Zaprionus Coquillett, 1901 - Samoaia Malloch, 1934 - Liodrosophila Duda, 1922 - Dichaetophora Duda, 1940 - Scaptomyza Hardy, 1849 Several of the subgeneric and generic names are based on anagrams of Drosophila. These include: - Dorsilopha - Lordiphosa - Siphlodora - Phloridosa - Psilodorha # Drosophila species genome project Drosophila are extensively used as a model organism in genetics (including population genetics), cell-biology, biochemistry, and especially developmental biology. Therefore, extensive efforts are made to sequence drosphilid genomes. The genomes of the following species have been fully or partially sequenced so far: - Drosophila (Sophophora) melanogaster - Drosophila (Sophophora) simulans - Drosophila (Sophophora) sechellia - Drosophila (Sophophora) yakuba - Drosophila (Sophophora) erecta - Drosophila (Sophophora) ananassae - Drosophila (Sophophora) pseudoobscura - Drosophila (Sophophora) persimilis - Drosophila (Sophophora) willistoni - Drosophila (Drosophila) mojavensis - Drosophila (Drosophila) virilis - Drosophila (Drosophila) grimshawi The data will be used for many purposes, including evolutionary genome comparisons. D. simulans and D. sechellia are sister species, and provide viable offspring when crossed, while D. melanogaster and D. simulans produce infertile hybrid offspring. The Drosophila genome is often compared with the genomes of more distantly related species such as the honeybee Apis mellifera or the mosquito Anopheles gambiae. Curated data are available at FlyBase.	Drosophila Drosophila is a genus of small flies, belonging to the family Drosophilidae, whose members are often called "fruit flies" or more appropriately vinegar flies, wine flies, pomace flies, grape flies, and picked fruit-flies, a reference to the characteristic of many species to linger around overripe or rotting fruit. A second, related fly family, the Tephritidae, are also called fruit flies; these feed primarily on unripe or ripe fruit, with many species being regarded as destructive agricultural pests, especially the Mediterranean fruit fly. One species of Drosophila in particular, D. melanogaster, has been heavily used in research in genetics and is a common model organism in developmental biology. Indeed, the terms "fruit fly" and "Drosophila" are often used synonymously with D. melanogaster in modern biological literature. The entire genus, however, contains about 1,500 species and is very diverse in appearance, behavior, and breeding habitat. Scientists who research Drosophila are often called Drosophilists. # Name The term "Drosophila", meaning "dew-loving", is a modern scientific Latin adaptation from Greek words δρόσος, drósos, "dew", and φίλος, phílos, "loving" with the Latin feminine suffix -a. # Morphology Drosophila are small flies, typically pale yellow to reddish brown to black, with red eyes. Many species, including the noted Hawaiian picture-wings, have distinct black patterns on the wings. The plumose (feathery) arista, bristling of the head and thorax, and wing venation are characters used to diagnose the family. Most are small, about 2–4 millimetres long, but some, especially many of the Hawaiian species, are larger than a house fly. # Life cycle and ecology ## Habitat Drosophila are found all around the world, with more species in the tropical regions. They can be found in deserts, tropical rainforest, cities, swamps, and alpine zones. Some northern species hibernate. Most species breed in various kinds of decaying plant and fungal material, including fruit, bark, slime fluxes, flowers, and mushrooms. A few species have switched to being parasites or predators. Many species can be attracted to baits of fermented bananas or mushrooms, but others are not attracted to any kind of baits. Males may congregate at patches of suitable breeding substrate to compete for the females, or form leks, conducting courtship in an area separate from breeding sites. Several Drosophila species, including D. melanogaster, D. immigrans, and D. simulans, are closely associated with humans, and are often referred to as domestic species. These and other species (D. subobscura, Zaprionus indianus) have been accidentally introduced around the world by human activities such as fruit transports. ## Reproduction Males of this genus are known to have the longest sperm cells of any organism on Earth, including one species, Drosophila bifurca, that have sperm that are 5.8 centimetres long.[1] The cells are mostly tail, and are delivered to the females in tangled coils. The other members of the genus Drosophila also make relatively few giant sperm cells, with D. bifurca's being the longest.[2] D. melanogaster sperm cells are a more modest 1.8 millimetres long, although this is still about 300 times as long as a human sperm. Drosophila vary widely in their reproductive capacity. Those such as D. melanogaster that breed in large, relatively rare resources have ovaries that mature 10–20 eggs at a time, so that they can be laid together on one site. Others that breed in more-abundant but less nutritious substrates, such as leaves, may only lay one egg per day. The eggs have one or more respiratory filaments near the anterior end; the tips of these extend above the surface and allow oxygen to reach the embryo. Larvae feed not on the vegetable matter itself but on the yeasts and microorganisms present on the decaying breeding substrate. Development time varies widely between species (between 7 and more than 60 days) and depends on the environmental factors such as temperature, breeding substrate, and crowding. ## Laboratory–cultured animals Drosophila melanogaster is a popular experimental animal because it is easily cultured in mass out of the wild, has a short generation time, and mutant animals are readily obtainable. In 1906 Thomas Hunt Morgan began his work on D. melanogaster and reported his first finding of a white (eyed) mutant in 1910 to the academic community. He was in search of a model organism to study genetic heredity and required a species that could randomly acquire genetic mutation that would visibly manifest as morphological changes in the adult animal. His work on Drosophila earned him the 1933 Nobel Prize in Medicine for identifying chromosomes as the vector of inheritance for genes. However, some species of Drosophila are difficult to culture in the laboratory, often because they breed on a single specific host in the wild. For some it can be done with particular recipes for rearing media, or by introducing chemicals such as sterols that are found in the natural host; for others it is (so far) impossible. In some cases, the larvae can develop on normal Drosophila lab medium but the female will not lay eggs; for these it is often simply a matter of putting in a small piece of the natural host to receive the eggs. The Drosophila Stock Center in Tucson maintains cultures of hundreds of species for researchers. ## Predators Drosophila are prey for many generalist predators such as robber flies. In Hawaii, the introduction of yellowjackets from the mainland United States has led to the decline of many of the large species. The larvae are preyed on by other fly larvae, staphylinid beetles, and ants. # Systematics The genus Drosophila as currently defined is paraphyletic (see below) and contains 1450 described species,[3][4] while the estimated total number of species is estimated at thousands.[5] The majority of the species are members of two subgenera: Drosophila (~1,100 species) and Sophophora (including D. (S.) melanogaster; ~330 species). The Hawaiian species of Drosophila (estimated to be more than 500, with ~380 species described) are sometimes recognized as a separate genus or subgenus, Idiomyia,[3] but this is not widely accepted. About 250 species are part of the genus Scaptomyza, which arose from the Hawaiian Drosophila and later re-colonized continental areas. Evidence from phylogenetic studies suggests that the following genera arose from within the genus Drosophila: - Hirtodrosophila Duda, 1923 - Mycodrosophila Oldenburg, 1914 - Zaprionus Coquillett, 1901 - Samoaia Malloch, 1934 - Liodrosophila Duda, 1922 - Dichaetophora Duda, 1940 - Scaptomyza Hardy, 1849 Several of the subgeneric and generic names are based on anagrams of Drosophila. These include: - Dorsilopha - Lordiphosa - Siphlodora - Phloridosa - Psilodorha # Drosophila species genome project Drosophila are extensively used as a model organism in genetics (including population genetics), cell-biology, biochemistry, and especially developmental biology. Therefore, extensive efforts are made to sequence drosphilid genomes. The genomes of the following species have been fully or partially sequenced so far: - Drosophila (Sophophora) melanogaster [1] - Drosophila (Sophophora) simulans [2] - Drosophila (Sophophora) sechellia [3] - Drosophila (Sophophora) yakuba [4] - Drosophila (Sophophora) erecta [5] - Drosophila (Sophophora) ananassae [6] - Drosophila (Sophophora) pseudoobscura [7] - Drosophila (Sophophora) persimilis [8] - Drosophila (Sophophora) willistoni [9] - Drosophila (Drosophila) mojavensis [10] - Drosophila (Drosophila) virilis [11] - Drosophila (Drosophila) grimshawi [12] The data will be used for many purposes, including evolutionary genome comparisons. D. simulans and D. sechellia are sister species, and provide viable offspring when crossed, while D. melanogaster and D. simulans produce infertile hybrid offspring. The Drosophila genome is often compared with the genomes of more distantly related species such as the honeybee Apis mellifera or the mosquito Anopheles gambiae. Curated data are available at FlyBase.	https://www.wikidoc.org/index.php/Drosophila
c5b5047651c8577fc3b5ef2d6b24df23c552b818	wikidoc	Somnolence	Somnolence # Overview Somnolence (or "drowsiness") is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods. It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm. The disorder characterized by the latter condition is most commonly associated with users of prescription hypnotics, such as mirtazapine or zolpidem. It is considered a lesser impairment of consciousness than stupor or coma. # Causes ## Causes by Organ System ## Causes in Alphabetical Order - Apomorphine hydrochloride - Butorphanol - Cimetidine - Cycloserine - Cyproheptadine hydrochloride - Desloratadine - Estazolam - Granisetron - Mifepristone - Nabilone - Pyrantel pamoate - Pergolide - Ramelteon - Rilpivirine - Sodium oxybate - Tasimelteon - Terbutaline - Thioridazine hydrochloride # Causes - Advanced sleep phase disorder - African trypanosomiasis ("sleeping sickness") - Alice in Wonderland syndrome - Brain edema - Cerebral hypoxia - Chronic fatigue syndrome - Clinical depression, especially seasonal affective disorder - Dehydration - Delayed sleep phase syndrome - Desmopressin - Diabetic ketoacidosis as example, but not balanced diabetes mellitus - Drug Side Effect- Bicisate dihydrochloride,Brompheniramine maleate and Pseudoephedrine hydrochloride, caspofungin acetate, Clozapine, Cyclobenzaprine, Eletriptan, Fesoterodine, Ketorolac tromethamine, Levetiracetam, Loratadine, Naproxen sodium, Oxcarbazepine, Prochlorperazine, Progesterone - Encephalitis – (viral, bacterial or other agents) - Epilepsy - Fibromyalgia - Hydrocephalus - Hyperparathyroidism - Hypothermia - Hypothyroidism - Increased intracranial pressure; for example, brain tumors - Infectious mononucleosis (glandular fever) - Intracranial hemorrhage such as due to ruptured aneurysm - Lyme disease - Medications Analgesics: mostly prescribed or illicit opiates such as oxycontin or heroin Antiepileptics such as phenytoin, carbamazepine, gabapentin, topiramate Antidepressants: for instance sedating tricyclic antidepressants and mirtazapine. Somnolence is less common with SSRI and SNRI as well as MAOI. Antihistamines: diphenhydramine, doxylamine, Loratadine and Olopatadine Antipsychotics: clozapine, thioridazine, quetiapine, olanzapine, risperidone, and ziprasidone but not haloperidol Dopamine agonists used in the treatment of parkinson's disease e.g. pergolide, ropinirole and pramipexole. HIV medications for example, efavirenz Antihypertensive medications like amlodipine Hypnotics like zopiclone, or the benzodiazepine such as diazepam or nitrazepam and the barbiturate, such as amobarbital or secobarbital Central nervous system agents like Carisoprodol, Metaxalone Other agents impacting the central nervous system in sufficient or toxic doses Melatonin Spironolactone - Analgesics: mostly prescribed or illicit opiates such as oxycontin or heroin - Antiepileptics such as phenytoin, carbamazepine, gabapentin, topiramate - Antidepressants: for instance sedating tricyclic antidepressants and mirtazapine. Somnolence is less common with SSRI and SNRI as well as MAOI. - Antihistamines: diphenhydramine, doxylamine, Loratadine and Olopatadine - Antipsychotics: clozapine, thioridazine, quetiapine, olanzapine, risperidone, and ziprasidone but not haloperidol - Dopamine agonists used in the treatment of parkinson's disease e.g. pergolide, ropinirole and pramipexole. - HIV medications for example, efavirenz - Antihypertensive medications like amlodipine - Hypnotics like zopiclone, or the benzodiazepine such as diazepam or nitrazepam and the barbiturate, such as amobarbital or secobarbital - Central nervous system agents like Carisoprodol, Metaxalone - Other agents impacting the central nervous system in sufficient or toxic doses - Melatonin - Spironolactone - Sleep apnea - Starvation - Stroke - Traumatic brain injury - Treatment of primary insomina may cause somnolence: Flurazepam Benzodiazepine Quazepam Estazolam Temazepam Triazolam Benzodiazepine receptor agonists: Eszopiclone, Zolpidem, Zaleplon Melatonin receptor agonists: Ramelteon - Flurazepam - Benzodiazepine - Quazepam - Estazolam - Temazepam - Triazolam - Benzodiazepine receptor agonists: Eszopiclone, Zolpidem, Zaleplon - Melatonin receptor agonists: Ramelteon # Hazards Somnolence can be dangerous when performing tasks that require constant concentration, such as driving a vehicle. When a person is sufficiently fatigued, he or she may experience microsleeps (loss of concentration).	Somnolence Template:Search infobox For patient information, click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2] # Overview Somnolence (or "drowsiness") is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods. It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm. The disorder characterized by the latter condition is most commonly associated with users of prescription hypnotics, such as mirtazapine or zolpidem. It is considered a lesser impairment of consciousness than stupor or coma. # Causes ## Causes by Organ System ## Causes in Alphabetical Order - Apomorphine hydrochloride - Butorphanol - Cimetidine - Cycloserine - Cyproheptadine hydrochloride - Desloratadine - Estazolam - Granisetron - Mifepristone - Nabilone - Pyrantel pamoate - Pergolide - Ramelteon - Rilpivirine - Sodium oxybate - Tasimelteon - Terbutaline - Thioridazine hydrochloride # Causes - Advanced sleep phase disorder - African trypanosomiasis ("sleeping sickness") - Alice in Wonderland syndrome - Brain edema - Cerebral hypoxia - Chronic fatigue syndrome - Clinical depression, especially seasonal affective disorder - Dehydration - Delayed sleep phase syndrome - Desmopressin - Diabetic ketoacidosis as example, but not balanced diabetes mellitus - Drug Side Effect- Bicisate dihydrochloride,Brompheniramine maleate and Pseudoephedrine hydrochloride, caspofungin acetate, Clozapine, Cyclobenzaprine, Eletriptan, Fesoterodine, Ketorolac tromethamine, Levetiracetam, Loratadine, Naproxen sodium, Oxcarbazepine, Prochlorperazine, Progesterone - Encephalitis – (viral, bacterial or other agents) - Epilepsy - Fibromyalgia - Hydrocephalus - Hyperparathyroidism - Hypothermia - Hypothyroidism - Increased intracranial pressure; for example, brain tumors - Infectious mononucleosis (glandular fever) - Intracranial hemorrhage such as due to ruptured aneurysm - Lyme disease - Medications Analgesics: mostly prescribed or illicit opiates such as oxycontin or heroin Antiepileptics such as phenytoin, carbamazepine, gabapentin, topiramate Antidepressants: for instance sedating tricyclic antidepressants[1] and mirtazapine. Somnolence is less common with SSRI[2] and SNRI as well as MAOI. Antihistamines: diphenhydramine, doxylamine, Loratadine and Olopatadine Antipsychotics: clozapine, thioridazine, quetiapine, olanzapine, risperidone, and ziprasidone but not haloperidol Dopamine agonists used in the treatment of parkinson's disease e.g. pergolide, ropinirole and pramipexole. HIV medications for example, efavirenz Antihypertensive medications like amlodipine Hypnotics like zopiclone, or the benzodiazepine such as diazepam or nitrazepam and the barbiturate, such as amobarbital or secobarbital Central nervous system agents like Carisoprodol, Metaxalone Other agents impacting the central nervous system in sufficient or toxic doses Melatonin Spironolactone - Analgesics: mostly prescribed or illicit opiates such as oxycontin or heroin - Antiepileptics such as phenytoin, carbamazepine, gabapentin, topiramate - Antidepressants: for instance sedating tricyclic antidepressants[1] and mirtazapine. Somnolence is less common with SSRI[2] and SNRI as well as MAOI. - Antihistamines: diphenhydramine, doxylamine, Loratadine and Olopatadine - Antipsychotics: clozapine, thioridazine, quetiapine, olanzapine, risperidone, and ziprasidone but not haloperidol - Dopamine agonists used in the treatment of parkinson's disease e.g. pergolide, ropinirole and pramipexole. - HIV medications for example, efavirenz - Antihypertensive medications like amlodipine - Hypnotics like zopiclone, or the benzodiazepine such as diazepam or nitrazepam and the barbiturate, such as amobarbital or secobarbital - Central nervous system agents like Carisoprodol, Metaxalone - Other agents impacting the central nervous system in sufficient or toxic doses - Melatonin - Spironolactone - Sleep apnea - Starvation - Stroke - Traumatic brain injury - Treatment of primary insomina may cause somnolence: Flurazepam Benzodiazepine Quazepam Estazolam Temazepam Triazolam Benzodiazepine receptor agonists: Eszopiclone, Zolpidem, Zaleplon Melatonin receptor agonists: Ramelteon[3] - Flurazepam - Benzodiazepine - Quazepam - Estazolam - Temazepam - Triazolam - Benzodiazepine receptor agonists: Eszopiclone, Zolpidem, Zaleplon - Melatonin receptor agonists: Ramelteon[3] # Hazards Somnolence can be dangerous when performing tasks that require constant concentration, such as driving a vehicle. When a person is sufficiently fatigued, he or she may experience microsleeps (loss of concentration).	https://www.wikidoc.org/index.php/Drowsiness
f17e45a0cc08f60f9f19f4d892377c3976abea6b	wikidoc	Medication	Medication # Overview A medication, medicine or drug is any substance or combination of substances administered to human beings or animals to treat or prevent disease; alternatively to assist in medical diagnosis. Commercial medications are produced by pharmaceutical companies and are often patented. Copies of former patented drugs are called generic drugs. # Classification Medication can be usually classified in various ways, e.g. by its chemical properties, mode of administration, or biological system affected. An elaborate and widely used classification system is the Anatomical Therapeutic Chemical Classification System(ATC system). # Types of medication ## For the gastrointestinal tract or digestive system - Upper digestive tract: antacids, reflux suppressants, antiflatulents, antidopaminergics, proton pump inhibitors, H2-receptor antagonists, cytoprotectants, prostaglandin analogues - Lower digestive tract: laxatives, antispasmodics, antidiarrhoeals, bile acid sequestrants, opioids ## For the cardiovascular system - General: beta-receptor blocker, calcium channel blockers, diuretics, cardiac glycosides, antiarrhythmics, nitrate, antianginals, vasoconstrictor, vasodilator, peripheral activator - Affecting Blood pressure: ACE inhibitors, angiotensin receptor blockers, alpha blocker - Coagulation: anticoagulant, heparin, antiplatelet drug, fibrinolytic, anti-hemophilic factor, haemostatic drugs - Atherosclerosis/cholesterol agents: hypolipidaemic agents, statins. ## For the central nervous system hypnotic, anaesthetics, antipsychotic, antidepressant (including tricyclic antidepressants, monoamine oxidase inhibitor, lithium salt, selective serotonin reuptake inhibitor), anti-emetic, anticonvulsant and antiepileptic, anxiolytic, barbiturate, movement disorder drug, stimulant (including amphetamines), benzodiazepine, cyclopyrrolone, dopamine antagonist, antihistamine, cholinergic, anticholinergic, emetic, cannabinoids, 5-HT antagonist ## For pain & consciousness (analgesic drugs) The main classes of painkillers are NSAIDs, opioids and various orphans such as paracetamol, tricyclic antidepressants and anticonvulsants. ## For musculo-skeletal disorders NSAIDs (including COX-2 selective inhibitors), muscle relaxant, neuromuscular drug anticholinesterase ## For the eye - General: adrenergic neurone blocker, astringent, ocular lubricant - Diagnostic: topical anesthetics, sympathomimetics, parasympatholytics, mydriatics, cycloplegics - Anti-bacterial: antibiotics, topical antibiotics, sulfa drugs, aminoglycosides, fluoroquinolones - Anti-viral: - Anti-fungal: imidazoles, polyenes - Anti-inflammatory: NSAIDs, corticosteroids - Anti-allergy: mast cell inhibitors - Anti-glaucoma: adrenergic agonists, beta-blockers, carbonic anhydrase inhibitors/hyperosmotics, cholinergics, miotics, parasympathomimetics, prostaglandin agonists/prostaglandin inhibitors. nitroglycerin ## For the ear, nose and oropharynx sympathomimetic, antihistamine, anticholinergic, NSAIDs, steroid, antiseptic, local anesthetic, antifungal, cerumenolyti ## For the respiratory system bronchodilator, NSAIDs, anti-allergic, antitussive, mucolytic, decongestantcorticosteroid, beta-receptor antagonist, anticholinergic, steroid ## For endocrine problems androgen, antiandrogen, gonadotropin, corticosteroid, growth hormone, insulin, antidiabetic (sulfonylurea, biguanide/metformin, thiazolidinedione, insulin), thyroid hormones, antithyroid drugs, calcitonin, diphosponate, vasopressin analogues ## For the reproductive system or urinary system antifungal, alkalising agent, quinolones, antibiotic, cholinergic, anticholinergic, anticholinesterase, antispasmodic, 5-alpha reductase inhibitor, selective alpha-1 blocker, sildenafil ## For contraception - Hormonal contraception - Ormeloxifene - Spermicide ## For obstetrics and gynecology NSAIDs, anticholinergic, haemostatic drug, antifibrinolytic, Hormone Replacement Therapy, bone regulator, beta-receptor agonist, follicle stimulating hormone, luteinising hormone, LHRH gamolenic acid, gonadotropin release inhibitor, progestogen, dopamine agonist, oestrogen, prostaglandin, gonadorelin, clomiphene, tamoxifen, Diethylstilbestrol ## For the skin emollient, anti-pruritic, antifungal, disinfectant, scabicide, pediculicide, tar products, vitamin A derivatives, vitamin D analogue, keratolytic, abrasive, systemic antibiotic, topical antibiotic, hormones, desloughing agent, exudate absorbent, fibrinolytic, proteolytic, sunscreen, antiperspirant, corticosteroid ## For infections and infestations antibiotic, antifungal, antileprotic, antituberculous drug, antimalarial, anthelmintic, amoebicide, antiviral, antiprotozoal ## For immunology vaccine, immunoglobulin, immunosuppressant, interferon, monoclonal antibody ## For allergic disorders anti-allergic, antihistamine, NSAIDs ## For nutrition tonic, iron preparation, electrolyte, parenteral nutritional supplement, vitamins, anti-obesity drug, anabolic drug, haematopoietic drug, food product drug ## For neoplastic disorders cytotoxic drug, sex hormones, aromatase inhibitor, somatostatin inhibitor, recombinant interleukins, G-CSF, erythropoietin ## For diagnostics contrast media ## Legal Considerations Medications may be divided into over-the-counter drugs (OTC) which may be available without special restrictions, and prescription only medicine (POM), which must be prescribed by a licensed medical practitioner. The precise distinction between OTC and prescription depends on the legal jurisdiction. The International Narcotics Control Board of the United Nations imposes a world law of prohibition of certain medications. They publish a lengthy list of chemicals and plants whose trade and consumption (where applicable) is forbidden. OTC medications are sold without restriction as they are considered safe enough that most people will not hurt themselves accidentally by taking it as instructed. Many countries, such as the United Kingdom have a third category of pharmacy medicines which can only be sold in registered pharmacies, by or under the supervision of a pharmacist. ## Naming of drugs It may be preferable to refer to drugs by their generic names rather than their brand names. ## Other/related topics Polypharmacy: suggests that multiple use of prescribed and non-prescribed medications, (use of 5 or more), can have adverse effects on the recipient. Zoopharmacognosy: Animal usage of drugs and non-foods.	Medication Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A medication, medicine or drug is any substance or combination of substances administered to human beings or animals to treat or prevent disease; alternatively to assist in medical diagnosis. Commercial medications are produced by pharmaceutical companies and are often patented. Copies of former patented drugs are called generic drugs. # Classification Medication can be usually classified in various ways, e.g. by its chemical properties, mode of administration, or biological system affected. An elaborate and widely used classification system is the Anatomical Therapeutic Chemical Classification System(ATC system). # Types of medication ## For the gastrointestinal tract or digestive system - Upper digestive tract: antacids, reflux suppressants, antiflatulents, antidopaminergics, proton pump inhibitors, H2-receptor antagonists, cytoprotectants, prostaglandin analogues - Lower digestive tract: laxatives, antispasmodics, antidiarrhoeals, bile acid sequestrants, opioids ## For the cardiovascular system - General: beta-receptor blocker, calcium channel blockers, diuretics, cardiac glycosides, antiarrhythmics, nitrate, antianginals, vasoconstrictor, vasodilator, peripheral activator - Affecting Blood pressure: ACE inhibitors, angiotensin receptor blockers, alpha blocker - Coagulation: anticoagulant, heparin, antiplatelet drug, fibrinolytic, anti-hemophilic factor, haemostatic drugs - Atherosclerosis/cholesterol agents: hypolipidaemic agents, statins. ## For the central nervous system hypnotic, anaesthetics, antipsychotic, antidepressant (including tricyclic antidepressants, monoamine oxidase inhibitor, lithium salt, selective serotonin reuptake inhibitor), anti-emetic, anticonvulsant and antiepileptic, anxiolytic, barbiturate, movement disorder drug, stimulant (including amphetamines), benzodiazepine, cyclopyrrolone, dopamine antagonist, antihistamine, cholinergic, anticholinergic, emetic, cannabinoids, 5-HT antagonist ## For pain & consciousness (analgesic drugs) The main classes of painkillers are NSAIDs, opioids and various orphans such as paracetamol, tricyclic antidepressants and anticonvulsants. ## For musculo-skeletal disorders NSAIDs (including COX-2 selective inhibitors), muscle relaxant, neuromuscular drug anticholinesterase ## For the eye - General: adrenergic neurone blocker, astringent, ocular lubricant - Diagnostic: topical anesthetics, sympathomimetics, parasympatholytics, mydriatics, cycloplegics - Anti-bacterial: antibiotics, topical antibiotics, sulfa drugs, aminoglycosides, fluoroquinolones - Anti-viral: - Anti-fungal: imidazoles, polyenes - Anti-inflammatory: NSAIDs, corticosteroids - Anti-allergy: mast cell inhibitors - Anti-glaucoma: adrenergic agonists, beta-blockers, carbonic anhydrase inhibitors/hyperosmotics, cholinergics, miotics, parasympathomimetics, prostaglandin agonists/prostaglandin inhibitors. nitroglycerin ## For the ear, nose and oropharynx sympathomimetic, antihistamine, anticholinergic, NSAIDs, steroid, antiseptic, local anesthetic, antifungal, cerumenolyti ## For the respiratory system bronchodilator, NSAIDs, anti-allergic, antitussive, mucolytic, decongestantcorticosteroid, beta-receptor antagonist, anticholinergic, steroid ## For endocrine problems androgen, antiandrogen, gonadotropin, corticosteroid, growth hormone, insulin, antidiabetic (sulfonylurea, biguanide/metformin, thiazolidinedione, insulin), thyroid hormones, antithyroid drugs, calcitonin, diphosponate, vasopressin analogues ## For the reproductive system or urinary system antifungal, alkalising agent, quinolones, antibiotic, cholinergic, anticholinergic, anticholinesterase, antispasmodic, 5-alpha reductase inhibitor, selective alpha-1 blocker, sildenafil ## For contraception - Hormonal contraception - Ormeloxifene - Spermicide ## For obstetrics and gynecology NSAIDs, anticholinergic, haemostatic drug, antifibrinolytic, Hormone Replacement Therapy, bone regulator, beta-receptor agonist, follicle stimulating hormone, luteinising hormone, LHRH gamolenic acid, gonadotropin release inhibitor, progestogen, dopamine agonist, oestrogen, prostaglandin, gonadorelin, clomiphene, tamoxifen, Diethylstilbestrol ## For the skin emollient, anti-pruritic, antifungal, disinfectant, scabicide, pediculicide, tar products, vitamin A derivatives, vitamin D analogue, keratolytic, abrasive, systemic antibiotic, topical antibiotic, hormones, desloughing agent, exudate absorbent, fibrinolytic, proteolytic, sunscreen, antiperspirant, corticosteroid ## For infections and infestations antibiotic, antifungal, antileprotic, antituberculous drug, antimalarial, anthelmintic, amoebicide, antiviral, antiprotozoal ## For immunology vaccine, immunoglobulin, immunosuppressant, interferon, monoclonal antibody ## For allergic disorders anti-allergic, antihistamine, NSAIDs ## For nutrition tonic, iron preparation, electrolyte, parenteral nutritional supplement, vitamins, anti-obesity drug, anabolic drug, haematopoietic drug, food product drug ## For neoplastic disorders cytotoxic drug, sex hormones, aromatase inhibitor, somatostatin inhibitor, recombinant interleukins, G-CSF, erythropoietin ## For diagnostics contrast media ## Legal Considerations Medications may be divided into over-the-counter drugs (OTC) which may be available without special restrictions, and prescription only medicine (POM), which must be prescribed by a licensed medical practitioner. The precise distinction between OTC and prescription depends on the legal jurisdiction. The International Narcotics Control Board of the United Nations imposes a world law of prohibition of certain medications. They publish a lengthy list of chemicals and plants whose trade and consumption (where applicable) is forbidden. OTC medications are sold without restriction as they are considered safe enough that most people will not hurt themselves accidentally by taking it as instructed. Many countries, such as the United Kingdom have a third category of pharmacy medicines which can only be sold in registered pharmacies, by or under the supervision of a pharmacist. ## Naming of drugs It may be preferable to refer to drugs by their generic names rather than their brand names[1][2][3][4]. ## Other/related topics Polypharmacy: suggests that multiple use of prescribed and non-prescribed medications, (use of 5 or more), can have adverse effects on the recipient. Zoopharmacognosy: Animal usage of drugs and non-foods.	https://www.wikidoc.org/index.php/Drug-induced
e376a68aeb2f3c5e48b124dc4dbfa51d650c554d	wikidoc	Drug abuse	Drug abuse # Overview Drug abuse has a wide range of definitions related to taking a psychoactive drug or performance enhancing drug for a non-therapeutic or non-medical effect. Some of the most commonly abused drugs include alcohol, amphetamines, barbiturates, benzodiazepines, cocaine, methaqualone, and opium alkaloids. Use of these drugs may lead to criminal penalty in addition to possible physical, social, and psychological harm, both strongly depending on local jurisdiction. Other definitions of drug abuse fall into four main categories: public health definitions, mass communication and vernacular usage, medical definitions, and political and criminal justice definitions. # Definitions ## Public health definitions Public health practitioners have attempted to look at drug abuse from a broader perspective than the individual, emphasising the role of society, culture and availability. Rather than accepting the loaded terms alcohol or drug "abuse," many public health professionals have adopted phrases such as "alcohol and drug problems" or "harmful/problematic use" of drugs. The Health Officers Council of British Columbia — in their 2005 policy discussion paper, A Public Health Approach to Drug Control in Canada — has adopted a public health model of psychoactive substance use that challenges the simplistic black-and-white construction of the binary (or complementary) antonyms "use" vs. "abuse". This model explicitly recognizes a spectrum of use, ranging from beneficial use to chronic dependence (see diagram to the right). ## Mass communication and vernacular usage The term "drug abuse" may be used in newspapers, television, etc. in an ambiguous, catch-all sense rather than as a medical or legal term, sometimes disapprovingly to refer to any drug use at all, particularly of illicit drugs. A common misconception perpetuated by mainstream media and anti-drug campaigns is that "if you do drugs once, you're automatically an addict". ## Medical definitions In the modern medical profession, the two most used diagnostic tools in the world, the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) and the World Health Organization's International Statistical Classification of Diseases and Related Health Problems (ICD), no longer recognise 'drug abuse' as a current medical diagnosis. Instead, they have adopted substance abuse as a blanket term to include drug abuse and other things. However, other definitions differ; they may entail psychological or physical dependence, and may focus on treatment and prevention in terms of the social consequences of substance uses. ### Historical positions of the American Psychiatric Association In the early 1950s, the first edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders referred to both alcohol and drug abuse as part of Sociopathic Personality Disturbances, which were thought to be symptoms of deeper psychological disorders or moral weakness . By the third edition, in the 1980s, drug abuse was grouped into 'substance abuse'. In 1972, the American Psychiatric Association created a definition that used legality, social acceptability, and even cultural familiarity as qualifying factors: …as a general rule, we reserve the term drug abuse to apply to the illegal, nonmedical use of a limited number of substances, most of them drugs, which have properties of altering the mental state in ways that are considered by social norms and defined by statute to be inappropriate, undesirable, harmful, threatening, or, at minimum, culture-alien. ### Historical positions of the American Medical Association In 1966, the American Medical Association's Committee on Alcoholism and Addiction defined abuse of stimulants (amphetamines, primarily) in terms of "medical supervision": …"use" refers to the proper place of stimulants in medical practice; "misuse" applies to the physician's role in initiating a potentially dangerous course of therapy; and "abuse" refers to self-administration of these drugs without medical supervision and particularly in large doses that may lead to psychological dependency, tolerance and abnormal behavior. ### Handbook on Drug and Alcohol Abuse The Handbook on Drug and Alcohol Abuse defines drug abuse as "nonmedical use of drugs, both drugs that have and those that do not have generally accepted medical value". ## Political and criminal justice definitions Most countries have legislation designed to criminalise some drug use. Usually however the legislative process is self-referential, defining abuse in terms of what is made illegal. The legislation concerns lists of drugs specified by the legislation. These drugs are often called illegal drugs but, generally, what was illegal is their unlicensed production, supply and possession. The drugs are also called controlled drugs or controlled substances. # Abuse potential Depending on the actual compound, drug abuse may lead to health problems, social problems, physical dependence, or psychological addiction. Some drugs that are subject to abuse have central nervous system (CNS) effects, which produce changes in mood, levels of awareness or perceptions and sensations. Most of these drugs also alter systems other than the CNS. But, not all centrally acting drugs are subject to abuse, which suggests that altering consciousness is not sufficient for a drug to have abuse potential. Among drugs that are abused, some appear to be more likely to lead to uncontrolled use than others, suggesting a possible hierarchy of drug-induced effects relative to abuse potential. # Approaches to managing drug abuse In addition to being a major public health problem, some consider drug abuse to be a social problem with far-reaching implications. Stress, poverty, domestic and societal violence, and various diseases (i.e., injecting drug users as a source for HIV/AIDS) are sometimes thought to be spread by drug use. Studies have also shown that individuals dependent on illicit drugs experience higher rates of comorbid psychiatric syndromes. ## Harm reduction One alternative involves replacing failed law enforcement policies with harm-reduction strategies, which focus on reducing the societal costs of drug abuse and other drug use. Techniques include education to avoid overdose, needle exchange programs to reduce the spread of blood-borne diseases, and opioid substitution therapy to reduce crime related to the procurement of drugs. This pragmatic approach is known as the harm reduction paradigm. Harm reduction also addresses special populations, such as drug-using parents, pregnant drug users and users with psychiatric comorbidity. The philosophy of harm reduction accepts that drug use is part of the community, but that it must be addressed as a public health issue rather than a criminal one. Harm-reduction measures are at odds with the prevailing framework of international drug control, which rests on law enforcement and the criminalization of behaviors related to illicit drug use. However, harm-reduction has had a notable impact and is slowly gaining popularity. In Brazil alone, a comprehensive harm-reduction and drug-access program successfully reduced AIDS mortality among injection drug users by 50%. ## Abstinence-Based Abstinence-based approaches set as a goal complete abstinence from all addictive substances, including both licit and illicit, prescribed and unprescribed. While the harm-reduction approach has been demonstrated to work well with opioids, the abstinence-based approach is the medical community standard of care for sedative (including alcohol) dependence. ## Medical treatment Beyond the sociological issues, many drugs of abuse can lead to addiction, chemical dependency, or adverse health effects, such as lung cancer or emphysema from cigarette smoking. Medical treatment therefore centers on two aspects: 1) breaking the addiction, 2) treating the health problems. Most countries have health facilities that specialize in the treatment of drug abuse, although access may be limited to larger population centers and the social taboos regarding drug use may make those who need the medical treatment reluctant to take advantage of it. For example, it is estimated that only fifteen percent of injection drug abusers thought to be in need are receiving treatment. Patients may require acute and long-term maintenance treatment and relapse prevention, complemented by suitable rehabilitation. ## Pharmacotherapy The development of pharmacotherapies for drug dependency treatment are currently in progress. New immunotherapies that prevent drugs like cocaine, methamphetamine, phencyclidine, nicotine, and opioids from reaching the brain are in the early stages of testing as is ibogaine, an alkaloid found in the Tabernanthe iboga plant of West Central Africa. Medications such as Buprenorphine, which block the drugs active site in the brain are another new option for the treatment of opioid addiction. Depot forms of medications, which require only weekly or monthly dosing, are also under investigation. Traditionally, new pharmacotherapies are quickly adopted in primary care settings, however, drugs for substance abuse treatment have faced many barriers. Naltrexone, a drug originally marketed under the name "ReVia," and now marketed in intramuscular formulation as "Vivitrol" or in oral formulation as a generic, is a medication approved for the treatment of alcohol dependence. This drug has reached very few patients. This may be due to a number of factors, including resistance by Addiction Medicine specialists and lack of resources. ## Legal approaches Most governments have designed legislation to criminalise certain types of drug use. These drugs are often called "illegal drugs" but generally what is illegal is their unlicensed production, distribution, and possession. These drugs are also called "controlled substances". Even for simple possession, legal punishment can be quite severe (including the death penalty in some countries). Laws vary across countries, and even within them, and have fluctuated widely throughout history. Attempts by government-sponsored drug control policy to interdict drug supply and eliminate drug abuse have been largely unsuccessful. In spite of the huge efforts by the U.S., drug supply and purity has reached an all time high, with the vast majority of resources spent on interdiction and law enforcement instead of public health. In the United States, the number of nonviolent drug offenders in prison exceeds by 100,000 the total incarcerated population in the EU, despite the fact that the EU has 100 million more citizens. Despite drug legislation (and some might argue because of it), large, organized criminal drug cartels operate world-wide. Advocates of decriminalization argue that drug prohibition makes drug dealing a lucrative business, leading to much of the associated criminal activity.	Drug abuse For patient information click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Drug abuse has a wide range of definitions related to taking a psychoactive drug or performance enhancing drug for a non-therapeutic or non-medical effect. Some of the most commonly abused drugs include alcohol, amphetamines, barbiturates, benzodiazepines, cocaine, methaqualone, and opium alkaloids. Use of these drugs may lead to criminal penalty in addition to possible physical, social, and psychological harm, both strongly depending on local jurisdiction.[2] Other definitions of drug abuse fall into four main categories: public health definitions, mass communication and vernacular usage, medical definitions, and political and criminal justice definitions. # Definitions ## Public health definitions Public health practitioners have attempted to look at drug abuse from a broader perspective than the individual, emphasising the role of society, culture and availability. Rather than accepting the loaded terms alcohol or drug "abuse," many public health professionals have adopted phrases such as "alcohol and drug problems" or "harmful/problematic use" of drugs. The Health Officers Council of British Columbia — in their 2005 policy discussion paper, A Public Health Approach to Drug Control in Canada — has adopted a public health model of psychoactive substance use that challenges the simplistic black-and-white construction of the binary (or complementary) antonyms "use" vs. "abuse". This model explicitly recognizes a spectrum of use, ranging from beneficial use to chronic dependence (see diagram to the right). ## Mass communication and vernacular usage The term "drug abuse" may be used in newspapers, television, etc. in an ambiguous, catch-all sense[3] rather than as a medical or legal term, sometimes disapprovingly to refer to any drug use at all, particularly of illicit drugs[4]. A common misconception perpetuated by mainstream media and anti-drug campaigns is that "if you do drugs once, you're automatically an addict". ## Medical definitions In the modern medical profession, the two most used diagnostic tools in the world, the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM) and the World Health Organization's International Statistical Classification of Diseases and Related Health Problems (ICD), no longer recognise 'drug abuse' as a current medical diagnosis. Instead, they have adopted substance abuse as a blanket term to include drug abuse and other things. However, other definitions differ; they may entail psychological or physical dependence, and may focus on treatment and prevention in terms of the social consequences of substance uses. ### Historical positions of the American Psychiatric Association In the early 1950s, the first edition of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders referred to both alcohol and drug abuse as part of Sociopathic Personality Disturbances, which were thought to be symptoms of deeper psychological disorders or moral weakness [3]. By the third edition, in the 1980s, drug abuse was grouped into 'substance abuse'. In 1972, the American Psychiatric Association created a definition that used legality, social acceptability, and even cultural familiarity as qualifying factors: …as a general rule, we reserve the term drug abuse to apply to the illegal, nonmedical use of a limited number of substances, most of them drugs, which have properties of altering the mental state in ways that are considered by social norms and defined by statute to be inappropriate, undesirable, harmful, threatening, or, at minimum, culture-alien. [5] ### Historical positions of the American Medical Association In 1966, the American Medical Association's Committee on Alcoholism and Addiction defined abuse of stimulants (amphetamines, primarily) in terms of "medical supervision": …"use" refers to the proper place of stimulants in medical practice; "misuse" applies to the physician's role in initiating a potentially dangerous course of therapy; and "abuse" refers to self-administration of these drugs without medical supervision and particularly in large doses that may lead to psychological dependency, tolerance and abnormal behavior. ### Handbook on Drug and Alcohol Abuse The Handbook on Drug and Alcohol Abuse defines drug abuse as "nonmedical use of drugs, both drugs that have and those that do not have generally accepted medical value".[6] ## Political and criminal justice definitions Most countries have legislation designed to criminalise some drug use. Usually however the legislative process is self-referential, defining abuse in terms of what is made illegal. The legislation concerns lists of drugs specified by the legislation. These drugs are often called illegal drugs but, generally, what was illegal is their unlicensed production, supply and possession. The drugs are also called controlled drugs or controlled substances. # Abuse potential Depending on the actual compound, drug abuse may lead to health problems, social problems, physical dependence, or psychological addiction. Some drugs that are subject to abuse have central nervous system (CNS) effects, which produce changes in mood, levels of awareness or perceptions and sensations. Most of these drugs also alter systems other than the CNS. But, not all centrally acting drugs are subject to abuse, which suggests that altering consciousness is not sufficient for a drug to have abuse potential. Among drugs that are abused, some appear to be more likely to lead to uncontrolled use than others, suggesting a possible hierarchy of drug-induced effects relative to abuse potential.[7] # Approaches to managing drug abuse In addition to being a major public health problem, some consider drug abuse to be a social problem with far-reaching implications. Stress, poverty, domestic and societal violence, and various diseases (i.e., injecting drug users as a source for HIV/AIDS) are sometimes thought to be spread by drug use. Studies have also shown that individuals dependent on illicit drugs experience higher rates of comorbid psychiatric syndromes. ## Harm reduction One alternative involves replacing failed law enforcement policies with harm-reduction strategies, which focus on reducing the societal costs of drug abuse and other drug use. Techniques include education to avoid overdose, needle exchange programs to reduce the spread of blood-borne diseases, and opioid substitution therapy to reduce crime related to the procurement of drugs. This pragmatic approach is known as the harm reduction paradigm. Harm reduction also addresses special populations, such as drug-using parents, pregnant drug users and users with psychiatric comorbidity. The philosophy of harm reduction accepts that drug use is part of the community, but that it must be addressed as a public health issue rather than a criminal one.[8] Harm-reduction measures are at odds with the prevailing framework of international drug control, which rests on law enforcement and the criminalization of behaviors related to illicit drug use. However, harm-reduction has had a notable impact and is slowly gaining popularity. In Brazil alone, a comprehensive harm-reduction and drug-access program successfully reduced AIDS mortality among injection drug users by 50%.[9] ## Abstinence-Based Abstinence-based approaches set as a goal complete abstinence from all addictive substances, including both licit and illicit, prescribed and unprescribed. While the harm-reduction approach has been demonstrated to work well with opioids, the abstinence-based approach is the medical community standard of care for sedative (including alcohol) dependence. ## Medical treatment Beyond the sociological issues, many drugs of abuse can lead to addiction, chemical dependency, or adverse health effects, such as lung cancer or emphysema from cigarette smoking. Medical treatment therefore centers on two aspects: 1) breaking the addiction, 2) treating the health problems. Most countries have health facilities that specialize in the treatment of drug abuse, although access may be limited to larger population centers and the social taboos regarding drug use may make those who need the medical treatment reluctant to take advantage of it. For example, it is estimated that only fifteen percent of injection drug abusers thought to be in need are receiving treatment.[10] Patients may require acute and long-term maintenance treatment and relapse prevention, complemented by suitable rehabilitation. [11] ## Pharmacotherapy The development of pharmacotherapies for drug dependency treatment are currently in progress. New immunotherapies that prevent drugs like cocaine, methamphetamine, phencyclidine, nicotine, and opioids from reaching the brain are in the early stages of testing as is ibogaine, an alkaloid found in the Tabernanthe iboga plant of West Central Africa. Medications such as Buprenorphine, which block the drugs active site in the brain are another new option for the treatment of opioid addiction. Depot forms of medications, which require only weekly or monthly dosing, are also under investigation. Traditionally, new pharmacotherapies are quickly adopted in primary care settings, however, drugs for substance abuse treatment have faced many barriers. Naltrexone, a drug originally marketed under the name "ReVia," and now marketed in intramuscular formulation as "Vivitrol" or in oral formulation as a generic, is a medication approved for the treatment of alcohol dependence. This drug has reached very few patients. This may be due to a number of factors, including resistance by Addiction Medicine specialists and lack of resources. [12] ## Legal approaches Most governments have designed legislation to criminalise certain types of drug use. These drugs are often called "illegal drugs" but generally what is illegal is their unlicensed production, distribution, and possession. These drugs are also called "controlled substances". Even for simple possession, legal punishment can be quite severe (including the death penalty in some countries). Laws vary across countries, and even within them, and have fluctuated widely throughout history. Attempts by government-sponsored drug control policy to interdict drug supply and eliminate drug abuse have been largely unsuccessful. In spite of the huge efforts by the U.S., drug supply and purity has reached an all time high, with the vast majority of resources spent on interdiction and law enforcement instead of public health. In the United States, the number of nonviolent drug offenders in prison exceeds by 100,000 the total incarcerated population in the EU, despite the fact that the EU has 100 million more citizens. Despite drug legislation (and some might argue because of it), large, organized criminal drug cartels operate world-wide. Advocates of decriminalization argue that drug prohibition makes drug dealing a lucrative business, leading to much of the associated criminal activity.	https://www.wikidoc.org/index.php/Drug_abuse
c4ad284fecde80e04d92a790b5e183dd4531df8f	wikidoc	Dummy edit	Dummy edit # Dummy edit A dummy edit is a change in wikitext that has little or no effect on the rendered page, but saves a useful dummy edit summary. The dummy edit summary can be used for text messaging, and correcting a previous edit summary such as an accidental marking of a previous edit as "minor" (see Help:Minor edit). Text messaging via the edit summary is a way of communicating with other editors. Text messages may be seen by dotted IP number editors who don't have a user talk page, or editors who haven't read the subject's talk page, if it exists. Each edit summary can hold 200 text characters. A dummy edit should be checkboxed "minor" by logged-in editors. - Changing the number of newlines in the edit text. Changing from 0 to 1 or from 2 to 3 (or vice versa) has no effect on the rendered page. Changing from 1 to 2 newlines makes a rendered difference that may not be a dummy edit. Adding newlines to the end of the article will not save as a dummy edit (see below). - Changing the number of spaces. Changing one space character to two or more (or vice versa) also has no effect on the rendered page. Multiple space characters always render as a single space, unless the line begins with a leading space. # Null edit A null edit occurs if a page save is made when the wikitext is not changed, which is useful for refreshing the cache. A null edit will not record an edit, make any entry in the page history, in Recent Changes, etc., and the edit summary is discarded. - Opening the edit window and saving. A section edit save is sufficient, but can sometimes result in a dummy edit. - Adding newlines only to the end of the article and saving. This is also a null edit.	Dummy edit Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Dummy edit A dummy edit is a change in wikitext that has little or no effect on the rendered page, but saves a useful dummy edit summary. The dummy edit summary can be used for text messaging, and correcting a previous edit summary such as an accidental marking of a previous edit as "minor" (see Help:Minor edit). Text messaging via the edit summary is a way of communicating with other editors. Text messages may be seen by dotted IP number editors who don't have a user talk page, or editors who haven't read the subject's talk page, if it exists. Each edit summary can hold 200 text characters. A dummy edit should be checkboxed "minor" by logged-in editors. - Changing the number of newlines in the edit text. Changing from 0 to 1 or from 2 to 3 (or vice versa) has no effect on the rendered page. Changing from 1 to 2 newlines makes a rendered difference that may not be a dummy edit. Adding newlines to the end of the article will not save as a dummy edit (see below). - Changing the number of spaces. Changing one space character to two or more (or vice versa) also has no effect on the rendered page. Multiple space characters always render as a single space, unless the line begins with a leading space. # Null edit A null edit occurs if a page save is made when the wikitext is not changed, which is useful for refreshing the cache. A null edit will not record an edit, make any entry in the page history, in Recent Changes, etc., and the edit summary is discarded. - Opening the edit window and saving. A section edit save is sufficient, but can sometimes result in a dummy edit. - Adding newlines only to the end of the article and saving. This is also a null edit. Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Dummy_edit
26fce6478e5a1732f8e7813fa10a4dcd10c4e447	wikidoc	Dura mater	Dura mater # Overview The dura mater (from the Latin "hard mother"), or pachymeninx, is the tough and inflexible outermost of the three layers of the meninges surrounding the brain and spinal cord. (The other two meningeal layers are the pia mater and the arachnoid mater.) The dura mater is not as tightly fitting around the spinal cord, extending past the spinal cord (at the second lumbar vertebra) to about the second sacral vertebra. # Layers and reflections The dura mater has two layers: - a superficial layer, which is actually the skull's inner periosteum - a deep layer, the dura mater proper. The dura separates into two layers at dural reflections, places where the inner dural layer is reflected as sheet-like protrusions into the cranial cavity. There are two main dural reflections: - The tentorium cerebelli exists between and separates the cerebellum and brainstem from the occipital lobes of the cerebrum. - The falx cerebri, which separates the two hemispheres of the brain, is located in the longitudinal cerebral fissure between the hemispheres. # Drainage The two layers of dura mater run together throughout most of the skull. Where they separate, the gap between them is called a dural venous sinus. These sinuses drain blood and cerebrospinal fluid from the brain and empty into the internal jugular vein. They drain via the arachnoid villi, which are outgrowths of the arachnoid mater (the middle meningeal layer) that extend into the venous sinuses. These villi act as one-way valves. Meningeal veins, which course through the dura mater, and bridging veins, which drain the underlying neural tissue and puncture the dura mater, empty into these dural sinuses. # Clinical significance A subdural hematoma occurs when there is an abnormal collection of blood between the dura and the arachnoid, usually as a result of torn bridging veins secondary to head trauma. An epidural hematoma is a collection of blood between the dura and the inner surface of the skull, and is usually due to arterial bleeding. The American Red Cross and some other agencies accepting blood donations consider dura mater transplants, along with receipt of pituitary-derived growth hormone, a risk factor due to concerns about Creutzfeldt-Jakob disease.	Dura mater Template:Infobox Anatomy # Overview The dura mater (from the Latin "hard mother"), or pachymeninx, is the tough and inflexible outermost of the three layers of the meninges surrounding the brain and spinal cord. (The other two meningeal layers are the pia mater and the arachnoid mater.) The dura mater is not as tightly fitting around the spinal cord, extending past the spinal cord (at the second lumbar vertebra) to about the second sacral vertebra. # Layers and reflections The dura mater has two layers: - a superficial layer, which is actually the skull's inner periosteum - a deep layer, the dura mater proper. The dura separates into two layers at dural reflections, places where the inner dural layer is reflected as sheet-like protrusions into the cranial cavity. There are two main dural reflections: - The tentorium cerebelli exists between and separates the cerebellum and brainstem from the occipital lobes of the cerebrum.[1] - The falx cerebri, which separates the two hemispheres of the brain, is located in the longitudinal cerebral fissure between the hemispheres.[2] # Drainage The two layers of dura mater run together throughout most of the skull. Where they separate, the gap between them is called a dural venous sinus. These sinuses drain blood and cerebrospinal fluid from the brain and empty into the internal jugular vein. They drain via the arachnoid villi, which are outgrowths of the arachnoid mater (the middle meningeal layer) that extend into the venous sinuses. These villi act as one-way valves. Meningeal veins, which course through the dura mater, and bridging veins, which drain the underlying neural tissue and puncture the dura mater, empty into these dural sinuses. # Clinical significance A subdural hematoma occurs when there is an abnormal collection of blood between the dura and the arachnoid, usually as a result of torn bridging veins secondary to head trauma. An epidural hematoma is a collection of blood between the dura and the inner surface of the skull, and is usually due to arterial bleeding. The American Red Cross and some other agencies accepting blood donations consider dura mater transplants, along with receipt of pituitary-derived growth hormone, a risk factor due to concerns about Creutzfeldt-Jakob disease.[3]	https://www.wikidoc.org/index.php/Dura
cdeabeb082673210bafb6335eb2e6c055172e988	wikidoc	Durvalumab	Durvalumab # 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 Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is FDA approved for the treatment of locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Common adverse reactions include fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection, or cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Durvalumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: - Have disease progression during or following platinum-containing chemotherapy. - Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. - This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. - Durvalumab is indicated for the treatment of patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. - The recommended dose of durvalumab is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks, until disease progression or unacceptable toxicity. - The recommended dose of durvalumab is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression, unacceptable toxicity, or a maximum of 12 months. - No dose reductions are recommended. Withhold or discontinue durvalumab to manage adverse reactions as described in Table 1. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding durvalumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding durvalumab 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 Durvalumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding durvalumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding durvalumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None. # Warnings - Durvalumab can cause immune-mediated pneumonitis, defined as requiring use of corticosteroids. Fatal cases have been reported. - Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent for moderate (Grade 2) pneumonitis or prednisone 1 to 4 mg per kg per day or equivalent for more severe (Grade 3-4) pneumonitis, followed by taper. Interrupt or permanently discontinue durvalumab based on the severity. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, pneumonitis occurred in 5% of patients, including Grade 3 (0.8%), Grade 4 (< 0.1%) and Grade 5 (0.3%) immune-mediated pneumonitis. The median time to onset was 1.8 months (range: 1 day to 13.9 months) and the median time to resolution was 4.9 months (range: 0 days to 13.7 months). Pneumonitis led to discontinuation of durvalumab in 1.5% of the 1889 patients. Pneumonitis resolved in 54% of patients. Systemic corticosteroids were required in 3.5% of the 1889 patients, with 2.5% requiring high-dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) and 0.1% requiring infliximab. - The incidence of pneumonitis (including radiation pneumonitis) was higher in patients in the PACIFIC study who completed treatment with definitive chemoradiation within 42 days prior to initiation of durvalumab (34%) compared to patients in other clinical studies (2.3%) in which radiation therapy was generally not administered immediately prior to initiation of durvalumab. - In the PACIFIC study, the incidence of Grade 3 pneumonitis was 3.4% and of Grade 5 pneumonitis was 1.1% in the durvalumab arm. The median time to onset of pneumonitis was 1.8 months and the median duration was 2.1 months (range: 3 days to 18.7 months). Pneumonitis led to discontinuation of durvalumab in 6% of patients. Pneumonitis resolved in 47% of patients experiencing pneumonitis. Systemic corticosteroids were required in 21% of patients, with 12% requiring high-dose corticosteroids and 0.1% requiring infliximab. - Durvalumab can cause immune-mediated hepatitis, defined as requiring use of corticosteroids. Fatal cases have been reported. - Monitor patients for signs and symptoms of hepatitis, during and after discontinuation of durvalumab, including clinical chemistry monitoring. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent, followed by taper for Grade 2 or higher elevations of ALT, AST, and/or total bilirubin. Interrupt or permanently discontinue IMFINZI based on the severity. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, hepatitis occurred in 12% of patients, including Grade 3 (4.4%), Grade 4 (0.4%) and Grade 5 (0.2%) immune-mediated hepatitis. The median time to onset was 1.2 months (range: 1 day to 13.6 months). Hepatitis led to discontinuation of durvalumab in 0.7% of the 1889 patients. Hepatitis resolved in 49% of patients. Systemic corticosteroids were required in 2.7% of patients, with 1.7% requiring high-dose corticosteroids and 0.1% requiring mycophenolate. - Durvalumab can cause immune-mediated colitis, defined as requiring use of corticosteroids. - Monitor patients for signs and symptoms of diarrhea or colitis. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) or more severe (Grade 3-4) colitis, followed by taper. Interrupt or permanently discontinue durvalumab based on the severity. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, diarrhea or colitis occurred in 18% of patients, including Grade 3 (1%) and Grade 4 (0.1%) immune-mediated colitis. The median time to onset was 1.4 months (range: 1 day to 14 months). Diarrhea or colitis lead to discontinuation of durvalumab in 0.4% of the 1889 patients. Diarrhea or colitis resolved in 78% of the patients. Systemic corticosteroids were required in 1.9% of patients, with 1% requiring high-dose corticosteroids and 0.1% requiring other immunosuppressants (e.g., infliximab, mycophenolate). - Durvalumab can cause immune-mediated endocrinopathies, including thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus and hypophysitis/hypopituitarism. - Thyroid Disorders: Monitor thyroid function prior to and periodically during treatment with durvalumab. Initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated. Continue durvalumab for hypothyroidism and interrupt for hyperthyroidism based on the severity . - In clinical studies enrolling 1889 patients who received durvalumab, hypothyroidism occurred in 11% of patients and hyperthyroidism occurred in 7% of patients. Thyroiditis occurred in 0.9% of patients, including Grade 3 (< 0.1%) thyroiditis. Hypothyroidism was preceded by thyroiditis or hyperthyroidism in 25% of patients. - Adrenal Insufficiency: Monitor patients for clinical signs and symptoms of adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate prednisone 1 to 2 mg per kg per day or equivalent, followed by corticosteroid taper and hormone replacement as clinically indicated. Interrupt durvalumab based on the severity. - In clinical studies enrolling 1889 patients who received durvalumab, adrenal insufficiency occurred in 0.7% of patients, including Grade 3 (< 0.1%) adrenal insufficiency. Systemic corticosteroids were required in 0.4% of patients, including 0.1% of patients who required high-dose corticosteroids. - Type 1 Diabetes Mellitus: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Interrupt durvalumab based on the severity. - In clinical studies enrolling 1889 patients who received durvalumab, type 1 diabetes mellitus occurred in < 0.1 % of patients. The median time to onset was 1.4 months. - Hypophysitis: For Grade 2 or higher hypophysitis, initiate prednisone 1 to 2 mg per kg per day or equivalent, followed by corticosteroid taper and hormone replacement therapy as clinically indicated. Interrupt durvalumab based on the severity. - Hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in < 0.1% of 1889 patients who received durvalumab in clinical studies. - Durvalumab can cause immune-mediated nephritis defined as evidence of renal dysfunction, requirement for corticosteroids. Fatal cases have occurred. - Monitor patients for abnormal renal function tests prior to and periodically during treatment with durvalumab. Initiate prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) or severe (Grade 3-4) nephritis, followed by taper. Interrupt or permanently discontinue durvalumab based on the severity. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, nephritis (reported as any of the following increased creatinine or urea, acute kidney injury, renal failure, decreased glomerular filtration rate, tubulointerstitial nephritis, decreased creatinine clearance, glomerulonephritis, and nephritis) occurred in 6.3% of patients including Grade 3 (1.1%), Grade 4 (0.2%) and Grade 5 (0.1%) immune-mediated nephritis. The median time to onset was 2 months (range: 1 day to 14.2 months). Durvalumab was discontinued in 0.3% of the 1889 patients. Nephritis resolved in 50% of patients. Systemic corticosteroids were required in 0.6% of patients, with 0.4% receiving high-dose corticosteroids. - Durvalumab can cause immune-mediated rash; bullous dermatitis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN) have occurred with other products in this class. - Monitor for signs and symptoms of rash. Initiate prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) rash or dermatitis lasting for more than 1 week or severe (Grade 3-4) rash or dermatitis followed by taper. Interrupt or permanently discontinue durvalumab based on the severity. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, 26% of patients developed rash or dermatitis and 0.4% of the patients developed vitiligo. Rash or dermatitis led to discontinuation of durvalumab in 0.1% of the 1889 patients. Rash resolved in 62% of patients. Systemic corticosteroids were required in 2.0% of patients, including high-dose corticosteroids in 1% of patients. - Durvalumab can cause severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. While immune-mediated reactions usually manifest during treatment with durvalumab, immune-mediated adverse reactions can also manifest after discontinuation of durvalumab. - For suspected Grade 2 immune-mediated adverse reactions, exclude other causes and initiate corticosteroids as clinically indicated. For severe (Grade 3 or 4) adverse reactions, administer corticosteroids, prednisone 1 to 4 mg per kg per day or equivalent, followed by taper. Interrupt or permanently discontinue durvalumab, based on the severity of the reaction. If uveitis occurs in combination with other immune-mediated adverse reactions, evaluate for Vogt-Koyanagi-Harada syndrome, which has been observed with other products in this class and may require treatment with systemic steroids to reduce the risk of permanent vision loss. - The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in 1889 patients who received durvalumab: aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, and ocular inflammatory toxicity, including uveitis and keratitis. The following clinically significant, immune-mediated adverse reactions have been reported with other products in this class: bullous dermatitis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), pancreatitis, systemic inflammatory response syndrome, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, iritis, encephalitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome and Vogt-Koyanagi-Harada syndrome. - Durvalumab can cause serious infections, including fatal cases. - Monitor patients for signs and symptoms of infection. For Grade 3 or higher infections, withhold durvalumab and resume once clinically stable. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, infections occurred in 43% of patients, including Grade 3 (8%), Grade 4 (1.9%), and Grade 5 (1.0%). In the urothelial carcinoma cohort in Study 1108 the most common Grade 3 or higher infection was urinary tract infections, which occurred in 4% of patients. In the PACIFIC study the most common Grade 3 or higher infection was pneumonia, which occurred in 5% of patients. The overall incidence of infections in durvalumab-treated patients (56%) in the PACIFIC study was higher compared to patients in other studies (38%) in which radiation therapy was generally not administered immediately prior to initiation of durvalumab. - Durvalumab can cause severe or life-threatening infusion-related reactions. - Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue durvalumab based on the severity. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. - In clinical studies enrolling 1889 patients with various cancers, infusion-related reactions occurred in 2.2% of patients, including Grade 3 (0.3%). - Based on its mechanism of action and data from animal studies, durvalumab can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of durvalumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased premature delivery, fetal loss and premature neonatal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with durvalumab and for at least 3 months after the last dose of durvalumab. # 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 in the Warnings and Precautions section reflect exposure to durvalumab in 1889 patients from the PACIFIC study (a randomized, placebo-controlled study that enrolled 475 patients with Stage III NSCLC), Study 1108 (an open-label, single-arm, multicohort study that enrolled 191 patients with urothelial carcinoma and 779 patients with various other solid tumors), and an additional open-label, single-arm trial that enrolled 444 patients with metastatic lung cancer, an indication for which durvalumab is not approved. Across all studies, durvalumab was administered at a dose of 10 mg/kg intravenously every 2 weeks. Among the 1889 patients, 38% were exposed for 6 months or more and 18% were exposed for 12 months or more. - The data described in this section reflect exposure to durvalumab in patients with locally advanced or metastatic urothelial carcinoma enrolled in Study 1108 and in patients with Stage III NSCLC enrolled in the PACIFIC study. - The safety data described in Table 2 reflect exposure to durvalumab in 182 patients with locally advanced or metastatic urothelial carcinoma in the urothelial carcinoma cohort of Study 1108 whose disease has progressed during or after one standard platinum-based regimen. Patients received durvalumab 10 mg/kg intravenously every 2 weeks. The median duration of exposure was 2.3 months (range: 1 day to 12.1 months). - Thirty-one percent (31%) of patients had a drug delay or interruption for an adverse reaction. The most common (> 2%) were liver injury (4.9%), urinary tract infection (3.3%), acute kidney injury (3.3%), and musculoskeletal pain (2.7%). - The most common adverse reactions (≥ 15%) were fatigue (39%), musculoskeletal pain (24%), constipation (21%), decreased appetite (19%), nausea (16%), peripheral edema (15%) and urinary tract infection (15%). The most common Grade 3 or 4 adverse reactions (≥ 3%) were fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration. - Eight patients (4.4%) who were treated with durvalumab experienced Grade 5 adverse reactions of cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis. Three additional patients were experiencing infection and disease progression at the time of death. durvalumab was discontinued for adverse reactions in 3.3% of patients. Serious adverse reactions occurred in 46% of patients. The most frequent serious adverse reactions (> 2%) were acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain and pyrexia/tumor associated fever (2.7% each). - Table 2 summarizes the adverse reactions that occurred in ≥ 10% of patients, while Table 3 summarizes the Grade 3 - 4 laboratory abnormalities that occurred in ≥ 1% of patients treated with durvalumab in the urothelial carcinoma cohort of Study 1108. - The safety of durvalumab in patients with Stage III NSCLC who completed concurrent platinum-based chemoradiotherapy within 42 days prior to initiation of study drug was evaluated in the PACIFIC study, a multicenter, randomized, double-blind, placebo-controlled study. A total of 475 patients received durvalumab 10 mg/kg intravenously every 2 weeks. The study excluded patients who had disease progression following chemoradiation, with active or prior autoimmune disease within 2 years of initiation of the study or with medical conditions that required systemic immunosuppression. - The study population characteristics were: median age of 64 years (range: 23 to 90), 45% age 65 years or older, 70% male, 69% White, 27% Asian, 75% former smoker, 16% current smoker, and 51% had WHO performance status of 1. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy. The median duration of exposure to durvalumab was 10 months (range: 0.2 to 12.6). - Durvalumab was discontinued due to adverse reactions in 15% of patients. The most common adverse reactions leading to durvalumab discontinuation were pneumonitis or radiation pneumonitis in 6% of patients. Serious adverse reactions occurred in 29% of patients receiving durvalumab. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in < 2% of patients and were similar across arms. The most common adverse reactions (occurring in ≥ 20% of patients) were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnea and rash. - Table 4 summarizes the adverse reactions that occurred in at least 10% of patients treated with durvalumab. - Other adverse reactions occurring in less than 10% of patients treated with durvalumab were dysphonia, dysuria, night sweats, peripheral edema, and increased susceptibility to infections. - Table 5 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with durvalumab. - As with all therapeutic proteins, there is a potential for immunogenicity. 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 the incidence of antibodies to durvalumab to the incidence of antibodies to other products may be misleading. - Due to the limitations in assay performance, the incidence of antibody development in patients receiving durvalumab may be underestimated. Of 1570 patients who were treated with durvalumab 10 mg/kg every 2 weeks and evaluable for the presence of anti-drug antibodies (ADAs), 45 (2.9%) patients tested positive for treatment-emergent ADAs. The development of treatment-emergent ADA against durvalumab appears to have no clinically relevant effect on its pharmacokinetic profile. There are insufficient numbers of patients with ADA to determine whether ADA alters the safety or efficacy of durvalumab. ## Postmarketing Experience There is limited information regarding Durvalumab Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Durvalumab Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Based on its mechanism of action and data from animal studies, durvalumab can cause fetal harm when administered to a pregnant woman. There are no data on the use of durvalumab in pregnant women. - In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery resulted in an increase in premature delivery, fetal loss and premature neonatal death. Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a fetus. - 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. - As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth) and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Durvalumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Durvalumab during labor and delivery. ### Nursing Mothers - There is no information regarding the presence of durvalumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG1 is excreted in human milk. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death. - Because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with durvalumab and for at least 3 months after the last dose. - In lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature neonatal death. ### Pediatric Use - The safety and effectiveness of durvalumab have not been established in pediatric patients. ### Geriatic Use - Of the 182 patients treated with durvalumab in patients with urothelial carcinoma, 112 patients were 65 years or older and 34 patients were 75 years or older. The overall response rate in patients 65 years or older was 15% (17/112) and was 12% (4/34) in patients 75 years or older. Grade 3 or 4 adverse reactions occurred in 38% (42/112) of patients 65 years or older and 35% (12/34) of patients 75 years or older. - Of the 476 patients treated with durvalumab in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Durvalumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Durvalumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Durvalumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Durvalumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males Females - Based on its mechanism of action and data from animal studies, durvalumab can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with durvalumab and for at least 3 months following the last dose of durvaluab. ### Immunocompromised Patients There is no FDA guidance one the use of Durvalumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. - Do not shake the vial. - Withdraw the required volume from the vial(s) of durvalumab and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL. - Discard partially used or empty vials of durvalumab. - Durvalumab does not contain a preservative. - Administer infusion solution immediately once prepared. If infusion solution is not administered immediately and needs to be stored, the total time from vial puncture to the start of the administration should not exceed: - 24 hours in a refrigerator at 2°C to 8°C (36°F to 46°F) - 4 hours at room temperature up to 25°C (77°F) - Do not freeze. - Do not shake. - Administer infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter. - Do not co-administer other drugs through the same infusion line. ### Monitoring - Tumor response indicates efficacy - Chemistry: During and after therapy - Liver function: During each treatment cycle - Thyroid function: Prior to initiation and periodically throughout treatment - Blood glucose: During treatment - Renal function: Prior to and during each treatment cycle - Signs or symptoms of endocrinopathies - Signs or symptoms of adrenal insufficiency - Signs or symptoms of diabetes - Signs or symptoms of hypophysitis or hypopituitarism - Signs or symptoms of immune thrombotic thrombocytopenia - Signs and symptoms of infusion-related reactions - Signs and symptoms of diarrhea or colitis - Signs and symptoms of hepatitis: During and after therapy - Signs and symptoms of infection - Signs and symptoms of pneumonitis - Signs and symptoms of rash # IV Compatibility There is limited information regarding the compatibility of Durvalumab and IV administrations. # Overdosage - There is no information on overdose with durvalumab. # Pharmacology ## Mechanism of Action - Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production. - Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC). - PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models. ## Structure There is limited information regarding Durvalumab Structure in the drug label. ## Pharmacodynamics - The exposure-response relationships of efficacy and safety are unknown. - Durvalumab is unlikely to prolong the QT/QTc interval. ## Pharmacokinetics - The pharmacokinetics of durvalumab was studied in 1902 patients with doses ranging from 0.1 mg/kg (0.01 times the approved recommended dosage) to 20 mg/kg (2 times the approved recommended dosage) administered once every two, three or four weeks. - PK exposure increased more than dose-proportionally at doses < 3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses ≥ to 3 mg/kg every 2 weeks. Steady state was achieved at approximately 16 weeks. - The geometric mean (% coefficient of variation ) steady state volume of distribution was 5.6 (18%) L. - Durvalumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of approximately 23% (57%) resulting in a geometric mean (CV%) steady state clearance (CLss) of 8.2 mL/h (39%) at day 365; the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life, based on baseline CL was approximately 18 (24%) days. - Age (19–96 years), body weight (34-149 kg), sex, albumin levels, lactate dehydrogenase (LDH) levels, creatinine levels, soluble PD-L1, tumor type, race, mild renal impairment (creatinine clearance (CLcr) 60 to 89 mL/min), moderate renal impairment (CLcr 30 to 59 mL/min), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5x ULN and any AST), or ECOG/WHO performance status had no clinically significant effect on the pharmacokinetics of durvalumab. - The effect of severe renal impairment (CLcr 15 to 29 mL/min) or moderate hepatic impairment (bilirubin > 1.5 to 3x ULN and any AST) or severe hepatic impairment (bilirubin > 3x ULN and any AST) on the pharmacokinetics of durvalumab is unknown. ## Nonclinical Toxicology - The carcinogenic and genotoxic potential of durvalumab have not been evaluated. - Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to 3 months duration, there were no notable effects on the male and female reproductive organs. - In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus. # Clinical Studies - The efficacy of durvalumab was evaluated in the urothelial carcinoma cohort of Study 1108 (NCT01693562), a multicenter, multi-cohort, open-label clinical trial. In Study 1108, 182 patients with locally advanced or metastatic urothelial carcinoma were enrolled. Patients had progressed while on or after a platinum-based therapy, including those who progressed within 12 months of receiving therapy in a neo-adjuvant or adjuvant setting. These patients had initiated durvalumab at least 13 weeks prior to the data cut-off date. The trial excluded patients with a history of immunodeficiency; medical conditions that required systemic immunosuppression (not to exceed 10 mg per day of prednisone or equivalent); history of severe autoimmune disease; untreated CNS metastases; HIV; active tuberculosis, or hepatitis B or C infection. All patients received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or disease progression. Tumor assessments were performed at Weeks 6, 12 and 16, then every 8 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were confirmed Overall Response Rate (ORR) according to RECIST v1.1 as assessed by Blinded Independent Central Review (BICR), and duration of response (DoR). - The median age was 67 years (range: 34 to 88), 72% were male, 64% were White. Sixty-six percent (66%) of patients had visceral metastasis (bone, liver, or lung), including 34% with liver metastasis. Lymph node only metastasis were present in 13% of patients. Sixty-six percent (66%) of patients had ECOG score of 1 and 41% of patients had a baseline creatinine clearance < 60 mL/min. The Bellmunt risk score (which includes ECOG score, baseline hemoglobin, and liver metastases) was 0 in 23%, 1 in 38%, 2 in 29%, and 3 in 9% of patients. Twenty percent (20%) of patients had disease progression following platinum-containing neoadjuvant or adjuvant chemotherapy as their only prior line of therapy. Seventy percent (70%) of patients received prior cisplatin, 30% prior carboplatin and 35% received ≥ 2 prior lines of systemic therapy. - Tumor specimens were evaluated prospectively for PD-L1 expression on tumor cells (TC) and immune cells (IC) at a central laboratory using the VENTANA PD-L1 (SP263) Assay. Of the 182 patients, 52% were classified as PD-L1 high (if ICs involve > 1% of the tumor area, TC ≥ 25% or IC ≥ 25%; if ICs involve ≤ 1% of the tumor area, TC ≥ 25% or IC = 100%), 40% as PD-L1 low/negative (did not meet criterion for PD-L1 high), and samples for 8% were not evaluable. - Table 6 summarizes the results in the urothelial carcinoma cohort of Study 1108. The median follow-up time was 5.6 months. In 37 patients who had received only neoadjuvant or adjuvant therapy prior to study entry, 24% responded. - Among the total 31 responding patients, 45% had ongoing responses of 6 months or longer and 16% had ongoing responses of 12 months or longer. - The efficacy of durvalumab was evaluated in the PACIFIC study (NCT02125461), a multicenter, randomized, double-blind, placebo-controlled study in patients with unresectable Stage III NSCLC who completed at least 2 cycles of concurrent platinum-based chemotherapy and definitive radiation within 42 days prior to initiation of the study drug and had a WHO performance status of 0 or 1. The study excluded patients who had progressed following concurrent chemoradiation, patients with active or prior documented autoimmune disease within 2 years of initiation of the study or patients with medical conditions that required systemic immunosuppression. Randomization was stratified by sex, age (< 65 years vs. ≥ 65 years) and smoking history (smoker vs. non-smoker). Patients were randomized 2:1 to receive durvalumab 10 mg/kg or placebo intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed RECIST 1.1-defined progression. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were progression-free survival (PFS) as assessed by a BICR RECIST 1.1 and overall survival (OS). Additional efficacy outcome measures included ORR assessed by BICR. - A total of 713 patients were randomized: 476 patients to the durvalumab arm and 237 to the placebo arm. The study population characteristics were: median age of 64 years (range: 23 to 90); 70% male; 69% White and 27% Asian; 16% current smokers, 75% former smokers and 9% never smokers; 51% WHO performance status of 1; 53% with Stage IIIA and 45% were Stage IIIB; 46% with squamous and 54% with non-squamous histology. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy; 99% of patients received concomitant platinum-based chemotherapy (55% cisplatin-based, 42% carboplatin-based chemotherapy and 2% switched between cisplatin and carboplatin). - The pre-specified interim PFS analysis based on 371 events (81% of total planned events) demonstrated a statistically significant improvement in PFS in patients randomized to durvalumab compared to placebo. Results are presented in Table 7 and Figure 1. OS data were not mature at the time of the interim PFS analysis. # How Supplied - IMFINZI (durvalumab) Injection is a clear to opalescent, colorless to slightly yellow solution supplied in a carton containing one single-dose vial either as: - 500 mg/10 mL (NDC 0310-4611-50) - 120 mg/2.4 mL (NDC 0310-4500-12) ## Storage - Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. - Do not freeze. Do not shake. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling. - Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of durvalumab, including: - Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath. - Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding. - Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain. - Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, or hypophysitis. - Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis. - Dermatological Reactions: Advise patients to contact their healthcare provider immediately signs or symptoms of severe dermatological reactions. - Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of aseptic meningitis, thrombocytopenic purpura, myocarditis, hemolytic anemia, myositis, uveitis and keratitis. - Infection: Advise patients to contact their healthcare provider immediately for infection. - Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions. - Embryo-Fetal Toxicity: Advise females of reproductive potential that durvalumab can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy. - Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of durvalumab. - Lactation: Advise female patients not to breastfeed while taking durvalumab and for at least 3 months after the last dose. # Precautions with Alcohol Alcohol-Durvalumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Imfinzi # Look-Alike Drug Names There is limited information regarding Durvalumab Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Durvalumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand, Anmol Pitliya, M.B.B.S. 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 Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that is FDA approved for the treatment of locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Common adverse reactions include fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection, or cough, fatigue, pneumonitis/radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Durvalumab is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: - Have disease progression during or following platinum-containing chemotherapy. - Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. - This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. - Durvalumab is indicated for the treatment of patients with unresectable Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. - The recommended dose of durvalumab is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks, until disease progression or unacceptable toxicity. - The recommended dose of durvalumab is 10 mg/kg administered as an intravenous infusion over 60 minutes every 2 weeks until disease progression, unacceptable toxicity, or a maximum of 12 months. - No dose reductions are recommended. Withhold or discontinue durvalumab to manage adverse reactions as described in Table 1. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding durvalumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding durvalumab 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 Durvalumab FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding durvalumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding durvalumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None. # Warnings - Durvalumab can cause immune-mediated pneumonitis, defined as requiring use of corticosteroids. Fatal cases have been reported. - Monitor patients for signs and symptoms of pneumonitis. Evaluate patients with suspected pneumonitis with radiographic imaging. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent for moderate (Grade 2) pneumonitis or prednisone 1 to 4 mg per kg per day or equivalent for more severe (Grade 3-4) pneumonitis, followed by taper. Interrupt or permanently discontinue durvalumab based on the severity. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, pneumonitis occurred in 5% of patients, including Grade 3 (0.8%), Grade 4 (< 0.1%) and Grade 5 (0.3%) immune-mediated pneumonitis. The median time to onset was 1.8 months (range: 1 day to 13.9 months) and the median time to resolution was 4.9 months (range: 0 days to 13.7 months). Pneumonitis led to discontinuation of durvalumab in 1.5% of the 1889 patients. Pneumonitis resolved in 54% of patients. Systemic corticosteroids were required in 3.5% of the 1889 patients, with 2.5% requiring high-dose corticosteroids (prednisone ≥ 40 mg per day or equivalent) and 0.1% requiring infliximab. - The incidence of pneumonitis (including radiation pneumonitis) was higher in patients in the PACIFIC study who completed treatment with definitive chemoradiation within 42 days prior to initiation of durvalumab (34%) compared to patients in other clinical studies (2.3%) in which radiation therapy was generally not administered immediately prior to initiation of durvalumab. - In the PACIFIC study, the incidence of Grade 3 pneumonitis was 3.4% and of Grade 5 pneumonitis was 1.1% in the durvalumab arm. The median time to onset of pneumonitis was 1.8 months and the median duration was 2.1 months (range: 3 days to 18.7 months). Pneumonitis led to discontinuation of durvalumab in 6% of patients. Pneumonitis resolved in 47% of patients experiencing pneumonitis. Systemic corticosteroids were required in 21% of patients, with 12% requiring high-dose corticosteroids and 0.1% requiring infliximab. - Durvalumab can cause immune-mediated hepatitis, defined as requiring use of corticosteroids. Fatal cases have been reported. - Monitor patients for signs and symptoms of hepatitis, during and after discontinuation of durvalumab, including clinical chemistry monitoring. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent, followed by taper for Grade 2 or higher elevations of ALT, AST, and/or total bilirubin. Interrupt or permanently discontinue IMFINZI based on the severity. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, hepatitis occurred in 12% of patients, including Grade 3 (4.4%), Grade 4 (0.4%) and Grade 5 (0.2%) immune-mediated hepatitis. The median time to onset was 1.2 months (range: 1 day to 13.6 months). Hepatitis led to discontinuation of durvalumab in 0.7% of the 1889 patients. Hepatitis resolved in 49% of patients. Systemic corticosteroids were required in 2.7% of patients, with 1.7% requiring high-dose corticosteroids and 0.1% requiring mycophenolate. - Durvalumab can cause immune-mediated colitis, defined as requiring use of corticosteroids. - Monitor patients for signs and symptoms of diarrhea or colitis. Administer corticosteroids, prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) or more severe (Grade 3-4) colitis, followed by taper. Interrupt or permanently discontinue durvalumab based on the severity. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, diarrhea or colitis occurred in 18% of patients, including Grade 3 (1%) and Grade 4 (0.1%) immune-mediated colitis. The median time to onset was 1.4 months (range: 1 day to 14 months). Diarrhea or colitis lead to discontinuation of durvalumab in 0.4% of the 1889 patients. Diarrhea or colitis resolved in 78% of the patients. Systemic corticosteroids were required in 1.9% of patients, with 1% requiring high-dose corticosteroids and 0.1% requiring other immunosuppressants (e.g., infliximab, mycophenolate). - Durvalumab can cause immune-mediated endocrinopathies, including thyroid disorders, adrenal insufficiency, type 1 diabetes mellitus and hypophysitis/hypopituitarism. - Thyroid Disorders: Monitor thyroid function prior to and periodically during treatment with durvalumab. Initiate hormone replacement therapy or medical management of hyperthyroidism as clinically indicated. Continue durvalumab for hypothyroidism and interrupt for hyperthyroidism based on the severity [see DOSAGE AND ADMINISTRATION (2.3)]. - In clinical studies enrolling 1889 patients who received durvalumab, hypothyroidism occurred in 11% of patients and hyperthyroidism occurred in 7% of patients. Thyroiditis occurred in 0.9% of patients, including Grade 3 (< 0.1%) thyroiditis. Hypothyroidism was preceded by thyroiditis or hyperthyroidism in 25% of patients. - Adrenal Insufficiency: Monitor patients for clinical signs and symptoms of adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate prednisone 1 to 2 mg per kg per day or equivalent, followed by corticosteroid taper and hormone replacement as clinically indicated. Interrupt durvalumab based on the severity. - In clinical studies enrolling 1889 patients who received durvalumab, adrenal insufficiency occurred in 0.7% of patients, including Grade 3 (< 0.1%) adrenal insufficiency. Systemic corticosteroids were required in 0.4% of patients, including 0.1% of patients who required high-dose corticosteroids. - Type 1 Diabetes Mellitus: Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Interrupt durvalumab based on the severity. - In clinical studies enrolling 1889 patients who received durvalumab, type 1 diabetes mellitus occurred in < 0.1 % of patients. The median time to onset was 1.4 months. - Hypophysitis: For Grade 2 or higher hypophysitis, initiate prednisone 1 to 2 mg per kg per day or equivalent, followed by corticosteroid taper and hormone replacement therapy as clinically indicated. Interrupt durvalumab based on the severity. - Hypopituitarism leading to adrenal insufficiency and diabetes insipidus occurred in < 0.1% of 1889 patients who received durvalumab in clinical studies. - Durvalumab can cause immune-mediated nephritis defined as evidence of renal dysfunction, requirement for corticosteroids. Fatal cases have occurred. - Monitor patients for abnormal renal function tests prior to and periodically during treatment with durvalumab. Initiate prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) or severe (Grade 3-4) nephritis, followed by taper. Interrupt or permanently discontinue durvalumab based on the severity. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, nephritis (reported as any of the following increased creatinine or urea, acute kidney injury, renal failure, decreased glomerular filtration rate, tubulointerstitial nephritis, decreased creatinine clearance, glomerulonephritis, and nephritis) occurred in 6.3% of patients including Grade 3 (1.1%), Grade 4 (0.2%) and Grade 5 (0.1%) immune-mediated nephritis. The median time to onset was 2 months (range: 1 day to 14.2 months). Durvalumab was discontinued in 0.3% of the 1889 patients. Nephritis resolved in 50% of patients. Systemic corticosteroids were required in 0.6% of patients, with 0.4% receiving high-dose corticosteroids. - Durvalumab can cause immune-mediated rash; bullous dermatitis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN) have occurred with other products in this class. - Monitor for signs and symptoms of rash. Initiate prednisone 1 to 2 mg per kg per day or equivalent, for moderate (Grade 2) rash or dermatitis lasting for more than 1 week or severe (Grade 3-4) rash or dermatitis followed by taper. Interrupt or permanently discontinue durvalumab based on the severity. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, 26% of patients developed rash or dermatitis and 0.4% of the patients developed vitiligo. Rash or dermatitis led to discontinuation of durvalumab in 0.1% of the 1889 patients. Rash resolved in 62% of patients. Systemic corticosteroids were required in 2.0% of patients, including high-dose corticosteroids in 1% of patients. - Durvalumab can cause severe and fatal immune-mediated adverse reactions. These immune-mediated reactions may involve any organ system. While immune-mediated reactions usually manifest during treatment with durvalumab, immune-mediated adverse reactions can also manifest after discontinuation of durvalumab. - For suspected Grade 2 immune-mediated adverse reactions, exclude other causes and initiate corticosteroids as clinically indicated. For severe (Grade 3 or 4) adverse reactions, administer corticosteroids, prednisone 1 to 4 mg per kg per day or equivalent, followed by taper. Interrupt or permanently discontinue durvalumab, based on the severity of the reaction. If uveitis occurs in combination with other immune-mediated adverse reactions, evaluate for Vogt-Koyanagi-Harada syndrome, which has been observed with other products in this class and may require treatment with systemic steroids to reduce the risk of permanent vision loss. - The following clinically significant, immune-mediated adverse reactions occurred at an incidence of less than 1% each in 1889 patients who received durvalumab: aseptic meningitis, hemolytic anemia, immune thrombocytopenic purpura, myocarditis, myositis, and ocular inflammatory toxicity, including uveitis and keratitis. The following clinically significant, immune-mediated adverse reactions have been reported with other products in this class: bullous dermatitis, Stevens Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), pancreatitis, systemic inflammatory response syndrome, rhabdomyolysis, myasthenia gravis, histiocytic necrotizing lymphadenitis, demyelination, vasculitis, hemolytic anemia, iritis, encephalitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome and Vogt-Koyanagi-Harada syndrome. - Durvalumab can cause serious infections, including fatal cases. - Monitor patients for signs and symptoms of infection. For Grade 3 or higher infections, withhold durvalumab and resume once clinically stable. - In clinical studies enrolling 1889 patients with various cancers who received durvalumab, infections occurred in 43% of patients, including Grade 3 (8%), Grade 4 (1.9%), and Grade 5 (1.0%). In the urothelial carcinoma cohort in Study 1108 the most common Grade 3 or higher infection was urinary tract infections, which occurred in 4% of patients. In the PACIFIC study the most common Grade 3 or higher infection was pneumonia, which occurred in 5% of patients. The overall incidence of infections in durvalumab-treated patients (56%) in the PACIFIC study was higher compared to patients in other studies (38%) in which radiation therapy was generally not administered immediately prior to initiation of durvalumab. - Durvalumab can cause severe or life-threatening infusion-related reactions. - Monitor for signs and symptoms of infusion-related reactions. Interrupt, slow the rate of, or permanently discontinue durvalumab based on the severity. For Grade 1 or 2 infusion-related reactions, consider using pre-medications with subsequent doses. - In clinical studies enrolling 1889 patients with various cancers, infusion-related reactions occurred in 2.2% of patients, including Grade 3 (0.3%). - Based on its mechanism of action and data from animal studies, durvalumab can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of durvalumab to cynomolgus monkeys from the onset of organogenesis through delivery resulted in increased premature delivery, fetal loss and premature neonatal death. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with durvalumab and for at least 3 months after the last dose of durvalumab. # 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 in the Warnings and Precautions section reflect exposure to durvalumab in 1889 patients from the PACIFIC study (a randomized, placebo-controlled study that enrolled 475 patients with Stage III NSCLC), Study 1108 (an open-label, single-arm, multicohort study that enrolled 191 patients with urothelial carcinoma and 779 patients with various other solid tumors), and an additional open-label, single-arm trial that enrolled 444 patients with metastatic lung cancer, an indication for which durvalumab is not approved. Across all studies, durvalumab was administered at a dose of 10 mg/kg intravenously every 2 weeks. Among the 1889 patients, 38% were exposed for 6 months or more and 18% were exposed for 12 months or more. - The data described in this section reflect exposure to durvalumab in patients with locally advanced or metastatic urothelial carcinoma enrolled in Study 1108 and in patients with Stage III NSCLC enrolled in the PACIFIC study. - The safety data described in Table 2 reflect exposure to durvalumab in 182 patients with locally advanced or metastatic urothelial carcinoma in the urothelial carcinoma cohort of Study 1108 whose disease has progressed during or after one standard platinum-based regimen. Patients received durvalumab 10 mg/kg intravenously every 2 weeks. The median duration of exposure was 2.3 months (range: 1 day to 12.1 months). - Thirty-one percent (31%) of patients had a drug delay or interruption for an adverse reaction. The most common (> 2%) were liver injury (4.9%), urinary tract infection (3.3%), acute kidney injury (3.3%), and musculoskeletal pain (2.7%). - The most common adverse reactions (≥ 15%) were fatigue (39%), musculoskeletal pain (24%), constipation (21%), decreased appetite (19%), nausea (16%), peripheral edema (15%) and urinary tract infection (15%). The most common Grade 3 or 4 adverse reactions (≥ 3%) were fatigue, urinary tract infection, musculoskeletal pain, abdominal pain, dehydration, and general physical health deterioration. - Eight patients (4.4%) who were treated with durvalumab experienced Grade 5 adverse reactions of cardiorespiratory arrest, general physical health deterioration, sepsis, ileus, pneumonitis, or immune-mediated hepatitis. Three additional patients were experiencing infection and disease progression at the time of death. durvalumab was discontinued for adverse reactions in 3.3% of patients. Serious adverse reactions occurred in 46% of patients. The most frequent serious adverse reactions (> 2%) were acute kidney injury (4.9%), urinary tract infection (4.4%), musculoskeletal pain (4.4%), liver injury (3.3%), general physical health deterioration (3.3%), sepsis, abdominal pain and pyrexia/tumor associated fever (2.7% each). - Table 2 summarizes the adverse reactions that occurred in ≥ 10% of patients, while Table 3 summarizes the Grade 3 - 4 laboratory abnormalities that occurred in ≥ 1% of patients treated with durvalumab in the urothelial carcinoma cohort of Study 1108. - The safety of durvalumab in patients with Stage III NSCLC who completed concurrent platinum-based chemoradiotherapy within 42 days prior to initiation of study drug was evaluated in the PACIFIC study, a multicenter, randomized, double-blind, placebo-controlled study. A total of 475 patients received durvalumab 10 mg/kg intravenously every 2 weeks. The study excluded patients who had disease progression following chemoradiation, with active or prior autoimmune disease within 2 years of initiation of the study or with medical conditions that required systemic immunosuppression. - The study population characteristics were: median age of 64 years (range: 23 to 90), 45% age 65 years or older, 70% male, 69% White, 27% Asian, 75% former smoker, 16% current smoker, and 51% had WHO performance status of 1. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy. The median duration of exposure to durvalumab was 10 months (range: 0.2 to 12.6). - Durvalumab was discontinued due to adverse reactions in 15% of patients. The most common adverse reactions leading to durvalumab discontinuation were pneumonitis or radiation pneumonitis in 6% of patients. Serious adverse reactions occurred in 29% of patients receiving durvalumab. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonitis or radiation pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation pneumonitis and fatal pneumonia occurred in < 2% of patients and were similar across arms. The most common adverse reactions (occurring in ≥ 20% of patients) were cough, fatigue, pneumonitis or radiation pneumonitis, upper respiratory tract infections, dyspnea and rash. - Table 4 summarizes the adverse reactions that occurred in at least 10% of patients treated with durvalumab. - Other adverse reactions occurring in less than 10% of patients treated with durvalumab were dysphonia, dysuria, night sweats, peripheral edema, and increased susceptibility to infections. - Table 5 summarizes the laboratory abnormalities that occurred in at least 20% of patients treated with durvalumab. - As with all therapeutic proteins, there is a potential for immunogenicity. 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 the incidence of antibodies to durvalumab to the incidence of antibodies to other products may be misleading. - Due to the limitations in assay performance, the incidence of antibody development in patients receiving durvalumab may be underestimated. Of 1570 patients who were treated with durvalumab 10 mg/kg every 2 weeks and evaluable for the presence of anti-drug antibodies (ADAs), 45 (2.9%) patients tested positive for treatment-emergent ADAs. The development of treatment-emergent ADA against durvalumab appears to have no clinically relevant effect on its pharmacokinetic profile. There are insufficient numbers of patients with ADA to determine whether ADA alters the safety or efficacy of durvalumab. ## Postmarketing Experience There is limited information regarding Durvalumab Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Durvalumab Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Based on its mechanism of action and data from animal studies, durvalumab can cause fetal harm when administered to a pregnant woman. There are no data on the use of durvalumab in pregnant women. - In animal reproduction studies, administration of durvalumab to pregnant cynomolgus monkeys from the confirmation of pregnancy through delivery resulted in an increase in premature delivery, fetal loss and premature neonatal death. Human immunoglobulin G1 (IgG1) is known to cross the placental barrier; therefore, durvalumab has the potential to be transmitted from the mother to the developing fetus. Apprise pregnant women of the potential risk to a fetus. - 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. - As reported in the literature, the PD-1/PD-L1 pathway plays a central role in preserving pregnancy by maintaining maternal immune tolerance to the fetus. In mouse allogeneic pregnancy models, disruption of PD-L1 signaling was shown to result in an increase in fetal loss. The effects of durvalumab on prenatal and postnatal development were evaluated in reproduction studies in cynomolgus monkeys. Durvalumab was administered from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth) and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab. Based on its mechanism of action, fetal exposure to durvalumab may increase the risk of developing immune-mediated disorders or altering the normal immune response and immune-mediated disorders have been reported in PD-1 knockout mice. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Durvalumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Durvalumab during labor and delivery. ### Nursing Mothers - There is no information regarding the presence of durvalumab in human milk, the effects on the breastfed infant, or the effects on milk production. Human IgG1 is excreted in human milk. Durvalumab was present in the milk of lactating cynomolgus monkeys and was associated with premature neonatal death. - Because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with durvalumab and for at least 3 months after the last dose. - In lactating cynomolgus monkeys, durvalumab was present in breast milk at about 0.15% of maternal serum concentrations after administration of durvalumab from the confirmation of pregnancy through delivery at exposure levels approximately 6 to 20 times higher than those observed at the recommended clinical dose of 10 mg/kg (based on AUC). Administration of durvalumab resulted in premature neonatal death. ### Pediatric Use - The safety and effectiveness of durvalumab have not been established in pediatric patients. ### Geriatic Use - Of the 182 patients treated with durvalumab in patients with urothelial carcinoma, 112 patients were 65 years or older and 34 patients were 75 years or older. The overall response rate in patients 65 years or older was 15% (17/112) and was 12% (4/34) in patients 75 years or older. Grade 3 or 4 adverse reactions occurred in 38% (42/112) of patients 65 years or older and 35% (12/34) of patients 75 years or older. - Of the 476 patients treated with durvalumab in the PACIFIC study, 45% were 65 years or older, while 7.6% were 75 years or older. No overall differences in safety or effectiveness were observed between patients 65 years or older and younger patients. The PACIFIC study did not include sufficient numbers of patients aged 75 years and over to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Durvalumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Durvalumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Durvalumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Durvalumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males Females - Based on its mechanism of action and data from animal studies, durvalumab can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with durvalumab and for at least 3 months following the last dose of durvaluab. ### Immunocompromised Patients There is no FDA guidance one the use of Durvalumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Visually inspect drug product for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the vial if the solution is cloudy, discolored, or visible particles are observed. - Do not shake the vial. - Withdraw the required volume from the vial(s) of durvalumab and transfer into an intravenous bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Mix diluted solution by gentle inversion. Do not shake the solution. The final concentration of the diluted solution should be between 1 mg/mL and 15 mg/mL. - Discard partially used or empty vials of durvalumab. - Durvalumab does not contain a preservative. - Administer infusion solution immediately once prepared. If infusion solution is not administered immediately and needs to be stored, the total time from vial puncture to the start of the administration should not exceed: - 24 hours in a refrigerator at 2°C to 8°C (36°F to 46°F) - 4 hours at room temperature up to 25°C (77°F) - Do not freeze. - Do not shake. - Administer infusion solution intravenously over 60 minutes through an intravenous line containing a sterile, low-protein binding 0.2 or 0.22 micron in-line filter. - Do not co-administer other drugs through the same infusion line. ### Monitoring - Tumor response indicates efficacy - Chemistry: During and after therapy - Liver function: During each treatment cycle - Thyroid function: Prior to initiation and periodically throughout treatment - Blood glucose: During treatment - Renal function: Prior to and during each treatment cycle - Signs or symptoms of endocrinopathies - Signs or symptoms of adrenal insufficiency - Signs or symptoms of diabetes - Signs or symptoms of hypophysitis or hypopituitarism - Signs or symptoms of immune thrombotic thrombocytopenia - Signs and symptoms of infusion-related reactions - Signs and symptoms of diarrhea or colitis - Signs and symptoms of hepatitis: During and after therapy - Signs and symptoms of infection - Signs and symptoms of pneumonitis - Signs and symptoms of rash # IV Compatibility There is limited information regarding the compatibility of Durvalumab and IV administrations. # Overdosage - There is no information on overdose with durvalumab. # Pharmacology ## Mechanism of Action - Expression of programmed cell death ligand-1 (PD-L1) can be induced by inflammatory signals (e.g., IFN-gamma) and can be expressed on both tumor cells and tumor-associated immune cells in the tumor microenvironment. PD-L1 blocks T-cell function and activation through interaction with PD-1 and CD80 (B7.1). By binding to its receptors, PD-L1 reduces cytotoxic T-cell activity, proliferation, and cytokine production. - Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cell-mediated cytotoxicity (ADCC). - PD-L1 blockade with durvalumab led to increased T-cell activation in vitro and decreased tumor size in co-engrafted human tumor and immune cell xenograft mouse models. ## Structure There is limited information regarding Durvalumab Structure in the drug label. ## Pharmacodynamics - The exposure-response relationships of efficacy and safety are unknown. - Durvalumab is unlikely to prolong the QT/QTc interval. ## Pharmacokinetics - The pharmacokinetics of durvalumab was studied in 1902 patients with doses ranging from 0.1 mg/kg (0.01 times the approved recommended dosage) to 20 mg/kg (2 times the approved recommended dosage) administered once every two, three or four weeks. - PK exposure increased more than dose-proportionally at doses < 3 mg/kg (0.3 times the approved recommended dosage) and dose proportionally at doses ≥ to 3 mg/kg every 2 weeks. Steady state was achieved at approximately 16 weeks. - The geometric mean (% coefficient of variation [CV%]) steady state volume of distribution was 5.6 (18%) L. - Durvalumab clearance decreases over time, with a mean maximal reduction (CV%) from baseline values of approximately 23% (57%) resulting in a geometric mean (CV%) steady state clearance (CLss) of 8.2 mL/h (39%) at day 365; the decrease in CLss is not considered clinically relevant. The geometric mean (CV%) terminal half-life, based on baseline CL was approximately 18 (24%) days. - Age (19–96 years), body weight (34-149 kg), sex, albumin levels, lactate dehydrogenase (LDH) levels, creatinine levels, soluble PD-L1, tumor type, race, mild renal impairment (creatinine clearance (CLcr) 60 to 89 mL/min), moderate renal impairment (CLcr 30 to 59 mL/min), mild hepatic impairment (bilirubin ≤ ULN and AST > ULN or bilirubin > 1 to 1.5x ULN and any AST), or ECOG/WHO performance status had no clinically significant effect on the pharmacokinetics of durvalumab. - The effect of severe renal impairment (CLcr 15 to 29 mL/min) or moderate hepatic impairment (bilirubin > 1.5 to 3x ULN and any AST) or severe hepatic impairment (bilirubin > 3x ULN and any AST) on the pharmacokinetics of durvalumab is unknown. ## Nonclinical Toxicology - The carcinogenic and genotoxic potential of durvalumab have not been evaluated. - Animal fertility studies have not been conducted with durvalumab. In repeat-dose toxicology studies with durvalumab in sexually mature cynomolgus monkeys of up to 3 months duration, there were no notable effects on the male and female reproductive organs. - In animal models, inhibition of PD-L1/PD-1 signaling increased the severity of some infections and enhanced inflammatory responses. M. tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival compared with wild-type controls, which correlated with increased bacterial proliferation and inflammatory responses in these animals. PD-L1 and PD-1 knockout mice have also shown decreased survival following infection with lymphocytic choriomeningitis virus. # Clinical Studies - The efficacy of durvalumab was evaluated in the urothelial carcinoma cohort of Study 1108 (NCT01693562), a multicenter, multi-cohort, open-label clinical trial. In Study 1108, 182 patients with locally advanced or metastatic urothelial carcinoma were enrolled. Patients had progressed while on or after a platinum-based therapy, including those who progressed within 12 months of receiving therapy in a neo-adjuvant or adjuvant setting. These patients had initiated durvalumab at least 13 weeks prior to the data cut-off date. The trial excluded patients with a history of immunodeficiency; medical conditions that required systemic immunosuppression (not to exceed 10 mg per day of prednisone or equivalent); history of severe autoimmune disease; untreated CNS metastases; HIV; active tuberculosis, or hepatitis B or C infection. All patients received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or disease progression. Tumor assessments were performed at Weeks 6, 12 and 16, then every 8 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were confirmed Overall Response Rate (ORR) according to RECIST v1.1 as assessed by Blinded Independent Central Review (BICR), and duration of response (DoR). - The median age was 67 years (range: 34 to 88), 72% were male, 64% were White. Sixty-six percent (66%) of patients had visceral metastasis (bone, liver, or lung), including 34% with liver metastasis. Lymph node only metastasis were present in 13% of patients. Sixty-six percent (66%) of patients had ECOG score of 1 and 41% of patients had a baseline creatinine clearance < 60 mL/min. The Bellmunt risk score (which includes ECOG score, baseline hemoglobin, and liver metastases) was 0 in 23%, 1 in 38%, 2 in 29%, and 3 in 9% of patients. Twenty percent (20%) of patients had disease progression following platinum-containing neoadjuvant or adjuvant chemotherapy as their only prior line of therapy. Seventy percent (70%) of patients received prior cisplatin, 30% prior carboplatin and 35% received ≥ 2 prior lines of systemic therapy. - Tumor specimens were evaluated prospectively for PD-L1 expression on tumor cells (TC) and immune cells (IC) at a central laboratory using the VENTANA PD-L1 (SP263) Assay. Of the 182 patients, 52% were classified as PD-L1 high (if ICs involve > 1% of the tumor area, TC ≥ 25% or IC ≥ 25%; if ICs involve ≤ 1% of the tumor area, TC ≥ 25% or IC = 100%), 40% as PD-L1 low/negative (did not meet criterion for PD-L1 high), and samples for 8% were not evaluable. - Table 6 summarizes the results in the urothelial carcinoma cohort of Study 1108. The median follow-up time was 5.6 months. In 37 patients who had received only neoadjuvant or adjuvant therapy prior to study entry, 24% responded. - Among the total 31 responding patients, 45% had ongoing responses of 6 months or longer and 16% had ongoing responses of 12 months or longer. - The efficacy of durvalumab was evaluated in the PACIFIC study (NCT02125461), a multicenter, randomized, double-blind, placebo-controlled study in patients with unresectable Stage III NSCLC who completed at least 2 cycles of concurrent platinum-based chemotherapy and definitive radiation within 42 days prior to initiation of the study drug and had a WHO performance status of 0 or 1. The study excluded patients who had progressed following concurrent chemoradiation, patients with active or prior documented autoimmune disease within 2 years of initiation of the study or patients with medical conditions that required systemic immunosuppression. Randomization was stratified by sex, age (< 65 years vs. ≥ 65 years) and smoking history (smoker vs. non-smoker). Patients were randomized 2:1 to receive durvalumab 10 mg/kg or placebo intravenously every 2 weeks for up to 12 months or until unacceptable toxicity or confirmed RECIST 1.1-defined progression. Assessment of tumor status was performed every 8 weeks. The major efficacy outcome measures were progression-free survival (PFS) as assessed by a BICR RECIST 1.1 and overall survival (OS). Additional efficacy outcome measures included ORR assessed by BICR. - A total of 713 patients were randomized: 476 patients to the durvalumab arm and 237 to the placebo arm. The study population characteristics were: median age of 64 years (range: 23 to 90); 70% male; 69% White and 27% Asian; 16% current smokers, 75% former smokers and 9% never smokers; 51% WHO performance status of 1; 53% with Stage IIIA and 45% were Stage IIIB; 46% with squamous and 54% with non-squamous histology. All patients received definitive radiotherapy as per protocol, of which 92% received a total radiation dose of 54 Gy to 66 Gy; 99% of patients received concomitant platinum-based chemotherapy (55% cisplatin-based, 42% carboplatin-based chemotherapy and 2% switched between cisplatin and carboplatin). - The pre-specified interim PFS analysis based on 371 events (81% of total planned events) demonstrated a statistically significant improvement in PFS in patients randomized to durvalumab compared to placebo. Results are presented in Table 7 and Figure 1. OS data were not mature at the time of the interim PFS analysis. # How Supplied - IMFINZI (durvalumab) Injection is a clear to opalescent, colorless to slightly yellow solution supplied in a carton containing one single-dose vial either as: - 500 mg/10 mL (NDC 0310-4611-50) - 120 mg/2.4 mL (NDC 0310-4500-12) ## Storage - Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. - Do not freeze. Do not shake. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling. - Inform patients of the risk of immune-mediated adverse reactions that may require corticosteroid treatment and interruption or discontinuation of durvalumab, including: - Pneumonitis: Advise patients to contact their healthcare provider immediately for any new or worsening cough, chest pain, or shortness of breath. - Hepatitis: Advise patients to contact their healthcare provider immediately for jaundice, severe nausea or vomiting, pain on the right side of abdomen, lethargy, or easy bruising or bleeding. - Colitis: Advise patients to contact their healthcare provider immediately for diarrhea, blood or mucus in stools, or severe abdominal pain. - Endocrinopathies: Advise patients to contact their healthcare provider immediately for signs or symptoms of hypothyroidism, hyperthyroidism, adrenal insufficiency, type 1 diabetes mellitus, or hypophysitis. - Nephritis: Advise patients to contact their healthcare provider immediately for signs or symptoms of nephritis. - Dermatological Reactions: Advise patients to contact their healthcare provider immediately signs or symptoms of severe dermatological reactions. - Other Immune-Mediated Adverse Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of aseptic meningitis, thrombocytopenic purpura, myocarditis, hemolytic anemia, myositis, uveitis and keratitis. - Infection: Advise patients to contact their healthcare provider immediately for infection. - Infusion-Related Reactions: Advise patients to contact their healthcare provider immediately for signs or symptoms of infusion-related reactions. - Embryo-Fetal Toxicity: Advise females of reproductive potential that durvalumab can cause harm to a fetus and to inform their healthcare provider of a known or suspected pregnancy. - Advise females of reproductive potential to use effective contraception during treatment and for at least 3 months after the last dose of durvalumab. - Lactation: Advise female patients not to breastfeed while taking durvalumab and for at least 3 months after the last dose. # Precautions with Alcohol Alcohol-Durvalumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Imfinzi # Look-Alike Drug Names There is limited information regarding Durvalumab Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Durvalumab
138dcad49cee712ab8a555b9b36f3a519f94f715	wikidoc	Nefazodone	Nefazodone # 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 Nefazodone is a 5-HT2 Antagonists that is FDA approved for the {{{indicationType}}} of major depressive disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cardiovascular: orthostatic hypotension (2.8% to 4), gastrointestinal: constipation (10% to 17% ), nausea (14% to 23% ), xerostomia (25% ), neurologic: asthenia (7% to 13% ), confusion (7% ), dizziness (11% to 22% ), headache (26% to 52% ), lightheadedness (10% ), somnolence (16% to 32% ),ophthalmic: blurred vision (3% to 9% ). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Major depressive disorder ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Nefazodone in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Nefazodone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information about FDA-labeled indications and dosage information of Nefazodone in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Nefazodone in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Nefazodone in pediatric patients. # Contraindications - Coadministration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine with nefazodone hydrochloride is contraindicated (see Warnings and Precautions). - Nefazodone hydrochloride tablets are contraindicated in patients who were withdrawn from nefazodone because of evidence of liver injury (see Boxed Warning). Nefazodone hydrochloride tablets are also contraindicated in patients who have demonstrated hypersensitivity to nefazodone hydrochloride, its inactive ingredients, or other phenylpiperazine antidepressants. - The coadministration of triazolam and nefazodone causes a significant increase in the plasma level of triazolam (see Warnings and Precautions), and a 75% reduction in the initial triazolam dosage is recommended if the two drugs are to be given together. Because not all commercially available dosage forms of triazolam permit a sufficient dosage reduction, the coadministration of triazolam and nefazodone should be avoided for most patients, including the elderly. # Warnings ### Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for nefazodone hydrochloride tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. ### Screening Patients for Bipolar Disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that nefazodone hydrochloride tablets is not approved for use in treating bipolar depression. ### Hepatotoxicity (See Boxed Warning.) - Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone. - The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years of nefazodone treatment. This represents a rate of about 3 to 4 times the estimated background rate of liver failure. This rate is an underestimate because of under reporting, and the true risk could be considerably greater than this. A large cohort study of antidepressant users found no cases of liver failure leading to death or transplant among nefazodone users in about 30,000 patient-years of exposure. The spontaneous report data and the cohort study results provide estimates of the upper and lower limits of the risk of liver failure in nefazodone-treated patients, but are not capable of providing a precise risk estimate. - The time to liver injury for the reported liver failure cases resulting in death or transplant generally ranged from 2 weeks to 6 months on nefazodone therapy. Although some reports described dark urine and nonspecific prodromal symptoms (e.g., anorexia, malaise, and gastrointestinal symptoms), other reports did not describe the onset of clear prodromal symptoms prior to the onset of jaundice. - The physician may consider the value of liver function testing. Periodic serum transaminase testing has not been proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. - Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment. - Nefazodone should be discontinued if clinical signs or symptoms suggest liver failure (see Precautions: Information for Patients). Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels ≥ 3 times the upper limit of Normal, while on nefazodone should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if nefazodone is reintroduced. Accordingly, such patients should not be considered for re-treatment. # Adverse Reactions ## Clinical Trials Experience - Associated With Discontinuation of Treatment - Approximately 16% of the 3496 patients who received nefazodone in worldwide premarketing clinical trials discontinued treatment due to an adverse experience. The more common (≥ 1%) events in clinical trials associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for nefazodone compared to placebo) included: nausea (3.5%), dizziness (1.9%), insomnia (1.5%), asthenia (1.3%), and agitation (1.2%). ### Incidence in Controlled Trials - Commonly Observed Adverse Events in Controlled Clinical Trials - The most commonly observed adverse events associated with the use of nefazodone (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., significantly higher incidence for nefazodone compared to placebo, p ≤ 0.05), derived from the table below, were: somnolence, dry mouth, nausea, dizziness, constipation, asthenia, lightheadedness, blurred vision, confusion, and abnormal vision. - Adverse Events Occurring at an Incidence of 1% or More Among Nefazodone-Treated Patients - The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among nefazodone-treated patients who participated in short-term (6 to 8 week) placebo-controlled trials in which patients were dosed with nefazodone to ranges of 300 to 600 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using standard Costart-based Dictionary terminology. - The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. - Events reported by at least 1% of patients treated with nefazodone and more frequent than the placebo group are included; incidence is rounded to the nearest 1% (< 1% indicates an incidence less than 0.5%). Events for which the nefazodone incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, accidental injury, chest pain, neck pain, palpitation, migraine, sweating, flatulence, vomiting, anorexia, tooth disorder, weight gain, edema, myalgia, cramp, agitation, anxiety, depression, hypesthesia, CNS stimulation, dysphoria, emotional lability, sinusitis, rhinitis, dysmenorrhea, dysuria. - Vasodilatation – flushing, feeling warm. - Abnormal vision – scotoma, visual trails.# Incidence adjusted for gender. - Dose Dependency of Adverse Events - The table that follows enumerates adverse events that were more frequent in the nefazodone dose range of 300 to 600 mg/day than in the nefazodone dose range of up to 300 mg/day. This table shows only those adverse events for which there was a statistically significant difference (p ≤ 0.05) in incidence between the nefazodone dose ranges as well as a difference between the high dose range and placebo. - Visual Disturbances - In controlled clinical trials, blurred vision occurred in 9% of nefazodone-treated patients compared to 3% of placebo-treated patients. In these same trials abnormal vision, including scotomata and visual trails, occurred in 7% of nefazodone-treated patients compared to 1% of placebo-treated (see Treatment-Emergent Adverse Experience table, above). Dose-dependency was observed for these events in these trials, with none of the scotomata and visual trails at doses below 300 mg/day. However, scotomata and visual trails observed at doses below 300 mg/day have been reported in postmarketing experience with nefazodone (see Precautions, Information for Patients). - Vital Sign Changes - (See Precautions, Postural Hypotension.) - Weight Changes - In a pooled analysis of placebo-controlled premarketing studies, there were no differences between nefazodone and placebo groups in the proportions of patients meeting criteria for potentially important increases or decreases in body weight (a change of ≥ 7%). - Laboratory Changes - Of the serum chemistry, serum hematology, and urinalysis parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistical trend between nefazodone and placebo for hematocrit, i.e., 2.8% of nefazodone patients met criteria for a potentially important decrease in hematocrit (≤ 37% male or ≤ 32% female) compared to 1.5% of placebo patients (0.05 < p ≤ 0.10). Decreases in hematocrit, presumably dilutional, have been reported with many other drugs that block alpha1-adrenergic receptors. There was no apparent clinical significance of the observed changes in the few patients meeting these criteria. - ECG Changes - Of the ECG parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistically significant difference between nefazodone and placebo for sinus bradycardia, i.e., 1.5% of nefazodone patients met criteria for a potentially important decrease in heart rate (≤ 50 bpm and a decrease of ≥ 15 bpm) compared to 0.4% of placebo patients (p < 0.05). There was no obvious clinical significance of the observed changes in the few patients meeting these criteria. - Other Events Observed During the Premarketing Evaluation of Nefazodone - During its premarketing assessment, multiple doses of nefazodone were administered to 3496 patients in clinical studies, including more than 250 patients treated for at least one year. The conditions and duration of exposure to nefazodone varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. - In the tabulations that follow, reported adverse events were classified using standard Costart-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 3496 patients exposed to multiple doses of nefazodone who experienced an event of the type cited on at least one occasion while receiving nefazodone. All reported events are included except those already listed in the Treatment-Emergent Adverse Experience Incidence table, those events listed in other safety-related sections of this insert, those adverse experiences subsumed under Costart terms that are either overly general or excessively specific so as to be uninformative, those events for which a drug cause was very remote, and those events which were not serious and occurred in fewer than two patients. - It is important to emphasize that, although the events reported occurred during treatment with nefazodone, they were not necessarily caused by it. - Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. - Body as a whole – Infrequent: allergic reaction, malaise, photosensitivity reaction, face edema, hangover effect, abdomen enlarged, hernia, pelvic pain, and halitosis. Rare: cellulitis. - Cardiovascular system – Infrequent: tachycardia, hypertension, syncope, ventricular extrasystoles, and angina pectoris. Rare: AV block, congestive heart failure, hemorrhage, pallor, and varicose vein. - Dermatological system – Infrequent: dry skin, acne, alopecia, urticaria, maculopapular rash,vesiculobullous rash, and eczema. - Gastrointestinal system – Frequent: gastroenteritis. Infrequent: eructation, periodontal abscess, abnormal liver function tests, gingivitis, colitis, gastritis, mouth ulceration, stomatitis, esophagitis, peptic ulcer, and rectal hemorrhage. Rare: glossitis, hepatitis, dysphagia, gastrointestinal hemorrhage, oral moniliasis, and ulcerative colitis. - Hemic and lymphatic system – Infrequent: ecchymosis, anemia, leukopenia, and lymphadenopathy . - Metabolic and nutritional system – Infrequent: weight loss, gout, dehydration, lactic dehydrogenase increased, SGOT increased, and SGPT increased. Rare: hypercholesteremia and hypoglycemia. - Musculoskeletal system – Infrequent: arthritis, tenosynovitis, muscle stiffness, and bursitis. Rare: tendinous contracture. - Nervous system – Infrequent: vertigo, twitching, depersonalization, hallucinations, suicide attempt, apathy, euphoria, hostility, suicidal thoughts, abnormal gait, thinking abnormal, attention decreased, derealization, neuralgia, paranoid reaction, dysarthria, increased libido, suicide, and myoclonus. Rare: hyperkinesia, increased salivation, cerebrovascular accident, hyperesthesia, hypotonia, ptosis, and neuroleptic malignant syndrome. - Respiratory system – Frequent: dyspnea and bronchitis. Infrequent:asthma, pneumonia, laryngitis, voice alteration, epistaxis, hiccup. Rare: hyperventilation and yawn. - Special senses – Frequent: eye pain. Infrequent: dry eye, ear pain, abnormality of accommodation, diplopia, conjunctivitis, mydriasis, keratoconjunctivitis, hyperacusis, and photophobia. Rare: deafness, glaucoma, night blindness, and taste loss. - Urogenital system – Frequent: impotence. Infrequent: cystitis, urinary urgency, metrorrhagiaa, amenorrheaa, polyuria, vaginal hemorrhagea, breast enlargementa, menorrhagiaa, urinary incontinence, abnormal ejaculationa, hematuria, nocturia, and kidney calculus. Rare: uterine fibroids enlarged, uterine hemorrhagea, anorgasmia, and oliguria. - Adjusted for gender. - Postmarketing experience with nefazodone has shown an adverse experience profile similar to that seen during the premarketing evaluation of nefazodone. Voluntary reports of adverse events temporally associated with nefazodone have been received since market introduction that are not listed above and for which a causal relationship has not been established. These include: - Anaphylactic reactions; angioedema; convulsions (including grand mal seizures); galactorrhea; gynecomastia (male); hyponatremia; liver necrosis and liver failure, in some cases leading to liver transplantation and/or death (see Warnings); priapism (see Precautions); prolactin increased; rhabdomyolysis involving patients receiving the combination of nefazodone and lovastatin or simvastatin (see Precautions); serotonin syndrome; and Stevens-Johnson syndrome; and thrombocytopenia. ## Postmarketing Experience - Postmarketing experience with nefazodone has shown an adverse experience profile similar to that seen during the premarketing evaluation of nefazodone. Voluntary reports of adverse events temporally associated with nefazodone have been received since market introduction that are not listed above and for which a causal relationship has not been established. These include: Anaphylactic reactions; angioedema; convulsions (including grand mal seizures); galactorrhea; gynecomastia (male); hyponatremia; liver necrosis and liver failure, in some cases leading to liver transplantation and/or death (see Warnings); priapism (see Precautions); prolactin increased; rhabdomyolysis involving patients receiving the combination of nefazodone and lovastatin or simvastatin (see Precautions); serotonin syndrome; and Stevens-Johnson syndrome; and thrombocytopenia. # Drug Interactions - Drugs Highly Bound to Plasma Protein - Because nefazodone is highly bound to plasma protein (see Clinical Pharmacology, Pharmacokinetics), administration of nefazodone to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of nefazodone by other highly bound drugs. - Warfarin – There were no effects on the prothrombin or bleeding times or upon the pharmacokinetics of R-warfarin when nefazodone (200 mg BID) was administered for 1 week to subjects who had been pretreated for 2 weeks with warfarin. Although the coadministration of nefazodone did decrease the subjects’ exposure to S-warfarin by 12%, the lack of effects on the prothrombin and bleeding times indicates this modest change is not clinically significant. Although these results suggest no adjustments in warfarin dosage are required when nefazodone is administered to patients stabilized on warfarin, such patients should be monitored as required by standard medical practices. - CNS-Active Drugs - Monoamine Oxidase Inhibitors – See Warnings - Haloperidol – When a single oral 5 mg dose of haloperidol was coadministered with nefazodone (200 mg BID) at steady state, haloperidol apparent clearance decreased by 35% with no significant increase in peak haloperidol plasma concentrations or time of peak. This change is of unknown clinical significance. Pharmacodynamic effects of haloperidol were generally not altered significantly. There were no changes in the pharmacokinetic parameters for nefazodone. Dosage adjustment of haloperidol may be necessary when coadministered with nefazodone. - Lorazepam – When lorazepam (2 mg BID) and nefazodone (200 mg BID) were coadministered to steady state, there was no change in any pharmacokinetic parameter for either drug compared to each drug administered alone. Therefore, dosage adjustment is not necessary for either drug when coadministered. - Triazolam/Alprazolam – See Contrandications and Warnings. - Alcohol – Although nefazodone did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of nefazodone and alcohol in depressed patients is not advised. - Buspirone – In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg BID) with nefazodone (250 mg BID) resulted in marked increases in plasma buspirone concentrations (increases up to 20 fold in Cmax and up to 50 fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-pyrimidinylpiperazine. With 5 mg BID doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (17%) and mCPP (9%). Subjects receiving nefazodone 250 mg BID and buspirone 5 mg BID experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg QD) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. - Pimozide – See Contraindications, Warnings, and Precautions, Pharmacokinetics of Nefazodone in ‘Poor Metabolizers’ and Potential Interaction With Drugs That Inhibit and/or Are Metabolized by Cytochrome P450 Isozymes. - Fluoxetine – When fluoxetine (20 mg QD) and nefazodone (200 mg BID) were administered at steady state there were no changes in the pharmacokinetic parameters for fluoxetine or its metabolite, norfluoxetine. Similarly, there were no changes in the pharmacokinetic parameters of nefazodone or HO-NEF; however, the mean AUC levels of the nefazodone metabolites mCPP and triazole-dione increased by 3 to 6 fold and 1.3 fold, respectively. When a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient adverse events such as headache, lightheadedness, nausea, or paresthesia, possibly due to the elevated mCPP levels. Patients who are switched from fluoxetine to nefazodone without an adequate washout period may experience similar transient adverse events. The possibility of this happening can be minimized by allowing a washout period before initiating nefazodone therapy and by reducing the initial dose of nefazodone. Because of the long half-life of fluoxetine and its metabolites, this washout period may range from one to several weeks depending on the dose of fluoxetine and other individual patient variables. - Phenytoin – Pretreatment for 7 days with 200 mg BID of nefazodone had no effect on the pharmacokinetics of a single 300 mg oral dose of phenytoin. However, due to the nonlinear pharmacokinetics ofphenytoin, the failure to observe a significant effect on the single-dose pharmacokinetics of phenytoin does not preclude the possibility of a clinically significant interaction with nefazodone when phenytoin is dosed chronically. However, no change in the initial dosage of phenytoin is considered necessary and any subsequent adjustment of phenytoin dosage should be guided by usual clinical practices. - Desipramine – When nefazodone (150 mg BID) and desipramine (75 mg QD) were administered together there were no changes in the pharmacokinetics of desipramine or its metabolite, 2-hydroxy desipramine. There were also no changes in the pharmacokinetics of nefazodone or its triazole-dione metabolite, but the AUC and Cmax of mCPP increased by 44% and 48%, respectively, while the AUC of HO-NEF decreased by 19%. No changes in doses of either nefazodone or desipramine are necessary when the two drugs are given concomitantly. Subsequent dose adjustments should be made on the basis of clinical response. - Lithium – In 13 healthy subjects the coadministration of nefazodone (200 mg BID) with lithium (500 mg BID) for 5 days (steady-state conditions) was found to be well tolerated. When the two drugs were coadministered, there were no changes in the steady-state pharmacokinetics of either lithium, nefazodone, or its metabolite HO-NEF; however, there were small decreases in the steady-state plasma concentrations of two nefazodone metabolites, mCPP and triazole-dione, which are considered not to be of clinical significance. Therefore, no dosage adjustment of either lithium or nefazodone is required when they are coadministered. - Carbamazepine – The coadministration of nefazodone (200 mg BID) for 5 days to 12 healthy subjects on carbamazepine who had achieved steady state (200 mg BID) was found to be well tolerated. Steady-state conditions for carbamazepine, nefazodone, and several of their metabolites were achieved by day 5 of coadministration. With coadministration of the two drugs there were significant increases in the steady-state Cmax and AUC of carbamazepine (23% and 23%, respectively), while the steady-state Cmax and the AUC of the carbamazepine metabolite, 10,11 epoxycarbamazepine, decreased by 21% and 20%, respectively. The coadministration of the two drugs significantly reduced the steady-state Cmax and AUC of nefazodone by 86% and 93%, respectively. Similar reductions in the Cmax and AUC of HO-NEF were also observed (85% and 94%), while the reductions in Cmax and AUC of mCPP and triazole-dione were more modest (13% and 44% for the former and 28% and 57% for the latter). Due to the potential for coadministration of carbamazepine to result in insufficient plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant effect for nefazodone, it is recommended that nefazodone not be used in combination with carbamazepine (see Contraindications And Warnings). - General Anesthetics – Little is known about the potential for interaction between nefazodone and general anesthetics; therefore, prior to elective surgery, nefazodone hydrochloride should be discontinued for as long as clinically feasible. - Other CNS-Active Drugs – The use of nefazodone in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised if concomitant administration of nefazodone and such drugs is required. - Cimetidine - When nefazodone (200 mg BID) and cimetidine (300 mg QID) were coadministered for one week, no change in the steady-state pharmacokinetics of either nefazodone or cimetidine was observed compared to each dosed alone. Therefore, dosage adjustment is not necessary for either drug when coadministered. - Theophylline - When nefazodone (200 mg BID) was given to patients being treated with theophylline (600 to 1200 mg/day) for chronic obstructive pulmonary disease, there was no change in the steady-state pharmacokinetics of either nefazodone or theophylline. FEV1 measurements taken when theophylline and nefazodone were coadministered did not differ from baseline dosage (i.e., when theophylline was administered alone). Therefore, dosage adjustment is not necessary for either drug when coadministered. - Cardiovascular-Active Drugs - Digoxin – When nefazodone (200 mg BID) and digoxin (0.2 mg QD) were coadministered for 9 days to healthy male volunteers (n = 18) who were phenotyped as CYP2D6 extensive metabolizers, Cmax, Cmin, and AUC of digoxin were increased by 29%, 27%, and 15%, respectively. Digoxin had no effects on the pharmacokinetics of nefazodone and its active metabolites. Because of the narrow therapeutic index of digoxin, caution should be exercised when nefazodone and digoxin are coadministered; plasma level monitoring for digoxin is recommended. - Propranolol – The coadministration of nefazodone (200 mg BID) and propranolol (40 mg BID) for 5.5 days to healthy male volunteers (n = 18), including 3 poor and 15 extensive CYP2D6 metabolizers, resulted in 30% and 14% reductions in Cmax and AUC of propranolol, respectively, and a 14% reduction in Cmax for the metabolite, 4-hydroxypropranolol. The kinetics of nefazodone, hydroxynefazodone, and triazole-dione were not affected by coadministration of propranolol. However, Cmax, Cmin, and AUC of m-chlorophenylpiperazine were increased by 23%, 54%, and 28%, respectively. No change in initial dose of either drug is necessary and dose adjustments should be made on the basis of clinical response. - HMG-CoA Reductase Inhibitors – When single 40 mg doses of simvastatin or atorvastatin, both substrates of CYP3A4, were given to healthy adult volunteers who had received nefazodone hydrochloride, 200 mg BID for 6 days, approximately 20 fold increases in plasma concentrations of simvastatin and simvastatin acid and 3 to 4 fold increases in plasma concentrations of atorvastatin and atorvastatin lactone were seen. These effects appear to be due to the inhibition of CYP3A4 by nefazodone because, in the same study, nefazodone had no significant effect on the plasma concentrations of pravastatin, which is not metabolized by CYP3A4 to a clinically significant extent. - There have been rare reports of rhabdomyolysis involving patients receiving the combination of nefazodone and either simvastatin or lovastatin, also a substrate of CYP3A4 (see Adverse Reactions, Postintroduction Clinical Experience). Rhabdomyolysis has been observed in patients receiving HMG-CoA reductase inhibitors administered alone (at recommended dosages) and in particular, for certain drugs in this class, when given in combination with inhibitors of the CYP3A4 isozyme. - Caution should be used if nefazodone is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, such as simvastatin, atorvastatin, and lovastatin, and dosage adjustments of these HMG-CoA reductase inhibitors are recommended. Since metabolic interactions are unlikely between nefazodone and HMG-CoA reductase inhibitors that undergo little or no metabolism by the CYP3A4 isozyme, such as pravastatin or fluvastatin, dosage adjustments should not be necessary. ### Immunosuppressive Agents - There have been reports of increased blood concentrations of cyclosporine and tacrolimus into toxic ranges when patients received these drugs concomitantly with nefazodone. Both cyclosporine and tacrolimus are substrates of CYP3A4, and nefazodone is known to inhibit this enzyme. If either cyclosporine or tacrolimus is administered with nefazodone, blood concentrations of the immunosuppressive agent should be monitored and dosage adjusted accordingly. - Pharmacokinetics of Nefazodone in ‘Poor Metabolizers’ and Potential Interaction With Drugs That Inhibit and/or Are Metabolized by Cytochrome P450 Isozymes - CYP3A4 Isozyme – Nefazodone has been shown in vitro to be an inhibitor of CYP3A4. This is consistent with the interactions observed between nefazodone and triazolam, alprazolam, buspirone, atorvastatin, and simvastatin, drugs metabolized by this isozyme. Consequently, caution is indicated in the combined use of nefazodone with any drugs known to be metabolized by CYP3A4. In particular, the combined use of nefazodone with triazolam should be avoided for most patients, including the elderly. The combined use of nefazodone with terfenadine, astemizole, cisapride, or pimozide is contraindicated (see Contraindications and Warnings). - CYP2D6 Isozyme – A subset (3% to 10%) of the population has reduced activity of the drug-metabolizing enzyme CYP2D6. Such individuals are referred to commonly as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants. The pharmacokinetics of nefazodone and its major metabolites are not altered in these “poor metabolizers.” Plasma concentrations of one minor metabolite (mCPP) are increased in this population; the adjustment of nefazodone dosage is not required when administered to “poor metabolizers.” Nefazodone and its metabolites have been shown in vitro to be extremely weak inhibitors of CYP2D6. Thus, it is not likely that nefazodone will decrease the metabolic clearance of drugs metabolized by this isozyme. - CYP1A2 Isozyme – Nefazodone and its metabolites have been shown in vitro not to inhibit CYP1A2. Thus, metabolic interactions between nefazodone and drugs metabolized by this isozyme are unlikely. - [Electroconvulsive therapy # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Reproduction studies have been performed in pregnant rabbits and rats at daily doses up to 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively, the maximum human daily dose on a mg/m2 basis). No malformations were observed in the offspring as a result of nefazodone treatment. However, increased early pup mortality was seen in rats at a dose approximately five times the maximum human dose, and decreased pup weights were seen at this and lower doses, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. The no-effect dose for rat pup mortality was 1.3 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Nefazodone 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 Nefazodone in women who are pregnant. ### Labor and Delivery The effect of nefazodone on labor and delivery in humans is unknown. ### Nursing Mothers It is not known whether nefazodone or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nefazodone is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in the pediatric population have not been established (see BOXED WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 286 pediatric patients with MDD have been conducted with nefazodone, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of nefazodone hydrochloride tablets in a child or adolescent must balance the potential risks with the clinical need. ### Geriatic Use - Of the approximately 7000 patients in clinical studies who received nefazodone for the treatment of depression, 18% were 65 years and older, while 5% were 75 years and older. Based on monitoring of adverse events, vital signs, electrocardiograms, and results of laboratory tests, no overall differences in safety between elderly and younger patients were observed in clinical studies. Efficacy in the elderly has not been demonstrated in placebo-controlled trials. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Due to the increased systemic exposure to nefazodone seen in single-dose studies in elderly patients (see Clinical Pharmacology, Pharmacokinetics), treatment should be initiated at half the usual dose, but titration upward should take place over the same range as in younger patients (see Dosage and Administration). The usual precautions should be observed in elderly patients who have concomitant medical illnesses or who are receiving concomitant drugs. ### Gender There is no FDA guidance on the use of Nefazodone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nefazodone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nefazodone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nefazodone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nefazodone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nefazodone in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Nefazodone Administration in the drug label. ### Monitoring There is limited information regarding Nefazodone Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Nefazodone and IV administrations. # Overdosage Human Experience - In premarketing clinical studies, there were seven reports of nefazodone overdose alone or in combination with other pharmacological agents. The amount of nefazodone ingested ranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose of nefazodone included nausea, vomiting, and somnolence. One nonstudy participant took 2000 to 3000 mg of nefazodone with methocarbamol and alcohol; this person reportedly experienced a convulsion (type not documented). None of these patients died. - In postmarketing experience, overdose with nefazodone alone and in combination with alcohol and/or other substances has been reported. Commonly reported symptoms were similar to those reported from overdose in premarketing experience. While there have been rare reports of fatalities in patients taking overdoses of nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to nefazodone has been established. ## Overdosage Management= - Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. - Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. - Activated charcoal should be administered. Due to the wide distribution of nefazodone in body tissues, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for nefazodone are known. - In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). # Pharmacology ## Mechanism of Action The mechanism of action of nefazodone, as with other antidepressants, is unknown. ## Structure Nefazodone hydrochloride tablets USP are an antidepressant for oral administration with a chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclics, tetracyclics, or monoamine oxidase inhibitors (MAOI). Nefazodone hydrochloride is a synthetically derived phenylpiperazine antidepressant. The chemical name for nefazodone hydrochloride is 2-propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one monohydrochloride. The structural formula is: C25H32CIN5O2HCl M.W. 506.5 Nefazodone hydrochloride is a nonhygroscopic, white crystalline solid. It is freely soluble in chloroform, soluble in propylene glycol, and slightly soluble in polyethylene glycol and water. Nefazodone hydrochloride tablets USP are supplied as capsule-shaped tablets containing 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg of nefazodone hydrochloride and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and povidone. Additionally, the 50 mg tablets include ferric oxide red as a colorant, the 150 mg tablets include ferric oxide red and yellow as colorants, and the 200 mg tablets include ferric oxide yellow as a colorant. ## Pharmacodynamics - Preclinical studies have shown that nefazodone inhibits neuronal uptake of serotonin and norepinephrine. - Nefazodone occupies central 5-HT2 receptors at nanomolar concentrations, and acts as an antagonist at this receptor. Nefazodone was shown to antagonize alpha1-adrenergic receptors, a property which may be associated with postural hypotension. In vitro binding studies showed that nefazodone had no significant affinity for the following receptors: alpha2 and beta adrenergic, 5-HT1A, cholinergic, dopaminergic, or benzodiazepine. ## Pharmacokinetics Nefazodone is rapidly and completely absorbed but is subject to extensive metabolism, so that its absolute bioavailability is low, about 20%, and variable. Peak plasma concentrations occur at about one hour and the half-life of nefazodone is 2 to 4 hours. - Both nefazodone and its pharmacologically similar metabolite, hydroxynefazodone, exhibit nonlinear kinetics for both dose and time, with AUC and Cmax increasing more than proportionally with dose increases and more than expected upon multiple dosing over time, compared to single dosing. For example, in a multiple-dose study involving BID dosing with 50, 100, and 200 mg, the AUC for nefazodone and hydroxynefazodone increased by about 4 fold with an increase in dose from 200 to 400 mg per day; Cmax increased by about 3 fold with the same dose increase. In a multiple-dose study involving BID dosing with 25, 50, 100, and 150 mg, the accumulation ratios for nefazodone and hydroxynefazodone AUC, after 5 days of BID dosing relative to the first dose, ranged from approximately 3 to 4 at the lower doses (50 to 100 mg/day) and from 5 to 7 at the higher doses (200 to 300 mg/day); there were also approximately 2 to 4 fold increases in Cmax after 5 days of BID dosing relative to the first dose, suggesting extensive and greater than predicted accumulation of nefazodone and its hydroxy metabolite with multiple dosing. Steady-state plasma nefazodone and metabolite concentrations are attained within 4 to 5 days of initiation of BID dosing or upon dose increase or decrease. - Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine. Attempts to characterize three metabolites identified in plasma, hydroxynefazodone (HO-NEF), meta-chlorophenylpiperazine (mCPP), and a triazole-dione metabolite, have been carried out. The AUC (expressed as a multiple of the AUC for nefazodone dosed at 100 mg BID) and elimination half-lives for these three metabolites were as follows: - HO-NEF possesses a pharmacological profile qualitatively and quantitatively similar to that of nefazodone. mCPP has some similarities to nefazodone, but also has agonist activity at some serotonergic receptor subtypes. The pharmacological profile of the triazole-dione metabolite has not yet been well characterized. In addition to the above compounds, several other metabolites were present in plasma but have not been tested for pharmacological activity. - After oral administration of radiolabeled nefazodone, the mean half-life of total label ranged between 11 and 24 hours. Approximately 55% of the administered radioactivity was detected in urine and about 20 to 30% in feces. ### Distribution - Nefazodone is widely distributed in body tissues, including the central nervous system (CNS). In humans the volume of distribution of nefazodone ranges from 0.22 to 0.87 L/kg. - Protein Binding - At concentrations of 25 to 2500 ng/mL nefazodone is extensively (> 99%) bound to human plasma proteins in vitro. The administration of 200 mg BID of nefazodone for 1 week did not increase the fraction of unbound warfarin in subjects whose prothrombin times had been prolonged by warfarin therapy to 120 to 150% of the laboratory control (see Precautions, Drug Interactions). While nefazodone did not alter the in vitro protein binding of chlorpromazine, desipramine, diazepam, diphenylhydantoin, lidocaine, prazosin, propranolol, or verapamil, it is unknown whether displacement of either nefazodone or these drugs occurs in vivo. There was a 5% decrease in the protein binding of haloperidol; this is probably of no clinical significance. - Effect of Food - Food delays the absorption of nefazodone and decreases the bioavailability of nefazodone by approximately 20%. - Renal Disease - In studies involving 29 renally impaired patients, renal impairment (creatinine clearances ranging from 7 to 60 mL/min/1.73 m2) had no effect on steady-state nefazodone plasma concentrations. - Liver Disease - In a multiple-dose study of patients with liver cirrhosis, the AUC values for nefazodone and HO-NEF at steady state were approximately 25% greater than those observed in normal volunteers. - Age/Gender Effects - After single doses of 300 mg to younger (18 to 45 years) and older patients (> 65 years), Cmax and AUC for nefazodone and hydroxynefazodone were up to twice as high in the older patients. With multiple doses, however, differences were much smaller, 10 to 20%. A similar result was seen for gender, with a higher Cmax and AUC in women after single doses but no difference after multiple doses. - Treatment with nefazodone should be initiated at half the usual dose in elderly patients, especially women (see DOSAGE AND ADMINISTRATION), but the therapeutic dose range is similar in younger and older patients. - Clinical Efficacy Trial Results - Studies in Outpatients With Depression - During its premarketing development, the efficacy of nefazodone was evaluated at doses within the therapeutic range in five well-controlled, short-term (6 to 8 weeks) clinical investigations. These trials enrolled outpatients meeting DSM-III or DSM-IIIR criteria for major depression. Among these trials, two demonstrated the effectiveness of nefazodone, and two provided additional support for that conclusion. - One trial was a 6 week dose-titration study comparing nefazodone in two dose ranges (up to 300 mg/day and up to 600 mg/day , on a BID schedule) and placebo. The second trial was an 8 week dose-titration study comparing nefazodone (up to 600 mg/day; mean modal dose was 375 mg/day), imipramine (up to 300 mg/day), and placebo, all on a BID schedule. Both studies demonstrated nefazodone, at doses titrated between 300 mg to 600 mg/day (therapeutic dose range), to be superior to placebo on at least three of the following four measures: 17 Item Hamilton Depression Rating Scale or HDRS (total score), Hamilton Depressed Mood item, Clinical Global Impressions (CGI) Severity score, and CGI Improvement score. Significant differences were also found for certain factors of the HDRS (e.g., anxiety factor, sleep disturbance factor, and retardation factor). In the two supportive studies, nefazodone was titrated up to 500 or 600 mg/day (mean modal doses of 462 mg/day and 363 mg/day). In the fifth study, the differentiation in response rates between nefazodone and placebo was not statistically significant. Three additional trials were conducted using subtherapeutic doses of nefazodone. - Overall, approximately two thirds of patients in these trials were women, and an analysis of the effects of gender on outcome did not suggest any differential responsiveness on the basis of sex. There were too few elderly patients in these trials to reveal possible age-related differences in response. - Since its initial marketing as an antidepressant drug product, additional clinical investigations of nefazodone have been conducted. These studies explored nefazodone’s use under conditions not evaluated fully at the time initial marketing approval was granted. - Studies in “Inpatients” - Two studies were conducted to evaluate nefazodone’s effectiveness in hospitalized depressed patients. These were 6 week, dose-titration trials comparing nefazodone (up to 600 mg/day) and placebo, on a BID schedule. In one study, nefazodone was superior to placebo. In this study, the mean modal dose of nefazodone was 503 mg/day, and 85% of these inpatients were melancholic; at baseline, patients were distributed at the higher end of the 7 point CGI Severity scale, as follows: 4 = moderately ill (17%); 5 = markedly ill (48%); 6 = severely ill (32%). In the other study, the differentiation in response rates between nefazodone and placebo was not statistically significant. This result may be explained by the “high” rate of spontaneous improvement among the patients randomized to placebo. - Studies of “Relapse Prevention in Patients Recently Recovered (Clinically) From Depression” - Two studies were conducted to assess nefazodone’s capacity to maintain a clinical remission in acutely depressed patients who were judged to have responded adequately (HDRS total score ≤ 10) after a 16 week period of open treatment with nefazodone (titration up to 600 mg/day). In one study, nefazodone was superior to placebo. In this study, patients (n = 131) were randomized to continuation on nefazodone or placebo for an additional 36 weeks (1 year total). This study demonstrated a significantly lower relapse rate (HDRS total score ≥ 18) for patients taking nefazodone compared to those on placebo. The second study was of appropriate design and power, but the sample of patients admitted for evaluation did not suffer relapses at a high enough incidence to provide a meaningful test of nefazodone’s efficacy for this use. - Comparisons of Clinical Trial Results - Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the findings of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one or more of the confounding factors just enumerated. ## Nonclinical Toxicology There is limited information regarding Nefazodone Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Nefazodone Clinical Studies in the drug label. # How Supplied Nefazodone hydrochloride tablets USP, 50 mg, are light-pink to pink (mottled), capsule-shaped, beveled-edged tablets, debossed “7178” on one side and debossed “93” on the other side. They are available in bottles of 100. Nefazodone hydrochloride tablets USP, 100 mg, are white to off-white, capsule-shaped tablets, debossed “1024” on one side and scored on the other side with a debossed “93” on one side of the score. They are available in bottles of 60. Nefazodone hydrochloride tablets USP, 150 mg, are peach (mottled), capsule-shaped tablets, debossed “7113” on one side and scored on the other side with a debossed “93” on one side of the score. They are available in bottles of 60. Nefazodone hydrochloride tablets USP, 200 mg, are light-yellow to yellow (mottled), capsule-shaped tablets, debossed “1025” on one side and debossed “93” on the other side. They are available in bottles of 60. Nefazodone hydrochloride tablets USP, 250 mg, are white to off-white, capsule-shaped tablets, debossed “1026” on one side and debossed “93” on the other side. They are available in bottles of 60. ## Storage Store at 20° to 25°C (68° to 77°F) . Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Read this information completely before using nefazodone. - Read the information each time you get more medicine. There may be new information. This leaflet provides a summary about nefazodone and does not include everything there is to know about your medicine. This information is not meant to take the place of talking with your doctor. ### What is the most important information that I should know about nefazodone? - Rarely, people who take nefazodone can develop serious liver problems. If you get any of the following symptoms while taking nefazodone, call your doctor right away because you may be developing a liver problem: - Yellowing of the skin or whites of eyes (jaundice) - Unusually dark urine - Loss of appetite that lasts several days or longer - Nausea - Abdominal (lower stomach) pain - People who currently have liver problems should not take nefazodone. ### What is nefazodone? - Nefazodone is a medicine used to treat depression. Nefazodone is thought to treat depression by correcting an imbalance in the amounts of certain natural chemicals, such as serotonin and norepinephrine, which are in your brain. ### Who should not take nefazodone? - Do not take nefazodone if you - Are allergic to nefazodone or the related medicine Desyrel® (trazodone). - Are taking Seldane® (terfenadine), an antihistamine; Hismanal® (astemizole), an antihistamine; Propulsid® (cisapride), used for heartburn; Halcion® (triazolam), used for insomnia; Orap® (pimozide), used to treat Tourette’s syndrome; or Tegretol® (carbamazepine), used to control seizures. - Currently have liver problems. - Are taking or have taken within the last 14 days one of the medicines for depression known as monoamine oxidase inhibitors (MAOIs), such as Nardil® or Parnate®. - Be sure to tell your doctor if you - Have ever had liver problems; - Are taking any other medicine, vitamin supplement, or herbal remedy, including those sold without a prescription (over-the-counter); - Have heart problems or have had a heart attack or stroke; - Have had manic episodes (extreme agitation or excitability); - Have ever attempted suicide; - Have had convulsions (seizures); - Are pregnant or breast-feeding. ### How should I take nefazodone? - Take nefazodone at the same time every day exactly as prescribed by your doctor. You may take nefazodone with or without food. - It may take a while for you to feel that nefazodone is working. You may not feel the full effect for several weeks. Once you feel better, it is important to keep taking nefazodone as directed by your doctor. - If you miss a dose of nefazodone, skip that dose and continue with your regular schedule. Never take 2 doses at the same time. - If you think that you have taken more nefazodone than prescribed, contact your doctor, local poison control center, or emergency room right away. ### What should I avoid while taking nefazodone? - Do not drive or operate possibly dangerous machinery (such as an automobile, power mower, or power tool) or participate in any hazardous activity that requires full mental alertness until you know how nefazodone affects you. - Before taking nefazodone, tell your doctor about any medicines you are taking, including vitamin supplements, herbal remedies, and any non-prescription (over-the-counter) medicines. Some of these medicines may affect how nefazodone works and should not be used in combination without talking to your doctor. - Do not drink alcoholic beverages while taking nefazodone. - Tell your doctor if you are pregnant, planning to become pregnant, or become pregnant while taking nefazodone. It is not known whether nefazodone can harm your unborn baby. - Talk with your doctor before taking nefazodone if you are breast-feeding. It is not known whether nefazodone can pass through your breast milk to the baby. ### What are the possible side effects of nefazodone? - The most common side effects of nefazodone are sleepiness, dry mouth, nausea, dizziness, constipation, weakness, lightheadedness, problems with vision, and confusion. - Call your doctor right away if you have any of the following side effects: - Yellowing of the skin or whites of eyes (jaundice) - Unusually dark urine - Loss of appetite that lasts several days or longer - Severe nausea - Abdominal (lower stomach) pain - Rash or hives - Seizure (convulsion) - Fainting - Erection that lasts too long - Tell your doctor right away about any side effects that you have or discomfort that you experience. Do not change your dose or stop taking nefazodone without talking with your doctor first. - Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Your doctor has prescribed nefazodone for you and you alone. Do not give nefazodone to other people even if they have the same condition. It may harm them. - This leaflet provides a summary of the most important information about nefazodone. If you would like more information, talk with your doctor or pharmacist. You can ask for information about nefazodone that is written for healthcare professionals. Seldane® is a registered trademark of Hoechst Marion Roussel Inc. (now Aventis Pharmaceuticals). Hismanal® and Propulsid® are registered trademarks of Janssen Pharmaceutica Products, L.P. Nardil® is a registered trademark of Parke-Davis. Parnate® is a registered trademark of SmithKline Beecham Pharmaceuticals. Halcion® is a registered trademark of Pharmacia & Upjohn. Orap® is a registered trademark of Gate Pharmaceuticals, a division of TEVA Pharmaceuticals USA. Tegretol® is a registered trademark of Novartis Pharmaceuticals Corporation. Manufactured In Israel By: TEVA PHARMACEUTICAL IND. LTD. Jerusalem, 91010, Israel Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev. A 8/2008 This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Rx only Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: What else do I need to know about antidepressant medicines? Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Manufactured In Israel By: TEVA PHARMACEUTICAL IND. LTD. Jerusalem, 91010, Israel Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev. E 5/2008 # Precautions with Alcohol Alcohol-Nefazodone 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 Nefazodone Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Nefazodone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Nefazodone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Chetan Lokhande, M.B.B.S [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Nefazodone is a 5-HT2 Antagonists that is FDA approved for the {{{indicationType}}} of major depressive disorder. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cardiovascular: orthostatic hypotension (2.8% to 4), gastrointestinal: constipation (10% to 17% ), nausea (14% to 23% ), xerostomia (25% ), neurologic: asthenia (7% to 13% ), confusion (7% ), dizziness (11% to 22% ), headache (26% to 52% ), lightheadedness (10% ), somnolence (16% to 32% ),ophthalmic: blurred vision (3% to 9% ). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Major depressive disorder ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Nefazodone in adult patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Nefazodone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information about FDA-labeled indications and dosage information of Nefazodone in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information about Off-Label Guideline-Supported Use of Nefazodone in pediatric patients. ### Non–Guideline-Supported Use There is limited information about Off-Label Non–Guideline-Supported Use of Nefazodone in pediatric patients. # Contraindications - Coadministration of terfenadine, astemizole, cisapride, pimozide, or carbamazepine with nefazodone hydrochloride is contraindicated (see Warnings and Precautions). - Nefazodone hydrochloride tablets are contraindicated in patients who were withdrawn from nefazodone because of evidence of liver injury (see Boxed Warning). Nefazodone hydrochloride tablets are also contraindicated in patients who have demonstrated hypersensitivity to nefazodone hydrochloride, its inactive ingredients, or other phenylpiperazine antidepressants. - The coadministration of triazolam and nefazodone causes a significant increase in the plasma level of triazolam (see Warnings and Precautions), and a 75% reduction in the initial triazolam dosage is recommended if the two drugs are to be given together. Because not all commercially available dosage forms of triazolam permit a sufficient dosage reduction, the coadministration of triazolam and nefazodone should be avoided for most patients, including the elderly. # Warnings ### Clinical Worsening and Suicide Risk - Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. - The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. - No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. - It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. - All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. - The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. - Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. - Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for nefazodone hydrochloride tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. ### Screening Patients for Bipolar Disorder - A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that nefazodone hydrochloride tablets is not approved for use in treating bipolar depression. ### Hepatotoxicity (See Boxed Warning.) - Cases of life-threatening hepatic failure have been reported in patients treated with nefazodone. - The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years of nefazodone treatment. This represents a rate of about 3 to 4 times the estimated background rate of liver failure. This rate is an underestimate because of under reporting, and the true risk could be considerably greater than this. A large cohort study of antidepressant users found no cases of liver failure leading to death or transplant among nefazodone users in about 30,000 patient-years of exposure. The spontaneous report data and the cohort study results provide estimates of the upper and lower limits of the risk of liver failure in nefazodone-treated patients, but are not capable of providing a precise risk estimate. - The time to liver injury for the reported liver failure cases resulting in death or transplant generally ranged from 2 weeks to 6 months on nefazodone therapy. Although some reports described dark urine and nonspecific prodromal symptoms (e.g., anorexia, malaise, and gastrointestinal symptoms), other reports did not describe the onset of clear prodromal symptoms prior to the onset of jaundice. - The physician may consider the value of liver function testing. Periodic serum transaminase testing has not been proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. - Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment. - Nefazodone should be discontinued if clinical signs or symptoms suggest liver failure (see Precautions: Information for Patients). Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels ≥ 3 times the upper limit of Normal, while on nefazodone should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if nefazodone is reintroduced. Accordingly, such patients should not be considered for re-treatment. # Adverse Reactions ## Clinical Trials Experience - Associated With Discontinuation of Treatment - Approximately 16% of the 3496 patients who received nefazodone in worldwide premarketing clinical trials discontinued treatment due to an adverse experience. The more common (≥ 1%) events in clinical trials associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate approximately twice or greater for nefazodone compared to placebo) included: nausea (3.5%), dizziness (1.9%), insomnia (1.5%), asthenia (1.3%), and agitation (1.2%). ### Incidence in Controlled Trials - Commonly Observed Adverse Events in Controlled Clinical Trials - The most commonly observed adverse events associated with the use of nefazodone (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., significantly higher incidence for nefazodone compared to placebo, p ≤ 0.05), derived from the table below, were: somnolence, dry mouth, nausea, dizziness, constipation, asthenia, lightheadedness, blurred vision, confusion, and abnormal vision. - Adverse Events Occurring at an Incidence of 1% or More Among Nefazodone-Treated Patients - The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among nefazodone-treated patients who participated in short-term (6 to 8 week) placebo-controlled trials in which patients were dosed with nefazodone to ranges of 300 to 600 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using standard Costart-based Dictionary terminology. - The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied. - Events reported by at least 1% of patients treated with nefazodone and more frequent than the placebo group are included; incidence is rounded to the nearest 1% (< 1% indicates an incidence less than 0.5%). Events for which the nefazodone incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, accidental injury, chest pain, neck pain, palpitation, migraine, sweating, flatulence, vomiting, anorexia, tooth disorder, weight gain, edema, myalgia, cramp, agitation, anxiety, depression, hypesthesia, CNS stimulation, dysphoria, emotional lability, sinusitis, rhinitis, dysmenorrhea, dysuria. - Vasodilatation – flushing, feeling warm. - Abnormal vision – scotoma, visual trails.# Incidence adjusted for gender. - Dose Dependency of Adverse Events - The table that follows enumerates adverse events that were more frequent in the nefazodone dose range of 300 to 600 mg/day than in the nefazodone dose range of up to 300 mg/day. This table shows only those adverse events for which there was a statistically significant difference (p ≤ 0.05) in incidence between the nefazodone dose ranges as well as a difference between the high dose range and placebo. - Visual Disturbances - In controlled clinical trials, blurred vision occurred in 9% of nefazodone-treated patients compared to 3% of placebo-treated patients. In these same trials abnormal vision, including scotomata and visual trails, occurred in 7% of nefazodone-treated patients compared to 1% of placebo-treated (see Treatment-Emergent Adverse Experience table, above). Dose-dependency was observed for these events in these trials, with none of the scotomata and visual trails at doses below 300 mg/day. However, scotomata and visual trails observed at doses below 300 mg/day have been reported in postmarketing experience with nefazodone (see Precautions, Information for Patients). - Vital Sign Changes - (See Precautions, Postural Hypotension.) - Weight Changes - In a pooled analysis of placebo-controlled premarketing studies, there were no differences between nefazodone and placebo groups in the proportions of patients meeting criteria for potentially important increases or decreases in body weight (a change of ≥ 7%). - Laboratory Changes - Of the serum chemistry, serum hematology, and urinalysis parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistical trend between nefazodone and placebo for hematocrit, i.e., 2.8% of nefazodone patients met criteria for a potentially important decrease in hematocrit (≤ 37% male or ≤ 32% female) compared to 1.5% of placebo patients (0.05 < p ≤ 0.10). Decreases in hematocrit, presumably dilutional, have been reported with many other drugs that block alpha1-adrenergic receptors. There was no apparent clinical significance of the observed changes in the few patients meeting these criteria. - ECG Changes - Of the ECG parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistically significant difference between nefazodone and placebo for sinus bradycardia, i.e., 1.5% of nefazodone patients met criteria for a potentially important decrease in heart rate (≤ 50 bpm and a decrease of ≥ 15 bpm) compared to 0.4% of placebo patients (p < 0.05). There was no obvious clinical significance of the observed changes in the few patients meeting these criteria. - Other Events Observed During the Premarketing Evaluation of Nefazodone - During its premarketing assessment, multiple doses of nefazodone were administered to 3496 patients in clinical studies, including more than 250 patients treated for at least one year. The conditions and duration of exposure to nefazodone varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories. - In the tabulations that follow, reported adverse events were classified using standard Costart-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 3496 patients exposed to multiple doses of nefazodone who experienced an event of the type cited on at least one occasion while receiving nefazodone. All reported events are included except those already listed in the Treatment-Emergent Adverse Experience Incidence table, those events listed in other safety-related sections of this insert, those adverse experiences subsumed under Costart terms that are either overly general or excessively specific so as to be uninformative, those events for which a drug cause was very remote, and those events which were not serious and occurred in fewer than two patients. - It is important to emphasize that, although the events reported occurred during treatment with nefazodone, they were not necessarily caused by it. - Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. - Body as a whole – Infrequent: allergic reaction, malaise, photosensitivity reaction, face edema, hangover effect, abdomen enlarged, hernia, pelvic pain, and halitosis. Rare: cellulitis. - Cardiovascular system – Infrequent: tachycardia, hypertension, syncope, ventricular extrasystoles, and angina pectoris. Rare: AV block, congestive heart failure, hemorrhage, pallor, and varicose vein. - Dermatological system – Infrequent: dry skin, acne, alopecia, urticaria, maculopapular rash,vesiculobullous rash, and eczema. - Gastrointestinal system – Frequent: gastroenteritis. Infrequent: eructation, periodontal abscess, abnormal liver function tests, gingivitis, colitis, gastritis, mouth ulceration, stomatitis, esophagitis, peptic ulcer, and rectal hemorrhage. Rare: glossitis, hepatitis, dysphagia, gastrointestinal hemorrhage, oral moniliasis, and ulcerative colitis. - Hemic and lymphatic system – Infrequent: ecchymosis, anemia, leukopenia, and lymphadenopathy . - Metabolic and nutritional system – Infrequent: weight loss, gout, dehydration, lactic dehydrogenase increased, SGOT increased, and SGPT increased. Rare: hypercholesteremia and hypoglycemia. - Musculoskeletal system – Infrequent: arthritis, tenosynovitis, muscle stiffness, and bursitis. Rare: tendinous contracture. - Nervous system – Infrequent: vertigo, twitching, depersonalization, hallucinations, suicide attempt, apathy, euphoria, hostility, suicidal thoughts, abnormal gait, thinking abnormal, attention decreased, derealization, neuralgia, paranoid reaction, dysarthria, increased libido, suicide, and myoclonus. Rare: hyperkinesia, increased salivation, cerebrovascular accident, hyperesthesia, hypotonia, ptosis, and neuroleptic malignant syndrome. - Respiratory system – Frequent: dyspnea and bronchitis. Infrequent:asthma, pneumonia, laryngitis, voice alteration, epistaxis, hiccup. Rare: hyperventilation and yawn. - Special senses – Frequent: eye pain. Infrequent: dry eye, ear pain, abnormality of accommodation, diplopia, conjunctivitis, mydriasis, keratoconjunctivitis, hyperacusis, and photophobia. Rare: deafness, glaucoma, night blindness, and taste loss. - Urogenital system – Frequent: impotence. Infrequent: cystitis, urinary urgency, metrorrhagiaa, amenorrheaa, polyuria, vaginal hemorrhagea, breast enlargementa, menorrhagiaa, urinary incontinence, abnormal ejaculationa, hematuria, nocturia, and kidney calculus. Rare: uterine fibroids enlarged, uterine hemorrhagea, anorgasmia, and oliguria. - Adjusted for gender. - Postmarketing experience with nefazodone has shown an adverse experience profile similar to that seen during the premarketing evaluation of nefazodone. Voluntary reports of adverse events temporally associated with nefazodone have been received since market introduction that are not listed above and for which a causal relationship has not been established. These include: - Anaphylactic reactions; angioedema; convulsions (including grand mal seizures); galactorrhea; gynecomastia (male); hyponatremia; liver necrosis and liver failure, in some cases leading to liver transplantation and/or death (see Warnings); priapism (see Precautions); prolactin increased; rhabdomyolysis involving patients receiving the combination of nefazodone and lovastatin or simvastatin (see Precautions); serotonin syndrome; and Stevens-Johnson syndrome; and thrombocytopenia. ## Postmarketing Experience - Postmarketing experience with nefazodone has shown an adverse experience profile similar to that seen during the premarketing evaluation of nefazodone. Voluntary reports of adverse events temporally associated with nefazodone have been received since market introduction that are not listed above and for which a causal relationship has not been established. These include: Anaphylactic reactions; angioedema; convulsions (including grand mal seizures); galactorrhea; gynecomastia (male); hyponatremia; liver necrosis and liver failure, in some cases leading to liver transplantation and/or death (see Warnings); priapism (see Precautions); prolactin increased; rhabdomyolysis involving patients receiving the combination of nefazodone and lovastatin or simvastatin (see Precautions); serotonin syndrome; and Stevens-Johnson syndrome; and thrombocytopenia. # Drug Interactions - Drugs Highly Bound to Plasma Protein - Because nefazodone is highly bound to plasma protein (see Clinical Pharmacology, Pharmacokinetics), administration of nefazodone to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of nefazodone by other highly bound drugs. - Warfarin – There were no effects on the prothrombin or bleeding times or upon the pharmacokinetics of R-warfarin when nefazodone (200 mg BID) was administered for 1 week to subjects who had been pretreated for 2 weeks with warfarin. Although the coadministration of nefazodone did decrease the subjects’ exposure to S-warfarin by 12%, the lack of effects on the prothrombin and bleeding times indicates this modest change is not clinically significant. Although these results suggest no adjustments in warfarin dosage are required when nefazodone is administered to patients stabilized on warfarin, such patients should be monitored as required by standard medical practices. - CNS-Active Drugs - Monoamine Oxidase Inhibitors – See Warnings - Haloperidol – When a single oral 5 mg dose of haloperidol was coadministered with nefazodone (200 mg BID) at steady state, haloperidol apparent clearance decreased by 35% with no significant increase in peak haloperidol plasma concentrations or time of peak. This change is of unknown clinical significance. Pharmacodynamic effects of haloperidol were generally not altered significantly. There were no changes in the pharmacokinetic parameters for nefazodone. Dosage adjustment of haloperidol may be necessary when coadministered with nefazodone. - Lorazepam – When lorazepam (2 mg BID) and nefazodone (200 mg BID) were coadministered to steady state, there was no change in any pharmacokinetic parameter for either drug compared to each drug administered alone. Therefore, dosage adjustment is not necessary for either drug when coadministered. - Triazolam/Alprazolam – See Contrandications and Warnings. - Alcohol – Although nefazodone did not potentiate the cognitive and psychomotor effects of alcohol in experiments with normal subjects, the concomitant use of nefazodone and alcohol in depressed patients is not advised. - Buspirone – In a study of steady-state pharmacokinetics in healthy volunteers, coadministration of buspirone (2.5 or 5 mg BID) with nefazodone (250 mg BID) resulted in marked increases in plasma buspirone concentrations (increases up to 20 fold in Cmax and up to 50 fold in AUC) and statistically significant decreases (about 50%) in plasma concentrations of the buspirone metabolite 1-pyrimidinylpiperazine. With 5 mg BID doses of buspirone, slight increases in AUC were observed for nefazodone (23%) and its metabolites hydroxynefazodone (17%) and mCPP (9%). Subjects receiving nefazodone 250 mg BID and buspirone 5 mg BID experienced lightheadedness, asthenia, dizziness, and somnolence, adverse events also observed with either drug alone. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg QD) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. - Pimozide – See Contraindications, Warnings, and Precautions, Pharmacokinetics of Nefazodone in ‘Poor Metabolizers’ and Potential Interaction With Drugs That Inhibit and/or Are Metabolized by Cytochrome P450 Isozymes. - Fluoxetine – When fluoxetine (20 mg QD) and nefazodone (200 mg BID) were administered at steady state there were no changes in the pharmacokinetic parameters for fluoxetine or its metabolite, norfluoxetine. Similarly, there were no changes in the pharmacokinetic parameters of nefazodone or HO-NEF; however, the mean AUC levels of the nefazodone metabolites mCPP and triazole-dione increased by 3 to 6 fold and 1.3 fold, respectively. When a 200 mg dose of nefazodone was administered to subjects who had been receiving fluoxetine for 1 week, there was an increased incidence of transient adverse events such as headache, lightheadedness, nausea, or paresthesia, possibly due to the elevated mCPP levels. Patients who are switched from fluoxetine to nefazodone without an adequate washout period may experience similar transient adverse events. The possibility of this happening can be minimized by allowing a washout period before initiating nefazodone therapy and by reducing the initial dose of nefazodone. Because of the long half-life of fluoxetine and its metabolites, this washout period may range from one to several weeks depending on the dose of fluoxetine and other individual patient variables. - Phenytoin – Pretreatment for 7 days with 200 mg BID of nefazodone had no effect on the pharmacokinetics of a single 300 mg oral dose of phenytoin. However, due to the nonlinear pharmacokinetics ofphenytoin, the failure to observe a significant effect on the single-dose pharmacokinetics of phenytoin does not preclude the possibility of a clinically significant interaction with nefazodone when phenytoin is dosed chronically. However, no change in the initial dosage of phenytoin is considered necessary and any subsequent adjustment of phenytoin dosage should be guided by usual clinical practices. - Desipramine – When nefazodone (150 mg BID) and desipramine (75 mg QD) were administered together there were no changes in the pharmacokinetics of desipramine or its metabolite, 2-hydroxy desipramine. There were also no changes in the pharmacokinetics of nefazodone or its triazole-dione metabolite, but the AUC and Cmax of mCPP increased by 44% and 48%, respectively, while the AUC of HO-NEF decreased by 19%. No changes in doses of either nefazodone or desipramine are necessary when the two drugs are given concomitantly. Subsequent dose adjustments should be made on the basis of clinical response. - Lithium – In 13 healthy subjects the coadministration of nefazodone (200 mg BID) with lithium (500 mg BID) for 5 days (steady-state conditions) was found to be well tolerated. When the two drugs were coadministered, there were no changes in the steady-state pharmacokinetics of either lithium, nefazodone, or its metabolite HO-NEF; however, there were small decreases in the steady-state plasma concentrations of two nefazodone metabolites, mCPP and triazole-dione, which are considered not to be of clinical significance. Therefore, no dosage adjustment of either lithium or nefazodone is required when they are coadministered. - Carbamazepine – The coadministration of nefazodone (200 mg BID) for 5 days to 12 healthy subjects on carbamazepine who had achieved steady state (200 mg BID) was found to be well tolerated. Steady-state conditions for carbamazepine, nefazodone, and several of their metabolites were achieved by day 5 of coadministration. With coadministration of the two drugs there were significant increases in the steady-state Cmax and AUC of carbamazepine (23% and 23%, respectively), while the steady-state Cmax and the AUC of the carbamazepine metabolite, 10,11 epoxycarbamazepine, decreased by 21% and 20%, respectively. The coadministration of the two drugs significantly reduced the steady-state Cmax and AUC of nefazodone by 86% and 93%, respectively. Similar reductions in the Cmax and AUC of HO-NEF were also observed (85% and 94%), while the reductions in Cmax and AUC of mCPP and triazole-dione were more modest (13% and 44% for the former and 28% and 57% for the latter). Due to the potential for coadministration of carbamazepine to result in insufficient plasma nefazodone and hydroxynefazodone concentrations for achieving an antidepressant effect for nefazodone, it is recommended that nefazodone not be used in combination with carbamazepine (see Contraindications And Warnings). - General Anesthetics – Little is known about the potential for interaction between nefazodone and general anesthetics; therefore, prior to elective surgery, nefazodone hydrochloride should be discontinued for as long as clinically feasible. - Other CNS-Active Drugs – The use of nefazodone in combination with other CNS-active drugs has not been systematically evaluated. Consequently, caution is advised if concomitant administration of nefazodone and such drugs is required. - Cimetidine - When nefazodone (200 mg BID) and cimetidine (300 mg QID) were coadministered for one week, no change in the steady-state pharmacokinetics of either nefazodone or cimetidine was observed compared to each dosed alone. Therefore, dosage adjustment is not necessary for either drug when coadministered. - Theophylline - When nefazodone (200 mg BID) was given to patients being treated with theophylline (600 to 1200 mg/day) for chronic obstructive pulmonary disease, there was no change in the steady-state pharmacokinetics of either nefazodone or theophylline. FEV1 measurements taken when theophylline and nefazodone were coadministered did not differ from baseline dosage (i.e., when theophylline was administered alone). Therefore, dosage adjustment is not necessary for either drug when coadministered. - Cardiovascular-Active Drugs - Digoxin – When nefazodone (200 mg BID) and digoxin (0.2 mg QD) were coadministered for 9 days to healthy male volunteers (n = 18) who were phenotyped as CYP2D6 extensive metabolizers, Cmax, Cmin, and AUC of digoxin were increased by 29%, 27%, and 15%, respectively. Digoxin had no effects on the pharmacokinetics of nefazodone and its active metabolites. Because of the narrow therapeutic index of digoxin, caution should be exercised when nefazodone and digoxin are coadministered; plasma level monitoring for digoxin is recommended. - Propranolol – The coadministration of nefazodone (200 mg BID) and propranolol (40 mg BID) for 5.5 days to healthy male volunteers (n = 18), including 3 poor and 15 extensive CYP2D6 metabolizers, resulted in 30% and 14% reductions in Cmax and AUC of propranolol, respectively, and a 14% reduction in Cmax for the metabolite, 4-hydroxypropranolol. The kinetics of nefazodone, hydroxynefazodone, and triazole-dione were not affected by coadministration of propranolol. However, Cmax, Cmin, and AUC of m-chlorophenylpiperazine were increased by 23%, 54%, and 28%, respectively. No change in initial dose of either drug is necessary and dose adjustments should be made on the basis of clinical response. - HMG-CoA Reductase Inhibitors – When single 40 mg doses of simvastatin or atorvastatin, both substrates of CYP3A4, were given to healthy adult volunteers who had received nefazodone hydrochloride, 200 mg BID for 6 days, approximately 20 fold increases in plasma concentrations of simvastatin and simvastatin acid and 3 to 4 fold increases in plasma concentrations of atorvastatin and atorvastatin lactone were seen. These effects appear to be due to the inhibition of CYP3A4 by nefazodone because, in the same study, nefazodone had no significant effect on the plasma concentrations of pravastatin, which is not metabolized by CYP3A4 to a clinically significant extent. - There have been rare reports of rhabdomyolysis involving patients receiving the combination of nefazodone and either simvastatin or lovastatin, also a substrate of CYP3A4 (see Adverse Reactions, Postintroduction Clinical Experience). Rhabdomyolysis has been observed in patients receiving HMG-CoA reductase inhibitors administered alone (at recommended dosages) and in particular, for certain drugs in this class, when given in combination with inhibitors of the CYP3A4 isozyme. - Caution should be used if nefazodone is administered in combination with HMG-CoA reductase inhibitors that are metabolized by CYP3A4, such as simvastatin, atorvastatin, and lovastatin, and dosage adjustments of these HMG-CoA reductase inhibitors are recommended. Since metabolic interactions are unlikely between nefazodone and HMG-CoA reductase inhibitors that undergo little or no metabolism by the CYP3A4 isozyme, such as pravastatin or fluvastatin, dosage adjustments should not be necessary. ### Immunosuppressive Agents - There have been reports of increased blood concentrations of cyclosporine and tacrolimus into toxic ranges when patients received these drugs concomitantly with nefazodone. Both cyclosporine and tacrolimus are substrates of CYP3A4, and nefazodone is known to inhibit this enzyme. If either cyclosporine or tacrolimus is administered with nefazodone, blood concentrations of the immunosuppressive agent should be monitored and dosage adjusted accordingly. - Pharmacokinetics of Nefazodone in ‘Poor Metabolizers’ and Potential Interaction With Drugs That Inhibit and/or Are Metabolized by Cytochrome P450 Isozymes - CYP3A4 Isozyme – Nefazodone has been shown in vitro to be an inhibitor of CYP3A4. This is consistent with the interactions observed between nefazodone and triazolam, alprazolam, buspirone, atorvastatin, and simvastatin, drugs metabolized by this isozyme. Consequently, caution is indicated in the combined use of nefazodone with any drugs known to be metabolized by CYP3A4. In particular, the combined use of nefazodone with triazolam should be avoided for most patients, including the elderly. The combined use of nefazodone with terfenadine, astemizole, cisapride, or pimozide is contraindicated (see Contraindications and Warnings). - CYP2D6 Isozyme – A subset (3% to 10%) of the population has reduced activity of the drug-metabolizing enzyme CYP2D6. Such individuals are referred to commonly as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants. The pharmacokinetics of nefazodone and its major metabolites are not altered in these “poor metabolizers.” Plasma concentrations of one minor metabolite (mCPP) are increased in this population; the adjustment of nefazodone dosage is not required when administered to “poor metabolizers.” Nefazodone and its metabolites have been shown in vitro to be extremely weak inhibitors of CYP2D6. Thus, it is not likely that nefazodone will decrease the metabolic clearance of drugs metabolized by this isozyme. - CYP1A2 Isozyme – Nefazodone and its metabolites have been shown in vitro not to inhibit CYP1A2. Thus, metabolic interactions between nefazodone and drugs metabolized by this isozyme are unlikely. - [Electroconvulsive therapy # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Reproduction studies have been performed in pregnant rabbits and rats at daily doses up to 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively, the maximum human daily dose on a mg/m2 basis). No malformations were observed in the offspring as a result of nefazodone treatment. However, increased early pup mortality was seen in rats at a dose approximately five times the maximum human dose, and decreased pup weights were seen at this and lower doses, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. The no-effect dose for rat pup mortality was 1.3 times the human dose on a mg/m2 basis. There are no adequate and well-controlled studies in pregnant women. Nefazodone 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 Nefazodone in women who are pregnant. ### Labor and Delivery The effect of nefazodone on labor and delivery in humans is unknown. ### Nursing Mothers It is not known whether nefazodone or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nefazodone is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in the pediatric population have not been established (see BOXED WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 286 pediatric patients with MDD have been conducted with nefazodone, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of nefazodone hydrochloride tablets in a child or adolescent must balance the potential risks with the clinical need. ### Geriatic Use - Of the approximately 7000 patients in clinical studies who received nefazodone for the treatment of depression, 18% were 65 years and older, while 5% were 75 years and older. Based on monitoring of adverse events, vital signs, electrocardiograms, and results of laboratory tests, no overall differences in safety between elderly and younger patients were observed in clinical studies. Efficacy in the elderly has not been demonstrated in placebo-controlled trials. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Due to the increased systemic exposure to nefazodone seen in single-dose studies in elderly patients (see Clinical Pharmacology, Pharmacokinetics), treatment should be initiated at half the usual dose, but titration upward should take place over the same range as in younger patients (see Dosage and Administration). The usual precautions should be observed in elderly patients who have concomitant medical illnesses or who are receiving concomitant drugs. ### Gender There is no FDA guidance on the use of Nefazodone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Nefazodone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Nefazodone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Nefazodone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Nefazodone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Nefazodone in patients who are immunocompromised. # Administration and Monitoring ### Administration There is limited information regarding Nefazodone Administration in the drug label. ### Monitoring There is limited information regarding Nefazodone Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Nefazodone and IV administrations. # Overdosage Human Experience<\b> - In premarketing clinical studies, there were seven reports of nefazodone overdose alone or in combination with other pharmacological agents. The amount of nefazodone ingested ranged from 1000 mg to 11,200 mg. Commonly reported symptoms from overdose of nefazodone included nausea, vomiting, and somnolence. One nonstudy participant took 2000 to 3000 mg of nefazodone with methocarbamol and alcohol; this person reportedly experienced a convulsion (type not documented). None of these patients died. - In postmarketing experience, overdose with nefazodone alone and in combination with alcohol and/or other substances has been reported. Commonly reported symptoms were similar to those reported from overdose in premarketing experience. While there have been rare reports of fatalities in patients taking overdoses of nefazodone, predominantly in combination with alcohol and/or other substances, no causal relationship to nefazodone has been established. ## Overdosage Management= - Treatment should consist of those general measures employed in the management of overdosage with any antidepressant. - Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients. - Activated charcoal should be administered. Due to the wide distribution of nefazodone in body tissues, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for nefazodone are known. - In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). # Pharmacology ## Mechanism of Action The mechanism of action of nefazodone, as with other antidepressants, is unknown. ## Structure Nefazodone hydrochloride tablets USP are an antidepressant for oral administration with a chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclics, tetracyclics, or monoamine oxidase inhibitors (MAOI). Nefazodone hydrochloride is a synthetically derived phenylpiperazine antidepressant. The chemical name for nefazodone hydrochloride is 2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(2-phenoxyethyl)-3H-1,2,4-triazol-3-one monohydrochloride. The structural formula is: C25H32CIN5O2•HCl M.W. 506.5 Nefazodone hydrochloride is a nonhygroscopic, white crystalline solid. It is freely soluble in chloroform, soluble in propylene glycol, and slightly soluble in polyethylene glycol and water. Nefazodone hydrochloride tablets USP are supplied as capsule-shaped tablets containing 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg of nefazodone hydrochloride and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and povidone. Additionally, the 50 mg tablets include ferric oxide red as a colorant, the 150 mg tablets include ferric oxide red and yellow as colorants, and the 200 mg tablets include ferric oxide yellow as a colorant. ## Pharmacodynamics - Preclinical studies have shown that nefazodone inhibits neuronal uptake of serotonin and norepinephrine. - Nefazodone occupies central 5-HT2 receptors at nanomolar concentrations, and acts as an antagonist at this receptor. Nefazodone was shown to antagonize alpha1-adrenergic receptors, a property which may be associated with postural hypotension. In vitro binding studies showed that nefazodone had no significant affinity for the following receptors: alpha2 and beta adrenergic, 5-HT1A, cholinergic, dopaminergic, or benzodiazepine. ## Pharmacokinetics Nefazodone is rapidly and completely absorbed but is subject to extensive metabolism, so that its absolute bioavailability is low, about 20%, and variable. Peak plasma concentrations occur at about one hour and the half-life of nefazodone is 2 to 4 hours. - Both nefazodone and its pharmacologically similar metabolite, hydroxynefazodone, exhibit nonlinear kinetics for both dose and time, with AUC and Cmax increasing more than proportionally with dose increases and more than expected upon multiple dosing over time, compared to single dosing. For example, in a multiple-dose study involving BID dosing with 50, 100, and 200 mg, the AUC for nefazodone and hydroxynefazodone increased by about 4 fold with an increase in dose from 200 to 400 mg per day; Cmax increased by about 3 fold with the same dose increase. In a multiple-dose study involving BID dosing with 25, 50, 100, and 150 mg, the accumulation ratios for nefazodone and hydroxynefazodone AUC, after 5 days of BID dosing relative to the first dose, ranged from approximately 3 to 4 at the lower doses (50 to 100 mg/day) and from 5 to 7 at the higher doses (200 to 300 mg/day); there were also approximately 2 to 4 fold increases in Cmax after 5 days of BID dosing relative to the first dose, suggesting extensive and greater than predicted accumulation of nefazodone and its hydroxy metabolite with multiple dosing. Steady-state plasma nefazodone and metabolite concentrations are attained within 4 to 5 days of initiation of BID dosing or upon dose increase or decrease. - Nefazodone is extensively metabolized after oral administration by n-dealkylation and aliphatic and aromatic hydroxylation, and less than 1% of administered nefazodone is excreted unchanged in urine. Attempts to characterize three metabolites identified in plasma, hydroxynefazodone (HO-NEF), meta-chlorophenylpiperazine (mCPP), and a triazole-dione metabolite, have been carried out. The AUC (expressed as a multiple of the AUC for nefazodone dosed at 100 mg BID) and elimination half-lives for these three metabolites were as follows: - HO-NEF possesses a pharmacological profile qualitatively and quantitatively similar to that of nefazodone. mCPP has some similarities to nefazodone, but also has agonist activity at some serotonergic receptor subtypes. The pharmacological profile of the triazole-dione metabolite has not yet been well characterized. In addition to the above compounds, several other metabolites were present in plasma but have not been tested for pharmacological activity. - After oral administration of radiolabeled nefazodone, the mean half-life of total label ranged between 11 and 24 hours. Approximately 55% of the administered radioactivity was detected in urine and about 20 to 30% in feces. ### Distribution - Nefazodone is widely distributed in body tissues, including the central nervous system (CNS). In humans the volume of distribution of nefazodone ranges from 0.22 to 0.87 L/kg. - Protein Binding - At concentrations of 25 to 2500 ng/mL nefazodone is extensively (> 99%) bound to human plasma proteins in vitro. The administration of 200 mg BID of nefazodone for 1 week did not increase the fraction of unbound warfarin in subjects whose prothrombin times had been prolonged by warfarin therapy to 120 to 150% of the laboratory control (see Precautions, Drug Interactions). While nefazodone did not alter the in vitro protein binding of chlorpromazine, desipramine, diazepam, diphenylhydantoin, lidocaine, prazosin, propranolol, or verapamil, it is unknown whether displacement of either nefazodone or these drugs occurs in vivo. There was a 5% decrease in the protein binding of haloperidol; this is probably of no clinical significance. - Effect of Food - Food delays the absorption of nefazodone and decreases the bioavailability of nefazodone by approximately 20%. - Renal Disease - In studies involving 29 renally impaired patients, renal impairment (creatinine clearances ranging from 7 to 60 mL/min/1.73 m2) had no effect on steady-state nefazodone plasma concentrations. - Liver Disease - In a multiple-dose study of patients with liver cirrhosis, the AUC values for nefazodone and HO-NEF at steady state were approximately 25% greater than those observed in normal volunteers. - Age/Gender Effects - After single doses of 300 mg to younger (18 to 45 years) and older patients (> 65 years), Cmax and AUC for nefazodone and hydroxynefazodone were up to twice as high in the older patients. With multiple doses, however, differences were much smaller, 10 to 20%. A similar result was seen for gender, with a higher Cmax and AUC in women after single doses but no difference after multiple doses. - Treatment with nefazodone should be initiated at half the usual dose in elderly patients, especially women (see DOSAGE AND ADMINISTRATION), but the therapeutic dose range is similar in younger and older patients. - Clinical Efficacy Trial Results - Studies in Outpatients With Depression - During its premarketing development, the efficacy of nefazodone was evaluated at doses within the therapeutic range in five well-controlled, short-term (6 to 8 weeks) clinical investigations. These trials enrolled outpatients meeting DSM-III or DSM-IIIR criteria for major depression. Among these trials, two demonstrated the effectiveness of nefazodone, and two provided additional support for that conclusion. - One trial was a 6 week dose-titration study comparing nefazodone in two dose ranges (up to 300 mg/day and up to 600 mg/day [mean modal dose for this group was about 400 mg/day], on a BID schedule) and placebo. The second trial was an 8 week dose-titration study comparing nefazodone (up to 600 mg/day; mean modal dose was 375 mg/day), imipramine (up to 300 mg/day), and placebo, all on a BID schedule. Both studies demonstrated nefazodone, at doses titrated between 300 mg to 600 mg/day (therapeutic dose range), to be superior to placebo on at least three of the following four measures: 17 Item Hamilton Depression Rating Scale or HDRS (total score), Hamilton Depressed Mood item, Clinical Global Impressions (CGI) Severity score, and CGI Improvement score. Significant differences were also found for certain factors of the HDRS (e.g., anxiety factor, sleep disturbance factor, and retardation factor). In the two supportive studies, nefazodone was titrated up to 500 or 600 mg/day (mean modal doses of 462 mg/day and 363 mg/day). In the fifth study, the differentiation in response rates between nefazodone and placebo was not statistically significant. Three additional trials were conducted using subtherapeutic doses of nefazodone. - Overall, approximately two thirds of patients in these trials were women, and an analysis of the effects of gender on outcome did not suggest any differential responsiveness on the basis of sex. There were too few elderly patients in these trials to reveal possible age-related differences in response. - Since its initial marketing as an antidepressant drug product, additional clinical investigations of nefazodone have been conducted. These studies explored nefazodone’s use under conditions not evaluated fully at the time initial marketing approval was granted. - Studies in “Inpatients” - Two studies were conducted to evaluate nefazodone’s effectiveness in hospitalized depressed patients. These were 6 week, dose-titration trials comparing nefazodone (up to 600 mg/day) and placebo, on a BID schedule. In one study, nefazodone was superior to placebo. In this study, the mean modal dose of nefazodone was 503 mg/day, and 85% of these inpatients were melancholic; at baseline, patients were distributed at the higher end of the 7 point CGI Severity scale, as follows: 4 = moderately ill (17%); 5 = markedly ill (48%); 6 = severely ill (32%). In the other study, the differentiation in response rates between nefazodone and placebo was not statistically significant. This result may be explained by the “high” rate of spontaneous improvement among the patients randomized to placebo. - Studies of “Relapse Prevention in Patients Recently Recovered (Clinically) From Depression” - Two studies were conducted to assess nefazodone’s capacity to maintain a clinical remission in acutely depressed patients who were judged to have responded adequately (HDRS total score ≤ 10) after a 16 week period of open treatment with nefazodone (titration up to 600 mg/day). In one study, nefazodone was superior to placebo. In this study, patients (n = 131) were randomized to continuation on nefazodone or placebo for an additional 36 weeks (1 year total). This study demonstrated a significantly lower relapse rate (HDRS total score ≥ 18) for patients taking nefazodone compared to those on placebo. The second study was of appropriate design and power, but the sample of patients admitted for evaluation did not suffer relapses at a high enough incidence to provide a meaningful test of nefazodone’s efficacy for this use. - Comparisons of Clinical Trial Results - Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the findings of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one or more of the confounding factors just enumerated. ## Nonclinical Toxicology There is limited information regarding Nefazodone Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Nefazodone Clinical Studies in the drug label. # How Supplied Nefazodone hydrochloride tablets USP, 50 mg, are light-pink to pink (mottled), capsule-shaped, beveled-edged tablets, debossed “7178” on one side and debossed “93” on the other side. They are available in bottles of 100. Nefazodone hydrochloride tablets USP, 100 mg, are white to off-white, capsule-shaped tablets, debossed “1024” on one side and scored on the other side with a debossed “93” on one side of the score. They are available in bottles of 60. Nefazodone hydrochloride tablets USP, 150 mg, are peach (mottled), capsule-shaped tablets, debossed “7113” on one side and scored on the other side with a debossed “93” on one side of the score. They are available in bottles of 60. Nefazodone hydrochloride tablets USP, 200 mg, are light-yellow to yellow (mottled), capsule-shaped tablets, debossed “1025” on one side and debossed “93” on the other side. They are available in bottles of 60. Nefazodone hydrochloride tablets USP, 250 mg, are white to off-white, capsule-shaped tablets, debossed “1026” on one side and debossed “93” on the other side. They are available in bottles of 60. ## Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Read this information completely before using nefazodone. - Read the information each time you get more medicine. There may be new information. This leaflet provides a summary about nefazodone and does not include everything there is to know about your medicine. This information is not meant to take the place of talking with your doctor. ### What is the most important information that I should know about nefazodone? - Rarely, people who take nefazodone can develop serious liver problems. If you get any of the following symptoms while taking nefazodone, call your doctor right away because you may be developing a liver problem: - Yellowing of the skin or whites of eyes (jaundice) - Unusually dark urine - Loss of appetite that lasts several days or longer - Nausea - Abdominal (lower stomach) pain - People who currently have liver problems should not take nefazodone. ### What is nefazodone? - Nefazodone is a medicine used to treat depression. Nefazodone is thought to treat depression by correcting an imbalance in the amounts of certain natural chemicals, such as serotonin and norepinephrine, which are in your brain. ### Who should not take nefazodone? - Do not take nefazodone if you - Are allergic to nefazodone or the related medicine Desyrel® (trazodone). - Are taking Seldane® (terfenadine), an antihistamine; Hismanal® (astemizole), an antihistamine; Propulsid® (cisapride), used for heartburn; Halcion® (triazolam), used for insomnia; Orap® (pimozide), used to treat Tourette’s syndrome; or Tegretol® (carbamazepine), used to control seizures. - Currently have liver problems. - Are taking or have taken within the last 14 days one of the medicines for depression known as monoamine oxidase inhibitors (MAOIs), such as Nardil® or Parnate®. - Be sure to tell your doctor if you - Have ever had liver problems; - Are taking any other medicine, vitamin supplement, or herbal remedy, including those sold without a prescription (over-the-counter); - Have heart problems or have had a heart attack or stroke; - Have had manic episodes (extreme agitation or excitability); - Have ever attempted suicide; - Have had convulsions (seizures); - Are pregnant or breast-feeding. ### How should I take nefazodone? - Take nefazodone at the same time every day exactly as prescribed by your doctor. You may take nefazodone with or without food. - It may take a while for you to feel that nefazodone is working. You may not feel the full effect for several weeks. Once you feel better, it is important to keep taking nefazodone as directed by your doctor. - If you miss a dose of nefazodone, skip that dose and continue with your regular schedule. Never take 2 doses at the same time. - If you think that you have taken more nefazodone than prescribed, contact your doctor, local poison control center, or emergency room right away. ### What should I avoid while taking nefazodone? - Do not drive or operate possibly dangerous machinery (such as an automobile, power mower, or power tool) or participate in any hazardous activity that requires full mental alertness until you know how nefazodone affects you. - Before taking nefazodone, tell your doctor about any medicines you are taking, including vitamin supplements, herbal remedies, and any non-prescription (over-the-counter) medicines. Some of these medicines may affect how nefazodone works and should not be used in combination without talking to your doctor. - Do not drink alcoholic beverages while taking nefazodone. - Tell your doctor if you are pregnant, planning to become pregnant, or become pregnant while taking nefazodone. It is not known whether nefazodone can harm your unborn baby. - Talk with your doctor before taking nefazodone if you are breast-feeding. It is not known whether nefazodone can pass through your breast milk to the baby. ### What are the possible side effects of nefazodone? - The most common side effects of nefazodone are sleepiness, dry mouth, nausea, dizziness, constipation, weakness, lightheadedness, problems with vision, and confusion. - Call your doctor right away if you have any of the following side effects: - Yellowing of the skin or whites of eyes (jaundice) - Unusually dark urine - Loss of appetite that lasts several days or longer - Severe nausea - Abdominal (lower stomach) pain - Rash or hives - Seizure (convulsion) - Fainting - Erection that lasts too long - Tell your doctor right away about any side effects that you have or discomfort that you experience. Do not change your dose or stop taking nefazodone without talking with your doctor first. - Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Your doctor has prescribed nefazodone for you and you alone. Do not give nefazodone to other people even if they have the same condition. It may harm them. - This leaflet provides a summary of the most important information about nefazodone. If you would like more information, talk with your doctor or pharmacist. You can ask for information about nefazodone that is written for healthcare professionals. Seldane® is a registered trademark of Hoechst Marion Roussel Inc. (now Aventis Pharmaceuticals). Hismanal® and Propulsid® are registered trademarks of Janssen Pharmaceutica Products, L.P. Nardil® is a registered trademark of Parke-Davis. Parnate® is a registered trademark of SmithKline Beecham Pharmaceuticals. Halcion® is a registered trademark of Pharmacia & Upjohn. Orap® is a registered trademark of Gate Pharmaceuticals, a division of TEVA Pharmaceuticals USA. Tegretol® is a registered trademark of Novartis Pharmaceuticals Corporation. Manufactured In Israel By: TEVA PHARMACEUTICAL IND. LTD. Jerusalem, 91010, Israel Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev. A 8/2008 This Patient Information Leaflet has been approved by the U.S. Food and Drug Administration. Medication Guide Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Rx only Read the Medication Guide that comes with your or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member’s, healthcare provider about: What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: What else do I need to know about antidepressant medicines? Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants. Manufactured In Israel By: TEVA PHARMACEUTICAL IND. LTD. Jerusalem, 91010, Israel Manufactured For: TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev. E 5/2008 # Precautions with Alcohol Alcohol-Nefazodone 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 Nefazodone Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Nefazodone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Dutonin
45ea559b06bb2654521444dea4dd74f45798fed8	wikidoc	Isradipine	Isradipine # 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 Isradipine is a Calcium Channel Blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include peripheral edema, flushing, dizziness, headache, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - The dosage of isradipine should be individualized. - Initial dose: 2.5 mg b.i.d. alone or in combination with a thiazide diuretic. - An antihypertensive response usually occurs within 2-3 hours. Maximal response may require 2-4 weeks. - If a satisfactory reduction in blood pressure does not occur after this period, the dose may be adjusted in increments of 5 mg/day at 2-4 week intervals up to a maximum of 20 mg/day. - Most patients, however, show no additional response to doses above 10 mg/day, and adverse effects are increased in frequency above 10 mg/day. - The bioavailability of isradipine (increased AUC) is increased in elderly patients (above 65 years of age), patients with hepatic functional impairment, and patients with mild renal impairment. Ordinarily, the starting dose should still be 2.5 mg b.i.d. in these patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Isradipine sandbox in adult patients. ### Non–Guideline-Supported Use ### Angina - Dosing information - 7.5 mg - 2.5-7.5 mg PO tid # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for Isradipine 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 Isradipine sandbox in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Isradipine sandbox in pediatric patients. # Contraindications Isradipine is contraindicated in individuals who have shown hypersensitivity to any of the ingredients in the formulation # Warnings None ## PRECAUTIONS ### General Blood Pressure: Because isradipine decreases peripheral resistance, like other calcium blockers isradipine may occasionally produce symptomatic hypotension. However, symptoms like syncope and severe dizziness have rarely been reported in hypertensive patients administered isradipine, particularly at the initial recommended doses. Use in Patients with Congestive Heart Failure: Although acute hemodynamic studies in patients with congestive heart failure have shown that isradipine reduced afterload without impairing myocardial contractility, it has a negative inotropic effect at high doses in vitro and possibly in some patients. Caution should be exercised when using isradipine in congestive heart failure patients, particularly in combination with a beta-blocker. # Adverse Reactions ## Clinical Trials Experience In multiple dose U.S. studies in hypertension, 1228 patients received isradipine alone or in combination with other agents, principally a thiazide diuretic, 934 of them in controlled comparisons with placebo or active agents. An additional 652 patients (which includes 374 normal volunteers) received isradipine in U.S. studies of conditions other than hypertension, and 1321 patients received isradipine in non-U.S. studies. About 500 patients received isradipine in long-term hypertension studies, 410 of them for at least 6 months. The adverse reaction rates given below are principally based on controlled hypertension studies, but rarer serious events are derived from all exposures to isradipine, including foreign marketing experience. Most adverse reactions were mild and related to the vasodilatory effects of isradipine (dizziness, edema, palpitations, flushing, tachycardia), and many were transient. About 5% of isradipine patients left studies prematurely because of adverse reactions (vs. 3% of placebo patients and 6% of active control patients), principally due to headache, edema, dizziness, palpitations, and gastrointestinal disturbances. The following table shows the most common adverse reactions, volunteered or elicited, considered by the investigator to be at least possibly drug related. The results for the isradipine treated patients are presented for all doses pooled together (reported by 1% or greater of patients receiving any dose of isradipine), and also for the two treatment regimens most applicable to the treatment of hypertension with isradipine: (1) initial and maintenance dose of 2.5 mg b.i.d., and (2) initial dose of 2.5 mg b.i.d. followed by maintenance dose of 5 mg b.i.d. †Initial dose of 2.5 mg b.i.d. followed by maintenance dose of 5 mg b.i.d. †† Initial dose of 2.5 mg b.i.d. followed by sequential titration to 5 mg b.i.d., 7.5 mg b.i.d., and maintenance dose of 10 mg b.i.d. *Propranolol, prazosin, hydrochlorothiazide, enalapril, captopril. Except for headache, which is not clearly drug-related (see previous table), the more frequent adverse reactions listed show little change, or increase slightly, in frequency over time, as shown in the following table:]] Edema, palpitations, fatigue, and flushing appear to be dose-related, especially at the higher doses of 15-20 mg/day. In open-label, long-term studies of up to two years in duration, the adverse events reported were generally the same as those reported in the short-term controlled trials. The overall frequencies of these adverse events were slightly higher in the long-term than in the controlled studies, but as in the controlled trials most adverse reactions were mild and transient. The following adverse experiences were reported in 0.5%-1% of the isradipine-treated patients in hypertensive studies, or are rare. More serious events from this and other data sources, including postmarketing exposure, are shown in italics. The relationship of these adverse events to isradipine administration is uncertain. Skin: pruritus, urticaria. Musculoskeletal: cramps of legs/feet. Respiratory: cough. Cardiovascular: shortness of breath, hypotension, atrial fibrillation, ventricular fibrillation, myocardial infarction, heart failure. Gastrointestinal: abdominal discomfort, constipation, diarrhea. Urogenital: nocturia. Nervous System: drowsiness, insomnia, lethargy, nervousness, impotence, decreased libido, depression, syncope, paresthesia (which includes numbness and tingling),transient ischemic attack, stroke. Autonomic: hyperhidrosis, visual disturbance, dry mouth, numbness. Miscellaneous: throat discomfort, leukopenia, elevated liver function tests. ## Postmarketing Experience FDA Package Insert for Isradipine contains no information regarding postmarketing experience. # Drug Interactions Nitroglycerin: Isradipine has been safely coadministered with nitroglycerin. Hydrochlorothiazide: A study in normal healthy volunteers has shown that concomitant administration of isradipine and hydrochlorothiazide does not result in altered pharmacokinetics of either drug. In a study in hypertensive patients, addition of isradipine to existing hydrochlorothiazide therapy did not result in any unexpected adverse effects, and isradipine had an additional antihypertensive effect. Propranolol: In a single dose study in normal volunteers, co-administration of propranolol had a small effect on the rate but no effect on the extent of isradipine bioavailability. Significant increases in AUC (27%) and Cmax (58%) and decreases in tmax (23%) of propranolol were noted in this study. However, concomitant administration of 5 mg b.i.d. isradipine and 40 mg b.i.d. propranolol to healthy volunteers under steady-state conditions had no relevant effect on either drug’s bioavailability. AUC and Cmax differences were <20% between isradipine given singly and in combination with propranolol, and between propranolol given singly and in combination with isradipine. Cimetidine: In a study in healthy volunteers, a one-week course of cimetidine at 400 mg b.i.d. with a single 5 mg dose of isradipine on the sixth day showed an increase in isradipine mean peak plasma concentrations (36%) and significant increase in area under the curve (50%). If isradipine therapy is initiated in a patient currently receiving cimetidine, careful monitoring for adverse reactions is advised and downward dose adjustment may be required. Rifampicin: In a study with healthy volunteers, a six-day course of rifampicin at 600 mg/day followed by a single 5 mg dose of isradipine resulted in a reduction in isradipine levels to below detectable limits. If rifampicin therapy is required, isradipine concentrations and therapeutic effects are likely to be markedly reduced or abolished as a consequence of increased metabolism and higher clearance of isradipine. Warfarin: In a study with healthy volunteers, no clinically relevant pharmacokinetic or pharmacodynamic interaction between isradipine and racemic warfarin was seen when two single oral doses of warfarin (0.7 mg/kg body weight) were administered during 11 days of multiple-dose treatment with 5 mg b.i.d. isradipine. Neither racemic warfarin nor isradipine binding to plasma proteins in vitro was altered by the addition of the other drug. Digoxin: The concomitant administration of isradipine and digoxin in a single-dose pharmacokinetic study did not affect renal, nonrenal and total body clearance of digoxin. Fentanyl Anesthesia: Severe hypotension has been reported during fentanyl anesthesia with concomitant use of a beta-blocker and a calcium channel blocker. Even though such interactions have not been seen in clinical studies with isradipine, an increased volume of circulating fluids might be required if such an interaction were to occur. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Isradipine was administered orally to rats and rabbits during organogenesis. Treatment of pregnant rats with doses of 6, 20, or 60 mg/kg/day produced a significant reduction in maternal weight gain during treatment with the highest dose (150 times the maximum recommended human daily dose) but with no lasting effects on the mother or the offspring. Treatment of pregnant rabbits with doses of 1, 3, or 10 mg/kg/day (2.5, 7.5, and 25 times the maximum recommended human daily dose) produced decrements in maternal body weight gain and increased fetal resorption at the two higher doses. There was no evidence of embryotoxicity at doses which were not maternotoxic and no evidence of teratogenicity at any dose tested. In a peri/postnatal administration study in rats, reduced maternal body weight gain during late pregnancy at oral doses of 20 and 60 mg/kg/day isradipine was associated with reduced birth weights and decreased peri and postnatal pup survival. There are no adequate and well controlled studies in pregnant women. The use of isradipine during pregnancy should only be considered if the potential benefit outweighs potential risks. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Isradipine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Isradipine during labor and delivery. ### Nursing Mothers It is not known whether isradipine is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects of isradipine on nursing infants, a decision should be made as to whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Isradipine in geriatric settings. ### Gender There is no FDA guidance on the use of Isradipine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Isradipine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Isradipine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Isradipine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Isradipine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Isradipine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA Package Insert for Isradipine contains no information regarding drug monitoring . # IV Compatibility FDA Package Insert for Isradipine contains no information regarding IV compatibility. # Overdosage Minimal empirical data are available on isradipine overdosage. Three individual suicide attempts with dosages of isradipine reported to be from 20 mg up to 100 mg resulted in lethargy, sinus tachycardiaand, in the case of the person ingesting 100 mg, transient hypotension which responded to fluid therapy. A foreign report of the ingestion of 200 mg of isradipine with ethanol resulted only in flushing, tachycardiawith ST depression on ECG, and hypotension, all of which were reversible. The ingestion of 5 mg isradipine by a 22-month child and the accidental ingestion of 100 mg of isradipine by a 58-year old female did not result in any sequelae. Available data suggest that, as with other dihydropyridines, overdosage with isradipine might result in excessive peripheral vasodilation with subsequent marked and probably prolonged systemic hypotension, and tachycardia. Emesis, gastric lavage, administration of activated charcoal followed in 30 minutes by a saline cathartic would be reasonable therapy. Isradipine is highly protein-bound and not removed by hemodialysis. Overdosage characterized by clinically significant hypotension should be treated with active cardiovascular support including monitoring of cardiac and respiratory function, elevation of lower extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor (such as epinephrine, norepinephrine, or levarterenol) may be helpful in restoring a normotensive state, provided that there is no contraindication to its use. Refractory hypotension or AV conduction disturbances may be treated with intravenous calcium salts, or glucagon. Cimetidine should be withheld in such instances due to the risk of further increasing plasma isradipine levels. Significant lethality was observed in mice given oral doses of over 200 mg/kg and rabbits given about 50 mg/kg of isradipine. Rats tolerated doses of over 2000 mg/kg without effects on survival. # Pharmacology ## Mechanism of Action Isradipine is a dihydropyridine calcium channel blocker. It binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and smooth muscle. The effects observed in mechanistic experiments in vitro and studied in intact animals and man are compatible with this mechanism of action and are typical of the class. Except for diureticactivity, the mechanism of which is not clearly understood, the pharmacodynamic effects of isradipine observed in whole animals can also be explained by calcium channel blocking activity, especially dilating effects in arterioles which reduce systemic resistance and lower blood pressure, with a small increase in resting heart rate. Although like other dihydropyridine calcium channel blockers, isradipine has negative inotropic effects in vitro, studies conducted in intact anesthetized animals have shown that the vasodilating effect occurs at doses lower than those which affect contractility. In patients with normal ventricular function, isradipine’s afterload reducing properties lead to some increase in cardiac output. Effects in patients with impaired ventricular function have not been fully studied. ## Structure Isradipine is a calcium antagonist available for oral administration in capsules containing 2.5 mg or 5 mg. The structural formula of isradipine is: Chemically, isradipine is 3,5-Pyridinedicarboxylic acid, 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-, methyl 1-methylethyl ester. Isradipine is a yellow, fine crystalline powder which is odorless or has a faint characteristic odor. Isradipine is practically insoluble in water (<10 mg/L at 37ºC), but is soluble in ethanol and freely soluble in acetone, chloroform and methylene chloride. ## Active Ingredient: isradipine Inactive Ingredients: colloidal silicon dioxide, red iron oxide (2.5 mg capsule only, yellow iron oxide, gelatin, anhydrous lactose, magnesium stearate, sodium lauryl sulfate, starch (corn), titanium dioxide, black ink: black iron oxide, shellac and potassium hydroxide. ## Pharmacodynamics In man, peripheral vasodilation produced by isradipine is reflected by decreased systemic vascular resistance and increased cardiac output. Hemodynamic studies conducted in patients with normal left ventricular function produced, following intravenous isradipine administration, increases in cardiac index, stroke volume index, coronary sinus blood flow, heart rate and peak positive left ventricular dP/dt. Systemic, coronary, and pulmonary vascular resistance was decreased. These studies were conducted with doses of isradipine which produced clinically significant decreases in blood pressure. The clinical consequences of these hemodynamic effects, if any, have not been evaluated. Effects on heart rate are variable, dependent upon rate of administration and presence of underlying cardiac condition. While increases in both peak positive dP/dt and LV ejection fraction are seen when intravenous isradipine is given, it is impossible to conclude that these represent a positive inotropic effect due to simultaneous changes in preload and afterload. In patients with coronary artery disease undergoing atrial pacing during cardiac catheterization, intravenous isradipine diminished abnormalities of systolic performance. In patients with moderate left ventricular dysfunction, oral and intravenous isradipine in doses which reduce blood pressure by 12% to 30%, resulted in improvement in cardiac index without increase in heart rate, and with no change or reduction in pulmonary capillary wedge pressure. Combination of isradipine and propranolol did not significantly affect left ventricular dP/dt max. The clinical consequences of these effects have not been evaluated. ## Pharmacokinetics sradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%. Isradipine is detectable in plasma within 20 minutes after administration of single oral doses of 2.5-20 mg, and peak concentrations of approximately 1 ng/mL/mg dosed occur about 1.5 hours after drug administration. Administration of isradipine with food significantly increases the time to peak by about an hour, but has no effect on the total bioavailability (area under the curve) of the drug. Isradipine is 95% bound to plasma proteins. Both peak plasma concentration and AUC exhibit a linear relationship to dose over the 0-20 mg dose range. The elimination of isradipine is biphasic with an early half-life of 1 ½-2 hours, and a terminal half-life of about 8 hours. The total body clearance of isradipine is 1.4 L/min and the apparent volume od disturbance is 3 L/kg. Isradipine is completely metabolized prior to excretion, and no unchanged drug is detected in the urine. Six metabolites have been characterized in blood and urine, with the mono acids of the pyridine derivative and a cyclic lactone product accounting for >75% fo the material identified. Approximately 60%-65% of an administered dose is excreted in the urine and 25%-30% in the feces. Mild renal impairment (creatinine clearance 30 to 80 mL/min) increases the bioavailability (AUC) of isradipine by 45%. Progressive deterioration reverses this trend, and patients with severe renal failure (creatinine clearance <10 mL/min) who have been on hemodialysis show a 20% to 50% lower AUC than healthy volunteers. No pharmacokinetic information is available in drug therapy during hemodialysis. In elderly patients Cmax and AUC are increased by 13% and 40%, respectively; in patients with hepatic impairment, Cmax and AUC are increased by 32% and 52%, respectively. ## Electrophysiologic Effects In general, no detrimental effects on the cardiac conduction system were seen with the use of isradipine. Electrophysiologic studies were conducted on patients with normal sinus and atrioventricular node function. Intravenous isradipine in doses which reduce systolic blood pressure did not affect PR, QRS, AH- or HV- intervals. No changes were seen in Wenckebach cycle length, atrial, and ventricular refractory periods. Slight prolongation of QTc interval of 3% was seen in one study. Effects on sinus node recovery time (CSNRT) were mild or not seen. In patients with sick sinus syndrome, at doses which significantly reduced blood pressure, intravenous isradipine resulted in no depressant effect on sinus and atrioventricular node function. - AH = conduction time from low right atrium to His bundle deflection, or AV nodal conduction time; HV = conduction time through His bundle and the bundle branch-Purkinje system. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility Treatment of male rats for 2 years with 2.5, 12.5, or 62.5 mg/kg/day isradipine admixed with the diet (approximately 6, 31, and 156 times the maximum recommended daily dose based on a 50 kg man) resulted in dose dependent increases in the incidence of benign Leydig cell tumors and testicular hyperplasiarelative to untreated control animals. These findings, which were replicated in a subsequent experiment, may have been indirectly related to an effect of isradipine on circulating gonadotropin levels in the rats; a comparable endocrine effect was not evident in male patients receiving therapeutic doses of the drug on a chronic basis. Treatment of mice for two years with 2.5, 15, or 80 mg/kg/day isradipine in the diet (approximately 6, 38, and 200 times the maximum recommended dose based on a 50 kg man) showed no evidence of oncogenicity. There was no evidence of mutagenic potential based on the results of a battery of mutagenic tests. No effect on fertility was observed in male and female rats treated with up to 60 mg/kg/day isradipine. # Clinical Studies FDA Package Insert for Isradipine contains no information regarding clinical studies. # How Supplied Isradipine Capsules, USP 2.5 mg are Filled Gelatin Capsules Size #3, Cap: White Opaque/Body: White Opaque with Imprint "A-263" on cap and body. Available in bottles of 100's and 500's. Isradipine Capsules, USP 5 mg are Filled Gelatin Capsules Size #3, Cap: Flesh Opaque/Body: Flesh Opaque with Imprint "A-264" on cap and body. Available in bottles of 100's and 500's. ## Storage Store 20°- 25°C (68°- 77°F) . Dispense contents in a tight, light-resistant container as defined in the USP, with a child-resistant closure as required. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information FDA Package Insert for Isradipine contains no information regarding Patient Counseling Information. # Precautions with Alcohol Alcohol-Isradipine sandbox interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Dynacirc - Dynacirc CR # Look-Alike Drug Names Dynacirc - Dynacin # Drug Shortage Status # Price	Isradipine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]; Turky Alkathery, M.D. [3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Isradipine is a Calcium Channel Blocker that is FDA approved for the treatment of hypertension. Common adverse reactions include peripheral edema, flushing, dizziness, headache, fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Hypertension - The dosage of isradipine should be individualized. - Initial dose: 2.5 mg b.i.d. alone or in combination with a thiazide diuretic. - An antihypertensive response usually occurs within 2-3 hours. Maximal response may require 2-4 weeks. - If a satisfactory reduction in blood pressure does not occur after this period, the dose may be adjusted in increments of 5 mg/day at 2-4 week intervals up to a maximum of 20 mg/day. - Most patients, however, show no additional response to doses above 10 mg/day, and adverse effects are increased in frequency above 10 mg/day. - The bioavailability of isradipine (increased AUC) is increased in elderly patients (above 65 years of age), patients with hepatic functional impairment, and patients with mild renal impairment. Ordinarily, the starting dose should still be 2.5 mg b.i.d. in these patients. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Isradipine sandbox in adult patients. ### Non–Guideline-Supported Use ### Angina - Dosing information - 7.5 mg [1] - 2.5-7.5 mg PO tid [2] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) FDA Package Insert for Isradipine 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 Isradipine sandbox in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Isradipine sandbox in pediatric patients. # Contraindications Isradipine is contraindicated in individuals who have shown hypersensitivity to any of the ingredients in the formulation # Warnings None ## PRECAUTIONS ### General Blood Pressure: Because isradipine decreases peripheral resistance, like other calcium blockers isradipine may occasionally produce symptomatic hypotension. However, symptoms like syncope and severe dizziness have rarely been reported in hypertensive patients administered isradipine, particularly at the initial recommended doses. Use in Patients with Congestive Heart Failure: Although acute hemodynamic studies in patients with congestive heart failure have shown that isradipine reduced afterload without impairing myocardial contractility, it has a negative inotropic effect at high doses in vitro and possibly in some patients. Caution should be exercised when using isradipine in congestive heart failure patients, particularly in combination with a beta-blocker. # Adverse Reactions ## Clinical Trials Experience In multiple dose U.S. studies in hypertension, 1228 patients received isradipine alone or in combination with other agents, principally a thiazide diuretic, 934 of them in controlled comparisons with placebo or active agents. An additional 652 patients (which includes 374 normal volunteers) received isradipine in U.S. studies of conditions other than hypertension, and 1321 patients received isradipine in non-U.S. studies. About 500 patients received isradipine in long-term hypertension studies, 410 of them for at least 6 months. The adverse reaction rates given below are principally based on controlled hypertension studies, but rarer serious events are derived from all exposures to isradipine, including foreign marketing experience. Most adverse reactions were mild and related to the vasodilatory effects of isradipine (dizziness, edema, palpitations, flushing, tachycardia), and many were transient. About 5% of isradipine patients left studies prematurely because of adverse reactions (vs. 3% of placebo patients and 6% of active control patients), principally due to headache, edema, dizziness, palpitations, and gastrointestinal disturbances. The following table shows the most common adverse reactions, volunteered or elicited, considered by the investigator to be at least possibly drug related. The results for the isradipine treated patients are presented for all doses pooled together (reported by 1% or greater of patients receiving any dose of isradipine), and also for the two treatment regimens most applicable to the treatment of hypertension with isradipine: (1) initial and maintenance dose of 2.5 mg b.i.d., and (2) initial dose of 2.5 mg b.i.d. followed by maintenance dose of 5 mg b.i.d. †Initial dose of 2.5 mg b.i.d. followed by maintenance dose of 5 mg b.i.d. †† Initial dose of 2.5 mg b.i.d. followed by sequential titration to 5 mg b.i.d., 7.5 mg b.i.d., and maintenance dose of 10 mg b.i.d. Propranolol, prazosin, hydrochlorothiazide, enalapril, captopril. Except for headache, which is not clearly drug-related (see previous table), the more frequent adverse reactions listed show little change, or increase slightly, in frequency over time, as shown in the following table:]] Edema, palpitations, fatigue, and flushing appear to be dose-related, especially at the higher doses of 15-20 mg/day. In open-label, long-term studies of up to two years in duration, the adverse events reported were generally the same as those reported in the short-term controlled trials. The overall frequencies of these adverse events were slightly higher in the long-term than in the controlled studies, but as in the controlled trials most adverse reactions were mild and transient. The following adverse experiences were reported in 0.5%-1% of the isradipine-treated patients in hypertensive studies, or are rare. More serious events from this and other data sources, including postmarketing exposure, are shown in italics. The relationship of these adverse events to isradipine administration is uncertain. Skin: pruritus, urticaria. Musculoskeletal: cramps of legs/feet. Respiratory: cough. Cardiovascular: shortness of breath, hypotension, atrial fibrillation, ventricular fibrillation, myocardial infarction, heart failure. Gastrointestinal: abdominal discomfort, constipation, diarrhea. Urogenital: nocturia. Nervous System: drowsiness, insomnia, lethargy, nervousness, impotence, decreased libido, depression, syncope, paresthesia (which includes numbness and tingling),transient ischemic attack, stroke. Autonomic: hyperhidrosis, visual disturbance, dry mouth, numbness. Miscellaneous: throat discomfort, leukopenia, elevated liver function tests. ## Postmarketing Experience FDA Package Insert for Isradipine contains no information regarding postmarketing experience. # Drug Interactions Nitroglycerin: Isradipine has been safely coadministered with nitroglycerin. Hydrochlorothiazide: A study in normal healthy volunteers has shown that concomitant administration of isradipine and hydrochlorothiazide does not result in altered pharmacokinetics of either drug. In a study in hypertensive patients, addition of isradipine to existing hydrochlorothiazide therapy did not result in any unexpected adverse effects, and isradipine had an additional antihypertensive effect. Propranolol: In a single dose study in normal volunteers, co-administration of propranolol had a small effect on the rate but no effect on the extent of isradipine bioavailability. Significant increases in AUC (27%) and Cmax (58%) and decreases in tmax (23%) of propranolol were noted in this study. However, concomitant administration of 5 mg b.i.d. isradipine and 40 mg b.i.d. propranolol to healthy volunteers under steady-state conditions had no relevant effect on either drug’s bioavailability. AUC and Cmax differences were <20% between isradipine given singly and in combination with propranolol, and between propranolol given singly and in combination with isradipine. Cimetidine: In a study in healthy volunteers, a one-week course of cimetidine at 400 mg b.i.d. with a single 5 mg dose of isradipine on the sixth day showed an increase in isradipine mean peak plasma concentrations (36%) and significant increase in area under the curve (50%). If isradipine therapy is initiated in a patient currently receiving cimetidine, careful monitoring for adverse reactions is advised and downward dose adjustment may be required. Rifampicin: In a study with healthy volunteers, a six-day course of rifampicin at 600 mg/day followed by a single 5 mg dose of isradipine resulted in a reduction in isradipine levels to below detectable limits. If rifampicin therapy is required, isradipine concentrations and therapeutic effects are likely to be markedly reduced or abolished as a consequence of increased metabolism and higher clearance of isradipine. Warfarin: In a study with healthy volunteers, no clinically relevant pharmacokinetic or pharmacodynamic interaction between isradipine and racemic warfarin was seen when two single oral doses of warfarin (0.7 mg/kg body weight) were administered during 11 days of multiple-dose treatment with 5 mg b.i.d. isradipine. Neither racemic warfarin nor isradipine binding to plasma proteins in vitro was altered by the addition of the other drug. Digoxin: The concomitant administration of isradipine and digoxin in a single-dose pharmacokinetic study did not affect renal, nonrenal and total body clearance of digoxin. Fentanyl Anesthesia: Severe hypotension has been reported during fentanyl anesthesia with concomitant use of a beta-blocker and a calcium channel blocker. Even though such interactions have not been seen in clinical studies with isradipine, an increased volume of circulating fluids might be required if such an interaction were to occur. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Isradipine was administered orally to rats and rabbits during organogenesis. Treatment of pregnant rats with doses of 6, 20, or 60 mg/kg/day produced a significant reduction in maternal weight gain during treatment with the highest dose (150 times the maximum recommended human daily dose) but with no lasting effects on the mother or the offspring. Treatment of pregnant rabbits with doses of 1, 3, or 10 mg/kg/day (2.5, 7.5, and 25 times the maximum recommended human daily dose) produced decrements in maternal body weight gain and increased fetal resorption at the two higher doses. There was no evidence of embryotoxicity at doses which were not maternotoxic and no evidence of teratogenicity at any dose tested. In a peri/postnatal administration study in rats, reduced maternal body weight gain during late pregnancy at oral doses of 20 and 60 mg/kg/day isradipine was associated with reduced birth weights and decreased peri and postnatal pup survival. There are no adequate and well controlled studies in pregnant women. The use of isradipine during pregnancy should only be considered if the potential benefit outweighs potential risks. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Isradipine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Isradipine during labor and delivery. ### Nursing Mothers It is not known whether isradipine is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse effects of isradipine on nursing infants, a decision should be made as to whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Isradipine in geriatric settings. ### Gender There is no FDA guidance on the use of Isradipine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Isradipine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Isradipine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Isradipine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Isradipine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Isradipine in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring FDA Package Insert for Isradipine contains no information regarding drug monitoring . # IV Compatibility FDA Package Insert for Isradipine contains no information regarding IV compatibility. # Overdosage Minimal empirical data are available on isradipine overdosage. Three individual suicide attempts with dosages of isradipine reported to be from 20 mg up to 100 mg resulted in lethargy, sinus tachycardiaand, in the case of the person ingesting 100 mg, transient hypotension which responded to fluid therapy. A foreign report of the ingestion of 200 mg of isradipine with ethanol resulted only in flushing, tachycardiawith ST depression on ECG, and hypotension, all of which were reversible. The ingestion of 5 mg isradipine by a 22-month child and the accidental ingestion of 100 mg of isradipine by a 58-year old female did not result in any sequelae. Available data suggest that, as with other dihydropyridines, overdosage with isradipine might result in excessive peripheral vasodilation with subsequent marked and probably prolonged systemic hypotension, and tachycardia. Emesis, gastric lavage, administration of activated charcoal followed in 30 minutes by a saline cathartic would be reasonable therapy. Isradipine is highly protein-bound and not removed by hemodialysis. Overdosage characterized by clinically significant hypotension should be treated with active cardiovascular support including monitoring of cardiac and respiratory function, elevation of lower extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor (such as epinephrine, norepinephrine, or levarterenol) may be helpful in restoring a normotensive state, provided that there is no contraindication to its use. Refractory hypotension or AV conduction disturbances may be treated with intravenous calcium salts, or glucagon. Cimetidine should be withheld in such instances due to the risk of further increasing plasma isradipine levels. Significant lethality was observed in mice given oral doses of over 200 mg/kg and rabbits given about 50 mg/kg of isradipine. Rats tolerated doses of over 2000 mg/kg without effects on survival. # Pharmacology ## Mechanism of Action Isradipine is a dihydropyridine calcium channel blocker. It binds to calcium channels with high affinity and specificity and inhibits calcium flux into cardiac and smooth muscle. The effects observed in mechanistic experiments in vitro and studied in intact animals and man are compatible with this mechanism of action and are typical of the class. Except for diureticactivity, the mechanism of which is not clearly understood, the pharmacodynamic effects of isradipine observed in whole animals can also be explained by calcium channel blocking activity, especially dilating effects in arterioles which reduce systemic resistance and lower blood pressure, with a small increase in resting heart rate. Although like other dihydropyridine calcium channel blockers, isradipine has negative inotropic effects in vitro, studies conducted in intact anesthetized animals have shown that the vasodilating effect occurs at doses lower than those which affect contractility. In patients with normal ventricular function, isradipine’s afterload reducing properties lead to some increase in cardiac output. Effects in patients with impaired ventricular function have not been fully studied. ## Structure Isradipine is a calcium antagonist available for oral administration in capsules containing 2.5 mg or 5 mg. The structural formula of isradipine is: Chemically, isradipine is 3,5-Pyridinedicarboxylic acid, 4-(4-benzofurazanyl)-1,4-dihydro-2,6-dimethyl-, methyl 1-methylethyl ester. Isradipine is a yellow, fine crystalline powder which is odorless or has a faint characteristic odor. Isradipine is practically insoluble in water (<10 mg/L at 37ºC), but is soluble in ethanol and freely soluble in acetone, chloroform and methylene chloride. ## Active Ingredient: isradipine Inactive Ingredients: colloidal silicon dioxide, red iron oxide (2.5 mg capsule only, yellow iron oxide, gelatin, anhydrous lactose, magnesium stearate, sodium lauryl sulfate, starch (corn), titanium dioxide, black ink: black iron oxide, shellac and potassium hydroxide. ## Pharmacodynamics In man, peripheral vasodilation produced by isradipine is reflected by decreased systemic vascular resistance and increased cardiac output. Hemodynamic studies conducted in patients with normal left ventricular function produced, following intravenous isradipine administration, increases in cardiac index, stroke volume index, coronary sinus blood flow, heart rate and peak positive left ventricular dP/dt. Systemic, coronary, and pulmonary vascular resistance was decreased. These studies were conducted with doses of isradipine which produced clinically significant decreases in blood pressure. The clinical consequences of these hemodynamic effects, if any, have not been evaluated. Effects on heart rate are variable, dependent upon rate of administration and presence of underlying cardiac condition. While increases in both peak positive dP/dt and LV ejection fraction are seen when intravenous isradipine is given, it is impossible to conclude that these represent a positive inotropic effect due to simultaneous changes in preload and afterload. In patients with coronary artery disease undergoing atrial pacing during cardiac catheterization, intravenous isradipine diminished abnormalities of systolic performance. In patients with moderate left ventricular dysfunction, oral and intravenous isradipine in doses which reduce blood pressure by 12% to 30%, resulted in improvement in cardiac index without increase in heart rate, and with no change or reduction in pulmonary capillary wedge pressure. Combination of isradipine and propranolol did not significantly affect left ventricular dP/dt max. The clinical consequences of these effects have not been evaluated. ## Pharmacokinetics sradipine is 90%-95% absorbed and is subject to extensive first-pass metabolism, resulting in a bioavailability of about 15%-24%. Isradipine is detectable in plasma within 20 minutes after administration of single oral doses of 2.5-20 mg, and peak concentrations of approximately 1 ng/mL/mg dosed occur about 1.5 hours after drug administration. Administration of isradipine with food significantly increases the time to peak by about an hour, but has no effect on the total bioavailability (area under the curve) of the drug. Isradipine is 95% bound to plasma proteins. Both peak plasma concentration and AUC exhibit a linear relationship to dose over the 0-20 mg dose range. The elimination of isradipine is biphasic with an early half-life of 1 ½-2 hours, and a terminal half-life of about 8 hours. The total body clearance of isradipine is 1.4 L/min and the apparent volume od disturbance is 3 L/kg. Isradipine is completely metabolized prior to excretion, and no unchanged drug is detected in the urine. Six metabolites have been characterized in blood and urine, with the mono acids of the pyridine derivative and a cyclic lactone product accounting for >75% fo the material identified. Approximately 60%-65% of an administered dose is excreted in the urine and 25%-30% in the feces. Mild renal impairment (creatinine clearance 30 to 80 mL/min) increases the bioavailability (AUC) of isradipine by 45%. Progressive deterioration reverses this trend, and patients with severe renal failure (creatinine clearance <10 mL/min) who have been on hemodialysis show a 20% to 50% lower AUC than healthy volunteers. No pharmacokinetic information is available in drug therapy during hemodialysis. In elderly patients Cmax and AUC are increased by 13% and 40%, respectively; in patients with hepatic impairment, Cmax and AUC are increased by 32% and 52%, respectively. ## Electrophysiologic Effects In general, no detrimental effects on the cardiac conduction system were seen with the use of isradipine. Electrophysiologic studies were conducted on patients with normal sinus and atrioventricular node function. Intravenous isradipine in doses which reduce systolic blood pressure did not affect PR, QRS, AH or HV* intervals. No changes were seen in Wenckebach cycle length, atrial, and ventricular refractory periods. Slight prolongation of QTc interval of 3% was seen in one study. Effects on sinus node recovery time (CSNRT) were mild or not seen. In patients with sick sinus syndrome, at doses which significantly reduced blood pressure, intravenous isradipine resulted in no depressant effect on sinus and atrioventricular node function. - AH = conduction time from low right atrium to His bundle deflection, or AV nodal conduction time; HV = conduction time through His bundle and the bundle branch-Purkinje system. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility Treatment of male rats for 2 years with 2.5, 12.5, or 62.5 mg/kg/day isradipine admixed with the diet (approximately 6, 31, and 156 times the maximum recommended daily dose based on a 50 kg man) resulted in dose dependent increases in the incidence of benign Leydig cell tumors and testicular hyperplasiarelative to untreated control animals. These findings, which were replicated in a subsequent experiment, may have been indirectly related to an effect of isradipine on circulating gonadotropin levels in the rats; a comparable endocrine effect was not evident in male patients receiving therapeutic doses of the drug on a chronic basis. Treatment of mice for two years with 2.5, 15, or 80 mg/kg/day isradipine in the diet (approximately 6, 38, and 200 times the maximum recommended dose based on a 50 kg man) showed no evidence of oncogenicity. There was no evidence of mutagenic potential based on the results of a battery of mutagenic tests. No effect on fertility was observed in male and female rats treated with up to 60 mg/kg/day isradipine. # Clinical Studies FDA Package Insert for Isradipine contains no information regarding clinical studies. # How Supplied Isradipine Capsules, USP 2.5 mg are Filled Gelatin Capsules Size #3, Cap: White Opaque/Body: White Opaque with Imprint "A-263" on cap and body. Available in bottles of 100's and 500's. Isradipine Capsules, USP 5 mg are Filled Gelatin Capsules Size #3, Cap: Flesh Opaque/Body: Flesh Opaque with Imprint "A-264" on cap and body. Available in bottles of 100's and 500's. ## Storage Store 20°- 25°C (68°- 77°F) [see USP Controlled Room Temperature]. Dispense contents in a tight, light-resistant container as defined in the USP, with a child-resistant closure as required. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information FDA Package Insert for Isradipine contains no information regarding Patient Counseling Information. # Precautions with Alcohol Alcohol-Isradipine sandbox interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Dynacirc - Dynacirc CR # Look-Alike Drug Names Dynacirc - Dynacin[3] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Dynacirc
37686e9bfe4cbfb167d989751afa96d1ecf5905f	wikidoc	Dysgenesis	Dysgenesis Dysgenesis may refer to: - Dysgenesis (embryology), which indicates abnormal organ development during embryonic growth and development - Anterior segment dysgenesis, a failure of the normal development of the tissues of the anterior segment of the eye - "Hybrid dysgenesis", which relates to a high mutation rate in certain Drosophila strains caused by the transposition of P elements - The study of dysgenics, a theory that deterioration of hereditary qualities can occur in offspring due to survival of or reproduction by less well-adapted individuals	Dysgenesis Dysgenesis may refer to: - Dysgenesis (embryology), which indicates abnormal organ development during embryonic growth and development - Anterior segment dysgenesis, a failure of the normal development of the tissues of the anterior segment of the eye - "Hybrid dysgenesis", which relates to a high mutation rate in certain Drosophila strains caused by the transposition of P elements - The study of dysgenics, a theory that deterioration of hereditary qualities can occur in offspring due to survival of or reproduction by less well-adapted individuals	https://www.wikidoc.org/index.php/Dysgenesis
cebb89610dd1f0b620b4c479c7fab420da76f5f5	wikidoc	Dysprosody	Dysprosody # Overview Dysprosody is a type of speech disorder that occurs following a lesion of the nondominant hemisphere of the brain. In dysprosody, the patient has difficulty in the expression or comprehension of the emotional components of speech, such as melody, emphasis, inflection, and gesturing. # Expressive dysprosody Expressive dysprosody is characterized by an inability to express inflection or emotion in speech. It results from a lesion of the area corresponding to Broca's area but on the nondominant hemisphere. # Receptive dysprosody Receptive dysprosody is characterized by an inability to comprehend inflection or emotion in speech. It results from a lesion of the area corresponding to Wenicke's area but on the nondominant hemisphere.	Dysprosody Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Dysprosody is a type of speech disorder that occurs following a lesion of the nondominant hemisphere of the brain. In dysprosody, the patient has difficulty in the expression or comprehension of the emotional components of speech, such as melody, emphasis, inflection, and gesturing.[1] # Expressive dysprosody Expressive dysprosody is characterized by an inability to express inflection or emotion in speech. It results from a lesion of the area corresponding to Broca's area but on the nondominant hemisphere.[2] # Receptive dysprosody Receptive dysprosody is characterized by an inability to comprehend inflection or emotion in speech. It results from a lesion of the area corresponding to Wenicke's area but on the nondominant hemisphere.[3]	https://www.wikidoc.org/index.php/Dysprosody
ed7dd32f122ae7b4e29822ede217e15ce3913d9a	wikidoc	Dystrophin	Dystrophin Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex (DAPC). Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere. The DMD gene, encoding the dystrophin protein, is one of the longest human genes known, covering 2.3 megabases (0.08% of the human genome) at locus Xp21. The primary transcript in muscle measures about 2,100 kilobases and takes 16 hours to transcribe; the mature mRNA measures 14.0 kilobases. The 79-exon muscle transcript codes for a protein of 3685 amino acid residues. # Function Dystrophin is a protein located between the sarcolemma and the outermost layer of myofilaments in the muscle fiber (myofiber). It is a cohesive protein, linking actin filaments to other support proteins that reside on the inside surface of each muscle fiber's plasma membrane (sarcolemma). These support proteins on the inside surface of the sarcolemma in turn links to two other consecutive proteins for a total of three linking proteins. The final linking protein is attached to the fibrous endomysium of the entire muscle fiber. Dystrophin supports muscle fiber strength, and the absence of dystrophin reduces muscle stiffness, increases sarcolemmal deformability, and compromises the mechanical stability of costameres and their connections to nearby myofibrils. This has been shown in recent studies where biomechanical properties of the sarcolemma and its links through costameres to the contractile apparatus were measured, and helps to prevent muscle fiber injury. Movement of thin filaments (actin) creates a pulling force on the extracellular connective tissue that eventually becomes the tendon of the muscle. The dystrophin associated protein complex also helps scaffold various signalling and channel proteins, implicating the DAPC in regulation of signalling processes. # Pathology Dystrophin deficiency has been definitively established as one of the root causes of the general class of myopathies collectively referred to as muscular dystrophy. The large cytosolic protein was first identified in 1987 by Louis M. Kunkel, after concurrent works by Kunkel and Robert G. Worton to characterize the mutated gene that causes Duchenne muscular dystrophy (DMD). Normal skeletal muscle tissue contains only small amounts of dystrophin (about 0.002% of total muscle protein), but its absence (or abnormal expression) leads to the development of a severe and currently incurable constellation of symptoms most readily characterized by several aberrant intracellular signaling pathways that ultimately yield pronounced myofiber necrosis as well as progressive muscle weakness and fatigability. Most DMD patients become wheelchair-dependent early in life, and the gradual development of cardiac hypertrophy—a result of severe myocardial fibrosis—typically results in premature death in the first two or three decades of life. Variants (mutations) in the DMD gene that lead to the production of too little or a defective, internally shortened but partially functional dystrophin protein, result in a display of a much milder dystrophic phenotype in affected patients, resulting in the disease known as Becker's muscular dystrophy (BMD). In some cases, the patient's phenotype is such that experts may decide differently on whether a patient should be diagnosed with DMD or BMD. The theory currently most commonly used to predict whether a variant will result in a DMD or BMD phenotype, is the reading frame rule. Though its role in airway smooth muscle is not well established, recent research indicates that dystrophin along with other subunits of dystrophin glycoprotein complex is associated with phenotype maturation. # Interactions Dystrophin has been shown to interact with: - DTNA, - SNTA1, and - SNTB1. # Neanderthal admixture A variant of the DMD gene, which is on the X chromosome, named B006, appears to be an introgression from a Neanderthal-modern human mating.	Dystrophin Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex (DAPC). Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere. The DMD gene, encoding the dystrophin protein, is one of the longest human genes known, covering 2.3 megabases (0.08% of the human genome) at locus Xp21. The primary transcript in muscle measures about 2,100 kilobases and takes 16 hours to transcribe;[1] the mature mRNA measures 14.0 kilobases.[2] The 79-exon muscle transcript[3] codes for a protein of 3685 amino acid residues.[4] # Function Dystrophin is a protein located between the sarcolemma and the outermost layer of myofilaments in the muscle fiber (myofiber). It is a cohesive protein, linking actin filaments to other support proteins that reside on the inside surface of each muscle fiber's plasma membrane (sarcolemma). These support proteins on the inside surface of the sarcolemma in turn links to two other consecutive proteins for a total of three linking proteins. The final linking protein is attached to the fibrous endomysium of the entire muscle fiber. Dystrophin supports muscle fiber strength, and the absence of dystrophin reduces muscle stiffness, increases sarcolemmal deformability, and compromises the mechanical stability of costameres and their connections to nearby myofibrils. This has been shown in recent studies where biomechanical properties of the sarcolemma and its links through costameres to the contractile apparatus were measured,[5] and helps to prevent muscle fiber injury. Movement of thin filaments (actin) creates a pulling force on the extracellular connective tissue that eventually becomes the tendon of the muscle. The dystrophin associated protein complex also helps scaffold various signalling and channel proteins, implicating the DAPC in regulation of signalling processes.[6] # Pathology Dystrophin deficiency has been definitively established as one of the root causes of the general class of myopathies collectively referred to as muscular dystrophy. The large cytosolic protein was first identified in 1987 by Louis M. Kunkel,[7] after concurrent works by Kunkel and Robert G. Worton to characterize the mutated gene that causes Duchenne muscular dystrophy (DMD).[8][9] Normal skeletal muscle tissue contains only small amounts of dystrophin (about 0.002% of total muscle protein),[10] but its absence (or abnormal expression) leads to the development of a severe and currently incurable constellation of symptoms most readily characterized by several aberrant intracellular signaling pathways that ultimately yield pronounced myofiber necrosis as well as progressive muscle weakness and fatigability. Most DMD patients become wheelchair-dependent early in life, and the gradual development of cardiac hypertrophy—a result of severe myocardial fibrosis—typically results in premature death in the first two or three decades of life. Variants (mutations) in the DMD gene that lead to the production of too little or a defective, internally shortened but partially functional dystrophin protein, result in a display of a much milder dystrophic phenotype in affected patients, resulting in the disease known as Becker's muscular dystrophy (BMD). In some cases, the patient's phenotype is such that experts may decide differently on whether a patient should be diagnosed with DMD or BMD. The theory currently most commonly used to predict whether a variant will result in a DMD or BMD phenotype, is the reading frame rule.[11] Though its role in airway smooth muscle is not well established, recent research indicates that dystrophin along with other subunits of dystrophin glycoprotein complex is associated with phenotype maturation.[12] # Interactions Dystrophin has been shown to interact with: - DTNA,[13] - SNTA1,[14][15][16] and - SNTB1.[17] # Neanderthal admixture A variant of the DMD gene, which is on the X chromosome, named B006, appears to be an introgression from a Neanderthal-modern human mating.[18]	https://www.wikidoc.org/index.php/Dystrophin
acf9e0443beacfc4751272e8a9e6d8858dc043a3	wikidoc	E-selectin	E-selectin E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene. # Structure E selectin has a cassette structure: an N-terminal, C-type lectin domain, an EGF (epidermal-growth-factor)-like domain, 6 Sushi domain (SCR repeat) units, a transmembrane domain (TM) and an intracellular cytoplasmic tail (cyto). The three-dimensional structure of the ligand-binding region of human E-selectin has been determined at 2.0 Å resolution in 1994. The structure reveals limited contact between the two domains and a coordination of Ca2+ not predicted from other C-type lectins. Structure/function analysis indicates a defined region and specific amino-acid side chains that may be involved in ligand binding. The E-selectin bound to sialyl-LewisX (SLeX; NeuNAcα2,3Galβ1,4GlcNAc) tetrasaccharide was solved in 2000. # Gene and regulation In humans, E-selectin is encoded by the SELE gene. Its C-type lectin domain, EGF-like, SCR repeats, and transmembrane domains are each encoded by separate exons, whereas the E-selectin cytosolic domain derives from two exons. The E-selectin locus flanks the L-selectin locus on chromosome 1. Different from P-selectin, which is stored in vesicles called Weibel-Palade bodies, E-selectin is not stored in the cell and has to be transcribed, translated, and transported to the cell surface. The production of E-selectin is stimulated by the expression of P-selectin which in turn, is stimulated by tumor necrosis factor α (TNFα), interleukin-1 (IL-1) and lipopolysaccharide (LPS). It takes about two hours, after cytokine recognition, for E-selectin to be expressed on the endothelial cell's surface. Maximal expression of E-selectin occurs around 6–12 hours after cytokine stimulation, and levels returns to baseline within 24 hours. Shear forces are also found to affect E-selectin expression. A high laminar shear enhances acute endothelial cell response to interleukin-1β in naïve or shear-conditioned endothelial cells as may be found in the pathological setting of ischemia/reperfusion injury while conferring rapid E-selectin down regulation to protect against chronic inflammation. Phytoestrogens, plant compounds with estrogen-like biological activity, such as genistein, formononetin, biochanin A and daidzein, as well as a mixture of these phytoestrogens were found able to reduce E-selectin as well as VCAM-1 and ICAM-1 on cell surface and in culture supernatant. # Ligands E-selectin recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes. E-selectin ligands are expressed by neutrophils, monocytes, eosinophils, memory-effector T-like lymphocytes, and natural killer cells. Each of these cell types is found in acute and chronic inflammatory sites in association with expression of E-selectin, thus implicating E-selectin in the recruitment of these cells to such inflammatory sites. These carbohydrates include members of the Lewis X and Lewis A families found on monocytes, granulocytes, and T-lymphocytes. The glycoprotein ESL-1, present on neutrophils and myeloid cells, was the first counter-receptor for E-selectin to be described. It is a variant of the tyrosine kinase FGF glycoreceptor, raising the possibility that its binding to E-selectin is involved in initiating signaling in the bound cells P-selectin glycoprotein ligand-1 (PSGL-1) derived from human neutrophils is also a high-efficiency ligand for endothelium-expressed E-selectin under flow. It mediates the rolling of leukocytes on the activated endothelium surrounding an inflamed tissue. Both ESL-1 and PSGL-1 should bear sialyl Lewis a/x in order to bind E/P-selectins. E-selectin is found to mediate the adhesion of tumor cells to endothelial cells, by binding to E-selectin ligands on the tumor cells. E-selectin ligands also play a role in cancer metastasis. The role of these two E-selectin ligands in metastasis in vivo is poorly defined and remains to be firmly demonstrated. PSGL-1 was detected on the surfaces of bone-metastatic prostate tumor cells, suggesting that it may have a functional role in the bone tropism of prostate tumor cells. In cancer cells, CD44, death receptor-3 (DR3), LAMP1, and LAMP2 were identified as E-selectin ligands present on colon cancer cells., and CD44v, Mac2-BP, and gangliosides were identified as E-selectin ligands present on breast cancer cells. On human neutrophils the glycosphingolipid NeuAcα2-3Galβ1-4GlcNAcβ1-322Galβ1-4GlcβCer (and closely related structures) are functional E-selectin receptors. # Function ## Role in inflammation During inflammation, E-selectin plays an important part in recruiting leukocytes to the site of injury. The local release of cytokines IL-1 and TNF-α by Macrophages in the inflamed tissue induces the over-expression of E-selectin on endothelial cells of nearby blood vessels. Leukocytes in the blood expressing the correct ligand will bind with low affinity to E-selectin, also under the shear stress of blood flow, causing the leukocytes to "roll" along the internal surface of the blood vessel as temporary interactions are made and broken. As the inflammatory response progresses, chemokines released by injured tissue enter the blood vessels and activate the rolling leukocytes, which are now able to tightly bind to the endothelial surface and begin making their way into the tissue. P-selectin has a similar function, but is expressed on the endothelial cell surface within minutes as it is stored within the cell rather than produced on demand. ## Role in Cancer Cancer cells are able to infiltrate the inﬂammatory system by interacting with selectins. E-selectin mediates the adhesion of tumor cells to endothelial cells, by binding to E-selectin ligands expressed by neutrophils, monocytes, eosinophils, memory-effector T-like lymphocytes, natural killer cells or cancer cells. This interaction is associated with metastatic dissemination. However, the initial interaction between selectins and cancer cells are not sufficient to confer metastasis. As for leukocytes during inflammation, cancer cells bound to E-selectin are released into the circulation unless secondary adhesion mechanisms are activated. In some cases, cancer cells can interact with platelets and fibrinogen to form clots that further facilitate adhesion and spreading of the cancer cells to the endothelium of pulmonary vessels. The extravasation of circulating tumor cells in the host organ requires successive adhesive interactions between endothelial cells and their ligands or counter-receptors present on the cancer cells. Thus, the specificity of binding between E-selectin and its ligands determine the organ selectivity in cancer metastasis. Typically, the cancer cell/endothelial cell interactions imply first a selectin-mediated initial attachment and rolling of the circulating cancer cells on the endothelium. The rolling cancer cells then become activated by locally released chemokines present at the surface of endothelial cells. This triggers the activation of integrins from the cancer cells allowing their firmer adhesion to members of the Ig-CAM family such as ICAM, initiating the transendothelial migration and extravasation processes. The culture supernatants of cancer cells can trigger the expression of E-selectin by endothelial cells suggesting that cancer cells may release by themselves cytokines such as TNF-α, IL-1β or INF-γ that will directly activate endothelial cells to express E-selectin, P-selectin, ICAM-2 or VCAM. Adhesion of colon cancer cells to endothelial cells expressing E-selectin induces a reverse signaling in the cancer cells that increases their motile potential, and a forward signaling in the endothelial cells that increases interendothelial permeability and enables extravasation. For example, adhesion of colon carcinoma cells to endothelial cells involves the binding of E- selectin on endothelial cells to death receptor-3 (DR3) on cancer cells. This interaction induces the reverse activation of p38 and ERK MAP kinases in cancer cells, which increases their motile and survival potentials. Reciprocally, the interaction between DR3 and E-selectin triggers the forward activation of the same MAP kinase pathways in endothelial cells. This results in myosin-light chain (MLC)-mediated cell retraction and in dissociation of the VE-cadherin/β-catenin complex and thereby destruction of adherens junctions leading to increased endothelial permeability and extravasation of cancer cells. The process of E-selectin and endothelial adhesion receptor-mediated metastasis may be local. In particular, increased hepatic local metastasis of B16F1 melanoma cells is observed following exogenous IL-1a administration, which results from an increased vascular adhesion receptor expression, including E-selectin, VCAM-1 and ICAM-1, and tumor cell arrest in terminal portal venules. # Pathological relevance ## Critical illness polyneuromyopathy In cases of elevated blood glucose levels, such as in sepsis, E-selectin expression is higher than normal, resulting in greater microvascular permeability. The greater permeability leads to edema (swelling) of the skeletal endothelium (blood vessel linings), resulting in skeletal muscle ischemia (restricted blood supply) and eventually necrosis (cell death). This underlying pathology is the cause of the symptomatic disease critical illness polyneuromyopathy (CIPNM). Traditional Chinese herbal medicines, like berberine downregulate E-selectin. ## Pathogen attachment Study shows the adherence of porphyromonas gingivalis to human umbilical vein endothelial cells increases with the induction of E-selectin expression by TNF-α. An antibody to E-selectin and sialyl LewisX suppressed P. gingivalis adherence to stimulated HUVECs. P. gingivalis mutants lacking OmpA-like proteins Pgm6/7 had reduced adherence to stimulated HUVECs, but fimbriae-deficient mutants were not affected. E-selecin-mediated P. gingivalis adherence activated endothelial exocytosis. These results suggest that the interaction between host E-selectin and pathogen Pgm6/7 mediates P. gingivalis adherence to endothelial cells and may trigger vascular inflammation. ## Acute coronary syndrome The immunohistochemical expressions of E-selectin and PECAM-1 were significantly increased at intima in vulnerable plaques of acute coronary syndrome (ACS) group, especially in neovascular endothelial cells, and positively correlated with inflammatory cell density, suggesting that PECAM-1 and E-selectin might play an important role in inflammatory reaction and development of vulnerable plaque. E-selectin Ser128Arg polymorphism is associated with ACS, and it might be a risk factor for ACS. ## Nicotine-mediated induction Smoking is highly correlated with enhanced likelihood of atherosclerosis by inducing endothelial dysfunction. In endothelial cells, various cell-adhesion molecules including E-selectin, are shown to be upregulated upon exposure to nicotine, the addictive component of tobacco smoke. Nicotine-stimulated adhesion of monocytes to endothelial cells is dependent on the activation of α7-nAChRs, β-Arr1 and cSrc regulated increase in E2F1-mediated transcription of E-selectin gene. Therefore, agents such as RRD-251 that can target activity of E2F1 may have potential therapeutic benefit against cigarette smoke induced atherosclerosis. ## Cerebral aneurysm It's also found that E-selectin expression increased in human ruptured cerebral aneurysm tissues. E-selectin might be an important factor involved in the process of cerebral aneurysm formation and rupture, by promoting inflammation and weakening cerebral artery walls. ## As a biomarker E-selectin is also an emerging biomarker for the metastatic potential of some cancers including colorectal cancer and recurrences.	E-selectin E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.[1] # Structure E selectin has a cassette structure: an N-terminal, C-type lectin domain, an EGF (epidermal-growth-factor)-like domain, 6 Sushi domain (SCR repeat) units, a transmembrane domain (TM) and an intracellular cytoplasmic tail (cyto). The three-dimensional structure of the ligand-binding region of human E-selectin has been determined at 2.0 Å resolution in 1994.[2] The structure reveals limited contact between the two domains and a coordination of Ca2+ not predicted from other C-type lectins. Structure/function analysis indicates a defined region and specific amino-acid side chains that may be involved in ligand binding. The E-selectin bound to sialyl-LewisX (SLeX; NeuNAcα2,3Galβ1,4[Fucα1,3]GlcNAc) tetrasaccharide was solved in 2000.[3] # Gene and regulation In humans, E-selectin is encoded by the SELE gene. Its C-type lectin domain, EGF-like, SCR repeats, and transmembrane domains are each encoded by separate exons, whereas the E-selectin cytosolic domain derives from two exons. The E-selectin locus flanks the L-selectin locus on chromosome 1.[4] Different from P-selectin, which is stored in vesicles called Weibel-Palade bodies, E-selectin is not stored in the cell and has to be transcribed, translated, and transported to the cell surface. The production of E-selectin is stimulated by the expression of P-selectin which in turn, is stimulated by tumor necrosis factor α (TNFα), interleukin-1 (IL-1) and lipopolysaccharide (LPS).[5][6] It takes about two hours, after cytokine recognition, for E-selectin to be expressed on the endothelial cell's surface. Maximal expression of E-selectin occurs around 6–12 hours after cytokine stimulation, and levels returns to baseline within 24 hours.[6] Shear forces are also found to affect E-selectin expression. A high laminar shear enhances acute endothelial cell response to interleukin-1β in naïve or shear-conditioned endothelial cells as may be found in the pathological setting of ischemia/reperfusion injury while conferring rapid E-selectin down regulation to protect against chronic inflammation.[7] Phytoestrogens, plant compounds with estrogen-like biological activity, such as genistein, formononetin, biochanin A and daidzein, as well as a mixture of these phytoestrogens were found able to reduce E-selectin as well as VCAM-1 and ICAM-1 on cell surface and in culture supernatant.[8] # Ligands E-selectin recognizes and binds to sialylated carbohydrates present on the surface proteins of certain leukocytes. E-selectin ligands are expressed by neutrophils, monocytes, eosinophils, memory-effector T-like lymphocytes, and natural killer cells. Each of these cell types is found in acute and chronic inflammatory sites in association with expression of E-selectin, thus implicating E-selectin in the recruitment of these cells to such inflammatory sites. These carbohydrates include members of the Lewis X and Lewis A families found on monocytes, granulocytes, and T-lymphocytes.[9] The glycoprotein ESL-1, present on neutrophils and myeloid cells, was the first counter-receptor for E-selectin to be described. It is a variant of the tyrosine kinase FGF glycoreceptor, raising the possibility that its binding to E-selectin is involved in initiating signaling in the bound cells P-selectin glycoprotein ligand-1 (PSGL-1) derived from human neutrophils is also a high-efficiency ligand for endothelium-expressed E-selectin under flow.[10] It mediates the rolling of leukocytes on the activated endothelium surrounding an inflamed tissue. Both ESL-1 and PSGL-1 should bear sialyl Lewis a/x in order to bind E/P-selectins.[11] E-selectin is found to mediate the adhesion of tumor cells to endothelial cells, by binding to E-selectin ligands on the tumor cells. E-selectin ligands also play a role in cancer metastasis. The role of these two E-selectin ligands in metastasis in vivo is poorly defined and remains to be firmly demonstrated. PSGL-1 was detected on the surfaces of bone-metastatic prostate tumor cells, suggesting that it may have a functional role in the bone tropism of prostate tumor cells.[12] In cancer cells, CD44, death receptor-3 (DR3), LAMP1, and LAMP2 were identified as E-selectin ligands present on colon cancer cells.,[13] and CD44v, Mac2-BP, and gangliosides were identified as E-selectin ligands present on breast cancer cells.[14][15][16] On human neutrophils the glycosphingolipid NeuAcα2-3Galβ1-4GlcNAcβ1-3[Galβ1-4(Fucα1-3)GlcNAcβ1-3]2[Galβ1-4GlcNAcβ1-3]2Galβ1-4GlcβCer (and closely related structures) are functional E-selectin receptors.[17] # Function ## Role in inflammation During inflammation, E-selectin plays an important part in recruiting leukocytes to the site of injury. The local release of cytokines IL-1 and TNF-α by Macrophages in the inflamed tissue induces the over-expression of E-selectin on endothelial cells of nearby blood vessels.[18] Leukocytes in the blood expressing the correct ligand will bind with low affinity to E-selectin, also under the shear stress of blood flow, causing the leukocytes to "roll" along the internal surface of the blood vessel as temporary interactions are made and broken. As the inflammatory response progresses, chemokines released by injured tissue enter the blood vessels and activate the rolling leukocytes, which are now able to tightly bind to the endothelial surface and begin making their way into the tissue.[9] P-selectin has a similar function, but is expressed on the endothelial cell surface within minutes as it is stored within the cell rather than produced on demand.[9] ## Role in Cancer Cancer cells are able to infiltrate the inﬂammatory system by interacting with selectins. E-selectin mediates the adhesion of tumor cells to endothelial cells, by binding to E-selectin ligands expressed by neutrophils, monocytes, eosinophils, memory-effector T-like lymphocytes, natural killer cells or cancer cells. This interaction is associated with metastatic dissemination. However, the initial interaction between selectins and cancer cells are not sufficient to confer metastasis. As for leukocytes during inflammation, cancer cells bound to E-selectin are released into the circulation unless secondary adhesion mechanisms are activated. In some cases, cancer cells can interact with platelets and fibrinogen to form clots that further facilitate adhesion and spreading of the cancer cells to the endothelium of pulmonary vessels. The extravasation of circulating tumor cells in the host organ requires successive adhesive interactions between endothelial cells and their ligands or counter-receptors present on the cancer cells.[19] Thus, the specificity of binding between E-selectin and its ligands determine the organ selectivity in cancer metastasis. Typically, the cancer cell/endothelial cell interactions imply first a selectin-mediated initial attachment and rolling of the circulating cancer cells on the endothelium. The rolling cancer cells then become activated by locally released chemokines present at the surface of endothelial cells. This triggers the activation of integrins from the cancer cells allowing their firmer adhesion to members of the Ig-CAM family such as ICAM, initiating the transendothelial migration and extravasation processes.[20] The culture supernatants of cancer cells can trigger the expression of E-selectin by endothelial cells suggesting that cancer cells may release by themselves cytokines such as TNF-α, IL-1β or INF-γ that will directly activate endothelial cells to express E-selectin, P-selectin, ICAM-2 or VCAM. Adhesion of colon cancer cells to endothelial cells expressing E-selectin induces a reverse signaling in the cancer cells that increases their motile potential, and a forward signaling in the endothelial cells that increases interendothelial permeability and enables extravasation. For example, adhesion of colon carcinoma cells to endothelial cells involves the binding of E- selectin on endothelial cells to death receptor-3 (DR3) on cancer cells. This interaction induces the reverse activation of p38 and ERK MAP kinases in cancer cells, which increases their motile and survival potentials. Reciprocally, the interaction between DR3 and E-selectin triggers the forward activation of the same MAP kinase pathways in endothelial cells. This results in myosin-light chain (MLC)-mediated cell retraction and in dissociation of the VE-cadherin/β-catenin complex and thereby destruction of adherens junctions leading to increased endothelial permeability and extravasation of cancer cells.[13] The process of E-selectin and endothelial adhesion receptor-mediated metastasis may be local. In particular, increased hepatic local metastasis of B16F1 melanoma cells is observed following exogenous IL-1a administration, which results from an increased vascular adhesion receptor expression, including E-selectin, VCAM-1 and ICAM-1, and tumor cell arrest in terminal portal venules.[21] # Pathological relevance ## Critical illness polyneuromyopathy In cases of elevated blood glucose levels, such as in sepsis, E-selectin expression is higher than normal, resulting in greater microvascular permeability. The greater permeability leads to edema (swelling) of the skeletal endothelium (blood vessel linings), resulting in skeletal muscle ischemia (restricted blood supply) and eventually necrosis (cell death). This underlying pathology is the cause of the symptomatic disease critical illness polyneuromyopathy (CIPNM).[22] Traditional Chinese herbal medicines, like berberine downregulate E-selectin.[23] ## Pathogen attachment Study shows the adherence of porphyromonas gingivalis to human umbilical vein endothelial cells increases with the induction of E-selectin expression by TNF-α. An antibody to E-selectin and sialyl LewisX suppressed P. gingivalis adherence to stimulated HUVECs. P. gingivalis mutants lacking OmpA-like proteins Pgm6/7 had reduced adherence to stimulated HUVECs, but fimbriae-deficient mutants were not affected. E-selecin-mediated P. gingivalis adherence activated endothelial exocytosis. These results suggest that the interaction between host E-selectin and pathogen Pgm6/7 mediates P. gingivalis adherence to endothelial cells and may trigger vascular inflammation.[24] ## Acute coronary syndrome The immunohistochemical expressions of E-selectin and PECAM-1 were significantly increased at intima in vulnerable plaques of acute coronary syndrome (ACS) group, especially in neovascular endothelial cells, and positively correlated with inflammatory cell density, suggesting that PECAM-1 and E-selectin might play an important role in inflammatory reaction and development of vulnerable plaque. E-selectin Ser128Arg polymorphism is associated with ACS, and it might be a risk factor for ACS.[25] ## Nicotine-mediated induction Smoking is highly correlated with enhanced likelihood of atherosclerosis by inducing endothelial dysfunction. In endothelial cells, various cell-adhesion molecules including E-selectin, are shown to be upregulated upon exposure to nicotine, the addictive component of tobacco smoke. Nicotine-stimulated adhesion of monocytes to endothelial cells is dependent on the activation of α7-nAChRs, β-Arr1 and cSrc regulated increase in E2F1-mediated transcription of E-selectin gene. Therefore, agents such as RRD-251 that can target activity of E2F1 may have potential therapeutic benefit against cigarette smoke induced atherosclerosis.[26] ## Cerebral aneurysm It's also found that E-selectin expression increased in human ruptured cerebral aneurysm tissues. E-selectin might be an important factor involved in the process of cerebral aneurysm formation and rupture, by promoting inflammation and weakening cerebral artery walls.[27] ## As a biomarker E-selectin is also an emerging biomarker for the metastatic potential of some cancers including colorectal cancer and recurrences.[28]	https://www.wikidoc.org/index.php/E-selectin
77f595bceb1b98dadf92e0366a36a47ac5def93a	wikidoc	EHF (gene)	EHF (gene) ETS homologous factor is a protein that in humans is encoded by the EHF gene. This gene encodes a protein that belongs to an ETS transcription factor subfamily characterized by epithelial-specific expression (ESEs). The encoded protein acts as a transcriptional repressor and may be associated with asthma susceptibility. This protein may be involved in epithelial differentiation and carcinogenesis. # Further reading Cangemi, R., Mensah, A., Albertini, V., Jain, A., Mello-Grand, M., Chiorino, G., Catapano, C.V. & Carbone, G.M. Reduced expression and tumor suppressor function of the ETS transcription factor ESE-3 in prostate cancer. Oncogene 27, 2877-2885 (2008). Albino D, Longoni N, Curti L, Mello-Grand M, Pinton S, Civenni G, Thalmann G, D'Ambrosio G, Sarti M, Sessa F, Chiorino G, Catapano CV, Carbone GM. ESE3/EHF controls epithelial cell differentiation and its loss leads to prostate tumors with mesenchymal and stem-like features. Cancer Res. 2012 Jun 1;72(11):2889-900. Kunderfranco, P., Mello-Grand, M., Cangemi, R., Pellini, S., Mensah, A., Albertini, V., Malek, A., Chiorino, G., Catapano, C.V. & Carbone, G.M. ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer. PLoS One 5, e10547 (2010).	EHF (gene) ETS homologous factor is a protein that in humans is encoded by the EHF gene.[1][2] This gene encodes a protein that belongs to an ETS transcription factor subfamily characterized by epithelial-specific expression (ESEs). The encoded protein acts as a transcriptional repressor and may be associated with asthma susceptibility. This protein may be involved in epithelial differentiation and carcinogenesis.[2] # Further reading Cangemi, R., Mensah, A., Albertini, V., Jain, A., Mello-Grand, M., Chiorino, G., Catapano, C.V. & Carbone, G.M. Reduced expression and tumor suppressor function of the ETS transcription factor ESE-3 in prostate cancer. Oncogene 27, 2877-2885 (2008). Albino D, Longoni N, Curti L, Mello-Grand M, Pinton S, Civenni G, Thalmann G, D'Ambrosio G, Sarti M, Sessa F, Chiorino G, Catapano CV, Carbone GM. ESE3/EHF controls epithelial cell differentiation and its loss leads to prostate tumors with mesenchymal and stem-like features. Cancer Res. 2012 Jun 1;72(11):2889-900. Kunderfranco, P., Mello-Grand, M., Cangemi, R., Pellini, S., Mensah, A., Albertini, V., Malek, A., Chiorino, G., Catapano, C.V. & Carbone, G.M. ETS transcription factors control transcription of EZH2 and epigenetic silencing of the tumor suppressor gene Nkx3.1 in prostate cancer. PLoS One 5, e10547 (2010).	https://www.wikidoc.org/index.php/EHF_(gene)
875d1e6dfab937bfe1a8b10eeaf908412c07afb9	wikidoc	EN1 (gene)	EN1 (gene) Homeobox protein engrailed-1 is a protein that in humans is encoded by the EN1 gene. # Function Homeobox-containing genes are thought to have a role in controlling development. In Drosophila, the engrailed (en) gene plays an important role during development in segmentation, where it is required for the formation of posterior compartments. Different mutations in the mouse homologs, En1 and En2, produced different developmental defects that frequently are lethal. The human engrailed homologs 1 and 2 encode homeodomain-containing proteins and have been implicated in the control of pattern formation during development of the central nervous system. Engrailed (En) 1 is a homeobox gene that helps primarily regulate development in the dorsal midbrain and anterior hindbrain (cerebellum and colliculi) of humans. The expression of En1 is regulated until 13 days after fertilization by Fgf8, which controls the development of the forebrain and hindbrain. En1 is first expressed in this region on day 9.5 after fertilization for about 12 hours until En2 is expressed. After En2 expression, En1 is expressed again in other tissues such as somites and limb ectoderm throughout development. A knockout mouse model with the En1 homeobox deleted was developed; mice died less than 24 hours after birth because they refused to feed, although they had the physical ability. The brains of the mice were studied and most of the cerebellum, colliculi, and cranial nerves 3 and 4 were missing. There was clear deletion in the mid-hindbrain, isthmus, junction region that began at day 9.5 after fertilization. All of the mice demonstrated marked forepaw deformities including fusion of digits and sixth digits. The 13th ribs and sternums displayed delayed and abnormal ossification. The mouse model demonstrated that the expression of En1 is critical in the correct development of the brain, limbs, and sternum.	EN1 (gene) Homeobox protein engrailed-1 is a protein that in humans is encoded by the EN1 gene.[1][2] # Function Homeobox-containing genes are thought to have a role in controlling development. In Drosophila, the engrailed (en) gene plays an important role during development in segmentation, where it is required for the formation of posterior compartments. Different mutations in the mouse homologs, En1 and En2, produced different developmental defects that frequently are lethal. The human engrailed homologs 1 and 2 encode homeodomain-containing proteins and have been implicated in the control of pattern formation during development of the central nervous system.[2] Engrailed (En) 1 is a homeobox gene that helps primarily regulate development in the dorsal midbrain and anterior hindbrain (cerebellum and colliculi) of humans. The expression of En1 is regulated until 13 days after fertilization by Fgf8, which controls the development of the forebrain and hindbrain. En1 is first expressed in this region on day 9.5 after fertilization for about 12 hours until En2 is expressed. After En2 expression, En1 is expressed again in other tissues such as somites and limb ectoderm throughout development.[3] A knockout mouse model with the En1 homeobox deleted was developed; mice died less than 24 hours after birth because they refused to feed, although they had the physical ability. The brains of the mice were studied and most of the cerebellum, colliculi, and cranial nerves 3 and 4 were missing. There was clear deletion in the mid-hindbrain, isthmus, junction region that began at day 9.5 after fertilization. All of the mice demonstrated marked forepaw deformities including fusion of digits and sixth digits. The 13th ribs and sternums displayed delayed and abnormal ossification. The mouse model demonstrated that the expression of En1 is critical in the correct development of the brain, limbs, and sternum.[4]	https://www.wikidoc.org/index.php/EN1_(gene)
339662b72a46b6a3d1a70afe78fddaf1ee23d732	wikidoc	EN2 (gene)	EN2 (gene) Homeobox protein engrailed-2 is a protein that in humans is encoded by the EN2 gene. It is a member of the engrailed gene family. # Function Homeobox-containing genes are thought to have a role in controlling development. In Drosophila, the 'engrailed' (en) gene plays an important role during development in segmentation, where it is required for the formation of posterior compartments. Different mutations in the mouse homologs, En1 and En2, produced different developmental defects that frequently are lethal. The human engrailed homologs 1 and 2 encode homeodomain-containing proteins and have been implicated in the control of pattern formation during development of the central nervous system. # Description The Engrailed-2 gene encodes for the Engrailed-2 homeobox transcription factor. The signaling molecule, fibroblast growth factor 8 (FGF8), controls the expression of the En2 gene. The isthmus organizer expresses varying concentrations of FGF8 that influence the En2 transcription factor. En2 transcription factor is involved in patterning the midbrain of the central nervous system during embryonic development. Specifically, it is required for proper positioning of folia in the developing hemispheres. It continues to regulate foliation throughout nervous system development. En2 patterns cerebellum foliation in the mediolateral axis. Several birth defects can arise from inadequate or abnormal En2 expression. Scientists use a mice model to study the effects of En2 knockout alleles on development. When the En2 gene is knocked out, vermis foliation patterning becomes extremely altered. Along with decreased cerebellum foliation complexity, mutations in the En2 gene result in a depleted vermis or an overly simplified foliation pattern. The Engrailed genes are essential to proper neural circuit development. # In cancer diagnosis A method for diagnosing prostate cancer by detection of EN2 in urine has been developed. The results of a clinical trial of 288 men suggest that EN2 could be a marker for prostate cancer which might prove more reliable than current methods that use prostate-specific antigen (PSA). If effective, a urine test is considered easier and less embarrassing for the patient than blood tests or rectal examinations and, therefore, less likely to discourage early diagnosis. At the time of the report, it was not clear whether or not the EN2 test could distinguish between aggressive tumours that would require intervention and relatively benign ones that would not. ## Licensing and marketing The EN2 test for prostate cancer has been licensed to Zeus Scientific, as they reported in March 2013. In that announcement they said they expected the test to be submitted to the US-FDA in a year, and available worldwide in 2 years.	EN2 (gene) Homeobox protein engrailed-2 is a protein that in humans is encoded by the EN2 gene.[1] It is a member of the engrailed gene family. # Function Homeobox-containing genes are thought to have a role in controlling development. In Drosophila, the 'engrailed' (en) gene plays an important role during development in segmentation, where it is required for the formation of posterior compartments. Different mutations in the mouse homologs, En1 and En2, produced different developmental defects that frequently are lethal. The human engrailed homologs 1 and 2 encode homeodomain-containing proteins and have been implicated in the control of pattern formation during development of the central nervous system.[1] # Description The Engrailed-2 gene encodes for the Engrailed-2 homeobox transcription factor. The signaling molecule, fibroblast growth factor 8 (FGF8), controls the expression of the En2 gene. The isthmus organizer expresses varying concentrations of FGF8 that influence the En2 transcription factor. En2 transcription factor is involved in patterning the midbrain of the central nervous system during embryonic development. Specifically, it is required for proper positioning of folia in the developing hemispheres. It continues to regulate foliation throughout nervous system development. En2 patterns cerebellum foliation in the mediolateral axis. Several birth defects can arise from inadequate or abnormal En2 expression. Scientists use a mice model to study the effects of En2 knockout alleles on development. When the En2 gene is knocked out, vermis foliation patterning becomes extremely altered. Along with decreased cerebellum foliation complexity, mutations in the En2 gene result in a depleted vermis or an overly simplified foliation pattern. The Engrailed genes are essential to proper neural circuit development. # In cancer diagnosis A method for diagnosing prostate cancer by detection of EN2 in urine has been developed. The results of a clinical trial of 288 men suggest that EN2 could be a marker for prostate cancer which might prove more reliable than current methods that use prostate-specific antigen (PSA). If effective, a urine test is considered easier and less embarrassing for the patient than blood tests or rectal examinations and, therefore, less likely to discourage early diagnosis. At the time of the report, it was not clear whether or not the EN2 test could distinguish between aggressive tumours that would require intervention and relatively benign ones that would not.[2] ## Licensing and marketing The EN2 test for prostate cancer has been licensed to Zeus Scientific, as they reported in March 2013. In that announcement they said they expected the test to be submitted to the US-FDA in a year,[3] and available worldwide in 2 years.[4]	https://www.wikidoc.org/index.php/EN2_(gene)
f64a27a7976796254820df3bac67eed9853464e3	wikidoc	Lamivudine	Lamivudine # 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 Lamivudine is a nucleoside analogue reverse transcriptase inhibitor that is FDA approved for the treatment of HIV-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Human immunodeficiency virus (HIV-1) infection - Dosage: 300 mg daily or 150 mg q12h - In combination with other antiretroviral agents. ### Chronic Hepatitis B (HBV) infection - Dosage: 100 mg daily ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of lamivudine in adult patients. ### Non–Guideline-Supported Use ### Posttransplant Prophylaxis for Hepatitis B - Dosage: 100mg daily - In combination with HBIG. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Human immunodeficiency virus (HIV-1) infection ### Chronic Hepatitis B (HBV) infection - Dosage: patients aged 2 to 17 years is 3 mg per kg once daily up to a maximum daily dosage of 100 mg. - The oral solution formulation should be prescribed for patients requiring a dosage less than 100 mg or if unable to swallow tablets. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of lamivudine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of lamivudine in pediatric patients. # Contraindications - Hypersensitivity to lamivudine or to any component of the tablets or oral solution. # Warnings ### Lactic Acidosis and Severe Hepatomegaly With Steatosis - Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. - A majority of these cases have been in women. - Obesity and prolonged nucleoside exposure may be risk factors. - Particular caution should be exercised when administering lamivudine to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors. Treatment with lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). ### Patients With HIV-1 and Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis - In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic hepatitis B, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. - These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. - Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. - The causal relationship to discontinuation of lamivudine treatment is unknown. - Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. - There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis. Important Differences Among Lamivudine-Containing Products - lamivudine Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) than lamivudine-HBV Tablets and lamivudine-HBV Oral Solution. - lamivudine-HBV was developed for patients with chronic hepatitis B. - The formulation and dosage of lamivudine in lamivudine-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. - If treatment with lamivudine-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment. - If a decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, lamivudine Tablets, lamivudine Oral Solution, lamivudine/zidovudine Tablets, abacavir sulfate and lamivudine) Tablets, or abacavir sulfate, lamivudine, and zidovudine) Tablets should be used as part of an appropriate combination regimen. Emergence of Lamivudine-Resistant HBV - In non–HIV-1-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response. - Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. ### Use With Other Lamivudine- and Emtricitabine-Containing Products - lamivudine should not be administered concomitantly with other lamivudine-containing products including lamivudine-HBV Tablets, lamivudine Oral Solution, lamivudine/zidovudine Tablets, abacavir sulfate and lamivudine Tablets, or abacavir sulfate, lamivudine, and zidovudine or emtricitabine-containing products, including efavirenz, emtricitabine, and tenofovir, emtricitabine, emtricitabine and tenofovir, or rilpivirine/emtricitabine/tenofovir. ### Use With Interferon- and Ribavirin-Based Regimens - In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. - Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. - Patients receiving interferon alfa with or without ribavirin and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. - Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh >6). ### Pancreatitis - In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, lamivudine should be used with caution. - Treatment with lamivudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur. ### Immune Reconstitution Syndrome - Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine. - During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia , or tuberculosis), which may necessitate further evaluation and treatment. - Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment. ### Fat Redistribution - Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. - The mechanism and long-term consequences of these events are currently unknown. - A causal relationship 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. ### Adults Population The safety profile of lamivudine in adults is primarily based on 3,568 HIV-1-infected subjects in 7 clinical trials. The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea and cough. Selected clinical adverse reactions in ≥5% of subjects during therapy with lamivudine 150 mg twice daily plus zidovudine 200 mg 3 times daily for up to 24 weeks are listed in Table 3. Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received lamivudine in controlled clinical trials. Lamivudine 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for 48 weeks were similar. Selected laboratory abnormalities observed during therapy are summarized in Table 4. The frequencies of selected laboratory abnormalities reported subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar. ### Pediatric Population Lamivudine Oral Solution has been studied in 638 pediatric subjects aged 3 months to 18 years in 3 clinical trials. Selected clinical adverse reactions and physical findings with a ≥5% frequency during therapy with lamivudine 4 mg/kg twice daily plus zidovudine 160 mg/m2 3 times daily in therapy-naive (≤56 days of antiretroviral therapy) pediatric subjects are listed in Table 5. Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside‑experienced pediatric subjects receiving lamivudine alone or in combination with other antiretroviral agents. In an open‑label dose‑escalation trial (NUCA2002), 14 subjects (14%) developed pancreatitis while receiving monotherapy with lamivudine. Three of these subjects died of complications of pancreatitis. In a second open‑label trial (NUCA2005), 12 subjects (18%) developed pancreatitis. In Trial ACTG300, pancreatitis was not observed in 236 subjects randomized to lamivudine plus zidovudine. Pancreatitis was observed in 1 subject in this trial who received open‑label lamivudine in combination with zidovudin and ritonavir following discontinuation of didanosine monotherapy. Paresthesias and Peripheral Neuropathies: Paresthesias and peripheral neuropathies were reported in 15 subjects (15%) in Trial NUCA2002, 6 subjects (9%) in Trial NUCA2005, and 2 subjects (<1%) in Trial ACTG300. Selected laboratory abnormalities experienced by therapy‑naive (56 days of antiretroviral therapy) pediatric subjects are listed in Table 6. Limited short-term safety information is available from 2 small, uncontrolled trials in South Africa in neonates receiving lamivudine with or without zidovudine for the first week of life following maternal treatment starting at Week 38 or 36 of gestation. Selected adverse reactions reported in these neonates included increased liver function tests, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections, and sepsis; 3 neonates died (1 from gastroenteritis with acidosis and convulsions, 1 from traumatic injury, and 1 from unknown causes). Two other nonfatal gastroenteritis or diarrhea cases were reported, including 1 with convulsions; 1 infant had transient renal insufficiency associated with dehydration. The absence of control groups limits assessments of causality, but it should be assumed that perinatally exposed infants may be at risk for adverse reactions comparable to those reported in pediatric and adult HIV-1-infected patients treated with lamivudine-containing combination regimens. Long-term effects of in utero and infant lamivudine exposure are not known. ## Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported during postmarketing use of lamivudine. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. Body as a Whole - Redistribution/accumulation of body fat. General - Weakness. Endocrine and Metabolic - Hyperglycemia. Hemic and Lymphatic - Anemia (including pure red cell aplasia and severe anemias progressing on therapy). Hepatic and Pancreatic - Lactic acidosis and hepatic steatosis - Posttreatment exacerbation of hepatitis B Hypersensitivity - Anaphylaxis - Urticaria. Musculoskeletal - Muscle weakness - CPK elevation - Rhabdomyolysis Skin - Alopecia - Pruritus # Drug Interactions - Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. - The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim). - No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine. - Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients, Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. - Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. - Use of lamivudine in combination with zalcitabine is not recommended. - No change in dose of either drug is recommended. - There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP-SMX such as those used to treat PCP. - A drug interaction trial showed no clinically significant interaction between lamivudine and zidovudine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled trials of lamivudine in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. Lamivudine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trial assessed pharmacokinetics in: 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, lamivudine amniotic fluid specimens were collected following natural rupture of membranes. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily). It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients. Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a Pregnancy Registry has been established. Pregnancy Category (AUS): B3 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lamivudine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Lamivudine during labor and delivery. ### Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for serious adverse reactions in nursing infants and HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving lamivudine. Lamivudine is excreted into human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine. ### Pediatric Use The safety and effectiveness of twice-daily lamivudine in combination with other antiretroviral agents have been established in pediatric patients 3 months and older. ### Geriatic Use Clinical trials of lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly. ### Gender There is no FDA guidance on the use of Lamivudine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Lamivudine with respect to specific racial populations. ### Renal Impairment Dosing of lamivudine is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2. No additional dosing of lamivudine is required after routine (4-hour) hemodialysis or peritoneal dialysis. Although there are insufficient data to recommend a specific dose adjustment of lamivudine in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered. ### Hepatic Impairment There is no FDA guidance on the use of Lamivudine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Lamivudine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Lamivudine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Patients with HIV-1 and Hepatitis B Virus Co-infection should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. # IV Compatibility There is limited information regarding the compatibility of Lamivudine and IV administrations. # Overdosage There is no known antidote for lamivudine. One case of an adult ingesting 6 g of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Two cases of pediatric overdose were reported in Trial ACTG300. One case involved a single dose of 7 mg/kg of lamivudine; the second case involved use of 5 mg/kg of lamivudine twice daily for 30 days. There were no clinical signs or symptoms noted in either case. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required. # Pharmacology ## Mechanism of Action - Lamivudine is an antiviral agent. - Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). - The principal mode of action of 3TC-TP is the inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. - 3TC-TP is a weak inhibitor of mammalian DNA polymerases α, β, and γ. ## Structure - Lamivudine is a synthetic nucleoside analogue with activity against HIV-1 and HBV. - The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. - Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. - It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3. - Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of lamivudine in the drug label. ## Pharmacokinetics ### Pharmacokinetics in Adults - The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult subjects after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg/kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg/kg. - The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg/day administered to HBV-infected subjects. - The steady-state pharmacokinetic properties of the lamivudine 300-mg tablet once daily for 7 days compared with the lamivudine 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects. - Lamivudine 300 mg once daily resulted in lamivudine exposures that were similar to lamivudine 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen. - Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss; however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. - The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known. - Lamivudine was rapidly absorbed after oral administration in HIV-1-infected subjects. - Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. - After oral administration of 2 mg/kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL (mean ± SD). - The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg. - The accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg/kg twice daily. - An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected subjects on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3.2 ± 1.3 hours) compared with the fasted state (Tmax: 0.9 ± 0.3 hours); Cmax in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC∞) in the fed and fasted states; therefore, lamivudine Tablets and Oral Solution may be administered with or without food. - The apparent volume of distribution after IV administration of lamivudine to 20 subjects was 1.3 ± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. - Volume of distribution was independent of dose and did not correlate with body weight. - Binding of lamivudine to human plasma proteins is low (<36%). - In vitro studies showed that over the concentration range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration. - Metabolism of lamivudine is a minor route of elimination. - In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose of lamivudine in 6 HIV-1-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined. - The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. - In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL/min (mean ± SD). - In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL/min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine. - In most single-dose trials in HIV-1-infected subjects, HBV‑infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. - In HIV-1-infected subjects, total clearance was 398.5 ± 69.1 mL/min (mean ± SD). - Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg/kg. ### Special Populations - The pharmacokinetic properties of lamivudine have been determined in a small group of HIV-1-infected adults with impaired renal function (Table 7). - Exposure (AUC∞), Cmax, and half-life increased with diminishing renal function (as expressed by creatinine clearance). - Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment. - Based on a trial in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration. - Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis. - It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis. - The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known. - The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function. - Pharmacokinetic parameters were not altered by diminishing hepatic function; therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function. - Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease. ### Pharmacokinetics in Pediatric Patients - In Trial NUCA2002, pharmacokinetic properties of lamivudine were assessed in a subset of 57 HIV-1-infected pediatric subjects (age range: 4.8 months to 16 years, weight range: 5 to 66 kg) after oral and IV administration of 1, 2, 4, 8, 12, and 20 mg/kg/day. - In the 9 infants and children (age range: 5 months to 12 years) receiving oral solution 4 mg/kg twice daily (the usual recommended pediatric dose), absolute bioavailability was 66% ± 26% (mean ± SD), which was less than the 86% ± 16% (mean ± SD) observed in adults. - The mechanism for the diminished absolute bioavailability of lamivudine in infants and children is unknown. Systemic clearance decreased with increasing age in pediatric subjects, as shown in Figure 1. - After oral administration of lamivudine 4 mg/kg twice daily to 11 pediatric subjects ranging in age from 4 months to 14 years, Cmax was 1.1 ± 0.6 mcg/mL and half-life was 2.0 ± 0.6 hours. (In adults with similar blood sampling, the half‑life was 3.7 ± 1 hours.) - Total exposure to lamivudine, as reflected by mean AUC values, was comparable between pediatric subjects receiving an 8-mg/kg/day dose and adults receiving a 4-mg/kg/day dose. - Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine. - CSF samples were collected between 2 and 4 hours postdose. - At the dose of 8 mg/kg/day, CSF lamivudine concentrations in 8 subjects ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL. - Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants aged up to 1 week in 2 trials in South Africa. In these trials, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric subjects (aged >3 months) studied previously. - There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old. ### Pharmacokinetics in Geriatric Patients - The pharmacokinetics of lamivudine after administration of lamivudine to patients over 65 years have not been studied. ### Drug Interactions - There was no significant pharmacokineti interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects. - In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects. - Lamivudine and TMP-SMX were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. - Coadministration of TMP-SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. *The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine. - No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr). ## Nonclinical Toxicology Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at the recommended therapeutic dose for HIV-1 infection. Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg/kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection. In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring. Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta. # Clinical Studies The use of lamivudine is based on the results of clinical trials in HIV‑1-infected subjects in combination regimens with other antiretroviral agents. Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials. ### Adults NUCB3007 (CAESAR) was a multi-center, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone or zidovudine with didanosine or zalcitabine ) to the addition of lamivudine or lamivudine plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV-1-infected adults with 25 to 250 CD4+ cells/mm3 (median = 122 cells/mm3) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on trial was 12 months. Results are summarized in Table 8. Dual Nucleoside Analogue Trials: Principal clinical trial in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These trials demonstrated the antiviral effect of lamivudine in a 2-drug combination. More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression. Dose Regimen Comparison Surrogate Endpoint Trials in Therapy-Naive Adults: EPV20001 was a multi-center, double-blind, controlled trial in which subjects were randomized 1:1 to receive lamivudine 300 mg once daily or lamivudine 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), Caucasian (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm3 (median = 362 cells/mm3), and median baseline plasma HIV-1 RNA of 4.66 log10 copies/mL. Outcomes of treatment through 48 weeks are summarized in Figure 2 and Table 9. Roche AMPLICOR HIV-1 MONITOR. Responders at each visit are subjects who had achieved and maintained HIV-1 RNA <400 copies/mL without discontinuation by that visit. The proportions of subjects with HIV-1 RNA <50 copies/mL (via Roche Ultrasensitive assay) through Week 48 were 61% for subjects receiving lamivudine 300 mg once daily and 63% for subjects receiving lamivudine 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells/mm3 at Week 48 in subjects receiving lamivudine 300 mg once daily and 146 cells/mm3for subjects receiving lamivudine 150 mg twice daily. A small, randomized, open-label pilot trial, EPV40001, was conducted in Thailand. A total of 159 treatment-naive adult subjects (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells/mm3, median plasma HIV-1 RNA 4.8 log10 copies/mL) were enrolled. Two of the treatment arms in this trial provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily. In intent-to-treat analyses of 48-week data, the proportions of subjects with HIV-1 RNA below 400 copies/mL were 61% (33/54) in the group randomized to once-daily lamivudine and 75% (39/52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies/mL were 54% (29/54) in the once-daily lamivudine group and 67% (35/52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells/mm3 in the once-daily lamivudine group and 216 cells/mm3 in the all-twice-daily group. ### Pediatric Subjects Clinical Endpoint Trial: ACTG300 was a multi-center, randomized, double-blind trial that provided for comparison of lamivudine plus zidovudine with didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive (56 days of antiretroviral therapy) pediatric subjects were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-Caucasian. The mean baseline CD4+ cell count was 868 cells/mm3 (mean: 1,060 cells/mm3 and range:0 to 4,650 cells/mm3 for subjects aged 5 years; mean: 419 cells/mm3 and range: 0 to 1,555 cells/mm3 for subjects aged >5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL. The median duration on trial was 10.1 months for the subjects receiving lamivudine plus zidovudine and 9.2 months for subjects receiving didanosine monotherapy. Results are summarized in Table 10. # How Supplied - White, diamond-shaped, scored, film-coated tablets debossed with “GX CJ7” on both sides. - Bottle of 60 tablets (NDC 49702-203-18) with child-resistant closure. - Gray, modified diamond-shaped, film-coated tablets engraved with “GX EJ7” on one side and plain on the reverse side. - Bottle of 30 tablets (NDC 49702-204-13) with child-resistant closure. - A clear, colorless to pale yellow, strawberry-banana-flavored liquid, contains 10 mg of lamivudine in each 1 mL. - Plastic bottle of 240 mL (NDC 49702-205-48) with child-resistant closure. This product does not require reconstitution. ## Storage - Store Lamivudine Tablets at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). - Store in tightly closed bottles at 25°C (77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Advice for the Patient - Patients should be informed that some HIV medicines, including lamivudine, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly). - Patients co-infected with HIV-1 and HBV should be informed that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. - Patients should be advised to discuss any changes in regimen with their physician. Patients should be advised that lamivudine Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) as lamivudine-HBV Tablets and Oral Solution. If a decision is made to include lamivudine in the HIV-1 treatment regimen of a patient co-infected with HIV-1 and HBV, the formulation and dosage of lamivudine in lamivudine (not lamivudine-HBV) should be used. Lamivudine should not be coadministered with drugs containing lamivudine or emtricitabine, including lamivudine/zidovudine Tablets, abacavir sulfate and lamivudine Tablets, abacavir sulfate, lamivudine, and zidovudine, efavirenz, emtricitabine, and tenofovir, , emtricitabine and tenofovir, or rilpivirine/emtricitabine/tenofovir. Patients with HIV-1/HCV co-infection should be informed that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Parents or guardians should be advised to monitor pediatric patients for signs and symptoms of pancreatitis. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including lamivudine, and that the cause and long-term health effects of these conditions are not known at this time. Diabetic patients should be advised that each 15-mL dose of lamivudine Oral Solution contains 3 grams of sucrose. Lamivudine is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using lamivudine. Patients should be advised to avoid doing things that can spread HIV-1 infection to others. - Do not share needles or other injection equipment. - Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. - Do not have any kind of sex without protection. - Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood. - Do not breastfeed. Lamivudine is excreted in human breast milk. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. - Patients should be informed to take all HIV medications exactly as prescribed. # Precautions with Alcohol Alcohol-lamivudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - EPIVIR - EPIVIR HBV - EPIVIR A/F # Look-Alike Drug Names There is limited information regarding Lamivudine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Lamivudine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Stefano Giannoni [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 Lamivudine is a nucleoside analogue reverse transcriptase inhibitor that is FDA approved for the treatment of HIV-1 infection. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Human immunodeficiency virus (HIV-1) infection - Dosage: 300 mg daily or 150 mg q12h - In combination with other antiretroviral agents. ### Chronic Hepatitis B (HBV) infection - Dosage: 100 mg daily ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of lamivudine in adult patients. ### Non–Guideline-Supported Use ### Posttransplant Prophylaxis for Hepatitis B - Dosage: 100mg daily [1] - In combination with HBIG. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Human immunodeficiency virus (HIV-1) infection ### Chronic Hepatitis B (HBV) infection - Dosage: patients aged 2 to 17 years is 3 mg per kg once daily up to a maximum daily dosage of 100 mg. - The oral solution formulation should be prescribed for patients requiring a dosage less than 100 mg or if unable to swallow tablets. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of lamivudine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of lamivudine in pediatric patients. # Contraindications - Hypersensitivity to lamivudine or to any component of the tablets or oral solution. # Warnings ### Lactic Acidosis and Severe Hepatomegaly With Steatosis - Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including lamivudine and other antiretrovirals. - A majority of these cases have been in women. - Obesity and prolonged nucleoside exposure may be risk factors. - Particular caution should be exercised when administering lamivudine to any patient with known risk factors for liver disease; however, cases also have been reported in patients with no known risk factors. Treatment with lamivudine should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations). ### Patients With HIV-1 and Hepatitis B Virus Co-infection Posttreatment Exacerbations of Hepatitis - In clinical trials in non-HIV-1-infected patients treated with lamivudine for chronic hepatitis B, clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. - These exacerbations have been detected primarily by serum ALT elevations in addition to re-emergence of HBV DNA. Although most events appear to have been self-limited, fatalities have been reported in some cases. - Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV. - The causal relationship to discontinuation of lamivudine treatment is unknown. - Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. - There is insufficient evidence to determine whether re-initiation of lamivudine alters the course of posttreatment exacerbations of hepatitis. Important Differences Among Lamivudine-Containing Products - lamivudine Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) than lamivudine-HBV Tablets and lamivudine-HBV Oral Solution. - lamivudine-HBV was developed for patients with chronic hepatitis B. - The formulation and dosage of lamivudine in lamivudine-HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV. - If treatment with lamivudine-HBV is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment. - If a decision is made to administer lamivudine to patients co-infected with HIV-1 and HBV, lamivudine Tablets, lamivudine Oral Solution, lamivudine/zidovudine Tablets, abacavir sulfate and lamivudine) Tablets, or abacavir sulfate, lamivudine, and zidovudine) Tablets should be used as part of an appropriate combination regimen. Emergence of Lamivudine-Resistant HBV - In non–HIV-1-infected patients treated with lamivudine for chronic hepatitis B, emergence of lamivudine-resistant HBV has been detected and has been associated with diminished treatment response. - Emergence of hepatitis B virus variants associated with resistance to lamivudine has also been reported in HIV-1-infected patients who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. ### Use With Other Lamivudine- and Emtricitabine-Containing Products - lamivudine should not be administered concomitantly with other lamivudine-containing products including lamivudine-HBV Tablets, lamivudine Oral Solution, lamivudine/zidovudine Tablets, abacavir sulfate and lamivudine Tablets, or abacavir sulfate, lamivudine, and zidovudine or emtricitabine-containing products, including efavirenz, emtricitabine, and tenofovir, emtricitabine, emtricitabine and tenofovir, or rilpivirine/emtricitabine/tenofovir. ### Use With Interferon- and Ribavirin-Based Regimens - In vitro studies have shown ribavirin can reduce the phosphorylation of pyrimidine nucleoside analogues such as lamivudine. - Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients, hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. - Patients receiving interferon alfa with or without ribavirin and lamivudine should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Discontinuation of lamivudine should be considered as medically appropriate. - Dose reduction or discontinuation of interferon alfa, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh >6). ### Pancreatitis - In pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis, lamivudine should be used with caution. - Treatment with lamivudine should be stopped immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur. ### Immune Reconstitution Syndrome - Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine. - During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. - Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment. ### Fat Redistribution - Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. - The mechanism and long-term consequences of these events are currently unknown. - A causal relationship 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 with rates in the clinical trials of another drug and may not reflect the rates observed in practice. ### Adults Population The safety profile of lamivudine in adults is primarily based on 3,568 HIV-1-infected subjects in 7 clinical trials. The most common adverse reactions are headache, nausea, malaise, fatigue, nasal signs and symptoms, diarrhea and cough. Selected clinical adverse reactions in ≥5% of subjects during therapy with lamivudine 150 mg twice daily plus zidovudine 200 mg 3 times daily for up to 24 weeks are listed in Table 3. Pancreatitis: Pancreatitis was observed in 9 out of 2,613 adult subjects (0.3%) who received lamivudine in controlled clinical trials. Lamivudine 300 mg Once Daily: The types and frequencies of clinical adverse reactions reported in subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) for 48 weeks were similar. Selected laboratory abnormalities observed during therapy are summarized in Table 4. The frequencies of selected laboratory abnormalities reported subjects receiving lamivudine 300 mg once daily or lamivudine 150 mg twice daily (in 3-drug combination regimens in EPV20001 and EPV40001) were similar. ### Pediatric Population Lamivudine Oral Solution has been studied in 638 pediatric subjects aged 3 months to 18 years in 3 clinical trials. Selected clinical adverse reactions and physical findings with a ≥5% frequency during therapy with lamivudine 4 mg/kg twice daily plus zidovudine 160 mg/m2 3 times daily in therapy-naive (≤56 days of antiretroviral therapy) pediatric subjects are listed in Table 5. Pancreatitis: Pancreatitis, which has been fatal in some cases, has been observed in antiretroviral nucleoside‑experienced pediatric subjects receiving lamivudine alone or in combination with other antiretroviral agents. In an open‑label dose‑escalation trial (NUCA2002), 14 subjects (14%) developed pancreatitis while receiving monotherapy with lamivudine. Three of these subjects died of complications of pancreatitis. In a second open‑label trial (NUCA2005), 12 subjects (18%) developed pancreatitis. In Trial ACTG300, pancreatitis was not observed in 236 subjects randomized to lamivudine plus zidovudine. Pancreatitis was observed in 1 subject in this trial who received open‑label lamivudine in combination with zidovudin and ritonavir following discontinuation of didanosine monotherapy. Paresthesias and Peripheral Neuropathies: Paresthesias and peripheral neuropathies were reported in 15 subjects (15%) in Trial NUCA2002, 6 subjects (9%) in Trial NUCA2005, and 2 subjects (<1%) in Trial ACTG300. Selected laboratory abnormalities experienced by therapy‑naive (56 days of antiretroviral therapy) pediatric subjects are listed in Table 6. Limited short-term safety information is available from 2 small, uncontrolled trials in South Africa in neonates receiving lamivudine with or without zidovudine for the first week of life following maternal treatment starting at Week 38 or 36 of gestation. Selected adverse reactions reported in these neonates included increased liver function tests, anemia, diarrhea, electrolyte disturbances, hypoglycemia, jaundice and hepatomegaly, rash, respiratory infections, and sepsis; 3 neonates died (1 from gastroenteritis with acidosis and convulsions, 1 from traumatic injury, and 1 from unknown causes). Two other nonfatal gastroenteritis or diarrhea cases were reported, including 1 with convulsions; 1 infant had transient renal insufficiency associated with dehydration. The absence of control groups limits assessments of causality, but it should be assumed that perinatally exposed infants may be at risk for adverse reactions comparable to those reported in pediatric and adult HIV-1-infected patients treated with lamivudine-containing combination regimens. Long-term effects of in utero and infant lamivudine exposure are not known. ## Postmarketing Experience In addition to adverse reactions reported from clinical trials, the following adverse reactions have been reported during postmarketing use of lamivudine. Because these reactions are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. Body as a Whole - Redistribution/accumulation of body fat. General - Weakness. Endocrine and Metabolic - Hyperglycemia. Hemic and Lymphatic - Anemia (including pure red cell aplasia and severe anemias progressing on therapy). Hepatic and Pancreatic - Lactic acidosis and hepatic steatosis - Posttreatment exacerbation of hepatitis B Hypersensitivity - Anaphylaxis - Urticaria. Musculoskeletal - Muscle weakness - CPK elevation - Rhabdomyolysis Skin - Alopecia - Pruritus # Drug Interactions - Lamivudine is predominantly eliminated in the urine by active organic cationic secretion. - The possibility of interactions with other drugs administered concurrently should be considered, particularly when their main route of elimination is active renal secretion via the organic cationic transport system (e.g., trimethoprim). - No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine. - Although no evidence of a pharmacokinetic or pharmacodynamic interaction (e.g., loss of HIV-1/HCV virologic suppression) was seen when ribavirin was coadministered with lamivudine in HIV-1/HCV co-infected patients, Hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. - Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of one another. - Use of lamivudine in combination with zalcitabine is not recommended. - No change in dose of either drug is recommended. - There is no information regarding the effect on lamivudine pharmacokinetics of higher doses of TMP-SMX such as those used to treat PCP. - A drug interaction trial showed no clinically significant interaction between lamivudine and zidovudine. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled trials of lamivudine in pregnant women. Animal reproduction studies in rats and rabbits revealed no evidence of teratogenicity. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. Lamivudine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Lamivudine pharmacokinetics were studied in pregnant women during 2 clinical trials conducted in South Africa. The trial assessed pharmacokinetics in: 16 women at 36 weeks gestation using 150 mg lamivudine twice daily with zidovudine, 10 women at 38 weeks gestation using 150 mg lamivudine twice daily with zidovudine, and 10 women at 38 weeks gestation using lamivudine 300 mg twice daily without other antiretrovirals. These trials were not designed or powered to provide efficacy information. Lamivudine pharmacokinetics in pregnant women were similar to those seen in non-pregnant adults and in postpartum women. Lamivudine concentrations were generally similar in maternal, neonatal, and umbilical cord serum samples. In a subset of subjects, lamivudine amniotic fluid specimens were collected following natural rupture of membranes. Amniotic fluid concentrations of lamivudine were typically 2 times greater than maternal serum levels and ranged from 1.2 to 2.5 mcg/mL (150 mg twice daily) and 2.1 to 5.2 mcg/mL (300 mg twice daily). It is not known whether risks of adverse events associated with lamivudine are altered in pregnant women compared with other HIV-1-infected patients. Animal reproduction studies performed at oral doses up to 130 and 60 times the adult dose in rats and rabbits, respectively, revealed no evidence of teratogenicity due to lamivudine. Increased early embryolethality occurred in rabbits at exposure levels similar to those in humans. However, there was no indication of this effect in rats at exposure levels up to 35 times those in humans. Based on animal studies, lamivudine crosses the placenta and is transferred to the fetus. Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to lamivudine, a Pregnancy Registry has been established. Pregnancy Category (AUS): B3 There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lamivudine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Lamivudine during labor and delivery. ### Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Because of the potential for serious adverse reactions in nursing infants and HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving lamivudine. Lamivudine is excreted into human milk. Samples of breast milk obtained from 20 mothers receiving lamivudine monotherapy (300 mg twice daily) or combination therapy (150 mg lamivudine twice daily and 300 mg zidovudine twice daily) had measurable concentrations of lamivudine. ### Pediatric Use The safety and effectiveness of twice-daily lamivudine in combination with other antiretroviral agents have been established in pediatric patients 3 months and older. ### Geriatic Use Clinical trials of lamivudine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. In particular, because lamivudine is substantially excreted by the kidney and elderly patients are more likely to have decreased renal function, renal function should be monitored and dosage adjustments should be made accordingly. ### Gender There is no FDA guidance on the use of Lamivudine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Lamivudine with respect to specific racial populations. ### Renal Impairment Dosing of lamivudine is adjusted in accordance with renal function. Dosage adjustments are listed in Table 2. No additional dosing of lamivudine is required after routine (4-hour) hemodialysis or peritoneal dialysis. Although there are insufficient data to recommend a specific dose adjustment of lamivudine in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval should be considered. ### Hepatic Impairment There is no FDA guidance on the use of Lamivudine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Lamivudine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Lamivudine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Patients with HIV-1 and Hepatitis B Virus Co-infection should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. # IV Compatibility There is limited information regarding the compatibility of Lamivudine and IV administrations. # Overdosage There is no known antidote for lamivudine. One case of an adult ingesting 6 g of lamivudine was reported; there were no clinical signs or symptoms noted and hematologic tests remained normal. Two cases of pediatric overdose were reported in Trial ACTG300. One case involved a single dose of 7 mg/kg of lamivudine; the second case involved use of 5 mg/kg of lamivudine twice daily for 30 days. There were no clinical signs or symptoms noted in either case. Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event. If overdose occurs, the patient should be monitored, and standard supportive treatment applied as required. # Pharmacology ## Mechanism of Action - Lamivudine is an antiviral agent. - Intracellularly, lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). - The principal mode of action of 3TC-TP is the inhibition of HIV-1 reverse transcriptase (RT) via DNA chain termination after incorporation of the nucleotide analogue into viral DNA. - 3TC-TP is a weak inhibitor of mammalian DNA polymerases α, β, and γ. ## Structure - Lamivudine is a synthetic nucleoside analogue with activity against HIV-1 and HBV. - The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. - Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. - It has a molecular formula of C8H11N3O3S and a molecular weight of 229.3. - Lamivudine is a white to off-white crystalline solid with a solubility of approximately 70 mg/mL in water at 20°C. ## Pharmacodynamics - There is limited information regarding Pharmacodynamics of lamivudine in the drug label. ## Pharmacokinetics ### Pharmacokinetics in Adults - The pharmacokinetic properties of lamivudine have been studied in asymptomatic, HIV-1-infected adult subjects after administration of single intravenous (IV) doses ranging from 0.25 to 8 mg/kg, as well as single and multiple (twice-daily regimen) oral doses ranging from 0.25 to 10 mg/kg. - The pharmacokinetic properties of lamivudine have also been studied as single and multiple oral doses ranging from 5 mg to 600 mg/day administered to HBV-infected subjects. - The steady-state pharmacokinetic properties of the lamivudine 300-mg tablet once daily for 7 days compared with the lamivudine 150-mg tablet twice daily for 7 days were assessed in a crossover trial in 60 healthy subjects. - Lamivudine 300 mg once daily resulted in lamivudine exposures that were similar to lamivudine 150 mg twice daily with respect to plasma AUC24,ss; however, Cmax,ss was 66% higher and the trough value was 53% lower compared with the 150-mg twice-daily regimen. - Intracellular lamivudine triphosphate exposures in peripheral blood mononuclear cells were also similar with respect to AUC24,ss and Cmax24,ss; however, trough values were lower compared with the 150-mg twice-daily regimen. Inter-subject variability was greater for intracellular lamivudine triphosphate concentrations versus lamivudine plasma trough concentrations. - The clinical significance of observed differences for both plasma lamivudine concentrations and intracellular lamivudine triphosphate concentrations is not known. - Lamivudine was rapidly absorbed after oral administration in HIV-1-infected subjects. - Absolute bioavailability in 12 adult subjects was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. - After oral administration of 2 mg/kg twice a day to 9 adults with HIV-1, the peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL (mean ± SD). - The area under the plasma concentration versus time curve (AUC) and Cmax increased in proportion to oral dose over the range from 0.25 to 10 mg/kg. - The accumulation ratio of lamivudine in HIV-1-positive asymptomatic adults with normal renal function was 1.50 following 15 days of oral administration of 2 mg/kg twice daily. - An investigational 25-mg dosage form of lamivudine was administered orally to 12 asymptomatic, HIV-1-infected subjects on 2 occasions, once in the fasted state and once with food (1,099 kcal; 75 grams fat, 34 grams protein, 72 grams carbohydrate). Absorption of lamivudine was slower in the fed state (Tmax: 3.2 ± 1.3 hours) compared with the fasted state (Tmax: 0.9 ± 0.3 hours); Cmax in the fed state was 40% ± 23% (mean ± SD) lower than in the fasted state. There was no significant difference in systemic exposure (AUC∞) in the fed and fasted states; therefore, lamivudine Tablets and Oral Solution may be administered with or without food. - The apparent volume of distribution after IV administration of lamivudine to 20 subjects was 1.3 ± 0.4 L/kg, suggesting that lamivudine distributes into extravascular spaces. - Volume of distribution was independent of dose and did not correlate with body weight. - Binding of lamivudine to human plasma proteins is low (<36%). - In vitro studies showed that over the concentration range of 0.1 to 100 mcg/mL, the amount of lamivudine associated with erythrocytes ranged from 53% to 57% and was independent of concentration. - Metabolism of lamivudine is a minor route of elimination. - In man, the only known metabolite of lamivudine is the trans-sulfoxide metabolite. Within 12 hours after a single oral dose of lamivudine in 6 HIV-1-infected adults, 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Serum concentrations of this metabolite have not been determined. - The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. - In 9 healthy subjects given a single 300-mg oral dose of lamivudine, renal clearance was 199.7 ± 56.9 mL/min (mean ± SD). - In 20 HIV-1-infected subjects given a single IV dose, renal clearance was 280.4 ± 75.2 mL/min (mean ± SD), representing 71% ± 16% (mean ± SD) of total clearance of lamivudine. - In most single-dose trials in HIV-1-infected subjects, HBV‑infected subjects, or healthy subjects with serum sampling for 24 hours after dosing, the observed mean elimination half-life (t½) ranged from 5 to 7 hours. - In HIV-1-infected subjects, total clearance was 398.5 ± 69.1 mL/min (mean ± SD). - Oral clearance and elimination half-life were independent of dose and body weight over an oral dosing range of 0.25 to 10 mg/kg. ### Special Populations - The pharmacokinetic properties of lamivudine have been determined in a small group of HIV-1-infected adults with impaired renal function (Table 7). - Exposure (AUC∞), Cmax, and half-life increased with diminishing renal function (as expressed by creatinine clearance). - Apparent total oral clearance (Cl/F) of lamivudine decreased as creatinine clearance decreased. Tmax was not significantly affected by renal function. Based on these observations, it is recommended that the dosage of lamivudine be modified in patients with renal impairment. - Based on a trial in otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance from a mean of 64 to 88 mL/min; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration. - Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance. Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis. - It is not known whether lamivudine can be removed by continuous (24-hour) hemodialysis. - The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known. - The pharmacokinetic properties of lamivudine have been determined in adults with impaired hepatic function. - Pharmacokinetic parameters were not altered by diminishing hepatic function; therefore, no dose adjustment for lamivudine is required for patients with impaired hepatic function. - Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease. ### Pharmacokinetics in Pediatric Patients - In Trial NUCA2002, pharmacokinetic properties of lamivudine were assessed in a subset of 57 HIV-1-infected pediatric subjects (age range: 4.8 months to 16 years, weight range: 5 to 66 kg) after oral and IV administration of 1, 2, 4, 8, 12, and 20 mg/kg/day. - In the 9 infants and children (age range: 5 months to 12 years) receiving oral solution 4 mg/kg twice daily (the usual recommended pediatric dose), absolute bioavailability was 66% ± 26% (mean ± SD), which was less than the 86% ± 16% (mean ± SD) observed in adults. - The mechanism for the diminished absolute bioavailability of lamivudine in infants and children is unknown. Systemic clearance decreased with increasing age in pediatric subjects, as shown in Figure 1. - After oral administration of lamivudine 4 mg/kg twice daily to 11 pediatric subjects ranging in age from 4 months to 14 years, Cmax was 1.1 ± 0.6 mcg/mL and half-life was 2.0 ± 0.6 hours. (In adults with similar blood sampling, the half‑life was 3.7 ± 1 hours.) - Total exposure to lamivudine, as reflected by mean AUC values, was comparable between pediatric subjects receiving an 8-mg/kg/day dose and adults receiving a 4-mg/kg/day dose. - Distribution of lamivudine into cerebrospinal fluid (CSF) was assessed in 38 pediatric subjects after multiple oral dosing with lamivudine. - CSF samples were collected between 2 and 4 hours postdose. - At the dose of 8 mg/kg/day, CSF lamivudine concentrations in 8 subjects ranged from 5.6% to 30.9% (mean ± SD of 14.2% ± 7.9%) of the concentration in a simultaneous serum sample, with CSF lamivudine concentrations ranging from 0.04 to 0.3 mcg/mL. - Limited, uncontrolled pharmacokinetic and safety data are available from administration of lamivudine (and zidovudine) to 36 infants aged up to 1 week in 2 trials in South Africa. In these trials, lamivudine clearance was substantially reduced in 1-week-old neonates relative to pediatric subjects (aged >3 months) studied previously. - There is insufficient information to establish the time course of changes in clearance between the immediate neonatal period and the age-ranges >3 months old. ### Pharmacokinetics in Geriatric Patients - The pharmacokinetics of lamivudine after administration of lamivudine to patients over 65 years have not been studied. ### Drug Interactions - There was no significant pharmacokineti interaction between lamivudine and interferon alfa in a trial of 19 healthy male subjects. - In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV-1/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n = 18), stavudine (n = 10), or zidovudine (n = 6) were coadministered as part of a multi-drug regimen to HIV-1/HCV co-infected subjects. - Lamivudine and TMP-SMX were coadministered to 14 HIV-1-positive subjects in a single-center, open-label, randomized, crossover trial. Each subject received treatment with a single 300-mg dose of lamivudine and TMP 160 mg/SMX 800 mg once a day for 5 days with concomitant administration of lamivudine 300 mg with the fifth dose in a crossover design. - Coadministration of TMP-SMX with lamivudine resulted in an increase of 43% ± 23% (mean ± SD) in lamivudine AUC∞, a decrease of 29% ± 13% in lamivudine oral clearance, and a decrease of 30% ± 36% in lamivudine renal clearance. *The pharmacokinetic properties of TMP and SMX were not altered by coadministration with lamivudine. - No clinically significant alterations in lamivudine or zidovudine pharmacokinetics were observed in 12 asymptomatic HIV-1-infected adult subjects given a single dose of zidovudine (200 mg) in combination with multiple doses of lamivudine (300 mg q 12 hr). ## Nonclinical Toxicology Long-term carcinogenicity studies with lamivudine in mice and rats showed no evidence of carcinogenic potential at exposures up to 10 times (mice) and 58 times (rats) those observed in humans at the recommended therapeutic dose for HIV-1 infection. Lamivudine was not active in a microbial mutagenicity screen or an in vitro cell transformation assay, but showed weak in vitro mutagenic activity in a cytogenetic assay using cultured human lymphocytes and in the mouse lymphoma assay. However, lamivudine showed no evidence of in vivo genotoxic activity in the rat at oral doses of up to 2,000 mg/kg, producing plasma levels of 35 to 45 times those in humans at the recommended dose for HIV-1 infection. In a study of reproductive performance, lamivudine administered to rats at doses up to 4,000 mg/kg/day, producing plasma levels 47 to 70 times those in humans, revealed no evidence of impaired fertility and no effect on the survival, growth, and development to weaning of the offspring. Reproduction studies have been performed in rats and rabbits at orally administered doses up to 4,000 mg/kg/day and 1,000 mg/kg/day, respectively, producing plasma levels up to approximately 35 times that for the adult HIV dose. No evidence of teratogenicity due to lamivudine was observed. Evidence of early embryolethality was seen in the rabbit at exposure levels similar to those observed in humans, but there was no indication of this effect in the rat at exposure levels up to 35 times those in humans. Studies in pregnant rats and rabbits showed that lamivudine is transferred to the fetus through the placenta. # Clinical Studies The use of lamivudine is based on the results of clinical trials in HIV‑1-infected subjects in combination regimens with other antiretroviral agents. Information from trials with clinical endpoints or a combination of CD4+ cell counts and HIV-1 RNA measurements is included below as documentation of the contribution of lamivudine to a combination regimen in controlled trials. ### Adults NUCB3007 (CAESAR) was a multi-center, double-blind, placebo-controlled trial comparing continued current therapy (zidovudine alone [62% of subjects] or zidovudine with didanosine or zalcitabine [38% of subjects]) to the addition of lamivudine or lamivudine plus an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), randomized 1:2:1. A total of 1,816 HIV-1-infected adults with 25 to 250 CD4+ cells/mm3 (median = 122 cells/mm3) at baseline were enrolled: median age was 36 years, 87% were male, 84% were nucleoside-experienced, and 16% were therapy-naive. The median duration on trial was 12 months. Results are summarized in Table 8. Dual Nucleoside Analogue Trials: Principal clinical trial in the initial development of lamivudine compared lamivudine/zidovudine combinations with zidovudine monotherapy or with zidovudine plus zalcitabine. These trials demonstrated the antiviral effect of lamivudine in a 2-drug combination. More recent uses of lamivudine in treatment of HIV-1 infection incorporate it into multiple-drug regimens containing at least 3 antiretroviral drugs for enhanced viral suppression. Dose Regimen Comparison Surrogate Endpoint Trials in Therapy-Naive Adults: EPV20001 was a multi-center, double-blind, controlled trial in which subjects were randomized 1:1 to receive lamivudine 300 mg once daily or lamivudine 150 mg twice daily, in combination with zidovudine 300 mg twice daily and efavirenz 600 mg once daily. A total of 554 antiretroviral treatment-naive HIV-1-infected adults enrolled: male (79%), Caucasian (50%), median age of 35 years, baseline CD4+ cell counts of 69 to 1,089 cells/mm3 (median = 362 cells/mm3), and median baseline plasma HIV-1 RNA of 4.66 log10 copies/mL. Outcomes of treatment through 48 weeks are summarized in Figure 2 and Table 9. Roche AMPLICOR HIV-1 MONITOR. Responders at each visit are subjects who had achieved and maintained HIV-1 RNA <400 copies/mL without discontinuation by that visit. The proportions of subjects with HIV-1 RNA <50 copies/mL (via Roche Ultrasensitive assay) through Week 48 were 61% for subjects receiving lamivudine 300 mg once daily and 63% for subjects receiving lamivudine 150 mg twice daily. Median increases in CD4+ cell counts were 144 cells/mm3 at Week 48 in subjects receiving lamivudine 300 mg once daily and 146 cells/mm3for subjects receiving lamivudine 150 mg twice daily. A small, randomized, open-label pilot trial, EPV40001, was conducted in Thailand. A total of 159 treatment-naive adult subjects (male 32%, Asian 100%, median age 30 years, baseline median CD4+ cell count 380 cells/mm3, median plasma HIV-1 RNA 4.8 log10 copies/mL) were enrolled. Two of the treatment arms in this trial provided a comparison between lamivudine 300 mg once daily (n = 54) and lamivudine 150 mg twice daily (n = 52), each in combination with zidovudine 300 mg twice daily and abacavir 300 mg twice daily. In intent-to-treat analyses of 48-week data, the proportions of subjects with HIV-1 RNA below 400 copies/mL were 61% (33/54) in the group randomized to once-daily lamivudine and 75% (39/52) in the group randomized to receive all 3 drugs twice daily; the proportions with HIV-1 RNA below 50 copies/mL were 54% (29/54) in the once-daily lamivudine group and 67% (35/52) in the all-twice-daily group; and the median increases in CD4+ cell counts were 166 cells/mm3 in the once-daily lamivudine group and 216 cells/mm3 in the all-twice-daily group. ### Pediatric Subjects Clinical Endpoint Trial: ACTG300 was a multi-center, randomized, double-blind trial that provided for comparison of lamivudine plus zidovudine with didanosine monotherapy. A total of 471 symptomatic, HIV-1-infected therapy-naive (56 days of antiretroviral therapy) pediatric subjects were enrolled in these 2 treatment arms. The median age was 2.7 years (range: 6 weeks to 14 years), 58% were female, and 86% were non-Caucasian. The mean baseline CD4+ cell count was 868 cells/mm3 (mean: 1,060 cells/mm3 and range:0 to 4,650 cells/mm3 for subjects aged 5 years; mean: 419 cells/mm3 and range: 0 to 1,555 cells/mm3 for subjects aged >5 years) and the mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL. The median duration on trial was 10.1 months for the subjects receiving lamivudine plus zidovudine and 9.2 months for subjects receiving didanosine monotherapy. Results are summarized in Table 10. # How Supplied - White, diamond-shaped, scored, film-coated tablets debossed with “GX CJ7” on both sides. - Bottle of 60 tablets (NDC 49702-203-18) with child-resistant closure. - Gray, modified diamond-shaped, film-coated tablets engraved with “GX EJ7” on one side and plain on the reverse side. - Bottle of 30 tablets (NDC 49702-204-13) with child-resistant closure. - A clear, colorless to pale yellow, strawberry-banana-flavored liquid, contains 10 mg of lamivudine in each 1 mL. - Plastic bottle of 240 mL (NDC 49702-205-48) with child-resistant closure. This product does not require reconstitution. ## Storage - Store Lamivudine Tablets at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). - Store in tightly closed bottles at 25°C (77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Advice for the Patient - Patients should be informed that some HIV medicines, including lamivudine, can cause a rare, but serious condition called lactic acidosis with liver enlargement (hepatomegaly). - Patients co-infected with HIV-1 and HBV should be informed that deterioration of liver disease has occurred in some cases when treatment with lamivudine was discontinued. - Patients should be advised to discuss any changes in regimen with their physician. Patients should be advised that lamivudine Tablets and Oral Solution contain a higher dose of the same active ingredient (lamivudine) as lamivudine-HBV Tablets and Oral Solution. If a decision is made to include lamivudine in the HIV-1 treatment regimen of a patient co-infected with HIV-1 and HBV, the formulation and dosage of lamivudine in lamivudine (not lamivudine-HBV) should be used. Lamivudine should not be coadministered with drugs containing lamivudine or emtricitabine, including lamivudine/zidovudine Tablets, abacavir sulfate and lamivudine Tablets, abacavir sulfate, lamivudine, and zidovudine, efavirenz, emtricitabine, and tenofovir, [emtricitabine], emtricitabine and tenofovir, or rilpivirine/emtricitabine/tenofovir. Patients with HIV-1/HCV co-infection should be informed that hepatic decompensation (some fatal) has occurred in HIV-1/HCV co-infected patients receiving combination antiretroviral therapy for HIV-1 and interferon alfa with or without ribavirin. Parents or guardians should be advised to monitor pediatric patients for signs and symptoms of pancreatitis. Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including lamivudine, and that the cause and long-term health effects of these conditions are not known at this time. Diabetic patients should be advised that each 15-mL dose of lamivudine Oral Solution contains 3 grams of sucrose. Lamivudine is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using lamivudine. Patients should be advised to avoid doing things that can spread HIV-1 infection to others. - Do not share needles or other injection equipment. - Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades. - Do not have any kind of sex without protection. - Always practice safe sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with semen, vaginal secretions, or blood. - Do not breastfeed. Lamivudine is excreted in human breast milk. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk. - Patients should be informed to take all HIV medications exactly as prescribed. # Precautions with Alcohol Alcohol-lamivudine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - EPIVIR[2] - EPIVIR HBV - EPIVIR A/F # Look-Alike Drug Names There is limited information regarding Lamivudine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/EPIVIR
d976a87970e3e7f3f6575a33d720ba05dc5f714c	wikidoc	ERG (gene)	ERG (gene) ERG (ETS-related gene) is an oncogene. ERG is a member of the ETS (erythroblast transformation-specific) family of transcription factors. The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis. # Function Transcriptional regulator ERG is a nuclear protein that binds purine-rich sequences of DNA. Transcriptional regulator ERG is required for platelet adhesion to the subendothelium and regulates hematopoiesis. It has a DNA binding domain and a PNT (pointed) domain. ERG is expressed at higher levels in early myelocytes than in mature lymphocytes (types of white blood cells). Therefore, ERG may act as a regulator of differentiation of early hematopoietic cells. The Mld2 mutation, generated through an ENU mutagenesis screen, was the first non-functional allele of Erg. Homozygous Mld2 is embryonic lethal at day 13.5. Adult mice heterozygous for the Mld2 mutation have hematopoietic stem cell defects. This means that when the ERG gene was not actively transcribed and the ERG protein produced, a mouse's hematopoietic cells were unable to function properly. Since ERG is important to the ability of the hematopoietic cells to function and self-renew, there may be applications in using blood stem cells for tissue repair, transplantation and other therapeutic applications. # Cancer This gene can be classified as a proto-oncogene. During chromosomal translocations that occur in cell division, ERG can accidentally get stuck onto a different chromosome than where it belongs. This is analogous to another translocation, the Philadelphia chromosome. This results in fusion gene products, which can have bad consequences for cells. Examples of these fusion gene products would be TMPRSS2-ERG and NDRG1-ERG in prostate cancer, EWS-ERG in Ewing’s sarcoma, and FUS-ERG in acute myeloid leukemia. DNA binding protein ERG fuses with RNA binding proteins EWS and TLS/FUS in Ewing's sarcoma and acute myeloid leukemias respectively and function as transcriptional activators. ERG and its fusion proteins EWS-ERG and TLS/FUS-ERG inhibit apoptosis. ## TMPRSS2 gene fusion ERG can fuse with TMPRSS2 protein to form an oncogenic fusion gene that is commonly found in human prostate cancer, especially in hormone-refractory prostate cancer. This suggests that ERG overexpression may contribute to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling. The fusion gene is critical to the progression of cancer because it inhibits the androgen receptor expression and it binds and inhibits androgen receptors already present in the cell. Essentially TMPRSS2-ERG fusion disrupts the ability of the cells to differentiate into proper prostate cells creating unregulated and unorganized tissue. In 90% of prostate cancers overexpressing ERG, they also possess a fusion TMPRSS2-ERG protein, suggesting that this fusion is the predominant subtype in prostate cancer. ## EWS gene fusion Ewing's sarcoma is associated with chromosomal translocations, which typically results in fusion genes with transcriptional regulators. This means that the protein transcribes for with the gene could be produced in excess or under- produced resulting in unnatural activity in cells. Typically this is the first step in a cell's progression to malignancy. In about 10% of Ewing's Sarcoma cases have an EWS1-ERG fusion. ## Fusion with TLS/FUS In acute myeloid leukemia, the t(16;21) translocation in myeloid leukemia fuses TLS/FUS to ERG which disrupts the natural TLS/FUS RNA binding domain, and instead inserting the ERG DNA binding domain. # Location ERG is located on chromosome 21. The ERG protein is expressed at a similar level throughout the body. # Interactions ERG has been shown to interact with: - C-jun, - ETS2, - EWSR1, - TLS, and - TMPRSS2.	ERG (gene) ERG (ETS-related gene) is an oncogene.[1][2][3] ERG is a member of the ETS (erythroblast transformation-specific) family of transcription factors.[4] The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis. # Function Transcriptional regulator ERG is a nuclear protein that binds purine-rich sequences of DNA.[5][6] Transcriptional regulator ERG is required for platelet adhesion to the subendothelium and regulates hematopoiesis. It has a DNA binding domain and a PNT (pointed) domain.[4] ERG is expressed at higher levels in early myelocytes than in mature lymphocytes (types of white blood cells). Therefore, ERG may act as a regulator of differentiation of early hematopoietic cells.[7] The Mld2 mutation, generated through an ENU mutagenesis screen, was the first non-functional allele of Erg. Homozygous Mld2 is embryonic lethal at day 13.5. Adult mice heterozygous for the Mld2 mutation have hematopoietic stem cell defects.[8] This means that when the ERG gene was not actively transcribed and the ERG protein produced, a mouse's hematopoietic cells were unable to function properly. Since ERG is important to the ability of the hematopoietic cells to function and self-renew, there may be applications in using blood stem cells for tissue repair, transplantation and other therapeutic applications.[9] # Cancer This gene can be classified as a proto-oncogene. During chromosomal translocations that occur in cell division, ERG can accidentally get stuck onto a different chromosome than where it belongs. This is analogous to another translocation, the Philadelphia chromosome. This results in fusion gene products, which can have bad consequences for cells. Examples of these fusion gene products would be TMPRSS2-ERG and NDRG1-ERG in prostate cancer, EWS-ERG in Ewing’s sarcoma, and FUS-ERG in acute myeloid leukemia.[10] DNA binding protein ERG fuses with RNA binding proteins EWS and TLS/FUS in Ewing's sarcoma and acute myeloid leukemias respectively and function as transcriptional activators.[11][12] ERG and its fusion proteins EWS-ERG and TLS/FUS-ERG inhibit apoptosis.[13] ## TMPRSS2 gene fusion ERG can fuse with TMPRSS2 protein to form an oncogenic fusion gene that is commonly found in human prostate cancer, especially in hormone-refractory prostate cancer. This suggests that ERG overexpression may contribute to development of androgen-independence in prostate cancer through disruption of androgen receptor signaling.[14] The fusion gene is critical to the progression of cancer because it inhibits the androgen receptor expression and it binds and inhibits androgen receptors already present in the cell. Essentially TMPRSS2-ERG fusion disrupts the ability of the cells to differentiate into proper prostate cells creating unregulated and unorganized tissue.[14] In 90% of prostate cancers overexpressing ERG, they also possess a fusion TMPRSS2-ERG protein, suggesting that this fusion is the predominant subtype in prostate cancer.[15] ## EWS gene fusion Ewing's sarcoma is associated with chromosomal translocations, which typically results in fusion genes with transcriptional regulators. This means that the protein transcribes for with the gene could be produced in excess or under- produced resulting in unnatural activity in cells. Typically this is the first step in a cell's progression to malignancy. In about 10% of Ewing's Sarcoma cases have an EWS1-ERG fusion.[4] ## Fusion with TLS/FUS In acute myeloid leukemia, the t(16;21) translocation in myeloid leukemia fuses TLS/FUS to ERG which disrupts the natural TLS/FUS RNA binding domain, and instead inserting the ERG DNA binding domain.[16] # Location ERG is located on chromosome 21.[2] The ERG protein is expressed at a similar level throughout the body.[4] # Interactions ERG has been shown to interact with: - C-jun,[17] - ETS2,[18] - EWSR1,[11] - TLS,[12] and - TMPRSS2.[14]	https://www.wikidoc.org/index.php/ERG_(gene)
f428c63e2ead8fcf75b27076adb3a7426ab12583	wikidoc	ERH (gene)	ERH (gene) In molecular biology, Enhancer of rudimentary homolog is a protein that in humans is encoded by the ERH gene. The Drosophila protein enhancer of rudimentary protein is a small protein of 104 amino acids. It has been found to be an enhancer of the rudimentary gene, involved in pyrimidine biosynthesis. From an evolutionary point of view, enhancer of rudimentary is highly conserved and has been found to exist in probably all multicellular eukaryotic organisms. It has been proposed that this protein plays a role in the cell cycle.	ERH (gene) In molecular biology, Enhancer of rudimentary homolog is a protein that in humans is encoded by the ERH gene.[1][2][3] The Drosophila protein enhancer of rudimentary protein is a small protein of 104 amino acids. It has been found to be an enhancer of the rudimentary gene, involved in pyrimidine biosynthesis.[4] From an evolutionary point of view, enhancer of rudimentary is highly conserved and has been found to exist in probably all multicellular eukaryotic organisms.[2] It has been proposed that this protein plays a role in the cell cycle.	https://www.wikidoc.org/index.php/ERH_(gene)
ffd3835074d3b85c08558c0a9c5f2c2c6b7b54ba	wikidoc	Economizer	Economizer Economizers, or in British English economisers, are mechanical devices intended to reduce energy consumption, or to perform another useful function like preheating a fluid. The term economizer is used for other purposes as well. Boiler, powerplant, and heating, ventilating, and air-conditioning (HVAC) uses are discussed in this article. In simple terms, an economizer is a heat exchanger. # Stirling engine Robert Stirling's innovative contribution to the design of hot air engines of 1816 was what he called the 'Economiser'. Now known as the regenerator, it stored heat from the hot portion of the engine as the air passed to the cold side, and released heat to the cooled air as it returned to the hot side. This innovation improved the efficiency of Stirling's engine enough to make it commercially successful in particular applications, and has since been a component of every air engine that is called a Stirling engine. # Boilers In boilers, economizers are heat exchange devices that heat fluids, usually water, up to but not normally beyond the boiling point of that fluid. Economizers are so named because they can make use of the enthalpy in fluid streams that are hot, but not hot enough to be used in a boiler, thereby recovering more useful enthalpy and improving the boiler's efficiency. They are a device fitted to a boiler which saves energy by using the exhaust gases from the boiler to preheat the cold water used to fill it (the feed water). ## History The first successful design of economizer was used to increase the steam-raising efficiency of the boilers of stationary steam engines. It was patented by Edward Green in 1845, and since then has been known as Green's economizer. It consisted of an array of vertical cast iron tubes connected to a tank of water above and below, between which the boiler's exhaust gases passed. This is the reverse arrangement to that of fire tubes in a boiler itself; there the hot gases pass through tubes immersed in water, whereas in an economizer the water passes through tubes surrounded by hot gases. The most successful feature of Green's design of economizer was its mechanical scraping apparatus, which was needed to keep the tubes free of deposits of soot. Economizers were eventually fitted to virtually all stationary steam engines in the decades following Green's invention. Some preserved stationary steam engine sites still have their Green's economizers although usually they are not used. One such preserved site is the Claymills Pumping Engines Trust in Staffordshire, England, which is in the process of restoring one set of economizers and the associated steam engine which drove them. # Powerplants Modern-day boilers, such as those in coal-fired power stations, are still fitted with economizers which are descendants of Green's original design. In this context they are often referred to as feedwater heaters and heat the condensate from turbines before it is pumped to the boilers. Economizers are commonly used as part of a HRSG in a combined cycle power plant. In an HRSG, water passes through an economizer, then a boiler and then a superheater. The economizer also prevents flooding of the boiler with liquid water that is too cold to be boiled given the flow rates and design of the boiler. A common application of economizers in steam powerplants is to capture the waste heat from boiler stack gases (flue gas) and transfer it to the boiler feedwater. This raises the temperature of the boiler feedwater thus lowering the needed energy input, in turn reducing the firing rates to accomplish the rated boiler output. Economizers lower stack temperatures which may cause condensation of acidic combustion gases and serious equipment corrosion damage if care is not taken in their design and material selection. # HVAC Air-side economizers can save energy in buildings by using cool outside air as a means of cooling the indoor space. When the enthalpy of the outside air is less than the enthalpy of the recirculated air, conditioning the outside air is more energy efficient than conditioning recirculated air. When the outside air is sufficiently cool, no additional conditioning of it is needed; this portion of the air-side economizer control scheme is called free cooling. Air-side economizers can reduce HVAC energy costs in cold and temperate climates while also potentially improving indoor air quality, but are most often not appropriate in hot and humid climates. For information on how economizers and other controls can affect energy efficiency and indoor air quality in buildings, see the U.S. Environmental Protection Agency report, "Energy Cost and IAQ Performance of Ventilation Systems and Controls" When the outside air's dry- and wet-bulb temperatures are low enough, water-side economizers use water cooled by a wet cooling tower to cool buildings without operating a chiller. They are historically know as the strainer cycle, but the water-side economizer is not a true thermodynamic cycle. Also, instead of passing the cooling tower water through a strainer and then to the cooling coils, which causes their fouling, more often a plate-and-frame heat exchanger is inserted between the cooling tower and chilled water loops. Good controls, and valves or dampers, as well as maintenance, are needed to ensure proper operation of the air- and water-side economizers. Examples of economizers in chillers would be Flasc Economizers, Flash Economizers, and Flash Flasc Economizers.	Economizer Economizers, or in British English economisers, are mechanical devices intended to reduce energy consumption, or to perform another useful function like preheating a fluid. The term economizer is used for other purposes as well. Boiler, powerplant, and heating, ventilating, and air-conditioning (HVAC) uses are discussed in this article. In simple terms, an economizer is a heat exchanger. # Stirling engine Robert Stirling's innovative contribution to the design of hot air engines of 1816 was what he called the 'Economiser'. Now known as the regenerator, it stored heat from the hot portion of the engine as the air passed to the cold side, and released heat to the cooled air as it returned to the hot side. This innovation improved the efficiency of Stirling's engine enough to make it commercially successful in particular applications, and has since been a component of every air engine that is called a Stirling engine. # Boilers In boilers, economizers are heat exchange devices that heat fluids, usually water, up to but not normally beyond the boiling point of that fluid. Economizers are so named because they can make use of the enthalpy in fluid streams that are hot, but not hot enough to be used in a boiler, thereby recovering more useful enthalpy and improving the boiler's efficiency. They are a device fitted to a boiler which saves energy by using the exhaust gases from the boiler to preheat the cold water used to fill it (the feed water). ## History The first successful design of economizer was used to increase the steam-raising efficiency of the boilers of stationary steam engines. It was patented by Edward Green in 1845, and since then has been known as Green's economizer. It consisted of an array of vertical cast iron tubes connected to a tank of water above and below, between which the boiler's exhaust gases passed. This is the reverse arrangement to that of fire tubes in a boiler itself; there the hot gases pass through tubes immersed in water, whereas in an economizer the water passes through tubes surrounded by hot gases. The most successful feature of Green's design of economizer was its mechanical scraping apparatus, which was needed to keep the tubes free of deposits of soot. Economizers were eventually fitted to virtually all stationary steam engines in the decades following Green's invention. Some preserved stationary steam engine sites still have their Green's economizers although usually they are not used. One such preserved site is the Claymills Pumping Engines Trust in Staffordshire, England, which is in the process of restoring one set of economizers and the associated steam engine which drove them. # Powerplants Modern-day boilers, such as those in coal-fired power stations, are still fitted with economizers which are descendants of Green's original design. In this context they are often referred to as feedwater heaters and heat the condensate from turbines before it is pumped to the boilers. Economizers are commonly used as part of a HRSG in a combined cycle power plant. In an HRSG, water passes through an economizer, then a boiler and then a superheater. The economizer also prevents flooding of the boiler with liquid water that is too cold to be boiled given the flow rates and design of the boiler. A common application of economizers in steam powerplants is to capture the waste heat from boiler stack gases (flue gas) and transfer it to the boiler feedwater. This raises the temperature of the boiler feedwater thus lowering the needed energy input, in turn reducing the firing rates to accomplish the rated boiler output. Economizers lower stack temperatures which may cause condensation of acidic combustion gases and serious equipment corrosion damage if care is not taken in their design and material selection. # HVAC Air-side economizers can save energy in buildings by using cool outside air as a means of cooling the indoor space. When the enthalpy of the outside air is less than the enthalpy of the recirculated air, conditioning the outside air is more energy efficient than conditioning recirculated air. When the outside air is sufficiently cool, no additional conditioning of it is needed; this portion of the air-side economizer control scheme is called free cooling. Air-side economizers can reduce HVAC energy costs in cold and temperate climates while also potentially improving indoor air quality, but are most often not appropriate in hot and humid climates. For information on how economizers and other controls can affect energy efficiency and indoor air quality in buildings, see the U.S. Environmental Protection Agency report, "Energy Cost and IAQ Performance of Ventilation Systems and Controls" [1] When the outside air's dry- and wet-bulb temperatures are low enough, water-side economizers use water cooled by a wet cooling tower to cool buildings without operating a chiller. They are historically know as the strainer cycle, but the water-side economizer is not a true thermodynamic cycle. Also, instead of passing the cooling tower water through a strainer and then to the cooling coils, which causes their fouling, more often a plate-and-frame heat exchanger is inserted between the cooling tower and chilled water loops. Good controls, and valves or dampers, as well as maintenance, are needed to ensure proper operation of the air- and water-side economizers. Examples of economizers in chillers would be Flasc Economizers, Flash Economizers, and Flash Flasc Economizers.	https://www.wikidoc.org/index.php/Economizer
7112da9bbf9b33714d809b138c8ac28727771729	wikidoc	Parasitism	Parasitism Parasitism is one version of symbiosis ("living together"), a phenomenon in which two organisms which are phylogenetically unrelated co-exist over a prolonged period of time, usually the lifetime of one of the individuals. The requirement for a prolonged interaction precludes predatory or episodic interactions (such as a mosquito feeding on a host), which are usually not seen as symbiotic relationships. Symbiosis encompasses commensalism ("eating at the same table", wherein two organisms co-exist in the same space, and one organism benefits while neither harming nor helping the other), through mutualism (wherein both species benefit from the interaction) to parasitism, wherein one organism, usually physically smaller of the two (the parasite) benefits and the other (the host) is harmed. (Various forms of "social parasitism", kleptoparasitism, and "cheating parasitism", as discussed below, are characterized by a less close association between a parasite and a host, however.) Especially in the field of medical parasitology, the term "parasite" has come to mean a eukaryotic, pathogenic organism. Thus, protozoan and metazoan infectious agents are classified as parasites while bacteria and viruses are not. Fungi are not discussed in textbooks of medical parasitology even though they are eukaryotic. They are saprophytes. # Classification Parasites that live inside the live body of the host are called endoparasites (e.g., hookworms that live in the host's gut) and those that live on the outside are called ectoparasites (e.g., some mites). An epiparasite is a parasite that feeds on another parasite. This relationship is also sometimes referred to as "hyperparasitoidism", especially in the insect world. For example a wasp or fly larva may be an endoparasite of an Ichneumon wasp larva, which is in turn an endoparasite of a wood-boring beetle larva. Therefore the ovipositing adult female hyperparasitoid must find the host of her host, namely the beetle larva, and oviposit into that beetle larva, after which her egg hatches within the beetle larva and seeks out the Ichneumon larva, ultimately burrowing into it and becoming an endoparasite. It is most likely that in this case, the ovipositing female adult hyperparasite locates the beetle larva by chemical cues it emits as a result of being parasitized itself by the Ichneumon wasp larva. Many endoparasites acquire hosts by gaining entrance to their tissue; others enter the host when it consumes certain raw foods, as in the case of the nematode Ascaris lumbricoides, an endoparasite of the human intestine. A. lumbricoides produces large numbers of eggs which are passed from the host's digestive tract and pancreas into the external environment, relying on other humans to inadvertently ingest them in places without good sanitation. Ectoparasites, on the other hand, often have elaborate mechanisms and strategies for finding hosts. Some aquatic leeches, for example, locate hosts by sensing movement and then confirm their identity through skin temperature and chemical cues before attaching. Parasitoids are parasites that use another organism's tissue for their own nutritional benefit until the host dies from loss of needed tissues or nutrients. Parasitoids are also known as necrotroph. In contrast, biotrophic parasites cannot survive in a dead host and therefore keep their hosts alive. Many viruses, for example, are biotrophic because they use the host's genetic and cellular processes to multiply. Some parasites are social parasites, taking advantage of interactions between members of a social host species such as ants or termites to their detriment. Kleptoparasitism involves the parasite stealing food that the host has caught or otherwise prepared. A specialized type of kleptoparasitism is brood parasitism, such as that engaged in by many species of cuckoo. Many cuckoos use other birds as "babysitters"; cuckoo young are raised and fed by adults of the host species, but adult cuckoos fend for themselves. Cheating or exploitation types of parasitism are often found in situations where there are generalized non-specific mutualisms between broad classes of organisms, such as mycorrhizal relationships between plants and many types of fungi. Some myco-heterotrophic plants behave as "mycorrhizal cheaters", establishing mycorrhiza-like interactions with a fungal symbiont, but taking carbon from the fungus (which the fungus, in turn, gets from other plants) rather than donating carbon. # Evolutionary aspects Biotrophic parasitism is an extremely successful mode of life. Depending on the definition used, as many as half of all animals have at least one parasitic phase in their life cycles, and it is also frequent in plants and fungi. Moreover, almost all free-living animals are host to one or more parasite taxa. The hosts of parasites often evolve elaborate defensive mechanisms as well. Plants often produce toxins, for example, which deter both parasitic fungi and bacteria as well as herbivores. Vertebrate immune systems can target most parasites through contact with bodily fluids. On a behavioral level, the itching sensation, and resulting scratching behavior is used to fend off parasites. Many parasites, particularly microorganisms, evolve adaptations to a particular host species; in such specific interactions the two species generally coevolve into a relatively stable relationship that does not kill the host quickly or at all (since this would be detrimental for the parasite as well). Sometimes, the study of parasite taxonomy can elucidate how their hosts are similar or related. For instance, there has been a dispute about whether Phoenicopteriformes (flamingos) are more closely related to Ciconiiformes (storks and related groups) or to Anseriformes (waterfowl and allies). Flamingos share parasites with ducks and geese, so these groups are thought to be more closely related to one another than either is to storks. Modern DNA methods, however, have shown that flamingos are not closely related to Anseriformes either. It is important to note that "benefit" and "harm" in the definition of parasitism apply to lineages, not individuals. Thus, if an organism becomes physically stronger as a result of infection but loses reproductive capabilities (as results from some flatworm infections of snails), that organism is harmed in an evolutionary sense and is thus parasitized. The harm caused to a host by a parasite can take many forms, from direct pathology, including various specialized types of tissue damage, such as castration, to more subtle effects such as modification of host behaviour.	Parasitism Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Parasitism is one version of symbiosis ("living together"), a phenomenon in which two organisms which are phylogenetically unrelated co-exist over a prolonged period of time, usually the lifetime of one of the individuals. The requirement for a prolonged interaction precludes predatory or episodic interactions (such as a mosquito feeding on a host), which are usually not seen as symbiotic relationships. Symbiosis encompasses commensalism ("eating at the same table", wherein two organisms co-exist in the same space, and one organism benefits while neither harming nor helping the other), through mutualism (wherein both species benefit from the interaction) to parasitism, wherein one organism, usually physically smaller of the two (the parasite) benefits and the other (the host) is harmed. (Various forms of "social parasitism", kleptoparasitism, and "cheating parasitism", as discussed below, are characterized by a less close association between a parasite and a host, however.) Especially in the field of medical parasitology, the term "parasite" has come to mean a eukaryotic, pathogenic organism. Thus, protozoan and metazoan infectious agents are classified as parasites while bacteria and viruses are not. Fungi are not discussed in textbooks of medical parasitology even though they are eukaryotic. They are saprophytes. # Classification Parasites that live inside the live body of the host are called endoparasites (e.g., hookworms that live in the host's gut) and those that live on the outside are called ectoparasites (e.g., some mites). An epiparasite is a parasite that feeds on another parasite. This relationship is also sometimes referred to as "hyperparasitoidism", especially in the insect world. For example a wasp or fly larva may be an endoparasite of an Ichneumon wasp larva, which is in turn an endoparasite of a wood-boring beetle larva. Therefore the ovipositing adult female hyperparasitoid must find the host of her host, namely the beetle larva, and oviposit into that beetle larva, after which her egg hatches within the beetle larva and seeks out the Ichneumon larva, ultimately burrowing into it and becoming an endoparasite. It is most likely that in this case, the ovipositing female adult hyperparasite locates the beetle larva by chemical cues it emits as a result of being parasitized itself by the Ichneumon wasp larva. Many endoparasites acquire hosts by gaining entrance to their tissue; others enter the host when it consumes certain raw foods, as in the case of the nematode Ascaris lumbricoides, an endoparasite of the human intestine. A. lumbricoides produces large numbers of eggs which are passed from the host's digestive tract and pancreas into the external environment, relying on other humans to inadvertently ingest them in places without good sanitation. Ectoparasites, on the other hand, often have elaborate mechanisms and strategies for finding hosts. Some aquatic leeches, for example, locate hosts by sensing movement and then confirm their identity through skin temperature and chemical cues before attaching. Parasitoids are parasites that use another organism's tissue for their own nutritional benefit until the host dies from loss of needed tissues or nutrients. Parasitoids are also known as necrotroph. In contrast, biotrophic parasites cannot survive in a dead host and therefore keep their hosts alive. Many viruses, for example, are biotrophic because they use the host's genetic and cellular processes to multiply. Some parasites are social parasites, taking advantage of interactions between members of a social host species such as ants or termites to their detriment. Kleptoparasitism involves the parasite stealing food that the host has caught or otherwise prepared. A specialized type of kleptoparasitism is brood parasitism, such as that engaged in by many species of cuckoo. Many cuckoos use other birds as "babysitters"; cuckoo young are raised and fed by adults of the host species, but adult cuckoos fend for themselves. Cheating or exploitation types of parasitism are often found in situations where there are generalized non-specific mutualisms between broad classes of organisms, such as mycorrhizal relationships between plants and many types of fungi. Some myco-heterotrophic plants behave as "mycorrhizal cheaters", establishing mycorrhiza-like interactions with a fungal symbiont, but taking carbon from the fungus (which the fungus, in turn, gets from other plants) rather than donating carbon. # Evolutionary aspects Biotrophic parasitism is an extremely successful mode of life. Depending on the definition used, as many as half of all animals have at least one parasitic phase in their life cycles, and it is also frequent in plants and fungi. Moreover, almost all free-living animals are host to one or more parasite taxa. The hosts of parasites often evolve elaborate defensive mechanisms as well. Plants often produce toxins, for example, which deter both parasitic fungi and bacteria as well as herbivores. Vertebrate immune systems can target most parasites through contact with bodily fluids. On a behavioral level, the itching sensation, and resulting scratching behavior is used to fend off parasites. Many parasites, particularly microorganisms, evolve adaptations to a particular host species; in such specific interactions the two species generally coevolve into a relatively stable relationship that does not kill the host quickly or at all (since this would be detrimental for the parasite as well). Sometimes, the study of parasite taxonomy can elucidate how their hosts are similar or related. For instance, there has been a dispute about whether Phoenicopteriformes (flamingos) are more closely related to Ciconiiformes (storks and related groups) or to Anseriformes (waterfowl and allies). Flamingos share parasites with ducks and geese, so these groups are thought to be more closely related to one another than either is to storks. Modern DNA methods, however, have shown that flamingos are not closely related to Anseriformes either. It is important to note that "benefit" and "harm" in the definition of parasitism apply to lineages, not individuals. Thus, if an organism becomes physically stronger as a result of infection but loses reproductive capabilities (as results from some flatworm infections of snails), that organism is harmed in an evolutionary sense and is thus parasitized. The harm caused to a host by a parasite can take many forms, from direct pathology, including various specialized types of tissue damage, such as castration, to more subtle effects such as modification of host behaviour.	https://www.wikidoc.org/index.php/Ectoparasite
a3801f6b542cd3b38210bb0a0c392b45f3e2c23c	wikidoc	Eculizumab	Eculizumab # 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 Eculizumab is a monoclonal antibody that is FDA approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis and for patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, diarrhea, nausea, vomiting, anemia, backache, headache, insomnia, nasal congestion, nasopharyngitis, respiratory tract infection and fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Paroxysmal Nocturnal Hemoglobinuria (PNH) Eculizumab is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. Dosage: - 600 mg weekly for the first 4 weeks, followed by - 900 mg for the fifth dose 1 week later, then - 900 mg every 2 weeks thereafter. ### Atypical Hemolytic Uremic Syndrome (aHUS) Eculizumab is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Dosage: - 900 mg weekly for the first 4 weeks, followed by - 1200 mg for the fifth dose 1 week later, then - 1200 mg every 2 weeks thereafter. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eculizumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eculizumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Atypical Hemolytic Uremic Syndrome (aHUS) - Eculizumab is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. - For patients less than 18 years of age, administer eculizumab based upon body weight, according to the following schedule: ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eculizumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eculizumab in pediatric patients. # Contraindications - Patients with unresolved serious Neisseria meningitidis infection. - Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying eculizumab treatment outweigh the risks of developing a meningococcal infection # Warnings ### Serious Meningococcal Infections - The use of eculizumab increases a patient's susceptibility to serious meningococcal infections (septicemia and/or meningitis). Life-threatening and fatal meningococcal infections have occurred in patients treated with eculizumab. - Administer a polyvalent meningococcal vaccine according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients with complement deficiencies. Revaccinate patients in accordance with ACIP recommendations, considering the duration of eculizumab therapy. - Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of eculizumab. If urgent eculizumab therapy is indicated in an unvaccinated patient, administer the meningococcal vaccine as soon as possible. In prospective clinical studies, 75/100 patients with aHUS were treated with eculizumab less than 2 weeks after meningococcal vaccination and 64 of these 75 patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after meningococcal vaccination. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving eculizumab have not been established. - Vaccination reduces, but does not eliminate, the risk of meningococcal infections. In clinical studies, 2 out of 196 PNH patients developed serious meningococcal infections while receiving treatment with eculizumab; both had been vaccinated. In clinical studies among non-PNH patients, meningococcal meningitis occurred in one unvaccinated patient. In addition, 3 out of 130 previously vaccinated patients with aHUS developed meningococcal infections while receiving treatment with eculizumab. - Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if an infection is suspected. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Discontinue eculizumab in patients who are undergoing treatment for serious meningococcal infections. ### Eculizumab REMS - Because of the risk of meningococcal infections, eculizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the eculizumab REMS, prescribers must enroll in the program. - Prescribers must counsel patients about the risk of meningococcal infection, provide the patients with the REMS educational materials, and ensure patients are vaccinated with a meningococcal vaccine. ### Other Infections - eculizumab blocks terminal complement activation; therefore patients may have increased susceptibility to infections, especially with encapsulated bacteria. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with eculizumab may be at increased risk of developing serious infections due to Streptococcuspneumoniae and Haemophilus influenza type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenza type b (Hib) infections according to ACIP guidelines. Use caution when administering eculizumab to patients with any systemic infection. ### Monitoring Disease Manifestations After eculizumab Discontinuation - Monitor patients after discontinuing eculizumab for at least 8 weeks to detect hemolysis. - After discontinuing eculizumab, monitor patients with aHUS for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. In aHUS clinical trials, 18 patients (5 in the prospective studies) discontinued eculizumab treatment. TMA complications occurred following a missed dose in 5 patients, and eculizumab was reinitiated in 4 of these 5 patients. Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of two, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during eculizumab treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during eculizumab treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during eculizumab treatment. If TMA complications occur after eculizumab discontinuation, consider reinstitution of eculizumab treatment, plasma therapy , or appropriate organ-specific supportive measures. ### Thrombosis Prevention and Management - The effect of withdrawal of anticoagulant therapy during eculizumab treatment has not been established. Therefore, treatment with eculizumab should not alter anticoagulant management. ### Infusion Reactions - As with all protein products, administration of eculizumab may result in infusion reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion reaction which required discontinuation of eculizumab. Interrupt eculizumab infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur. # 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. Meningococcal infections are the most important adverse reactions experienced by patients receiving eculizumab. In PNH clinical studies, two patients experienced meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis occurred in one unvaccinated patient. Meningococcal sepsis occurred in one previously vaccinated patient enrolled in the retrospective aHUS study during the post-study follow-up period. ### PNH The data described below reflect exposure to eculizumab in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or symptoms of intravascular hemolysis. eculizumab was studied in a placebo-controlled clinical study (in which 43 patients received eculizumab and 44, placebo); a single arm clinical study and a long term extension study. 182 patients were exposed for greater than one year. All patients received the recommended eculizumab dose regimen. In the placebo-controlled clinical study, serious adverse reactions occurred among 4 (9%) patients receiving eculizumab and 9 (21%) patients receiving placebo. The serious reactions included infections and progression of PNH. No deaths occurred in the study and no patients receiving eculizumab experienced a thrombotic event; one thrombotic event occurred in a patient receiving placebo. Among 193 patients with PNH treated with eculizumab in the single arm, clinical study or the follow-up study, the adverse reactions were similar to those reported in the placebo-controlled clinical study. Serious adverse reactions occurred among 16% of the patients in these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). ### aHUS The safety of eculizumab therapy in patients with aHUS was evaluated in four prospective, single-arm studies, three in adult and adolescent patients (aHUS Studies 1, 2, and 4), one in pediatric and adolescent patients (aHUS Study 5) and one retrospective study (aHUS Study 3). The data described below were derived from 78 adult and adolescent patients with aHUS enrolled in aHUS Study 1, aHUS Study 2, and aHUS Study 4. All patients received the recommended dosage of eculizumab. Median exposure was 67 weeks (range: 2-145 weeks). Table 5 summarizes all adverse events reported in at least 10% of patients in aHUS Studies 1, 2, and 4 combined. In aHUS Studies 1, 2, and 4 combined, 60% (47/78) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were infections (24%), hypertension (5%), chronic renal failure (5%), and renal impairment (5%). Five patients discontinued eculizumab due to adverse events; three due to worsening renal function, one due to new diagnosis of Systemic Lupus Erythematosus, and one due to meningoccal meningitis. aHUS Study 5 included 22 pediatric and adolescent patients, of which 18 patients were less than 12 years of age. All patients received the recommended dosage of eculizumab. Median exposure was 44 weeks (range: 1 dose-87 weeks). In aHUS Study 5, 59% (13/22) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were hypertension (9%), viral gastroenteritis (9%), pyrexia (9%), and upper respiratory infection (9%). One patient discontinued eculizumab due to an adverse event (severe agitation). Analysis of retrospectively collected adverse event data from pediatric and adult patients enrolled in aHUS Study 3 (N=30) revealed a safety profile that was similar to that which was observed in the two prospective studies. aHUS Study 3 included 19 pediatric patients less than 18 years of age. Overall, the safety of eculizumab in pediatric patients with aHUS enrolled in Study 3 appeared similar to that observed in adult patients. The most common (≥15%) adverse events occurring in pediatric patients are presented in Table 7. ### Immunogenicity As with all proteins, there is a potential for immunogenicity with eculizumab. The immunogenicity of eculizumab has been evaluated using two different immunoassays for the detection of anti-eculizumab antibodies: a direct enzyme-linked immunosorbent assay (ELISA) using the Fab fragment of eculizumab as target was used for the PNH indication; and an electro-chemiluminescence (ECL) bridging assay using the eculizumab whole molecule as target was used for the aHUS indication, as well as for additional patients with PNH. In the PNH population, antibodies to eculizumab were detected in 3/196 (2%) patients with PNH treated with eculizumab using the ELISA assay and in 5/161 (3%) patients treated with eculizumab using the ECL assay. In patients with aHUS treated with eculizumab, antibodies to eculizumab were detected in 3/100 (3%) using the ECL assay. An ECL based neutralizing HAHA assay with a low sensitivity of 2 mcg/mL was performed to detect neutralizing antibodies for the 3 patients with aHUS and also for the 5 patients with PNH with positive samples using the ECL assay. 2/161 patients in the PNH group (1.2%) and 1/100 patients in the aHUS group (1%) had low positive values for neutralizing antibodies. No apparent correlation of antibody development to clinical response was observed in either indication. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to eculizumab in an ELISA-based assay and/or an ECL-based assay and are highly dependent on the sensitivity and specificity of the assay used. Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to eculizumab with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of eculizumab. 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 eculizumab exposure. Cases of serious or fatal meningococcal infections have been reported. # Drug Interactions Drug interaction studies have not been performed with eculizumab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of eculizumab in pregnant women. eculizumab, a recombinant IgG molecule (humanized anti-C5 antibody), is expected to cross the placenta. Animal studies using a mouse analogue of the eculizumab molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose. eculizumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ### Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human eculizumab dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eculizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Eculizumab during labor and delivery. ### Nursing Mothers It is not known whether eculizumab is excreted into human milk. IgG is excreted in human milk, so it is expected that eculizumab will be present in human milk. However, published data suggest that antibodies in human milk do not enter the neonatal and infant circulation in substantial amounts. Caution should be exercised when eculizumab is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or limited systemic exposure to eculizumab should be weighed against the known benefits of human milk feeding. ### Pediatric Use The safety and effectiveness of eculizumab for the treatment of PNH in pediatric patients below the age of 18 years have not been established. Four clinical studies assessing the safety and effectiveness of eculizumab for the treatment of aHUS included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients. Administer vaccinations for the prevention of infection due to Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenza type b (Hib) according to ACIP guidelines. ### Geriatic Use Nineteen patients 65 years of age or older (15 with PNH and 4 with aHUS) were treated with eculizumab. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Eculizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Eculizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Eculizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Eculizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males Effects of eculizumab upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of eculizumab had no adverse effects on mating or fertility. ### Immunocompromised Patients There is no FDA guidance one the use of Eculizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration Intravenous ### Monitoring There is limited information regarding Eculizumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Eculizumab and IV administrations. # Overdosage No cases of eculizumab overdose have been reported during clinical studies. # Pharmacology ## Mechanism of Action Eculizumab, the active ingredient in eculizumab, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. eculizumab inhibits terminal complement mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. A genetic mutation in patients with PNH leads to the generation of populations of abnormal RBCs (known as PNH cells) that are deficient in terminal complement inhibitors, rendering PNH RBCs sensitive to persistent terminal complement-mediated destruction. The destruction and loss of these PNH cells (intravascular hemolysis) results in low RBC counts (anemia), and also fatigue, difficulty in functioning, pain, dark urine, shortness of breath, and blood clots. In aHUS, impairment in the regulation of complement activity leads to uncontrolled terminal complement activation, resulting in platelet activation, endothelial cell damage and thrombotic microangiopathy. ## Structure Eculizumab is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa. ## Pharmacodynamics In the PNH placebo-controlled clinical study, eculizumab when administered as recommended reduced hemolysis as shown by the reduction of serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L). In the single arm clinical study, eculizumab maintained this effect through 52 weeks. ## Pharmacokinetics A population PK analysis with a standard 1-compartmental model was conducted on the multiple dose PK data from 40 PNH patients receiving the recommended eculizumab regimen. In this model, the clearance of eculizumab for a typical PNH patient weighing 70 kg was 22 mL/hr and the volume of distribution was 7.7 L. The half-life was 272 ± 82 hrs (mean ± SD). The mean observed peak and trough serum concentrations of eculizumab by week 26 were 194 ± 76 mcg/mL and 97 ± 60 mcg/mL, respectively. A second population PK analysis with a standard 1 compartmental model was conducted on the multiple dose PK data from 57 aHUS patients receiving the recommended eculizumab regimen in studies 1, 2 and 3. In this model, the clearance of eculizumab for a typical aHUS patient weighing 70 kg was 14.6 mL/hr and the volume of distribution was 6.14 L. The elimination half-life was 291 h (approximately 12.1 days). The clearance and half-life of eculizumab were also evaluated during plasma exchange interventions. Plasma exchange increased the clearance of eculizumab to 3660 mL/hr and reduced the half-life to 1.26 hours. Supplemental dosing is recommended when eculizumab is administered to aHUS patients receiving plasma infusion or exchange. Dedicated studies have not been conducted to evaluate the PK of eculizumab in special patient populations identified by gender, race, age (geriatric), or the presence of renal or hepatic impairment. Pediatric and adolescent patients (less than 18 years of age) and patients with renal impairment were included in the aHUS clinical studies. Population PK analysis showed age, gender, race, and renal function do not influence the PK of eculizumab. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis - Long-term animal carcinogenicity studies of eculizumab have not been conducted. - Genotoxicity studies have not been conducted with eculizumab. # Clinical Studies ### PNH The safety and efficacy of eculizumab in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (Study 1); PNH patients were also treated with eculizumab in a single arm 52 week study (Study 2); and in a long term extension study. Patients received meningococcal vaccination prior to receipt of eculizumab. In all studies, the dose of eculizumab was 600 mg study drug every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. eculizumab was administered as an intravenous infusion over 25 - 45 minutes. PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either eculizumab (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the hemoglobin concentration (the "set-point") which would define each patient's hemoglobin stabilization and transfusion outcomes. The hemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Endpoints related to hemolysis included the numbers of patients achieving hemoglobin stabilization, the number of RBC units transfused, fatigue, and health-related quality of life. To achieve a designation of hemoglobin stabilization, a patient had to maintain a hemoglobin concentration above the hemoglobin set-point and avoid any RBC transfusion for the entire 26 week period. Hemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications. Patients treated with eculizumab had significantly reduced (p 25 units). After 3 weeks of eculizumab treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of eculizumab on thrombotic events could not be determined. Percentage of patients with stabilized hemoglobin levels: PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received eculizumab over a 52-week period. Concomitant medications included anti-thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Overall, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular hemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in a reduced need for RBC transfusion and less fatigue. 187 eculizumab-treated PNH patients were enrolled in a long term extension study. All patients sustained a reduction in intravascular hemolysis over a total eculizumab exposure time ranging from 10 to 54 months. There were fewer thrombotic events with eculizumab treatment than during the same period of time prior to treatment. However, the majority of patients received concomitant anticoagulants; the effects of anticoagulant withdrawal during eculizumab therapy was not studied. ### aHUS Five single-arm studies evaluated the safety and efficacy of eculizumab for the treatment of aHUS. Patients with aHUS received meningococcal vaccination prior to receipt of eculizumab or received prophylactic treatment with antibiotics until 2 weeks after vaccination. In all studies, the dose of eculizumab in adult and adolescent patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg 7 ± 2 days later, then 1200 mg every 14 ± 2 days thereafter. The dosage regimen for pediatric patients weighing less than 40 kg enrolled in aHUS Study 3 and Study 5 was based on body weight. Efficacy evaluations were based on thrombotic microangiopathy (TMA) endpoints. Endpoints related to TMA included the following: - platelet count change from baseline - hematologic normalization (maintenance of normal platelet counts and LDH levels for at least four weeks) - complete TMA response (hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of four weeks) - TMA-event free status (absence for at least 12 weeks of a decrease in platelet count of >25% from baseline, plasma exchange or plasma infusion, and new dialysis requirement) - Daily TMA intervention rate (defined as the number of plasma exchange or plasma infusion interventions and the number of new dialyses required per patient per day). aHUS Study 1 enrolled patients who displayed signs of thrombotic microangiopathy (TMA) despite receiving at least four PE/PI treatments the week prior to screening. One patient had no PE/PI the week prior to screening because of PE/PI intolerance. In order to qualify for enrollment, patients were required to have a platelet count ≤150 x 109/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 28 (range: 17 to 68 years). Patients enrolled in aHUS Study 1 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 70%-121%. Seventy-six percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 10 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study 1. Patients in aHUS Study 1 received eculizumab for a minimum of 26 weeks. In aHUS Study 1, the median duration of eculizumab therapy was approximately 100 weeks (range: 2 weeks to 145 weeks). Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. The mean eGFR (± SD) increased from 23 ± 15 mL/min/1.73m2 at baseline to 56 ± 40 mL/min/1.73m2 by 26 weeks; this effect was maintained through 2 years (56 ± 30 mL/min/1.73m2). Four of the five patients who required dialysis at baseline were able to discontinue dialysis. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In aHUS Study 1, mean platelet count (± SD) increased from 109 ± 32 x109/L at baseline to 169 ± 72 x109/L by one week; this effect was maintained through 26 weeks (210 ± 68 x109/L), and 2 years (205 ± 46 x109/L). When treatment was continued for more than 26 weeks, two additional patients achieved Hematologic Normalization as well as Complete TMA response. Hematologic Normalization and Complete TMA response were maintained by all responders. In aHUS Study 1, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. aHUS Study 2 enrolled patients undergoing chronic PE/PI who generally did not display hematologic signs of ongoing thrombotic microangiopathy (TMA). All patients had received PT at least once every two weeks, but no more than three times per week, for a minimum of eight weeks prior to the first eculizumab dose. Patients on chronic dialysis were permitted to enroll in aHUS Study 2. The median patient age was 28 years (range: 13 to 63 years). Patients enrolled in aHUS Study 2 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 37%-118%. Seventy percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 12 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study 2. Patients in aHUS Study 2 received eculizumab for a minimum of 26 weeks. In aHUS Study 2, the median duration of eculizumab therapy was approximately 114 weeks (range: 26 to 129 weeks). Renal function, as measured by eGFR, was maintained during eculizumab therapy. The mean eGFR (± SD) was 31 ± 19 mL/min/1.73m2 at baseline, and was maintained through 26 weeks (37 ± 21 mL/min/1.73m2) and 2 years (40 ± 18 mL/min/1.73m2). No patient required new dialysis with eculizumab. Reduction in terminal complement activity was observed in all patients after the commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. Platelet counts were maintained at normal levels despite the elimination of PE/PI. The mean platelet count (± SD) was 228 ± 78 x 109/L at baseline, 233 ± 69 x 109/L at week 26, and 224 ± 52 x 109/L at 2 years. When treatment was continued for more than 26 weeks, six additional patients achieved Complete TMA response. Complete TMA Response and Hematologic Normalization were maintained by all responders. In aHUS Study 2, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. The efficacy results for the aHUS retrospective study (aHUS Study 3) were generally consistent with results of the two prospective studies. eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline. Mean platelet count (± SD) increased from 171 ± 83 x109/L at baseline to 233 ±109 x109/L after one week of therapy; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 254 ± 79 x109/L). A total of 19 pediatric patients (ages 2 months to 17 years) received eculizumab in aHUS Study 3. The median duration of eculizumab therapy was 16 weeks (range 4 to 70 weeks) for children <2 years of age (n=5), 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n=10), and 38 weeks (range 1 to 69 weeks) for patients 12 to <18 years of age (n=4). Fifty three percent of pediatric patients had an identified complement regulatory factor mutation or auto-antibody. Overall, the efficacy results for these pediatric patients appeared consistent with what was observed in patients enrolled in aHUS Studies 1 and 2 (Table 14). No pediatric patient required new dialysis during treatment with eculizumab. aHUS Study 4 enrolled patients who displayed signs of thrombotic microangiopathy (TMA). In order to qualify for enrollment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in aHUS Study 4 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 28%-116%. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 15 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study 4. Patients in aHUS Study 4 received eculizumab for a minimum of 26 weeks. In aHUS Study 4, the median duration of eculizumab therapy was approximately 50 weeks (range: 13 weeks to 86 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 17 ± 12 mL/min/1.73m2 at baseline to 47 ± 24 mL/min/1.73m2 by 26 weeks. Twenty of the 24 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In aHUS Study 4, mean platelet count (± SD) increased from 119 ± 66 x109/L at baseline to 200 ± 84 x109/L by one week; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 252 ± 70 x109/L). In aHUS Study 4, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. aHUS Study 5 enrolled patients who were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH above the upper limits of normal, serum creatinine level ≥97 percentile for age without the need for chronic dialysis. The median patient age was 6.5 (range: 5 months to 17 years). Patients enrolled in aHUS Study 5 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 38%-121%. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Patients in aHUS Study 5 received eculizumab for a minimum of 26 weeks. In aHUS Study 5, the median duration of eculizumab therapy was approximately 44 weeks (range: 1 dose to 88 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 33 ± 30 mL/min/1.73m2 at baseline to 98 ± 44 mL/min/1.73m2 by 26 weeks. Among the 20 patients with a CKD stage ≥2 at baseline, 17 (85%) achieved a CKD improvement of ≥1 stage. Among the 16 patients ages 1 month to <12 years with a CKD stage ≥2 at baseline, 14 (88%) achieved a CKD improvement by ≥1 stage. Nine of the 11 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Responses were observed across all ages from 5 months to 17 years of age. Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. The mean platelet count (± SD) increased from 88 ± 42 x109/L at baseline to 281 ± 123 x109/L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 x109/L). In aHUS Study 5, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. # How Supplied Eculizumab is supplied as 300 mg single-use vials containing 30 mL of 10 mg/mL sterile, preservative-free eculizumab solution per vial. ## Storage Store at 2-8º C (36-46º F) and protected from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Prior to treatment, patients should fully understand the risks and benefits of eculizumab, in particular the risk of meningococcal infection. Ensure that patients receive the Medication Guide. Inform patients that they are required to receive a meningococcal vaccination at least 2 weeks prior to receiving the first dose of eculizumab, if they have not previously been vaccinated. They are required to be revaccinated according to current medical guidelines for meningococcal vaccine use while on eculizumab therapy. Inform patients that vaccination may not prevent meningococcal infection. Inform patients about the signs and symptoms of meningococcal infection, and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms are as follows: - headache with nausea or vomiting - headache and fever - headache with a stiff neck or stiff back - fever of 103° F (39.4° C) or higher - fever and a rash - confusion - muscle aches with flu-like symptoms - eyes sensitive to light Inform patients that they will be given a eculizumab Patient Safety Information Card that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. Inform patients that there may be an increased risk of other types of infections, particularly those due to encapsulated bacteria. Additionally, Aspergillus infections have occured in immunocompromised and neutropenic patients. Inform parents or caregivers of children receiving eculizumab for the treatment of aHUS that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenza type b (Hib) according to current medical guidelines. Inform patients with PNH that they may develop hemolysis due to PNH when eculizumab is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following eculizumab discontinuation. Inform patients with aHUS that there is a potential for TMA complications due to aHUS when eculizumab is discontinued and that they will be monitored by their healthcare professional for at least 12 weeks following eculizumab discontinuation. Inform patients who discontinue eculizumab to keep the eculizumab Patient Safety Information Card with them for three months after the last eculizumab dose, because the increased risk of meningococcal infection persists for several weeks following discontinuation of eculizumab. # Precautions with Alcohol Alcohol-Eculizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Soliris # Look-Alike Drug Names There is limited information regarding Eculizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Eculizumab 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. # Black Box Warning # Overview Eculizumab is a monoclonal antibody that is FDA approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis and for patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hypertension, diarrhea, nausea, vomiting, anemia, backache, headache, insomnia, nasal congestion, nasopharyngitis, respiratory tract infection and fever. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Paroxysmal Nocturnal Hemoglobinuria (PNH) Eculizumab is indicated for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. Dosage: - 600 mg weekly for the first 4 weeks, followed by - 900 mg for the fifth dose 1 week later, then - 900 mg every 2 weeks thereafter. ### Atypical Hemolytic Uremic Syndrome (aHUS) Eculizumab is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Dosage: - 900 mg weekly for the first 4 weeks, followed by - 1200 mg for the fifth dose 1 week later, then - 1200 mg every 2 weeks thereafter. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eculizumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eculizumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Atypical Hemolytic Uremic Syndrome (aHUS) - Eculizumab is indicated for the treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. - For patients less than 18 years of age, administer eculizumab based upon body weight, according to the following schedule: ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eculizumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eculizumab in pediatric patients. # Contraindications - Patients with unresolved serious Neisseria meningitidis infection. - Patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying eculizumab treatment outweigh the risks of developing a meningococcal infection # Warnings ### Serious Meningococcal Infections - The use of eculizumab increases a patient's susceptibility to serious meningococcal infections (septicemia and/or meningitis). Life-threatening and fatal meningococcal infections have occurred in patients treated with eculizumab. - Administer a polyvalent meningococcal vaccine according to the most current Advisory Committee on Immunization Practices (ACIP) recommendations for patients with complement deficiencies. Revaccinate patients in accordance with ACIP recommendations, considering the duration of eculizumab therapy. - Immunize patients without a history of meningococcal vaccination at least 2 weeks prior to receiving the first dose of eculizumab. If urgent eculizumab therapy is indicated in an unvaccinated patient, administer the meningococcal vaccine as soon as possible. In prospective clinical studies, 75/100 patients with aHUS were treated with eculizumab less than 2 weeks after meningococcal vaccination and 64 of these 75 patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after meningococcal vaccination. The benefits and risks of antibiotic prophylaxis for prevention of meningococcal infections in patients receiving eculizumab have not been established. - Vaccination reduces, but does not eliminate, the risk of meningococcal infections. In clinical studies, 2 out of 196 PNH patients developed serious meningococcal infections while receiving treatment with eculizumab; both had been vaccinated. In clinical studies among non-PNH patients, meningococcal meningitis occurred in one unvaccinated patient. In addition, 3 out of 130 previously vaccinated patients with aHUS developed meningococcal infections while receiving treatment with eculizumab. - Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if an infection is suspected. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Discontinue eculizumab in patients who are undergoing treatment for serious meningococcal infections. ### Eculizumab REMS - Because of the risk of meningococcal infections, eculizumab is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the eculizumab REMS, prescribers must enroll in the program. - Prescribers must counsel patients about the risk of meningococcal infection, provide the patients with the REMS educational materials, and ensure patients are vaccinated with a meningococcal vaccine. ### Other Infections - eculizumab blocks terminal complement activation; therefore patients may have increased susceptibility to infections, especially with encapsulated bacteria. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with eculizumab may be at increased risk of developing serious infections due to Streptococcuspneumoniae and Haemophilus influenza type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenza type b (Hib) infections according to ACIP guidelines. Use caution when administering eculizumab to patients with any systemic infection. ### Monitoring Disease Manifestations After eculizumab Discontinuation - Monitor patients after discontinuing eculizumab for at least 8 weeks to detect hemolysis. - After discontinuing eculizumab, monitor patients with aHUS for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. In aHUS clinical trials, 18 patients (5 in the prospective studies) discontinued eculizumab treatment. TMA complications occurred following a missed dose in 5 patients, and eculizumab was reinitiated in 4 of these 5 patients. Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of two, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during eculizumab treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during eculizumab treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during eculizumab treatment. If TMA complications occur after eculizumab discontinuation, consider reinstitution of eculizumab treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures. ### Thrombosis Prevention and Management - The effect of withdrawal of anticoagulant therapy during eculizumab treatment has not been established. Therefore, treatment with eculizumab should not alter anticoagulant management. ### Infusion Reactions - As with all protein products, administration of eculizumab may result in infusion reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion reaction which required discontinuation of eculizumab. Interrupt eculizumab infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur. # 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. Meningococcal infections are the most important adverse reactions experienced by patients receiving eculizumab. In PNH clinical studies, two patients experienced meningococcal sepsis. Both patients had previously received a meningococcal vaccine. In clinical studies among patients without PNH, meningococcal meningitis occurred in one unvaccinated patient. Meningococcal sepsis occurred in one previously vaccinated patient enrolled in the retrospective aHUS study during the post-study follow-up period. ### PNH The data described below reflect exposure to eculizumab in 196 adult patients with PNH, age 18-85, of whom 55% were female. All had signs or symptoms of intravascular hemolysis. eculizumab was studied in a placebo-controlled clinical study (in which 43 patients received eculizumab and 44, placebo); a single arm clinical study and a long term extension study. 182 patients were exposed for greater than one year. All patients received the recommended eculizumab dose regimen. In the placebo-controlled clinical study, serious adverse reactions occurred among 4 (9%) patients receiving eculizumab and 9 (21%) patients receiving placebo. The serious reactions included infections and progression of PNH. No deaths occurred in the study and no patients receiving eculizumab experienced a thrombotic event; one thrombotic event occurred in a patient receiving placebo. Among 193 patients with PNH treated with eculizumab in the single arm, clinical study or the follow-up study, the adverse reactions were similar to those reported in the placebo-controlled clinical study. Serious adverse reactions occurred among 16% of the patients in these studies. The most common serious adverse reactions were: viral infection (2%), headache (2%), anemia (2%), and pyrexia (2%). ### aHUS The safety of eculizumab therapy in patients with aHUS was evaluated in four prospective, single-arm studies, three in adult and adolescent patients (aHUS Studies 1, 2, and 4), one in pediatric and adolescent patients (aHUS Study 5) and one retrospective study (aHUS Study 3). The data described below were derived from 78 adult and adolescent patients with aHUS enrolled in aHUS Study 1, aHUS Study 2, and aHUS Study 4. All patients received the recommended dosage of eculizumab. Median exposure was 67 weeks (range: 2-145 weeks). Table 5 summarizes all adverse events reported in at least 10% of patients in aHUS Studies 1, 2, and 4 combined. In aHUS Studies 1, 2, and 4 combined, 60% (47/78) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were infections (24%), hypertension (5%), chronic renal failure (5%), and renal impairment (5%). Five patients discontinued eculizumab due to adverse events; three due to worsening renal function, one due to new diagnosis of Systemic Lupus Erythematosus, and one due to meningoccal meningitis. aHUS Study 5 included 22 pediatric and adolescent patients, of which 18 patients were less than 12 years of age. All patients received the recommended dosage of eculizumab. Median exposure was 44 weeks (range: 1 dose-87 weeks). In aHUS Study 5, 59% (13/22) of patients experienced a serious adverse event (SAE). The most commonly reported SAEs were hypertension (9%), viral gastroenteritis (9%), pyrexia (9%), and upper respiratory infection (9%). One patient discontinued eculizumab due to an adverse event (severe agitation). Analysis of retrospectively collected adverse event data from pediatric and adult patients enrolled in aHUS Study 3 (N=30) revealed a safety profile that was similar to that which was observed in the two prospective studies. aHUS Study 3 included 19 pediatric patients less than 18 years of age. Overall, the safety of eculizumab in pediatric patients with aHUS enrolled in Study 3 appeared similar to that observed in adult patients. The most common (≥15%) adverse events occurring in pediatric patients are presented in Table 7. ### Immunogenicity As with all proteins, there is a potential for immunogenicity with eculizumab. The immunogenicity of eculizumab has been evaluated using two different immunoassays for the detection of anti-eculizumab antibodies: a direct enzyme-linked immunosorbent assay (ELISA) using the Fab fragment of eculizumab as target was used for the PNH indication; and an electro-chemiluminescence (ECL) bridging assay using the eculizumab whole molecule as target was used for the aHUS indication, as well as for additional patients with PNH. In the PNH population, antibodies to eculizumab were detected in 3/196 (2%) patients with PNH treated with eculizumab using the ELISA assay and in 5/161 (3%) patients treated with eculizumab using the ECL assay. In patients with aHUS treated with eculizumab, antibodies to eculizumab were detected in 3/100 (3%) using the ECL assay. An ECL based neutralizing HAHA assay with a low sensitivity of 2 mcg/mL was performed to detect neutralizing antibodies for the 3 patients with aHUS and also for the 5 patients with PNH with positive samples using the ECL assay. 2/161 patients in the PNH group (1.2%) and 1/100 patients in the aHUS group (1%) had low positive values for neutralizing antibodies. No apparent correlation of antibody development to clinical response was observed in either indication. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to eculizumab in an ELISA-based assay and/or an ECL-based assay and are highly dependent on the sensitivity and specificity of the assay used. Additionally, the observed incidence of antibody positivity in the assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to eculizumab with the incidence of antibodies to other products may be misleading. ## Postmarketing Experience The following adverse reactions have been identified during post-approval use of eculizumab. 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 eculizumab exposure. Cases of serious or fatal meningococcal infections have been reported. # Drug Interactions Drug interaction studies have not been performed with eculizumab. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C There are no adequate and well-controlled studies of eculizumab in pregnant women. eculizumab, a recombinant IgG molecule (humanized anti-C5 antibody), is expected to cross the placenta. Animal studies using a mouse analogue of the eculizumab molecule (murine anti-C5 antibody) showed increased rates of developmental abnormalities and an increased rate of dead and moribund offspring at doses 2-8 times the human dose. eculizumab should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ### Animal Data Animal reproduction studies were conducted in mice using doses of a murine anti-C5 antibody that approximated 2-4 times (low dose) and 4-8 times (high dose) the recommended human eculizumab dose, based on a body weight comparison. When animal exposure to the antibody occurred in the time period from before mating until early gestation, no decrease in fertility or reproductive performance was observed. When maternal exposure to the antibody occurred during organogenesis, two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose; however, the exposure did not increase fetal loss or neonatal death. When maternal exposure to the antibody occurred in the time period from implantation through weaning, a higher number of male offspring became moribund or died (1/25 controls, 2/25 low dose group, 5/25 high dose group). Surviving offspring had normal development and reproductive function. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eculizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Eculizumab during labor and delivery. ### Nursing Mothers It is not known whether eculizumab is excreted into human milk. IgG is excreted in human milk, so it is expected that eculizumab will be present in human milk. However, published data suggest that antibodies in human milk do not enter the neonatal and infant circulation in substantial amounts. Caution should be exercised when eculizumab is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or limited systemic exposure to eculizumab should be weighed against the known benefits of human milk feeding. ### Pediatric Use The safety and effectiveness of eculizumab for the treatment of PNH in pediatric patients below the age of 18 years have not been established. Four clinical studies assessing the safety and effectiveness of eculizumab for the treatment of aHUS included a total of 47 pediatric patients (ages 2 months to 17 years). The safety and effectiveness of eculizumab for the treatment of aHUS appear similar in pediatric and adult patients. Administer vaccinations for the prevention of infection due to Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenza type b (Hib) according to ACIP guidelines. ### Geriatic Use Nineteen patients 65 years of age or older (15 with PNH and 4 with aHUS) were treated with eculizumab. Although there were no apparent age-related differences observed in these studies, the number of patients aged 65 and over is not sufficient to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Eculizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Eculizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Eculizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Eculizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males Effects of eculizumab upon fertility have not been studied in animals. Intravenous injections of male and female mice with a murine anti-C5 antibody at up to 4-8 times the equivalent of the clinical dose of eculizumab had no adverse effects on mating or fertility. ### Immunocompromised Patients There is no FDA guidance one the use of Eculizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration Intravenous ### Monitoring There is limited information regarding Eculizumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Eculizumab and IV administrations. # Overdosage No cases of eculizumab overdose have been reported during clinical studies. # Pharmacology ## Mechanism of Action Eculizumab, the active ingredient in eculizumab, is a monoclonal antibody that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. eculizumab inhibits terminal complement mediated intravascular hemolysis in PNH patients and complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS. A genetic mutation in patients with PNH leads to the generation of populations of abnormal RBCs (known as PNH cells) that are deficient in terminal complement inhibitors, rendering PNH RBCs sensitive to persistent terminal complement-mediated destruction. The destruction and loss of these PNH cells (intravascular hemolysis) results in low RBC counts (anemia), and also fatigue, difficulty in functioning, pain, dark urine, shortness of breath, and blood clots. In aHUS, impairment in the regulation of complement activity leads to uncontrolled terminal complement activation, resulting in platelet activation, endothelial cell damage and thrombotic microangiopathy. ## Structure Eculizumab is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa. ## Pharmacodynamics In the PNH placebo-controlled clinical study, eculizumab when administered as recommended reduced hemolysis as shown by the reduction of serum LDH levels from 2200 ± 1034 U/L (mean ± SD) at baseline to 700 ± 388 U/L by week one and maintained the effect through the end of the study at week 26 (327 ± 433 U/L). In the single arm clinical study, eculizumab maintained this effect through 52 weeks. ## Pharmacokinetics A population PK analysis with a standard 1-compartmental model was conducted on the multiple dose PK data from 40 PNH patients receiving the recommended eculizumab regimen. In this model, the clearance of eculizumab for a typical PNH patient weighing 70 kg was 22 mL/hr and the volume of distribution was 7.7 L. The half-life was 272 ± 82 hrs (mean ± SD). The mean observed peak and trough serum concentrations of eculizumab by week 26 were 194 ± 76 mcg/mL and 97 ± 60 mcg/mL, respectively. A second population PK analysis with a standard 1 compartmental model was conducted on the multiple dose PK data from 57 aHUS patients receiving the recommended eculizumab regimen in studies 1, 2 and 3. In this model, the clearance of eculizumab for a typical aHUS patient weighing 70 kg was 14.6 mL/hr and the volume of distribution was 6.14 L. The elimination half-life was 291 h (approximately 12.1 days). The clearance and half-life of eculizumab were also evaluated during plasma exchange interventions. Plasma exchange increased the clearance of eculizumab to 3660 mL/hr and reduced the half-life to 1.26 hours. Supplemental dosing is recommended when eculizumab is administered to aHUS patients receiving plasma infusion or exchange. Dedicated studies have not been conducted to evaluate the PK of eculizumab in special patient populations identified by gender, race, age (geriatric), or the presence of renal or hepatic impairment. Pediatric and adolescent patients (less than 18 years of age) and patients with renal impairment were included in the aHUS clinical studies. Population PK analysis showed age, gender, race, and renal function do not influence the PK of eculizumab. ## Nonclinical Toxicology ### Carcinogenesis, Mutagenesis - Long-term animal carcinogenicity studies of eculizumab have not been conducted. - Genotoxicity studies have not been conducted with eculizumab. # Clinical Studies ### PNH The safety and efficacy of eculizumab in PNH patients with hemolysis were assessed in a randomized, double-blind, placebo-controlled 26 week study (Study 1); PNH patients were also treated with eculizumab in a single arm 52 week study (Study 2); and in a long term extension study. Patients received meningococcal vaccination prior to receipt of eculizumab. In all studies, the dose of eculizumab was 600 mg study drug every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. eculizumab was administered as an intravenous infusion over 25 - 45 minutes. PNH patients with at least four transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microliter were randomized to either eculizumab (n = 43) or placebo (n = 44). Prior to randomization, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the hemoglobin concentration (the "set-point") which would define each patient's hemoglobin stabilization and transfusion outcomes. The hemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Endpoints related to hemolysis included the numbers of patients achieving hemoglobin stabilization, the number of RBC units transfused, fatigue, and health-related quality of life. To achieve a designation of hemoglobin stabilization, a patient had to maintain a hemoglobin concentration above the hemoglobin set-point and avoid any RBC transfusion for the entire 26 week period. Hemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications. Patients treated with eculizumab had significantly reduced (p< 0.001) hemolysis resulting in improvements in anemia as indicated by increased hemoglobin stabilization and reduced need for RBC transfusions compared to placebo treated patients (see Table 9). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 - 14 units; 15 - 25 units; > 25 units). After 3 weeks of eculizumab treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of eculizumab on thrombotic events could not be determined. Percentage of patients with stabilized hemoglobin levels: PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microliter received eculizumab over a 52-week period. Concomitant medications included anti-thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Overall, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular hemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in a reduced need for RBC transfusion and less fatigue. 187 eculizumab-treated PNH patients were enrolled in a long term extension study. All patients sustained a reduction in intravascular hemolysis over a total eculizumab exposure time ranging from 10 to 54 months. There were fewer thrombotic events with eculizumab treatment than during the same period of time prior to treatment. However, the majority of patients received concomitant anticoagulants; the effects of anticoagulant withdrawal during eculizumab therapy was not studied. ### aHUS Five single-arm studies [four prospective (aHUS Studies 1, 2, 4 and 5) and one retrospective (aHUS Study 3)] evaluated the safety and efficacy of eculizumab for the treatment of aHUS. Patients with aHUS received meningococcal vaccination prior to receipt of eculizumab or received prophylactic treatment with antibiotics until 2 weeks after vaccination. In all studies, the dose of eculizumab in adult and adolescent patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1200 mg 7 ± 2 days later, then 1200 mg every 14 ± 2 days thereafter. The dosage regimen for pediatric patients weighing less than 40 kg enrolled in aHUS Study 3 and Study 5 was based on body weight. Efficacy evaluations were based on thrombotic microangiopathy (TMA) endpoints. Endpoints related to TMA included the following: - platelet count change from baseline - hematologic normalization (maintenance of normal platelet counts and LDH levels for at least four weeks) - complete TMA response (hematologic normalization plus at least a 25% reduction in serum creatinine for a minimum of four weeks) - TMA-event free status (absence for at least 12 weeks of a decrease in platelet count of >25% from baseline, plasma exchange or plasma infusion, and new dialysis requirement) - Daily TMA intervention rate (defined as the number of plasma exchange or plasma infusion interventions and the number of new dialyses required per patient per day). aHUS Study 1 enrolled patients who displayed signs of thrombotic microangiopathy (TMA) despite receiving at least four PE/PI treatments the week prior to screening. One patient had no PE/PI the week prior to screening because of PE/PI intolerance. In order to qualify for enrollment, patients were required to have a platelet count ≤150 x 109/L, evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 28 (range: 17 to 68 years). Patients enrolled in aHUS Study 1 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 70%-121%. Seventy-six percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 10 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study 1. Patients in aHUS Study 1 received eculizumab for a minimum of 26 weeks. In aHUS Study 1, the median duration of eculizumab therapy was approximately 100 weeks (range: 2 weeks to 145 weeks). Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. The mean eGFR (± SD) increased from 23 ± 15 mL/min/1.73m2 at baseline to 56 ± 40 mL/min/1.73m2 by 26 weeks; this effect was maintained through 2 years (56 ± 30 mL/min/1.73m2). Four of the five patients who required dialysis at baseline were able to discontinue dialysis. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In aHUS Study 1, mean platelet count (± SD) increased from 109 ± 32 x109/L at baseline to 169 ± 72 x109/L by one week; this effect was maintained through 26 weeks (210 ± 68 x109/L), and 2 years (205 ± 46 x109/L). When treatment was continued for more than 26 weeks, two additional patients achieved Hematologic Normalization as well as Complete TMA response. Hematologic Normalization and Complete TMA response were maintained by all responders. In aHUS Study 1, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. aHUS Study 2 enrolled patients undergoing chronic PE/PI who generally did not display hematologic signs of ongoing thrombotic microangiopathy (TMA). All patients had received PT at least once every two weeks, but no more than three times per week, for a minimum of eight weeks prior to the first eculizumab dose. Patients on chronic dialysis were permitted to enroll in aHUS Study 2. The median patient age was 28 years (range: 13 to 63 years). Patients enrolled in aHUS Study 2 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 37%-118%. Seventy percent of patients had an identified complement regulatory factor mutation or auto-antibody. Table 12 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study 2. Patients in aHUS Study 2 received eculizumab for a minimum of 26 weeks. In aHUS Study 2, the median duration of eculizumab therapy was approximately 114 weeks (range: 26 to 129 weeks). Renal function, as measured by eGFR, was maintained during eculizumab therapy. The mean eGFR (± SD) was 31 ± 19 mL/min/1.73m2 at baseline, and was maintained through 26 weeks (37 ± 21 mL/min/1.73m2) and 2 years (40 ± 18 mL/min/1.73m2). No patient required new dialysis with eculizumab. Reduction in terminal complement activity was observed in all patients after the commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. Platelet counts were maintained at normal levels despite the elimination of PE/PI. The mean platelet count (± SD) was 228 ± 78 x 109/L at baseline, 233 ± 69 x 109/L at week 26, and 224 ± 52 x 109/L at 2 years. When treatment was continued for more than 26 weeks, six additional patients achieved Complete TMA response. Complete TMA Response and Hematologic Normalization were maintained by all responders. In aHUS Study 2, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. The efficacy results for the aHUS retrospective study (aHUS Study 3) were generally consistent with results of the two prospective studies. eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline. Mean platelet count (± SD) increased from 171 ± 83 x109/L at baseline to 233 ±109 x109/L after one week of therapy; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 254 ± 79 x109/L). A total of 19 pediatric patients (ages 2 months to 17 years) received eculizumab in aHUS Study 3. The median duration of eculizumab therapy was 16 weeks (range 4 to 70 weeks) for children <2 years of age (n=5), 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n=10), and 38 weeks (range 1 to 69 weeks) for patients 12 to <18 years of age (n=4). Fifty three percent of pediatric patients had an identified complement regulatory factor mutation or auto-antibody. Overall, the efficacy results for these pediatric patients appeared consistent with what was observed in patients enrolled in aHUS Studies 1 and 2 (Table 14). No pediatric patient required new dialysis during treatment with eculizumab. aHUS Study 4 enrolled patients who displayed signs of thrombotic microangiopathy (TMA). In order to qualify for enrollment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in aHUS Study 4 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 28%-116%. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 15 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS Study 4. Patients in aHUS Study 4 received eculizumab for a minimum of 26 weeks. In aHUS Study 4, the median duration of eculizumab therapy was approximately 50 weeks (range: 13 weeks to 86 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 17 ± 12 mL/min/1.73m2 at baseline to 47 ± 24 mL/min/1.73m2 by 26 weeks. Twenty of the 24 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In aHUS Study 4, mean platelet count (± SD) increased from 119 ± 66 x109/L at baseline to 200 ± 84 x109/L by one week; this effect was maintained through 26 weeks (mean platelet count (± SD) at week 26: 252 ± 70 x109/L). In aHUS Study 4, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. aHUS Study 5 enrolled patients who were required to have a platelet count < lower limit of normal range (LLN), evidence of hemolysis such as an elevation in serum LDH above the upper limits of normal, serum creatinine level ≥97 percentile for age without the need for chronic dialysis. The median patient age was 6.5 (range: 5 months to 17 years). Patients enrolled in aHUS Study 5 were required to have ADAMTS13 activity level above 5%; observed range of values in the trial were 38%-121%. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Patients in aHUS Study 5 received eculizumab for a minimum of 26 weeks. In aHUS Study 5, the median duration of eculizumab therapy was approximately 44 weeks (range: 1 dose to 88 weeks). Renal function, as measured by eGFR, was improved during eculizumab therapy. The mean eGFR (± SD) increased from 33 ± 30 mL/min/1.73m2 at baseline to 98 ± 44 mL/min/1.73m2 by 26 weeks. Among the 20 patients with a CKD stage ≥2 at baseline, 17 (85%) achieved a CKD improvement of ≥1 stage. Among the 16 patients ages 1 month to <12 years with a CKD stage ≥2 at baseline, 14 (88%) achieved a CKD improvement by ≥1 stage. Nine of the 11 patients who required dialysis at study baseline were able to discontinue dialysis during eculizumab treatment. Responses were observed across all ages from 5 months to 17 years of age. Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. The mean platelet count (± SD) increased from 88 ± 42 x109/L at baseline to 281 ± 123 x109/L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 x109/L). In aHUS Study 5, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. # How Supplied Eculizumab is supplied as 300 mg single-use vials containing 30 mL of 10 mg/mL sterile, preservative-free eculizumab solution per vial. ## Storage Store at 2-8º C (36-46º F) and protected from light. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Prior to treatment, patients should fully understand the risks and benefits of eculizumab, in particular the risk of meningococcal infection. Ensure that patients receive the Medication Guide. Inform patients that they are required to receive a meningococcal vaccination at least 2 weeks prior to receiving the first dose of eculizumab, if they have not previously been vaccinated. They are required to be revaccinated according to current medical guidelines for meningococcal vaccine use while on eculizumab therapy. Inform patients that vaccination may not prevent meningococcal infection. Inform patients about the signs and symptoms of meningococcal infection, and strongly advise patients to seek immediate medical attention if these signs or symptoms occur. These signs and symptoms are as follows: - headache with nausea or vomiting - headache and fever - headache with a stiff neck or stiff back - fever of 103° F (39.4° C) or higher - fever and a rash - confusion - muscle aches with flu-like symptoms - eyes sensitive to light Inform patients that they will be given a eculizumab Patient Safety Information Card that they should carry with them at all times. This card describes symptoms which, if experienced, should prompt the patient to immediately seek medical evaluation. Inform patients that there may be an increased risk of other types of infections, particularly those due to encapsulated bacteria. Additionally, Aspergillus infections have occured in immunocompromised and neutropenic patients. Inform parents or caregivers of children receiving eculizumab for the treatment of aHUS that their child should be vaccinated against Streptococcus pneumoniae and Haemophilus influenza type b (Hib) according to current medical guidelines. Inform patients with PNH that they may develop hemolysis due to PNH when eculizumab is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following eculizumab discontinuation. Inform patients with aHUS that there is a potential for TMA complications due to aHUS when eculizumab is discontinued and that they will be monitored by their healthcare professional for at least 12 weeks following eculizumab discontinuation. Inform patients who discontinue eculizumab to keep the eculizumab Patient Safety Information Card with them for three months after the last eculizumab dose, because the increased risk of meningococcal infection persists for several weeks following discontinuation of eculizumab. # Precautions with Alcohol Alcohol-Eculizumab interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Soliris [1] # Look-Alike Drug Names There is limited information regarding Eculizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Eculizumab
87c32cc3a1b9aee5bb859aa22d90b62470ce1f05	wikidoc	Edentulism	Edentulism Edentulism is the condition of being toothless to at least some degree; it is the result of tooth loss. Loss of some teeth results in partial edentulism, while loss of all teeth results in complete edentulism. Even organisms that never possessed teeth can be referred to as being edentulous, such as members of the former zoological classification order of Edentata, which included anteaters, sloths and armadillos, all of which possess no anterior teeth and either no or poorly-developed posterior teeth. # Importance of teeth and consequences of edentulism For people, the relevance and functionality of teeth can be easily taken for granted, but a closer examination of their considerable significance will demonstrate how they are actually very important. Among other things, teeth serve to: - support the lips and cheeks, providing for a fuller, more aesthetically pleasing appearance - maintain an individual's vertical dimension of occlusion - along with the tongue and lips, allow for the proper pronunciation of various sounds - preserve and maintain the height of the alveolar ridge - cut, grind, and otherwise chew food ## Facial support and aesthetics When an individual's mouth is at rest, the teeth in the opposing jaws are nearly touching; there is what is referred to as a freeway space of roughly 2-3 mm. However, this distance is partially maintained as a result of the teeth limiting any further closure past the point of maximum intercuspation. When there are no teeth present in the mouth, the natural vertical dimension of occlusion is lost and the mouth as a tendency to overclose. This causes the cheeks to exhibit a "sunken-in" appearance and wrinkle lines to form at the commisures. Additionally, the anterior teeth, when present, serve to properly support the lips and provide for certain aesthetic features, such as an acute nasiolabial angle. Loss of muscle tone and skin elasticity due to old age, when most individuals begin to experience edentulism, tend to further exacerbate this condition. The tongue, which consists of a very dynamic group of muscles, tends to fill the space it is allowed, and in the absence of teeth, will broaden out. This makes it initially difficult to fabricate both complete dentures and removable partial dentures for patients exhibiting complete and partial edentulism, respectively; however, once the space is "taken back" by the prosthetic teeth, the tongue will return to a narrower body. ## Vertical dimension of occlusion As stated, the position of maximal closure in the presence of teeth is referred to as maximum intercuspation, and the vertical jaw relationship in this position is referred to as the vertical dimension of occlusion. With the loss of teeth, there is a decrease in this vertical dimension, as the mouth is allowed to overclose when there are no teeth present to block further upward movement of the mandible towards the maxilla. This may contribute, as explained above, to a sunken-in appearance of the cheeks, because there is now "too much" cheek than is needed to extend from the maxilla to the mandible when in an overclosed position. If this situation is left untreated for a many years, the muscles and tendons of the mandible and the TMJ may manifest with alterred tone and elasticity. ## Pronunciation The teeth play a major role in speech. Some letter sounds require the lips and/or tongue to make contact with teeth for proper pronunciation of the sound, and lack of teeth will obviously affect the way in which an edentulous individual can pronounce these sounds. For example, the fricative consonant sounds of the English language s, z, x, d, n, l, j, t, th, ch and sh are achieved with tongue-to-tooth contact, and the fricative f and v are achieved through lip-to-tooth contact. These sounds are very difficult to properly enunciate for the edentulous individual. ## Preservation of alveolar ridge height The alveolar ridges are columns of bone that surround and anchor the teeth and run the entire length, mesiodistally, of both the maxillary and mandibular dental arches. The alveolar bone is unique in that it exists for the sake of the teeth that it retains; when the teeth are absent, the bone slowly resorbs. The maxilla resorbs in a superioposterior direction, and the mandible resorbs in an inferioanterior direction, thus eventually converting an individual's occlusal scheme from a Class I to a Class III. In addition to this resorption of bone in the vertical and anterioposterior dimensions, the alveolus also resorbs faciolingually, thus diminishing the width of the ridge. What initially began as a sort of tall, broad, bell curve-shaped ridge (in the faciolingual dimension) eventually becomes a short, narrow, stumpy sort of what doesn't even appear to be a ridge. Resorption is exacerbated by pressure on the bone; thus, long-term complete denture wearers will experience more drastic ridges to their ridges that non-denture wearers. Those individuals who do wear dentures can decrease the amount of bone loss by retaining some tooth roots in the form of overdenture abutments or have implants placed. Note that the depiction above shows a very excessive change and that this many take many years of denture wear to achieve. Ridge resorption may also alter the form of the ridges to less predictable shapes, such as bulbous ridges with undercuts or even sharp, thin, knife-edged ridges, depending of which of many possible factors influenced the resorption. ## Masticatory efficiency Physiologically, teeth provide for greater chewing ability. They allow us to masticate food thoroughly, increasing the surface area necessary to allow for the enzymes present in the saliva, as well as in the stomach and intestines, to digest our food. Chewing also allows food to be prepared into small boli that are more readily swallowed than haphazard chunks of considerable size. For those who are even partially endentulous, it may become extremely difficult to chew food efficiently enough to swallow comfortably, although this is entirely dependent upon which teeth are lost. When an individual loses enough posterior teeth to make it difficult to chew, he or she may need to cut their food into very small pieces and learn how to make use of their anterior teeth to chew. If enough posterior teeth are missing, this will not only affect their chewing abilities, but also their occlusion; posterior teeth, in a mutually protected occlusion, help to protect the anterior teeth and the vertical dimension of occlusion and, when missing, the anterior teeth begin to bear a greater amount of force for which they are structurally prepared. Thus, loss of posterior teeth will cause the anterior teeth to splay. This can be prevented by obtaining dental prostheses, such as removable partial dentures, bridges or implant-supported crowns. In addition to reestablishing a protected occlusion, these prostheses can greatly improve one's chewing abilities. As a consequence of a lack of certain nutrition due to altered eating habits, various health problems can occur, from the mild to the extreme. Lack of certain vitamins (A, E and C) and low levels of riboflavin and thyamin can produce a variety of conditions, ranging from constipation, weight loss, arthritis and rheumatism. There are more serious conditions such as heart disease and Parkinson's disease and even to the extreme, certain types of Cancer. Numerous studies linking edentulism with instances of disease and medical conditions have been reported. In a cross-sectional study, Hamasha and others found significant differences between edentulous and dentate individuals with respect to rates of atherosclerotic vascular disease, heart failure, ischemic heart disease and joint disease. # Etiology The etiology, or cause of edentulism, can be multifaceted. While the extraction of non-restorable or non-strategic teeth by a dentist does contribute to edentulism, the predominant cause of tooth loss in developed countries is periodontal disease. While the teeth may remain completely decay-free, the bone surrounding and providing support to the teeth may resorb and disappear, giving rise to tooth mobility and eventual tooth loss. In the photo at right, tooth #21 (the lower left first premolar, to the right of #22, the lower left canine) exhibits 50% bone loss, presenting with a distal horizontal defect and a mesial vertical defect. Tooth #22 exhibits roughly 30% bone loss.	Edentulism Edentulism is the condition of being toothless to at least some degree; it is the result of tooth loss. Loss of some teeth results in partial edentulism, while loss of all teeth results in complete edentulism. Even organisms that never possessed teeth can be referred to as being edentulous, such as members of the former zoological classification order of Edentata, which included anteaters, sloths and armadillos, all of which possess no anterior teeth and either no or poorly-developed posterior teeth. # Importance of teeth and consequences of edentulism For people, the relevance and functionality of teeth can be easily taken for granted, but a closer examination of their considerable significance will demonstrate how they are actually very important. Among other things, teeth serve to: - support the lips and cheeks, providing for a fuller, more aesthetically pleasing appearance - maintain an individual's vertical dimension of occlusion - along with the tongue and lips, allow for the proper pronunciation of various sounds - preserve and maintain the height of the alveolar ridge - cut, grind, and otherwise chew food ## Facial support and aesthetics When an individual's mouth is at rest, the teeth in the opposing jaws are nearly touching; there is what is referred to as a freeway space of roughly 2-3 mm. However, this distance is partially maintained as a result of the teeth limiting any further closure past the point of maximum intercuspation. When there are no teeth present in the mouth, the natural vertical dimension of occlusion is lost and the mouth as a tendency to overclose. This causes the cheeks to exhibit a "sunken-in" appearance and wrinkle lines to form at the commisures. Additionally, the anterior teeth, when present, serve to properly support the lips and provide for certain aesthetic features, such as an acute nasiolabial angle. Loss of muscle tone and skin elasticity due to old age, when most individuals begin to experience edentulism, tend to further exacerbate this condition. The tongue, which consists of a very dynamic group of muscles, tends to fill the space it is allowed, and in the absence of teeth, will broaden out.[1] This makes it initially difficult to fabricate both complete dentures and removable partial dentures for patients exhibiting complete and partial edentulism, respectively; however, once the space is "taken back" by the prosthetic teeth, the tongue will return to a narrower body. ## Vertical dimension of occlusion As stated, the position of maximal closure in the presence of teeth is referred to as maximum intercuspation, and the vertical jaw relationship in this position is referred to as the vertical dimension of occlusion. With the loss of teeth, there is a decrease in this vertical dimension, as the mouth is allowed to overclose when there are no teeth present to block further upward movement of the mandible towards the maxilla. This may contribute, as explained above, to a sunken-in appearance of the cheeks, because there is now "too much" cheek than is needed to extend from the maxilla to the mandible when in an overclosed position. If this situation is left untreated for a many years, the muscles and tendons of the mandible and the TMJ may manifest with alterred tone and elasticity. ## Pronunciation The teeth play a major role in speech. Some letter sounds require the lips and/or tongue to make contact with teeth for proper pronunciation of the sound, and lack of teeth will obviously affect the way in which an edentulous individual can pronounce these sounds. For example, the fricative consonant sounds of the English language s, z, x, d, n, l, j, t, th, ch and sh are achieved with tongue-to-tooth contact, and the fricative f and v are achieved through lip-to-tooth contact. These sounds are very difficult to properly enunciate for the edentulous individual. ## Preservation of alveolar ridge height The alveolar ridges are columns of bone that surround and anchor the teeth and run the entire length, mesiodistally, of both the maxillary and mandibular dental arches. The alveolar bone is unique in that it exists for the sake of the teeth that it retains; when the teeth are absent, the bone slowly resorbs. The maxilla resorbs in a superioposterior direction, and the mandible resorbs in an inferioanterior direction, thus eventually converting an individual's occlusal scheme from a Class I to a Class III. In addition to this resorption of bone in the vertical and anterioposterior dimensions, the alveolus also resorbs faciolingually, thus diminishing the width of the ridge. What initially began as a sort of tall, broad, bell curve-shaped ridge (in the faciolingual dimension) eventually becomes a short, narrow, stumpy sort of what doesn't even appear to be a ridge. Resorption is exacerbated by pressure on the bone; thus, long-term complete denture wearers will experience more drastic ridges to their ridges that non-denture wearers. Those individuals who do wear dentures can decrease the amount of bone loss by retaining some tooth roots in the form of overdenture abutments or have implants placed. Note that the depiction above shows a very excessive change and that this many take many years of denture wear to achieve. Ridge resorption may also alter the form of the ridges to less predictable shapes, such as bulbous ridges with undercuts or even sharp, thin, knife-edged ridges, depending of which of many possible factors influenced the resorption. ## Masticatory efficiency Physiologically, teeth provide for greater chewing ability. They allow us to masticate food thoroughly, increasing the surface area necessary to allow for the enzymes present in the saliva, as well as in the stomach and intestines, to digest our food. Chewing also allows food to be prepared into small boli that are more readily swallowed than haphazard chunks of considerable size. For those who are even partially endentulous, it may become extremely difficult to chew food efficiently enough to swallow comfortably, although this is entirely dependent upon which teeth are lost. When an individual loses enough posterior teeth to make it difficult to chew, he or she may need to cut their food into very small pieces and learn how to make use of their anterior teeth to chew. If enough posterior teeth are missing, this will not only affect their chewing abilities, but also their occlusion; posterior teeth, in a mutually protected occlusion, help to protect the anterior teeth and the vertical dimension of occlusion and, when missing, the anterior teeth begin to bear a greater amount of force for which they are structurally prepared. Thus, loss of posterior teeth will cause the anterior teeth to splay. This can be prevented by obtaining dental prostheses, such as removable partial dentures, bridges or implant-supported crowns. In addition to reestablishing a protected occlusion, these prostheses can greatly improve one's chewing abilities. As a consequence of a lack of certain nutrition due to altered eating habits, various health problems can occur, from the mild to the extreme. Lack of certain vitamins (A, E and C) and low levels of riboflavin and thyamin can produce a variety of conditions, ranging from constipation, weight loss, arthritis and rheumatism. There are more serious conditions such as heart disease and Parkinson's disease and even to the extreme, certain types of Cancer. Numerous studies linking edentulism with instances of disease and medical conditions have been reported. In a cross-sectional study, Hamasha and others found significant differences between edentulous and dentate individuals with respect to rates of atherosclerotic vascular disease, heart failure, ischemic heart disease and joint disease.[2] # Etiology The etiology, or cause of edentulism, can be multifaceted. While the extraction of non-restorable or non-strategic teeth by a dentist does contribute to edentulism, the predominant cause of tooth loss in developed countries is periodontal disease. While the teeth may remain completely decay-free, the bone surrounding and providing support to the teeth may resorb and disappear, giving rise to tooth mobility and eventual tooth loss. In the photo at right, tooth #21 (the lower left first premolar, to the right of #22, the lower left canine) exhibits 50% bone loss, presenting with a distal horizontal defect and a mesial vertical defect. Tooth #22 exhibits roughly 30% bone loss.	https://www.wikidoc.org/index.php/Edentulism
72666b88706545da489e0cb16255187c4728d4bd	wikidoc	Efalizumab	Efalizumab # Overview Efalizumab (trade name Raptiva, Genentech, Merck Serono) is a formerly available medication designed to treat autoimmune diseases, originally marketed to treat psoriasis. As implied by the suffix -zumab, it is a recombinant humanized monoclonal antibody administered once weekly by subcutaneous injection. Efalizumab binds to the CD11a subunit of lymphocyte function-associated antigen 1 and acts as an immunosuppressant by inhibiting lymphocyte activation and cell migration out of blood vessels into tissues. Efalizumab was associated with fatal brain infections and was withdrawn from the market in 2009. Known side effects include bacterial sepsis, viral meningitis, invasive fungal disease and progressive multifocal leukoencephalopathy (PML), a brain infection caused by reactivation of latent JC virus infection. Four cases of PML were reported in plaque psoriasis patients, an incidence of approximately one in 500 treated patients. Due to the risk of PML, the European Medicines Agency and the FDA recommended suspension from the market in the European Union and the United States, respectively. In April 2009, Genentech Inc. announced a phased voluntary withdrawal of Raptiva from the U.S. market.	Efalizumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Efalizumab (trade name Raptiva, Genentech, Merck Serono) is a formerly available medication designed to treat autoimmune diseases, originally marketed to treat psoriasis. As implied by the suffix -zumab, it is a recombinant humanized monoclonal antibody administered once weekly by subcutaneous injection. Efalizumab binds to the CD11a subunit of lymphocyte function-associated antigen 1 and acts as an immunosuppressant by inhibiting lymphocyte activation and cell migration out of blood vessels into tissues. Efalizumab was associated with fatal brain infections and was withdrawn from the market in 2009.[1] Known side effects include bacterial sepsis, viral meningitis, invasive fungal disease and progressive multifocal leukoencephalopathy (PML), a brain infection caused by reactivation of latent JC virus infection.[2][3] Four cases of PML were reported in plaque psoriasis patients, an incidence of approximately one in 500 treated patients.[1] Due to the risk of PML, the European Medicines Agency and the FDA recommended suspension from the market in the European Union and the United States, respectively.[4] In April 2009, Genentech Inc. announced a phased voluntary withdrawal of Raptiva from the U.S. market.[1][5]	https://www.wikidoc.org/index.php/Efalizumab
fe758bab826a2b7c7037529ad04efb68c09495ec	wikidoc	Eicosanoid	Eicosanoid # Overview In biochemistry, eicosanoids are signaling molecules derived from omega-3 (ω-3) or omega-6 (ω-6) fats. They exert complex control over many bodily systems, especially in inflammation, immunity and as messengers in the central nervous system. The networks of controls that depend upon eicosanoids are among the most complex in the human body. The ω-6 eicosanoids are generally pro-inflammatory; ω-3's are much less so. The amounts of these fats in a person's diet will affect the body's eicosanoid-controlled functions, with effects on cardiovascular disease, triglycerides, blood pressure, and arthritis. Anti-inflammatory drugs such as aspirin and NSAIDs act by downregulating eicosanoid synthesis. There are four families of eicosanoids—the prostaglandins, prostacyclins, the thromboxanes and the leukotrienes. For each, there are two or three separate series, derived either from an ω-3 or ω-6 essential fatty acid. These series' different activities largely explain the health effects of ω-3 and ω-6 fats. # Nomenclature "Eicosanoid" (eicosa-, Greek for "twenty"; see icosahedron) is the collective term for oxygenated derivatives of three different 20-carbon essential fatty acids: - Eicosapentaenoic acid (EPA), an ω-3 fatty acid with 5 double bonds; - Arachidonic acid (AA), an ω-6 fatty acid, with 4 double bonds; - Dihomo-gamma-linolenic acid (DGLA), an ω-6, with 3 double bonds. Current usage limits the term to the leukotrienes (LT) and three types of prostanoids—prostaglandins (PG) prostacyclins (PGI), and thromboxanes (TX). This is the definition used in this article. However, several other classes can technically be termed eicosanoid, including the hepoxilins, resolvins, isofurans, isoprostanes, lipoxins, epoxyeicosatrienoic acids (EETs) and some endocannabinoids. A particular eicosanoid is denoted by a four-character abbreviation, composed of: - Its two letter abbreviation (above), - One A-B-C sequence-letter; and - A subscript, indicating the number of double bonds. Examples are: - The EPA-derived prostanoids have three double bonds, (e.g. PGG3, PGH3, PGI3, TXA3) while its leukotrienes have five, (LTB5). - The AA-derived prostanoids have two double bonds, (e.g. PGG2, PGH2, PGI2, TXA2) while its leukotrienes have four, (LTB4). Two families of enzymes catalyze fatty acid oxygenation to produce the eicosanoids: - Cyclooxygenase, or COX, which comes in at least three isoforms, COX-1, -2, -3 – leading to the prostanoids. - Lipoxygenase, in several forms. 5-lipoxygenase (5-LO) generates the leukotrienes. # Biosynthesis Eicosanoids are a class of oxygenated fatty acids, found widely in a variety of microorganisms, plants and animals. In humans, eicosanoids are local hormones that are released by most cells, act on that same cell or nearby cells (i.e., they are autocrine and paracrine mediators), and then are rapidly inactivated. They are potent in the nanomolar range. Eicosanoids are not stored within cells, but are synthesized as required. They derive from fatty acids which are incorporated as esters into larger molecules—the phospholipids and diacylglycerols—found in the cell membrane and nuclear membrane. The first step of eicosanoid biosynthesis occurs when cell is activated by mechanical trauma, cytokines, growth factors or other stimuli. (The stimulus may even be an eicosanoid from a neighboring cell; the pathways are complex.) This triggers the release of a phospholipase at the cell wall. The phospholipase travels to the nuclear membrane. There, the phospholipase catalyzes ester hydrolysis of phospholipid (by A2) or diacylglycerol (by phospholipase C). This frees a 20-carbon essential fatty acid. This hydrolysis appears to be the rate-determining step for eicosanoid formation. The fatty acids may be released by any of several phospholipases. Of these, type IV cytosolic phospholipase A2 (cPLA2) is the key actor, as cells lacking cPLA2 are generally devoid of eicosanoid synthesis. The phospholipase cPLA2 is specific for phospholipids that contain AA, EPA or GPLA at the SN2 position. Interestingly, cPLA2 may also release the lysophospholipid that becomes platelet-activating factor. ## Peroxidation and reactive oxygen species Next, the free fatty acid is oxygenated along any of several pathways; see the Pathways table. The eicosanoid pathways (via lipoxygenase or COX) add molecular oxygen (O2). Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidation proceeds with high stereospecificity. The oxidation of lipids is hazardous to cells, particularly when close to the nucleus. There are elaborate mechanisms to prevent unwanted oxidation. COX, the lipoxygenases and the phospholipases are tightly controlled—there are at least eight proteins activated to coordinate generation of leukotrienes. Several of these exist in multiple isoforms. Oxidation by either COX or lipoxygenase releases reactive oxygen species (ROS) and the initial products in eicosanoid generation are themselves highly reactive peroxides. LTA4 can form adducts with tissue DNA. Other reactions of lipoxygenases generate cellular damage; murine models implicate 15-lipoxygenase in the pathogenesis of atherosclerosis. The oxidation in eicosanoid generation is compartmentalized; this limits the peroxides' damage. The enzymes which are biosynthetic for eicosanoids (e.g. glutathione-S-transferases, epoxide hydrolases and carrier proteins) belong to families whose functions are largely involved with cellular detoxification. This suggests that eicosanoid signaling may have evolved from the detoxification of ROS. The cell must realize some benefit from generating lipid hydroperoxides close-by its nucleus. PGs and LTs may signal or regulate DNA-transcription there; LTB4 is ligand for PPARα. (See diagram at PPAR). ## Biosynthesis of prostanoids Cyclooxygenase (COX) catalyzes the conversion of the free essential fatty acids to prostanoids by a two-step process. First, two molecules of O2 are added as two peroxide linkages, and a 5-member carbon ring is forged near the middle of the fatty acid chain. This forms the short-lived, unstable intermediate Prostaglandin G (PGG). Next, one of the peroxide linkages sheds a single oxygen, forming PGH. (See diagrams and more detail of these steps at Cyclooxygenase). All three classes of prostanoids originate from PGH. All have distinctive rings in the center of the molecule. They differ in their structures. The PGH compounds (parents to all the rest) have a 5-carbon ring, bridged by two oxygens (a peroxide.) As the example in Structures of Selected Eicosanoids figure shows, the derived prostaglandins contain a single, unsaturated 5-carbon ring. In prostacyclins, this ring is conjoined to another oxygen-containing ring. In thromboxanes the ring becomes a 6-member ring with one oxygen. The leukotrienes do not have rings. (See more detail, including the enzymes involved, in diagrams at Prostanoid.) ## Biosynthesis of leukotrienes The enzyme 5-lipoxygenase (5-LO) uses 5-lipoxygenase activating protein (FLAP) to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). The enzyme 5-LO acts again on 5-HETE to convert it into leukotriene A4 (LTA4), which may be converted into LTB4 by the enzyme leukotriene A4 epoxide hydrolase. Eosinophils, mast cells, and alveolar macrophages use the enzyme leukotriene C4 synthase to conjugate glutathione with LTA4 to make LTC4, which is transported outside the cell, where a glutamic acid moiety is removed from it to make LTD4. The leukotriene LTD4 is then cleaved by dipeptidases to make LTE4. The leukotrienes LTC4, LTD4 and LTE4 all contain cysteine and are collectively known as the cysteinyl leukotrienes. # Function and pharmacology Eicosanoids have a short half-life, ranging from seconds to minutes. Dietary antioxidants inhibit the generation of some inflammatory eicosanoids, e.g. trans-resveratrol against thromboxane and some leukotrienes. Most eicosanoid receptors are members of the G protein-coupled receptor superfamily; see the Receptors table or the article eicosanoid receptors. ## The ω-3 and ω-6 series Arachidonic acid (AA; 20:4 ω-6) sits at the head of the 'arachidonic acid cascade'—more than twenty different eicosanoid-mediated signaling paths controlling a wide array of cellular functions, especially those regulating inflammation, immunity and the central nervous system. In the inflammatory response, two other groups of dietary essential fatty acids form cascades that parallel and compete with the arachidonic acid cascade. EPA (20:5 ω-3) provides the most important competing cascade. DGLA (20:3 ω-6) provides a third, less prominent cascade. These two parallel cascades soften the inflammatory effects of AA and its products. Low dietary intake of these less-inflammatory essential fatty acids, especially the ω-3s, has been linked to several inflammation-related diseases, and perhaps some mental illnesses. The U.S. National Institutes of Health and the National Library of Medicine state that there is 'A' level evidence ('strong scientific evidence') that increased dietary ω-3 improves outcomes in hypertriglyceridemia, secondary cardiovascular disease prevention and hypertension. There is 'B' level evidence ('good scientific evidence') for increased dietary ω-3 in primary prevention of cardiovascular disease, rheumatoid arthritis and protection from ciclosporin toxicity in organ transplant patients. They also note more preliminary evidence showing that dietary ω-3 can ease symptoms in several psychiatric disorders. Besides the influence on eicosanoids, dietary polyunsaturated fats modulate immune response through three other molecular mechanisms. They (a) alter membrane composition and function, including the composition of lipid rafts; (b) change cytokine biosynthesis and (c) directly activate gene transcription. Of these, the action on eicosanoids is the best explored. ## Mechanisms of ω-3 action The eicosanoids from AA generally promote inflammation. Those from EPA and from GLA (via DGLA) are generally less inflammatory, or inactive, or even anti-inflammatory. The figure shows the ω-3 and -6 synthesis chains, along with the major eicosanoids from AA, EPA and DGLA. Dietary ω-3 and GLA counter the inflammatory effects of AA's eicosanoids in three ways along the eicosanoid pathways. - Displacement—Dietary ω-3 decreases tissue concentrations of AA. Animal studies show that increased dietary ω-3 results in decreased AA in brain and other tissue. Linolenic acid (18:3 ω-3) contributes to this by displacing linoleic acid (18:2 ω-6) from the elongase and desaturase enzymes that produce AA. EPA inhibits phospholipase A2's release of AA from cell membrane. Other mechanisms involving the transport of EFAs may also play a role. The reverse is also true – high dietary linoleic acid decreases the body's conversion of α-linolenic acid to EPA. However, the effect is not as strong; the desaturase has a higher affinity for α-linolenic acid than it has for linoleic acid. - Competitive inhibition—DGLA and EPA compete with AA for access to the cyclooxygenase and lipoxygenase enzymes. So the presence of DGLA and EPA in tissues lowers the output of AA's eicosanoids. For example, dietary GLA increases tissue DGLA and lowers TXB2. Likewise, EPA inhibits the production of series-2 PG and TX. Although DGLA forms no LTs, a DGLA derivative blocks the transformation of AA to LTs. EPA lowers the formation of the AA-derived cysteinyl leukotrienes (series-4 LTC, LTD, LTE) forming the much less active series-5 instead. Another ω-3 fat, DHA (22:5 ω-3), does not form eicosanoids but inhibits the formation of AA-derived prostanoids. - Counteraction—Some DGLA and EPA derived eicosanoids counteract their AA derived counterparts. For example, DGLA yields PGE1, which powerfully counteracts PGE2. It also yields the leukotriene LTB5 which impedes the action of the AA-derived LTB4. ## Complexity of pathways Eicosanoid signaling paths are complex. It is therefore difficult to characterize the action of any particular eicosanoid. For example, PGE2 binds four receptors, dubbed EP1–4. Each is coded by a separate gene, and some exist in multiple isoforms. Each EP receptor in turn couples to a G protein. The EP2, EP4 and one isoform of the EP3 receptors couple to Gs. This increases intracellular cAMP and is anti-inflammatory. EP1 and other EP3 isoforms couple to Gq. This leads to increased intracellular calcium and is pro-inflammatory. Finally, yet another EP3 isoform couples to Gi, which both decreases cAMP and increases calcium. Many immune-system cells express multiple receptors that couple these apparently opposing pathways. Presumably, EPA-derived PGE3 has a somewhat different effect of on this system, but it is not well-characterized. ## Role in inflammation Since antiquity, the cardinal signs of inflammation have been known as: calor (warmth), dolor (pain), tumor (swelling) and rubor (redness). The eicosanoids are involved with each of these signs. Redness—An insect's sting will trigger the classic inflammatory response. Short acting vasoconstrictors—PGI2 and TXA2—are released quickly after the injury. The site may momentarily turn pale. Then TXA2 mediates the release of the vasodilators PGE2 and LTB4. The blood vessels engorge and the injury reddens. Swelling—LTB4 makes the blood vessels more permeable. Plasma leaks out into the connective tissues, and they swell. The process also looses pro-inflammatory cytokines. Pain—The cytokines increase COX-2 activity. This elevates levels of PGE2, sensitizing pain neurons. Heat—PGE2 is a also potent pyretic agent. Aspirin and NSAIDS—drugs that block the COX pathways and stop prostanoid synthesis—limit fever or the heat of localized inflammation. ## Action of prostanoids Prostanoids mediate local symptoms of inflammation: vasoconstriction or vasodilation, coagulation, pain and fever. Inhibition of cyclooxygenase, specifically the inducible COX-2 isoform, is the hallmark of NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin. COX-2 is responsible for pain and inflammation, while COX-1 is responsible for platelet clotting actions. Prostanoids play pivotal functions inflammation, platelet aggregation, and vasoconstriction/relaxation. Prostanoids activate the PPARγ members of the steroid/thyroid family of nuclear hormone receptors, directly influencing gene transcription. ## Action of leukotrienes Leukotrienes play an important role in inflammation. There is a neuroendocrine role for LTC4 in luteinizing hormone secretion. LTB4 causes adhesion and chemotaxis of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in neutrophils. Blocking leukotriene receptors can play a role in the management of inflammatory diseases such as asthma (by the drugs montelukast and zafirlukast), psoriasis, and rheumatoid arthritis. The slow reacting substance of anaphylaxis comprises the cysteinyl leukotrienes. These have a clear role in pathophysiological conditions such as asthma, allergic rhinitis and other nasal allergies, and have been implicated in atherosclerosis and inflammatory gastrointestinal diseases. They are potent bronchoconstrictors, increase vascular permeability in postcapillary venules, and stimulate mucus secretion. They are released from the lung tissue of asthmatic subjects exposed to specific allergens and play a pathophysiological role in immediate hypersensitivity reactions. Along with PGD, they function in effector cell trafficking, antigen presentation, immune cell activation, matrix deposition, and fibrosis. # History In 1930, gynecologist Raphael Kurzrok and pharmacologist Charles Leib characterized prostaglandin as a component of semen. Between 1929 and 1932, Burr and Burr showed that restricting fat from animal's diets led to a deficiency disease, and first described the essential fatty acids. In 1935, von Euler identified prostaglandin. In 1964, Bergström and Samuelsson linked these observations when they showed that the "classical" eicosanoids were derived from arachidonic acid, which had earlier been considered to be one of the essential fatty acids. In 1971, Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis. Von Euler received the Nobel Prize in medicine in 1970, which Samuelsson, Vane, and Bergström also received in 1982. E. J. Corey received it in chemistry in 1990 largely for his synthesis of prostaglandins.	Eicosanoid # Overview In biochemistry, eicosanoids are signaling molecules derived from omega-3 (ω-3) or omega-6 (ω-6) fats. They exert complex control over many bodily systems, especially in inflammation, immunity and as messengers in the central nervous system. The networks of controls that depend upon eicosanoids are among the most complex in the human body. The ω-6 eicosanoids are generally pro-inflammatory; ω-3's are much less so. The amounts of these fats in a person's diet will affect the body's eicosanoid-controlled functions, with effects on cardiovascular disease, triglycerides, blood pressure, and arthritis. Anti-inflammatory drugs such as aspirin and NSAIDs act by downregulating eicosanoid synthesis. There are four families of eicosanoids—the prostaglandins, prostacyclins, the thromboxanes and the leukotrienes. For each, there are two or three separate series, derived either from an ω-3 or ω-6 essential fatty acid. These series' different activities largely explain the health effects of ω-3 and ω-6 fats.[1][2][3][4] # Nomenclature "Eicosanoid" (eicosa-, Greek for "twenty"; see icosahedron) is the collective term[5] for oxygenated derivatives of three different 20-carbon essential fatty acids: - Eicosapentaenoic acid (EPA), an ω-3 fatty acid with 5 double bonds; - Arachidonic acid (AA), an ω-6 fatty acid, with 4 double bonds; - Dihomo-gamma-linolenic acid (DGLA), an ω-6, with 3 double bonds. Current usage limits the term to the leukotrienes (LT) and three types of prostanoids—prostaglandins (PG) prostacyclins (PGI), and thromboxanes (TX). This is the definition used in this article. However, several other classes can technically be termed eicosanoid, including the hepoxilins, resolvins, isofurans, isoprostanes, lipoxins, epoxyeicosatrienoic acids (EETs) and some endocannabinoids. A particular eicosanoid is denoted by a four-character abbreviation, composed of: - Its two letter abbreviation (above),[6] - One A-B-C sequence-letter;[7] and - A subscript, indicating the number of double bonds. Examples are: - The EPA-derived prostanoids have three double bonds, (e.g. PGG3, PGH3, PGI3, TXA3) while its leukotrienes have five, (LTB5). - The AA-derived prostanoids have two double bonds, (e.g. PGG2, PGH2, PGI2, TXA2) while its leukotrienes have four, (LTB4). Two families of enzymes catalyze fatty acid oxygenation to produce the eicosanoids: - Cyclooxygenase, or COX, which comes in at least three isoforms, COX-1, -2, -3 – leading to the prostanoids.[8] - Lipoxygenase, in several forms. 5-lipoxygenase (5-LO) generates the leukotrienes. # Biosynthesis Eicosanoids are a class of oxygenated fatty acids, found widely in a variety of microorganisms, plants and animals. In humans, eicosanoids are local hormones that are released by most cells, act on that same cell or nearby cells (i.e., they are autocrine and paracrine mediators), and then are rapidly inactivated. They are potent in the nanomolar range. Eicosanoids are not stored within cells, but are synthesized as required. They derive from fatty acids which are incorporated as esters into larger molecules—the phospholipids and diacylglycerols—found in the cell membrane and nuclear membrane. The first step of eicosanoid biosynthesis occurs when cell is activated by mechanical trauma, cytokines, growth factors or other stimuli. (The stimulus may even be an eicosanoid from a neighboring cell; the pathways are complex.) This triggers the release of a phospholipase at the cell wall. The phospholipase travels to the nuclear membrane. There, the phospholipase catalyzes ester hydrolysis of phospholipid (by A2) or diacylglycerol (by phospholipase C). This frees a 20-carbon essential fatty acid. This hydrolysis appears to be the rate-determining step for eicosanoid formation. The fatty acids may be released by any of several phospholipases. Of these, type IV cytosolic phospholipase A2 (cPLA2) is the key actor, as cells lacking cPLA2 are generally devoid of eicosanoid synthesis. The phospholipase cPLA2 is specific for phospholipids that contain AA, EPA or GPLA at the SN2 position. Interestingly, cPLA2 may also release the lysophospholipid that becomes platelet-activating factor.[9] ## Peroxidation and reactive oxygen species Next, the free fatty acid is oxygenated along any of several pathways; see the Pathways table. The eicosanoid pathways (via lipoxygenase or COX) add molecular oxygen (O2). Although the fatty acid is symmetric, the resulting eicosanoids are chiral; the oxidation proceeds with high stereospecificity. The oxidation of lipids is hazardous to cells, particularly when close to the nucleus. There are elaborate mechanisms to prevent unwanted oxidation. COX, the lipoxygenases and the phospholipases are tightly controlled—there are at least eight proteins activated to coordinate generation of leukotrienes. Several of these exist in multiple isoforms.[4] Oxidation by either COX or lipoxygenase releases reactive oxygen species (ROS) and the initial products in eicosanoid generation are themselves highly reactive peroxides. LTA4 can form adducts with tissue DNA. Other reactions of lipoxygenases generate cellular damage; murine models implicate 15-lipoxygenase in the pathogenesis of atherosclerosis.[10][11] The oxidation in eicosanoid generation is compartmentalized; this limits the peroxides' damage. The enzymes which are biosynthetic for eicosanoids (e.g. glutathione-S-transferases, epoxide hydrolases and carrier proteins) belong to families whose functions are largely involved with cellular detoxification. This suggests that eicosanoid signaling may have evolved from the detoxification of ROS. The cell must realize some benefit from generating lipid hydroperoxides close-by its nucleus. PGs and LTs may signal or regulate DNA-transcription there; LTB4 is ligand for PPARα.[2] (See diagram at PPAR). ## Biosynthesis of prostanoids Cyclooxygenase (COX) catalyzes the conversion of the free essential fatty acids to prostanoids by a two-step process. First, two molecules of O2 are added as two peroxide linkages, and a 5-member carbon ring is forged near the middle of the fatty acid chain. This forms the short-lived, unstable intermediate Prostaglandin G (PGG). Next, one of the peroxide linkages sheds a single oxygen, forming PGH. (See diagrams and more detail of these steps at Cyclooxygenase). All three classes of prostanoids originate from PGH. All have distinctive rings in the center of the molecule. They differ in their structures. The PGH compounds (parents to all the rest) have a 5-carbon ring, bridged by two oxygens (a peroxide.) As the example in Structures of Selected Eicosanoids figure shows, the derived prostaglandins contain a single, unsaturated 5-carbon ring. In prostacyclins, this ring is conjoined to another oxygen-containing ring. In thromboxanes the ring becomes a 6-member ring with one oxygen. The leukotrienes do not have rings. (See more detail, including the enzymes involved, in diagrams at Prostanoid.) ## Biosynthesis of leukotrienes The enzyme 5-lipoxygenase (5-LO) uses 5-lipoxygenase activating protein (FLAP) to convert arachidonic acid into 5-hydroperoxyeicosatetraenoic acid (5-HPETE), which spontaneously reduces to 5-hydroxyeicosatetraenoic acid (5-HETE). The enzyme 5-LO acts again on 5-HETE to convert it into leukotriene A4 (LTA4), which may be converted into LTB4 by the enzyme leukotriene A4 epoxide hydrolase. Eosinophils, mast cells, and alveolar macrophages use the enzyme leukotriene C4 synthase to conjugate glutathione with LTA4 to make LTC4, which is transported outside the cell, where a glutamic acid moiety is removed from it to make LTD4. The leukotriene LTD4 is then cleaved by dipeptidases to make LTE4. The leukotrienes LTC4, LTD4 and LTE4 all contain cysteine and are collectively known as the cysteinyl leukotrienes. # Function and pharmacology Eicosanoids have a short half-life, ranging from seconds to minutes. Dietary antioxidants inhibit the generation of some inflammatory eicosanoids, e.g. trans-resveratrol against thromboxane and some leukotrienes.[12] Most eicosanoid receptors are members of the G protein-coupled receptor superfamily; see the Receptors table or the article eicosanoid receptors. ## The ω-3 and ω-6 series Arachidonic acid (AA; 20:4 ω-6) sits at the head of the 'arachidonic acid cascade'—more than twenty different eicosanoid-mediated signaling paths controlling a wide array of cellular functions, especially those regulating inflammation, immunity and the central nervous system.[3] In the inflammatory response, two other groups of dietary essential fatty acids form cascades that parallel and compete with the arachidonic acid cascade. EPA (20:5 ω-3) provides the most important competing cascade. DGLA (20:3 ω-6) provides a third, less prominent cascade. These two parallel cascades soften the inflammatory effects of AA and its products. Low dietary intake of these less-inflammatory essential fatty acids, especially the ω-3s, has been linked to several inflammation-related diseases, and perhaps some mental illnesses. The U.S. National Institutes of Health and the National Library of Medicine state that there is 'A' level evidence ('strong scientific evidence') that increased dietary ω-3 improves outcomes in hypertriglyceridemia, secondary cardiovascular disease prevention and hypertension. There is 'B' level evidence ('good scientific evidence') for increased dietary ω-3 in primary prevention of cardiovascular disease, rheumatoid arthritis and protection from ciclosporin toxicity in organ transplant patients. They also note more preliminary evidence showing that dietary ω-3 can ease symptoms in several psychiatric disorders.[14] Besides the influence on eicosanoids, dietary polyunsaturated fats modulate immune response through three other molecular mechanisms. They (a) alter membrane composition and function, including the composition of lipid rafts; (b) change cytokine biosynthesis and (c) directly activate gene transcription.[13] Of these, the action on eicosanoids is the best explored. ## Mechanisms of ω-3 action The eicosanoids from AA generally promote inflammation. Those from EPA and from GLA (via DGLA) are generally less inflammatory, or inactive, or even anti-inflammatory. The figure shows the ω-3 and -6 synthesis chains, along with the major eicosanoids from AA, EPA and DGLA. Dietary ω-3 and GLA counter the inflammatory effects of AA's eicosanoids in three ways along the eicosanoid pathways. - Displacement—Dietary ω-3 decreases tissue concentrations of AA. Animal studies show that increased dietary ω-3 results in decreased AA in brain and other tissue.[15] Linolenic acid (18:3 ω-3) contributes to this by displacing linoleic acid (18:2 ω-6) from the elongase and desaturase enzymes that produce AA. EPA inhibits phospholipase A2's release of AA from cell membrane.[16] Other mechanisms involving the transport of EFAs may also play a role. The reverse is also true – high dietary linoleic acid decreases the body's conversion of α-linolenic acid to EPA. However, the effect is not as strong; the desaturase has a higher affinity for α-linolenic acid than it has for linoleic acid.[17] - Competitive inhibition—DGLA and EPA compete with AA for access to the cyclooxygenase and lipoxygenase enzymes. So the presence of DGLA and EPA in tissues lowers the output of AA's eicosanoids. For example, dietary GLA increases tissue DGLA and lowers TXB2.[18][19] Likewise, EPA inhibits the production of series-2 PG and TX.[20] Although DGLA forms no LTs, a DGLA derivative blocks the transformation of AA to LTs.[21] EPA lowers the formation of the AA-derived cysteinyl leukotrienes (series-4 LTC, LTD, LTE) forming the much less active series-5 instead.[22] Another ω-3 fat, DHA (22:5 ω-3), does not form eicosanoids but inhibits the formation of AA-derived prostanoids.[23] - Counteraction—Some DGLA and EPA derived eicosanoids counteract their AA derived counterparts. For example, DGLA yields PGE1, which powerfully counteracts PGE2.[24] It also yields the leukotriene LTB5 which impedes the action of the AA-derived LTB4.[25] ## Complexity of pathways Eicosanoid signaling paths are complex. It is therefore difficult to characterize the action of any particular eicosanoid. For example, PGE2 binds four receptors, dubbed EP1–4. Each is coded by a separate gene, and some exist in multiple isoforms. Each EP receptor in turn couples to a G protein. The EP2, EP4 and one isoform of the EP3 receptors couple to Gs. This increases intracellular cAMP and is anti-inflammatory. EP1 and other EP3 isoforms couple to Gq. This leads to increased intracellular calcium and is pro-inflammatory. Finally, yet another EP3 isoform couples to Gi, which both decreases cAMP and increases calcium. Many immune-system cells express multiple receptors that couple these apparently opposing pathways.[26] Presumably, EPA-derived PGE3 has a somewhat different effect of on this system, but it is not well-characterized. ## Role in inflammation Since antiquity, the cardinal signs of inflammation have been known as: calor (warmth), dolor (pain), tumor (swelling) and rubor (redness). The eicosanoids are involved with each of these signs. Redness—An insect's sting will trigger the classic inflammatory response. Short acting vasoconstrictors—PGI2 and TXA2—are released quickly after the injury. The site may momentarily turn pale. Then TXA2 mediates the release of the vasodilators PGE2 and LTB4. The blood vessels engorge and the injury reddens. Swelling—LTB4 makes the blood vessels more permeable. Plasma leaks out into the connective tissues, and they swell. The process also looses pro-inflammatory cytokines. Pain—The cytokines increase COX-2 activity. This elevates levels of PGE2, sensitizing pain neurons. Heat—PGE2 is a also potent pyretic agent. Aspirin and NSAIDS—drugs that block the COX pathways and stop prostanoid synthesis—limit fever or the heat of localized inflammation. ## Action of prostanoids Prostanoids mediate local symptoms of inflammation: vasoconstriction or vasodilation, coagulation, pain and fever. Inhibition of cyclooxygenase, specifically the inducible COX-2 isoform, is the hallmark of NSAIDs (non-steroidal anti-inflammatory drugs), such as aspirin. COX-2 is responsible for pain and inflammation, while COX-1 is responsible for platelet clotting actions. Prostanoids play pivotal functions inflammation, platelet aggregation, and vasoconstriction/relaxation. Prostanoids activate the PPARγ members of the steroid/thyroid family of nuclear hormone receptors, directly influencing gene transcription.[27] ## Action of leukotrienes Leukotrienes play an important role in inflammation. There is a neuroendocrine role for LTC4 in luteinizing hormone secretion.[28] LTB4 causes adhesion and chemotaxis of leukocytes and stimulates aggregation, enzyme release, and generation of superoxide in neutrophils.[29] Blocking leukotriene receptors can play a role in the management of inflammatory diseases such as asthma (by the drugs montelukast and zafirlukast), psoriasis, and rheumatoid arthritis. The slow reacting substance of anaphylaxis comprises the cysteinyl leukotrienes. These have a clear role in pathophysiological conditions such as asthma, allergic rhinitis and other nasal allergies, and have been implicated in atherosclerosis and inflammatory gastrointestinal diseases.[30] They are potent bronchoconstrictors, increase vascular permeability in postcapillary venules, and stimulate mucus secretion. They are released from the lung tissue of asthmatic subjects exposed to specific allergens and play a pathophysiological role in immediate hypersensitivity reactions.[29] Along with PGD, they function in effector cell trafficking, antigen presentation, immune cell activation, matrix deposition, and fibrosis.[31] # History In 1930, gynecologist Raphael Kurzrok and pharmacologist Charles Leib characterized prostaglandin as a component of semen. Between 1929 and 1932, Burr and Burr showed that restricting fat from animal's diets led to a deficiency disease, and first described the essential fatty acids.[32] In 1935, von Euler identified prostaglandin. In 1964, Bergström and Samuelsson linked these observations when they showed that the "classical" eicosanoids were derived from arachidonic acid, which had earlier been considered to be one of the essential fatty acids.[33] In 1971, Vane showed that aspirin and similar drugs inhibit prostaglandin synthesis.[34] Von Euler received the Nobel Prize in medicine in 1970, which Samuelsson, Vane, and Bergström also received in 1982. E. J. Corey received it in chemistry in 1990 largely for his synthesis of prostaglandins.	https://www.wikidoc.org/index.php/Eicosanoid
811fc169c8c4b15ef0adc0dcf8dcc1f4c7d6ec32	wikidoc	Elderberry	Elderberry Elder or Elderberry (Sambucus) is a genus of between 5–30 species of shrubs or small trees (two species herbaceous), formerly treated in the honeysuckle family Caprifoliaceae, but now shown by genetic evidence to be correctly classified in the moschatel family Adoxaceae. The genus is native to temperate to subtropical regions of both the Northern Hemisphere and the Southern Hemisphere; the genus is more widespread in the Northern Hemisphere, with Southern Hemisphere occurrence restricted to parts of Australasia and South America. The leaves are opposite, pinnate, with 5-9 leaflets (rarely 3 or 11), each leaf 5-30 cm long, the leaflets with a serrated margin. They bear large clusters of small white or cream coloured flowers in the late spring, that are followed by clusters of small red, bluish or black (rarely yellow or white) berries. Species have lifespans between 80 and 100 years. The berries are a very valuable food resource for many birds. Elders are used as food plants by the larvae of some Lepidoptera species including Brown-tail, Buff Ermine, Dot Moth, Emperor Moth, The Engrailed, Swallow-tailed Moth and The V-pug. The crushed foliage and immature fruit have a strong fetid smell. Dead elder wood is the preferred habitat of the mushroom Auricularia auricula-judae, also known as "Judas' ear fungus". Valley elderberry longhorn beetle in California are very often found around red or blue elderberry bushes. Females lay their eggs on the bark. Larvae hatch and burrow into the stems. # Species groups - The common elder complex is variously treated as a single species Sambucus nigra found in the warmer parts of Europe and North America with several regional varieties or subspecies, or else as a group of several similar species. The flowers are in flat corymbs, and the berries are black to glaucous blue; they are larger shrubs, reaching 5–8 m tall, occasionally small trees up to 15 m tall and with a stem diameter of up to 30–60 cm. Sambucus australis (Southern Elder; temperate eastern South America) Sambucus canadensis (American Elder; eastern North America; with blue-black berries) Sambucus cerulea (syn. S. caerulea, S. glauca; Blueberry Elder; western North America; with blue berries) Sambucus javanica (Chinese Elder; southeastern Asia) Sambucus mexicana (Mexican Elder; Mexico and Central America; with blue-black berries) Sambucus nigra (Black Elder; Europe and western Asia; with black berries) Sambucus palmensis (Canary Islands Elder; Canary Islands; with black berries) Sambucus peruviana (Peruvian Elder; northwest South America; with black berries) Sambucus simpsonii (Florida Elder; southeastern United States; with blue-black berries) Sambucus peruviana (Andean Elder; northern South America; with blue-black berries) Sambucus velutina (Velvet Elder; southwestern North America; with blue-black berries) - Sambucus australis (Southern Elder; temperate eastern South America) - Sambucus canadensis (American Elder; eastern North America; with blue-black berries) - Sambucus cerulea (syn. S. caerulea, S. glauca; Blueberry Elder; western North America; with blue berries) - Sambucus javanica (Chinese Elder; southeastern Asia) - Sambucus mexicana (Mexican Elder; Mexico and Central America; with blue-black berries) - Sambucus nigra (Black Elder; Europe and western Asia; with black berries) - Sambucus palmensis (Canary Islands Elder; Canary Islands; with black berries) - Sambucus peruviana (Peruvian Elder; northwest South America; with black berries) - Sambucus simpsonii (Florida Elder; southeastern United States; with blue-black berries) - Sambucus peruviana (Andean Elder; northern South America; with blue-black berries) - Sambucus velutina (Velvet Elder; southwestern North America; with blue-black berries) - The Blackberry Elder Sambucus melanocarpa of western North America is intermediate between the preceding and next groups. The flowers are in rounded panicles, but the berries are black; it is a small shrub, rarely exceeding 3–4 m tall. Some botanists include it in the red-berried elder group. - The red-berried elder complex is variously treated as a single species Sambucus racemosa found throughout the colder parts of the Northern Hemisphere with several regional varieties or subspecies, or else as a group of several similar species. The flowers are in rounded panicles, and the berries are bright red; they are smaller shrubs, rarely exceeding 3–4 m tall. Sambucus callicarpa (Pacific Coast Red Elder; west coast of North America) Sambucus chinensis (Chinese Red Elder; eastern Asia, in mountains) Sambucus latipinna (Korean Red Elder; Korea, southeast Siberia) Sambucus microbotrys (Mountain Red Elder; southwest North America, in mountains) Sambucus pubens (American Red Elder; northern North America) Sambucus racemosa (European Red Elder or Red-berried Elder; northern Europe, northwest Asia) Sambucus sieboldiana (Japanese Red Elder; Japan and Korea) Sambucus tigranii (Caucasus Red Elder; southwest Asia, in mountains) Sambucus williamsii (North China Red Elder; northeast Asia) - Sambucus callicarpa (Pacific Coast Red Elder; west coast of North America) - Sambucus chinensis (Chinese Red Elder; eastern Asia, in mountains) - Sambucus latipinna (Korean Red Elder; Korea, southeast Siberia) - Sambucus microbotrys (Mountain Red Elder; southwest North America, in mountains) - Sambucus pubens (American Red Elder; northern North America) - Sambucus racemosa (European Red Elder or Red-berried Elder; northern Europe, northwest Asia) - Sambucus sieboldiana (Japanese Red Elder; Japan and Korea) - Sambucus tigranii (Caucasus Red Elder; southwest Asia, in mountains) - Sambucus williamsii (North China Red Elder; northeast Asia) - The Australian elder group comprises two species from Australasia. The flowers are in rounded panicles, and the berries white or yellow; they are shrubs growing to 3 m high. Sambucus australasica (Yellow Elder; New Guinea, eastern Australia) Sambucus gaudichaudiana (Australian Elder or White Elder; shady areas of south eastern Australia) - Sambucus australasica (Yellow Elder; New Guinea, eastern Australia) - Sambucus gaudichaudiana (Australian Elder or White Elder; shady areas of south eastern Australia) - The dwarf elders are, by contrast to the other species, herbaceous plants, producing new stems each year from a perennial root system; they grow to 1.5–2 m tall, each stem terminating in a large flat umbel which matures into a dense cluster of glossy berries. Sambucus adnata (Asian Dwarf Elder; Himalaya and eastern Asia; berries red) Sambucus ebulus (European Dwarf Elder; central and southern Europe, northwest Africa and southwest Asia; berries black) - Sambucus adnata (Asian Dwarf Elder; Himalaya and eastern Asia; berries red) - Sambucus ebulus (European Dwarf Elder; central and southern Europe, northwest Africa and southwest Asia; berries black) # Uses Both flowers and berries can be made into elderberry wine, and in Hungary an elderberry brandy is produced (requiring 50 kg of fruit to produce 1 litre of brandy). The alcoholic drink sambuca is made by infusing elderberries and anise into alcohol. The berries are best not eaten raw as they are mildly poisonous, causing vomiting, particularly if eaten unripe. The mild cyanide toxicity is destroyed by cooking. The berries can also be made into jam, pies or Pontack sauce. All green parts of the plant are poisonous, containing cyanogenic glycosides (Vedel & Lange 1960). The flowers may be used to make an herbal tea, which is believed as a remedy for colds and fever. In Europe, the flowers are made into a syrup or cordial (in Romanian: Socată), which is diluted with water before drinking. The popularity of this traditional drink has recently encouraged some commercial soft drink producers to introduce elderflower-flavoured drinks (Fanta Shokata). The flowers can also be used to make a mildly alcoholic, sparkling elderflower 'champagne'. A few clinical studies have shown effectiveness of Sambucol, a formulation based on an extract of elderberry, in the treatment of both adults and children with either type A or B influenza. Sambucol reduced both the severity and duration of flu symptoms in otherwise healthy subjects, but should not be considered a substitute for influenza vaccination in high risk individuals . An in vitro study of Sambucol showed possible effectivness against the H5N1 avian influenza virus . # Folklore The elder was formerly held to be unlucky to have in the garden. If an elder tree was cut down, a spirit known as the Elder Mother would be released and take her revenge; shown in one way by a poem known as the Wiccan Rede where one line reads, "Elder be the Lady's tree, burn it not or cursed you'll be." This may derive from ancient Pagan beliefs, which held the elder sacred to the Moon Goddess. The tree could only safely be cut while chanting a rhyme to the Elder Mother. # Trivia - The box elder is not an elder at all, but an alternative name for the Manitoba Maple. # References and external links - ↑ Howard, Michael. Traditional Folk Remedies (Century, 1987); pp. 134-5 - Germplasm Resources Information Network: Sambucus - National Institute of Health - Medline page on Sambucus nigra L. - Vedel, H., & Lange, J. (1960). Trees and Bushes in Wood and Hedgerow. Methuen & Co Ltd. - Elder bush info and recipes from the BBC Guide to Life, the Universe, and Everything website. - Grieve, 'A Modern Herbal' (1931) - Black Elder (Sambucus nigra) Black Elder (Sambucus nigra) - American Elders in flower, Pamplico, South Carolina, USA American Elders in flower, Pamplico, South Carolina, USA - American Elder flowers American Elder flowers - Elderberry fruit heads, Yauhannah, South Carolina, USA Elderberry fruit heads, Yauhannah, South Carolina, USA - Red-berried Elder (Sambucus racemosa) Red-berried Elder (Sambucus racemosa) - Ripe elderberries in August Ripe elderberries in August bg:Бъз da:Hyld de:Holunder eo:Sambuko hr:Bazga is:Yllir it:Sambucus ka:ანწლი lt:Šeivamedis hu:Bodza nl:Vlier (plant) nn:Hyll qu:Rayan sl:Bezeg	Elderberry Elder or Elderberry (Sambucus) is a genus of between 5–30 species of shrubs or small trees (two species herbaceous), formerly treated in the honeysuckle family Caprifoliaceae, but now shown by genetic evidence to be correctly classified in the moschatel family Adoxaceae. The genus is native to temperate to subtropical regions of both the Northern Hemisphere and the Southern Hemisphere; the genus is more widespread in the Northern Hemisphere, with Southern Hemisphere occurrence restricted to parts of Australasia and South America. The leaves are opposite, pinnate, with 5-9 leaflets (rarely 3 or 11), each leaf 5-30 cm long, the leaflets with a serrated margin. They bear large clusters of small white or cream coloured flowers in the late spring, that are followed by clusters of small red, bluish or black (rarely yellow or white) berries. Species have lifespans between 80 and 100 years. The berries are a very valuable food resource for many birds. Elders are used as food plants by the larvae of some Lepidoptera species including Brown-tail, Buff Ermine, Dot Moth, Emperor Moth, The Engrailed, Swallow-tailed Moth and The V-pug. The crushed foliage and immature fruit have a strong fetid smell. Dead elder wood is the preferred habitat of the mushroom Auricularia auricula-judae, also known as "Judas' ear fungus". Valley elderberry longhorn beetle in California are very often found around red or blue elderberry bushes. Females lay their eggs on the bark. Larvae hatch and burrow into the stems. # Species groups - The common elder complex is variously treated as a single species Sambucus nigra found in the warmer parts of Europe and North America with several regional varieties or subspecies, or else as a group of several similar species. The flowers are in flat corymbs, and the berries are black to glaucous blue; they are larger shrubs, reaching 5–8 m tall, occasionally small trees up to 15 m tall and with a stem diameter of up to 30–60 cm. Sambucus australis (Southern Elder; temperate eastern South America) Sambucus canadensis (American Elder; eastern North America; with blue-black berries) Sambucus cerulea (syn. S. caerulea, S. glauca; Blueberry Elder; western North America; with blue berries) Sambucus javanica (Chinese Elder; southeastern Asia) Sambucus mexicana (Mexican Elder; Mexico and Central America; with blue-black berries) Sambucus nigra (Black Elder; Europe and western Asia; with black berries) Sambucus palmensis (Canary Islands Elder; Canary Islands; with black berries) Sambucus peruviana (Peruvian Elder; northwest South America; with black berries) Sambucus simpsonii (Florida Elder; southeastern United States; with blue-black berries) Sambucus peruviana (Andean Elder; northern South America; with blue-black berries) Sambucus velutina (Velvet Elder; southwestern North America; with blue-black berries) - Sambucus australis (Southern Elder; temperate eastern South America) - Sambucus canadensis (American Elder; eastern North America; with blue-black berries) - Sambucus cerulea (syn. S. caerulea, S. glauca; Blueberry Elder; western North America; with blue berries) - Sambucus javanica (Chinese Elder; southeastern Asia) - Sambucus mexicana (Mexican Elder; Mexico and Central America; with blue-black berries) - Sambucus nigra (Black Elder; Europe and western Asia; with black berries) - Sambucus palmensis (Canary Islands Elder; Canary Islands; with black berries) - Sambucus peruviana (Peruvian Elder; northwest South America; with black berries) - Sambucus simpsonii (Florida Elder; southeastern United States; with blue-black berries) - Sambucus peruviana (Andean Elder; northern South America; with blue-black berries) - Sambucus velutina (Velvet Elder; southwestern North America; with blue-black berries) - The Blackberry Elder Sambucus melanocarpa of western North America is intermediate between the preceding and next groups. The flowers are in rounded panicles, but the berries are black; it is a small shrub, rarely exceeding 3–4 m tall. Some botanists include it in the red-berried elder group. - The red-berried elder complex is variously treated as a single species Sambucus racemosa found throughout the colder parts of the Northern Hemisphere with several regional varieties or subspecies, or else as a group of several similar species. The flowers are in rounded panicles, and the berries are bright red; they are smaller shrubs, rarely exceeding 3–4 m tall. Sambucus callicarpa (Pacific Coast Red Elder; west coast of North America) Sambucus chinensis (Chinese Red Elder; eastern Asia, in mountains) Sambucus latipinna (Korean Red Elder; Korea, southeast Siberia) Sambucus microbotrys (Mountain Red Elder; southwest North America, in mountains) Sambucus pubens (American Red Elder; northern North America) Sambucus racemosa (European Red Elder or Red-berried Elder; northern Europe, northwest Asia) Sambucus sieboldiana (Japanese Red Elder; Japan and Korea) Sambucus tigranii (Caucasus Red Elder; southwest Asia, in mountains) Sambucus williamsii (North China Red Elder; northeast Asia) - Sambucus callicarpa (Pacific Coast Red Elder; west coast of North America) - Sambucus chinensis (Chinese Red Elder; eastern Asia, in mountains) - Sambucus latipinna (Korean Red Elder; Korea, southeast Siberia) - Sambucus microbotrys (Mountain Red Elder; southwest North America, in mountains) - Sambucus pubens (American Red Elder; northern North America) - Sambucus racemosa (European Red Elder or Red-berried Elder; northern Europe, northwest Asia) - Sambucus sieboldiana (Japanese Red Elder; Japan and Korea) - Sambucus tigranii (Caucasus Red Elder; southwest Asia, in mountains) - Sambucus williamsii (North China Red Elder; northeast Asia) - The Australian elder group comprises two species from Australasia. The flowers are in rounded panicles, and the berries white or yellow; they are shrubs growing to 3 m high. Sambucus australasica (Yellow Elder; New Guinea, eastern Australia) Sambucus gaudichaudiana (Australian Elder or White Elder; shady areas of south eastern Australia) - Sambucus australasica (Yellow Elder; New Guinea, eastern Australia) - Sambucus gaudichaudiana (Australian Elder or White Elder; shady areas of south eastern Australia) - The dwarf elders are, by contrast to the other species, herbaceous plants, producing new stems each year from a perennial root system; they grow to 1.5–2 m tall, each stem terminating in a large flat umbel which matures into a dense cluster of glossy berries. Sambucus adnata (Asian Dwarf Elder; Himalaya and eastern Asia; berries red) Sambucus ebulus (European Dwarf Elder; central and southern Europe, northwest Africa and southwest Asia; berries black) - Sambucus adnata (Asian Dwarf Elder; Himalaya and eastern Asia; berries red) - Sambucus ebulus (European Dwarf Elder; central and southern Europe, northwest Africa and southwest Asia; berries black) # Uses Both flowers and berries can be made into elderberry wine, and in Hungary an elderberry brandy is produced (requiring 50 kg of fruit to produce 1 litre of brandy). The alcoholic drink sambuca is made by infusing elderberries[citation needed] and anise into alcohol. The berries are best not eaten raw as they are mildly poisonous, causing vomiting, particularly if eaten unripe. The mild cyanide toxicity is destroyed by cooking. The berries can also be made into jam, pies or Pontack sauce. All green parts of the plant are poisonous, containing cyanogenic glycosides (Vedel & Lange 1960). The flowers may be used to make an herbal tea, which is believed as a remedy for colds and fever. In Europe, the flowers are made into a syrup or cordial (in Romanian: Socată), which is diluted with water before drinking. The popularity of this traditional drink has recently encouraged some commercial soft drink producers to introduce elderflower-flavoured drinks (Fanta Shokata). The flowers can also be used to make a mildly alcoholic, sparkling elderflower 'champagne'. A few clinical studies have shown effectiveness of Sambucol, a formulation based on an extract of elderberry, in the treatment of both adults and children with either type A or B influenza. Sambucol reduced both the severity and duration of flu symptoms in otherwise healthy subjects, but should not be considered a substitute for influenza vaccination in high risk individuals [1]. An in vitro study of Sambucol showed possible effectivness against the H5N1 avian influenza virus [2]. # Folklore The elder was formerly held to be unlucky to have in the garden. If an elder tree was cut down, a spirit known as the Elder Mother would be released and take her revenge; shown in one way by a poem known as the Wiccan Rede where one line reads, "Elder be the Lady's tree, burn it not or cursed you'll be." This may derive from ancient Pagan beliefs, which held the elder sacred to the Moon Goddess. The tree could only safely be cut while chanting a rhyme to the Elder Mother.[1] # Trivia Template:Trivia - The box elder is not an elder at all, but an alternative name for the Manitoba Maple. # References and external links - ↑ Howard, Michael. Traditional Folk Remedies (Century, 1987); pp. 134-5 - Germplasm Resources Information Network: Sambucus - National Institute of Health - Medline page on Sambucus nigra L. - Vedel, H., & Lange, J. (1960). Trees and Bushes in Wood and Hedgerow. Methuen & Co Ltd. - Elder bush info and recipes from the BBC Guide to Life, the Universe, and Everything website. - Grieve, 'A Modern Herbal' (1931) - Black Elder (Sambucus nigra) Black Elder (Sambucus nigra) - American Elders in flower, Pamplico, South Carolina, USA American Elders in flower, Pamplico, South Carolina, USA - American Elder flowers American Elder flowers - Elderberry fruit heads, Yauhannah, South Carolina, USA Elderberry fruit heads, Yauhannah, South Carolina, USA - Red-berried Elder (Sambucus racemosa) Red-berried Elder (Sambucus racemosa) - Ripe elderberries in August Ripe elderberries in August bg:Бъз da:Hyld de:Holunder eo:Sambuko hr:Bazga is:Yllir it:Sambucus ka:ანწლი lt:Šeivamedis hu:Bodza nl:Vlier (plant) nn:Hyll qu:Rayan sl:Bezeg Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Elderberry
2297cf5036781e50d980a081b2351b52abc84c25	wikidoc	Elecampane	Elecampane Elecampane, also called Horse-heal (Inula helenium) or Marchalan (in Welsh), is a perennial composite plant common in many parts of Great Britain, and ranges throughout central and Southern Europe, and in Asia as far eastwards as the Himalayas. It is a rather rigid herb, the stem of which attains a height of from 3 to 5 feet; the leaves are large and toothed, the lower ones stalked, the rest embracing the stem; the flowers are yellow, 2 inches broad, and have many rays, each three-notched at the extremity. The root is thick, branching and mucilaginous, and has a warm, bitter taste and a camphoraceous odor. For medicinal purposes it should be procured from plants not more than two or three years old. Besides inulin, C12H20O10, a body isomeric with starch, the root contains helenin, C6H8O, a stearoptene, which may be prepared in white acicular crystals, insoluble in water, but freely soluble in alcohol. When freed from the accompanying inula-camphor by repeated crystallization from alcohol, helenin melts at 110° C. By the ancients the root was employed both as a medicine and as a condiment, and in England it was formerly in great repute as an aromatic tonic and stimulant of the secretory organs. As a drug, however, the root is now seldom resorted to except in veterinary practice, though it is undoubtedly possessed of antiseptic properties. In France and Switzerland it is used in the manufacture of absinthe. # Folklore The plant's specific name, helenium, derives from Helen of Troy; elecampane is said to have sprung up from where her tears fell. It was sacred to the ancient Celts, and once had the name "elfwort". # Herbalism John Gerard recommended elecampane for "the shortness of breath"; today herbalists prescribe it as an expectorant and for water retention; it also is claimed to have antiseptic properties. It has minor applications as a tonic and to bring on menstruation.	Elecampane Elecampane, also called Horse-heal (Inula helenium) or Marchalan (in Welsh), is a perennial composite plant common in many parts of Great Britain, and ranges throughout central and Southern Europe, and in Asia as far eastwards as the Himalayas. It is a rather rigid herb, the stem of which attains a height of from 3 to 5 feet; the leaves are large and toothed, the lower ones stalked, the rest embracing the stem; the flowers are yellow, 2 inches broad, and have many rays, each three-notched at the extremity. The root is thick, branching and mucilaginous, and has a warm, bitter taste and a camphoraceous odor. For medicinal purposes it should be procured from plants not more than two or three years old. Besides inulin, C12H20O10, a body isomeric with starch, the root contains helenin, C6H8O, a stearoptene, which may be prepared in white acicular crystals, insoluble in water, but freely soluble in alcohol. When freed from the accompanying inula-camphor by repeated crystallization from alcohol, helenin melts at 110° C. By the ancients the root was employed both as a medicine and as a condiment, and in England it was formerly in great repute as an aromatic tonic and stimulant of the secretory organs. As a drug, however, the root is now seldom resorted to except in veterinary practice, though it is undoubtedly possessed of antiseptic properties. In France and Switzerland it is used in the manufacture of absinthe. # Folklore The plant's specific name, helenium, derives from Helen of Troy; elecampane is said to have sprung up from where her tears fell. It was sacred to the ancient Celts, and once had the name "elfwort".[1] # Herbalism John Gerard recommended elecampane for "the shortness of breath"; today herbalists prescribe it as an expectorant and for water retention; it also is claimed to have antiseptic properties. It has minor applications as a tonic and to bring on menstruation.[2]	https://www.wikidoc.org/index.php/Elecampane
0cd4ebe2569e955b6d9aa7abb6d43a79c63f2f28	wikidoc	Micrograph	Micrograph A micrograph, microphotograph or photomicrograph is a photograph or similar image taken through a microscope or similar device to show a magnified image of an item. Canadian inventor Reginald Aubrey Fessenden is credited with inventing photomicrography. To produce a micrograph, a camera may be affixed to a microscope either in place of the eyepiece or a specialist microscope may be used which has a camera and eyepiece arrangement. A prepared specimen is put under the microscope in the usual way and photographs taken. Alternatively, the image may be scanned and stored electronically and displayed on a screen and/or printed. Micrographs are widely used in forensic engineering and forensic science, especially for recording Trace evidence. It is also routinely used in scanning electron microscopy, often combined with energy-dispersive X-ray spectroscopy so that the area of the sample selected for analysis is directly visible. # Types ## Light micrograph A light micrograph is a micrograph prepared using a light microscope, a process referred to as photomicroscopy (a portmanteau term of the words photography and microscopy). At a basic level, photomicroscopy may be performed simply by hooking up a regular camera to a microscope, thereby enabling the user to take photographs at reasonably high magnification. Photomicroscopists take photographs of many biologic subjects such as cells and proteins and insect eyes. Roman Vishniac was a pioneer in the field of photomicroscopy, specializing in the photography of living creatures in full motion. He also made major developments in light-interruption photography and color photomicroscopy. ## Electron micrograph An electron micrograph is a micrograph prepared using an electron microscope.	Micrograph A micrograph, microphotograph or photomicrograph is a photograph or similar image taken through a microscope or similar device to show a magnified image of an item. Canadian inventor Reginald Aubrey Fessenden is credited with inventing photomicrography. To produce a micrograph, a camera may be affixed to a microscope either in place of the eyepiece or a specialist microscope may be used which has a camera and eyepiece arrangement. A prepared specimen is put under the microscope in the usual way and photographs taken. Alternatively, the image may be scanned and stored electronically and displayed on a screen and/or printed. Micrographs are widely used in forensic engineering and forensic science, especially for recording Trace evidence. It is also routinely used in scanning electron microscopy, often combined with energy-dispersive X-ray spectroscopy so that the area of the sample selected for analysis is directly visible. # Types ## Light micrograph A light micrograph is a micrograph prepared using a light microscope, a process referred to as photomicroscopy (a portmanteau term of the words photography and microscopy). At a basic level, photomicroscopy may be performed simply by hooking up a regular camera to a microscope, thereby enabling the user to take photographs at reasonably high magnification. Photomicroscopists take photographs of many biologic subjects such as cells and proteins and insect eyes. Roman Vishniac was a pioneer in the field of photomicroscopy, specializing in the photography of living creatures in full motion. He also made major developments in light-interruption photography and color photomicroscopy. ## Electron micrograph An electron micrograph is a micrograph prepared using an electron microscope. # External links - Cheap options in Microphotography - from olympuszuiko.com - Make a Micrograph -- This interactive Flash presentation shows how researchers create a three-color micrograph. From the research department of Children's Hospital Boston. cs:Mikrofotografie de:Mikrofotografie Template:WikiDoc Sources Template:Jb1	https://www.wikidoc.org/index.php/Electron-micrograph
87440a009244655b11a34cb41171f3d22001df7b	wikidoc	Eletriptan	Eletriptan # 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 Eletriptan is a serotonin (5-HT1B/1D) receptor agonist that is FDA approved for the {{{indicationType}}} of migraine with or without aura in adults. Common adverse reactions include asthenia, nausea, dizziness, and somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The maximum recommended single dose is 40 mg. - In controlled clinical trials, single doses of 20 mg and 40 mg were effective for the acute treatment of migraine in adults. A greater proportion of patients had a response following a 40 mg dose than following a 20 mg dose. - If the migraine has not resolved by 2 hours after taking RELPAX, or returns after transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose should not exceed 80 mg. - The safety of treating an average of more than 3 migraine attacks in a 30-day period has not been established. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eletriptan in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eletriptan in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Eletriptan in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eletriptan in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eletriptan in pediatric patients. # Contraindications - Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal's angina. - Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. - History of stroke, transient ischemic attack (TIA), or history or current evidence of hemiplegic or basilar migraine because these patients are at a higher risk of stroke. - Peripheral vascular disease. - Ischemic bowel disease. - Uncontrolled hypertension. - Recent use (i.e., within 24 hours) of another 5-hydroxytryptamine1 (5-HT1) agonist, ergotamine-containing medication, or ergot-type medication such as dihydroergotamine (DHE) or methysergide. - Hypersensitivity to RELPAX (angioedema and anaphylaxis seen). - Recent use (i.e., within at least 72 hours) of the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, or nelfinavir. # Warnings ### Precautions - Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina - RELPAX is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of RELPAX. Some of these reactions occurred in patients without known CAD. RELPAX may cause coronary artery vasospasm (Prinzmetal's angina), even in patients without a history of CAD. - Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving RELPAX. Do not use RELPAX if there is evidence of CAD or coronary artery vasospasm. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first RELPAX dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following administration of RELPAX. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of RELPAX. - Arrhythmias - Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue RELPAX if these disturbances occur. RELPAX is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. - Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure - Sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with RELPAX and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. RELPAX is contraindicated in patients with CAD or Prinzmetal's variant angina. - Cerebrovascular Events - Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. - Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical of migraine, other potentially serious neurological conditions need to be excluded. RELPAX is contraindicated in patients with a history of stroke or TIA. - Other Vasospasm Reactions - RELPAX may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of a vasospastic reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional RELPAX doses. - Medication Overuse Headache - Overuse of acute migraine drugs (e.g. ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused acute migraine drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. - Serotonin Syndrome - Serotonin syndrome may occur with RELPAX, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue RELPAX if serotonin syndrome is suspected. - Increase in Blood Pressure - Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with RELPAX. RELPAX is contraindicated in patients with uncontrolled hypertension. - Anaphylactic/Anaphylactoid Reactions - There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving RELPAX. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. RELPAX is contraindicated in patients with a history of hypersensitivity reaction to RELPAX. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. - Among 4,597 patients who treated the first migraine headache with RELPAX in short-term placebo-controlled trials, the most common adverse reactions reported with treatment with RELPAX were asthenia, nausea, dizziness, and somnolence. These reactions appear to be dose-related. - In long-term open-label studies where patients were allowed to treat multiple migraine attacks for up to 1 year, 128 (8.3%) out of 1,544 patients discontinued treatment due to adverse reactions. - Table 1 lists adverse reactions that occurred in the subset of 5,125 migraineurs who received eletriptan doses of 20 mg, 40 mg and 80 mg or placebo in worldwide placebo-controlled clinical trials. - Only adverse reactions that were more frequent in a RELPAX treatment group compared to the placebo group with an incidence greater than or equal to 2% are included in Table 1. - The frequency of adverse reactions in clinical trials did not increase when up to 2 doses of RELPAX were taken within 24 hours. The incidence of adverse reactions in controlled clinical trials was not affected by gender, age, or race of the patients. Adverse reaction frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (e.g., SSRIs, beta blockers, calcium channel blockers, tricyclic antidepressants), estrogen replacement therapy or oral contraceptives. ## Postmarketing Experience - The following adverse reaction(s) have been identified during post approval use of RELPAX. 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. Seizure Vomiting # Drug Interactions - Ergot-Containing Drugs Including Other 5-HT1B/1D Agonists - Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine or methysergide) and RELPAX within 24 hours of each other is contraindicated. Concomitant use of other 5-HT1 agonists within 24 hours of RELPAX treatment is contraindicated. - CYP3A4 Inhibitors - Potent CYP3A4 inhibitors significantly increase the exposure of RELPAX. RELPAX should not be used within at least 72 hours of treatment with potent CYP3A4 inhibitors. - Selective Serotonin Reuptake Inhibitors/Serotonin and Norepinephrine Reuptake Inhibitors and Serotonin Syndrome - Cases of serotonin syndrome have been reported during co-administration of triptans and SSRIs, SNRIs, TCAs and MAO inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. In reproductive toxicity studies in pregnant animals, oral administration of eletriptan was associated with developmental toxicity (decreased fetal and pup weights and an increased incidence of fetal structural abnormalities) at clinically relevant plasma exposures. RELPAX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus - When pregnant rats were administered eletriptan during the period of organogenesis at doses of 10, 30 or 100 mg/kg/day, fetal weights were decreased and the incidences of vertebral and sternebral variations were increased at 100 mg/kg/day (approximately 12 times the maximum recommended human dose of 80 mg/day on a mg/m2 basis). The 30 and 100 mg/kg/day doses were also maternally toxic, as evidenced by decreased maternal body weight gain during gestation. The no-effect dose for developmental toxicity in rats was 30 mg/kg/day, which is approximately 4 times the MRHD on a mg/m2 basis. - When doses of 5, 10, or 50 mg/kg/day were given to pregnant rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg/day, which is approximately 12 times the MRHD on a mg/m2 basis. The incidences of fused sternebrae and vena cava deviations were increased at all doses. Maternal toxicity was not evident at any dose. A no-effect dose for developmental toxicity in rabbits was not established; the lowest dose tested (5 mg/kg/day) is similar to the MRHD on a mg/m2 basis. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eletriptan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Eletriptan during labor and delivery. ### Nursing Mothers - Eletriptan is excreted in human milk. Caution should be exercised when RELPAX is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. - The efficacy of RELPAX Tablets (40 mg) in patients 11–17 was not established in a randomized, placebo-controlled trial of 274 adolescent migraineurs. Adverse reactions observed were similar in nature to those reported in clinical trials in adults. Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse reactions that are similar in nature to those reported rarely in adults. Long-term safety of eletriptan was studied in 76 adolescent patients who received treatment for up to one year. A similar profile of adverse reactions to that of adults was observed. The long-term safety of eletriptan in pediatric patients has not been established. ### Geriatic Use - Blood pressure was increased to a greater extent in elderly subjects than in young subjects. The pharmacokinetic disposition of eletriptan in the elderly is similar to that seen in younger adults. In clinical trials, there were no apparent differences in efficacy or the incidence of adverse reactions between patients under 65 years of age and those 65 and above. ### Gender There is no FDA guidance on the use of Eletriptan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Eletriptan with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Eletriptan in patients with renal impairment. ### Hepatic Impairment - The effect of severe hepatic impairment on RELPAX metabolism has not been evaluated. RELPAX is not recommended for use in patients with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Eletriptan in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Eletriptan in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Eletriptan in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Eletriptan in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The elimination half-life of eletriptan is about 4 hours, therefore monitoring of patients after overdose with eletriptan should continue for at least 20 hours or longer while symptoms or signs persist. ### Management - There is no specific antidote to eletriptan. - It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentration of eletriptan. ## Chronic Overdose There is limited information regarding Chronic Overdose of Eletriptan in the drug label. # Pharmacology ## Mechanism of Action - Eletriptan binds with high affinity to 5-HT1B, 5-HT1D and 5-HT1F receptors, has modest affinity for 5-HT1A, 5-HT1E, 5-HT2B and 5-HT7 receptors. - Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of RELPAX for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release. ## Structure - RELPAX (eletriptan hydrobromide) tablets contain eletriptan hydrobromide, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Eletriptan hydrobromide is chemically designated as (R)-3--5--1H-indole monohydrobromide, and it has the following chemical structure: - The empirical formula is C22H26N2O2S . HBr, representing a molecular weight of 463.43. Eletriptan hydrobromide is a white to light pale colored powder that is readily soluble in water. - Each RELPAX Tablet for oral administration contains 24.2 or 48.5 mg of eletriptan hydrobromide equivalent to 20 mg or 40 mg of eletriptan, respectively. Each tablet also contains the inactive ingredients microcrystalline cellulose NF, lactose monohydrate NF, croscarmellose sodium NF, magnesium stearate NF, titanium dioxide USP, hypromellose, triacetin USP and FD&C Yellow No. 6 aluminum lake. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Eletriptan in the drug label. ## Pharmacokinetics - Absorption - Eletriptan is well absorbed after oral administration with peak plasma levels occurring approximately 1.5 hours after dosing to healthy subjects. In patients with moderate to severe migraine the median Tmax is 2.0 hours. The mean absolute bioavailability of eletriptan is approximately 50%. The oral pharmacokinetics are slightly more than dose-proportional over the clinical dose range. The AUC and Cmax of eletriptan are increased by approximately 20 to 30% following oral administration with a high fat meal. RELPAX can be taken with or without food. - Distribution - The volume of distribution of eletriptan following IV administration is 138L. Plasma protein binding is moderate and approximately 85%. - Metabolism - The N-demethylated metabolite of eletriptan is the only known active metabolite. This metabolite causes vasoconstriction similar to eletriptan in animal models. Though the half-life of the metabolite is estimated to be about 13 hours, the plasma concentration of the N-demethylated metabolite is 10–20% of parent drug and is unlikely to contribute significantly to the overall effect of the parent compound. - In vitro studies indicate that eletriptan is primarily metabolized by cytochrome P-450 enzyme CYP3A4. - Elimination - The terminal elimination half-life of eletriptan is approximately 4 hours. Mean renal clearance (CLR) following oral administration is approximately 3.9 L/h. Non-renal clearance accounts for about 90% of the total clearance. - Special Populations - Age - The pharmacokinetics of eletriptan are generally unaffected by age. Blood pressure was increased to a greater extent in elderly subjects than in young subjects. The pharmacokinetic disposition of eletriptan in the elderly is similar to that seen in younger adults. - There is a statistically significant increased half-life (from about 4.4 hours to 5.7 hours) between elderly (65 to 93 years of age) and younger adult subjects (18 to 45 years of age). - Gender - The pharmacokinetics of eletriptan are unaffected by gender. - Race - A comparison of pharmacokinetic studies run in western countries with those run in Japan has indicated an approximate 35% reduction in the exposure of eletriptan in Japanese male volunteers compared to western males. Population pharmacokinetic analysis of two clinical studies indicates no evidence of pharmacokinetic differences between Caucasians and non-Caucasian patients. - Menstrual Cycle - In a study of 16 healthy females, the pharmacokinetics of eletriptan remained consistent throughout the phases of the menstrual cycle. - Renal Impairment - There was no significant change in clearance observed in subjects with mild, moderate or severe renal impairment, though blood pressure elevations were observed in this population. - Hepatic Impairment - Subjects with mild or moderate hepatic impairment demonstrated an increase in both AUC (34%) and half-life. The Cmax was increased by 18%. No dose adjustment is necessary in subjects with mild or moderate hepatic impairment. The effects of severe hepatic impairment on eletriptan metabolism have not been evaluated. - Drug Interaction Studies - CYP3A4 inhibitors - In vitro studies have shown that eletriptan is metabolized by the CYP3A4 enzyme. A clinical study demonstrated about a 3-fold increase in Cmax and about a 6-fold increase in the AUC of eletriptan when combined with ketoconazole. The half-life increased from 5 hours to 8 hours and the Tmax increased from 2.8 hours to 5.4 hours. Another clinical study demonstrated about a 2-fold increase in Cmax and about a 4-fold increase in AUC when erythromycin was co-administered with eletriptan. It has also been shown that co-administration of verapamil and eletriptan yields about a 2-fold increase in Cmax and about a 3-fold increase in AUC of eletriptan, and that co-administration of fluconazole and eletriptan yields about a 1.4-fold increase in Cmax and about a 2-fold increase in AUC of eletriptan. - RELPAX is contraindicated within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir. RELPAX should not be used within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition. - Propranolol - The Cmax and AUC of eletriptan were increased by 10 and 33%, respectively, in the presence of propranolol. No interactive increases in blood pressure were observed. No dosage adjustment appears to be needed for patients taking propranolol. - The effect of eletriptan on other drugs: The effect of eletriptan on enzymes other than cytochrome P450 has not been investigated. In vitro human liver microsome studies suggest that eletriptan has little potential to inhibit CYP1A2, 2C9, 2E1 and 3A4 at concentrations up to 100 µM. While eletriptan has an effect on CYP2D6 at high concentration, this effect should not interfere with metabolism of other drugs when eletriptan is used at recommended doses. There is no in vitro or in vivo evidence that clinical doses of eletriptan will induce drug metabolizing enzymes. Therefore, eletriptan is unlikely to cause clinically important drug interactions mediated by these enzymes. ## Nonclinical Toxicology - Carcinogenesis - Eletriptan was administered to rats and mice in the diet for 104 weeks. In rats, the incidence of testicular interstitial cell adenomas was increased at the high dose of 75 mg/kg/day, but not at 15 mg/kg/day, a dose associated with plasma exposures (AUC) approximately 2 times that in humans at the MRHD of 80 mg/day. In mice, the incidence of hepatocellular adenomas was increased at the high dose of 400 mg/kg/day, but not a dose of 90 mg/kg/day, associated with plasma AUC approximately 7 times that in humans at the MRHD. - Mutagenesis - Eletriptan was negative in in vitro (bacteria reverse mutation (Ames), mammalian cell gene mutation (CHO/ HGPRT), chromosomal aberration assay in human lymphocytes) and in vivo (mouse micronucleus) assays. - Impairment of Fertility - In a fertility and early embryonic development study, eletriptan (50, 100, or 200 mg/kg/day) was orally administered to male and female rats prior to and throughout mating and continuing in females to implantation. Plasma exposures (AUC) were 4, 8 and 16 times in males and 7, 14 and 28 times in females, respectively, that in humans at the MRHD. Dose-related decreases in the number of corpora lutea, implants, and viable fetuses per dam were observed at all doses. Prolongation of the estrus cycle was observed at the highest dose tested. Male fertility parameters were not affected. # Clinical Studies - The efficacy of RELPAX in the acute treatment of migraines was evaluated in eight randomized, double-blind placebo-controlled studies. All eight studies used 40 mg. Seven studies evaluated an 80 mg dose and two studies included a 20 mg dose. - In all eight studies, randomized patients treated their headaches as outpatients. Seven studies enrolled adults and one study enrolled adolescents (age 11 to 17). Patients treated in the seven adult studies were predominantly female (85%) and Caucasian (94%) with a mean age of 40 years (range 18 to 78). In all studies, patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 2 hours after dosing. Associated symptoms such as nausea, vomiting, photophobia and phonophobia were also assessed. - Maintenance of response was assessed for up to 24 hours post dose. In the adult studies, a second dose of RELPAX or other medication was allowed 2 to 24 hours after the initial treatment for both persistent and recurrent headaches. The incidence and time to use of these additional treatments were also recorded. - In the seven adult studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients receiving RELPAX at all doses compared to those who received placebo. The two-hour response rates from these controlled clinical studies are summarized in Table 2. - Comparisons of the performance of different drugs based upon results obtained in different clinical trials are never reliable. Because studies are generally conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study. - The estimated probability of achieving an initial headache response within 2 hours following treatment is depicted in Figure 1. - Figure 1 shows the Kaplan-Meier plot of probability over time of obtaining headache response (no or mild pain) following treatment with eletriptan. The plot is based on 7 placebo-controlled, outpatient trials in adults providing evidence of efficacy (Studies 1 through 7). Patients not achieving headache response or taking additional treatment prior to 2 hours were censored at 2 hours. - For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of RELPAX as compared to placebo. - Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of taking a second dose or other medications for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2. - This Kaplan-Meier plot is based on data obtained in 7 placebo-controlled trials in adults (Studies 1 through 7). Patients were instructed to take a second dose of study medication as follows: a) in the event of no response at 2 hours (studies 2 and 4–7) or at 4 hours (study 3); b) in the event of headache recurrence within 24 hours (studies 2–7). Patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. It should be noted that the protocols did not allow re-medication within 2 hours post dose. - The efficacy of RELPAX was unaffected by the duration of attack, gender or age of the patient, relationship to menses, or concomitant use of estrogen replacement therapy/oral contraceptives or frequently used migraine prophylactic drugs. - In a single study in adolescents (n=274), there were no statistically significant differences between treatment groups. The headache response rate at 2 hours was 57% for both RELPAX 40 mg Tablets and placebo. # How Supplied - RELPAX Tablets containing 20 mg or 40 mg eletriptan (base) as the hydrobromide salt. RELPAX Tablets are orange, round, convex shaped, film-coated tablets with appropriate debossing. - They are supplied in the following strengths and package configurations: - RELPAX Tablets ## Storage There is limited information regarding Eletriptan Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Myocardial Ischemia and/or Infarction, Prinzmetal's Angina, Other Vasospastic Reactions, and Cerebrovascular Events - Inform patients that RELPAX may cause serious cardiovascular adverse reactions such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular reactions can occur without warning symptoms, instruct patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and instruct them to ask for medical advice when observing any indicative sign or symptoms. Instruct patients to seek medical advice if they have symptoms of other vasospastic reactions. - Anaphylactic/Anaphylactoid Reactions - Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving RELPAX. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. - Medication Overuse Headache - Inform patients that use of drugs to treat acute migraines for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary)]. - Serotonin Syndrome - Inform patients about the risk of serotonin syndrome with the use of RELPAX or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). - Pregnancy - Inform patients that RELPAX should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. - Nursing Mothers - Inform patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed. # Precautions with Alcohol - Alcohol-Eletriptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - RELPAX® # Look-Alike Drug Names There is limited information regarding Eletriptan Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Eletriptan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Eletriptan is a serotonin (5-HT1B/1D) receptor agonist that is FDA approved for the {{{indicationType}}} of migraine with or without aura in adults. Common adverse reactions include asthenia, nausea, dizziness, and somnolence. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - The maximum recommended single dose is 40 mg. - In controlled clinical trials, single doses of 20 mg and 40 mg were effective for the acute treatment of migraine in adults. A greater proportion of patients had a response following a 40 mg dose than following a 20 mg dose. - If the migraine has not resolved by 2 hours after taking RELPAX, or returns after transient improvement, a second dose may be administered at least 2 hours after the first dose. The maximum daily dose should not exceed 80 mg. - The safety of treating an average of more than 3 migraine attacks in a 30-day period has not been established. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eletriptan in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eletriptan in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Eletriptan in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eletriptan in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eletriptan in pediatric patients. # Contraindications - Ischemic coronary artery disease (CAD) (angina pectoris, history of myocardial infarction, or documented silent ischemia) or coronary artery vasospasm, including Prinzmetal's angina. - Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. - History of stroke, transient ischemic attack (TIA), or history or current evidence of hemiplegic or basilar migraine because these patients are at a higher risk of stroke. - Peripheral vascular disease. - Ischemic bowel disease. - Uncontrolled hypertension. - Recent use (i.e., within 24 hours) of another 5-hydroxytryptamine1 (5-HT1) agonist, ergotamine-containing medication, or ergot-type medication such as dihydroergotamine (DHE) or methysergide. - Hypersensitivity to RELPAX (angioedema and anaphylaxis seen). - Recent use (i.e., within at least 72 hours) of the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, or nelfinavir. # Warnings ### Precautions - Myocardial Ischemia, Myocardial Infarction, and Prinzmetal's Angina - RELPAX is contraindicated in patients with ischemic or vasospastic CAD. There have been rare reports of serious cardiac adverse reactions, including acute myocardial infarction, occurring within a few hours following administration of RELPAX. Some of these reactions occurred in patients without known CAD. RELPAX may cause coronary artery vasospasm (Prinzmetal's angina), even in patients without a history of CAD. - Perform a cardiovascular evaluation in triptan-naïve patients who have multiple cardiovascular risk factors (e.g., increased age, diabetes, hypertension, smoking, obesity, strong family history of CAD) prior to receiving RELPAX. Do not use RELPAX if there is evidence of CAD or coronary artery vasospasm. For patients with multiple cardiovascular risk factors who have a negative cardiovascular evaluation, consider administering the first RELPAX dose in a medically-supervised setting and performing an electrocardiogram (ECG) immediately following administration of RELPAX. For such patients, consider periodic cardiovascular evaluation in intermittent long-term users of RELPAX. - Arrhythmias - Life-threatening disturbances of cardiac rhythm including ventricular tachycardia and ventricular fibrillation leading to death have been reported within a few hours following the administration of 5-HT1 agonists. Discontinue RELPAX if these disturbances occur. RELPAX is contraindicated in patients with Wolff-Parkinson-White syndrome or arrhythmias associated with other cardiac accessory conduction pathway disorders. - Chest, Throat, Neck and/or Jaw Pain/Tightness/Pressure - Sensations of tightness, pain, and pressure in the chest, throat, neck, and jaw commonly occur after treatment with RELPAX and are usually non-cardiac in origin. However, perform a cardiac evaluation if these patients are at high cardiac risk. RELPAX is contraindicated in patients with CAD or Prinzmetal's variant angina. - Cerebrovascular Events - Cerebral hemorrhage, subarachnoid hemorrhage, and stroke have occurred in patients treated with 5-HT1 agonists, and some have resulted in fatalities. In a number of cases, it appears possible that the cerebrovascular events were primary, the 5-HT1 agonist having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine, when they were not. - Before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with symptoms atypical of migraine, other potentially serious neurological conditions need to be excluded. RELPAX is contraindicated in patients with a history of stroke or TIA. - Other Vasospasm Reactions - RELPAX may cause non-coronary vasospastic reactions, such as peripheral vascular ischemia, gastrointestinal vascular ischemia and infarction (presenting with abdominal pain and bloody diarrhea), and Raynaud's syndrome. In patients who experience symptoms or signs suggestive of a vasospastic reaction following the use of any 5-HT1 agonist, rule out a vasospastic reaction before receiving additional RELPAX doses. - Medication Overuse Headache - Overuse of acute migraine drugs (e.g. ergotamine, triptans, opioids, or combination of these drugs for 10 or more days per month) may lead to exacerbation of headache (medication overuse headache). Medication overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused acute migraine drugs and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary. - Serotonin Syndrome - Serotonin syndrome may occur with RELPAX, particularly during co-administration with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and monoamine oxidase (MAO) inhibitors. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms usually occurs within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Discontinue RELPAX if serotonin syndrome is suspected. - Increase in Blood Pressure - Significant elevation in blood pressure, including hypertensive crisis with acute impairment of organ systems, has been reported on rare occasions in patients treated with 5-HT1 agonists, including patients without a history of hypertension. Monitor blood pressure in patients treated with RELPAX. RELPAX is contraindicated in patients with uncontrolled hypertension. - Anaphylactic/Anaphylactoid Reactions - There have been reports of anaphylaxis, anaphylactoid, and hypersensitivity reactions including angioedema in patients receiving RELPAX. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. RELPAX is contraindicated in patients with a history of hypersensitivity reaction to RELPAX. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. - Among 4,597 patients who treated the first migraine headache with RELPAX in short-term placebo-controlled trials, the most common adverse reactions reported with treatment with RELPAX were asthenia, nausea, dizziness, and somnolence. These reactions appear to be dose-related. - In long-term open-label studies where patients were allowed to treat multiple migraine attacks for up to 1 year, 128 (8.3%) out of 1,544 patients discontinued treatment due to adverse reactions. - Table 1 lists adverse reactions that occurred in the subset of 5,125 migraineurs who received eletriptan doses of 20 mg, 40 mg and 80 mg or placebo in worldwide placebo-controlled clinical trials. - Only adverse reactions that were more frequent in a RELPAX treatment group compared to the placebo group with an incidence greater than or equal to 2% are included in Table 1. - The frequency of adverse reactions in clinical trials did not increase when up to 2 doses of RELPAX were taken within 24 hours. The incidence of adverse reactions in controlled clinical trials was not affected by gender, age, or race of the patients. Adverse reaction frequencies were also unchanged by concomitant use of drugs commonly taken for migraine prophylaxis (e.g., SSRIs, beta blockers, calcium channel blockers, tricyclic antidepressants), estrogen replacement therapy or oral contraceptives. ## Postmarketing Experience - The following adverse reaction(s) have been identified during post approval use of RELPAX. 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. Seizure Vomiting # Drug Interactions - Ergot-Containing Drugs Including Other 5-HT1B/1D Agonists - Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or ergot-type medications (like dihydroergotamine [DHE] or methysergide) and RELPAX within 24 hours of each other is contraindicated. Concomitant use of other 5-HT1 agonists within 24 hours of RELPAX treatment is contraindicated. - CYP3A4 Inhibitors - Potent CYP3A4 inhibitors significantly increase the exposure of RELPAX. RELPAX should not be used within at least 72 hours of treatment with potent CYP3A4 inhibitors. - Selective Serotonin Reuptake Inhibitors/Serotonin and Norepinephrine Reuptake Inhibitors and Serotonin Syndrome - Cases of serotonin syndrome have been reported during co-administration of triptans and SSRIs, SNRIs, TCAs and MAO inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. In reproductive toxicity studies in pregnant animals, oral administration of eletriptan was associated with developmental toxicity (decreased fetal and pup weights and an increased incidence of fetal structural abnormalities) at clinically relevant plasma exposures. RELPAX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus - When pregnant rats were administered eletriptan during the period of organogenesis at doses of 10, 30 or 100 mg/kg/day, fetal weights were decreased and the incidences of vertebral and sternebral variations were increased at 100 mg/kg/day (approximately 12 times the maximum recommended human dose [MRHD] of 80 mg/day on a mg/m2 basis). The 30 and 100 mg/kg/day doses were also maternally toxic, as evidenced by decreased maternal body weight gain during gestation. The no-effect dose for developmental toxicity in rats was 30 mg/kg/day, which is approximately 4 times the MRHD on a mg/m2 basis. - When doses of 5, 10, or 50 mg/kg/day were given to pregnant rabbits throughout organogenesis, fetal weights were decreased at 50 mg/kg/day, which is approximately 12 times the MRHD on a mg/m2 basis. The incidences of fused sternebrae and vena cava deviations were increased at all doses. Maternal toxicity was not evident at any dose. A no-effect dose for developmental toxicity in rabbits was not established; the lowest dose tested (5 mg/kg/day) is similar to the MRHD on a mg/m2 basis. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eletriptan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Eletriptan during labor and delivery. ### Nursing Mothers - Eletriptan is excreted in human milk. Caution should be exercised when RELPAX is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. - The efficacy of RELPAX Tablets (40 mg) in patients 11–17 was not established in a randomized, placebo-controlled trial of 274 adolescent migraineurs. Adverse reactions observed were similar in nature to those reported in clinical trials in adults. Postmarketing experience with other triptans includes a limited number of reports that describe pediatric patients who have experienced clinically serious adverse reactions that are similar in nature to those reported rarely in adults. Long-term safety of eletriptan was studied in 76 adolescent patients who received treatment for up to one year. A similar profile of adverse reactions to that of adults was observed. The long-term safety of eletriptan in pediatric patients has not been established. ### Geriatic Use - Blood pressure was increased to a greater extent in elderly subjects than in young subjects. The pharmacokinetic disposition of eletriptan in the elderly is similar to that seen in younger adults. In clinical trials, there were no apparent differences in efficacy or the incidence of adverse reactions between patients under 65 years of age and those 65 and above. ### Gender There is no FDA guidance on the use of Eletriptan with respect to specific gender populations. ### Race There is no FDA guidance on the use of Eletriptan with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Eletriptan in patients with renal impairment. ### Hepatic Impairment - The effect of severe hepatic impairment on RELPAX metabolism has not been evaluated. RELPAX is not recommended for use in patients with severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Eletriptan in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Eletriptan in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Eletriptan in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Eletriptan in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - The elimination half-life of eletriptan is about 4 hours, therefore monitoring of patients after overdose with eletriptan should continue for at least 20 hours or longer while symptoms or signs persist. ### Management - There is no specific antidote to eletriptan. - It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentration of eletriptan. ## Chronic Overdose There is limited information regarding Chronic Overdose of Eletriptan in the drug label. # Pharmacology ## Mechanism of Action - Eletriptan binds with high affinity to 5-HT1B, 5-HT1D and 5-HT1F receptors, has modest affinity for 5-HT1A, 5-HT1E, 5-HT2B and 5-HT7 receptors. - Migraines are likely due to local cranial vasodilatation and/or to the release of sensory neuropeptides (vasoactive intestinal peptide, substance P and calcitonin gene-related peptide) through nerve endings in the trigeminal system. The therapeutic activity of RELPAX for the treatment of migraine headache is thought to be due to the agonist effects at the 5-HT1B/1D receptors on intracranial blood vessels (including the arterio-venous anastomoses) and sensory nerves of the trigeminal system which result in cranial vessel constriction and inhibition of pro-inflammatory neuropeptide release. ## Structure - RELPAX (eletriptan hydrobromide) tablets contain eletriptan hydrobromide, which is a selective 5-hydroxytryptamine 1B/1D (5-HT1B/1D) receptor agonist. Eletriptan hydrobromide is chemically designated as (R)-3-[(1-Methyl-2-pyrrolidinyl)methyl]-5-[2-(phenylsulfonyl)ethyl]-1H-indole monohydrobromide, and it has the following chemical structure: - The empirical formula is C22H26N2O2S . HBr, representing a molecular weight of 463.43. Eletriptan hydrobromide is a white to light pale colored powder that is readily soluble in water. - Each RELPAX Tablet for oral administration contains 24.2 or 48.5 mg of eletriptan hydrobromide equivalent to 20 mg or 40 mg of eletriptan, respectively. Each tablet also contains the inactive ingredients microcrystalline cellulose NF, lactose monohydrate NF, croscarmellose sodium NF, magnesium stearate NF, titanium dioxide USP, hypromellose, triacetin USP and FD&C Yellow No. 6 aluminum lake. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Eletriptan in the drug label. ## Pharmacokinetics - Absorption - Eletriptan is well absorbed after oral administration with peak plasma levels occurring approximately 1.5 hours after dosing to healthy subjects. In patients with moderate to severe migraine the median Tmax is 2.0 hours. The mean absolute bioavailability of eletriptan is approximately 50%. The oral pharmacokinetics are slightly more than dose-proportional over the clinical dose range. The AUC and Cmax of eletriptan are increased by approximately 20 to 30% following oral administration with a high fat meal. RELPAX can be taken with or without food. - Distribution - The volume of distribution of eletriptan following IV administration is 138L. Plasma protein binding is moderate and approximately 85%. - Metabolism - The N-demethylated metabolite of eletriptan is the only known active metabolite. This metabolite causes vasoconstriction similar to eletriptan in animal models. Though the half-life of the metabolite is estimated to be about 13 hours, the plasma concentration of the N-demethylated metabolite is 10–20% of parent drug and is unlikely to contribute significantly to the overall effect of the parent compound. - In vitro studies indicate that eletriptan is primarily metabolized by cytochrome P-450 enzyme CYP3A4. - Elimination - The terminal elimination half-life of eletriptan is approximately 4 hours. Mean renal clearance (CLR) following oral administration is approximately 3.9 L/h. Non-renal clearance accounts for about 90% of the total clearance. - Special Populations - Age - The pharmacokinetics of eletriptan are generally unaffected by age. Blood pressure was increased to a greater extent in elderly subjects than in young subjects. The pharmacokinetic disposition of eletriptan in the elderly is similar to that seen in younger adults. - There is a statistically significant increased half-life (from about 4.4 hours to 5.7 hours) between elderly (65 to 93 years of age) and younger adult subjects (18 to 45 years of age). - Gender - The pharmacokinetics of eletriptan are unaffected by gender. - Race - A comparison of pharmacokinetic studies run in western countries with those run in Japan has indicated an approximate 35% reduction in the exposure of eletriptan in Japanese male volunteers compared to western males. Population pharmacokinetic analysis of two clinical studies indicates no evidence of pharmacokinetic differences between Caucasians and non-Caucasian patients. - Menstrual Cycle - In a study of 16 healthy females, the pharmacokinetics of eletriptan remained consistent throughout the phases of the menstrual cycle. - Renal Impairment - There was no significant change in clearance observed in subjects with mild, moderate or severe renal impairment, though blood pressure elevations were observed in this population. - Hepatic Impairment - Subjects with mild or moderate hepatic impairment demonstrated an increase in both AUC (34%) and half-life. The Cmax was increased by 18%. No dose adjustment is necessary in subjects with mild or moderate hepatic impairment. The effects of severe hepatic impairment on eletriptan metabolism have not been evaluated. - Drug Interaction Studies - CYP3A4 inhibitors - In vitro studies have shown that eletriptan is metabolized by the CYP3A4 enzyme. A clinical study demonstrated about a 3-fold increase in Cmax and about a 6-fold increase in the AUC of eletriptan when combined with ketoconazole. The half-life increased from 5 hours to 8 hours and the Tmax increased from 2.8 hours to 5.4 hours. Another clinical study demonstrated about a 2-fold increase in Cmax and about a 4-fold increase in AUC when erythromycin was co-administered with eletriptan. It has also been shown that co-administration of verapamil and eletriptan yields about a 2-fold increase in Cmax and about a 3-fold increase in AUC of eletriptan, and that co-administration of fluconazole and eletriptan yields about a 1.4-fold increase in Cmax and about a 2-fold increase in AUC of eletriptan. - RELPAX is contraindicated within at least 72 hours of treatment with the following potent CYP3A4 inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir and nelfinavir. RELPAX should not be used within 72 hours with drugs that have demonstrated potent CYP3A4 inhibition. - Propranolol - The Cmax and AUC of eletriptan were increased by 10 and 33%, respectively, in the presence of propranolol. No interactive increases in blood pressure were observed. No dosage adjustment appears to be needed for patients taking propranolol. - The effect of eletriptan on other drugs: The effect of eletriptan on enzymes other than cytochrome P450 has not been investigated. In vitro human liver microsome studies suggest that eletriptan has little potential to inhibit CYP1A2, 2C9, 2E1 and 3A4 at concentrations up to 100 µM. While eletriptan has an effect on CYP2D6 at high concentration, this effect should not interfere with metabolism of other drugs when eletriptan is used at recommended doses. There is no in vitro or in vivo evidence that clinical doses of eletriptan will induce drug metabolizing enzymes. Therefore, eletriptan is unlikely to cause clinically important drug interactions mediated by these enzymes. ## Nonclinical Toxicology - Carcinogenesis - Eletriptan was administered to rats and mice in the diet for 104 weeks. In rats, the incidence of testicular interstitial cell adenomas was increased at the high dose of 75 mg/kg/day, but not at 15 mg/kg/day, a dose associated with plasma exposures (AUC) approximately 2 times that in humans at the MRHD of 80 mg/day. In mice, the incidence of hepatocellular adenomas was increased at the high dose of 400 mg/kg/day, but not a dose of 90 mg/kg/day, associated with plasma AUC approximately 7 times that in humans at the MRHD. - Mutagenesis - Eletriptan was negative in in vitro (bacteria reverse mutation (Ames), mammalian cell gene mutation (CHO/ HGPRT), chromosomal aberration assay in human lymphocytes) and in vivo (mouse micronucleus) assays. - Impairment of Fertility - In a fertility and early embryonic development study, eletriptan (50, 100, or 200 mg/kg/day) was orally administered to male and female rats prior to and throughout mating and continuing in females to implantation. Plasma exposures (AUC) were 4, 8 and 16 times in males and 7, 14 and 28 times in females, respectively, that in humans at the MRHD. Dose-related decreases in the number of corpora lutea, implants, and viable fetuses per dam were observed at all doses. Prolongation of the estrus cycle was observed at the highest dose tested. Male fertility parameters were not affected. # Clinical Studies - The efficacy of RELPAX in the acute treatment of migraines was evaluated in eight randomized, double-blind placebo-controlled studies. All eight studies used 40 mg. Seven studies evaluated an 80 mg dose and two studies included a 20 mg dose. - In all eight studies, randomized patients treated their headaches as outpatients. Seven studies enrolled adults and one study enrolled adolescents (age 11 to 17). Patients treated in the seven adult studies were predominantly female (85%) and Caucasian (94%) with a mean age of 40 years (range 18 to 78). In all studies, patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 2 hours after dosing. Associated symptoms such as nausea, vomiting, photophobia and phonophobia were also assessed. - Maintenance of response was assessed for up to 24 hours post dose. In the adult studies, a second dose of RELPAX or other medication was allowed 2 to 24 hours after the initial treatment for both persistent and recurrent headaches. The incidence and time to use of these additional treatments were also recorded. - In the seven adult studies, the percentage of patients achieving headache response 2 hours after treatment was significantly greater among patients receiving RELPAX at all doses compared to those who received placebo. The two-hour response rates from these controlled clinical studies are summarized in Table 2. - Comparisons of the performance of different drugs based upon results obtained in different clinical trials are never reliable. Because studies are generally conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study. - The estimated probability of achieving an initial headache response within 2 hours following treatment is depicted in Figure 1. - Figure 1 shows the Kaplan-Meier plot of probability over time of obtaining headache response (no or mild pain) following treatment with eletriptan. The plot is based on 7 placebo-controlled, outpatient trials in adults providing evidence of efficacy (Studies 1 through 7). Patients not achieving headache response or taking additional treatment prior to 2 hours were censored at 2 hours. - For patients with migraine-associated photophobia, phonophobia, and nausea at baseline, there was a decreased incidence of these symptoms following administration of RELPAX as compared to placebo. - Two to 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of taking a second dose or other medications for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2. - This Kaplan-Meier plot is based on data obtained in 7 placebo-controlled trials in adults (Studies 1 through 7). Patients were instructed to take a second dose of study medication as follows: a) in the event of no response at 2 hours (studies 2 and 4–7) or at 4 hours (study 3); b) in the event of headache recurrence within 24 hours (studies 2–7). Patients not using additional treatments were censored at 24 hours. The plot includes both patients who had headache response at 2 hours and those who had no response to the initial dose. It should be noted that the protocols did not allow re-medication within 2 hours post dose. - The efficacy of RELPAX was unaffected by the duration of attack, gender or age of the patient, relationship to menses, or concomitant use of estrogen replacement therapy/oral contraceptives or frequently used migraine prophylactic drugs. - In a single study in adolescents (n=274), there were no statistically significant differences between treatment groups. The headache response rate at 2 hours was 57% for both RELPAX 40 mg Tablets and placebo. # How Supplied - RELPAX Tablets containing 20 mg or 40 mg eletriptan (base) as the hydrobromide salt. RELPAX Tablets are orange, round, convex shaped, film-coated tablets with appropriate debossing. - They are supplied in the following strengths and package configurations: - RELPAX Tablets ## Storage There is limited information regarding Eletriptan Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Myocardial Ischemia and/or Infarction, Prinzmetal's Angina, Other Vasospastic Reactions, and Cerebrovascular Events - Inform patients that RELPAX may cause serious cardiovascular adverse reactions such as myocardial infarction or stroke, which may result in hospitalization and even death. Although serious cardiovascular reactions can occur without warning symptoms, instruct patients to be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and instruct them to ask for medical advice when observing any indicative sign or symptoms. Instruct patients to seek medical advice if they have symptoms of other vasospastic reactions. - Anaphylactic/Anaphylactoid Reactions - Inform patients that anaphylactic/anaphylactoid reactions have occurred in patients receiving RELPAX. Such reactions can be life threatening or fatal. In general, anaphylactic reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens. - Medication Overuse Headache - Inform patients that use of drugs to treat acute migraines for 10 or more days per month may lead to an exacerbation of headache, and encourage patients to record headache frequency and drug use (e.g., by keeping a headache diary)]. - Serotonin Syndrome - Inform patients about the risk of serotonin syndrome with the use of RELPAX or other triptans, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). - Pregnancy - Inform patients that RELPAX should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. - Nursing Mothers - Inform patients to notify their healthcare provider if they are breastfeeding or plan to breastfeed. # Precautions with Alcohol - Alcohol-Eletriptan interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - RELPAX®[1] # Look-Alike Drug Names There is limited information regarding Eletriptan Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Eletriptan
76dbab420ca2d05a3ee705d98bde2e9da36d19bc	wikidoc	Eliglustat	Eliglustat # 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 Eliglustat is a glucosylceramide synthase inhibitor that is FDA approved for the treatment of adult patients with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test. Common adverse reactions include fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - Eliglustat is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test. Limitations of Use: - Patients who are CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate concentrations of eliglustat to achieve a therapeutic effect . - A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers). # Dosage Patient Selection - Select patients with Gaucher disease type 1 based on their CYP2D6 metabolizer status. It is recommended patient genotypes be established using an FDA-cleared test for determining CYP2D6 genotype. Recommended Adult Dosage - The recommended dosage of eliglustat is 84 mg twice daily in CYP2D6 EMs and IMs. The recommended dosage in CYP2D6 PMs is 84 mg once daily; appropriate adverse event monitoring is recommended. The predicted exposures with 84 mg once daily in patients who are CYP2D6 PMs are expected to be similar to exposures observed with 84 mg twice daily in CYP2D6 IMs. - Some inhibitors of CYP2D6 and CYP3A are contraindicated with eliglustat depending on the patient's metabolizer status. Co-administration of eliglustat with other CYP2D6 and CYP3A inhibitors may require dosage adjustment depending on the patient's CYP2D6 metabolizer status to reduce the risk of potentially significant adverse reactions. - Reduce the dosage of eliglustat to 84 mg once daily for: - CYP2D6 EMs and IMs taking strong or moderate CYP2D6 inhibitors - CYP2D6 EMs taking strong or moderate CYP3A inhibitors # DOSAGE FORMS AND STRENGTHS - Eliglustat is supplied as 84 mg hard gelatin capsules, with a pearl blue-green opaque cap and pearl white opaque body imprinted with "GZ02" in black. Each capsule contains 100 mg eliglustat tartrate, which is equivalent to 84 mg of eliglustat. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eliglustat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eliglustat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Eliglustat in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eliglustat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eliglustat in pediatric patients. # Contraindications - Eliglustat is contraindicated in the following patients due to the risk of significantly increased eliglustat plasma concentrations which may result in prolongation of the PR, QTc, and/or QRS cardiac intervals that could result in cardiac arrhythmias. See TABLE 3 and TABLE 4 for examples of drugs in each of the categories described: - EMs or IMs taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor. - IMs or PMs taking a strong CYP3A inhibitor. # Warnings Drug-Drug Interactions - Eliglustat is a CYP2D6 and CYP3A substrate. Drugs that inhibit CYP2D6 and CYP3A metabolism pathways may significantly increase the exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac intervals that could result in cardiac arrhythmias. Some drugs that are inhibitors of CYP2D6 and CYP3A are contraindicated with eliglustat depending on the patient's CYP2D6 metabolizer status. ECG Changes and Potential for Cardiac Arrhythmias - Use of eliglustat in patients with pre-existing cardiac conditions has not been studied during clinical trials. Because eliglustat is predicted to cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated eliglustat plasma concentrations, use of eliglustat is not recommended in patients with pre-existing cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, and in combination with Class IA (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications # 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 most common adverse reactions to eliglustat (occurring in ≥10% of the 126 GD1 patients treated with eliglustat across Trials 1 and 2) were fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain. The adverse reaction profile of eliglustat is based on two controlled studies, Trials 1 and 2. Table 1 presents the profile from the 9-month double-blind, randomized, placebo-controlled trial of 40 treatment-naïve patients (Trial 1). Patients were between the ages of 16 and 63 on the date of the first dose of study drug, and included 20 males and 20 females. - Table 2 presents the profile from the 12-month open-label, randomized, imiglucerase-controlled trial of 159 treated patients switching from enzyme replacement therapy (ERT) (Trial 2). Patients were between the ages of 18 and 69 on the date of the first dose of eliglustat, and included 87 females and 72 males. In an uncontrolled study, with up to 4 years of treatment, in 26 patients, the types and incidences of adverse reactions were similar to Trials 1 and 2. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Eliglustat in the drug label. # Drug Interactions ## Potential for Other Drugs to Affect Eliglustat Eliglustat is a CYP2D6 and CYP3A substrate. CYP2D6 and CYP3A Inhibitors - Drugs that inhibit CYP2D6 and CYP3A pathways may significantly increase the exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac interval which could result in cardiac arrhythmias: - Some inhibitors of CYP2D6 and CYP3A are contraindicated with eliglustat depending on the patient's CYP2D6 metabolizer status. - Co-administration of eliglustat with other CYP2D6 and CYP3A inhibitors may require dosage adjustment depending on the patient's CYP2D6 metabolizer status to reduce the risk of potential significant adverse reactions. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Eliglustat in women who are pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eliglustat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Eliglustat during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Eliglustat with respect to nursing mothers. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Eliglustat with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Eliglustat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Eliglustat with respect to specific racial populations. ### Renal Impairment - There is no dosage adjustment required for patients with mild renal impairment. Eliglustat has not been studied in patients with moderate to severe renal impairment or end-stage renal disease (ESRD). Use of eliglustat in these patients is not recommended. ### Hepatic Impairment - Eliglustat has not been studied in patients with hepatic impairment. Use of eliglustat is not recommended in all stages of hepatic impairment or cirrhosis. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Eliglustat in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Eliglustat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Eliglustat in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Eliglustat in the drug label. # Overdosage - The highest eliglustat plasma concentration experienced to date occurred in a single-dose, dose escalation study in healthy subjects, in a subject taking a dose equivalent to approximately 21 times the recommended dose for GD1 patients. At the time of the highest plasma concentration (59-fold higher than normal therapeutic conditions), the subject experienced dizziness marked by disequilibrium, hypotension, bradycardia, nausea, and vomiting. - In the event of acute overdose, the patient should be carefully observed and given symptomatic and supportive treatment. - Hemodialysis is unlikely to be beneficial given that eliglustat has a large volume of distribution # Pharmacology ## Mechanism of Action - Gaucher disease is caused by a deficiency of the lysosomal enzyme acid β-glucosidase. Acid β-glucosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency causes an accumulation of glucosylceramide (GL-1) primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells". Eliglustat is a specific inhibitor of glucosylceramide synthase (IC50 = 10 ng/mL), and acts as a substrate reduction therapy for GD1. In clinical trials eliglustat reduced spleen and liver size, and improved anemia and thrombocytopenia. - In this lysosomal storage disorder (LSD), clinical features are reflective of the accumulation of Gaucher cells in the liver, spleen, bone marrow, and other organs. The accumulation of Gaucher cells in the liver, spleen, and bone marrow leads to organomegaly and skeletal disease. Presence of Gaucher cells in the bone marrow and spleen lead to clinically significant anemia and thrombocytopenia. ## Structure CERDELGA (eliglustat) capsules contain eliglustat tartrate, which is a small molecule inhibitor of glucosylceramide synthase that resembles the ceramide substrate for the enzyme, with the chemical name N-((1R,2R)-1-(2,3-dihydrobenzodioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (2R,3R)-2,3-dihydroxysuccinate. Its molecular weight is 479.59, and the empirical formula is C23H36N2O4+½(C4H6O6) with the following chemical structure: Each capsule of CERDELGA for oral use contains 84 mg of eliglustat, equivalent to 100 mg of eliglustat tartrate (hemitartrate salt). The inactive ingredients are microcrystalline cellulose, lactose monohydrate, hypromellose and glyceryl behenate, gelatin, candurin silver fine, yellow iron oxide, and FD&C blue 2. ## Pharmacodynamics Electrocardiographic Evaluation - QTc interval prolongation was studied in a double-blind, single dose, placebo- and positive-controlled crossover study in 42 healthy subjects. Concentration-related increases were observed for the placebo-corrected change from baseline in the PR, QRS, and QTc intervals. Based on PK/PD modeling, eliglustat plasma concentrations of 500 ng/mL are predicted to cause mean (upper bound of the 95% one-sided confidence interval) increases in the PR, QRS, and QTcF intervals of 22 (26), 7 (10), and 13 (19) msec, respectively. At the highest geometric mean concentrations of 237 ng/mL following a single supratherapeutic dose tested in the thorough QT study, CERDELGA did not prolong the QT/QTc interval to any clinically relevant extent. ## Pharmacokinetics - At a given dose, the systemic exposure (Cmax and AUC) depends on the CYP2D6 phenotype. In CYP2D6 EMs and IMs, the eliglustat pharmacokinetics is time-dependent and the systemic exposure increases in a more than dose proportional manner. After multiple oral doses of 84 mg twice daily in EMs, eliglustat systemic exposure (AUC0-12) increased up to about 2-fold at steady state compared to after the first dose (AUC0-∞). The pharmacokinetics of eliglustat in CYP2D6 PMs is expected to be linear and time-independent. Compared to EMs, the systemic exposure following 84 mg twice daily at steady state is 7- to 9-fold higher in PMs. Absorption - In CYP2D6 EMs, median time to reach maximum plasma concentrations (tmax) occurs at 1.5 to 2 hours following multiple doses of eliglustat 84 mg twice daily. The corresponding mean Cmax values range from 12.1 to 25.0 ng/mL in EMs. The mean AUCtau values range from 76.3 to 143 hrng/mL in EMs. The Cmax and AUCtau in one IM subject receiving multiple doses of eliglustat 84 mg two time daily was 44.6 ng/mL and 306 hrng/mL, respectively. The oral bioavailability is low in EMs (<5%) following single dose of eliglustat 84 mg due to significant first-pass metabolism. - In PMs, median tmax occurs at 3 hours following multiple doses of eliglustat 84 mg twice daily. The corresponding mean Cmax and AUCtau values range from 113 to 137 ng/mL and 922 to 1057 hrng/mL, respectively. - Oral dosing of eliglustat 84 mg once daily has not been studied in PMs. The predicted Cmax and AUC0-24hr in PMs using physiologically-based pharmacokinetic (PBPK) model with 84 mg once daily are 75 ng/mL and 956 hrng/mL, respectively. - Administration of eliglustat with a high fat meal resulted in a 15% decrease in Cmax but no change in AUC. Food does not have a clinically relevant effect on eliglustat pharmacokinetics. Distribution - Eliglustat is moderately bound to human plasma proteins (76 to 83%). In the blood, it is mainly distributed in plasma and not red blood cells. After intravenous (IV) administration, the volume of distribution of eliglustat was 835 L in CYP2D6 EMs, suggesting wide distribution to tissues (eliglustat is only for oral use). Metabolism and Elimination - Eliglustat is extensively metabolized with high clearance, mainly by CYP2D6 and to a lesser extent CYP3A4. Primary metabolic pathways of eliglustat involve sequential oxidation of the octanoyl moiety followed by oxidation of the 2,3-dihydro-1,4-benzodioxane moiety, or a combination of the two pathways, resulting in multiple oxidative metabolites. No active metabolites have been identified. - After oral administration of 84 mg -eliglustat, the majority of the administered dose is excreted in urine (41.8%) and feces (51.4%), mainly as metabolites. After 42 mg IV administration in healthy volunteers, mean (CV%) of eliglustat total body clearance was 88 L/h (8.8%) in CYP2D6 EMs (eliglustat is only for oral use). Following multiple oral doses of eliglustat 84 mg twice daily, eliglustat terminal elimination half-life (T1/2) was approximately 6.5 hours in EMs and 8.9 hours in PMs. Specific Populations - Based on population PK analysis, there was no effect of mild renal impairment on eliglustat PK. Furthermore, gender, body weight, age, and race had no clinically relevant impact on the pharmacokinetics of eliglustat. Drug Interactions - Effect of Other Drugs on Eliglustat - In vitro, eliglustat is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4. Eliglustat is also a substrate of P-glycoprotein (P-gp). - Co-administration of eliglustat with CYP2D6 Inhibitors - Systemic exposure (Cmax and AUCtau) of eliglustat increased 7.0-fold and 8.4-fold, respectively, following co-administration of eliglustat 84 mg twice daily with paroxetine (a strong CYP2D6 inhibitor) 30 mg once daily in EMs (N=30), respectively. - Simulations using PBPK models suggested that paroxetine may increase the Cmax and AUCtau of eliglustat 2.1- and 2.3-fold in IMs, respectively. - Compared to paroxetine, the effects of terbinafine (a moderate inhibitor of CYP2D6) on the exposure of eliglustat in EMs or IMs were predicted to be smaller. Simulations using PBPK models suggested that terbinafine may increase the Cmax and AUCtau of eliglustat 3.8- and 4.5-fold in EMs, respectively. Both Cmax and AUCtau increased 1.6-fold in IMs. Co-administration of Eliglustat with CYP3A Inhibitors CYP2D6 EMs and IMs: - Following co-administration of eliglustat 84 mg twice daily with ketoconazole (a strong CYP3A inhibitor) 400 mg once daily, the systemic exposure (Cmax and AUCtau) of eliglustat increased 4.0-fold and 4.4-fold in EMs (N=31). - Simulations using PBPK models suggested that ketoconazole may increase the Cmax and AUCtau of eliglustat 4.4- and 5.4-fold in IMs, respectively. - Compared to ketoconazole, the effects of fluconazole (a moderate inhibitor of CYP3A) on the exposure of eliglustat in EMs or IMs were predicted to be smaller. Simulations using PBPK models suggested that fluconazole may increase the Cmax and AUCtau of eliglustat 2.8- and 3.2-fold in EMs, respectively, and 2.5- to 2.9-fold in IMs, respectively. CYP2D6 PMs: - The effect of CYP3A inhibitors on the systemic exposure of eliglustat in PMs has not been evaluated in clinical studies. Simulations using PBPK models suggest that ketoconazole may increase the Cmax and AUC0-24h of eliglustat 4.3- and 6.2-fold when co-administered with eliglustat 84 mg once daily in PMs. Simulations using PBPK models suggested that fluconazole may increase the Cmax and AUC0-24h of eliglustat 2.4- and 3.0-fold, respectively, when co-administered with eliglustat 84 mg once daily. Co-administration of Eliglustat with CYP2D6 and CYP3A inhibitors - Simulations using PBPK models suggested that concomitant use of eliglustat 84 mg twice daily with paroxetine and ketoconazole may increase the Cmax and AUCtau of eliglustat 16.7- and 24.2-fold in EMs, respectively. The predicted Cmax and AUCtau of eliglustat increased 7.5- to 9.8-fold in IMs, respectively. - Simulations using PBPK models suggested that concomitant use of eliglustat 84 mg twice daily with terbinafine and fluconazole may increase the Cmax and AUCtau of eliglustat 10.2- and 13.6-fold in EMs. The predicted Cmax and AUCtau of eliglustat increased 4.2- to 5.0-fold in IMs, respectively. Effect of CYP3A inducers on Eliglustat PK - Systemic exposures (Cmax and AUCtau) of eliglustat decreased by approximately 90% in EMs and IMs, following co-administration of eliglustat 127 mg twice daily with rifampin (a strong CYP3A inducer) 600 mg PO once daily. The only approved dose of eliglustat is 84 mg. Systemic exposures of eliglustat decreased by approximately 95% following co-administration of eliglustat 84 mg twice daily with rifampin 600 mg PO once daily in PMs. Effect of OATP (organic anion transporting polypeptide) Inhibitors on Eliglustat PK - Systemic exposures of eliglustat were similar with or without co-administration of single 600 mg IV dose of rifampin (a potent OATP inhibitor) regardless of subjects' CYP2D6 phenotypes. Effect of P-gp Inhibitors on Eliglustat PK - The effect of P-gp inhibitors on the systemic exposure of eliglustat has not been studied clinically. Effect of Gastric pH-Modifying Agents on Eliglustat PK - Gastric pH-modifying agents (Maalox®, Tums®, Protonix®) did not have a clinically relevant effect on eliglustat exposure. Drug Interactions - Effect of eliglustat on the PK of Other Drugs - Eliglustat is an inhibitor of P-gp and CYP2D6. - Following multiple doses of eliglustat 127 mg twice daily, systemic exposures (Cmax and AUC) to metoprolol (a CYP2D6 substrate) increased compared to metoprolol administration alone. Mean Cmax and AUC increased by 1.7- and 2.3-fold, respectively, in EMs and by 1.2- and 1.6-fold, respectively in IMs. The only approved dose of eliglustat is 84 mg. - Following multiple doses of eliglustat 127 mg twice daily in EMs and IMs or 84 mg twice daily in PMs, systemic exposures (Cmax and AUC) to digoxin (a P-gp substrate, with narrow therapeutic index) increased compared to digoxin administration alone. Mean Cmax and AUC increased by 1.7- and 1.5-fold, respectively. The only approved dose of eliglustat is 84 mg. - In vitro, eliglustat is a weak inhibitor of CYP3A. Repeated doses of eliglustat 84 mg twice daily did not change the exposures to norethindrone (1.0 mg) and ethinyl estradiol (0.035 mg). Therefore, eliglustat is not expected to impact the efficacy or safety of oral contraceptives containing norethindrone and ethinyl estradiol. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis - Carcinogenic potential of eliglustat was assessed in 2-year carcinogenicity studies in rats and mice. In Sprague-Dawley rats, eliglustat was administered by oral gavage at doses up to 75 mg/kg/day in males (about 3.6 times the recommended human daily dose of 84 mg twice daily, based on body surface area) and 50 mg/kg/day in females (about 2.4 times the recommended human daily dose based on body surface area). In CD-1 mice, eliglustat was administered to males and females at up to 75 mg/kg/day (about 1.8 times the recommended human daily dose based on body surface area) via dietary admixture. Eliglustat did not produce any treatment-related neoplasms in rats or mice. Mutagenesis - Eliglustat was negative in the Ames test, chromosome aberration test in human peripheral blood lymphocytes, mouse lymphoma gene mutation assay and in vivo oral mouse micronucleus test. Impairment of Fertility - In a fertility and early embryonic development study in rats, eliglustat increased pre-implantation loss at 30 (about 1.5 times the recommended human oral dose based on body surface area) and 100 mg/kg/day (about 5 times the recommended human oral dose based on body surface area). - In mature male rats, eliglustat showed reversible adverse effects on sperm morphology, testes (germ cell necrosis), and sloughed cells in the epididymis at 200 mg/kg/day (about 10 times the recommended human oral dose based on body surface area). Similar effects on sperm were not seen in mature Cynomolgus monkeys at 72 mg/kg/day (about 7 times the recommended human oral dose based on body surface area). # Clinical Studies - The efficacy of eliglustat was evaluated in three clinical trials in patients with Gaucher disease type 1. ## Eliglustat in Treatment-Naïve GD1 Patients – Trial 1 - Trial 1 was a randomized, double-blind, placebo-controlled, multicenter clinical study evaluating the efficacy and safety of eliglustat in 40 treatment-naïve GD1 patients 16 years of age or older (median age 30.4 years) with pre-existing splenomegaly and hematological abnormalities. Patients were required to have received no treatment with substrate reduction therapy within 6 months or ERT within 9 months prior to randomization; all but 5 patients in the study had no prior therapy. Patients were stratified according to baseline spleen volume (≤ 20 or > 20 multiples of normal ) and randomized in a 1:1 ratio to receive eliglustat or placebo for the duration of the 9-month blinded primary analysis period. The eliglustat treatment group was comprised of IM (5%), EM (90%) and URM (5%) patients. Patients randomized to eliglustat treatment received a starting dose of 42 mg twice daily, with a dose increase to 84 mg twice daily possible at Week 4 based on the plasma trough concentration at Week 2. The majority of patients (17 ) received a dose escalation to 84 mg twice daily at Week 4, and 3 (15%) continued to receive 42 mg twice daily for the duration of the 9-month blinded primary analysis period. - The primary endpoint was the percentage change in spleen volume (in MN) from baseline to 9 months as compared to placebo. Secondary endpoints were absolute change in hemoglobin level, percentage change in liver volume (in MN), and percentage change in platelet count from baseline to 9 months compared to placebo. - At baseline, mean spleen volumes were 12.5 and 13.9 MN in the placebo and eliglustat groups, respectively, and mean liver volumes were 1.4 MN for both groups. Mean hemoglobin levels were 12.8 and 12.1 g/dL, and platelet counts were 78.5 and 75.1 x 109/L, respectively. - During the 9-month primary analysis period, eliglustat demonstrated statistically significant improvements in all primary and secondary endpoints compared to placebo, as shown in Table 6. - In an uncontrolled study of treatment naïve GD1 patients, improvements in spleen and liver volume, hemoglobin level, and platelet count continued through the 4 year treatment period. ## Patients Switching from Enzyme Replacement Therapy to Eliglustat – Trial 2 - Trial 2 was a randomized, open-label, active-controlled, non-inferiority, multicenter clinical study evaluating the efficacy and safety of eliglustat compared with imiglucerase in 159 treated GD1 patients (median age 37.4 years) previously treated with enzyme replacement therapy (≥3 years of enzyme replacement therapy, dosed at 30-130 U/kg/month in at least 6 of the prior 9 months) who met pre-specified therapeutic goals at baseline. Pre-specified baseline therapeutic goals included: no bone crisis and free of symptomatic bone disease within the last year; mean hemoglobin level of ≥ 11 g/dL in females and ≥ 12 g/dL in males; mean platelet count ≥ 100,000/mm3; spleen volume < 10 times normal and liver volume < 1.5 times normal. - Patients were randomized 2:1 to receive eliglustat or imiglucerase for the duration of the 12-month primary analysis period. Seventy-five percent of patients randomized to eliglustat were previously treated with imiglucerase; 21% with velaglucerase alfa and 4% were unreported. Patients randomized to eliglustat treatment received a starting dose of 42 mg twice daily, with dose increases to 84 mg twice daily and 127 mg twice daily possible at Weeks 4 and 8 based on plasma trough concentrations of eliglustat at Weeks 2 and 6, respectively. The percentage of patients receiving the 3 possible eliglustat doses was: 42 mg twice daily (20%), 84 mg twice daily (32%) and 127 mg twice daily (48%). The eliglustat treatment group was comprised of PM (4%), IM (10%), EM (80%) and URM (4%) patients. - At baseline, mean spleen volumes were 2.6 and 3.2 MN in the imiglucerase and eliglustat groups, respectively, and liver volumes were 0.9 MN in both groups. Mean hemoglobin levels were 13.8 and 13.6 g/dL, and platelet counts were 192 and 207 x 109/L, respectively. - The primary composite endpoint required stability in all four component domains (hemoglobin level, platelet count, liver volume, and spleen volume) based on changes between baseline and 12 months. Stability was defined by the following pre-specified thresholds of change: hemoglobin level <1.5 g/dL decrease, platelet count < 25% decrease, liver volume <20% increase and spleen volume <25% increase. The percentages of patients meeting the criteria for stability in the individual components of the composite endpoint were assessed as secondary efficacy endpoints. - Eliglustat met the criteria to be declared non-inferior to imiglucerase in maintaining patient stability. After 12 months of treatment, the percentage of patients meeting the primary composite endpoint was 84.8% for the eliglustat group compared to 93.6% for the imiglucerase group. The lower bound of the 95% CI of the 8.8% difference, -17.6%, was within the pre-specified non-inferiority margin of -25%. At Month 12, the percentages of CERDELGA and imiglucerase patients respectively, who met stability criteria for the individual components of the composite endpoint were: hemoglobin level, 94.9% and 100%; platelet count, 92.9% and 100%; spleen volume, 95.8% and 100%; and liver volume, 96.0% and 93.6%. Of the patients who did not meet stability criteria for the individual components, 12 of 15 CERDELGA patients and 3 of 3 imiglucerase patients remained within therapeutic goals for GD1. - Mean changes from baseline in the hematological and visceral parameters through 12 months of treatment are shown in Table 7. There were no clinically meaningful differences between groups for any of the four parameters. # How Supplied - Eliglustat is supplied as 84 mg hard gelatin capsules, with a pearl blue-green opaque cap and pearl white opaque body imprinted with "GZ02" in black. - Eliglustat 84 mg capsules are supplied as: NDC-58468-0220-1 – Carton containing 4 packs of capsules (56 capsules total). Each pack is composed of 1 blister card of 14 capsules and a cardboard wallet. NDC-58468-0220-2 – Carton containing 1 pack of capsules (14 capsules total). Each pack is comprised of 1 blister card of 14 capsules and a cardboard wallet. ## Storage - Store at 68 °F - 77 °F (20 °C - 25 °C) with excursions permitted between 59 °F and 86 °F (15 °C to 30 °C) . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). Drug Interactions - Advise patients to discuss all the medications they are taking, including any herbal supplements or vitamins with their healthcare provider. ECG Changes and Potential for Cardiac Arrhythmias - Advise patients to inform their healthcare provider of the following: history of congestive heart failure; recent acute myocardial infarction; bradycardia; heart block; ventricular arrhythmia; and long QT syndrome. - Advise patients to inform their healthcare provider if they develop new symptoms such as palpitations, fainting, and dizziness. Administration Instructions Advise patients: - Swallow capsules whole, preferably with water, and do not crush, dissolve, or open the capsules. - CERDELGA can be taken with or without food. - If a dose of CERDELGA is missed, take the prescribed dose at the next scheduled time; do not double the next dose. - Avoid consumption of grapefruit or its juice. - For patients currently treated with imiglucerase, velaglucerase alfa, or taliglucerase alfa, CERDELGA may be administered 24 hours after the last dose of the previous enzyme replacement therapy (ERT). # Precautions with Alcohol - Alcohol-Eliglustat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - CERDELGA # Look-Alike Drug Names There is limited information regarding Eliglustat Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Eliglustat Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Eliglustat is a glucosylceramide synthase inhibitor that is FDA approved for the treatment of adult patients with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test. Common adverse reactions include fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) # Indications - Eliglustat is indicated for the long-term treatment of adult patients with Gaucher disease type 1 (GD1) who are CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), or poor metabolizers (PMs) as detected by an FDA-cleared test. Limitations of Use: - Patients who are CYP2D6 ultra-rapid metabolizers (URMs) may not achieve adequate concentrations of eliglustat to achieve a therapeutic effect . - A specific dosage cannot be recommended for those patients whose CYP2D6 genotype cannot be determined (indeterminate metabolizers). # Dosage Patient Selection - Select patients with Gaucher disease type 1 based on their CYP2D6 metabolizer status. It is recommended patient genotypes be established using an FDA-cleared test for determining CYP2D6 genotype. Recommended Adult Dosage - The recommended dosage of eliglustat is 84 mg twice daily in CYP2D6 EMs and IMs. The recommended dosage in CYP2D6 PMs is 84 mg once daily; appropriate adverse event monitoring is recommended. The predicted exposures with 84 mg once daily in patients who are CYP2D6 PMs are expected to be similar to exposures observed with 84 mg twice daily in CYP2D6 IMs. - Some inhibitors of CYP2D6 and CYP3A are contraindicated with eliglustat depending on the patient's metabolizer status. Co-administration of eliglustat with other CYP2D6 and CYP3A inhibitors may require dosage adjustment depending on the patient's CYP2D6 metabolizer status to reduce the risk of potentially significant adverse reactions. - Reduce the dosage of eliglustat to 84 mg once daily for: - CYP2D6 EMs and IMs taking strong or moderate CYP2D6 inhibitors - CYP2D6 EMs taking strong or moderate CYP3A inhibitors # DOSAGE FORMS AND STRENGTHS - Eliglustat is supplied as 84 mg hard gelatin capsules, with a pearl blue-green opaque cap and pearl white opaque body imprinted with "GZ02" in black. Each capsule contains 100 mg eliglustat tartrate, which is equivalent to 84 mg of eliglustat. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eliglustat in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eliglustat in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Eliglustat in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eliglustat in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eliglustat in pediatric patients. # Contraindications - Eliglustat is contraindicated in the following patients due to the risk of significantly increased eliglustat plasma concentrations which may result in prolongation of the PR, QTc, and/or QRS cardiac intervals that could result in cardiac arrhythmias. See TABLE 3 and TABLE 4 for examples of drugs in each of the categories described: - EMs or IMs taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor. - IMs or PMs taking a strong CYP3A inhibitor. # Warnings Drug-Drug Interactions - Eliglustat is a CYP2D6 and CYP3A substrate. Drugs that inhibit CYP2D6 and CYP3A metabolism pathways may significantly increase the exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac intervals that could result in cardiac arrhythmias. Some drugs that are inhibitors of CYP2D6 and CYP3A are contraindicated with eliglustat depending on the patient's CYP2D6 metabolizer status. ECG Changes and Potential for Cardiac Arrhythmias - Use of eliglustat in patients with pre-existing cardiac conditions has not been studied during clinical trials. Because eliglustat is predicted to cause increases in ECG intervals (PR, QTc, and QRS) at substantially elevated eliglustat plasma concentrations, use of eliglustat is not recommended in patients with pre-existing cardiac disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmia), long QT syndrome, and in combination with Class IA (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications # 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 most common adverse reactions to eliglustat (occurring in ≥10% of the 126 GD1 patients treated with eliglustat across Trials 1 and 2) were fatigue, headache, nausea, diarrhea, back pain, pain in extremities, and upper abdominal pain. The adverse reaction profile of eliglustat is based on two controlled studies, Trials 1 and 2. Table 1 presents the profile from the 9-month double-blind, randomized, placebo-controlled trial of 40 treatment-naïve patients (Trial 1). Patients were between the ages of 16 and 63 on the date of the first dose of study drug, and included 20 males and 20 females. - Table 2 presents the profile from the 12-month open-label, randomized, imiglucerase-controlled trial of 159 treated patients switching from enzyme replacement therapy (ERT) (Trial 2). Patients were between the ages of 18 and 69 on the date of the first dose of eliglustat, and included 87 females and 72 males. In an uncontrolled study, with up to 4 years of treatment, in 26 patients, the types and incidences of adverse reactions were similar to Trials 1 and 2. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Eliglustat in the drug label. # Drug Interactions ## Potential for Other Drugs to Affect Eliglustat Eliglustat is a CYP2D6 and CYP3A substrate. CYP2D6 and CYP3A Inhibitors - Drugs that inhibit CYP2D6 and CYP3A pathways may significantly increase the exposure to eliglustat and result in prolongation of the PR, QTc, and/or QRS cardiac interval which could result in cardiac arrhythmias: - Some inhibitors of CYP2D6 and CYP3A are contraindicated with eliglustat depending on the patient's CYP2D6 metabolizer status. - Co-administration of eliglustat with other CYP2D6 and CYP3A inhibitors may require dosage adjustment depending on the patient's CYP2D6 metabolizer status to reduce the risk of potential significant adverse reactions. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): There is no FDA guidance on usage of Eliglustat in women who are pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eliglustat in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Eliglustat during labor and delivery. ### Nursing Mothers There is no FDA guidance on the use of Eliglustat with respect to nursing mothers. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use There is no FDA guidance on the use of Eliglustat with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Eliglustat with respect to specific gender populations. ### Race There is no FDA guidance on the use of Eliglustat with respect to specific racial populations. ### Renal Impairment - There is no dosage adjustment required for patients with mild renal impairment. Eliglustat has not been studied in patients with moderate to severe renal impairment or end-stage renal disease (ESRD). Use of eliglustat in these patients is not recommended. ### Hepatic Impairment - Eliglustat has not been studied in patients with hepatic impairment. Use of eliglustat is not recommended in all stages of hepatic impairment or cirrhosis. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Eliglustat in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Eliglustat in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Eliglustat in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Eliglustat in the drug label. # Overdosage - The highest eliglustat plasma concentration experienced to date occurred in a single-dose, dose escalation study in healthy subjects, in a subject taking a dose equivalent to approximately 21 times the recommended dose for GD1 patients. At the time of the highest plasma concentration (59-fold higher than normal therapeutic conditions), the subject experienced dizziness marked by disequilibrium, hypotension, bradycardia, nausea, and vomiting. - In the event of acute overdose, the patient should be carefully observed and given symptomatic and supportive treatment. - Hemodialysis is unlikely to be beneficial given that eliglustat has a large volume of distribution # Pharmacology ## Mechanism of Action - Gaucher disease is caused by a deficiency of the lysosomal enzyme acid β-glucosidase. Acid β-glucosidase catalyzes the conversion of the sphingolipid glucocerebroside into glucose and ceramide. The enzymatic deficiency causes an accumulation of glucosylceramide (GL-1) primarily in the lysosomal compartment of macrophages, giving rise to foam cells or "Gaucher cells". Eliglustat is a specific inhibitor of glucosylceramide synthase (IC50 = 10 ng/mL), and acts as a substrate reduction therapy for GD1. In clinical trials eliglustat reduced spleen and liver size, and improved anemia and thrombocytopenia. - In this lysosomal storage disorder (LSD), clinical features are reflective of the accumulation of Gaucher cells in the liver, spleen, bone marrow, and other organs. The accumulation of Gaucher cells in the liver, spleen, and bone marrow leads to organomegaly and skeletal disease. Presence of Gaucher cells in the bone marrow and spleen lead to clinically significant anemia and thrombocytopenia. ## Structure CERDELGA (eliglustat) capsules contain eliglustat tartrate, which is a small molecule inhibitor of glucosylceramide synthase that resembles the ceramide substrate for the enzyme, with the chemical name N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (2R,3R)-2,3-dihydroxysuccinate. Its molecular weight is 479.59, and the empirical formula is C23H36N2O4+½(C4H6O6) with the following chemical structure: Each capsule of CERDELGA for oral use contains 84 mg of eliglustat, equivalent to 100 mg of eliglustat tartrate (hemitartrate salt). The inactive ingredients are microcrystalline cellulose, lactose monohydrate, hypromellose and glyceryl behenate, gelatin, candurin silver fine, yellow iron oxide, and FD&C blue 2. ## Pharmacodynamics Electrocardiographic Evaluation - QTc interval prolongation was studied in a double-blind, single dose, placebo- and positive-controlled crossover study in 42 healthy subjects. Concentration-related increases were observed for the placebo-corrected change from baseline in the PR, QRS, and QTc intervals. Based on PK/PD modeling, eliglustat plasma concentrations of 500 ng/mL are predicted to cause mean (upper bound of the 95% one-sided confidence interval) increases in the PR, QRS, and QTcF intervals of 22 (26), 7 (10), and 13 (19) msec, respectively. At the highest geometric mean concentrations of 237 ng/mL following a single supratherapeutic dose tested in the thorough QT study, CERDELGA did not prolong the QT/QTc interval to any clinically relevant extent. ## Pharmacokinetics - At a given dose, the systemic exposure (Cmax and AUC) depends on the CYP2D6 phenotype. In CYP2D6 EMs and IMs, the eliglustat pharmacokinetics is time-dependent and the systemic exposure increases in a more than dose proportional manner. After multiple oral doses of 84 mg twice daily in EMs, eliglustat systemic exposure (AUC0-12) increased up to about 2-fold at steady state compared to after the first dose (AUC0-∞). The pharmacokinetics of eliglustat in CYP2D6 PMs is expected to be linear and time-independent. Compared to EMs, the systemic exposure following 84 mg twice daily at steady state is 7- to 9-fold higher in PMs. Absorption - In CYP2D6 EMs, median time to reach maximum plasma concentrations (tmax) occurs at 1.5 to 2 hours following multiple doses of eliglustat 84 mg twice daily. The corresponding mean Cmax values range from 12.1 to 25.0 ng/mL in EMs. The mean AUCtau values range from 76.3 to 143 hrng/mL in EMs. The Cmax and AUCtau in one IM subject receiving multiple doses of eliglustat 84 mg two time daily was 44.6 ng/mL and 306 hrng/mL, respectively. The oral bioavailability is low in EMs (<5%) following single dose of eliglustat 84 mg due to significant first-pass metabolism. - In PMs, median tmax occurs at 3 hours following multiple doses of eliglustat 84 mg twice daily. The corresponding mean Cmax and AUCtau values range from 113 to 137 ng/mL and 922 to 1057 hrng/mL, respectively. - Oral dosing of eliglustat 84 mg once daily has not been studied in PMs. The predicted Cmax and AUC0-24hr in PMs using physiologically-based pharmacokinetic (PBPK) model with 84 mg once daily are 75 ng/mL and 956 hrng/mL, respectively. - Administration of eliglustat with a high fat meal resulted in a 15% decrease in Cmax but no change in AUC. Food does not have a clinically relevant effect on eliglustat pharmacokinetics. Distribution - Eliglustat is moderately bound to human plasma proteins (76 to 83%). In the blood, it is mainly distributed in plasma and not red blood cells. After intravenous (IV) administration, the volume of distribution of eliglustat was 835 L in CYP2D6 EMs, suggesting wide distribution to tissues (eliglustat is only for oral use). Metabolism and Elimination - Eliglustat is extensively metabolized with high clearance, mainly by CYP2D6 and to a lesser extent CYP3A4. Primary metabolic pathways of eliglustat involve sequential oxidation of the octanoyl moiety followed by oxidation of the 2,3-dihydro-1,4-benzodioxane moiety, or a combination of the two pathways, resulting in multiple oxidative metabolites. No active metabolites have been identified. - After oral administration of 84 mg [14C]-eliglustat, the majority of the administered dose is excreted in urine (41.8%) and feces (51.4%), mainly as metabolites. After 42 mg IV administration in healthy volunteers, mean (CV%) of eliglustat total body clearance was 88 L/h (8.8%) in CYP2D6 EMs (eliglustat is only for oral use). Following multiple oral doses of eliglustat 84 mg twice daily, eliglustat terminal elimination half-life (T1/2) was approximately 6.5 hours in EMs and 8.9 hours in PMs. Specific Populations - Based on population PK analysis, there was no effect of mild renal impairment on eliglustat PK. Furthermore, gender, body weight, age, and race had no clinically relevant impact on the pharmacokinetics of eliglustat. Drug Interactions - Effect of Other Drugs on Eliglustat - In vitro, eliglustat is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4. Eliglustat is also a substrate of P-glycoprotein (P-gp). - Co-administration of eliglustat with CYP2D6 Inhibitors - Systemic exposure (Cmax and AUCtau) of eliglustat increased 7.0-fold and 8.4-fold, respectively, following co-administration of eliglustat 84 mg twice daily with paroxetine (a strong CYP2D6 inhibitor) 30 mg once daily in EMs (N=30), respectively. - Simulations using PBPK models suggested that paroxetine may increase the Cmax and AUCtau of eliglustat 2.1- and 2.3-fold in IMs, respectively. - Compared to paroxetine, the effects of terbinafine (a moderate inhibitor of CYP2D6) on the exposure of eliglustat in EMs or IMs were predicted to be smaller. Simulations using PBPK models suggested that terbinafine may increase the Cmax and AUCtau of eliglustat 3.8- and 4.5-fold in EMs, respectively. Both Cmax and AUCtau increased 1.6-fold in IMs. Co-administration of Eliglustat with CYP3A Inhibitors CYP2D6 EMs and IMs: - Following co-administration of eliglustat 84 mg twice daily with ketoconazole (a strong CYP3A inhibitor) 400 mg once daily, the systemic exposure (Cmax and AUCtau) of eliglustat increased 4.0-fold and 4.4-fold in EMs (N=31). - Simulations using PBPK models suggested that ketoconazole may increase the Cmax and AUCtau of eliglustat 4.4- and 5.4-fold in IMs, respectively. - Compared to ketoconazole, the effects of fluconazole (a moderate inhibitor of CYP3A) on the exposure of eliglustat in EMs or IMs were predicted to be smaller. Simulations using PBPK models suggested that fluconazole may increase the Cmax and AUCtau of eliglustat 2.8- and 3.2-fold in EMs, respectively, and 2.5- to 2.9-fold in IMs, respectively. CYP2D6 PMs: - The effect of CYP3A inhibitors on the systemic exposure of eliglustat in PMs has not been evaluated in clinical studies. Simulations using PBPK models suggest that ketoconazole may increase the Cmax and AUC0-24h of eliglustat 4.3- and 6.2-fold when co-administered with eliglustat 84 mg once daily in PMs. Simulations using PBPK models suggested that fluconazole may increase the Cmax and AUC0-24h of eliglustat 2.4- and 3.0-fold, respectively, when co-administered with eliglustat 84 mg once daily. Co-administration of Eliglustat with CYP2D6 and CYP3A inhibitors - Simulations using PBPK models suggested that concomitant use of eliglustat 84 mg twice daily with paroxetine and ketoconazole may increase the Cmax and AUCtau of eliglustat 16.7- and 24.2-fold in EMs, respectively. The predicted Cmax and AUCtau of eliglustat increased 7.5- to 9.8-fold in IMs, respectively. - Simulations using PBPK models suggested that concomitant use of eliglustat 84 mg twice daily with terbinafine and fluconazole may increase the Cmax and AUCtau of eliglustat 10.2- and 13.6-fold in EMs. The predicted Cmax and AUCtau of eliglustat increased 4.2- to 5.0-fold in IMs, respectively. Effect of CYP3A inducers on Eliglustat PK - Systemic exposures (Cmax and AUCtau) of eliglustat decreased by approximately 90% in EMs and IMs, following co-administration of eliglustat 127 mg twice daily with rifampin (a strong CYP3A inducer) 600 mg PO once daily. The only approved dose of eliglustat is 84 mg. Systemic exposures of eliglustat decreased by approximately 95% following co-administration of eliglustat 84 mg twice daily with rifampin 600 mg PO once daily in PMs. Effect of OATP (organic anion transporting polypeptide) Inhibitors on Eliglustat PK - Systemic exposures of eliglustat were similar with or without co-administration of single 600 mg IV dose of rifampin (a potent OATP inhibitor) regardless of subjects' CYP2D6 phenotypes. Effect of P-gp Inhibitors on Eliglustat PK - The effect of P-gp inhibitors on the systemic exposure of eliglustat has not been studied clinically. Effect of Gastric pH-Modifying Agents on Eliglustat PK - Gastric pH-modifying agents (Maalox®, Tums®, Protonix®) did not have a clinically relevant effect on eliglustat exposure. Drug Interactions - Effect of eliglustat on the PK of Other Drugs - Eliglustat is an inhibitor of P-gp and CYP2D6. - Following multiple doses of eliglustat 127 mg twice daily, systemic exposures (Cmax and AUC) to metoprolol (a CYP2D6 substrate) increased compared to metoprolol administration alone. Mean Cmax and AUC increased by 1.7- and 2.3-fold, respectively, in EMs and by 1.2- and 1.6-fold, respectively in IMs. The only approved dose of eliglustat is 84 mg. - Following multiple doses of eliglustat 127 mg twice daily in EMs and IMs or 84 mg twice daily in PMs, systemic exposures (Cmax and AUC) to digoxin (a P-gp substrate, with narrow therapeutic index) increased compared to digoxin administration alone. Mean Cmax and AUC increased by 1.7- and 1.5-fold, respectively. The only approved dose of eliglustat is 84 mg. - In vitro, eliglustat is a weak inhibitor of CYP3A. Repeated doses of eliglustat 84 mg twice daily did not change the exposures to norethindrone (1.0 mg) and ethinyl estradiol (0.035 mg). Therefore, eliglustat is not expected to impact the efficacy or safety of oral contraceptives containing norethindrone and ethinyl estradiol. ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis - Carcinogenic potential of eliglustat was assessed in 2-year carcinogenicity studies in rats and mice. In Sprague-Dawley rats, eliglustat was administered by oral gavage at doses up to 75 mg/kg/day in males (about 3.6 times the recommended human daily dose of 84 mg twice daily, based on body surface area) and 50 mg/kg/day in females (about 2.4 times the recommended human daily dose based on body surface area). In CD-1 mice, eliglustat was administered to males and females at up to 75 mg/kg/day (about 1.8 times the recommended human daily dose based on body surface area) via dietary admixture. Eliglustat did not produce any treatment-related neoplasms in rats or mice. Mutagenesis - Eliglustat was negative in the Ames test, chromosome aberration test in human peripheral blood lymphocytes, mouse lymphoma gene mutation assay and in vivo oral mouse micronucleus test. Impairment of Fertility - In a fertility and early embryonic development study in rats, eliglustat increased pre-implantation loss at 30 (about 1.5 times the recommended human oral dose based on body surface area) and 100 mg/kg/day (about 5 times the recommended human oral dose based on body surface area). - In mature male rats, eliglustat showed reversible adverse effects on sperm morphology, testes (germ cell necrosis), and sloughed cells in the epididymis at 200 mg/kg/day (about 10 times the recommended human oral dose based on body surface area). Similar effects on sperm were not seen in mature Cynomolgus monkeys at 72 mg/kg/day (about 7 times the recommended human oral dose based on body surface area). # Clinical Studies - The efficacy of eliglustat was evaluated in three clinical trials in patients with Gaucher disease type 1. ## Eliglustat in Treatment-Naïve GD1 Patients – Trial 1 - Trial 1 was a randomized, double-blind, placebo-controlled, multicenter clinical study evaluating the efficacy and safety of eliglustat in 40 treatment-naïve GD1 patients 16 years of age or older (median age 30.4 years) with pre-existing splenomegaly and hematological abnormalities. Patients were required to have received no treatment with substrate reduction therapy within 6 months or ERT within 9 months prior to randomization; all but 5 patients in the study had no prior therapy. Patients were stratified according to baseline spleen volume (≤ 20 or > 20 multiples of normal [MN]) and randomized in a 1:1 ratio to receive eliglustat or placebo for the duration of the 9-month blinded primary analysis period. The eliglustat treatment group was comprised of IM (5%), EM (90%) and URM (5%) patients. Patients randomized to eliglustat treatment received a starting dose of 42 mg twice daily, with a dose increase to 84 mg twice daily possible at Week 4 based on the plasma trough concentration at Week 2. The majority of patients (17 [85%]) received a dose escalation to 84 mg twice daily at Week 4, and 3 (15%) continued to receive 42 mg twice daily for the duration of the 9-month blinded primary analysis period. - The primary endpoint was the percentage change in spleen volume (in MN) from baseline to 9 months as compared to placebo. Secondary endpoints were absolute change in hemoglobin level, percentage change in liver volume (in MN), and percentage change in platelet count from baseline to 9 months compared to placebo. - At baseline, mean spleen volumes were 12.5 and 13.9 MN in the placebo and eliglustat groups, respectively, and mean liver volumes were 1.4 MN for both groups. Mean hemoglobin levels were 12.8 and 12.1 g/dL, and platelet counts were 78.5 and 75.1 x 109/L, respectively. - During the 9-month primary analysis period, eliglustat demonstrated statistically significant improvements in all primary and secondary endpoints compared to placebo, as shown in Table 6. - In an uncontrolled study of treatment naïve GD1 patients, improvements in spleen and liver volume, hemoglobin level, and platelet count continued through the 4 year treatment period. ## Patients Switching from Enzyme Replacement Therapy to Eliglustat – Trial 2 - Trial 2 was a randomized, open-label, active-controlled, non-inferiority, multicenter clinical study evaluating the efficacy and safety of eliglustat compared with imiglucerase in 159 treated GD1 patients (median age 37.4 years) previously treated with enzyme replacement therapy (≥3 years of enzyme replacement therapy, dosed at 30-130 U/kg/month in at least 6 of the prior 9 months) who met pre-specified therapeutic goals at baseline. Pre-specified baseline therapeutic goals included: no bone crisis and free of symptomatic bone disease within the last year; mean hemoglobin level of ≥ 11 g/dL in females and ≥ 12 g/dL in males; mean platelet count ≥ 100,000/mm3; spleen volume < 10 times normal and liver volume < 1.5 times normal. - Patients were randomized 2:1 to receive eliglustat or imiglucerase for the duration of the 12-month primary analysis period. Seventy-five percent of patients randomized to eliglustat were previously treated with imiglucerase; 21% with velaglucerase alfa and 4% were unreported. Patients randomized to eliglustat treatment received a starting dose of 42 mg twice daily, with dose increases to 84 mg twice daily and 127 mg twice daily possible at Weeks 4 and 8 based on plasma trough concentrations of eliglustat at Weeks 2 and 6, respectively. The percentage of patients receiving the 3 possible eliglustat doses was: 42 mg twice daily (20%), 84 mg twice daily (32%) and 127 mg twice daily (48%). The eliglustat treatment group was comprised of PM (4%), IM (10%), EM (80%) and URM (4%) patients. - At baseline, mean spleen volumes were 2.6 and 3.2 MN in the imiglucerase and eliglustat groups, respectively, and liver volumes were 0.9 MN in both groups. Mean hemoglobin levels were 13.8 and 13.6 g/dL, and platelet counts were 192 and 207 x 109/L, respectively. - The primary composite endpoint required stability in all four component domains (hemoglobin level, platelet count, liver volume, and spleen volume) based on changes between baseline and 12 months. Stability was defined by the following pre-specified thresholds of change: hemoglobin level <1.5 g/dL decrease, platelet count < 25% decrease, liver volume <20% increase and spleen volume <25% increase. The percentages of patients meeting the criteria for stability in the individual components of the composite endpoint were assessed as secondary efficacy endpoints. - Eliglustat met the criteria to be declared non-inferior to imiglucerase in maintaining patient stability. After 12 months of treatment, the percentage of patients meeting the primary composite endpoint was 84.8% for the eliglustat group compared to 93.6% for the imiglucerase group. The lower bound of the 95% CI of the 8.8% difference, -17.6%, was within the pre-specified non-inferiority margin of -25%. At Month 12, the percentages of CERDELGA and imiglucerase patients respectively, who met stability criteria for the individual components of the composite endpoint were: hemoglobin level, 94.9% and 100%; platelet count, 92.9% and 100%; spleen volume, 95.8% and 100%; and liver volume, 96.0% and 93.6%. Of the patients who did not meet stability criteria for the individual components, 12 of 15 CERDELGA patients and 3 of 3 imiglucerase patients remained within therapeutic goals for GD1. - Mean changes from baseline in the hematological and visceral parameters through 12 months of treatment are shown in Table 7. There were no clinically meaningful differences between groups for any of the four parameters. # How Supplied - Eliglustat is supplied as 84 mg hard gelatin capsules, with a pearl blue-green opaque cap and pearl white opaque body imprinted with "GZ02" in black. - Eliglustat 84 mg capsules are supplied as: NDC-58468-0220-1 – Carton containing 4 packs of capsules (56 capsules total). Each pack is composed of 1 blister card of 14 capsules and a cardboard wallet. NDC-58468-0220-2 – Carton containing 1 pack of capsules (14 capsules total). Each pack is comprised of 1 blister card of 14 capsules and a cardboard wallet. ## Storage - Store at 68 °F - 77 °F (20 °C - 25 °C) with excursions permitted between 59 °F and 86 °F (15 °C to 30 °C) [see USP Controlled Room Temperature]. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Advise the patient to read the FDA-approved patient labeling (Medication Guide). Drug Interactions - Advise patients to discuss all the medications they are taking, including any herbal supplements or vitamins with their healthcare provider. ECG Changes and Potential for Cardiac Arrhythmias - Advise patients to inform their healthcare provider of the following: history of congestive heart failure; recent acute myocardial infarction; bradycardia; heart block; ventricular arrhythmia; and long QT syndrome. - Advise patients to inform their healthcare provider if they develop new symptoms such as palpitations, fainting, and dizziness. Administration Instructions Advise patients: - Swallow capsules whole, preferably with water, and do not crush, dissolve, or open the capsules. - CERDELGA can be taken with or without food. - If a dose of CERDELGA is missed, take the prescribed dose at the next scheduled time; do not double the next dose. - Avoid consumption of grapefruit or its juice. - For patients currently treated with imiglucerase, velaglucerase alfa, or taliglucerase alfa, CERDELGA may be administered 24 hours after the last dose of the previous enzyme replacement therapy (ERT). # Precautions with Alcohol - Alcohol-Eliglustat interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - CERDELGA # Look-Alike Drug Names There is limited information regarding Eliglustat Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Eliglustat
f42bf6795d68a644483dfb403186ea74b883a5bc	wikidoc	Epirubicin	Epirubicin # 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 Epirubicin is an antineoplastic agent that is FDA approved for the treatment of patients with evidence of axillary node tumor involvement following resection of primary breast cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia , flushing , itching, rash, diarrhea , nausea and vomiting, anemia , leukopenia,neutropenia, thrombocytopenia ,lethargy ,conjunctivitis, keratitis ,amenorrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Epirubicin Injection is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer - When possible, to reduce the risk of developing cardiotoxicity in patients receiving Epirubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, Epirubicin -based therapy should be delayed until the other agents have cleared from the circulation . - Administer Epirubicin Injection by intravenous infusion. Give Epirubicin in repeated 3- to 4-week cycles. The total dose of Epirubicin may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. The recommended dosages of Epirubicin are as follows: - The recommended dose of Epirubicin is 100 to 120 mg/m2. The following regimens are recommended: Patients administered the 120-mg/m2 regimen of Epirubicin should receive prophylactic antibiotic therapy. - Epirubicin dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm3, absolute neutrophil counts (ANC) <250/mm3, neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce Epirubicin Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle. Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are ≥100,000/mm3, ANC ≥1500/mm3, and nonhematologic toxicities have recovered to ≤ Grade 1. - Consider administering a lower starting dose (75–90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow depression, or in the presence of neoplastic bone marrow infiltration. For patients receiving a divided dose of Epirubicin (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000–100,000/mm3 and ANC is 1000 to 1499/mm3. If Day 8 platelet counts are <75,000/mm3, ANC <1000/mm3, or Grades 3/4 nonhematologic toxicity has occurred, omit the Day 8 dose. - Recommendations regarding use of Epirubicin in patients with hepatic impairment are not available because patients with hepatic abnormalities were not included in the adjuvant trials. In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions are recommended: - Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times upper limit of normal 1/2 of recommended starting dose - Bilirubin > 3 mg/dL or AST > 4 times upper limit of normal 1/4 of recommended starting dose - While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, consider lower doses in patients with severe renal impairment (serum creatinine > 5 mg/dL) - Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15–25ºC). - Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of anticancer drugs should be used when handling and preparing Epirubicin . Several guidelines on this subject have been published.1–4 . - Take the following protective measures when handling Epirubicin : - Train personnel in appropriate techniques for reconstitution and handling. - Exclude pregnant staff from working with this drug. - Wear protective clothing: goggles, gowns, and disposable gloves and masks when handling Epirubicin . - Define a designated area for syringe preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic-backed, absorbent paper. - Place all items used for reconstitution, administration, or cleaning (including gloves) in high-risk, waste-disposal bags for high temperature incineration. - Treat spillage or leakage with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. Place all contaminated and cleaning materials in high-risk, waste-disposal bags for incineration. Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Seek medical attention. Always wash hands after removing gloves. - Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix Epirubicin with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation. - Epirubicin can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe. - Administer Epirubicin into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution). Patients receiving initial therapy at the recommended starting doses of 100–120 mg/m2 should generally have Epirubicin infused over 15–20 minutes. For patients who require lower Epirubicin starting doses due to organ dysfunction or who require modification of Epirubicin doses during therapy, the Epirubicin infusion time may be proportionally decreased, but should not be less than 3 minutes. This technique is intended to minimize the risk of thrombosis or perivenous extravasation, which could lead to severe cellulitis, vesication, or tissue necrosis. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein. Use Epirubicin within 24 hours of first penetration of the rubber stopper. Discard any unused solution. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Epirubicin in adult patients. ### Non–Guideline-Supported Use - Intravesicular administration of epirubicin 50 milligrams weekly for 8 weeks - Epirubicin 75 to 90 milligrams/square meter every 3 weeks produced objective responses in 50% to 75% of patients with advanced non-Hodgkin's lymphoma, including previously treated patients There is limited information regarding Off-Label Non–Guideline-Supported Use of Epirubicin in adult patients. - High-dose epirubicin regimens include doses of 120 milligrams/square meter (mg/m(2)) every 3 weeks - Epirubicin 90 milligrams/square meter (mg/m(2)) given as an intravenous push injection every 3 weeks for a maximum of 12 courses (1000 mg/m(2)) - Epirubicin 20 to 25 milligrams/square meter (mg/m(2)) weekly or 50 to 150 mg/m(2) every 3 to 4 weeks # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness of ELLENCE have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - Safety and effectiveness of Epirubicin have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF. ### Non–Guideline-Supported Use - Safety and effectiveness of Epirubicin have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF. # Contraindications - Patients should not be treated with Epirubicin Injection if they have any of the following conditions: - Cardiomyopathy and/or heart failure, recent myocardial infarction or severe arrhythmias - Previous treatment with maximum cumulative dose of anthracyclines . - Hypersensitivity to Epirubicin , other anthracyclines, or anthracenediones # Warnings - Administer Epirubicin Injection only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Before beginning treatment with Epirubicin , patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment. Also, precede initial treatment with Epirubicin by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Carefully monitor patients during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to Epirubicin . - Epirubicin Injection is administered by intravenous infusion. Venous sclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Extravasation of Epirubicin during the infusion may cause local pain, severe tissue lesions (vesication, severe cellulitis), and necrosis. Administer Epirubicin slowly into the tubing of a freely running intravenous infusion. Patients receiving initial therapy at the recommended starting doses of 100–120 mg/m2 should generally have Epirubicin infused over 15–20 minutes. For patients who require lower Epirubicin starting doses due to organ dysfunction or who require modification of Epirubicin doses during therapy, the Epirubicin infusion time may be proportionally decreased, but should not be less than 3 minutes . If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Immediately terminate infusion and restart in another vein if a burning or stinging sensation indicates perivenous infiltration. Perivenous infiltration may occur without causing pain. Facial flushing, as well as local erythematous streaking along the vein, may be indicative of excessively rapid administration. It may precede local phlebitis or thrombophlebitis. Give prophylactic antibiotic therapy to patients administered the 120-mg/m2 regimen of Epirubicin as a component of combination chemotherapy - Epirubicin can suppress bone marrow function as manifested by leukopenia, thrombocytopenia and anemia , and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy. - Cardiotoxicity is a known risk of anthracycline treatment. Anthracycline-induced cardiac toxicity may be manifested by early (or acute) or late (delayed) events. Early cardiac toxicity of Epirubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes, but tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not considered an indication for the suspension of Epirubicin treatment. Delayed cardiac toxicity results from a characteristic cardiomyopathy that is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF) such as tachycardia, dyspnea, pulmonary edema, dependent edema, hepatomegaly, ascites, pleural effusion, gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy. This toxicity appears to be dependent on the cumulative dose of Epirubicin and represents the cumulative dose-limiting toxicity of the drug. If it occurs, delayed cardiotoxicity usually develops late in the course of therapy with Epirubicin or within 2 to 3 months after completion of treatment, but later events (several months to years after treatment termination) have been reported. - Given the risk of cardiomyopathy, exceed a cumulative dose of 900 mg/m2 Epirubicin only with extreme caution. Risk factors may increase the risk of Epirubicin cardiotoxicity . Although not formally tested, it is probable that the toxicity of Epirubicin and other anthracyclines or anthracenediones is additive. Cardiac toxicity with Epirubicin may occur at lower cumulative doses whether or not cardiac risk factors are present. - Although endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy, this invasive examination is not practically performed on a routine basis. ECG changes such as dysrhythmias, a reduction of the QRS voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity. The risk of serious cardiac impairment may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of Epirubicin at the first sign of impaired function. The preferred method for repeated assessment of cardiac function is evaluation of LVEF measured by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Perform repeated MUGA or ECHO determinations of LVEF, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict and the risk-benefit of continuing treatment with Epirubicin in patients with impaired cardiac function must be carefully evaluated. - Do not administer Epirubicin in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving Epirubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity . - The occurrence of secondary acute myelogenous leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines. Secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukemias can have a short 1- to 3-year latency period. - Epirubicin is mutagenic, clastogenic, and carcinogenic in animals . - The major route of elimination of epirubicin is the hepatobiliary system. Evaluate serum total bilirubin and AST levels before and during treatment with Epirubicin . Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients . Patients with severe hepatic impairment have not been evaluated; therefore, do not use Epirubicin in this patient population. - Assess serum creatinine before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL . Patients undergoing dialysis have not been studied. - As with other cytotoxic agents, Epirubicin may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of highly chemosensitive neoplastic cells (tumor-lysis syndrome). Other metabolic abnormalities may also occur. While not generally a problem in patients with breast cancer, consider the potential for tumor-lysis syndrome in potentially susceptible patients and consider monitoring serum uric acid, potassium, calcium, phosphate, and creatinine immediately after initial chemotherapy administration. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome. - Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin, may result in serious or fatal infections. Avoid vaccination with a live vaccine in patients receiving Epirubicin . Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished. - Epirubicin is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of Epirubicin , particularly when given in conjunction with other emetigenic drugs . - As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of Epirubicin . - Cimetidine increased the AUC of epirubicin by 50%. Stop Cimetidine treatment during treatment with Epirubicin . - Epirubicin can cause fetal harm when administered to a pregnant woman. Epirubicin was embryolethal and teratogenic in rats and rabbits. There are no adequate and well-controlled studies of Epirubicin in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and should use effective contraceptive methods - Males with female sexual partners of childbearing potential should use contraception during and after cessation of Epirubicin therapy. Epirubicin may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain - Assess blood counts, including absolute neutrophil counts, and liver function before and during each cycle of therapy with Epirubicin . Perform repeated evaluations of LVEF during therapy . - As with other anthracyclines, administration of Epirubicin after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation. # 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 practice. - Integrated safety data are available from two studies (Studies MA-5 and GFEA-05) evaluating Epirubicin -containing combination regimens in patients with early breast cancer. Of the 1260 patients treated in these studies, 620 patients received the higher-dose Epirubicin regimen (FEC-100/CEF-120), 280 patients received the lower-dose Epirubicin regimen (FEC-50), and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors were not used in these trials. Clinically relevant acute adverse events are summarized in Table 1. - Table 2 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials. - Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving Epirubicin . However, an association between anthracyclines such as Epirubicin and ALL has not been clearly established. ### Overview of Acute and Delayed Toxicities - Dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with Epirubicin and represents the most common acute dose-limiting toxicity of this drug. In most cases, the white blood cell (WBC) nadir is reached 10 to 14 days from drug administration. Leukopenia/neutropenia is usually transient, with WBC and neutrophil counts generally returning to normal values by Day 21 after drug administration. As with other cytotoxic agents, Epirubicin at the recommended dose in combination with cyclophosphamide and fluorouracil can produce severe leukopenia and neutropenia. Severe thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, septicemia, septic shock, hemorrhage, tissue hypoxia, symptomatic anemia, or death. If myelosuppressive complications occur, use appropriate supportive measures (e.g., intravenous antibiotics, colony-stimulating factors, transfusions). Myelosuppression requires careful monitoring. Assess total and differential WBC, red blood cell (RBC), and platelet counts before and during each cycle of therapy with Epirubicin . - A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with Epirubicin . Clinical manifestations of mucositis may include a pain or burning sensation, erythema, erosions, ulcerations, bleeding, or infections. Mucositis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations; most patients recover from this adverse event by the third week of therapy. Hyperpigmentation of the oral mucosa may also occur. Nausea, vomiting, and occasionally diarrhea and abdominal pain can also occur. Severe vomiting and diarrhea may produce dehydration. Antiemetics may reduce nausea and vomiting; consider prophylactic use of antiemetics before therapy . - Alopecia occurs frequently, but is usually reversible, with hair regrowth occurring within 2 to 3 months from the termination of therapy. Flushes, skin and nail hyperpigmentation, photosensitivity, and hypersensitivity to irradiated skin (radiation-recall reaction) have been observed. Urticaria and anaphylaxis have been reported in patients treated with Epirubicin ; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock. - In a retrospective survey, including 9144 patients, mostly with solid tumors in advanced stages, the probability of developing CHF increased with increasing cumulative doses of Epirubicin (Figure 1). The estimated risk of Epirubicin -treated patients developing clinically evident CHF was 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. The risk of developing CHF in the absence of other cardiac risk factors increased steeply after an Epirubicin cumulative dose of 900 mg/m2 . - In another retrospective survey of 469 Epirubicin -treated patients with metastatic or early breast cancer, the reported risk of CHF was comparable to that observed in the larger study of over 9000 patients. - Other serious drug-related cardiovascular adverse events that occurred during clinical trials with Epirubicin , administered in different indications, include ventricular tachycardia, AV block, bundle branch block, bradycardia and thromboembolism. - An analysis of 7110 patients who received adjuvant treatment with Epirubicin in controlled clinical trials as a component of poly-chemotherapy regimens for early breast cancer, showed a cumulative risk of secondary acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) of about 0.27% (approximate 95% CI, 0.14–0.40) at 3 years, 0.46% (approximate 95% CI, 0.28–0.65) at 5 years, and 0.55% (approximate 95% CI, 0.33–0.78) at 8 years. The risk of developing AML/MDS increased with increasing Epirubicin cumulative doses as shown in Figure 2. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of Epirubicin . 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. - Infections and infestations: sepsis, pneumonia - Immune system disorders: anaphylaxis - Metabolism and nutrition disorders: dehydration, hyperuricemia - Vascular disorders: shock, haemorrhage, embolism arterial, thrombophlebitis, phlebitis - Respiratory, thoracic and mediastinal disorders: pulmonary embolism - Gastrointestinal disorders: erosions, ulcerations, pain or burning sensation, bleeding, hyperpigmentation of the oral mucosa - Skin and subcutaneous tissue disorders: erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction), urticaria - Renal and urinary disorders: red coloration of urine for 1 to 2 days after administration - General disorders and administration site conditions: fever, chills - Injury, poisoning and procedural complications: chemical cystitis (following intravesical administration) # Drug Interactions - Do not administer epirubicin in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving epirubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity - Concomitant use of Epirubicin with other cardioactive compounds that could cause heart failure (e.g., calcium channel blockers), requires close monitoring of cardiac function throughout treatment. - Cimetidine increases the exposure to epirubicin . Stop Cimetidine during treatment with Epirubicin . - Epirubicin used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects. - The administration of epirubicin immediately prior to or after paclitaxel increased the systemic exposure of epirubicin, epirubicinol and 7-deoxydoxorubicin aglycone . - The administration of epirubicin immediately prior to or after docetaxel did not have an effect on the systemic exposure of epirubicin, but increased the systemic exposure of epirubicinol and 7-deoxydoxorubicin aglycone . - There are few data regarding the coadministration of radiation therapy and Epirubicin . In adjuvant trials of Epirubicin -containing CEF-120 or FEC-100 chemotherapies, breast irradiation was delayed until after chemotherapy was completed. This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature. A small number of patients received Epirubicin -based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of Epirubicin with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of Epirubicin after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation. - Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity. - There are no known interactions between Epirubicin and laboratory tests. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Epirubicin can cause fetal harm when administered to a pregnant woman. Administration of 0.8 mg/kg/day intravenously of epirubicin to rats (about 0.04 times the maximum recommended single human dose on a body surface area basis) during Days 5 to 15 of gestation was embryotoxic (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight), but was not teratogenic up to this dose. Administration of 2 mg/kg/day intravenously of epirubicin to rats (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 9 and 10 of gestation was embryotoxic (increased late resorptions, post-implantation losses, and dead fetuses; and decreased live fetuses), retarded fetal growth (decreased body weight), and caused decreased placental weight. This dose was also teratogenic, causing numerous external (anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily gastrointestinal, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations. Administration of intravenous epirubicin to rabbits at doses up to 0.2 mg/kg/day (about 0.02 times the maximum recommended single human dose on a body surface area basis) during Days 6 to 18 of gestation was not embryotoxic or teratogenic, but a maternally toxic dose of 0.32 mg/kg/day increased abortions and delayed ossification. Administration of a maternally toxic intravenous dose of 1 mg/kg/day epirubicin to rabbits (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 10 to 12 of gestation induced abortion, but no other signs of embryofetal toxicity or teratogenicity were observed. When doses up to 0.5 mg/kg/day epirubicin were administered to rat dams from Day 17 of gestation to Day 21 after delivery (about 0.025 times the maximum recommended single human dose on a body surface area basis), no permanent changes were observed in the development, functional activity, behavior, or reproductive performance of the offspring. - There are no adequate and well-controlled studies of Epirubicin in pregnant women. Two pregnancies have been reported in women taking epirubicin. A 34-year-old woman, 28 weeks pregnant at her diagnosis of breast cancer, was treated with cyclophosphamide and epirubicin every 3 weeks for 3 cycles. She received the last dose at 34 weeks of pregnancy and delivered a healthy baby at 35 weeks. A second 34-year-old woman with breast cancer metastatic to the liver was randomized to FEC-50 but was removed from study because of pregnancy. She experienced a spontaneous abortion. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Epirubicin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Epirubicin during labor and delivery. ### Nursing Mothers - Epirubicin was excreted into the milk of rats treated with 0.50 mg/kg/day of epirubicin during peri- and postnatal periods. It is not known whether this drug is excreted in human milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Epirubicin , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness of Epirubicin have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF. The pharmacokinetics of epirubicin in pediatric patients have not been evaluated. ### Geriatic Use - Although a lower starting dose of Epirubicin was not used in trials in elderly female patients, particular care should be taken in monitoring toxicity when Epirubicin is administered to female patients ≥ 70 years of age ### Gender There is no FDA guidance on the use of Epirubicin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Epirubicin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Epirubicin in patients with renal impairment. ### Hepatic Impairment - Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in patients with hepatic dysfunction. Do not treat patients with severe hepatic impairment with Epirubicin . Reduce the starting dose for patients with less severe hepatic impairment. ### Females of Reproductive Potential and Males - No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol, have been observed in patients with serum creatinine 5 mg/dL), as a reduction in plasma clearance was reported in these patients .Patients on dialysis have not been studied ### Immunocompromised Patients There is no FDA guidance one the use of Epirubicin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Epirubicin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Epirubicin in the drug label. # Overdosage - There is no known antidote for overdoses of Epirubicin . A 36-year-old man with non-Hodgkin's lymphoma received a daily 95 mg/m2 dose of Epirubicin Injection for 5 consecutive days. Five days later, he developed bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding. No signs of acute cardiac toxicity were observed. He was treated with antibiotics, colony-stimulating factors, and antifungal agents, and recovered completely. A 63-year-old woman with breast cancer and liver metastasis received a single 320 mg/m2 dose of Epirubicin . She was hospitalized with hyperthermia and developed multiple organ failure (respiratory and renal), with lactic acidosis, increased lactate dehydrogenase, and anuria. Death occurred within 24 hours after administration of Epirubicin . Additional instances of administration of doses higher than recommended have been reported at doses ranging from 150 to 250 mg/m2. The observed adverse events in these patients were qualitatively similar to known toxicities of epirubicin. Most of the patients recovered with appropriate supportive care. - If an overdose occurs, provide supportive treatment (including antibiotic therapy, blood and platelet transfusions, colony-stimulating factors, and intensive care as needed) until the recovery of toxicities. Delayed CHF has been observed months after anthracycline administration. Observe patients carefully over time for signs of CHF and provided with appropriate supportive therapy. # Pharmacology ## Mechanism of Action - Epirubicin is an anthracycline cytotoxic agent. Although it is known that anthracyclines can interfere with a number of biochemical and biological functions within eukaryotic cells, the precise mechanisms of epirubicin's cytotoxic and/or antiproliferative properties have not been completely elucidated. - Epirubicin forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs, with consequent inhibition of nucleic acid (DNA and RNA) and protein synthesis. - Such intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also inhibits DNA helicase activity, preventing the enzymatic separation of double-stranded DNA and interfering with replication and transcription. Epirubicin is also involved in oxidation/reduction reactions by generating cytotoxic free radicals. The antiproliferative and cytotoxic activity of epirubicin is thought to result from these or other possible mechanisms. Epirubicin is cytotoxic in vitro to a variety of established murine and human cell lines and primary cultures of human tumors. It is also active in vivo against a variety of murine tumors and human xenografts in athymic mice, including breast tumors. ## Structure - Epirubicin Injection (epirubicin hydrochloride injection) is an anthracycline cytotoxic agent, intended for intravenous administration. Epirubicin is supplied as a sterile, clear, red solution and is available in polypropylene vials containing 50 and 200 mg of epirubicin hydrochloride as a preservative-free, ready-to-use solution. Each milliliter of solution contains 2 mg of epirubicin hydrochloride. Inactive ingredients include sodium chloride, USP, and water for injection, USP. The pH of the solution has been adjusted to 3.0 with hydrochloric acid, NF. - Epirubicin hydrochloride is the 4-epimer of doxorubicin and is a semi-synthetic derivative of daunorubicin. The chemical name is (8S-cis)-10--7,8,9,10-tetrahydro6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione hydrochloride. The active ingredient is a red-orange hygroscopic powder, with the empirical formula C27 H29 NO11 HCl and a molecular weight of 579.95. The structural formula is as follows: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Epirubicin in the drug label. ## Pharmacokinetics - Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/m2 and plasma clearance is not affected by the duration of infusion or administration schedule. Pharmacokinetic parameters for epirubicin following 6- to 10-minute, single-dose intravenous infusions of Epirubicin at doses of 60 to 150 mg/m2 in patients with solid tumors are shown in Table 4. The plasma concentration declined in a triphasic manner with mean half-lives for the alpha, beta, and gamma phases of about 3 minutes, 2.5 hours, and 33 hours, respectively. - Following intravenous administration, epirubicin is rapidly and widely distributed into the tissues. Binding of epirubicin to plasma proteins, predominantly albumin, is about 77% and is not affected by drug concentration. Epirubicin also appears to concentrate in red blood cells; whole blood concentrations are approximately twice those of plasma. - Epirubicin is extensively and rapidly metabolized by the liver and is also metabolized by other organs and cells, including red blood cells. Four main metabolic routes have been identified: - reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; - conjugation of both the unchanged drug and epirubicinol with glucuronic acid; - loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and - loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol has in vitro cytotoxic activity one-tenth that of epirubicin. As plasma levels of epirubicinol are lower than those of the unchanged drug, they are unlikely to reach in vivo concentrations sufficient for cytotoxicity. No significant activity or toxicity has been reported for the other metabolites. - Epirubicin and its major metabolites are eliminated through biliary excretion and, to a lesser extent, by urinary excretion. Mass-balance data from 1 patient found about 60% of the total radioactive dose in feces (34%) and urine (27%). These data are consistent with those from 3 patients with extrahepatic obstruction and percutaneous drainage, in whom approximately 35% and 20% of the administered dose were recovered as epirubicin or its major metabolites in bile and urine, respectively, in the 4 days after treatment. - A population analysis of plasma data from 36 cancer patients (13 males and 23 females, 20 to 73 years) showed that age affects plasma clearance of epirubicin in female patients. The predicted plasma clearance for a female patient of 70 years of age was about 35% lower than that for a female patient of 25 years of age. An insufficient number of males > 50 years of age were included in the study to draw conclusions about age-related alterations in clearance in males. Although a lower Epirubicin starting dose does not appear necessary in elderly female patients, and was not used in clinical trials, particular care should be taken in monitoring toxicity when Epirubicin is administered to female patients > 70 years of age. - In patients ≤ 50 years of age, mean clearance values in adult male and female patients were similar. The clearance of epirubicin is decreased in elderly women. - The influence of race on the pharmacokinetics of epirubicin has not been evaluated. - Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in patients with hepatic dysfunction. In a study of the effect of hepatic dysfunction, patients with solid tumors were classified into 3 groups. Patients in Group 1 (n=22) had serum AST (SGOT) levels above the upper limit of normal (median: 93 IU/L) and normal serum bilirubin levels (median: 0.5 mg/dL) and were given Epirubicin doses of 12.5 to 90 mg/m2. Patients in Group 2 had alterations in both serum AST (median: 175 IU/L) and bilirubin levels (median: 2.7 mg/dL) and were treated with an Epirubicin dose of 25 mg/m2 (n=8). Their pharmacokinetics were compared to those of patients with normal serum AST and bilirubin values, who received Epirubicin doses of 12.5 to 120 mg/m2. The median plasma clearance of epirubicin was decreased compared to patients with normal hepatic function by about 30% in patients in Group 1 and by 50% in patients in Group 2. Patients with more severe hepatic impairment have not been evaluated - No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol, have been observed in patients with serum creatinine < 5 mg/dL. A 50% reduction in plasma clearance was reported in four patients with serum creatinine ≥ 5 mg/dL . Patients on dialysis have not been studied. - The administration of paclitaxel (175–225 mg/m2 as a 3-hour infusion) immediately before or after epirubicin (90 mg/m2 as bolus) caused variable increases in the systemic exposure (mean AUC) of epirubicin ranging from 5% to 109%. At same doses of epirubicin and paclitaxel, the mean AUC of the inactive metabolites of epirubicin (epirubicinol and 7-deoxy-aglycone) increased by 120% and 70%, respectively, when paclitaxel was immediately administered after epirubicin. Epirubicin had no effect on the exposure of paclitaxel whether it was administered before or after paclitaxel. - The administration of docetaxel (70 mg/m2 as 1-hour infusion) immediately before or after epirubicin (90 mg/m2 as bolus) had no effect on the systemic exposure (mean AUC) of epirubicin. However, the mean AUC of epirubicinol and 7-deoxy-aglycone increased by 22.5% and 95%, respectively, when docetaxel was immediately administered after epirubicin compared to epirubicin alone. Epirubicin had no effect on the exposure of docetaxel whether it was administered before or after docetaxel. - Coadministration of cimetidine (400 mg twice daily for 7 days starting 5 days before chemotherapy) increased the mean AUC of epirubicin (100 mg/m2) by 50% and decreased its plasma clearance by 30%. - No systematic in vitro or in vivo evaluation has been performed to examine the potential for inhibition or induction by epirubicin of oxidative cytochrome P-450 isoenzymes. ## Nonclinical Toxicology - Conventional long-term animal studies to evaluate the carcinogenic potential of epirubicin have not been conducted, but intravenous administration of a single 3.6 mg/kg epirubicin dose to female rats (about 0.2 times the maximum recommended human dose on a body surface area basis) approximately doubled the incidence of mammary tumors (primarily fibroadenomas) observed at 1 year. Administration of 0.5 mg/kg epirubicin intravenously to rats (about 0.025 times the maximum recommended human dose on a body surface area basis) every 3 weeks for ten doses increased the incidence of subcutaneous fibromas in males over an 18-month observation period. In addition, subcutaneous administration of 0.75 or 1.0 mg/kg/day (about 0.015 times the maximum recommended human dose on a body surface area basis) to newborn rats for 4 days on both the first and tenth day after birth for a total of eight doses increased the incidence of animals with tumors compared to controls during a 24-month observation period. - Epirubicin was mutagenic in vitro to bacteria (Ames test) either in the presence or absence of metabolic activation and to mammalian cells (HGPRT assay in V79 Chinese hamster lung fibroblasts) in the absence but not in the presence of metabolic activation. Epirubicin was clastogenic in vitro(chromosome aberrations in human lymphocytes) both in the presence and absence of metabolic activation and was also clastogenic in vivo (chromosome aberration in mouse bone marrow). - In fertility studies in rats, males were given epirubicin daily for 9 weeks and mated with females that were given epirubicin daily for 2 weeks prior to mating and through Day 7 of gestation. When 0.3 mg/kg/day (about 0.015 times the maximum recommended human single dose on a body surface area basis) was administered to both sexes, no pregnancies resulted. No effects on mating behavior or fertility were observed at 0.1 mg/kg/day, but male rats had atrophy of the testes and epididymis, and reduced spermatogenesis. The 0.1 mg/kg/day dose also caused embryolethality. An increased incidence of fetal growth retardation was observed in these studies at 0.03 mg/kg/day (about 0.0015 times the maximum recommended human single dose on a body surface area basis). Multiple daily doses of epirubicin to rabbits and dogs also caused atrophy of male reproductive organs. Single 20.5 and 12 mg/kg doses of intravenous epirubicin caused testicular atrophy in mice and rats, respectively (both approximately 0.5 times the maximum recommended human dose on a body surface area basis). A single dose of 16.7 mg/kg epirubicin caused uterine atrophy in rats. # Clinical Studies - Two randomized, open-label, multicenter studies evaluated the use of Epirubicin Injection 100 to 120 mg/m2 in combination with cyclophosphamide and fluorouracil for the adjuvant treatment of patients with axillary-node positive breast cancer and no evidence of distant metastatic disease (Stage II or III). Study MA-5 evaluated 120 mg/m2 of Epirubicin per course in combination with cyclophosphamide and fluorouracil (CEF-120 regimen). This study randomized premenopausal and perimenopausal women with one or more positive lymph nodes to an Epirubicin -containing CEF-120 regimen or to a CMF regimen. Study GFEA-05 evaluated the use of 100 mg/m2 of Epirubicin per course in combination with fluorouracil and cyclophosphamide (FEC-100). This study randomized pre- and postmenopausal women to the FEC-100 regimen or to a lower-dose FEC-50 regimen. In the GFEA-05 study, eligible patients were either required to have ≥ 4 nodes involved with tumor or, if only 1 to 3 nodes were positive, to have negative estrogen- and progesterone-receptors and a histologic tumor grade of 2 or 3. A total of 1281 women participated in these studies. Patients with T4 tumors were not eligible for either study. Table 5 shows the treatment regimens that the patients received. Relapse-free survival was defined as time to occurrence of a local, regional, or distant recurrence, or disease-related death. Patients with contralateral breast cancer, second primary malignancy, or death from causes other than breast cancer were censored at the time of the last visit prior to these events. - In the MA-5 trial, the median age of the study population was 45 years. Approximately 60% of patients had 1 to 3 involved nodes and approximately 40% had ≥ 4 nodes involved with tumor. In the GFEA-05 study, the median age was 51 years and approximately half of the patients were postmenopausal. About 17% of the study population had 1 to 3 positive nodes and 80% of patients had ≥ 4 involved lymph nodes. Demographic and tumor characteristics were well-balanced between treatment arms in each study. - Relapse-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier methods in the intent-to-treat (ITT) patient populations in each study. Results were initially analyzed after up to 5 years of follow-up and these results are presented in the text below and in Table 6. Results after up to 10 years of follow-up are presented in Table 6. In Study MA-5, Epirubicin -containing combination therapy (CEF-120) showed significantly longer RFS than CMF (5-year estimates were 62% versus 53%, stratified logrank for the overall RFS p=0.013). The estimated reduction in the risk of relapse was 24% at 5 years. The OS was also greater for the Epirubicin -containing CEF-120 regimen than for the CMF regimen (5-year estimate 77% versus 70%; stratified logrank for overall survival p=0.043; non-stratified logrank p=0.13). The estimated reduction in the risk of death was 29% at 5 years. - In Study GFEA-05, patients treated with the higher-dose Epirubicin regimen (FEC-100) had a significantly longer 5-year RFS (estimated 65% versus 52%, logrank for the overall RFS p=0.007) and OS (estimated 76% versus 65%, logrank for the overall survival p=0.007) than patients given the lower dose regimen (FEC-50). The estimated reduction in risk of relapse was 32% at 5 years. The estimated reduction in the risk of death was 31% at 5 years. Results of follow-up up to 10 years (median follow-up = 8.8 years and 8.3 years, respectively, for Study MA-5 and Study GFEA-05) are presented in Table 6. - Although the trials were not powered for subgroup analyses, in the MA-5 study, improvements in favor of CEF-120 vs. CMF were observed, in RFS and OS both in patients with 1–3 node positive and in those with ≥4 node positive tumor involvement. In the GFEA-05 study, improvements in RFS and OS were observed in both pre- and postmenopausal women treated with FEC-100 compared to FEC-50. # How Supplied - Epirubicin Injection is available in polypropylene single-use CYTOSAFE™ vials containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use solution in the following strengths: ## Storage - Store refrigerated between 2ºC and 8ºC (36ºF and 46ºF). Do not freeze. Protect from light.Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15–25ºC). Solution for injection should be used within 24 hours after removal from refrigeration. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients of the expected adverse effects of Epirubicin , including gastrointestinal symptoms (nausea, vomiting, diarrhea, and stomatitis), alopecia and potential neutropenic complications. - Patients should understand that there is a risk of irreversible myocardial damage associated with treatment with Epirubicin , as well as a risk of treatment-related leukemia. - Patients should consult their physician if vomiting, dehydration, fever, evidence of infection, symptoms of CHF, or injection-site pain occurs following therapy with Epirubicin . - Advise patients that their urine may appear red for 1 to 2 days after administration of Epirubicin and that they should not be alarmed. - Because Epirubicin may induce chromosomal damage in sperm, advise men undergoing treatment with Epirubicin to use effective contraceptive methods. Women treated with Epirubicin may develop irreversible amenorrhea, or premature menopause. # Precautions with Alcohol - Alcohol-Epirubicin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Epirubicin ® # Look-Alike Drug Names - EPIrubicin - eriBULin< # Drug Shortage Status # Price	Epirubicin Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Epirubicin is an antineoplastic agent that is FDA approved for the treatment of patients with evidence of axillary node tumor involvement following resection of primary breast cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include alopecia , flushing , itching, rash, diarrhea , nausea and vomiting, anemia , leukopenia,neutropenia, thrombocytopenia ,lethargy ,conjunctivitis, keratitis ,amenorrhea. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Epirubicin Injection is indicated as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer - When possible, to reduce the risk of developing cardiotoxicity in patients receiving Epirubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, Epirubicin -based therapy should be delayed until the other agents have cleared from the circulation . - Administer Epirubicin Injection by intravenous infusion. Give Epirubicin in repeated 3- to 4-week cycles. The total dose of Epirubicin may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. The recommended dosages of Epirubicin are as follows: - The recommended dose of Epirubicin is 100 to 120 mg/m2. The following regimens are recommended: Patients administered the 120-mg/m2 regimen of Epirubicin should receive prophylactic antibiotic therapy. - Epirubicin dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm3, absolute neutrophil counts (ANC) <250/mm3, neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce Epirubicin Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle. Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are ≥100,000/mm3, ANC ≥1500/mm3, and nonhematologic toxicities have recovered to ≤ Grade 1. - Consider administering a lower starting dose (75–90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow depression, or in the presence of neoplastic bone marrow infiltration. For patients receiving a divided dose of Epirubicin (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000–100,000/mm3 and ANC is 1000 to 1499/mm3. If Day 8 platelet counts are <75,000/mm3, ANC <1000/mm3, or Grades 3/4 nonhematologic toxicity has occurred, omit the Day 8 dose. - Recommendations regarding use of Epirubicin in patients with hepatic impairment are not available because patients with hepatic abnormalities were not included in the adjuvant trials. In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions are recommended: - Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times upper limit of normal 1/2 of recommended starting dose - Bilirubin > 3 mg/dL or AST > 4 times upper limit of normal 1/4 of recommended starting dose - While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, consider lower doses in patients with severe renal impairment (serum creatinine > 5 mg/dL) - Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15–25ºC). - Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of anticancer drugs should be used when handling and preparing Epirubicin . Several guidelines on this subject have been published.1–4 . - Take the following protective measures when handling Epirubicin : - Train personnel in appropriate techniques for reconstitution and handling. - Exclude pregnant staff from working with this drug. - Wear protective clothing: goggles, gowns, and disposable gloves and masks when handling Epirubicin . - Define a designated area for syringe preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic-backed, absorbent paper. - Place all items used for reconstitution, administration, or cleaning (including gloves) in high-risk, waste-disposal bags for high temperature incineration. - Treat spillage or leakage with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. Place all contaminated and cleaning materials in high-risk, waste-disposal bags for incineration. Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Seek medical attention. Always wash hands after removing gloves. - Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix Epirubicin with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation. - Epirubicin can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe. - Administer Epirubicin into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution). Patients receiving initial therapy at the recommended starting doses of 100–120 mg/m2 should generally have Epirubicin infused over 15–20 minutes. For patients who require lower Epirubicin starting doses due to organ dysfunction or who require modification of Epirubicin doses during therapy, the Epirubicin infusion time may be proportionally decreased, but should not be less than 3 minutes. This technique is intended to minimize the risk of thrombosis or perivenous extravasation, which could lead to severe cellulitis, vesication, or tissue necrosis. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein. Use Epirubicin within 24 hours of first penetration of the rubber stopper. Discard any unused solution. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Epirubicin in adult patients. ### Non–Guideline-Supported Use - Intravesicular administration of epirubicin 50 milligrams weekly for 8 weeks[1] - Epirubicin 75 to 90 milligrams/square meter every 3 weeks produced objective responses in 50% to 75% of patients with advanced non-Hodgkin's lymphoma, including previously treated patients[2] There is limited information regarding Off-Label Non–Guideline-Supported Use of Epirubicin in adult patients. - High-dose epirubicin regimens include doses of 120 milligrams/square meter (mg/m(2)) every 3 weeks [3] - Epirubicin 90 milligrams/square meter (mg/m(2)) given as an intravenous push injection every 3 weeks for a maximum of 12 courses (1000 mg/m(2))[3] - Epirubicin 20 to 25 milligrams/square meter (mg/m(2)) weekly or 50 to 150 mg/m(2) every 3 to 4 weeks [3] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Safety and effectiveness of ELLENCE have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - Safety and effectiveness of Epirubicin have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF. ### Non–Guideline-Supported Use - Safety and effectiveness of Epirubicin have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF. # Contraindications - Patients should not be treated with Epirubicin Injection if they have any of the following conditions: - Cardiomyopathy and/or heart failure, recent myocardial infarction or severe arrhythmias - Previous treatment with maximum cumulative dose of anthracyclines . - Hypersensitivity to Epirubicin , other anthracyclines, or anthracenediones # Warnings - Administer Epirubicin Injection only under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Before beginning treatment with Epirubicin , patients should recover from acute toxicities (such as stomatitis, neutropenia, thrombocytopenia, and generalized infections) of prior cytotoxic treatment. Also, precede initial treatment with Epirubicin by a careful baseline assessment of blood counts; serum levels of total bilirubin, AST, and creatinine; and cardiac function as measured by left ventricular ejection function (LVEF). Carefully monitor patients during treatment for possible clinical complications due to myelosuppression. Supportive care may be necessary for the treatment of severe neutropenia and severe infectious complications. Monitoring for potential cardiotoxicity is also important, especially with greater cumulative exposure to Epirubicin . - Epirubicin Injection is administered by intravenous infusion. Venous sclerosis may result from an injection into a small vessel or from repeated injections into the same vein. Extravasation of Epirubicin during the infusion may cause local pain, severe tissue lesions (vesication, severe cellulitis), and necrosis. Administer Epirubicin slowly into the tubing of a freely running intravenous infusion. Patients receiving initial therapy at the recommended starting doses of 100–120 mg/m2 should generally have Epirubicin infused over 15–20 minutes. For patients who require lower Epirubicin starting doses due to organ dysfunction or who require modification of Epirubicin doses during therapy, the Epirubicin infusion time may be proportionally decreased, but should not be less than 3 minutes . If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage. Immediately terminate infusion and restart in another vein if a burning or stinging sensation indicates perivenous infiltration. Perivenous infiltration may occur without causing pain. Facial flushing, as well as local erythematous streaking along the vein, may be indicative of excessively rapid administration. It may precede local phlebitis or thrombophlebitis. Give prophylactic antibiotic therapy to patients administered the 120-mg/m2 regimen of Epirubicin as a component of combination chemotherapy - Epirubicin can suppress bone marrow function as manifested by leukopenia, thrombocytopenia and anemia , and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy. - Cardiotoxicity is a known risk of anthracycline treatment. Anthracycline-induced cardiac toxicity may be manifested by early (or acute) or late (delayed) events. Early cardiac toxicity of Epirubicin consists mainly of sinus tachycardia and/or electrocardiogram (ECG) abnormalities such as non-specific ST-T wave changes, but tachyarrhythmias, including premature ventricular contractions and ventricular tachycardia, bradycardia, as well as atrioventricular and bundle-branch block have also been reported. These effects do not usually predict subsequent development of delayed cardiotoxicity, are rarely of clinical importance, and are generally not considered an indication for the suspension of Epirubicin treatment. Delayed cardiac toxicity results from a characteristic cardiomyopathy that is manifested by reduced LVEF and/or signs and symptoms of congestive heart failure (CHF) such as tachycardia, dyspnea, pulmonary edema, dependent edema, hepatomegaly, ascites, pleural effusion, gallop rhythm. Life-threatening CHF is the most severe form of anthracycline-induced cardiomyopathy. This toxicity appears to be dependent on the cumulative dose of Epirubicin and represents the cumulative dose-limiting toxicity of the drug. If it occurs, delayed cardiotoxicity usually develops late in the course of therapy with Epirubicin or within 2 to 3 months after completion of treatment, but later events (several months to years after treatment termination) have been reported. - Given the risk of cardiomyopathy, exceed a cumulative dose of 900 mg/m2 Epirubicin only with extreme caution. Risk factors [active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, concomitant use of other drugs with the ability to suppress cardiac contractility or cardiotoxic drugs, especially those with long half-lives (e.g., trastuzumab)] may increase the risk of Epirubicin cardiotoxicity . Although not formally tested, it is probable that the toxicity of Epirubicin and other anthracyclines or anthracenediones is additive. Cardiac toxicity with Epirubicin may occur at lower cumulative doses whether or not cardiac risk factors are present. - Although endomyocardial biopsy is recognized as the most sensitive diagnostic tool to detect anthracycline-induced cardiomyopathy, this invasive examination is not practically performed on a routine basis. ECG changes such as dysrhythmias, a reduction of the QRS voltage, or a prolongation beyond normal limits of the systolic time interval may be indicative of anthracycline-induced cardiomyopathy, but ECG is not a sensitive or specific method for following anthracycline-related cardiotoxicity. The risk of serious cardiac impairment may be decreased through regular monitoring of LVEF during the course of treatment with prompt discontinuation of Epirubicin at the first sign of impaired function. The preferred method for repeated assessment of cardiac function is evaluation of LVEF measured by multi-gated radionuclide angiography (MUGA) or echocardiography (ECHO). A baseline cardiac evaluation with an ECG and a MUGA scan or an ECHO is recommended, especially in patients with risk factors for increased cardiac toxicity. Perform repeated MUGA or ECHO determinations of LVEF, particularly with higher, cumulative anthracycline doses. The technique used for assessment should be consistent through follow-up. In patients with risk factors, particularly prior anthracycline or anthracenedione use, the monitoring of cardiac function must be particularly strict and the risk-benefit of continuing treatment with Epirubicin in patients with impaired cardiac function must be carefully evaluated. - Do not administer Epirubicin in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving Epirubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity . - The occurrence of secondary acute myelogenous leukemia, with or without a preleukemic phase, has been reported in patients treated with anthracyclines. Secondary leukemia is more common when such drugs are given in combination with DNA-damaging antineoplastic agents, when patients have been heavily pretreated with cytotoxic drugs, or when doses of the anthracyclines have been escalated. These leukemias can have a short 1- to 3-year latency period. - Epirubicin is mutagenic, clastogenic, and carcinogenic in animals . - The major route of elimination of epirubicin is the hepatobiliary system. Evaluate serum total bilirubin and AST levels before and during treatment with Epirubicin . Patients with elevated bilirubin or AST may experience slower clearance of drug with an increase in overall toxicity. Lower doses are recommended in these patients . Patients with severe hepatic impairment have not been evaluated; therefore, do not use Epirubicin in this patient population. - Assess serum creatinine before and during therapy. Dosage adjustment is necessary in patients with serum creatinine >5 mg/dL . Patients undergoing dialysis have not been studied. - As with other cytotoxic agents, Epirubicin may induce hyperuricemia as a consequence of the extensive purine catabolism that accompanies drug-induced rapid lysis of highly chemosensitive neoplastic cells (tumor-lysis syndrome). Other metabolic abnormalities may also occur. While not generally a problem in patients with breast cancer, consider the potential for tumor-lysis syndrome in potentially susceptible patients and consider monitoring serum uric acid, potassium, calcium, phosphate, and creatinine immediately after initial chemotherapy administration. Hydration, urine alkalinization, and prophylaxis with allopurinol to prevent hyperuricemia may minimize potential complications of tumor-lysis syndrome. - Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents including epirubicin, may result in serious or fatal infections. Avoid vaccination with a live vaccine in patients receiving Epirubicin . Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished. - Epirubicin is emetigenic. Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics should be considered before administration of Epirubicin , particularly when given in conjunction with other emetigenic drugs . - As with other cytotoxic agents, thrombophlebitis and thromboembolic phenomena, including pulmonary embolism (in some cases fatal) have been coincidentally reported with the use of Epirubicin . - Cimetidine increased the AUC of epirubicin by 50%. Stop Cimetidine treatment during treatment with Epirubicin . - Epirubicin can cause fetal harm when administered to a pregnant woman. Epirubicin was embryolethal and teratogenic in rats and rabbits. There are no adequate and well-controlled studies of Epirubicin in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of child-bearing potential should be advised to avoid becoming pregnant during treatment and should use effective contraceptive methods - Males with female sexual partners of childbearing potential should use contraception during and after cessation of Epirubicin therapy. Epirubicin may damage testicular tissue and spermatozoa. Possible sperm DNA damage raises concerns about loss of fertility and genetic abnormalities in fetuses. The duration of this effect is uncertain - Assess blood counts, including absolute neutrophil counts, and liver function before and during each cycle of therapy with Epirubicin . Perform repeated evaluations of LVEF during therapy . - As with other anthracyclines, administration of Epirubicin after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation. # 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 practice. - Integrated safety data are available from two studies (Studies MA-5 and GFEA-05) evaluating Epirubicin -containing combination regimens in patients with early breast cancer. Of the 1260 patients treated in these studies, 620 patients received the higher-dose Epirubicin regimen (FEC-100/CEF-120), 280 patients received the lower-dose Epirubicin regimen (FEC-50), and 360 patients received CMF. Serotonin-specific antiemetic therapy and colony-stimulating factors were not used in these trials. Clinically relevant acute adverse events are summarized in Table 1. - Table 2 describes the incidence of delayed adverse events in patients participating in the MA-5 and GFEA-05 trials. - Two cases of acute lymphoid leukemia (ALL) were also observed in patients receiving Epirubicin . However, an association between anthracyclines such as Epirubicin and ALL has not been clearly established. ### Overview of Acute and Delayed Toxicities - Dose-dependent, reversible leukopenia and/or neutropenia is the predominant manifestation of hematologic toxicity associated with Epirubicin and represents the most common acute dose-limiting toxicity of this drug. In most cases, the white blood cell (WBC) nadir is reached 10 to 14 days from drug administration. Leukopenia/neutropenia is usually transient, with WBC and neutrophil counts generally returning to normal values by Day 21 after drug administration. As with other cytotoxic agents, Epirubicin at the recommended dose in combination with cyclophosphamide and fluorouracil can produce severe leukopenia and neutropenia. Severe thrombocytopenia and anemia may also occur. Clinical consequences of severe myelosuppression include fever, infection, septicemia, septic shock, hemorrhage, tissue hypoxia, symptomatic anemia, or death. If myelosuppressive complications occur, use appropriate supportive measures (e.g., intravenous antibiotics, colony-stimulating factors, transfusions). Myelosuppression requires careful monitoring. Assess total and differential WBC, red blood cell (RBC), and platelet counts before and during each cycle of therapy with Epirubicin . - A dose-dependent mucositis (mainly oral stomatitis, less often esophagitis) may occur in patients treated with Epirubicin . Clinical manifestations of mucositis may include a pain or burning sensation, erythema, erosions, ulcerations, bleeding, or infections. Mucositis generally appears early after drug administration and, if severe, may progress over a few days to mucosal ulcerations; most patients recover from this adverse event by the third week of therapy. Hyperpigmentation of the oral mucosa may also occur. Nausea, vomiting, and occasionally diarrhea and abdominal pain can also occur. Severe vomiting and diarrhea may produce dehydration. Antiemetics may reduce nausea and vomiting; consider prophylactic use of antiemetics before therapy . - Alopecia occurs frequently, but is usually reversible, with hair regrowth occurring within 2 to 3 months from the termination of therapy. Flushes, skin and nail hyperpigmentation, photosensitivity, and hypersensitivity to irradiated skin (radiation-recall reaction) have been observed. Urticaria and anaphylaxis have been reported in patients treated with Epirubicin ; signs and symptoms of these reactions may vary from skin rash and pruritus to fever, chills, and shock. - In a retrospective survey, including 9144 patients, mostly with solid tumors in advanced stages, the probability of developing CHF increased with increasing cumulative doses of Epirubicin (Figure 1). The estimated risk of Epirubicin -treated patients developing clinically evident CHF was 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 700 mg/m2, and 3.3% at 900 mg/m2. The risk of developing CHF in the absence of other cardiac risk factors increased steeply after an Epirubicin cumulative dose of 900 mg/m2 . - In another retrospective survey of 469 Epirubicin -treated patients with metastatic or early breast cancer, the reported risk of CHF was comparable to that observed in the larger study of over 9000 patients. - Other serious drug-related cardiovascular adverse events that occurred during clinical trials with Epirubicin , administered in different indications, include ventricular tachycardia, AV block, bundle branch block, bradycardia and thromboembolism. - An analysis of 7110 patients who received adjuvant treatment with Epirubicin in controlled clinical trials as a component of poly-chemotherapy regimens for early breast cancer, showed a cumulative risk of secondary acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS) of about 0.27% (approximate 95% CI, 0.14–0.40) at 3 years, 0.46% (approximate 95% CI, 0.28–0.65) at 5 years, and 0.55% (approximate 95% CI, 0.33–0.78) at 8 years. The risk of developing AML/MDS increased with increasing Epirubicin cumulative doses as shown in Figure 2. ## Postmarketing Experience - The following adverse reactions have been identified during post-approval use of Epirubicin . 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. - Infections and infestations: sepsis, pneumonia - Immune system disorders: anaphylaxis - Metabolism and nutrition disorders: dehydration, hyperuricemia - Vascular disorders: shock, haemorrhage, embolism arterial, thrombophlebitis, phlebitis - Respiratory, thoracic and mediastinal disorders: pulmonary embolism - Gastrointestinal disorders: erosions, ulcerations, pain or burning sensation, bleeding, hyperpigmentation of the oral mucosa - Skin and subcutaneous tissue disorders: erythema, flushes, skin and nail hyperpigmentation, photosensitivity, hypersensitivity to irradiated skin (radiation-recall reaction), urticaria - Renal and urinary disorders: red coloration of urine for 1 to 2 days after administration - General disorders and administration site conditions: fever, chills - Injury, poisoning and procedural complications: chemical cystitis (following intravesical administration) # Drug Interactions - Do not administer epirubicin in combination with other cardiotoxic agents unless the patient's cardiac function is closely monitored. Patients receiving epirubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, may also be at an increased risk of developing cardiotoxicity - Concomitant use of Epirubicin with other cardioactive compounds that could cause heart failure (e.g., calcium channel blockers), requires close monitoring of cardiac function throughout treatment. - Cimetidine increases the exposure to epirubicin . Stop Cimetidine during treatment with Epirubicin . - Epirubicin used in combination with other cytotoxic drugs may show on-treatment additive toxicity, especially hematologic and gastrointestinal effects. - The administration of epirubicin immediately prior to or after paclitaxel increased the systemic exposure of epirubicin, epirubicinol and 7-deoxydoxorubicin aglycone . - The administration of epirubicin immediately prior to or after docetaxel did not have an effect on the systemic exposure of epirubicin, but increased the systemic exposure of epirubicinol and 7-deoxydoxorubicin aglycone . - There are few data regarding the coadministration of radiation therapy and Epirubicin . In adjuvant trials of Epirubicin -containing CEF-120 or FEC-100 chemotherapies, breast irradiation was delayed until after chemotherapy was completed. This practice resulted in no apparent increase in local breast cancer recurrence relative to published accounts in the literature. A small number of patients received Epirubicin -based chemotherapy concomitantly with radiation therapy but had chemotherapy interrupted in order to avoid potential overlapping toxicities. It is likely that use of Epirubicin with radiotherapy may sensitize tissues to the cytotoxic actions of irradiation. Administration of Epirubicin after previous radiation therapy may induce an inflammatory recall reaction at the site of the irradiation. - Epirubicin is extensively metabolized by the liver. Changes in hepatic function induced by concomitant therapies may affect epirubicin metabolism, pharmacokinetics, therapeutic efficacy, and/or toxicity. - There are no known interactions between Epirubicin and laboratory tests. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Epirubicin can cause fetal harm when administered to a pregnant woman. Administration of 0.8 mg/kg/day intravenously of epirubicin to rats (about 0.04 times the maximum recommended single human dose on a body surface area basis) during Days 5 to 15 of gestation was embryotoxic (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight), but was not teratogenic up to this dose. Administration of 2 mg/kg/day intravenously of epirubicin to rats (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 9 and 10 of gestation was embryotoxic (increased late resorptions, post-implantation losses, and dead fetuses; and decreased live fetuses), retarded fetal growth (decreased body weight), and caused decreased placental weight. This dose was also teratogenic, causing numerous external (anal atresia, misshapen tail, abnormal genital tubercle), visceral (primarily gastrointestinal, urinary, and cardiovascular systems), and skeletal (deformed long bones and girdles, rib abnormalities, irregular spinal ossification) malformations. Administration of intravenous epirubicin to rabbits at doses up to 0.2 mg/kg/day (about 0.02 times the maximum recommended single human dose on a body surface area basis) during Days 6 to 18 of gestation was not embryotoxic or teratogenic, but a maternally toxic dose of 0.32 mg/kg/day increased abortions and delayed ossification. Administration of a maternally toxic intravenous dose of 1 mg/kg/day epirubicin to rabbits (about 0.1 times the maximum recommended single human dose on a body surface area basis) on Days 10 to 12 of gestation induced abortion, but no other signs of embryofetal toxicity or teratogenicity were observed. When doses up to 0.5 mg/kg/day epirubicin were administered to rat dams from Day 17 of gestation to Day 21 after delivery (about 0.025 times the maximum recommended single human dose on a body surface area basis), no permanent changes were observed in the development, functional activity, behavior, or reproductive performance of the offspring. - There are no adequate and well-controlled studies of Epirubicin in pregnant women. Two pregnancies have been reported in women taking epirubicin. A 34-year-old woman, 28 weeks pregnant at her diagnosis of breast cancer, was treated with cyclophosphamide and epirubicin every 3 weeks for 3 cycles. She received the last dose at 34 weeks of pregnancy and delivered a healthy baby at 35 weeks. A second 34-year-old woman with breast cancer metastatic to the liver was randomized to FEC-50 but was removed from study because of pregnancy. She experienced a spontaneous abortion. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant Pregnancy Category (AUS): - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Epirubicin in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Epirubicin during labor and delivery. ### Nursing Mothers - Epirubicin was excreted into the milk of rats treated with 0.50 mg/kg/day of epirubicin during peri- and postnatal periods. It is not known whether this drug is excreted in human milk. Because many drugs, including other anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Epirubicin , a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - Safety and effectiveness of Epirubicin have not been established in pediatric patients. Pediatric patients may be at greater risk for anthracycline-induced acute manifestations of cardiotoxicity and for chronic CHF. The pharmacokinetics of epirubicin in pediatric patients have not been evaluated. ### Geriatic Use - Although a lower starting dose of Epirubicin was not used in trials in elderly female patients, particular care should be taken in monitoring toxicity when Epirubicin is administered to female patients ≥ 70 years of age ### Gender There is no FDA guidance on the use of Epirubicin with respect to specific gender populations. ### Race There is no FDA guidance on the use of Epirubicin with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Epirubicin in patients with renal impairment. ### Hepatic Impairment - Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in patients with hepatic dysfunction. Do not treat patients with severe hepatic impairment with Epirubicin . Reduce the starting dose for patients with less severe hepatic impairment. ### Females of Reproductive Potential and Males - No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol, have been observed in patients with serum creatinine < 5 mg/dL. Consider lower doses in patients with severe renal impairment (serum creatinine > 5 mg/dL), as a reduction in plasma clearance was reported in these patients .Patients on dialysis have not been studied ### Immunocompromised Patients There is no FDA guidance one the use of Epirubicin in patients who are immunocompromised. # Administration and Monitoring ### Administration - Intravenous ### Monitoring There is limited information regarding Monitoring of Epirubicin in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Epirubicin in the drug label. # Overdosage - There is no known antidote for overdoses of Epirubicin . A 36-year-old man with non-Hodgkin's lymphoma received a daily 95 mg/m2 dose of Epirubicin Injection for 5 consecutive days. Five days later, he developed bone marrow aplasia, grade 4 mucositis, and gastrointestinal bleeding. No signs of acute cardiac toxicity were observed. He was treated with antibiotics, colony-stimulating factors, and antifungal agents, and recovered completely. A 63-year-old woman with breast cancer and liver metastasis received a single 320 mg/m2 dose of Epirubicin . She was hospitalized with hyperthermia and developed multiple organ failure (respiratory and renal), with lactic acidosis, increased lactate dehydrogenase, and anuria. Death occurred within 24 hours after administration of Epirubicin . Additional instances of administration of doses higher than recommended have been reported at doses ranging from 150 to 250 mg/m2. The observed adverse events in these patients were qualitatively similar to known toxicities of epirubicin. Most of the patients recovered with appropriate supportive care. - If an overdose occurs, provide supportive treatment (including antibiotic therapy, blood and platelet transfusions, colony-stimulating factors, and intensive care as needed) until the recovery of toxicities. Delayed CHF has been observed months after anthracycline administration. Observe patients carefully over time for signs of CHF and provided with appropriate supportive therapy. # Pharmacology ## Mechanism of Action - Epirubicin is an anthracycline cytotoxic agent. Although it is known that anthracyclines can interfere with a number of biochemical and biological functions within eukaryotic cells, the precise mechanisms of epirubicin's cytotoxic and/or antiproliferative properties have not been completely elucidated. - Epirubicin forms a complex with DNA by intercalation of its planar rings between nucleotide base pairs, with consequent inhibition of nucleic acid (DNA and RNA) and protein synthesis. - Such intercalation triggers DNA cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also inhibits DNA helicase activity, preventing the enzymatic separation of double-stranded DNA and interfering with replication and transcription. Epirubicin is also involved in oxidation/reduction reactions by generating cytotoxic free radicals. The antiproliferative and cytotoxic activity of epirubicin is thought to result from these or other possible mechanisms. Epirubicin is cytotoxic in vitro to a variety of established murine and human cell lines and primary cultures of human tumors. It is also active in vivo against a variety of murine tumors and human xenografts in athymic mice, including breast tumors. ## Structure - Epirubicin Injection (epirubicin hydrochloride injection) is an anthracycline cytotoxic agent, intended for intravenous administration. Epirubicin is supplied as a sterile, clear, red solution and is available in polypropylene vials containing 50 and 200 mg of epirubicin hydrochloride as a preservative-free, ready-to-use solution. Each milliliter of solution contains 2 mg of epirubicin hydrochloride. Inactive ingredients include sodium chloride, USP, and water for injection, USP. The pH of the solution has been adjusted to 3.0 with hydrochloric acid, NF. - Epirubicin hydrochloride is the 4-epimer of doxorubicin and is a semi-synthetic derivative of daunorubicin. The chemical name is (8S-cis)-10-[(3-amino-2,3,6-trideoxy-α-L- arabino-hexopyranosyl)oxy]-7,8,9,10-tetrahydro6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione hydrochloride. The active ingredient is a red-orange hygroscopic powder, with the empirical formula C27 H29 NO11 HCl and a molecular weight of 579.95. The structural formula is as follows: ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Epirubicin in the drug label. ## Pharmacokinetics - Epirubicin pharmacokinetics are linear over the dose range of 60 to 150 mg/m2 and plasma clearance is not affected by the duration of infusion or administration schedule. Pharmacokinetic parameters for epirubicin following 6- to 10-minute, single-dose intravenous infusions of Epirubicin at doses of 60 to 150 mg/m2 in patients with solid tumors are shown in Table 4. The plasma concentration declined in a triphasic manner with mean half-lives for the alpha, beta, and gamma phases of about 3 minutes, 2.5 hours, and 33 hours, respectively. - Following intravenous administration, epirubicin is rapidly and widely distributed into the tissues. Binding of epirubicin to plasma proteins, predominantly albumin, is about 77% and is not affected by drug concentration. Epirubicin also appears to concentrate in red blood cells; whole blood concentrations are approximately twice those of plasma. - Epirubicin is extensively and rapidly metabolized by the liver and is also metabolized by other organs and cells, including red blood cells. Four main metabolic routes have been identified: - reduction of the C-13 keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol; - conjugation of both the unchanged drug and epirubicinol with glucuronic acid; - loss of the amino sugar moiety through a hydrolytic process with the formation of the doxorubicin and doxorubicinol aglycones; and - loss of the amino sugar moiety through a redox process with the formation of the 7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol has in vitro cytotoxic activity one-tenth that of epirubicin. As plasma levels of epirubicinol are lower than those of the unchanged drug, they are unlikely to reach in vivo concentrations sufficient for cytotoxicity. No significant activity or toxicity has been reported for the other metabolites. - Epirubicin and its major metabolites are eliminated through biliary excretion and, to a lesser extent, by urinary excretion. Mass-balance data from 1 patient found about 60% of the total radioactive dose in feces (34%) and urine (27%). These data are consistent with those from 3 patients with extrahepatic obstruction and percutaneous drainage, in whom approximately 35% and 20% of the administered dose were recovered as epirubicin or its major metabolites in bile and urine, respectively, in the 4 days after treatment. - A population analysis of plasma data from 36 cancer patients (13 males and 23 females, 20 to 73 years) showed that age affects plasma clearance of epirubicin in female patients. The predicted plasma clearance for a female patient of 70 years of age was about 35% lower than that for a female patient of 25 years of age. An insufficient number of males > 50 years of age were included in the study to draw conclusions about age-related alterations in clearance in males. Although a lower Epirubicin starting dose does not appear necessary in elderly female patients, and was not used in clinical trials, particular care should be taken in monitoring toxicity when Epirubicin is administered to female patients > 70 years of age. - In patients ≤ 50 years of age, mean clearance values in adult male and female patients were similar. The clearance of epirubicin is decreased in elderly women. - The influence of race on the pharmacokinetics of epirubicin has not been evaluated. - Epirubicin is eliminated by both hepatic metabolism and biliary excretion and clearance is reduced in patients with hepatic dysfunction. In a study of the effect of hepatic dysfunction, patients with solid tumors were classified into 3 groups. Patients in Group 1 (n=22) had serum AST (SGOT) levels above the upper limit of normal (median: 93 IU/L) and normal serum bilirubin levels (median: 0.5 mg/dL) and were given Epirubicin doses of 12.5 to 90 mg/m2. Patients in Group 2 had alterations in both serum AST (median: 175 IU/L) and bilirubin levels (median: 2.7 mg/dL) and were treated with an Epirubicin dose of 25 mg/m2 (n=8). Their pharmacokinetics were compared to those of patients with normal serum AST and bilirubin values, who received Epirubicin doses of 12.5 to 120 mg/m2. The median plasma clearance of epirubicin was decreased compared to patients with normal hepatic function by about 30% in patients in Group 1 and by 50% in patients in Group 2. Patients with more severe hepatic impairment have not been evaluated - No significant alterations in the pharmacokinetics of epirubicin or its major metabolite, epirubicinol, have been observed in patients with serum creatinine < 5 mg/dL. A 50% reduction in plasma clearance was reported in four patients with serum creatinine ≥ 5 mg/dL . Patients on dialysis have not been studied. - The administration of paclitaxel (175–225 mg/m2 as a 3-hour infusion) immediately before or after epirubicin (90 mg/m2 as bolus) caused variable increases in the systemic exposure (mean AUC) of epirubicin ranging from 5% to 109%. At same doses of epirubicin and paclitaxel, the mean AUC of the inactive metabolites of epirubicin (epirubicinol and 7-deoxy-aglycone) increased by 120% and 70%, respectively, when paclitaxel was immediately administered after epirubicin. Epirubicin had no effect on the exposure of paclitaxel whether it was administered before or after paclitaxel. - The administration of docetaxel (70 mg/m2 as 1-hour infusion) immediately before or after epirubicin (90 mg/m2 as bolus) had no effect on the systemic exposure (mean AUC) of epirubicin. However, the mean AUC of epirubicinol and 7-deoxy-aglycone increased by 22.5% and 95%, respectively, when docetaxel was immediately administered after epirubicin compared to epirubicin alone. Epirubicin had no effect on the exposure of docetaxel whether it was administered before or after docetaxel. - Coadministration of cimetidine (400 mg twice daily for 7 days starting 5 days before chemotherapy) increased the mean AUC of epirubicin (100 mg/m2) by 50% and decreased its plasma clearance by 30%. - No systematic in vitro or in vivo evaluation has been performed to examine the potential for inhibition or induction by epirubicin of oxidative cytochrome P-450 isoenzymes. ## Nonclinical Toxicology - Conventional long-term animal studies to evaluate the carcinogenic potential of epirubicin have not been conducted, but intravenous administration of a single 3.6 mg/kg epirubicin dose to female rats (about 0.2 times the maximum recommended human dose on a body surface area basis) approximately doubled the incidence of mammary tumors (primarily fibroadenomas) observed at 1 year. Administration of 0.5 mg/kg epirubicin intravenously to rats (about 0.025 times the maximum recommended human dose on a body surface area basis) every 3 weeks for ten doses increased the incidence of subcutaneous fibromas in males over an 18-month observation period. In addition, subcutaneous administration of 0.75 or 1.0 mg/kg/day (about 0.015 times the maximum recommended human dose on a body surface area basis) to newborn rats for 4 days on both the first and tenth day after birth for a total of eight doses increased the incidence of animals with tumors compared to controls during a 24-month observation period. - Epirubicin was mutagenic in vitro to bacteria (Ames test) either in the presence or absence of metabolic activation and to mammalian cells (HGPRT assay in V79 Chinese hamster lung fibroblasts) in the absence but not in the presence of metabolic activation. Epirubicin was clastogenic in vitro(chromosome aberrations in human lymphocytes) both in the presence and absence of metabolic activation and was also clastogenic in vivo (chromosome aberration in mouse bone marrow). - In fertility studies in rats, males were given epirubicin daily for 9 weeks and mated with females that were given epirubicin daily for 2 weeks prior to mating and through Day 7 of gestation. When 0.3 mg/kg/day (about 0.015 times the maximum recommended human single dose on a body surface area basis) was administered to both sexes, no pregnancies resulted. No effects on mating behavior or fertility were observed at 0.1 mg/kg/day, but male rats had atrophy of the testes and epididymis, and reduced spermatogenesis. The 0.1 mg/kg/day dose also caused embryolethality. An increased incidence of fetal growth retardation was observed in these studies at 0.03 mg/kg/day (about 0.0015 times the maximum recommended human single dose on a body surface area basis). Multiple daily doses of epirubicin to rabbits and dogs also caused atrophy of male reproductive organs. Single 20.5 and 12 mg/kg doses of intravenous epirubicin caused testicular atrophy in mice and rats, respectively (both approximately 0.5 times the maximum recommended human dose on a body surface area basis). A single dose of 16.7 mg/kg epirubicin caused uterine atrophy in rats. # Clinical Studies - Two randomized, open-label, multicenter studies evaluated the use of Epirubicin Injection 100 to 120 mg/m2 in combination with cyclophosphamide and fluorouracil for the adjuvant treatment of patients with axillary-node positive breast cancer and no evidence of distant metastatic disease (Stage II or III). Study MA-5 evaluated 120 mg/m2 of Epirubicin per course in combination with cyclophosphamide and fluorouracil (CEF-120 regimen). This study randomized premenopausal and perimenopausal women with one or more positive lymph nodes to an Epirubicin -containing CEF-120 regimen or to a CMF regimen. Study GFEA-05 evaluated the use of 100 mg/m2 of Epirubicin per course in combination with fluorouracil and cyclophosphamide (FEC-100). This study randomized pre- and postmenopausal women to the FEC-100 regimen or to a lower-dose FEC-50 regimen. In the GFEA-05 study, eligible patients were either required to have ≥ 4 nodes involved with tumor or, if only 1 to 3 nodes were positive, to have negative estrogen- and progesterone-receptors and a histologic tumor grade of 2 or 3. A total of 1281 women participated in these studies. Patients with T4 tumors were not eligible for either study. Table 5 shows the treatment regimens that the patients received. Relapse-free survival was defined as time to occurrence of a local, regional, or distant recurrence, or disease-related death. Patients with contralateral breast cancer, second primary malignancy, or death from causes other than breast cancer were censored at the time of the last visit prior to these events. - In the MA-5 trial, the median age of the study population was 45 years. Approximately 60% of patients had 1 to 3 involved nodes and approximately 40% had ≥ 4 nodes involved with tumor. In the GFEA-05 study, the median age was 51 years and approximately half of the patients were postmenopausal. About 17% of the study population had 1 to 3 positive nodes and 80% of patients had ≥ 4 involved lymph nodes. Demographic and tumor characteristics were well-balanced between treatment arms in each study. - Relapse-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier methods in the intent-to-treat (ITT) patient populations in each study. Results were initially analyzed after up to 5 years of follow-up and these results are presented in the text below and in Table 6. Results after up to 10 years of follow-up are presented in Table 6. In Study MA-5, Epirubicin -containing combination therapy (CEF-120) showed significantly longer RFS than CMF (5-year estimates were 62% versus 53%, stratified logrank for the overall RFS p=0.013). The estimated reduction in the risk of relapse was 24% at 5 years. The OS was also greater for the Epirubicin -containing CEF-120 regimen than for the CMF regimen (5-year estimate 77% versus 70%; stratified logrank for overall survival p=0.043; non-stratified logrank p=0.13). The estimated reduction in the risk of death was 29% at 5 years. - In Study GFEA-05, patients treated with the higher-dose Epirubicin regimen (FEC-100) had a significantly longer 5-year RFS (estimated 65% versus 52%, logrank for the overall RFS p=0.007) and OS (estimated 76% versus 65%, logrank for the overall survival p=0.007) than patients given the lower dose regimen (FEC-50). The estimated reduction in risk of relapse was 32% at 5 years. The estimated reduction in the risk of death was 31% at 5 years. Results of follow-up up to 10 years (median follow-up = 8.8 years and 8.3 years, respectively, for Study MA-5 and Study GFEA-05) are presented in Table 6. - Although the trials were not powered for subgroup analyses, in the MA-5 study, improvements in favor of CEF-120 vs. CMF were observed, in RFS and OS both in patients with 1–3 node positive and in those with ≥4 node positive tumor involvement. In the GFEA-05 study, improvements in RFS and OS were observed in both pre- and postmenopausal women treated with FEC-100 compared to FEC-50. # How Supplied - Epirubicin Injection is available in polypropylene single-use CYTOSAFE™ vials containing 2 mg epirubicin hydrochloride per mL as a sterile, preservative-free, ready-to-use solution in the following strengths: ## Storage - Store refrigerated between 2ºC and 8ºC (36ºF and 46ºF). Do not freeze. Protect from light.Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15–25ºC). Solution for injection should be used within 24 hours after removal from refrigeration. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Inform patients of the expected adverse effects of Epirubicin , including gastrointestinal symptoms (nausea, vomiting, diarrhea, and stomatitis), alopecia and potential neutropenic complications. - Patients should understand that there is a risk of irreversible myocardial damage associated with treatment with Epirubicin , as well as a risk of treatment-related leukemia. - Patients should consult their physician if vomiting, dehydration, fever, evidence of infection, symptoms of CHF, or injection-site pain occurs following therapy with Epirubicin . - Advise patients that their urine may appear red for 1 to 2 days after administration of Epirubicin and that they should not be alarmed. - Because Epirubicin may induce chromosomal damage in sperm, advise men undergoing treatment with Epirubicin to use effective contraceptive methods. Women treated with Epirubicin may develop irreversible amenorrhea, or premature menopause. # Precautions with Alcohol - Alcohol-Epirubicin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Epirubicin ® # Look-Alike Drug Names - EPIrubicin - eriBULin< # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ellence
3374d6839a1d9e25bf1ab134dbb97d1795a064e8	wikidoc	Elotuzumab	Elotuzumab # 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 Elotuzumab is a SLAMF7-directed immunostimulatory antibody that is FDA approved for the treatment of patients with multiple myeloma (in combination with lenalidomide and dexamethasone) who have received one to three prior therapies.. Common adverse reactions include fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, pneumonia (20%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Elotuzumab is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies. - Recommended Dosing - The recommended dosage of Elotuzumab is 10 mg/kg administered intravenously every week for the first two cycles and every 2 weeks thereafter in conjunction with the recommended dosing of lenalidomide and low-dose dexamethasone as described below. Continue treatment until disease progression or unacceptable toxicity. - Refer to the dexamethasone and lenalidomide prescribing information for additional information. - Patients must be premedicated before each dose of Elotuzumab. - Administer dexamethasone as follows: - On days that Elotuzumab is administered, give dexamethasone 28 mg orally between 3 and 24 hours before Elotuzumab plus 8 mg intravenously between 45 and 90 minutes before Elotuzumab. - On days that Elotuzumab is not administered but a dose of dexamethasone is scheduled (Days 8 and 22 of cycle 3 and all subsequent cycles), give 40 mg orally. - The recommended dosing is presented in Table 1. - Table 1: Recommended Dosing Schedule of Elotuzumab in Combination with Lenalidomide and Dexamethasone EMPLICITI: Elotuzumab's Brand name - Premedication - Dexamethasone - When Elotuzumab is used in combination with lenalidomide, divide dexamethasone into an oral and intravenous dose and administer as shown in Table 1. - Other Medications - In addition to dexamethasone, complete administration of the following medications 45 to 90 minutes prior to Elotuzumab infusion: - Dose Modifications - If the dose of one drug in the regimen is delayed, interrupted, or discontinued, the treatment with the other drugs may continue as scheduled. However, if dexamethasone is delayed or discontinued, base the decision whether to administer Elotuzumab on clinical judgment (i.e., risk of hypersensitivity). - If a Grade 2 or higher infusion reaction occurs during Elotuzumab administration, interrupt the infusion and institute appropriate medical and supportive measures. Upon resolution to Grade 1 or lower, restart Elotuzumab at 0.5 mL per minute and gradually increase at a rate of 0.5 mL per minute every 30 minutes as tolerated to the rate at which the infusion reaction occurred. Resume the escalation regimen if there is no recurrence of the infusion reaction (see Table 2). - In patients who experience an infusion reaction, monitor vital signs every 30 minutes for 2 hours after the end of the Elotuzumab infusion. If the infusion reaction recurs, stop the Elotuzumab infusion and do not restart on that day. Severe infusion reactions may require permanent discontinuation of Elotuzumab therapy and emergency treatment. - Dose delays and modifications for dexamethasone and lenalidomide should be performed as recommended in their Prescribing Information. - Table 2: Infusion Rate for Elotuzumab ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Elotuzumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Elotuzumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness 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 Elotuzumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Elotuzumab in pediatric patients. # Contraindications There are no contraindications to Elotuzumab. Because Elotuzumab is indicated for use in combination with lenalidomide and dexamethasone, healthcare providers should consult the prescribing information of these products for a complete description of contraindications before starting therapy. # Warnings Elotuzumab can cause infusion reactions. Infusion reactions were reported in approximately 10% of patients treated with Elotuzumab with lenalidomide and dexamethasone in the randomized trial in multiple myeloma. All reports of infusion reaction were Grade 3 or lower. Grade 3 infusion reactions occurred in 1% of patients. The most common symptoms of an infusion reaction included fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the trial, 5% of patients required interruption of the administration of Elotuzumab for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose. Administer premedication consisting of dexamethasone, antihistamines (H1 and H2 blockers) and acetaminophen prior to Elotuzumab infusion. Interrupt Elotuzumab infusion for Grade 2 or higher infusion reactions and institute appropriate medical management. In a clinical trial of patients with multiple myeloma (N=635), infections were reported in 81.4% of patients in the Elotuzumab combined with lenalidomide and dexamethasone (E-Ld) arm and 74.4% in lenalidomide and dexamethasone (Ld). Grade 3 to 4 infections were noted in 28% and 24.3% of E-Ld- and Ld-treated patients, respectively. Discontinuations due to infections occurred in 3.5% of E-Ld-treated and 4.1% of Ld-treated patients. Fatal infections were reported in 2.5% and 2.2% of E-Ld- and Ld-treated patients. Opportunistic infections were reported in 22% of patients in the E-Ld arm and 12.9% of patients in the Ld arm. Fungal infections occurred in 9.7% of patients in the E-Ld arm and 5.4% of patients in the Ld arm. Herpes zoster was reported in 13.5% of patients treated with E-Ld and 6.9% of patients treated with Ld. Monitor patients for development of infections and treat promptly. In a clinical trial of patients with multiple myeloma (N=635), invasive second primary malignancies (SPM) have been observed in 9.1% of patients treated with E-Ld and 5.7% of patients treated with Ld. The rate of hematologic malignancies were the same between E-Ld and Ld treatment arms (1.6%). Solid tumors were reported in 3.5% and 2.2% of E-Ld- and Ld-treated patients, respectively. Skin cancer was reported in 4.4% and 2.8% of patients treated with E-Ld and Ld, respectively. Monitor patients for the development of second primary malignancies. Elevations in liver enzymes (aspartate transaminase/alanine transaminase greater than 3 times the upper limit, total bilirubin greater than 2 times the upper limit, and alkaline phosphatase less than 2 times the upper limit) consistent with hepatotoxicity were reported in 2.5% and 0.6% of E-Ld- and Ld-treated patients in a clinical trial of patients with multiple myeloma (N=635). Two patients experiencing hepatotoxicity were not able to continue treatment; however, 6 out of 8 patients had resolution and were able to continue treatment. Monitor liver enzymes periodically. Stop Elotuzumab upon Grade 3 or higher elevation of liver enzymes. After return to baseline values, continuation of treatment may be considered. Elotuzumab is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPEP) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions are described in detail in other sections of the label: - Infusion reaction - Infections - Second Primary Malignancies - Hepatotoxicity - Interference with determination of complete response Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section are based on a randomized, open-label clinical trial in patients with previously treated multiple myeloma. In this study, Elotuzumab 10 mg/kg was administered with lenalidomide and dexamethasone. For adverse reaction evaluation, Elotuzumab combined with lenalidomide and dexamethasone was compared with lenalidomide and dexamethasone alone. The mean age of the population was 66 years and 57% of patients were 65 years of age or older. Sixty percent (60%) of the population were male, 84% were white, 10% were Asian, and 4% were black. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 47%, 1 in 44%, and 2 in 9% of patients. These data reflect exposure of 318 patients to Elotuzumab and 317 to control with a median number of cycles of 19 for Elotuzumab and 14 for control. Serious adverse reactions were reported in 65.4% of patients treated on the Elotuzumab arm and 56.5% for patients treated on the control arm. The most frequent serious adverse reactions in the Elotuzumab arm compared to the control arm were: pneumonia (15.4% vs. 11%), pyrexia (6.9% vs. 4.7%), respiratory tract infection (3.1% vs. 1.3%), anemia (2.8% vs. 1.9%), pulmonary embolism (3.1% vs. 2.5%), and acute renal failure (2.5% vs. 1.9%). The proportion of patients who discontinued any component of the treatment regimen due to adverse reactions as listed below was similar for both treatment arms; 6.0% for patients treated on the Elotuzumab arm and 6.3% for patients treated on the control. Adverse reactions occurring at a frequency of 10% or higher in the Elotuzumab arm and 5% or higher than the lenalidomide and dexamethasone arm for the randomized trial in multiple myeloma are presented in Table 4. - Table 4: Adverse Reactions with a 10% or Higher Incidence for Elotuzumab-Treated Patients and a 5% or Higher Incidence than Lenalidomide and Dexamethasone-Treated Patients EMPLICITI: Elotuzumab's Brand name Other clinically important adverse reactions reported in patients treated with Elotuzumab that did not meet the criteria for inclusion in Table 4 but occurred at a frequency of 5% or greater in the Elotuzumab group and at a frequency at least twice the control rate for the randomized trial in multiple myeloma are listed below: - General disorders and administration site conditions: chest pain - Immune system disorders: hypersensitivity - Nervous system disorders: hypoesthesia - Psychiatric disorders: mood altered - Skin and subcutaneous tissue disorders: night sweats Laboratory abnormalities worsening from baseline and occurring at a frequency of 10% or higher in the Elotuzumab group and 5% or higher than the lenalidomide and dexamethasone group (criteria met for all Grades or Grade 3/4) for the randomized trial in multiple myeloma are presented in Table 5. - Table 5:Laboratory Abnormalities Worsening from Baseline and with a 10% or Higher Incidence for Elotuzumab-Treated Patients and a 5% Higher Incidence than Lenalidomide and Dexamethasone-Treated Patients EMPLICITI: Elotuzumab's Brand name Vital sign abnormalities were assessed by treatment arm for the randomized trial in multiple myeloma and are presented in Table 6. Percentages are based on patients who had at least one on-treatment vital sign abnormality any time during the course of therapy. - Table 6: Vital Sign Abnormalities EMPLICITI: Elotuzumab's Brand name As with all therapeutic proteins, there is a potential for immunogenicity to Elotuzumab. Of 390 patients across four clinical studies who were treated with Elotuzumab and evaluable for the presence of anti-product antibodies, 72 patients (18.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. In 63 (88%) of these 72 patients, anti-product antibodies occurred within the first 2 months of the initiation of Elotuzumab treatment. Anti-product antibodies resolved by 2 to 4 months in 49 (78%) of these 63 patients. Neutralizing antibodies were detected in 19 of 299 patients in the randomized trial in multiple myeloma. 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 Elotuzumab with the incidences of antibodies to other products may be misleading. ## Postmarketing Experience There is limited information regarding Elotuzumab Postmarketing Experience in the drug label. # Drug Interactions No formal drug-drug interaction studies have been conducted with Elotuzumab. However, Elotuzumab is used in combination with lenalidomide and dexamethasone. Refer to the prescribing information for those products for important drug-drug interactions. - Laboratory Test Interference - Elotuzumab may be detected in the SPEP and serum immunofixation assays of myeloma patients and could interfere with correct response classification. A small peak in the early gamma region on SPEP that is IgGƙ on serum immunofixation may potentially be attributed to Elotuzumab, particularly in patients whose endogenous myeloma protein is IgA, IgM, IgD, or lambda light chain restricted. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N There are no studies with Elotuzumab with pregnant women to inform any drug associated risks. Animal reproduction studies have not been conducted with elotuzumab. Elotuzumab is administered in combination with lenalidomide and dexamethasone. Lenalidomide can cause embryo-fetal harm and is contraindicated for use in pregnancy. Refer to the lenalidomide and dexamethasone prescribing information for additional information. Lenalidomide is only available through a REMS program. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Elotuzumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Elotuzumab during labor and delivery. ### Nursing Mothers There is no information on the presence of Elotuzumab in human milk, the effect on the breast-fed infant, or the effect on milk production. Because of the potential for serious adverse reactions in breast-fed infants from elotuzumab administered with lenalidomide/dexamethasone, breastfeeding is not recommended. Refer to the lenalidomide and dexamethasone prescribing information for additional information. ### Pediatric Use Safety and effectiveness have not been established in pediatric patients. ### Geriatic Use Of the 646 patients across treatment groups in the randomized trial in multiple myeloma, 57% were 65 years of age or older; the number of patients 65 years or older was similar between treatment groups. No overall differences in efficacy or safety were observed between patients 65 years or older and younger patients (less than 65 years of age). ### Gender There is no FDA guidance on the use of Elotuzumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Elotuzumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Elotuzumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Elotuzumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males - Pregnancy Testing - Refer to the lenalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential. - When Elotuzumab is used with lenalidomide, there is a risk of fetal harm, including severe life-threatening human birth defects associated with lenalidomide, and the need to follow requirements regarding pregnancy avoidance, including testing. - Contraception - Refer to the lenalidomide labeling for contraception requirements prior to initiating treatment in females of reproductive potential and males. - Lenalidomide is present in the blood and semen of patients receiving the drug. Refer to the lenalidomide full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information. ### Immunocompromised Patients There is no FDA guidance one the use of Elotuzumab in patients who are immunocompromised. # Administration and Monitoring ### Administration Administer the entire Elotuzumab infusion with an infusion set and a sterile, nonpyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 micrometer) using an automated infusion pump. Initiate Elotuzumab infusion at a rate of 0.5 mL per minute. The infusion rate may be increased in a stepwise fashion as described in Table 2 if no infusion reactions develop. The maximum infusion rate should not exceed 2 mL per minute. Adjust the infusion rate following a Grade 2 or higher infusion reaction. In patients who have received 4 cycles of Elotuzumab treatment, the infusion rate may be increased to a maximum of 5 mL/min. Do not mix Elotuzumab with, or administer as an infusion with, other medicinal products. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of Elotuzumab with other agents. - Reconstitution and Preparation - Calculation of Dose - Table 3: Reconstitution Instructions for Elotuzumab EMPLICITI: Elotuzumab's Brand name - Reconstitution - Dilution Complete the Elotuzumab infusion within 24 hours of reconstitution of the Elotuzumab lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2ºC to 8ºC (36ºF-46ºF) and protected from light for up to 24 hours (a maximum of 8 hours of the total 24 hours can be at room temperature, 20°C to 25°C , and room light). ### Monitoring There is limited information regarding Elotuzumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Elotuzumab and IV administrations. # Overdosage The dose of Elotuzumab at which severe toxicity occurs is not known. Elotuzumab does not appear to be removed by dialysis as determined in a study of patients with renal impairment. In case of overdosage, monitor patients closely for signs or symptoms of adverse reactions and institute appropriate symptomatic treatment. # Pharmacology ## Mechanism of Action Elotuzumab is a humanized IgG1 monoclonal antibody that specifically targets the SLAMF7 (Signaling Lymphocytic Activation Molecule Family member 7) protein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on Natural Killer cells, plasma cells, and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage. Elotuzumab directly activates Natural Killer cells through both the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on myeloma cells and facilitates the interaction with Natural Killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity (ADCC). In preclinical models, the combination of elotuzumab and lenalidomide resulted in enhanced activation of Natural Killer cells that was greater than the effects of either agent alone and increased anti-tumor activity in vitro and in vivo. ## Structure Elotuzumab is a humanized recombinant monoclonal antibody directed to SLAMF7, a cell surface glycoprotein. Elotuzumab consists of the complementary determining regions (CDR) of the mouse antibody, MuLuc63, grafted onto human IgG1 heavy and kappa light chain frameworks. Elotuzumab is produced in NS0 cells by recombinant DNA technology. Elotuzumab has a theoretical mass of 148.1 kDa for the intact antibody. Elotuzumab is a sterile, nonpyrogenic, preservative-free lyophilized powder that is white to off-white, whole or fragmented cake in single-dose vials. Elotuzumab for Injection is supplied as 300 mg per vial and 400 mg per vial and requires reconstitution with Sterile Water for Injection, USP (13 mL and 17 mL, respectively) to obtain a solution with a concentration of 25 mg/mL. After reconstitution, each vial contains overfill to allow for withdrawal of 12 mL (300 mg) and 16 mL (400 mg). The reconstituted solution is colorless to slightly yellow, clear to slightly opalescent. Prior to intravenous infusion, the reconstituted solution is diluted with 230 mL of either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Each 300 mg single-dose vial of Elotuzumab also contains the following inactive ingredients: citric acid monohydrate (2.44 mg), polysorbate 80 (3.4 mg), sodium citrate (16.6 mg), and sucrose (510 mg). Each 400 mg single-dose vial of Elotuzumab also contains the following inactive ingredients: citric acid monohydrate (3.17 mg), polysorbate 80 (4.4 mg), sodium citrate (21.5 mg), and sucrose (660 mg). ## Pharmacodynamics - Cardiac Electrophysiology - Elotuzumab does not prolong the QT interval to any clinically relevant extent in combination with lenalidomide and dexamethasone at the recommended dose or as monotherapy (at a dose 2 times the recommended dose). ## Pharmacokinetics Elotuzumab exhibits nonlinear pharmacokinetics (PK) resulting in greater than proportional increases in area under the concentration-time curve (AUC) indicative of target-mediated clearance. The administration of the recommended 10 mg/kg Elotuzumab regimen in combination with lenalidomide/dexamethasone is predicted to result in geometric mean (CV%) steady-state trough concentrations of 194 μg/mL (52%). - Elimination: The clearance of elotuzumab decreased from a geometric mean (CV%) of 17.5 (21.2%) to 5.8 (31%) mL/day/kg with an increase in dose from 0.5 (i.e., 0.05 times the recommended dosage) to 20 mg/kg (i.e., 2 times the recommended dosage). Based on a population PK model, when elotuzumab is given in combination with lenalidomide and dexamethasone, approximately 97% of the maximum steady-state concentration is predicted to be eliminated with a geometric mean (CV%) of 82.4 (48%) days. - Specific Populations - Clinically significant differences were not observed in the pharmacokinetics of elotuzumab based on age (37-88 years), gender, race, baseline LDH, albumin, renal impairment ranging from mild to severe (creatinine clearance (CLcr) 15 to 89 mL/min) renal impairment, end-stage renal disease (CLcr less than 15 mL/min) with or without hemodialysis, and mild (NCI-CTEP) hepatic impairment. The pharmacokinetics of elotuzumab in patients with moderate to severe hepatic impairment is unknown. - Body weight: The clearance of elotuzumab increased with increasing body weight supporting a weight-based dose. ## Nonclinical Toxicology No carcinogenicity or mutagenicity data are available for elotuzumab in animals or humans. Fertility studies have not been performed for elotuzumab. # Clinical Studies The efficacy and safety of Elotuzumab in combination with lenalidomide and dexamethasone were evaluated in a randomized, open-label trial in patients with multiple myeloma who had received one to three prior therapies and had documented progression following their most recent therapy. Eligible patients were randomized in a 1:1 ratio to receive either Elotuzumab in combination with lenalidomide and low-dose dexamethasone or lenalidomide and low-dose dexamethasone. Treatment was administered in 4-week cycles until disease progression or unacceptable toxicity. Elotuzumab 10 mg/kg was administered intravenously each week for the first 2 cycles and every 2 weeks thereafter. Prior to Elotuzumab infusion, dexamethasone was administered as a divided dose: an oral dose of 28 mg and an intravenous dose of 8 mg. In the control group and on weeks without Elotuzumab, dexamethasone 40 mg was administered as a single oral dose weekly. Lenalidomide 25 mg was taken orally once daily for the first 3 weeks of each cycle. Assessment of tumor response was conducted every 4 weeks. A total of 646 patients were randomized to receive treatment: 321 to Elotuzumab in combination with lenalidomide and low-dose dexamethasone and 325 to lenalidomide and low-dose dexamethasone. Demographics and baseline disease characteristics were balanced between treatment arms. The median age was 66 years (range, 37-91); 57% of patients were 65 years or older; 60% of patients were male; whites comprised 84% of the study population, Asians 10%, and blacks 4%. The ECOG performance status was 0 in 47%, 1 in 44%, and 2 in 9% of patients, and ISS Stage was I in 43%, II in 32%, and III in 21% of patients. The cytogenetic categories of del 17p and t(4;14) were present in 32% and 9% of patients, respectively. The median number of prior therapies was 2. Thirty-five percent (35%) of patients were refractory (progression during or within 60 days of last therapy) and 65% were relapsed (progression after 60 days of last therapy). Prior therapies included stem cell transplant (55%), bortezomib (70%), melphalan (65%), thalidomide (48%), and lenalidomide (6%). The efficacy of Elotuzumab was evaluated by progression-free survival (PFS) as assessed by hazard ratio, and overall response rate (ORR) as determined by a blinded Independent Review Committee using the European Group for Blood and Marrow Transplantation (EBMT) response criteria. Efficacy results are shown in Table 7 and Figure 1. The median number of treatment cycles was 19 for the Elotuzumab group and 14 for the comparator arm with a minimum follow-up of two years. - Table 7: Efficacy Results EMPLICITI: Elotuzumab's Brand name - Figure 1: Progression-Free Survival EMPLICITI: Elotuzumab's Brand name The 1- and 2-year rates of PFS for Elotuzumab in combination with lenalidomide and dexamethasone treatment were 68% and 41%, respectively, compared with 57% and 27%, respectively, for lenalidomide and dexamethasone treatment. At the time of the interim analysis, there were 94 (29%) deaths in the Elotuzumab in combination with lenalidomide and dexamethasone study arm compared to 116 (36%) in the lenalidomide and dexamethasone study arm. # How Supplied Elotuzumab is white to off-white lyophilized powder available as follows: ## Storage Store Elotuzumab under refrigeration at 2°C to 8°C (36°F-46°F). Protect Elotuzumab from light by storing in the original package until time of use. Do not freeze or shake. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION). - Infusion Reactions - Elotuzumab may cause infusion reactions. Advise patients to contact their healthcare provider if they experience signs and symptoms of infusion reactions, including fever, chills, rash, or breathing problems within 24 hours of infusion. - Advise patients that they will be required to take the following oral medications prior to Elotuzumab dosing to reduce the risk of infusion reaction: - Pregnancy - Advise patients that lenalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Lenalidomide is only available through a REMS program. - Infections - Inform patients of the risk of developing infections during treatment with Elotuzumab, and to report any symptoms of infection. - Second Primary Malignancies - Inform patients of the risk of developing SPM during treatment with Elotuzumab. - Hepatotoxicity - Inform patients of the risk of hepatotoxicity during treatment with Elotuzumab and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. # Precautions with Alcohol Alcohol-Elotuzumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names EMPLICITI™ # Look-Alike Drug Names There is limited information regarding Elotuzumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Elotuzumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Martin Nino [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Elotuzumab is a SLAMF7-directed immunostimulatory antibody that is FDA approved for the treatment of patients with multiple myeloma (in combination with lenalidomide and dexamethasone) who have received one to three prior therapies.. Common adverse reactions include fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, pneumonia (20%). # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Elotuzumab is indicated in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who have received one to three prior therapies. - Recommended Dosing - The recommended dosage of Elotuzumab is 10 mg/kg administered intravenously every week for the first two cycles and every 2 weeks thereafter in conjunction with the recommended dosing of lenalidomide and low-dose dexamethasone as described below. Continue treatment until disease progression or unacceptable toxicity. - Refer to the dexamethasone and lenalidomide prescribing information for additional information. - Patients must be premedicated before each dose of Elotuzumab. - Administer dexamethasone as follows: - On days that Elotuzumab is administered, give dexamethasone 28 mg orally between 3 and 24 hours before Elotuzumab plus 8 mg intravenously between 45 and 90 minutes before Elotuzumab. - On days that Elotuzumab is not administered but a dose of dexamethasone is scheduled (Days 8 and 22 of cycle 3 and all subsequent cycles), give 40 mg orally. - The recommended dosing is presented in Table 1. - Table 1: Recommended Dosing Schedule of Elotuzumab in Combination with Lenalidomide and Dexamethasone EMPLICITI: Elotuzumab's Brand name - Premedication - Dexamethasone - When Elotuzumab is used in combination with lenalidomide, divide dexamethasone into an oral and intravenous dose and administer as shown in Table 1. - Other Medications - In addition to dexamethasone, complete administration of the following medications 45 to 90 minutes prior to Elotuzumab infusion: - Dose Modifications - If the dose of one drug in the regimen is delayed, interrupted, or discontinued, the treatment with the other drugs may continue as scheduled. However, if dexamethasone is delayed or discontinued, base the decision whether to administer Elotuzumab on clinical judgment (i.e., risk of hypersensitivity). - If a Grade 2 or higher infusion reaction occurs during Elotuzumab administration, interrupt the infusion and institute appropriate medical and supportive measures. Upon resolution to Grade 1 or lower, restart Elotuzumab at 0.5 mL per minute and gradually increase at a rate of 0.5 mL per minute every 30 minutes as tolerated to the rate at which the infusion reaction occurred. Resume the escalation regimen if there is no recurrence of the infusion reaction (see Table 2). - In patients who experience an infusion reaction, monitor vital signs every 30 minutes for 2 hours after the end of the Elotuzumab infusion. If the infusion reaction recurs, stop the Elotuzumab infusion and do not restart on that day. Severe infusion reactions may require permanent discontinuation of Elotuzumab therapy and emergency treatment. - Dose delays and modifications for dexamethasone and lenalidomide should be performed as recommended in their Prescribing Information. - Table 2: Infusion Rate for Elotuzumab ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Elotuzumab in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Elotuzumab in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) Safety and effectiveness 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 Elotuzumab in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Elotuzumab in pediatric patients. # Contraindications There are no contraindications to Elotuzumab. Because Elotuzumab is indicated for use in combination with lenalidomide and dexamethasone, healthcare providers should consult the prescribing information of these products for a complete description of contraindications before starting therapy. # Warnings Elotuzumab can cause infusion reactions. Infusion reactions were reported in approximately 10% of patients treated with Elotuzumab with lenalidomide and dexamethasone in the randomized trial in multiple myeloma. All reports of infusion reaction were Grade 3 or lower. Grade 3 infusion reactions occurred in 1% of patients. The most common symptoms of an infusion reaction included fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the trial, 5% of patients required interruption of the administration of Elotuzumab for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose. Administer premedication consisting of dexamethasone, antihistamines (H1 and H2 blockers) and acetaminophen prior to Elotuzumab infusion. Interrupt Elotuzumab infusion for Grade 2 or higher infusion reactions and institute appropriate medical management. In a clinical trial of patients with multiple myeloma (N=635), infections were reported in 81.4% of patients in the Elotuzumab combined with lenalidomide and dexamethasone (E-Ld) arm and 74.4% in lenalidomide and dexamethasone (Ld). Grade 3 to 4 infections were noted in 28% and 24.3% of E-Ld- and Ld-treated patients, respectively. Discontinuations due to infections occurred in 3.5% of E-Ld-treated and 4.1% of Ld-treated patients. Fatal infections were reported in 2.5% and 2.2% of E-Ld- and Ld-treated patients. Opportunistic infections were reported in 22% of patients in the E-Ld arm and 12.9% of patients in the Ld arm. Fungal infections occurred in 9.7% of patients in the E-Ld arm and 5.4% of patients in the Ld arm. Herpes zoster was reported in 13.5% of patients treated with E-Ld and 6.9% of patients treated with Ld. Monitor patients for development of infections and treat promptly. In a clinical trial of patients with multiple myeloma (N=635), invasive second primary malignancies (SPM) have been observed in 9.1% of patients treated with E-Ld and 5.7% of patients treated with Ld. The rate of hematologic malignancies were the same between E-Ld and Ld treatment arms (1.6%). Solid tumors were reported in 3.5% and 2.2% of E-Ld- and Ld-treated patients, respectively. Skin cancer was reported in 4.4% and 2.8% of patients treated with E-Ld and Ld, respectively. Monitor patients for the development of second primary malignancies. Elevations in liver enzymes (aspartate transaminase/alanine transaminase [AST/ALT] greater than 3 times the upper limit, total bilirubin greater than 2 times the upper limit, and alkaline phosphatase less than 2 times the upper limit) consistent with hepatotoxicity were reported in 2.5% and 0.6% of E-Ld- and Ld-treated patients in a clinical trial of patients with multiple myeloma (N=635). Two patients experiencing hepatotoxicity were not able to continue treatment; however, 6 out of 8 patients had resolution and were able to continue treatment. Monitor liver enzymes periodically. Stop Elotuzumab upon Grade 3 or higher elevation of liver enzymes. After return to baseline values, continuation of treatment may be considered. Elotuzumab is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPEP) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein. # Adverse Reactions ## Clinical Trials Experience The following adverse reactions are described in detail in other sections of the label: - Infusion reaction - Infections - Second Primary Malignancies - Hepatotoxicity - Interference with determination of complete response Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section are based on a randomized, open-label clinical trial in patients with previously treated multiple myeloma. In this study, Elotuzumab 10 mg/kg was administered with lenalidomide and dexamethasone. For adverse reaction evaluation, Elotuzumab combined with lenalidomide and dexamethasone was compared with lenalidomide and dexamethasone alone. The mean age of the population was 66 years and 57% of patients were 65 years of age or older. Sixty percent (60%) of the population were male, 84% were white, 10% were Asian, and 4% were black. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 47%, 1 in 44%, and 2 in 9% of patients. These data reflect exposure of 318 patients to Elotuzumab and 317 to control with a median number of cycles of 19 for Elotuzumab and 14 for control. Serious adverse reactions were reported in 65.4% of patients treated on the Elotuzumab arm and 56.5% for patients treated on the control arm. The most frequent serious adverse reactions in the Elotuzumab arm compared to the control arm were: pneumonia (15.4% vs. 11%), pyrexia (6.9% vs. 4.7%), respiratory tract infection (3.1% vs. 1.3%), anemia (2.8% vs. 1.9%), pulmonary embolism (3.1% vs. 2.5%), and acute renal failure (2.5% vs. 1.9%). The proportion of patients who discontinued any component of the treatment regimen due to adverse reactions as listed below was similar for both treatment arms; 6.0% for patients treated on the Elotuzumab arm and 6.3% for patients treated on the control. Adverse reactions occurring at a frequency of 10% or higher in the Elotuzumab arm and 5% or higher than the lenalidomide and dexamethasone arm for the randomized trial in multiple myeloma are presented in Table 4. - Table 4: Adverse Reactions with a 10% or Higher Incidence for Elotuzumab-Treated Patients and a 5% or Higher Incidence than Lenalidomide and Dexamethasone-Treated Patients [All Grades] EMPLICITI: Elotuzumab's Brand name Other clinically important adverse reactions reported in patients treated with Elotuzumab that did not meet the criteria for inclusion in Table 4 but occurred at a frequency of 5% or greater in the Elotuzumab group and at a frequency at least twice the control rate for the randomized trial in multiple myeloma are listed below: - General disorders and administration site conditions: chest pain - Immune system disorders: hypersensitivity - Nervous system disorders: hypoesthesia - Psychiatric disorders: mood altered - Skin and subcutaneous tissue disorders: night sweats Laboratory abnormalities worsening from baseline and occurring at a frequency of 10% or higher in the Elotuzumab group and 5% or higher than the lenalidomide and dexamethasone group (criteria met for all Grades or Grade 3/4) for the randomized trial in multiple myeloma are presented in Table 5. - Table 5:Laboratory Abnormalities Worsening from Baseline and with a 10% or Higher Incidence for Elotuzumab-Treated Patients and a 5% Higher Incidence than Lenalidomide and Dexamethasone-Treated Patients [Criteria met for All Grades or Grade 3/4] EMPLICITI: Elotuzumab's Brand name Vital sign abnormalities were assessed by treatment arm for the randomized trial in multiple myeloma and are presented in Table 6. Percentages are based on patients who had at least one on-treatment vital sign abnormality any time during the course of therapy. - Table 6: Vital Sign Abnormalities EMPLICITI: Elotuzumab's Brand name As with all therapeutic proteins, there is a potential for immunogenicity to Elotuzumab. Of 390 patients across four clinical studies who were treated with Elotuzumab and evaluable for the presence of anti-product antibodies, 72 patients (18.5%) tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. In 63 (88%) of these 72 patients, anti-product antibodies occurred within the first 2 months of the initiation of Elotuzumab treatment. Anti-product antibodies resolved by 2 to 4 months in 49 (78%) of these 63 patients. Neutralizing antibodies were detected in 19 of 299 patients in the randomized trial in multiple myeloma. 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 Elotuzumab with the incidences of antibodies to other products may be misleading. ## Postmarketing Experience There is limited information regarding Elotuzumab Postmarketing Experience in the drug label. # Drug Interactions No formal drug-drug interaction studies have been conducted with Elotuzumab. However, Elotuzumab is used in combination with lenalidomide and dexamethasone. Refer to the prescribing information for those products for important drug-drug interactions. - Laboratory Test Interference - Elotuzumab may be detected in the SPEP and serum immunofixation assays of myeloma patients and could interfere with correct response classification. A small peak in the early gamma region on SPEP that is IgGƙ on serum immunofixation may potentially be attributed to Elotuzumab, particularly in patients whose endogenous myeloma protein is IgA, IgM, IgD, or lambda light chain restricted. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): N There are no studies with Elotuzumab with pregnant women to inform any drug associated risks. Animal reproduction studies have not been conducted with elotuzumab. Elotuzumab is administered in combination with lenalidomide and dexamethasone. Lenalidomide can cause embryo-fetal harm and is contraindicated for use in pregnancy. Refer to the lenalidomide and dexamethasone prescribing information for additional information. Lenalidomide is only available through a REMS program. The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Elotuzumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Elotuzumab during labor and delivery. ### Nursing Mothers There is no information on the presence of Elotuzumab in human milk, the effect on the breast-fed infant, or the effect on milk production. Because of the potential for serious adverse reactions in breast-fed infants from elotuzumab administered with lenalidomide/dexamethasone, breastfeeding is not recommended. Refer to the lenalidomide and dexamethasone prescribing information for additional information. ### Pediatric Use Safety and effectiveness have not been established in pediatric patients. ### Geriatic Use Of the 646 patients across treatment groups in the randomized trial in multiple myeloma, 57% were 65 years of age or older; the number of patients 65 years or older was similar between treatment groups. No overall differences in efficacy or safety were observed between patients 65 years or older and younger patients (less than 65 years of age). ### Gender There is no FDA guidance on the use of Elotuzumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Elotuzumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Elotuzumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Elotuzumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males - Pregnancy Testing - Refer to the lenalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential. - When Elotuzumab is used with lenalidomide, there is a risk of fetal harm, including severe life-threatening human birth defects associated with lenalidomide, and the need to follow requirements regarding pregnancy avoidance, including testing. - Contraception - Refer to the lenalidomide labeling for contraception requirements prior to initiating treatment in females of reproductive potential and males. - Lenalidomide is present in the blood and semen of patients receiving the drug. Refer to the lenalidomide full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information. ### Immunocompromised Patients There is no FDA guidance one the use of Elotuzumab in patients who are immunocompromised. # Administration and Monitoring ### Administration Administer the entire Elotuzumab infusion with an infusion set and a sterile, nonpyrogenic, low-protein-binding filter (with a pore size of 0.2-1.2 micrometer) using an automated infusion pump. Initiate Elotuzumab infusion at a rate of 0.5 mL per minute. The infusion rate may be increased in a stepwise fashion as described in Table 2 if no infusion reactions develop. The maximum infusion rate should not exceed 2 mL per minute. Adjust the infusion rate following a Grade 2 or higher infusion reaction. In patients who have received 4 cycles of Elotuzumab treatment, the infusion rate may be increased to a maximum of 5 mL/min. Do not mix Elotuzumab with, or administer as an infusion with, other medicinal products. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of Elotuzumab with other agents. - Reconstitution and Preparation - Calculation of Dose - Table 3: Reconstitution Instructions for Elotuzumab EMPLICITI: Elotuzumab's Brand name - Reconstitution - Dilution Complete the Elotuzumab infusion within 24 hours of reconstitution of the Elotuzumab lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2ºC to 8ºC (36ºF-46ºF) and protected from light for up to 24 hours (a maximum of 8 hours of the total 24 hours can be at room temperature, 20°C to 25°C [68°F-77°F], and room light). ### Monitoring There is limited information regarding Elotuzumab Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Elotuzumab and IV administrations. # Overdosage The dose of Elotuzumab at which severe toxicity occurs is not known. Elotuzumab does not appear to be removed by dialysis as determined in a study of patients with renal impairment. In case of overdosage, monitor patients closely for signs or symptoms of adverse reactions and institute appropriate symptomatic treatment. # Pharmacology ## Mechanism of Action Elotuzumab is a humanized IgG1 monoclonal antibody that specifically targets the SLAMF7 (Signaling Lymphocytic Activation Molecule Family member 7) protein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on Natural Killer cells, plasma cells, and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage. Elotuzumab directly activates Natural Killer cells through both the SLAMF7 pathway and Fc receptors. Elotuzumab also targets SLAMF7 on myeloma cells and facilitates the interaction with Natural Killer cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity (ADCC). In preclinical models, the combination of elotuzumab and lenalidomide resulted in enhanced activation of Natural Killer cells that was greater than the effects of either agent alone and increased anti-tumor activity in vitro and in vivo. ## Structure Elotuzumab is a humanized recombinant monoclonal antibody directed to SLAMF7, a cell surface glycoprotein. Elotuzumab consists of the complementary determining regions (CDR) of the mouse antibody, MuLuc63, grafted onto human IgG1 heavy and kappa light chain frameworks. Elotuzumab is produced in NS0 cells by recombinant DNA technology. Elotuzumab has a theoretical mass of 148.1 kDa for the intact antibody. Elotuzumab is a sterile, nonpyrogenic, preservative-free lyophilized powder that is white to off-white, whole or fragmented cake in single-dose vials. Elotuzumab for Injection is supplied as 300 mg per vial and 400 mg per vial and requires reconstitution with Sterile Water for Injection, USP (13 mL and 17 mL, respectively) to obtain a solution with a concentration of 25 mg/mL. After reconstitution, each vial contains overfill to allow for withdrawal of 12 mL (300 mg) and 16 mL (400 mg). The reconstituted solution is colorless to slightly yellow, clear to slightly opalescent. Prior to intravenous infusion, the reconstituted solution is diluted with 230 mL of either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Each 300 mg single-dose vial of Elotuzumab also contains the following inactive ingredients: citric acid monohydrate (2.44 mg), polysorbate 80 (3.4 mg), sodium citrate (16.6 mg), and sucrose (510 mg). Each 400 mg single-dose vial of Elotuzumab also contains the following inactive ingredients: citric acid monohydrate (3.17 mg), polysorbate 80 (4.4 mg), sodium citrate (21.5 mg), and sucrose (660 mg). ## Pharmacodynamics - Cardiac Electrophysiology - Elotuzumab does not prolong the QT interval to any clinically relevant extent in combination with lenalidomide and dexamethasone at the recommended dose or as monotherapy (at a dose 2 times the recommended dose). ## Pharmacokinetics Elotuzumab exhibits nonlinear pharmacokinetics (PK) resulting in greater than proportional increases in area under the concentration-time curve (AUC) indicative of target-mediated clearance. The administration of the recommended 10 mg/kg Elotuzumab regimen in combination with lenalidomide/dexamethasone is predicted to result in geometric mean (CV%) steady-state trough concentrations of 194 μg/mL (52%). - Elimination: The clearance of elotuzumab decreased from a geometric mean (CV%) of 17.5 (21.2%) to 5.8 (31%) mL/day/kg with an increase in dose from 0.5 (i.e., 0.05 times the recommended dosage) to 20 mg/kg (i.e., 2 times the recommended dosage). Based on a population PK model, when elotuzumab is given in combination with lenalidomide and dexamethasone, approximately 97% of the maximum steady-state concentration is predicted to be eliminated with a geometric mean (CV%) of 82.4 (48%) days. - Specific Populations - Clinically significant differences were not observed in the pharmacokinetics of elotuzumab based on age (37-88 years), gender, race, baseline LDH, albumin, renal impairment ranging from mild to severe (creatinine clearance (CLcr) 15 to 89 mL/min) renal impairment, end-stage renal disease (CLcr less than 15 mL/min) with or without hemodialysis, and mild (NCI-CTEP) hepatic impairment. The pharmacokinetics of elotuzumab in patients with moderate to severe hepatic impairment is unknown. - Body weight: The clearance of elotuzumab increased with increasing body weight supporting a weight-based dose. ## Nonclinical Toxicology No carcinogenicity or mutagenicity data are available for elotuzumab in animals or humans. Fertility studies have not been performed for elotuzumab. # Clinical Studies The efficacy and safety of Elotuzumab in combination with lenalidomide and dexamethasone were evaluated in a randomized, open-label trial in patients with multiple myeloma who had received one to three prior therapies and had documented progression following their most recent therapy. Eligible patients were randomized in a 1:1 ratio to receive either Elotuzumab in combination with lenalidomide and low-dose dexamethasone or lenalidomide and low-dose dexamethasone. Treatment was administered in 4-week cycles until disease progression or unacceptable toxicity. Elotuzumab 10 mg/kg was administered intravenously each week for the first 2 cycles and every 2 weeks thereafter. Prior to Elotuzumab infusion, dexamethasone was administered as a divided dose: an oral dose of 28 mg and an intravenous dose of 8 mg. In the control group and on weeks without Elotuzumab, dexamethasone 40 mg was administered as a single oral dose weekly. Lenalidomide 25 mg was taken orally once daily for the first 3 weeks of each cycle. Assessment of tumor response was conducted every 4 weeks. A total of 646 patients were randomized to receive treatment: 321 to Elotuzumab in combination with lenalidomide and low-dose dexamethasone and 325 to lenalidomide and low-dose dexamethasone. Demographics and baseline disease characteristics were balanced between treatment arms. The median age was 66 years (range, 37-91); 57% of patients were 65 years or older; 60% of patients were male; whites comprised 84% of the study population, Asians 10%, and blacks 4%. The ECOG performance status was 0 in 47%, 1 in 44%, and 2 in 9% of patients, and ISS Stage was I in 43%, II in 32%, and III in 21% of patients. The cytogenetic categories of del 17p and t(4;14) were present in 32% and 9% of patients, respectively. The median number of prior therapies was 2. Thirty-five percent (35%) of patients were refractory (progression during or within 60 days of last therapy) and 65% were relapsed (progression after 60 days of last therapy). Prior therapies included stem cell transplant (55%), bortezomib (70%), melphalan (65%), thalidomide (48%), and lenalidomide (6%). The efficacy of Elotuzumab was evaluated by progression-free survival (PFS) as assessed by hazard ratio, and overall response rate (ORR) as determined by a blinded Independent Review Committee using the European Group for Blood and Marrow Transplantation (EBMT) response criteria. Efficacy results are shown in Table 7 and Figure 1. The median number of treatment cycles was 19 for the Elotuzumab group and 14 for the comparator arm with a minimum follow-up of two years. - Table 7: Efficacy Results EMPLICITI: Elotuzumab's Brand name - Figure 1: Progression-Free Survival EMPLICITI: Elotuzumab's Brand name The 1- and 2-year rates of PFS for Elotuzumab in combination with lenalidomide and dexamethasone treatment were 68% and 41%, respectively, compared with 57% and 27%, respectively, for lenalidomide and dexamethasone treatment. At the time of the interim analysis, there were 94 (29%) deaths in the Elotuzumab in combination with lenalidomide and dexamethasone study arm compared to 116 (36%) in the lenalidomide and dexamethasone study arm. # How Supplied Elotuzumab is white to off-white lyophilized powder available as follows: ## Storage Store Elotuzumab under refrigeration at 2°C to 8°C (36°F-46°F). Protect Elotuzumab from light by storing in the original package until time of use. Do not freeze or shake. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION). - Infusion Reactions - Elotuzumab may cause infusion reactions. Advise patients to contact their healthcare provider if they experience signs and symptoms of infusion reactions, including fever, chills, rash, or breathing problems within 24 hours of infusion. - Advise patients that they will be required to take the following oral medications prior to Elotuzumab dosing to reduce the risk of infusion reaction: - Pregnancy - Advise patients that lenalidomide has the potential to cause fetal harm and has specific requirements regarding contraception, pregnancy testing, blood and sperm donation, and transmission in sperm. Lenalidomide is only available through a REMS program. - Infections - Inform patients of the risk of developing infections during treatment with Elotuzumab, and to report any symptoms of infection. - Second Primary Malignancies - Inform patients of the risk of developing SPM during treatment with Elotuzumab. - Hepatotoxicity - Inform patients of the risk of hepatotoxicity during treatment with Elotuzumab and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. # Precautions with Alcohol Alcohol-Elotuzumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names EMPLICITI™ # Look-Alike Drug Names There is limited information regarding Elotuzumab Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Elotuzumab
649a25d2195c6ec83fb13287a4b31cc2dabf4157	wikidoc	Embryology	Embryology # Overview Embryology is the study of the development of an embryo. An embryo is defined as any vertebrate in a stage before birth or hatching. Embryology is more specific as it only encompasses the modern definition: an animal that is undergoing early development including the formation of primitive organ systems, the creation of fundamental tissues, and cleavage; especially involving the development of human individuals from the moment the blastocyst is implanted until the end of the eight week after conception. Past the eight week, the developing animal is called a fetus. # History After the 1950s, with the DNA helical structure being discovered by James D. Watson and Francis Crick, (in collaboration with Rosalind Franklin and Maurice Wilkins) and the increasing knowledge in the field of molecular biology, developmental biology emerged as the field of study that correlates the genes and such morphological changes; in other words, which genes are responsible for each morphological change that takes place in an embryo, and how these genes are regulated. # Vertebrate and invertebrate embryology Many principles of embryology apply to both invertebrate animals as well as to vertebrates. Therefore, study of invertebrate embryology has advanced the study of vertebrate embryology. However, there are many differences as well. For example, numerous invertebrate species release a larva before development is complete; at the end of the larval period, an animal for the first time looks like an offspring of its parents. Although invertebrate embryology is similar in some ways for different invertebrate animals, there are also countless variations. For instance, some insects proceed directly from egg to adult form whereas others develop through an elaborate sequence of changes. # Neuroembryology Neuroembryology refers to the development of an embryos nervous system. At the middle of the third week the neural plate appears which originates from the ectoderm.	Embryology Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Embryology is the study of the development of an embryo. An embryo is defined as any vertebrate in a stage before birth or hatching. Embryology is more specific as it only encompasses the modern definition: an animal that is undergoing early development including the formation of primitive organ systems, the creation of fundamental tissues, and cleavage; especially involving the development of human individuals from the moment the blastocyst is implanted until the end of the eight week after conception. Past the eight week, the developing animal is called a fetus. # History After the 1950s, with the DNA helical structure being discovered by James D. Watson and Francis Crick, (in collaboration with Rosalind Franklin and Maurice Wilkins) and the increasing knowledge in the field of molecular biology, developmental biology emerged as the field of study that correlates the genes and such morphological changes; in other words, which genes are responsible for each morphological change that takes place in an embryo, and how these genes are regulated. # Vertebrate and invertebrate embryology Many principles of embryology apply to both invertebrate animals as well as to vertebrates.[1] Therefore, study of invertebrate embryology has advanced the study of vertebrate embryology. However, there are many differences as well. For example, numerous invertebrate species release a larva before development is complete; at the end of the larval period, an animal for the first time looks like an offspring of its parents. Although invertebrate embryology is similar in some ways for different invertebrate animals, there are also countless variations. For instance, some insects proceed directly from egg to adult form whereas others develop through an elaborate sequence of changes. # Neuroembryology Neuroembryology refers to the development of an embryos nervous system. At the middle of the third week the neural plate appears which originates from the ectoderm.	https://www.wikidoc.org/index.php/Embryologic
0168e314bdd5b4dbf1c240048a96fec296d7a168	wikidoc	Emedastine	Emedastine # 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 Emedastine is an antihistamine that is FDA approved for the treatment of signs and symptoms of allergic conjunctivitis. Common adverse reactions include headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - emedastine is indicated for the temporary relief of the signs and symptoms of allergic conjunctivitis. - Emedastineis indicated for the temporary relief of the signs and symptoms of allergic conjunctivitis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Emedastine in adult patients. ### Non–Guideline-Supported Use - Asthma; Adjunct # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Emedastine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Emedastine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Emedastine in pediatric patients. # Contraindications - EMADINE® (emedastine difumarate ophthalmic solution) is contraindicated in persons with a known hypersensitivity to emedastine difumarate or any of its components. # Warnings - FOR TOPICAL OPHTHALMIC USE ONLY - NOT FOR INJECTION OR ORAL USE. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Emedastine Clinical Trials Experience in the drug label. ## Postmarketing Experience - In controlled clinical studies of emedastine lasting for 42 days, the most frequent adverse reaction was headache 11%. The following adverse experiences were reported in less than 5% of patients: Abnormal dreams, asthenia, bad taste, blurred vision, burning or stinging, corneal infiltrates, corneal staining, dermatitis, discomfort, dry eye, foreign body sensation, hyperemia, keratitis, pruritus, rhinitis, sinusitis and tearing. Some of these events were similar to the underlying disease being studied. # Drug Interactions There is limited information regarding Emedastine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Teratology and peri- and post-natal studies have been conducted with emedastine difumarate in rats and rabbits. At 15,000 times the maximum recommended ocular human use level, emedastine difumarate was shown not to be teratogenic in rats and rabbits and no effects on peri/post-natal development were observed in rats. However, at 70,000 times the maximum recommended ocular human use level, emedastine difumarate was shown to increase the incidence of external, visceral and skeletal anomalies in rats. There are, however, no adequate and well controlled studies in pregnant women. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Emedastine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Emedastine during labor and delivery. ### Nursing Mothers - Emedastine has been identified in breast milk in rats following oral administration. It is not known whether topical ocular administration could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, caution should be exercised when emedastine is administered to a nursing mother. ### Pediatric Use Safety and effectiveness in pediatric patients below the age of 3 years have not been established. ### 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 Emedastine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Emedastine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Emedastine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Emedastine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Emedastine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Emedastine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Emedastine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Emedastine in the drug label. # Overdosage - Somnolence and malaise have been reported following daily oral administration. Oral ingestion of the contents of a 15 mL DROP-TAINER® dispenser would be equivalent to 7.5 mg. In case of overdosage, treatment is symptomatic and supportive. # Pharmacology ## Mechanism of Action - Emedastine is a relatively selective, histamine H1 antagonist. In vitro examinations of emedastine's affinity for histamine receptors (H1: Ki=1.3 nM, H2: Ki=49,067 nM, and H3: Ki=12,430 nM) demonstrate relative selectivity for the H1 histamine receptor. - In vivo studies have shown concentration-dependent inhibition of histamine-stimulated vascular permeability in the conjunctiva following topical ocular administration. Emedastine appears to be devoid of effects on adrenergic, dopaminergic and serotonin receptors. ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Emedastine in the drug label. ## Pharmacokinetics - Following topical administration in man, emedastine was shown to have low systemic exposure. In a study involving 10 normal volunteers dosed bilaterally twice daily for 15 days with emedastine ophthalmic solution 0.05%, plasma concentrations of the parent compound were generally below the quantitation limit of the assay (<0.3 ng/mL). Samples in which emedastine was quantifiable ranged from 0.30 to 0.49 ng/mL. The elimination half-life of oral emedastine in plasma is 3-4 hours. Approximately 44% of the oral dose is recovered in the urine over 24 hours with only 3.6% of the dose excreted as parent drug. Two primary metabolites, 5- and 6-hydroxyemedastine, are excreted in the urine as both free and conjugated forms. The 5'-oxoanalogs of 5- and 6-hydroxyemedastine and the N-oxide are also formed as minor metabolites. - In an environmental study, patients with allergic conjunctivitis were treated with emedastine for six weeks. The results demonstrated that emedastine provides relief of the signs and symptoms of allergic conjunctivitis. In conjunctival antigen challenge studies, in which subjects were challenged with antigen both initially and up to four hours after dosing, emedastine was demonstrated to be significantly more effective than placebo in preventing ocular itching associated with allergic conjunctivitis. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Emedastine in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Emedastine in the drug label. # How Supplied - emedastine is supplied as follows: - 5 mL in opaque, plastic DROP-TAINER® dispenser. - 5 mL: NDC 0065-0325-05 ## Storage - STORAGE: Store at 4° - 30°C (39° - 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Emedastine in the drug label. # Precautions with Alcohol - Alcohol-Emedastine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - EMADINE® # Look-Alike Drug Names There is limited information regarding Emedastine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Emedastine 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 Emedastine is an antihistamine that is FDA approved for the treatment of signs and symptoms of allergic conjunctivitis. Common adverse reactions include headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - emedastine is indicated for the temporary relief of the signs and symptoms of allergic conjunctivitis. - Emedastineis indicated for the temporary relief of the signs and symptoms of allergic conjunctivitis. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Emedastine in adult patients. ### Non–Guideline-Supported Use - Asthma; Adjunct # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Emedastine in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Emedastine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Emedastine in pediatric patients. # Contraindications - EMADINE® (emedastine difumarate ophthalmic solution) is contraindicated in persons with a known hypersensitivity to emedastine difumarate or any of its components. # Warnings - FOR TOPICAL OPHTHALMIC USE ONLY - NOT FOR INJECTION OR ORAL USE. # Adverse Reactions ## Clinical Trials Experience There is limited information regarding Emedastine Clinical Trials Experience in the drug label. ## Postmarketing Experience - In controlled clinical studies of emedastine lasting for 42 days, the most frequent adverse reaction was headache 11%. The following adverse experiences were reported in less than 5% of patients: Abnormal dreams, asthenia, bad taste, blurred vision, burning or stinging, corneal infiltrates, corneal staining, dermatitis, discomfort, dry eye, foreign body sensation, hyperemia, keratitis, pruritus, rhinitis, sinusitis and tearing. Some of these events were similar to the underlying disease being studied. # Drug Interactions There is limited information regarding Emedastine Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B - Teratology and peri- and post-natal studies have been conducted with emedastine difumarate in rats and rabbits. At 15,000 times the maximum recommended ocular human use level, emedastine difumarate was shown not to be teratogenic in rats and rabbits and no effects on peri/post-natal development were observed in rats. However, at 70,000 times the maximum recommended ocular human use level, emedastine difumarate was shown to increase the incidence of external, visceral and skeletal anomalies in rats. There are, however, no adequate and well controlled studies in pregnant women. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Emedastine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Emedastine during labor and delivery. ### Nursing Mothers - Emedastine has been identified in breast milk in rats following oral administration. It is not known whether topical ocular administration could result in sufficient systemic absorption to produce detectable quantities in breast milk. Nevertheless, caution should be exercised when emedastine is administered to a nursing mother. ### Pediatric Use Safety and effectiveness in pediatric patients below the age of 3 years have not been established. ### 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 Emedastine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Emedastine with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Emedastine in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Emedastine in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Emedastine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Emedastine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Topical ### Monitoring There is limited information regarding Monitoring of Emedastine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Emedastine in the drug label. # Overdosage - Somnolence and malaise have been reported following daily oral administration. Oral ingestion of the contents of a 15 mL DROP-TAINER® dispenser would be equivalent to 7.5 mg. In case of overdosage, treatment is symptomatic and supportive. # Pharmacology ## Mechanism of Action - Emedastine is a relatively selective, histamine H1 antagonist. In vitro examinations of emedastine's affinity for histamine receptors (H1: Ki=1.3 nM, H2: Ki=49,067 nM, and H3: Ki=12,430 nM) demonstrate relative selectivity for the H1 histamine receptor. - In vivo studies have shown concentration-dependent inhibition of histamine-stimulated vascular permeability in the conjunctiva following topical ocular administration. Emedastine appears to be devoid of effects on adrenergic, dopaminergic and serotonin receptors. ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Emedastine in the drug label. ## Pharmacokinetics - Following topical administration in man, emedastine was shown to have low systemic exposure. In a study involving 10 normal volunteers dosed bilaterally twice daily for 15 days with emedastine ophthalmic solution 0.05%, plasma concentrations of the parent compound were generally below the quantitation limit of the assay (<0.3 ng/mL). Samples in which emedastine was quantifiable ranged from 0.30 to 0.49 ng/mL. The elimination half-life of oral emedastine in plasma is 3-4 hours. Approximately 44% of the oral dose is recovered in the urine over 24 hours with only 3.6% of the dose excreted as parent drug. Two primary metabolites, 5- and 6-hydroxyemedastine, are excreted in the urine as both free and conjugated forms. The 5'-oxoanalogs of 5- and 6-hydroxyemedastine and the N-oxide are also formed as minor metabolites. - In an environmental study, patients with allergic conjunctivitis were treated with emedastine for six weeks. The results demonstrated that emedastine provides relief of the signs and symptoms of allergic conjunctivitis. In conjunctival antigen challenge studies, in which subjects were challenged with antigen both initially and up to four hours after dosing, emedastine was demonstrated to be significantly more effective than placebo in preventing ocular itching associated with allergic conjunctivitis. ## Nonclinical Toxicology There is limited information regarding Nonclinical Toxicology of Emedastine in the drug label. # Clinical Studies There is limited information regarding Clinical Studies of Emedastine in the drug label. # How Supplied - emedastine is supplied as follows: - 5 mL in opaque, plastic DROP-TAINER® dispenser. - 5 mL: NDC 0065-0325-05 ## Storage - STORAGE: Store at 4° - 30°C (39° - 86°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Patient Counseling Information of Emedastine in the drug label. # Precautions with Alcohol - Alcohol-Emedastine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - EMADINE®[1] # Look-Alike Drug Names There is limited information regarding Emedastine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Emedastine
5f8a1c0242e6b4a6eefe5e21bbc4153ad47328de	wikidoc	Emicizumab	Emicizumab # 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 Emicizumab is a bispecific factor IXa- and factor X-directed antibody that is FDA approved for the prevention or reduction of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors. There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reactions, headache, and arthralgia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Emicizumab is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors. - The recommended dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly. Missed Dose - If a dose of Emicizumab is not administered on the scheduled day, administer as soon as possible before the day of the next scheduled dose, and then resume usual weekly dosing schedule. Do not double doses to make up for a missed dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Emicizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Emicizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Emicizumab is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors. - The recommended dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly. Missed Dose - If a dose of Emicizumab is not administered on the scheduled day, administer as soon as possible before the day of the next scheduled dose, and then resume usual weekly dosing schedule. Do not double doses to make up for a missed dose. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Emicizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Emicizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None # Warnings - Cases of thrombotic microangiopathy (TMA) were reported from clinical trials when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving Emicizumab prophylaxis. In clinical trials, thrombotic microangiopathy was reported in 1.6% of patients (3/189) and in 8.3% of patients (3/36) who received at least one dose of aPCC. Patients presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in ADAMTS13 activity. - Evidence of improvement was seen within one week following discontinuation of aPCC. One patient resumed Emicizumab following resolution of TMA. - Consider the benefits and risks if aPCC must be used in a patient receiving Emicizumab prophylaxis. Monitor for the development of TMA when administering aPCC. Immediately discontinue aPCC and interrupt Emicizumab prophylaxis if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage as clinically indicated. Consider the benefits and risks of resuming Emicizumab prophylaxis following complete resolution of TMA on a case-by-case basis. - Thrombotic events were reported from clinical trials when on average a cumulative amount of >100 U/kg/24 hours of aPCC was administered for 24 hours or more to patients receiving Emicizumab prophylaxis. In clinical trials, thrombotic events were reported in 1.1% of patients (2/189) and in 5.6% of patients (2/36) who received at least one dose of aPCC. - No thrombotic event required anticoagulation therapy. Evidence of improvement or resolution was seen within one month following discontinuation of aPCC. One patient resumed Emicizumab following resolution of thrombotic event. - Consider the benefits and risks if aPCC must be used in a patient receiving Emicizumab prophylaxis. Monitor for the development of thromboembolism when administering aPCC. Immediately discontinue aPCC and interrupt Emicizumab prophylaxis if clinical symptoms, imaging, or laboratory findings consistent with thromboembolism occur, and manage as clinically indicated. Consider the benefits and risks of resuming Emicizumab prophylaxis following complete resolution of thrombotic events on a case-by-case basis. - Emicizumab affects intrinsic pathway clotting-based laboratory tests, including activated clotting time (ACT), activated partial thromboplastin time (aPTT), and all assays based on aPTT, such as one-stage factor VIII (FVIII) activity (TABLE 1). Therefore, intrinsic pathway clotting-based laboratory test results in patients treated with Emicizumab should not be used to monitor Emicizumab activity, determine dosing for factor replacement or anti-coagulation, or measure FVIII inhibitor titers. Laboratory tests affected and unaffected by Emicizumab are shown in TABLE 1. # 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 following adverse reactions are based on pooled data from a randomized trial (HAVEN 1), single-arm trial (HAVEN 2), and a dose-finding trial, in which a total of 189 male patients with hemophilia A received at least one dose of Emicizumab as routine prophylaxis. Ninety-four patients (50%) were adults (18 years and older), 38 (20%) were adolescents (12 years up to less than 18 years), 55 (29%) were children (2 years up to less than 12 years), and two (1%) were infants (1 month up to less than 2 years). Seven of the 189 patients (4%) included in the safety population were patients without FVIII inhibitors from the dose-finding trial. The median duration of exposure across the studies was 38 weeks (0.8 to 177.2 weeks). - The most frequently reported adverse reactions observed in ≥ 10% of patients treated with at least one dose of Emicizumab were injection site reactions, headache, and arthralgia. - Four patients (2.1%) in the clinical trials receiving Emicizumab prophylaxis withdrew from treatment due to adverse reactions, which were thrombotic microangiopathy, skin necrosis and superficial thrombophlebitis, and injection site reaction. - Adverse reactions observed in patients who received Emicizumab are shown in TABLE 2. Characterization of aPCC treatment in pooled clinical trials - There were 125 instances of aPCC treatment in 36 patients, of which 13 instances (10.4%) consisted of on average a cumulative amount of >100 U/kg/24 hours of aPCC for 24 hours or more; two of the 13 were associated with thrombotic events and three of the 13 were associated with TMA (TABLE 3). No TMA or thrombotic events were associated with the remaining instances of aPCC treatment. Injection Site Reactions - In total, 35 patients (19%) reported injection site reactions (ISRs). All ISRs observed in Emicizumab clinical trials were reported as mild to moderate intensity and 88% resolved without treatment. The commonly reported ISR symptoms were injection site erythema (7.4%), injection site pruritus (5.3%), and injection site pain (5.3%). - As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to Emicizumab-kxwh in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. - The immunogenicity of Emicizumab was evaluated using an enzyme-linked immunosorbent assay (ELISA) or an electrochemiluminescence (ECL) assay. No patients tested positive for anti-Emicizumab antibodies in HAVEN 1 and HAVEN 2 (n = 171). Four patients tested positive for anti-Emicizumab antibodies in the dose-finding trial (n = 18). The anti-Emicizumab antibody positive rate may be under-reported due to the limitation of the assay. ## Postmarketing Experience There is limited information regarding Emicizumab Postmarketing Experience in the drug label. # Drug Interactions - Hypercoagulability with Concomitant Use of aPCC, rFVIIa, or FVIII - Drug-Laboratory Test Interactions - Clinical experience suggests that a drug interaction exists with Emicizumab and aPCC. - There is a possibility for hypercoagulability with rFVIIa or FVIII with Emicizumab based on preclinical experiments. - Emicizumab restores the tenase cofactor activity of missing activated factor VIII (FVIIIa). Coagulation laboratory tests based on intrinsic clotting (i.e., aPTT) measure the total clotting time including time needed for activation of FVIII to FVIIIa by thrombin. Such intrinsic pathway-based tests will yield overly shortened clotting times with Emicizumab, which does not require activation by thrombin. The overly shortened intrinsic clotting time will then disturb all single-factor assays based on aPTT, such as the one-stage FVIII activity assay; however, single-factor assays utilizing chromogenic or immuno-based methods are unaffected by Emicizumab and may be used to monitor coagulation parameters during treatment, with specific considerations for FVIII chromogenic activity assays as described below. - Chromogenic FVIII activity tests may be manufactured with either human or bovine coagulation proteins. Assays containing human coagulation factors are responsive to Emicizumab but may overestimate the clinical hemostatic potential of Emicizumab. In contrast, assays containing bovine coagulation factors are insensitive to Emicizumab (no activity measured) and can be used to monitor endogenous or infused FVIII activity, or to measure anti-FVIII inhibitors. - Emicizumab remains active in the presence of inhibitors against FVIII, so it will produce a false-negative result in clotting-based Bethesda assays for functional inhibition of FVIII. Instead, a chromogenic Bethesda assay utilizing a bovine-based FVIII chromogenic test that is insensitive to Emicizumab may be used. - Due to the long half-life of Emicizumab, effects on coagulation assays may persist for up to 6 months after the last dose. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - There are no available data on Emicizumab use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies have not been conducted with Emicizumab-kxwh. It is not known whether Emicizumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Emicizumab should be used during pregnancy only if the potential benefit for the mother outweighs the risk to the fetus. - All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Emicizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Emicizumab during labor and delivery. ### Nursing Mothers Risk Summary - There is no information regarding the presence of Emicizumab-kxwh in human milk, the effects on the breastfed child, or the effects on milk production. Human IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Emicizumab and any potential adverse effects on the breastfed child from Emicizumab or from the underlying maternal condition. ### Pediatric Use - The safety and efficacy of Emicizumab have been established in pediatric patients. Use of Emicizumab in pediatric patients with hemophilia A with FVIII inhibitors is supported by a randomized trial (HAVEN 1) and a single-arm trial (HAVEN 2). HAVEN 1 included pediatric patients in the following age group: 38 adolescents (12 years to less than 18 years). HAVEN 2 included pediatric patients in the following age groups: 55 children (2 years up to less than 12 years) and two infants (1 month up to less than 2 years). No differences in efficacy were observed between the different age groups. - In general, the adverse reactions in Emicizumab-treated pediatric patients were similar in type to those seen in adult patients with hemophilia A with FVIII inhibitors. - The steady-state plasma trough concentrations of Emicizumab-kxwh were comparable in adult and pediatric patients at equivalent weight-based doses. ### Geriatic Use - Clinical studies of Emicizumab did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Emicizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Emicizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Emicizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Emicizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males Contraception - Women of childbearing potential should use contraception while receiving Emicizumab. ### Immunocompromised Patients There is no FDA guidance one the use of Emicizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Emicizumab is intended for use under the guidance of a healthcare provider. After proper training in subcutaneous injection technique, a patient may self-inject, or the patient's caregiver may administer Emicizumab, if a healthcare provider determines that it is appropriate. Self-administration is not recommended for children aged less than 7 years old. The Emicizumab "INSTRUCTIONS FOR USE" contains more detailed instructions on the preparation and administration of Emicizumab. - Visually inspect Emicizumab for particulate matter and discoloration before administration. Emicizumab for subcutaneous administration is a colorless to slightly yellow solution. Do not use if particulate matter is visible or product is discolored. - A syringe, a transfer needle, and an injection needle are needed to withdraw Emicizumab solution from the vial and inject it subcutaneously. - Refer to the Emicizumab "INSTRUCTIONS FOR USE" for handling instructions when combining vials. Do not use different Emicizumab vials of different concentrations when combining vials to administer prescribed dose. - Administer doses of Emicizumab up to 1 mL with a 1 mL syringe. A 1 mL syringe fulfilling the following criteria may be used: Transparent polypropylene or polycarbonate syringe with Luer-Lok™ tip, graduation 0.01 mL, sterile, for injection only, single-use, latex-free and non-pyrogenic, commercially available in the US. - Administer doses of Emicizumab greater than 1 mL and up to 2 mL with a 2 mL or 3 mL syringe. A 2 mL or 3 mL syringe fulfilling the following criteria may be used: Transparent polypropylene or polycarbonate syringe with Luer-Lok™ tip, graduation 0.1 mL, sterile, for injection only, single-use, latex-free, and non-pyrogenic, commercially available in the US. - A transfer needle fulfilling the following criteria may be used: Stainless steel needle with Luer-Lok™ connection, sterile, 18 gauge, length 1½ inch, semi-blunted tip, single-use, latex-free, and non-pyrogenic, commercially available in the US. - An injection needle fulfilling the following criteria may be used: Stainless steel with Luer-Lok™ connection, sterile, 26 gauge, maximal length ½ inch, single-use, latex-free and non-pyrogenic, including needle safety feature, commercially available in the US. - Administer each injection at a different anatomic location (upper outer arms, thighs, or any quadrant of abdomen) than the previous injection. An injection should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. Administration of Emicizumab in the upper outer arm should only be performed by a caregiver or healthcare provider. - Discard any unused Emicizumab remaining in the single-dose vial. ### Monitoring - Prevention or reduction of bleeding events in patients with hemophilia A may indicate efficacy. - Extrinsic pathway clotting-based laboratory tests to determine Emicizumab-kxwh activity; determine dosing for factor replacement or anticoagulation, or measure FVIII inhibitor titers; do not use intrinsic pathway clotting-based laboratory test results, including activated clotting time (ACT), activated partial thromboplastin time (aPTT), and all assays based on aPTT such as one-stage factor VIII (FVIII) activity. - Thrombotic microangiopathy and thrombotic events: In patients concomitantly receiving activated prothrombin complex concentrate. # IV Compatibility There is limited information regarding the compatibility of Emicizumab and IV administrations. # Overdosage There is limited information regarding Emicizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Emicizumab bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective hemostasis. ## Structure There is limited information regarding Emicizumab Structure in the drug label. ## Pharmacodynamics There is limited information regarding Emicizumab Pharmacodynamics in the drug label. ## Pharmacokinetics - Emicizumab-kxwh exhibited dose-proportional pharmacokinetics over a dose range of 0.3 mg/kg (0.1 times approved recommended starting dosage) to 3 mg/kg once weekly following subcutaneous administration. Following multiple subcutaneous administrations of 3 mg/kg once weekly for the first 4 weeks in hemophilia A patients, mean (± SD) trough plasma concentrations of Emicizumab-kxwh increased to achieve 54.6 ± 14.3 μg/mL at Week 5. Trough plasma concentrations above 50 μg/mL were sustained thereafter with the recommended weekly dosage of 1.5 mg/kg; the mean (± SD) trough plasma concentrations of Emicizumab-kxwh at steady-state was 52.8 ± 13.5 µg/mL. Absorption - Following subcutaneous administration, the mean (± SD) absorption half-life was 1.7 ± 1 day. - The absolute bioavailability following subcutaneous administration of 1 mg/kg was between 80.4% and 93.1%. Similar pharmacokinetic profiles were observed following subcutaneous administration in the abdomen, upper arm, and thigh. Distribution - The mean apparent volume of distribution was 11.4 L (95% confidence interval (CI) ). Elimination - The mean apparent clearance (95% CI) was 0.24 L/day (0.22, 0.26) and the mean elimination apparent half-life (± SD) was 27.8 ± 8.1 days. Specific Populations - The pharmacokinetics of Emicizumab-kxwh are not influenced by age (3 years to 75 years), race (White 54%, Asian 30.5% and Black 8.5%), inhibitor status (inhibitor present, 92%), mild hepatic impairment (defined as total bilirubin 1× to ≤ 1.5× the upper limit of normal (ULN) and any aspartate transaminase (AST) level) and moderate hepatic impairment (defined as total bilirubin 1.5× to ≤ 3× the ULN and any AST level). - Body weight: The apparent clearance and volume of distribution of Emicizumab-kxwh increased with increasing body weight (14.2 kg to 131 kg). Dosing in mg/kg provides similar Emicizumab-kxwh exposure across body weight range. Drug Interaction Studies - No drug-drug interaction studies have been conducted with Emicizumab. ## Nonclinical Toxicology - Studies in animals investigating the carcinogenic effects of Emicizumab-kxwh have not been conducted. In vitro and in vivo testing of Emicizumab-kxwh for genotoxicity was not conducted. - Animal fertility studies have not been conducted; however, Emicizumab-kxwh did not cause any toxicological changes in the reproductive organs of male or female cynomolgus monkeys at doses of up to 30 mg/kg/week in subcutaneous general toxicity studies of up to 26-week duration and at doses of up to 100 mg/kg/week in a 4-week intravenous general toxicity study. # Clinical Studies - The efficacy of Emicizumab for routine prophylaxis in patients with hemophilia A with FVIII inhibitors was evaluated in two clinical trials . - The HAVEN 1 study (NCT02622321) was a randomized, multicenter, open-label, clinical trial in 109 adult and adolescent males (aged 12 to 75 years and > 40 kg) with hemophilia A with FVIII inhibitors who previously received either episodic (on-demand) or prophylactic treatment with bypassing agents. Patients received weekly Emicizumab prophylaxis (Arms A, C, and D), 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly thereafter, or no prophylaxis (Arm B). Dose up-titration to 3 mg/kg once weekly was allowed after 24 weeks on Emicizumab prophylaxis in case of suboptimal efficacy (i.e., ≥ 2 spontaneous and clinically significant bleeds). During the study, two patients underwent up-titration of their maintenance dose to 3 mg/kg once weekly. - Fifty-three patients previously treated with episodic (on-demand) bypassing agents were randomized in a 2:1 ratio to receive Emicizumab prophylaxis (Arm A) or no prophylaxis (Arm B), with stratification by prior 24-week bleed rate (< 9 or ≥ 9). Patients randomized to Arm B could switch to Emicizumab prophylaxis after completing at least 24 weeks without prophylaxis. - Forty-nine patients previously treated with prophylactic bypassing agents were enrolled into Arm C to receive Emicizumab prophylaxis. Seven patients previously treated with episodic (on-demand) bypassing agents who had participated in a non-interventional study (NIS) prior to enrollment, but were unable to enroll into HAVEN 1 prior to the closure of Arms A and B, were enrolled into Arm D to receive Emicizumab prophylaxis. - Efficacy was evaluated based on the annualized bleeding rate (ABR) requiring treatment with coagulation factors (minimum of 24 weeks or date of discontinuation) among patients previously treated with episodic bypassing agents who were randomized to Emicizumab prophylaxis (Arm A) compared with those receiving no prophylaxis (Arm B). The trial also evaluated the randomized comparison of Arms A and B for the efficacy of weekly Emicizumab prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds, as well as patient-reported symptoms and physical functioning. - The study also evaluated the efficacy of weekly Emicizumab prophylaxis compared with previous episodic (on-demand) and prophylactic bypassing agents in patients who had participated in the NIS prior to enrollment (Arms A and C, respectively). Only patients from the NIS were included in this comparison, because bleed and treatment data were collected with the same level of granularity in both periods. - The efficacy results of Emicizumab prophylaxis compared with no prophylaxis in bleed rate for treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds and treated target joint bleeds are shown in TABLE 4. - In the intra-patient analysis, Emicizumab prophylaxis resulted in a statistically significant (p = 0.0003) reduction (79%) in bleed rate for treated bleeds compared with previous bypassing agent prophylaxis collected in the NIS prior to enrollment (TABLE 5). - The study evaluated patient-reported hemophilia-related symptoms (painful swellings and presence of joint pain) and physical functioning (pain with movement and difficulty walking far) using the Physical Health Score of the Haemophilia-specific Quality of Life (Haem-A-QoL) questionnaire for patients aged ≥ 18 years. The weekly Emicizumab prophylaxis arm (Arm A) showed an improvement compared with the no prophylaxis arm (Arm B) in the Haem-A-QoL Physical Health Subscale score at the Week 25 assessment (TABLE 6). The improvement in the Physical Health Score was further supported by the Total Score as measured by the Haem-A-QoL at Week 25. - The HAVEN 2 study (NCT02795767) was a single-arm, multicenter, open-label, clinical study in pediatric males (age < 12 years, or 12 – 17 years who weigh < 40 kg) with hemophilia A with FVIII inhibitors. Patients received Emicizumab prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly thereafter. - The study evaluated the efficacy of weekly Emicizumab prophylaxis, including the efficacy of weekly Emicizumab prophylaxis compared with previous episodic (on-demand) and prophylactic bypassing agent treatment in patients who had participated in a non-interventional study (NIS) prior to enrollment (intra-patient analysis). - At the time of the interim analysis, efficacy was evaluated in 23 pediatric patients who were < 12 years old and had been receiving weekly Emicizumab prophylaxis for at least 12 weeks, including 19 patients age 6 to < 12 years and 4 patients age 2 to < 6 years. - Annualized bleed rate (ABR) and percent of patients with zero bleeds were calculated for 23 patients (TABLE 7). The median observation time for these patients was 38.1 weeks (12.7 – 41.6 weeks). - In the intra-patient analysis, 13 pediatric patients who had participated in the NIS had an ABR of 17.2 (95% CI ) on previous bypassing agent treatment (prophylactic treatment in 12 patients and on-demand treatment for one patient). Weekly Emicizumab prophylaxis resulted in an ABR for treated bleeds of 0.2 (95% CI ) based on negative binomial regression, corresponding to a 99% reduction in bleed rate. On Emicizumab prophylaxis, 11 patients (84.6%) had zero treated bleeds. # How Supplied - Emicizumab (Emicizumab-kxwh) injection is available as a sterile, preservative-free, colorless to slightly yellow solution in single-dose vials in the following dosage strengths: ## Storage - Store Emicizumab vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. - Store Emicizumab vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. - Prior to administration, if needed, unopened vials of Emicizumab may be stored out of and then returned to refrigeration. The temperature and total combined time out of refrigeration should not exceed 30°C (86°F) and 7 days (at a temperature below 30°C ), respectively. - Once removed from the vial, discard Emicizumab if not used immediately. - Discard any unused Emicizumab. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Use of Bypassing Agents - Inform the patient and/or caregiver that Emicizumab increases coagulation potential. Advise the patient and/or caregiver to discontinue prophylactic use of bypassing agents the day before starting Emicizumab prophylaxis. Discuss the use of bypassing agents with the patient and/or caregiver prior to starting Emicizumab prophylaxis. Thrombotic Microangiopathy Associated with Emicizumab and aPCC - Inform the patient and/or caregiver of the potential risk of thrombotic microangiopathy if aPCC is administered while receiving Emicizumab prophylaxis. Instruct the patient and/or caregiver to consult their healthcare provider if aPCC is required in cumulative doses exceeding 100 U/kg. Advise the patient and/or caregiver to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur. Thromboembolism Associated with Emicizumab and aPCC - Inform the patient and/or caregiver of the potential risk of thromboembolism if aPCC is administered while receiving Emicizumab prophylaxis. Instruct the patient and/or caregiver to consult their healthcare provider if aPCC is required in cumulative doses exceeding 100 U/kg. Advise the patient and/or caregiver to seek immediate medical attention if any signs or symptoms of thromboembolism occur. Laboratory Coagulation Test Interference - Inform the patient and/or caregiver that Emicizumab interferes with some laboratory tests that measure blood clotting and may cause a false reading. Advise the patient and/or caregiver that they should notify any healthcare provider about this possibility prior to any blood tests or medical procedures. Instruction on Injection Technique - Emicizumab is intended for use under the guidance of a healthcare provider. If a patient or caregiver is to administer subcutaneous Emicizumab, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous Emicizumab and the suitability for home use. - Advise the patient to follow the recommendations in the FDA-approved patient labeling regarding proper sharps disposal. # Precautions with Alcohol Alcohol-Emicizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Hemlibra # Look-Alike Drug Names There is limited information regarding Emicizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Emicizumab Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2], Anmol Pitliya, M.B.B.S. M.D.[3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Emicizumab is a bispecific factor IXa- and factor X-directed antibody that is FDA approved for the prevention or reduction of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors. There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reactions, headache, and arthralgia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Emicizumab is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors. - The recommended dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly. Missed Dose - If a dose of Emicizumab is not administered on the scheduled day, administer as soon as possible before the day of the next scheduled dose, and then resume usual weekly dosing schedule. Do not double doses to make up for a missed dose. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Emicizumab Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Emicizumab Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Emicizumab is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors. - The recommended dose is 3 mg/kg by subcutaneous injection once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly. Missed Dose - If a dose of Emicizumab is not administered on the scheduled day, administer as soon as possible before the day of the next scheduled dose, and then resume usual weekly dosing schedule. Do not double doses to make up for a missed dose. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Emicizumab Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Emicizumab Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None # Warnings - Cases of thrombotic microangiopathy (TMA) were reported from clinical trials when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate (aPCC) was administered for 24 hours or more to patients receiving Emicizumab prophylaxis. In clinical trials, thrombotic microangiopathy was reported in 1.6% of patients (3/189) and in 8.3% of patients (3/36) who received at least one dose of aPCC. Patients presented with thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, without severe deficiencies in ADAMTS13 activity. - Evidence of improvement was seen within one week following discontinuation of aPCC. One patient resumed Emicizumab following resolution of TMA. - Consider the benefits and risks if aPCC must be used in a patient receiving Emicizumab prophylaxis. Monitor for the development of TMA when administering aPCC. Immediately discontinue aPCC and interrupt Emicizumab prophylaxis if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage as clinically indicated. Consider the benefits and risks of resuming Emicizumab prophylaxis following complete resolution of TMA on a case-by-case basis. - Thrombotic events were reported from clinical trials when on average a cumulative amount of >100 U/kg/24 hours of aPCC was administered for 24 hours or more to patients receiving Emicizumab prophylaxis. In clinical trials, thrombotic events were reported in 1.1% of patients (2/189) and in 5.6% of patients (2/36) who received at least one dose of aPCC. - No thrombotic event required anticoagulation therapy. Evidence of improvement or resolution was seen within one month following discontinuation of aPCC. One patient resumed Emicizumab following resolution of thrombotic event. - Consider the benefits and risks if aPCC must be used in a patient receiving Emicizumab prophylaxis. Monitor for the development of thromboembolism when administering aPCC. Immediately discontinue aPCC and interrupt Emicizumab prophylaxis if clinical symptoms, imaging, or laboratory findings consistent with thromboembolism occur, and manage as clinically indicated. Consider the benefits and risks of resuming Emicizumab prophylaxis following complete resolution of thrombotic events on a case-by-case basis. - Emicizumab affects intrinsic pathway clotting-based laboratory tests, including activated clotting time (ACT), activated partial thromboplastin time (aPTT), and all assays based on aPTT, such as one-stage factor VIII (FVIII) activity (TABLE 1). Therefore, intrinsic pathway clotting-based laboratory test results in patients treated with Emicizumab should not be used to monitor Emicizumab activity, determine dosing for factor replacement or anti-coagulation, or measure FVIII inhibitor titers. Laboratory tests affected and unaffected by Emicizumab are shown in TABLE 1. # 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 following adverse reactions are based on pooled data from a randomized trial (HAVEN 1), single-arm trial (HAVEN 2), and a dose-finding trial, in which a total of 189 male patients with hemophilia A received at least one dose of Emicizumab as routine prophylaxis. Ninety-four patients (50%) were adults (18 years and older), 38 (20%) were adolescents (12 years up to less than 18 years), 55 (29%) were children (2 years up to less than 12 years), and two (1%) were infants (1 month up to less than 2 years). Seven of the 189 patients (4%) included in the safety population were patients without FVIII inhibitors from the dose-finding trial. The median duration of exposure across the studies was 38 weeks (0.8 to 177.2 weeks). - The most frequently reported adverse reactions observed in ≥ 10% of patients treated with at least one dose of Emicizumab were injection site reactions, headache, and arthralgia. - Four patients (2.1%) in the clinical trials receiving Emicizumab prophylaxis withdrew from treatment due to adverse reactions, which were thrombotic microangiopathy, skin necrosis and superficial thrombophlebitis, and injection site reaction. - Adverse reactions observed in patients who received Emicizumab are shown in TABLE 2. Characterization of aPCC treatment in pooled clinical trials - There were 125 instances of aPCC treatment in 36 patients, of which 13 instances (10.4%) consisted of on average a cumulative amount of >100 U/kg/24 hours of aPCC for 24 hours or more; two of the 13 were associated with thrombotic events and three of the 13 were associated with TMA (TABLE 3). No TMA or thrombotic events were associated with the remaining instances of aPCC treatment. Injection Site Reactions - In total, 35 patients (19%) reported injection site reactions (ISRs). All ISRs observed in Emicizumab clinical trials were reported as mild to moderate intensity and 88% resolved without treatment. The commonly reported ISR symptoms were injection site erythema (7.4%), injection site pruritus (5.3%), and injection site pain (5.3%). - As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to Emicizumab-kxwh in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. - The immunogenicity of Emicizumab was evaluated using an enzyme-linked immunosorbent assay (ELISA) or an electrochemiluminescence (ECL) assay. No patients tested positive for anti-Emicizumab antibodies in HAVEN 1 and HAVEN 2 (n = 171). Four patients tested positive for anti-Emicizumab antibodies in the dose-finding trial (n = 18). The anti-Emicizumab antibody positive rate may be under-reported due to the limitation of the assay. ## Postmarketing Experience There is limited information regarding Emicizumab Postmarketing Experience in the drug label. # Drug Interactions - Hypercoagulability with Concomitant Use of aPCC, rFVIIa, or FVIII - Drug-Laboratory Test Interactions - Clinical experience suggests that a drug interaction exists with Emicizumab and aPCC. - There is a possibility for hypercoagulability with rFVIIa or FVIII with Emicizumab based on preclinical experiments. - Emicizumab restores the tenase cofactor activity of missing activated factor VIII (FVIIIa). Coagulation laboratory tests based on intrinsic clotting (i.e., aPTT) measure the total clotting time including time needed for activation of FVIII to FVIIIa by thrombin. Such intrinsic pathway-based tests will yield overly shortened clotting times with Emicizumab, which does not require activation by thrombin. The overly shortened intrinsic clotting time will then disturb all single-factor assays based on aPTT, such as the one-stage FVIII activity assay; however, single-factor assays utilizing chromogenic or immuno-based methods are unaffected by Emicizumab and may be used to monitor coagulation parameters during treatment, with specific considerations for FVIII chromogenic activity assays as described below. - Chromogenic FVIII activity tests may be manufactured with either human or bovine coagulation proteins. Assays containing human coagulation factors are responsive to Emicizumab but may overestimate the clinical hemostatic potential of Emicizumab. In contrast, assays containing bovine coagulation factors are insensitive to Emicizumab (no activity measured) and can be used to monitor endogenous or infused FVIII activity, or to measure anti-FVIII inhibitors. - Emicizumab remains active in the presence of inhibitors against FVIII, so it will produce a false-negative result in clotting-based Bethesda assays for functional inhibition of FVIII. Instead, a chromogenic Bethesda assay utilizing a bovine-based FVIII chromogenic test that is insensitive to Emicizumab may be used. - Due to the long half-life of Emicizumab, effects on coagulation assays may persist for up to 6 months after the last dose. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - There are no available data on Emicizumab use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. Animal reproduction studies have not been conducted with Emicizumab-kxwh. It is not known whether Emicizumab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Emicizumab should be used during pregnancy only if the potential benefit for the mother outweighs the risk to the fetus. - All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defect and miscarriage in clinically recognized pregnancies is 2 – 4% and 15 – 20%, respectively. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Emicizumab in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Emicizumab during labor and delivery. ### Nursing Mothers Risk Summary - There is no information regarding the presence of Emicizumab-kxwh in human milk, the effects on the breastfed child, or the effects on milk production. Human IgG is known to be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Emicizumab and any potential adverse effects on the breastfed child from Emicizumab or from the underlying maternal condition. ### Pediatric Use - The safety and efficacy of Emicizumab have been established in pediatric patients. Use of Emicizumab in pediatric patients with hemophilia A with FVIII inhibitors is supported by a randomized trial (HAVEN 1) and a single-arm trial (HAVEN 2). HAVEN 1 included pediatric patients in the following age group: 38 adolescents (12 years to less than 18 years). HAVEN 2 included pediatric patients in the following age groups: 55 children (2 years up to less than 12 years) and two infants (1 month up to less than 2 years). No differences in efficacy were observed between the different age groups. - In general, the adverse reactions in Emicizumab-treated pediatric patients were similar in type to those seen in adult patients with hemophilia A with FVIII inhibitors. - The steady-state plasma trough concentrations of Emicizumab-kxwh were comparable in adult and pediatric patients at equivalent weight-based doses. ### Geriatic Use - Clinical studies of Emicizumab did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. ### Gender There is no FDA guidance on the use of Emicizumab with respect to specific gender populations. ### Race There is no FDA guidance on the use of Emicizumab with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Emicizumab in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Emicizumab in patients with hepatic impairment. ### Females of Reproductive Potential and Males Contraception - Women of childbearing potential should use contraception while receiving Emicizumab. ### Immunocompromised Patients There is no FDA guidance one the use of Emicizumab in patients who are immunocompromised. # Administration and Monitoring ### Administration - Emicizumab is intended for use under the guidance of a healthcare provider. After proper training in subcutaneous injection technique, a patient may self-inject, or the patient's caregiver may administer Emicizumab, if a healthcare provider determines that it is appropriate. Self-administration is not recommended for children aged less than 7 years old. The Emicizumab "INSTRUCTIONS FOR USE" contains more detailed instructions on the preparation and administration of Emicizumab. - Visually inspect Emicizumab for particulate matter and discoloration before administration. Emicizumab for subcutaneous administration is a colorless to slightly yellow solution. Do not use if particulate matter is visible or product is discolored. - A syringe, a transfer needle, and an injection needle are needed to withdraw Emicizumab solution from the vial and inject it subcutaneously. - Refer to the Emicizumab "INSTRUCTIONS FOR USE" for handling instructions when combining vials. Do not use different Emicizumab vials of different concentrations when combining vials to administer prescribed dose. - Administer doses of Emicizumab up to 1 mL with a 1 mL syringe. A 1 mL syringe fulfilling the following criteria may be used: Transparent polypropylene or polycarbonate syringe with Luer-Lok™ tip, graduation 0.01 mL, sterile, for injection only, single-use, latex-free and non-pyrogenic, commercially available in the US. - Administer doses of Emicizumab greater than 1 mL and up to 2 mL with a 2 mL or 3 mL syringe. A 2 mL or 3 mL syringe fulfilling the following criteria may be used: Transparent polypropylene or polycarbonate syringe with Luer-Lok™ tip, graduation 0.1 mL, sterile, for injection only, single-use, latex-free, and non-pyrogenic, commercially available in the US. - A transfer needle fulfilling the following criteria may be used: Stainless steel needle with Luer-Lok™ connection, sterile, 18 gauge, length 1½ inch, semi-blunted tip, single-use, latex-free, and non-pyrogenic, commercially available in the US. - An injection needle fulfilling the following criteria may be used: Stainless steel with Luer-Lok™ connection, sterile, 26 gauge, maximal length ½ inch, single-use, latex-free and non-pyrogenic, including needle safety feature, commercially available in the US. - Administer each injection at a different anatomic location (upper outer arms, thighs, or any quadrant of abdomen) than the previous injection. An injection should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact. Administration of Emicizumab in the upper outer arm should only be performed by a caregiver or healthcare provider. - Discard any unused Emicizumab remaining in the single-dose vial. ### Monitoring - Prevention or reduction of bleeding events in patients with hemophilia A may indicate efficacy. - Extrinsic pathway clotting-based laboratory tests to determine Emicizumab-kxwh activity; determine dosing for factor replacement or anticoagulation, or measure FVIII inhibitor titers; do not use intrinsic pathway clotting-based laboratory test results, including activated clotting time (ACT), activated partial thromboplastin time (aPTT), and all assays based on aPTT such as one-stage factor VIII (FVIII) activity. - Thrombotic microangiopathy and thrombotic events: In patients concomitantly receiving activated prothrombin complex concentrate. # IV Compatibility There is limited information regarding the compatibility of Emicizumab and IV administrations. # Overdosage There is limited information regarding Emicizumab overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Emicizumab bridges activated factor IX and factor X to restore the function of missing activated factor VIII that is needed for effective hemostasis. ## Structure There is limited information regarding Emicizumab Structure in the drug label. ## Pharmacodynamics There is limited information regarding Emicizumab Pharmacodynamics in the drug label. ## Pharmacokinetics - Emicizumab-kxwh exhibited dose-proportional pharmacokinetics over a dose range of 0.3 mg/kg (0.1 times approved recommended starting dosage) to 3 mg/kg once weekly following subcutaneous administration. Following multiple subcutaneous administrations of 3 mg/kg once weekly for the first 4 weeks in hemophilia A patients, mean (± SD) trough plasma concentrations of Emicizumab-kxwh increased to achieve 54.6 ± 14.3 μg/mL at Week 5. Trough plasma concentrations above 50 μg/mL were sustained thereafter with the recommended weekly dosage of 1.5 mg/kg; the mean (± SD) trough plasma concentrations of Emicizumab-kxwh at steady-state was 52.8 ± 13.5 µg/mL. Absorption - Following subcutaneous administration, the mean (± SD) absorption half-life was 1.7 ± 1 day. - The absolute bioavailability following subcutaneous administration of 1 mg/kg was between 80.4% and 93.1%. Similar pharmacokinetic profiles were observed following subcutaneous administration in the abdomen, upper arm, and thigh. Distribution - The mean apparent volume of distribution was 11.4 L (95% confidence interval (CI) [10.6, 12.1]). Elimination - The mean apparent clearance (95% CI) was 0.24 L/day (0.22, 0.26) and the mean elimination apparent half-life (± SD) was 27.8 ± 8.1 days. Specific Populations - The pharmacokinetics of Emicizumab-kxwh are not influenced by age (3 years to 75 years), race (White 54%, Asian 30.5% and Black 8.5%), inhibitor status (inhibitor present, 92%), mild hepatic impairment (defined as total bilirubin 1× to ≤ 1.5× the upper limit of normal (ULN) and any aspartate transaminase (AST) level) and moderate hepatic impairment (defined as total bilirubin 1.5× to ≤ 3× the ULN and any AST level). - Body weight: The apparent clearance and volume of distribution of Emicizumab-kxwh increased with increasing body weight (14.2 kg to 131 kg). Dosing in mg/kg provides similar Emicizumab-kxwh exposure across body weight range. Drug Interaction Studies - No drug-drug interaction studies have been conducted with Emicizumab. ## Nonclinical Toxicology - Studies in animals investigating the carcinogenic effects of Emicizumab-kxwh have not been conducted. In vitro and in vivo testing of Emicizumab-kxwh for genotoxicity was not conducted. - Animal fertility studies have not been conducted; however, Emicizumab-kxwh did not cause any toxicological changes in the reproductive organs of male or female cynomolgus monkeys at doses of up to 30 mg/kg/week in subcutaneous general toxicity studies of up to 26-week duration and at doses of up to 100 mg/kg/week in a 4-week intravenous general toxicity study. # Clinical Studies - The efficacy of Emicizumab for routine prophylaxis in patients with hemophilia A with FVIII inhibitors was evaluated in two clinical trials [an adult and adolescent study (HAVEN 1) and a pediatric study (HAVEN 2)]. - The HAVEN 1 study (NCT02622321) was a randomized, multicenter, open-label, clinical trial in 109 adult and adolescent males (aged 12 to 75 years and > 40 kg) with hemophilia A with FVIII inhibitors who previously received either episodic (on-demand) or prophylactic treatment with bypassing agents. Patients received weekly Emicizumab prophylaxis (Arms A, C, and D), 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly thereafter, or no prophylaxis (Arm B). Dose up-titration to 3 mg/kg once weekly was allowed after 24 weeks on Emicizumab prophylaxis in case of suboptimal efficacy (i.e., ≥ 2 spontaneous and clinically significant bleeds). During the study, two patients underwent up-titration of their maintenance dose to 3 mg/kg once weekly. - Fifty-three patients previously treated with episodic (on-demand) bypassing agents were randomized in a 2:1 ratio to receive Emicizumab prophylaxis (Arm A) or no prophylaxis (Arm B), with stratification by prior 24-week bleed rate (< 9 or ≥ 9). Patients randomized to Arm B could switch to Emicizumab prophylaxis after completing at least 24 weeks without prophylaxis. - Forty-nine patients previously treated with prophylactic bypassing agents were enrolled into Arm C to receive Emicizumab prophylaxis. Seven patients previously treated with episodic (on-demand) bypassing agents who had participated in a non-interventional study (NIS) prior to enrollment, but were unable to enroll into HAVEN 1 prior to the closure of Arms A and B, were enrolled into Arm D to receive Emicizumab prophylaxis. - Efficacy was evaluated based on the annualized bleeding rate (ABR) requiring treatment with coagulation factors (minimum of 24 weeks or date of discontinuation) among patients previously treated with episodic bypassing agents who were randomized to Emicizumab prophylaxis (Arm A) compared with those receiving no prophylaxis (Arm B). The trial also evaluated the randomized comparison of Arms A and B for the efficacy of weekly Emicizumab prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds, as well as patient-reported symptoms and physical functioning. - The study also evaluated the efficacy of weekly Emicizumab prophylaxis compared with previous episodic (on-demand) and prophylactic bypassing agents in patients who had participated in the NIS prior to enrollment (Arms A and C, respectively). Only patients from the NIS were included in this comparison, because bleed and treatment data were collected with the same level of granularity in both periods. - The efficacy results of Emicizumab prophylaxis compared with no prophylaxis in bleed rate for treated bleeds, all bleeds, treated spontaneous bleeds, treated joint bleeds and treated target joint bleeds are shown in TABLE 4. - In the intra-patient analysis, Emicizumab prophylaxis resulted in a statistically significant (p = 0.0003) reduction (79%) in bleed rate for treated bleeds compared with previous bypassing agent prophylaxis collected in the NIS prior to enrollment (TABLE 5). - The study evaluated patient-reported hemophilia-related symptoms (painful swellings and presence of joint pain) and physical functioning (pain with movement and difficulty walking far) using the Physical Health Score of the Haemophilia-specific Quality of Life (Haem-A-QoL) questionnaire for patients aged ≥ 18 years. The weekly Emicizumab prophylaxis arm (Arm A) showed an improvement compared with the no prophylaxis arm (Arm B) in the Haem-A-QoL Physical Health Subscale score at the Week 25 assessment (TABLE 6). The improvement in the Physical Health Score was further supported by the Total Score as measured by the Haem-A-QoL at Week 25. - The HAVEN 2 study (NCT02795767) was a single-arm, multicenter, open-label, clinical study in pediatric males (age < 12 years, or 12 – 17 years who weigh < 40 kg) with hemophilia A with FVIII inhibitors. Patients received Emicizumab prophylaxis at 3 mg/kg once weekly for the first 4 weeks followed by 1.5 mg/kg once weekly thereafter. - The study evaluated the efficacy of weekly Emicizumab prophylaxis, including the efficacy of weekly Emicizumab prophylaxis compared with previous episodic (on-demand) and prophylactic bypassing agent treatment in patients who had participated in a non-interventional study (NIS) prior to enrollment (intra-patient analysis). - At the time of the interim analysis, efficacy was evaluated in 23 pediatric patients who were < 12 years old and had been receiving weekly Emicizumab prophylaxis for at least 12 weeks, including 19 patients age 6 to < 12 years and 4 patients age 2 to < 6 years. - Annualized bleed rate (ABR) and percent of patients with zero bleeds were calculated for 23 patients (TABLE 7). The median observation time for these patients was 38.1 weeks (12.7 – 41.6 weeks). - In the intra-patient analysis, 13 pediatric patients who had participated in the NIS had an ABR of 17.2 (95% CI [12.4, 23.8]) on previous bypassing agent treatment (prophylactic treatment in 12 patients and on-demand treatment for one patient). Weekly Emicizumab prophylaxis resulted in an ABR for treated bleeds of 0.2 (95% CI [0.1, 0.8]) based on negative binomial regression, corresponding to a 99% reduction in bleed rate. On Emicizumab prophylaxis, 11 patients (84.6%) had zero treated bleeds. # How Supplied - Emicizumab (Emicizumab-kxwh) injection is available as a sterile, preservative-free, colorless to slightly yellow solution in single-dose vials in the following dosage strengths: ## Storage - Store Emicizumab vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. - Store Emicizumab vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake. - Prior to administration, if needed, unopened vials of Emicizumab may be stored out of and then returned to refrigeration. The temperature and total combined time out of refrigeration should not exceed 30°C (86°F) and 7 days (at a temperature below 30°C [86°F]), respectively. - Once removed from the vial, discard Emicizumab if not used immediately. - Discard any unused Emicizumab. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information Use of Bypassing Agents - Inform the patient and/or caregiver that Emicizumab increases coagulation potential. Advise the patient and/or caregiver to discontinue prophylactic use of bypassing agents the day before starting Emicizumab prophylaxis. Discuss the use of bypassing agents with the patient and/or caregiver prior to starting Emicizumab prophylaxis. Thrombotic Microangiopathy Associated with Emicizumab and aPCC - Inform the patient and/or caregiver of the potential risk of thrombotic microangiopathy if aPCC is administered while receiving Emicizumab prophylaxis. Instruct the patient and/or caregiver to consult their healthcare provider if aPCC is required in cumulative doses exceeding 100 U/kg. Advise the patient and/or caregiver to seek immediate medical attention if any signs or symptoms of thrombotic microangiopathy occur. Thromboembolism Associated with Emicizumab and aPCC - Inform the patient and/or caregiver of the potential risk of thromboembolism if aPCC is administered while receiving Emicizumab prophylaxis. Instruct the patient and/or caregiver to consult their healthcare provider if aPCC is required in cumulative doses exceeding 100 U/kg. Advise the patient and/or caregiver to seek immediate medical attention if any signs or symptoms of thromboembolism occur. Laboratory Coagulation Test Interference - Inform the patient and/or caregiver that Emicizumab interferes with some laboratory tests that measure blood clotting and may cause a false reading. Advise the patient and/or caregiver that they should notify any healthcare provider about this possibility prior to any blood tests or medical procedures. Instruction on Injection Technique - Emicizumab is intended for use under the guidance of a healthcare provider. If a patient or caregiver is to administer subcutaneous Emicizumab, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous Emicizumab and the suitability for home use. - Advise the patient to follow the recommendations in the FDA-approved patient labeling regarding proper sharps disposal. # Precautions with Alcohol Alcohol-Emicizumab interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Hemlibra # Look-Alike Drug Names There is limited information regarding Emicizumab Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Emicizumab
6f8482e910eb48b87945da3fd8372f8ce5781f38	wikidoc	Emissivity	Emissivity The emissivity of a material (usually written ε or e) is the ratio of energy radiated by a particular material to energy radiated by a black body at the same temperature. It is a measure of a material's ability to radiate absorbed energy. A true black body would have an \varepsilon=1 while any real object would have \varepsilon. Emissivity is a dimensionless quantity (does not have units). In general, the duller and blacker a material is, the closer its emissivity is to 1. The more reflective a material is, the lower its emissivity. Highly polished silver has an emissivity of about 0.02. # Explanation Emissivity depends on factors such as temperature, emission angle, and wavelength. A typical engineering assumption is to assume that a surface's spectral emissivity and absorptivity do not depend on wavelength, so that the emissivity is a constant. This is known as the grey body assumption. When dealing with non-black surfaces, the deviations from ideal black body behavior are determined by both the geometrical structure and the chemical composition, and follow Kirchhoff's law of thermal radiation: emissivity equals absorptivity (for an object in thermal equilibrium), so that an object that does not absorb all incident light will also emit less radiation than an ideal black body. # Emissivity of earth's atmosphere The emissivity of Earth's atmosphere varies according to cloud cover and the concentration of gases that absorb and emit energy in the thermal infrared (i.e., wavelengths around 8 to 14 micrometres). These gases are often called greenhouse gases, from their role in the greenhouse effect. The main naturally-occurring greenhouse gases are water vapor, carbon dioxide, methane, and ozone. The major constituents of the atmosphere, N2 and O2, do not absorb or emit in the thermal infrared. ## Astrophysical graybody The monochromatic flux density radiated by a greybody at frequency \nu through solid angle d\Omega is given by F_{\nu} = B_{\nu}(T) Q_{\nu} d\Omega where B_{\nu} is the Planck function for a blackbody at temperature T and emissivity Q_{\nu}. For a uniform medium of optical depth \tau_{\nu} radiative transfer means that the radiation will be reduced by a factor e^{-\tau} giving . The optical depth is often approximated by the ratio of the emitting frequency to the frequency where \tau=1 all raised to an exponent β. For cold dust clouds in the interstellar medium β is approximately two. Therefore Q becomes, Q_{\nu}=1-e^{-\tau_{\nu}}=1-e^{-(\nu/\nu_{\tau=1})^{\beta}} Emissivity between 2 walls {\varepsilon}_{1,2}=\frac{1}{{\frac{1}{\varepsilon_1}}+{\frac{1}{\varepsilon_2}}-1}	Emissivity The emissivity of a material (usually written ε or e) is the ratio of energy radiated by a particular material to energy radiated by a black body at the same temperature. It is a measure of a material's ability to radiate absorbed energy. A true black body would have an <math>\varepsilon=1</math> while any real object would have <math>\varepsilon<1</math>. Emissivity is a dimensionless quantity (does not have units). In general, the duller and blacker a material is, the closer its emissivity is to 1. The more reflective a material is, the lower its emissivity. Highly polished silver has an emissivity of about 0.02. # Explanation Emissivity depends on factors such as temperature, emission angle, and wavelength. A typical engineering assumption is to assume that a surface's spectral emissivity and absorptivity do not depend on wavelength, so that the emissivity is a constant. This is known as the grey body assumption. When dealing with non-black surfaces, the deviations from ideal black body behavior are determined by both the geometrical structure and the chemical composition, and follow Kirchhoff's law of thermal radiation: emissivity equals absorptivity (for an object in thermal equilibrium), so that an object that does not absorb all incident light will also emit less radiation than an ideal black body. # Emissivity of earth's atmosphere The emissivity of Earth's atmosphere varies according to cloud cover and the concentration of gases that absorb and emit energy in the thermal infrared (i.e., wavelengths around 8 to 14 micrometres). These gases are often called greenhouse gases, from their role in the greenhouse effect. The main naturally-occurring greenhouse gases are water vapor, carbon dioxide, methane, and ozone. The major constituents of the atmosphere, N2 and O2, do not absorb or emit in the thermal infrared. ## Astrophysical graybody The monochromatic flux density radiated by a greybody at frequency <math>\nu</math> through solid angle <math>d\Omega</math> is given by <math>F_{\nu} = B_{\nu}(T) Q_{\nu} d\Omega </math> where <math>B_{\nu}</math> is the Planck function for a blackbody at temperature T and emissivity <math>Q_{\nu}</math>. For a uniform medium of optical depth <math>\tau_{\nu}</math> radiative transfer means that the radiation will be reduced by a factor <math>e^{-\tau}</math> giving . The optical depth is often approximated by the ratio of the emitting frequency to the frequency where <math>\tau=1</math> all raised to an exponent β. For cold dust clouds in the interstellar medium β is approximately two. Therefore Q becomes, <math>Q_{\nu}=1-e^{-\tau_{\nu}}=1-e^{-(\nu/\nu_{\tau=1})^{\beta}}</math> Emissivity between 2 walls <math>{\varepsilon}_{1,2}=\frac{1}{{\frac{1}{\varepsilon_1}}+{\frac{1}{\varepsilon_2}}-1}</math>	https://www.wikidoc.org/index.php/Emissivity
ae22ef0f1e33f2d4b8b1da3537e1b47b6bbadeb4	wikidoc	Enamel rod	Enamel rod # Overview An Enamel rod is the basic unit of enamel. The antiquated term is enamel prism. Measuring 4 μm wide to 8 μm high, an enamel rod is a tightly packed, highly organized mass of hydroxyapatite crystals. In cross section, it is best compared to a keyhole with the top, or head, oriented toward the crown of the tooth and the bottom, or tail, oriented toward the root of the tooth. Enamel rods are found in rows along the tooth. Within each row, the long axis of the enamel rod generally is perpendicular to the underlying dentin. In permanent teeth, the enamel rods near the cementoenamel junction (CEJ) tilt slightly more toward the root of the tooth than would be expected. Knowing the orientation of enamel is very important in restorative dentistry because enamel unsupported by underlying dentin is prone to fracture and usually is avoided. The arrangement of crystals within each enamel rod is highly complex. For the most part, the enamel crystals are oriented parallel to the long axis of the rod. The further away the crystals are from the central axis, the more their own orientation diverges. The area around the enamel rod is known as interrod enamel. Interrod enamel has the same composition as the enamel rods. Nonetheless, a histologic distinction is made between the two because crystal orientation is different in each. The crystals lie nearly perpendicular to the enamel rod.	Enamel rod Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An Enamel rod is the basic unit of enamel. The antiquated term is enamel prism. Measuring 4 μm wide to 8 μm high, an enamel rod is a tightly packed, highly organized mass of hydroxyapatite crystals. In cross section, it is best compared to a keyhole with the top, or head, oriented toward the crown of the tooth and the bottom, or tail, oriented toward the root of the tooth. Enamel rods are found in rows along the tooth. Within each row, the long axis of the enamel rod generally is perpendicular to the underlying dentin. In permanent teeth, the enamel rods near the cementoenamel junction (CEJ) tilt slightly more toward the root of the tooth than would be expected. Knowing the orientation of enamel is very important in restorative dentistry because enamel unsupported by underlying dentin is prone to fracture and usually is avoided. The arrangement of crystals within each enamel rod is highly complex. For the most part, the enamel crystals are oriented parallel to the long axis of the rod. The further away the crystals are from the central axis, the more their own orientation diverges. The area around the enamel rod is known as interrod enamel. Interrod enamel has the same composition as the enamel rods. Nonetheless, a histologic distinction is made between the two because crystal orientation is different in each. The crystals lie nearly perpendicular to the enamel rod. Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Enamel_rod
76de930ad066ae90a25e2db5bc23661ee2fe970f	wikidoc	Enantiomer	Enantiomer # Overview In chemistry, enantiomers (from the Greek ἐνάντιος, opposite, and μέρος, part or portion) are stereoisomers that are nonsuperimposable complete mirror images of each other, much as one's left and right hands are "the same" but opposite. Enantiomers have, when present in a symmetric environment, identical chemical and physical properties except for their ability to rotate plane-polarized light by equal amounts but in opposite directions. A mixture of equal parts of an optically active isomer and its enantiomer is termed racemic and has a net rotation of plane-polarized light of zero. Two symmetrical enantiomers often do have different chemical properties related to other substances that are also enantiomers. Since many molecules in the bodies of living beings are enantiomers themselves, there is often a marked difference in the effects of two symmetrical enantiomers on living beings, including human beings. # Naming conventions There are several conventions used for naming chiral compounds, all displayed as a prefix before the chemical name of the substance: - (+)- versus (−)-; also written d- vs. l- - based on the substance's ability to rotate polarized light. - D- vs. L- - based on the actual geometry of each enantiomer, with the version synthesized from naturally occurring (+)-glyceraldehyde being considered the D- form. - (R)- vs. (S)- - based on the actual geometry of each enantiomer, using the Cahn-Ingold-Prelog priority rules to classify the form. Molecules with multiple stereogenic centers will have a corresponding number of letters; e.g. natural (+)-α-tocopherol is R,R,R-α-tocopherol. The (+)- vs. (−)- convention is the only one based on optical properties. The other two conventions are based on the actual geometry of each enantiomer. There is no correspondence between any convention. In nature, many chiral substances are only produced in one optical form, while (most) man-made chiral substances are racemic mixtures. The purity of enantiomers can be determined by optical rotation. # More definitions - Any non-racemic chiral substance is called scalemic. - A chiral substance is enantiopure or homochiral when only one of two possible enantiomers is present. - A chiral substance is enantioenriched or heterochiral when an excess of one enantiomer is present but not to the exclusion of the other. - Enantiomeric excess or ee is a measure for how much of one enantiomer is present compared to the other. For example, in a sample with 40% ee in R, the remaining 60% is racemic with 30% of R and 30% of S, so that the total amount of R is 70%. # Enantioselective preparations Several strategies exist for the preparation of enantiopure compounds. This first method is the separation of a racemic mixture into its isomers, a process called chiral resolution. Louis Pasteur in his pioneering work was able to isolate the isomers of tartaric acid because they crystallize from solution as crystals each with a different symmetry. A less common method is by enantiomer self-disproportionation. Other methods are chiral pool synthesis: using chiral starting material and maintaining the chirality; asymmetric induction, the use of chiral auxiliaries, chiral reagents, and chiral catalysts to favor the reaction of one diastereomer over another, and the use of biocatalysts. Enantioconvergent synthesis is the the synthesis of one enantiomer from a racemic precursor molecule utilizing both enantiomers. # Enantiopure medications Advances in industrial chemical processes have made it economical for pharmaceutical manufacturers to take drugs that were originally marketed in racemic form and market the individual enantiomers, each of which may have unique properties. For some drugs, such as zopiclone, only one enantiomer (eszopiclone) is active; the FDA has allowed such once-generic drugs to be patented and marketed under another name. In other cases, such as ibuprofen, it is not economically feasible to isolate a single enantiomer from a racemic mixture or to synthesize just the active one, and therefore a racemic mixture is marketed, with an essentially doubled recommended dose. Examples of racemic mixtures and the corresponding single-enantiomer products that have been marketed include: - Amphetamine (Benzedrine; street amphetamine is also racemic) and dextroamphetamine (Dexedrine) - Bupivacaine (Marcain) and levobupivacaine (Chirocaine) - Cetirizine (Zyrtec / Reactine) and levocetirizine (Xyzal) - Citalopram (Celexa / Cipramil) and escitalopram (Lexapro / Cipralex) - Methylphenidate (Ritalin) and dexmethylphenidate (Focalin) - Modafinil (Provigil) and armodafinil (Nuvigil) - Ofloxacin (Floxin) and levofloxacin (Levaquin) - Omeprazole (Prilosec) and esomeprazole (Nexium) - Salbutamol (Ventolin) and levalbuterol (Xopenex) - Zopiclone (Imovane) and eszopiclone (Lunesta) Thalidomide is an example of a racemic drug, in which one enantiomer produces a desirable antiemetic effect, whereas the other is toxic and produces a teratogenic side-effect. However, the enantiomers are converted into each other in vivo, so chemical processes may not be used to mitigate its toxicity.	Enantiomer # Overview In chemistry, enantiomers (from the Greek ἐνάντιος, opposite, and μέρος, part or portion) are stereoisomers that are nonsuperimposable complete mirror images of each other, much as one's left and right hands are "the same" but opposite. Enantiomers have, when present in a symmetric environment, identical chemical and physical properties except for their ability to rotate plane-polarized light by equal amounts but in opposite directions. A mixture of equal parts of an optically active isomer and its enantiomer is termed racemic and has a net rotation of plane-polarized light of zero. Two symmetrical enantiomers often do have different chemical properties related to other substances that are also enantiomers. Since many molecules in the bodies of living beings are enantiomers themselves, there is often a marked difference in the effects of two symmetrical enantiomers on living beings, including human beings. # Naming conventions There are several conventions used for naming chiral compounds, all displayed as a prefix before the chemical name of the substance: - (+)- versus (−)-; also written d- vs. l- - based on the substance's ability to rotate polarized light. - D- vs. L- - based on the actual geometry of each enantiomer, with the version synthesized from naturally occurring (+)-glyceraldehyde being considered the D- form. - (R)- vs. (S)- - based on the actual geometry of each enantiomer, using the Cahn-Ingold-Prelog priority rules to classify the form. Molecules with multiple stereogenic centers will have a corresponding number of letters; e.g. natural (+)-α-tocopherol is R,R,R-α-tocopherol. The (+)- vs. (−)- convention is the only one based on optical properties. The other two conventions are based on the actual geometry of each enantiomer. There is no correspondence between any convention. In nature, many chiral substances are only produced in one optical form, while (most) man-made chiral substances are racemic mixtures. The purity of enantiomers can be determined by optical rotation. # More definitions - Any non-racemic chiral substance is called scalemic. - A chiral substance is enantiopure or homochiral when only one of two possible enantiomers is present. - A chiral substance is enantioenriched or heterochiral when an excess of one enantiomer is present but not to the exclusion of the other. - Enantiomeric excess or ee is a measure for how much of one enantiomer is present compared to the other. For example, in a sample with 40% ee in R, the remaining 60% is racemic with 30% of R and 30% of S, so that the total amount of R is 70%. # Enantioselective preparations Several strategies exist for the preparation of enantiopure compounds. This first method is the separation of a racemic mixture into its isomers, a process called chiral resolution. Louis Pasteur in his pioneering work was able to isolate the isomers of tartaric acid because they crystallize from solution as crystals each with a different symmetry. A less common method is by enantiomer self-disproportionation. Other methods are chiral pool synthesis: using chiral starting material and maintaining the chirality; asymmetric induction, the use of chiral auxiliaries, chiral reagents, and chiral catalysts to favor the reaction of one diastereomer over another, and the use of biocatalysts. Enantioconvergent synthesis is the the synthesis of one enantiomer from a racemic precursor molecule utilizing both enantiomers. # Enantiopure medications Advances in industrial chemical processes have made it economical for pharmaceutical manufacturers to take drugs that were originally marketed in racemic form and market the individual enantiomers, each of which may have unique properties. For some drugs, such as zopiclone, only one enantiomer (eszopiclone) is active; the FDA has allowed such once-generic drugs to be patented and marketed under another name. In other cases, such as ibuprofen, it is not economically feasible to isolate a single enantiomer from a racemic mixture or to synthesize just the active one, and therefore a racemic mixture is marketed, with an essentially doubled recommended dose. Examples of racemic mixtures and the corresponding single-enantiomer products that have been marketed include: - Amphetamine (Benzedrine; street amphetamine is also racemic) and dextroamphetamine (Dexedrine) - Bupivacaine (Marcain) and levobupivacaine (Chirocaine) - Cetirizine (Zyrtec / Reactine) and levocetirizine (Xyzal) - Citalopram (Celexa / Cipramil) and escitalopram (Lexapro / Cipralex) - Methylphenidate (Ritalin) and dexmethylphenidate (Focalin) - Modafinil (Provigil) and armodafinil (Nuvigil) - Ofloxacin (Floxin) and levofloxacin (Levaquin) - Omeprazole (Prilosec) and esomeprazole (Nexium) - Salbutamol (Ventolin) and levalbuterol (Xopenex) - Zopiclone (Imovane) and eszopiclone (Lunesta) Thalidomide is an example of a racemic drug, in which one enantiomer produces a desirable antiemetic effect, whereas the other is toxic and produces a teratogenic side-effect. However, the enantiomers are converted into each other in vivo, so chemical processes may not be used to mitigate its toxicity. # External links - Infelicitous stereochemical nomenclatures for stereochemical nomenclature - US FDA's policy statement on the development of new stereoisomeric drugs Template:Chiral synthesis ar:إينانشيومير da:Enantiomer de:Enantiomer he:אננטיומר it:Enantiomero ms:Enantiomer nl:Enantiomeer fi:Enantiomeeri sv:Enantiomer Template:Jb1 Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Enantiomer
d53ab5d1dce725178189644d68d22caf1cc4ada3	wikidoc	Enasidenib	Enasidenib # 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 Enasidenib is a isocitrate dehydrogenase-2 inhibitor that is FDA approved for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Enasidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. - The recommended starting dose of Enasidenib is 100 mg taken orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. - Do not split or crush Enasidenib tablets. Administer Enasidenib tablets orally about the same time each day. If a dose of Enasidenib is vomited, missed, or not taken at the usual time, administer the dose as soon as possible on the same day, and return to the normal schedule the following day. - Assess blood counts and blood chemistries for leukocytosis and tumor lysis syndrome prior to the initiation of Enasidenib and monitor at a minimum of every 2 weeks for at least the first 3 months during treatment. Manage any abnormalities promptly. - Interrupt dosing or reduce dose for toxicities. See TABLE 1 for dosage modification guidelines. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Enasidenib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Enasidenib 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 Enasidenib FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Enasidenib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Enasidenib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None # Warnings - In the clinical trial, 14% of patients treated with Enasidenib experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for differentiation syndrome, symptoms in patients treated with Enasidenib included acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also been observed. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, and as early as 10 days and at up to 5 months after Enasidenib initiation. - If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt Enasidenib until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended. - Based on animal embryo-fetal toxicity studies, Enasidenib can cause embryo-fetal harm when administered to a pregnant woman. In animal embryo-fetal toxicity studies, Enasidenib caused embryo-fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area under the concentration-time curve (AUC) at the recommended human dose. Advise females of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. Advise males with female partners of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. Pregnant women, patients becoming pregnant while receiving Enasidenib, or male patients with pregnant female partners should be apprised of the potential risk to the fetus. # 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 single-agent Enasidenib is based on 214 patients with relapsed or refractory AML who were assigned to receive 100 mg daily . The median duration of exposure to Enasidenib was 4.3 months (range 0.3 to 23.6). The 30-day and 60-day mortality rates observed with Enasidenib were 4.2% (9/214) and 11.7% (25/214), respectively. - The most common adverse reactions (≥20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite. - Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure. - Overall, 92 of 214 patients (43%) required a dose interruption due to an adverse reaction; the most common adverse reactions leading to dose interruption were differentiation syndrome (4%) and leukocytosis (3%). Ten of 214 patients (5%) required a dose reduction due to an adverse reaction; no adverse reaction required dose reduction in more than 2 patients. Thirty-six of 214 patients (17%) permanently discontinued Enasidenib due to an adverse reaction; the most common adverse reaction leading to permanent discontinuation was leukocytosis (1%). - Adverse reactions reported in the trial are shown in TABLE 2. - Other clinically significant adverse reactions occurring in ≤10% of patients included: - Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary edema, acute respiratory distress syndrome. - Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in TABLE 3. ### Elevated Bilirubin - Enasidenib may interfere with bilirubin metabolism through inhibition of UGT1A1. Thirty-seven percent of patients (80/214) experienced total bilirubin elevations ≥2 x ULN at least one time. Of those patients who experienced total bilirubin elevations ≥2 x ULN, 35% had elevations within the first month of treatment, and 89% had no concomitant elevation of transaminases or other severe adverse events related to liver disorders. No patients required a dose reduction for hyperbilirubinemia; treatment was interrupted in 3.7% of patients, for a median of 6 days. Three patients (1.4%) discontinued Enasidenib permanently due to hyperbilirubinemia. ### Non-infectious Leukocytosis - Enasidenib can induce myeloid proliferation resulting in a rapid increase in white blood cell count. ### Tumor Lysis Syndrome - Enasidenib can induce myeloid proliferation resulting in a rapid reduction in tumor cells which may pose a risk for tumor lysis syndrome. ## Postmarketing Experience There is limited information regarding Enasidenib Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Enasidenib Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on animal embryo-fetal toxicity studies, Enasidenib can cause fetal harm when administered to a pregnant woman. There are no available data on Enasidenib use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of Enasidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 0.1 times the steady state clinical exposure based on the AUC at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. - Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data (Animal) - Enasidenib administered to pregnant rats at a dose of 30 mg/kg twice daily during organogenesis (gestation days 6-17) was associated with maternal toxicity and adverse embryo-fetal effects including post-implantation loss, resorptions, decreased viable fetuses, lower fetal birth weights, and skeletal variations. These effects occurred in rats at approximately 1.6 times the clinical exposure at the recommended human daily dose of 100 mg/day. - In pregnant rabbits treated during organogenesis (gestation days 7-19), Enasidenib was maternally toxic at doses equal to 5 mg/kg/day or higher (exposure approximately 0.1 to 0.6 times the steady state clinical exposure at the recommended daily dose) and caused spontaneous abortions at 5 mg/kg/day (exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enasidenib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Enasidenib during labor and delivery. ### Nursing Mothers Risk Summary - There are no data on the presence of Enasidenib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with Enasidenib and for at least 1 month after the last dose. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - No dosage adjustment is required for Enasidenib based on age. In the clinical study, 61% of 214 patients were aged 65 years or older, while 24% were older than 75 years. No overall differences in effectiveness or safety were observed between patients aged 65 years or older and younger patients. ### Gender There is no FDA guidance on the use of Enasidenib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Enasidenib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Enasidenib in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Enasidenib in patients with hepatic impairment. ### Females of Reproductive Potential and Males Pregnancy Testing - Based on animal embryo-fetal toxicity studies, Enasidenib can cause fetal harm when administered to a pregnant woman. - Obtain a pregnancy test on females of reproductive potential prior to starting treatment with Enasidenib. ### Contraception Females - Advise females of reproductive potential to avoid becoming pregnant while receiving Enasidenib. Advise females of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose. Coadministration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time. Males - Advise males with female partners of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. ### Infertility - Based on findings in animals, Enasidenib 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 Enasidenib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administer at the same time each day. - Do not split or crush tablets. - Missed dose or vomiting: Administer as soon as possible on the same day and return to the normal schedule the following day. ### Monitoring - Screen for presence of IDH2 mutations prior to initiation of treatment. - Disease response or stabilizations may indicate efficacy. - Blood counts and blood chemistries: Prior to treatment and at least every 2 weeks for the first 3 months during treatment. - Pregnancy test: Prior to treatment. # IV Compatibility There is limited information regarding the compatibility of Enasidenib and IV administrations. # Overdosage There is limited information regarding Enasidenib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Enasidenib is a small molecule inhibitor of the isocitrate dehydrogenase 2 (IDH2) enzyme. Enasidenib targets the mutant IDH2 variants R140Q, R172S, and R172K at approximately 40-fold lower concentrations than the wild-type enzyme in vitro. Inhibition of the mutant IDH2 enzyme by Enasidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2 mutated AML. In blood samples from patients with AML with mutated IDH2, Enasidenib decreased 2-HG levels, reduced blast counts and increased percentages of mature myeloid cells. ## Structure ## Pharmacodynamics Cardiac Electrophysiology - The potential for QTc prolongation with Enasidenib was evaluated in an open-label study in patients with advanced hematologic malignancies with an IDH2 mutation. Based on the QTc data for a single dose of 30 mg to 650 mg and multiple doses of 100 mg daily in the fasted state, no large mean changes in the QTc interval (>20 ms) were observed following treatment with Enasidenib. ## Pharmacokinetics - The peak plasma concentration (Cmax) is 1.3 mcg/mL after a single dose of 100 mg, and 13 mcg/mL (CV% 46.3) at steady state for 100 mg daily. The area under concentration time curve (AUC) of Enasidenib increases in an approximately dose proportional manner from 50 mg (0.5 times approved recommended dosage) to 450 mg (4.5 times approved recommended dosage) daily dose. Steady-state plasma levels are reached within 29 days of once-daily dosing. Accumulation is approximately 10-fold when administered once daily. ### Absorption - The absolute bioavailability after 100 mg oral dose of Enasidenib is approximately 57%. After a single oral dose, the median time to Cmax (Tmax) is 4 hours. ## =Distribution - The mean volume of distribution (Vd) of Enasidenib is 55.8 L (CV% 29). Human plasma protein binding of Enasidenib is 98.5% and of its metabolite AGI-16903 is 96.6% in vitro. - Enasidenib is not a substrate for P-glycoprotein or BCRP, while AGI-16903 is a substrate of both P-glycoprotein and BCRP. Enasidenib and AGI-16903 are not substrates of MRP2, OAT1, OAT3, OATP1B1, OATP1B3, and OCT2. ### Elimination - Enasidenib has a terminal half-life of 137 hours (CV% 41) and a mean total body clearance (CL/F) of 0.74 L/hour (CV% 71). Metabolism - Enasidenib accounted for 89% of the radioactivity in circulation and AGI-16903, the N-dealkylated metabolite, represented 10% of the circulating radioactivity. - In vitro studies suggest that metabolism of Enasidenib is mediated by multiple CYP enzymes (e.g., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UGTs (e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15). Further metabolism of the metabolite AGI-16903 is also mediated by multiple enzymes (e.g., CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9). Excretion - Eighty-nine percent (89%) of Enasidenib is eliminated in feces and 11% in the urine. Excretion of unchanged Enasidenib accounts for 34% of the radiolabeled drug in the feces and 0.4% in the urine. ### Specific Populations - No clinically meaningful effect on the pharmacokinetics of Enasidenib was observed for the following covariates: age (19 years to 100 years), race (White, Black, or Asian), mild hepatic impairment , renal impairment (defined as creatinine clearance ≥30 mL/min by Cockcroft-Gault formula), sex, body weight (39 kg to 136 kg), and body surface area. ### Drug Interaction Studies - In vitro studies suggest that Enasidenib inhibits the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and UGT1A1. Enasidenib inhibits P-gp, BCRP, OAT1, OATP1B1, OATP1B3, and OCT2, but not MRP2 or OAT3. Enasidenib induces CYP2B6 and CYP3A4. - In vitro studies suggest that the metabolite AGI-16903 inhibits the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. AGI-16903 inhibits BCRP, OAT1, OAT3, OATP1B1, and OCT2, but not P-gp, MRP2, or OATP1B3. - Coadministration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time. ## Nonclinical Toxicology - Carcinogenicity studies have not been performed with Enasidenib. - Enasidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Enasidenib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay, or in an in vivo rat bone marrow micronucleus assay. - Fertility studies in animals have not been conducted with Enasidenib. In repeat-dose toxicity studies with twice daily oral administration of Enasidenib in rats up to 90-days in duration, changes were reported in male and female reproductive organs including seminiferous tubular degeneration, hypospermia, atrophy of the seminal vesicle and prostate, decreased corpora lutea and increased atretic follicles in the ovaries, and atrophy in the uterus. # Clinical Studies - The efficacy of Enasidenib was evaluated in an open-label, single-arm, multicenter, two-cohort clinical trial (Study AG221-C-001, NCT01915498) of 199 adult patients with relapsed or refractory AML and an IDH2 mutation, who were assigned to receive 100 mg daily dose. Cohort 1 included 101 patients and Cohort 2 included 98 patients. IDH2 mutations were identified by a local diagnostic test and retrospectively confirmed by the Abbott RealTime™ IDH2 assay, or prospectively identified by the Abbott RealTime™ IDH2 assay, which is the FDA-approved test for selection of patients with AML for treatment with Enasidenib. Enasidenib was given orally at starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage adverse events. - The baseline demographic and disease characteristics are shown in TABLE 4. The baseline demographics and disease characteristics were similar in both study cohorts. - Efficacy was established on the basis of the rate of complete response (CR)/complete response with partial hematologic recovery (CRh), the duration of CR/CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in TABLE 5 and were similar in both cohorts. The median follow-up was 6.6 months (range, 0.4 to 27.7 months). Similar CR/CRh rates were observed in patients with either R140 or R172 mutation. - For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5 months) and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to 11.2 months). Of the 46 patients who achieved a best response of CR/CRh, 39 (85%) did so within 6 months of initiating Enasidenib. - Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day post baseline period. Of the 42 patients who were independent of both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post baseline period. # How Supplied - 50-mg tablet: Pale yellow to yellow oval-shaped film-coated tablet debossed “ENA” on one side and “50” on the other side. - 30-count bottles of 50-mg tablets with a desiccant canister (NDC 59572-705-30). - 100-mg tablet: Pale yellow to yellow capsule-shaped film-coated tablet debossed “ENA” on one side and “100” on the other side. - 30-count bottles of 100-mg tablets with a desiccant canister (NDC 59572-710-30). ## Storage - Store at 20°C-25°C (68°F-77°F); excursions permitted between 15°C-30°C (59°F-86°F). Keep the bottle tightly closed. Store in the original bottle (with a desiccant canister) to protect from moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Differentiation Syndrome - Advise patients on the risks of developing differentiation syndrome as early as 10 days and during the first 5 months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, bone pain, rapid weight gain or swelling of their arms or legs, to their healthcare provider for further evaluation. ### Tumor Lysis Syndrome - Advise patients on the risks of developing tumor lysis syndrome. Advise patients on the importance of maintaining high fluid intake, and the need for frequent monitoring of blood chemistry values. ### Gastrointestinal Adverse Reactions - Advise patients on risk of experiencing gastrointestinal reactions such as diarrhea, nausea, vomiting, decreased appetite, and changes in their sense of taste. Ask patients to report these events to their healthcare provider, and advise patients how to manage them. ### Elevated Blood Bilirubin - Inform patients that taking Enasidenib may cause elevated blood bilirubin, which is due to its mechanism of action, and not due to liver damage. Advise patients to report any changes to the color of their skin or the whites of their eyes to their healthcare provider for further evaluation. ### Embryo-Fetal Toxicity and Use of Contraceptives - Advise female patients with reproductive potential to use effective contraceptive methods while receiving Enasidenib and to avoid pregnancy while on treatment and for 1 month after completion of treatment. Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during Enasidenib treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. Coadministration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time. ### Lactation - Advise women not to breastfeed during treatment with Enasidenib and for at least 1 month after the final dose. ### Dosing and Storage Instructions - Advise patients not to chew or split the tablets but swallow whole with a cup of water. - Instruct patients that if they miss a dose or vomit after a dose of Enasidenib, to take it as soon as possible on the same day and return to normal schedule the following day. Warn patients not to take 2 doses to make up for the missed dose. - Keep Enasidenib in the original container. Keep the container tightly closed with desiccant canister inside to protect the tablets from moisture. # Precautions with Alcohol Alcohol-Enasidenib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Idhifa # Look-Alike Drug Names There is limited information regarding Enasidenib Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	Enasidenib Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2], Anmol Pitliya, M.B.B.S. M.D.[3] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Enasidenib is a isocitrate dehydrogenase-2 inhibitor that is FDA approved for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Enasidenib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. - The recommended starting dose of Enasidenib is 100 mg taken orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. - Do not split or crush Enasidenib tablets. Administer Enasidenib tablets orally about the same time each day. If a dose of Enasidenib is vomited, missed, or not taken at the usual time, administer the dose as soon as possible on the same day, and return to the normal schedule the following day. - Assess blood counts and blood chemistries for leukocytosis and tumor lysis syndrome prior to the initiation of Enasidenib and monitor at a minimum of every 2 weeks for at least the first 3 months during treatment. Manage any abnormalities promptly. - Interrupt dosing or reduce dose for toxicities. See TABLE 1 for dosage modification guidelines. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Enasidenib Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Enasidenib 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 Enasidenib FDA-Labeled Indications and Dosage (Pediatric) in the drug label. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Enasidenib Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label. ### Non–Guideline-Supported Use There is limited information regarding Enasidenib Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label. # Contraindications - None # Warnings - In the clinical trial, 14% of patients treated with Enasidenib experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for differentiation syndrome, symptoms in patients treated with Enasidenib included acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also been observed. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis, and as early as 10 days and at up to 5 months after Enasidenib initiation. - If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt Enasidenib until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended. - Based on animal embryo-fetal toxicity studies, Enasidenib can cause embryo-fetal harm when administered to a pregnant woman. In animal embryo-fetal toxicity studies, Enasidenib caused embryo-fetal toxicities starting at 0.1 times the steady state clinical exposure based on the area under the concentration-time curve (AUC) at the recommended human dose. Advise females of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. Advise males with female partners of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. Pregnant women, patients becoming pregnant while receiving Enasidenib, or male patients with pregnant female partners should be apprised of the potential risk to the fetus. # 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 single-agent Enasidenib is based on 214 patients with relapsed or refractory AML who were assigned to receive 100 mg daily [see Clinical Studies (14.1)]. The median duration of exposure to Enasidenib was 4.3 months (range 0.3 to 23.6). The 30-day and 60-day mortality rates observed with Enasidenib were 4.2% (9/214) and 11.7% (25/214), respectively. - The most common adverse reactions (≥20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite. - Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure. - Overall, 92 of 214 patients (43%) required a dose interruption due to an adverse reaction; the most common adverse reactions leading to dose interruption were differentiation syndrome (4%) and leukocytosis (3%). Ten of 214 patients (5%) required a dose reduction due to an adverse reaction; no adverse reaction required dose reduction in more than 2 patients. Thirty-six of 214 patients (17%) permanently discontinued Enasidenib due to an adverse reaction; the most common adverse reaction leading to permanent discontinuation was leukocytosis (1%). - Adverse reactions reported in the trial are shown in TABLE 2. - Other clinically significant adverse reactions occurring in ≤10% of patients included: - Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary edema, acute respiratory distress syndrome. - Changes in selected post-baseline laboratory values that were observed in patients with relapsed or refractory AML are shown in TABLE 3. ### Elevated Bilirubin - Enasidenib may interfere with bilirubin metabolism through inhibition of UGT1A1. Thirty-seven percent of patients (80/214) experienced total bilirubin elevations ≥2 x ULN at least one time. Of those patients who experienced total bilirubin elevations ≥2 x ULN, 35% had elevations within the first month of treatment, and 89% had no concomitant elevation of transaminases or other severe adverse events related to liver disorders. No patients required a dose reduction for hyperbilirubinemia; treatment was interrupted in 3.7% of patients, for a median of 6 days. Three patients (1.4%) discontinued Enasidenib permanently due to hyperbilirubinemia. ### Non-infectious Leukocytosis - Enasidenib can induce myeloid proliferation resulting in a rapid increase in white blood cell count. ### Tumor Lysis Syndrome - Enasidenib can induce myeloid proliferation resulting in a rapid reduction in tumor cells which may pose a risk for tumor lysis syndrome. ## Postmarketing Experience There is limited information regarding Enasidenib Postmarketing Experience in the drug label. # Drug Interactions There is limited information regarding Enasidenib Drug Interactions in the drug label. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Risk Summary - Based on animal embryo-fetal toxicity studies, Enasidenib can cause fetal harm when administered to a pregnant woman. There are no available data on Enasidenib use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal embryo-fetal toxicity studies, oral administration of Enasidenib to pregnant rats and rabbits during organogenesis was associated with embryo-fetal mortality and alterations to growth starting at 0.1 times the steady state clinical exposure based on the AUC at the recommended human dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, advise the patient of the potential risk to a fetus. - Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data (Animal) - Enasidenib administered to pregnant rats at a dose of 30 mg/kg twice daily during organogenesis (gestation days 6-17) was associated with maternal toxicity and adverse embryo-fetal effects including post-implantation loss, resorptions, decreased viable fetuses, lower fetal birth weights, and skeletal variations. These effects occurred in rats at approximately 1.6 times the clinical exposure at the recommended human daily dose of 100 mg/day. - In pregnant rabbits treated during organogenesis (gestation days 7-19), Enasidenib was maternally toxic at doses equal to 5 mg/kg/day or higher (exposure approximately 0.1 to 0.6 times the steady state clinical exposure at the recommended daily dose) and caused spontaneous abortions at 5 mg/kg/day (exposure approximately 0.1 times the steady state clinical exposure at the recommended daily dose). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Enasidenib in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Enasidenib during labor and delivery. ### Nursing Mothers Risk Summary - There are no data on the presence of Enasidenib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for adverse reactions in breastfed infants, advise women not to breastfeed during treatment with Enasidenib and for at least 1 month after the last dose. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. ### Geriatic Use - No dosage adjustment is required for Enasidenib based on age. In the clinical study, 61% of 214 patients were aged 65 years or older, while 24% were older than 75 years. No overall differences in effectiveness or safety were observed between patients aged 65 years or older and younger patients. ### Gender There is no FDA guidance on the use of Enasidenib with respect to specific gender populations. ### Race There is no FDA guidance on the use of Enasidenib with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Enasidenib in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Enasidenib in patients with hepatic impairment. ### Females of Reproductive Potential and Males Pregnancy Testing - Based on animal embryo-fetal toxicity studies, Enasidenib can cause fetal harm when administered to a pregnant woman. - Obtain a pregnancy test on females of reproductive potential prior to starting treatment with Enasidenib. ### Contraception Females - Advise females of reproductive potential to avoid becoming pregnant while receiving Enasidenib. Advise females of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose. Coadministration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time. Males - Advise males with female partners of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. ### Infertility - Based on findings in animals, Enasidenib 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 Enasidenib in patients who are immunocompromised. # Administration and Monitoring ### Administration - Administer at the same time each day. - Do not split or crush tablets. - Missed dose or vomiting: Administer as soon as possible on the same day and return to the normal schedule the following day. ### Monitoring - Screen for presence of IDH2 mutations prior to initiation of treatment. - Disease response or stabilizations may indicate efficacy. - Blood counts and blood chemistries: Prior to treatment and at least every 2 weeks for the first 3 months during treatment. - Pregnancy test: Prior to treatment. # IV Compatibility There is limited information regarding the compatibility of Enasidenib and IV administrations. # Overdosage There is limited information regarding Enasidenib overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately. # Pharmacology ## Mechanism of Action - Enasidenib is a small molecule inhibitor of the isocitrate dehydrogenase 2 (IDH2) enzyme. Enasidenib targets the mutant IDH2 variants R140Q, R172S, and R172K at approximately 40-fold lower concentrations than the wild-type enzyme in vitro. Inhibition of the mutant IDH2 enzyme by Enasidenib led to decreased 2-hydroxyglutarate (2-HG) levels and induced myeloid differentiation in vitro and in vivo in mouse xenograft models of IDH2 mutated AML. In blood samples from patients with AML with mutated IDH2, Enasidenib decreased 2-HG levels, reduced blast counts and increased percentages of mature myeloid cells. ## Structure ## Pharmacodynamics Cardiac Electrophysiology - The potential for QTc prolongation with Enasidenib was evaluated in an open-label study in patients with advanced hematologic malignancies with an IDH2 mutation. Based on the QTc data for a single dose of 30 mg to 650 mg and multiple doses of 100 mg daily in the fasted state, no large mean changes in the QTc interval (>20 ms) were observed following treatment with Enasidenib. ## Pharmacokinetics - The peak plasma concentration (Cmax) is 1.3 mcg/mL [% coefficient of variation (CV%) 56.4] after a single dose of 100 mg, and 13 mcg/mL (CV% 46.3) at steady state for 100 mg daily. The area under concentration time curve (AUC) of Enasidenib increases in an approximately dose proportional manner from 50 mg (0.5 times approved recommended dosage) to 450 mg (4.5 times approved recommended dosage) daily dose. Steady-state plasma levels are reached within 29 days of once-daily dosing. Accumulation is approximately 10-fold when administered once daily. ### Absorption - The absolute bioavailability after 100 mg oral dose of Enasidenib is approximately 57%. After a single oral dose, the median time to Cmax (Tmax) is 4 hours. ## =Distribution - The mean volume of distribution (Vd) of Enasidenib is 55.8 L (CV% 29). Human plasma protein binding of Enasidenib is 98.5% and of its metabolite AGI-16903 is 96.6% in vitro. - Enasidenib is not a substrate for P-glycoprotein or BCRP, while AGI-16903 is a substrate of both P-glycoprotein and BCRP. Enasidenib and AGI-16903 are not substrates of MRP2, OAT1, OAT3, OATP1B1, OATP1B3, and OCT2. ### Elimination - Enasidenib has a terminal half-life of 137 hours (CV% 41) and a mean total body clearance (CL/F) of 0.74 L/hour (CV% 71). Metabolism - Enasidenib accounted for 89% of the radioactivity in circulation and AGI-16903, the N-dealkylated metabolite, represented 10% of the circulating radioactivity. - In vitro studies suggest that metabolism of Enasidenib is mediated by multiple CYP enzymes (e.g., CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), and by multiple UGTs (e.g., UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15). Further metabolism of the metabolite AGI-16903 is also mediated by multiple enzymes (e.g., CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9). Excretion - Eighty-nine percent (89%) of Enasidenib is eliminated in feces and 11% in the urine. Excretion of unchanged Enasidenib accounts for 34% of the radiolabeled drug in the feces and 0.4% in the urine. ### Specific Populations - No clinically meaningful effect on the pharmacokinetics of Enasidenib was observed for the following covariates: age (19 years to 100 years), race (White, Black, or Asian), mild hepatic impairment [defined as total bilirubin ≤ upper limit of normal (ULN) and aspartate transaminase (AST) >ULN or total bilirubin 1 to 1.5 times ULN and any AST], renal impairment (defined as creatinine clearance ≥30 mL/min by Cockcroft-Gault formula), sex, body weight (39 kg to 136 kg), and body surface area. ### Drug Interaction Studies - In vitro studies suggest that Enasidenib inhibits the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and UGT1A1. Enasidenib inhibits P-gp, BCRP, OAT1, OATP1B1, OATP1B3, and OCT2, but not MRP2 or OAT3. Enasidenib induces CYP2B6 and CYP3A4. - In vitro studies suggest that the metabolite AGI-16903 inhibits the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2D6. AGI-16903 inhibits BCRP, OAT1, OAT3, OATP1B1, and OCT2, but not P-gp, MRP2, or OATP1B3. - Coadministration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time. ## Nonclinical Toxicology - Carcinogenicity studies have not been performed with Enasidenib. - Enasidenib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay. Enasidenib was not clastogenic in an in vitro human lymphocyte chromosomal aberration assay, or in an in vivo rat bone marrow micronucleus assay. - Fertility studies in animals have not been conducted with Enasidenib. In repeat-dose toxicity studies with twice daily oral administration of Enasidenib in rats up to 90-days in duration, changes were reported in male and female reproductive organs including seminiferous tubular degeneration, hypospermia, atrophy of the seminal vesicle and prostate, decreased corpora lutea and increased atretic follicles in the ovaries, and atrophy in the uterus. # Clinical Studies - The efficacy of Enasidenib was evaluated in an open-label, single-arm, multicenter, two-cohort clinical trial (Study AG221-C-001, NCT01915498) of 199 adult patients with relapsed or refractory AML and an IDH2 mutation, who were assigned to receive 100 mg daily dose. Cohort 1 included 101 patients and Cohort 2 included 98 patients. IDH2 mutations were identified by a local diagnostic test and retrospectively confirmed by the Abbott RealTime™ IDH2 assay, or prospectively identified by the Abbott RealTime™ IDH2 assay, which is the FDA-approved test for selection of patients with AML for treatment with Enasidenib. Enasidenib was given orally at starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage adverse events. - The baseline demographic and disease characteristics are shown in TABLE 4. The baseline demographics and disease characteristics were similar in both study cohorts. - Efficacy was established on the basis of the rate of complete response (CR)/complete response with partial hematologic recovery (CRh), the duration of CR/CRh, and the rate of conversion from transfusion dependence to transfusion independence. The efficacy results are shown in TABLE 5 and were similar in both cohorts. The median follow-up was 6.6 months (range, 0.4 to 27.7 months). Similar CR/CRh rates were observed in patients with either R140 or R172 mutation. - For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5 months) and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to 11.2 months). Of the 46 patients who achieved a best response of CR/CRh, 39 (85%) did so within 6 months of initiating Enasidenib. - Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day post baseline period. Of the 42 patients who were independent of both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post baseline period. # How Supplied - 50-mg tablet: Pale yellow to yellow oval-shaped film-coated tablet debossed “ENA” on one side and “50” on the other side. - 30-count bottles of 50-mg tablets with a desiccant canister (NDC 59572-705-30). - 100-mg tablet: Pale yellow to yellow capsule-shaped film-coated tablet debossed “ENA” on one side and “100” on the other side. - 30-count bottles of 100-mg tablets with a desiccant canister (NDC 59572-710-30). ## Storage - Store at 20°C-25°C (68°F-77°F); excursions permitted between 15°C-30°C (59°F-86°F). Keep the bottle tightly closed. Store in the original bottle (with a desiccant canister) to protect from moisture. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ### Differentiation Syndrome - Advise patients on the risks of developing differentiation syndrome as early as 10 days and during the first 5 months on treatment. Ask patients to immediately report any symptoms suggestive of differentiation syndrome, such as fever, cough or difficulty breathing, bone pain, rapid weight gain or swelling of their arms or legs, to their healthcare provider for further evaluation. ### Tumor Lysis Syndrome - Advise patients on the risks of developing tumor lysis syndrome. Advise patients on the importance of maintaining high fluid intake, and the need for frequent monitoring of blood chemistry values. ### Gastrointestinal Adverse Reactions - Advise patients on risk of experiencing gastrointestinal reactions such as diarrhea, nausea, vomiting, decreased appetite, and changes in their sense of taste. Ask patients to report these events to their healthcare provider, and advise patients how to manage them. ### Elevated Blood Bilirubin - Inform patients that taking Enasidenib may cause elevated blood bilirubin, which is due to its mechanism of action, and not due to liver damage. Advise patients to report any changes to the color of their skin or the whites of their eyes to their healthcare provider for further evaluation. ### Embryo-Fetal Toxicity and Use of Contraceptives - Advise female patients with reproductive potential to use effective contraceptive methods while receiving Enasidenib and to avoid pregnancy while on treatment and for 1 month after completion of treatment. Advise patients to notify their healthcare provider immediately in the event of a pregnancy or if pregnancy is suspected during Enasidenib treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with Enasidenib and for at least 1 month after the last dose of Enasidenib. Coadministration of Enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time. ### Lactation - Advise women not to breastfeed during treatment with Enasidenib and for at least 1 month after the final dose. ### Dosing and Storage Instructions - Advise patients not to chew or split the tablets but swallow whole with a cup of water. - Instruct patients that if they miss a dose or vomit after a dose of Enasidenib, to take it as soon as possible on the same day and return to normal schedule the following day. Warn patients not to take 2 doses to make up for the missed dose. - Keep Enasidenib in the original container. Keep the container tightly closed with desiccant canister inside to protect the tablets from moisture. # Precautions with Alcohol Alcohol-Enasidenib interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication. # Brand Names - Idhifa # Look-Alike Drug Names There is limited information regarding Enasidenib Look-Alike Drug Names in the drug label. # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Enasidenib
71ba84804d1aa347343892d2f41b7249ecd1be72	wikidoc	Etanercept	Etanercept # 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 Etanercept is an antirheumatic drug that is FDA approved for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reaction, rhinitis and upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### General Information ### Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients - Dosing informatinon - MTX, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be continued during treatment with Etanercept . - Recommended dosage: 50 mg twice weekly - Doses higher than 50 mg per week are not recommended. ### Adult Plaque Psoriasis Patients - Dosing informatinon - Recommended starting dose: 50 mg twice weekly , - Starting doses of 25 mg or 50 mg per week were shown to be efficacious. The proportion of responders was related to Etanercept dosage ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Etanercept in adult patients. ### Non–Guideline-Supported Use ### Behcet's syndrome - Dosing information - 25 mg twice weekly for 4 weeks ### Bone metastasis - Pain from metastases - Dosing information - 25 mg ### Crohn's disease - Dosing information - 25 mg SC twice weekly ### Hemophagocytic lymphohistiocytosis - Dosing information - Twice weekly injections (0.4 mg/kg) ### Hidradenitis suppurativa - Dosing information - 25 mg twice weekly ### Langerhans cell histiocytosis - Dosing information - 0.4 mg/kg SC twice weekly ### Myelosclerosis with myeloid metaplasia - Dosing information - 25 mg twice weekly 11877307 - 25 mg twice weekly subQ for at least 4 weeks ### Nephrotic syndrome - Dosing information - 25-mg SC injections twice weekly ### Pemphigoid - Dosing information - 25 mg subQ twice weekly ### Sarcoidosis - Dosing information - 25 mg twice weekly ### Sjögren's syndrome - Dosing information - 25 mg twice per week for 12 weeks ### TNF receptor-associated periodic fever syndrome (TRAPS) - Dosing information - 25 mg (adults) or 0.4 mg/kg (children) twice weekly ### Uveitis - Dosing information - 25 mg twice a week for 24 weeks # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### JIA Patients - Dosing informatinon - In JIA patients, glucocorticoids, NSAIDs, or analgesics may be continued during treatment with Etanercept . Higher doses of Etanercept have not been studied in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Etanercept in pediatric patients. ### Non–Guideline-Supported Use ### Graft versus host disease - Dosing information - 0.4 mg/kg SC twice weekly # Contraindications - Etanercept should not be administered to patients with sepsis. # Warnings ## Serious Infections - Patients treated with Etanercept are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. - Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and Tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease. - Treatment with Etanercept should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients: - With chronic or recurrent infection; - Who have been exposed to Tuberculosis; - With a history of an opportunistic infection; - Who have resided or traveled in areas of endemic Tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or - With underlying conditions that may predispose them to infection, such as advanced or poorly controlled diabetes. - Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Etanercept. - Etanercept should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with Etanercept should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated. Tuberculosis - Cases of reactivation of Tuberculosis or new Tuberculosis infections have been observed in patients receiving Etanercept , including patients who have previously received treatment for latent or active Tuberculosis. Data from clinical trials and preclinical studies suggest that the risk of reactivation of latent Tuberculosis infection is lower with Etanercept than with TNF-blocking monoclonal antibodies. Nonetheless, postmarketing cases of Tuberculosis reactivation have been reported for TNF blockers, including Etanercept . - Tuberculosis has developed in patients who tested negative for latent Tuberculosis prior to initiation of therapy. Patients should be evaluated for Tuberculosis risk factors and tested for latent infection prior to initiating Etanercept and periodically during therapy. Tests for latent Tuberculosis infection may be falsely negative while on therapy with Etanercept . - Treatment of latent Tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of Tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent Tuberculosis is needed prior to initiating Etanercept , even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). - Anti-Tuberculosis therapy should also be considered prior to initiation of Etanercept in patients with a past history of latent or active Tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent Tuberculosis but having risk factors for Tuberculosis infection. Consultation with a physician with expertise in the treatment of Tuberculosis is recommended to aid in the decision whether initiating anti-Tuberculosis therapy is appropriate for an individual patient. - Tuberculosis should be strongly considered in patients who develop a new infection during Etanercept treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of Tuberculosis, or who have had close contact with a person with active Tuberculosis. Invasive Fungal Infections - Cases of serious and sometimes fatal fungal infections, including histoplasmosis, have been reported with TNF blockers, including Etanercept . For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric anti-fungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric anti-fungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of anti-fungal therapy. In 38 Etanercept clinical trials and 4 cohort studies in all approved indications representing 27,169 patient-years of exposure (17,696 patients) from the United States and Canada, no histoplasmosis infections were reported among patients treated with Etanercept . ## Neurologic Events - Treatment with TNF-blocking agents, including Etanercept , has been associated with rare (< 0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barré syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with Etanercept therapy. Prescribers should exercise caution in considering the use of Etanercept in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders. ## Malignancies Lymphomas - In the controlled portions of clinical trials of TNF‑blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared to control patients. During the controlled portions of Etanercept trials in adult patients with RA, AS, and PsA, 2 Lymphomas were observed among 3306 Etanercept ‑treated patients versus 0 among 1521 control patients (duration of controlled treatment ranged from 3 to 36 months). - Among 6543 adult rheumatology (RA, PsA, AS) patients treated with Etanercept in controlled and uncontrolled portions of clinical trials, representing approximately 12,845 patient‑years of therapy, the observed rate of lymphoma was 0.10 cases per 100 patient‑years. This was 3‑fold higher than the rate of lymphoma expected in the general U.S. population based on the Surveillance, Epidemiology, and End Results (SEER) Database. An increased rate of lymphoma up to several-fold has been reported in the RA patient population, and may be further increased in patients with more severe disease activity. - Among 4410 adult PsO patients treated with Etanercept in clinical trials up to 36 months, representing approximately 4278 patient‑years of therapy, the observed rate of lymphoma was 0.05 cases per 100 patient‑years, which is comparable to the rate in the general population. No cases were observed in Etanercept - or placebo-treated patients during the controlled portions of these trials. Leukemia - Cases of acute and chronic Leukemia have been reported in association with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF-blocker therapy, patients with rheumatoid arthritis may be at higher risk (approximately 2-fold) than the general population for the development of leukemia. - During the controlled portions of Etanercept trials, 2 cases of Leukemia were observed among 5445 (0.06 cases per 100 patient-years) Etanercept -treated patients versus 0 among 2890 (0%) control patients (duration of controlled treatment ranged from 3 to 48 months). - Among 15,401 patients treated with Etanercept in controlled and open portions of clinical trials representing approximately 23,325 patient-years of therapy, the observed rate of Leukemia was 0.03 cases per 100 patient-years. Other Malignancies - Information is available from 10,953 adult patients with 17,123 patient-years and 696 pediatric patients with 1282 patient-years of experience across 45 Etanercept clinical studies. - For malignancies other than lymphoma and non-melanoma skin cancer, there was no difference in exposure-adjusted rates between the Etanercept and control arms in the controlled portions of clinical studies for all indications. Analysis of the malignancy rate in combined controlled and uncontrolled portions of studies has demonstrated that types and rates are similar to what is expected in the general U.S. population based on the SEER database and suggests no increase in rates over time. Whether treatment with Etanercept might influence the development and course of malignancies in adults is unknown. Melanoma and Non-melanoma skin cancer (NMSC) - Melanoma and non-melanoma skin cancer has been reported in patients treated with TNF antagonists including etanercept. - Among 15,401 patients treated with Etanercept in controlled and open portions of clinical trials representing approximately 23,325 patient-years of therapy, the observed rate of melanoma was 0.043 cases per 100 patient-years. - Among 3306 adult rheumatology (RA, PsA, AS) patients treated with Etanercept in controlled clinical trials representing approximately 2669 patient‑years of therapy, the observed rate of NMSC was 0.41 cases per 100 patient‑years vs 0.37 cases per 100 patient-years among 1521 control-treated patients representing 1077 patient-years. Among 1245 adult psoriasis patients treated with Etanercept in controlled clinical trials, representing approximately 283 patient‑years of therapy, the observed rate of NMSC was 3.54 cases per 100 patient-years vs 1.28 cases per 100 patient-years among 720 control-treated patients representing 156 patient-years. - Postmarketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with Etanercept . - Periodic skin examinations should be considered for all patients at increased risk for skin cancer. Pediatric Patients - Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy at ≤ 18 years of age), including Etanercept . Approximately half the cases were Lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports. - In clinical trials of 1140 pediatric patients representing 1927.2 patient-years of therapy, no malignancies, including lymphoma or NMSC, have been reported. Postmarketing Use - In global postmarketing adult and pediatric use, lymphoma and other malignancies have been reported. ## Patients With Heart Failure - Two clinical trials evaluating the use of Etanercept in the treatment of heart failure were terminated early due to lack of efficacy. One of these studies suggested higher mortality in Etanercept -treated patients compared to placebo. There have been postmarketing reports of worsening of congestive heart failure (CHF), with and without identifiable precipitating factors, in patients taking Etanercept . There have also been rare (< 0.1%) reports of new onset CHF, including CHF in patients without known preexisting cardiovascular disease. Some of these patients have been under 50 years of age. Physicians should exercise caution when using Etanercept in patients who also have heart failure, and monitor patients carefully. ## Hematologic Events - Rare (< 0.1%) reports of pancytopenia, including very rare (< 0.01%) reports of aplastic anemia, some with a fatal outcome, have been reported in patients treated with Etanercept . The causal relationship to Etanercept therapy remains unclear. Although no high-risk group has been identified, caution should be exercised in patients being treated with Etanercept who have a previous history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (eg, persistent fever, bruising, bleeding, pallor) while on Etanercept . Discontinuation of Etanercept therapy should be considered in patients with confirmed significant hematologic abnormalities. - Two percent of patients treated concurrently with Etanercept and Anakinra developed neutropenia (ANC < 1 x 109/L). While neutropenic, one patient developed cellulitis that resolved with antibiotic therapy. ## Hepatitis B Reactivation - Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant TNF-blocking agents, including very rare cases (< 0.01%) with Etanercept , has been reported. In some instances, hepatitis B reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to hepatitis B reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF-blocker therapy. Prescribers should exercise caution in prescribing TNF blockers in patients previously infected with HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-blocker therapy to prevent HBV reactivation. Patients previously infected with HBV and require treatment with Etanercept should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, consideration should be given to stopping Etanercept and initiating anti-viral therapy with appropriate supportive treatment. The safety of resuming Etanercept therapy after HBV reactivation is controlled is not known. Therefore, prescribers should weigh the risks and benefits when considering resumption of therapy in this situation. ## Allergic Reactions - Allergic reactions associated with administration of Etanercept during clinical trials have been reported in < 2% of patients. If an anaphylactic reaction or other serious allergic reaction occurs, administration of Etanercept should be discontinued immediately and appropriate therapy initiated. - Caution: The following components contain dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex: the needle cover of the prefilled syringe and the needle cover within the needle cap of the SureClick autoinjector. ## Immunizations - Live vaccines should not be given concurrently with Etanercept . It is recommended that pediatric patients, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines prior to initiating Etanercept therapy ## Autoimmunity - Treatment with Etanercept may result in the formation of autoantibodies and, rarely (< 0.1%), in the development of a lupus-like syndrome or autoimmune hepatitis, which may resolve following withdrawal of Etanercept . If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with Etanercept , treatment should be discontinued and the patient should be carefully evaluated. ## Immunosuppression - TNF mediates inflammation and modulates cellular immune responses. TNF-blocking agents, including Etanercept , affect host defenses against infections. The effect of TNF inhibition on the development and course of malignancies is not fully understood. In a study of 49 patients with RA treated with Etanercept , there was no evidence of depression of delayed‑type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector cell populations ## Use in Wegener’s granulomatosis Patients - The use of Etanercept in patients with Wegener’s granulomatosis receiving immunosuppressive agents is not recommended. In a study of patients with Wegener’s granulomatosis, the addition of Etanercept to standard therapy (including cyclophosphamide) was associated with a higher incidence of non-cutaneous solid malignancies and was not associated with improved clinical outcomes when compared with standard therapy alone ## Use with Anakinra or Abatacept - Use of Etanercept with Anakinra or Abatacept is not recommended. ## Use in Patients with Moderate to Severe Alcoholic Hepatitis - In a study of 48 hospitalized patients treated with Etanercept or placebo for moderate to severe alcoholic hepatitis, the mortality rate in patients treated with Etanercept was similar to patients treated with placebo at 1 month but significantly higher after 6 months. Physicians should use caution when using Etanercept in patients with moderate to severe alcoholic hepatitis. # Adverse Reactions ## Clinical Trials Experience Adverse Reactions in Adult Patients with Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, or Plaque Psoriasis - The data described below reflect exposure to Etanercept in 2219 adult patients with RA followed for up to 80 months, in 182 patients with PsA for up to 24 months, in 138 patients with AS for up to 6 months, and in 1204 adult patients with PsO for up to 18 months. - In controlled trials, the proportion of Etanercept ‑treated patients who discontinued treatment due to adverse events was approximately 4% in the indications studied. - 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 predict the rates observed in clinical practice. Infections - Infections, including viral, bacterial, and fungal infections, have been observed in adult and pediatric patients. Infections have been noted in all body systems and have been reported in patients receiving Etanercept alone or in combination with other immunosuppressive agents. - In controlled portions of trials, the types and severity of infection were similar between Etanercept and the respective control group (placebo or MTX for RA and PsA patients) in RA, PsA, AS and PsO patients. Rates of infections in RA and PsO patients are provided in Table 3 and Table 4, respectively. Infections consisted primarily of upper respiratory tract infection, sinusitis and influenza. - In controlled portions of trials in RA, PsA, AS and PsO, the rates of serious infection were similar (0.8% in placebo, 3.6% in MTX, and 1.4% in Etanercept /Etanercept + MTX‑treated groups). In clinical trials in rheumatologic indications, serious infections experienced by patients have included, but are not limited to, pneumonia, cellulitis, septic arthritis, bronchitis, gastroenteritis, pyelonephritis, sepsis, abscess and osteomyelitis. In clinical trials in PsO, serious infections experienced by patients have included, but are not limited to, pneumonia, cellulitis, gastroenteritis, abscess and osteomyelitis. The rate of serious infections was not increased in open‑label extension trials and was similar to that observed in Etanercept ‑ and placebo‑treated patients from controlled trials. - In 66 global clinical trials of 17,505 patients (21,015 patient-years of therapy), tuberculosis was observed in approximately 0.02% of patients. In 17,696 patients (27,169 patient-years of therapy) from 38 clinical trials and 4 cohort studies in the U.S. and Canada, tuberculosis was observed in approximately 0.006% of patients. These studies include reports of pulmonary and extrapulmonary tuberculosis Injection Site Reactions - In placebo-controlled trials in rheumatologic indications, approximately 37% of patients treated with Etanercept developed injection site reactions. In controlled trials in patients with PsO, 15% of patients treated with Etanercept developed injection site reactions during the first 3 months of treatment. All injection site reactions were described as mild to moderate (erythema, itching, pain, swelling, bleeding, bruising) and generally did not necessitate drug discontinuation. Injection site reactions generally occurred in the first month and subsequently decreased in frequency. The mean duration of injection site reactions was 3 to 5 days. Seven percent of patients experienced redness at a previous injection site when subsequent injections were given. Immunogenicity - Patients with RA, PsA, AS or PsO were tested at multiple time points for antibodies to etanercept. Antibodies to the TNF receptor portion or other protein components of the Etanercept drug product were detected at least once in sera of approximately 6% of adult patients with RA, PsA, AS or PsO. These antibodies were all non-neutralizing. Results from JIA patients were similar to those seen in adult RA patients treated with Etanercept . - In PsO studies that evaluated the exposure of etanercept for up to 120 weeks, the percentage of patients testing positive at the assessed time points of 24, 48, 72 and 96 weeks ranged from 3.6%-8.7% and were all non-neutralizing. The percentage of patients testing positive increased with an increase in the duration of study; however, the clinical significance of this finding is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed. The immunogenicity data of Etanercept beyond 120 weeks of exposure are unknown. - The data reflect the percentage of patients whose test results were considered positive for antibodies to etanercept in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of any antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to etanercept with the incidence of antibodies to other products may be misleading. Autoantibodies - Patients with RA had serum samples tested for autoantibodies at multiple time points. In RA Studies I and II, the percentage of patients evaluated for antinuclear antibodies (ANA) who developed new positive ANA (titer ≥ 1:40) was higher in patients treated with Etanercept (11%) than in placebo‑treated patients (5%). The percentage of patients who developed new positive anti‑double‑stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with Etanercept compared to 4% of placebo‑treated patients) and by Crithidia luciliae assay (3% of patients treated with Etanercept compared to none of placebo‑treated patients). The proportion of patients treated with Etanercept who developed anticardiolipin antibodies was similarly increased compared to placebo‑treated patients. In RA Study III, no pattern of increased autoantibody development was seen in Etanercept patients compared to MTX patients. Other Adverse Reactions - Table 3 summarizes adverse reactions reported in adult RA patients. The types of adverse reactions seen in patients with PsA or AS were similar to the types of adverse reactions seen in patients with RA. - In placebo-controlled PsO trials, the percentages of patients reporting adverse reactions in the 50 mg twice a week dose group were similar to those observed in the 25 mg twice a week dose group or placebo group. - Table 4 summarizes adverse reactions reported in adult PsO patients from Studies I and II. Adverse Reactions in Pediatric Patients - In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients. The types of infections reported in pediatric patients were generally mild and consistent with those commonly seen in the general pediatric population. Two JIA patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae. In open-label clinical studies of children with JIA, adverse reactions reported in those ages 2 to 4 years were similar to adverse reactions reported in older children. ## Postmarketing Experience - Adverse reactions have been reported during post approval use of Etanercept in adults and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Etanercept exposure. Adverse reactions are listed by body system below: - Opportunistic infections, including atypical mycobacterial infection, herpes zoster, aspergillosis and Pneumocystis jiroveci pneumonia, and protozoal infections have also been reported in postmarketing use. # Drug Interactions - Specific drug interaction studies have not been conducted with Etanercept . ## Vaccines - Most PsA patients receiving Etanercept were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower and fewer patients had 2-fold rises in titers compared to patients not receiving Etanercept . The clinical significance of this is unknown. Patients receiving Etanercept may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving Etanercept. - Patients with a significant exposure to varicella virus should temporarily discontinue Etanercept therapy and be considered for prophylactic treatment with varicella zoster immune globulin. ## Immune-Modulating Biologic Products - In a study in which patients with active RA were treated for up to 24 weeks with concurrent Etanercept and anakinra therapy, a 7% rate of serious infections was observed, which was higher than that observed with Etanercept alone (0%) and did not result in higher ACR response rates compared to Etanercept alone. The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure. Two percent of patients treated concurrently with Etanercept and anakinra developed neutropenia (ANC < 1 x 109/L). - In clinical studies, concurrent administration of abatacept and Etanercept resulted in increased incidences of serious adverse events, including infections, and did not demonstrate increased clinical benefit. ## Cyclophosphamide - The use of Etanercept in patients receiving concurrent cyclophosphamide therapy is not recommended. ## Sulfasalazine - Patients in a clinical study who were on established therapy with sulfasalazine, to which Etanercept was added, were noted to develop a mild decrease in mean neutrophil counts in comparison to groups treated with either Etanercept or sulfasalazine alone. The clinical significance of this observation is unknown. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Pregnancy Surveillance Program - There is a Pregnancy Surveillance Program that monitors outcomes in women exposed to Etanercept during pregnancy. Women who become pregnant during Etanercept treatment are encouraged to enroll. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Risk Summary - There are no adequate and well controlled studies in pregnant women. Based on limited data, etanercept concentration in cord blood at the time of delivery showed that etanercept crossed the placenta in small amounts. - Developmental toxicity studies have been performed in rats and rabbits at doses ranging from 60‑ to 100‑fold higher than the human dose and have revealed no evidence of harm to the fetus due to Etanercept . Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Human Data - Three case reports showed that cord blood levels of etanercept at delivery in infants, born to mothers administered etanercept during pregnancy, were between 3 and 32% of the maternal serum level. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etanercept in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Etanercept during labor and delivery. ### Nursing Mothers - Limited data from published literature show that etanercept is present in low levels in human milk and minimally absorbed by a breastfed infant. Caution should be exercised when Etanercept is administered to a nursing woman. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Etanercept and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. - Women who choose to continue Etanercept treatment while nursing are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. ### Pediatric Use - Etanercept has not been studied in children < 2 years of age with JIA. The safety and efficacy of Etanercept in pediatric patients with PsO have not been studied. Rare (< 0.1%) cases of IBD have been reported in JIA patients receiving Etanercept , which is not effective for the treatment of IBD. - The clinical significance of infant exposure to Etanercept in utero is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to exposed infants. ### Geriatic Use - A total of 480 RA patients ages 65 years or older have been studied in clinical trials. In PsO randomized clinical trials, a total of 138 out of 1965 patients treated with Etanercept or placebo were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but the number of geriatric PsO patients is too small to determine whether they respond differently from younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly. ### Gender There is no FDA guidance on the use of Etanercept with respect to specific gender populations. ### Race There is no FDA guidance on the use of Etanercept with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Etanercept in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Etanercept in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Etanercept in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Etanercept in patients who are immunocompromised. ### Use in Diabetics - There have been reports of hypoglycemia following initiation of Etanercept therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients. # Administration and Monitoring ### Administration - Etanercept is intended for use under the guidance and supervision of a physician. Patients may self-inject when deemed appropriate and if they receive medical follow-up, as necessary. Patients should not self-administer until they receive proper training in how to prepare and administer the correct dose. - The Etanercept (etanercept) “Instructions for Use” insert for each presentation contains more detailed instructions on the preparation of Etanercept . Preparation of Etanercept Using the Single-use Prefilled Syringe or Single-use Prefilled SureClick Autoinjector - For a more comfortable injection, leave Etanercept at room temperature for about 15 to 30 minutes before injecting. DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present. When using the Etanercept single-use prefilled syringe, check to see if the amount of liquid in the prefilled syringe falls between the two purple fill level indicator lines on the syringe. If the syringe does not have the right amount of liquid, DO NOT USE THAT SYRINGE. Preparation of Etanercept Using the Multiple-use Vial - Etanercept should be reconstituted aseptically with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol), giving a solution of 1.0 mL containing 25 mg of Etanercept. - A vial adapter is supplied for use when reconstituting the lyophilized powder. However, the vial adapter should not be used if multiple doses are going to be withdrawn from the vial. If the vial will be used for multiple doses, a 25‑gauge needle should be used for reconstituting and withdrawing Etanercept , and the supplied “Mixing Date:” sticker should be attached to the vial and the date of reconstitution entered. Reconstituted solution must be refrigerated at 36°F to 46°F (2°C to 8°C) and used within 14 days. Discard reconstituted solution after 14 days because product stability and sterility cannot be assured after 14 days. DO NOT store reconstituted Etanercept solution at room temperature. - For a more comfortable injection, leave the Etanercept dose tray at room temperature for about 15 to 30 minutes before injecting. - If using the vial adapter, twist the vial adapter onto the diluent syringe. Then, place the vial adapter over the Etanercept vial and insert the vial adapter into the vial stopper. Push down on the plunger to inject the diluent into the Etanercept vial. If using a 25‑gauge needle to reconstitute and withdraw Etanercept , the diluent should be injected very slowly into the Etanercept vial. It is normal for some foaming to occur. Keeping the diluent syringe in place, gently swirl the contents of the Etanercept vial during dissolution. To avoid excessive foaming, do not shake or vigorously agitate. - Generally, dissolution of Etanercept takes less than 10 minutes. Do not use the solution if discolored or cloudy, or if particulate matter remains. - Withdraw the correct dose of reconstituted solution into the syringe. Some foam or bubbles may remain in the vial. Remove the syringe from the vial adapter or remove the 25‑gauge needle from the syringe. Attach a 27‑gauge needle to inject Etanercept . The contents of one vial of Etanercept solution should not be mixed with, or transferred into, the contents of another vial of Etanercept . No other medications should be added to solutions containing Etanercept , and do not reconstitute Etanercept with other diluents. Do not filter reconstituted solution during preparation or administration. ### Monitoring - Prior to initiating Etanercept and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection # IV Compatibility - There is limited information about the IV Compatibility. # Overdosage - Toxicology studies have been performed in monkeys at doses up to 30 times the human dose with no evidence of dose-limiting toxicities. No dose-limiting toxicities have been observed during clinical trials of Etanercept . Single IV doses up to 60 mg/m2 (approximately twice the recommended dose) have been administered to healthy volunteers in an endotoxemia study without evidence of dose-limiting toxicities. # Pharmacology ## Mechanism of Action - TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of RA, polyarticular JIA, PsA, and AS and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of PsO. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, JIA, PsA, AS, and PsO. - Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR. - Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind TNF molecules. Etanercept inhibits binding of TNF-α and TNF-β (lymphotoxin alpha ) to cell surface TNFRs, rendering TNF biologically inactive. In in vitro studies, large complexes of etanercept with TNF-α were not detected and cells expressing transmembrane TNF (that binds Etanercept ) are not lysed in the presence or absence of complement. ## Structure - Etanercept (etanercept) is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. - The solution of Etanercept in the single-use prefilled syringe and the single-use prefilled SureClick autoinjector is clear and colorless, sterile, preservative-free, and is formulated at pH 6.3 ± 0.2. - Etanercept is also supplied in a multiple-use vial as a sterile, white, preservative-free, lyophilized powder. Reconstitution with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol) yields a multiple-use, clear, and colorless solution with a pH of 7.4 ± 0.3. ## Pharmacodynamics - Etanercept can modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (eg, E-selectin, and to a lesser extent, intercellular adhesion molecule-1 ), serum levels of cytokines (eg, IL-6), and serum levels of matrix metalloproteinase-3 (MMP-3 or stromelysin). Etanercept has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis. ## Pharmacokinetics - After administration of 25 mg of Etanercept by a single SC injection to 25 patients with RA, a mean ± standard deviation half‑life of 102 ± 30 hours was observed with a clearance of 160 ± 80 mL/hr. A maximum serum concentration (Cmax) of 1.1 ± 0.6 mcg/mL and time to Cmax of 69 ± 34 hours was observed in these patients following a single 25 mg dose. After 6 months of twice weekly 25 mg doses in these same RA patients, the mean Cmax was 2.4 ± 1.0 mcg/mL (N = 23). Patients exhibited a 2‑ to 7‑fold increase in peak serum concentrations and approximately 4‑fold increase in AUC0‑72 hr (range 1- to 17-fold) with repeated dosing. Serum concentrations in patients with RA have not been measured for periods of dosing that exceed 6 months. - In another study, serum concentration profiles at steady state were comparable among patients with RA treated with 50 mg Etanercept once weekly and those treated with 25 mg Etanercept twice weekly. The mean (± standard deviation) Cmax, Cmin, and partial AUC were 2.4 ± 1.5 mcg/mL, 1.2 ± 0.7 mcg/mL, and 297 ± 166 mcgh/mL, respectively, for patients treated with 50 mg Etanercept once weekly (N = 21); and 2.6 ± 1.2 mcg/mL, 1.4 ± 0.7 mcg/mL, and 316 ± 135 mcgh/mL for patients treated with 25 mg Etanercept twice weekly (N = 16). - Patients with JIA (ages 4 to 17 years) were administered 0.4 mg/kg of Etanercept twice weekly (up to a maximum dose of 50 mg per week) for up to 18 weeks. The mean serum concentration after repeated SC dosing was 2.1 mcg/mL, with a range of 0.7 to 4.3 mcg/mL. Limited data suggest that the clearance of etanercept is reduced slightly in children ages 4 to 8 years. Population pharmacokinetic analyses predict that the pharmacokinetic differences between the regimens of 0.4 mg/kg twice weekly and 0.8 mg/kg once weekly in JIA patients are of the same magnitude as the differences observed between twice weekly and weekly regimens in adult RA patients. In clinical studies with Etanercept , pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients. The pharmacokinetics of etanercept were unaltered by concomitant MTX in RA patients. No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on etanercept disposition. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term animal studies have not been conducted to evaluate the carcinogenic potential of etanercept or its effect on fertility. Mutagenesis studies were conducted in vitro and in vivo, and no evidence of mutagenic activity was observed. # Clinical Studies ## Adult Rheumatoid Arthritis - The safety and efficacy of Etanercept were assessed in four randomized, double-blind, controlled studies. The results of all four trials were expressed in percentage of patients with improvement in RA using ACR response criteria. - Study I evaluated 234 patients with active RA who were ≥ 18 years old, had failed therapy with at least one but no more than four disease-modifying antirheumatic drugs (DMARDs) (eg, hydroxychloroquine, oral or injectable gold, MTX, azathioprine, D-penicillamine, sulfasalazine), and had ≥ 12 tender joints, ≥ 10 swollen joints, and either erythrocyte sedimentation rate (ESR) ≥ 28 mm/hr, C-reactive protein (CRP) > 2.0 mg/dL, or morning stiffness for ≥ 45 minutes. Doses of 10 mg or 25 mg Etanercept or placebo were administered SC twice a week for 6 consecutive months. - Study II evaluated 89 patients and had similar inclusion criteria to Study I except that patients in Study II had additionally received MTX for at least 6 months with a stable dose (12.5 to 25 mg/week) for at least 4 weeks and they had at least 6 tender or painful joints. Patients in Study II received a dose of 25 mg Etanercept or placebo SC twice a week for 6 months in addition to their stable MTX dose. - Study III compared the efficacy of Etanercept to MTX in patients with active RA. This study evaluated 632 patients who were ≥ 18 years old with early (≤ 3 years disease duration) active RA, had never received treatment with MTX, and had ≥ 12 tender joints, ≥ 10 swollen joints, and either ESR ≥ 28 mm/hr, CRP > 2.0 mg/dL, or morning stiffness for ≥ 45 minutes. Doses of 10 mg or 25 mg Etanercept were administered SC twice a week for 12 consecutive months. The study was unblinded after all patients had completed at least 12 months (and a median of 17.3 months) of therapy. The majority of patients remained in the study on the treatment to which they were randomized through 2 years, after which they entered an extension study and received open-label 25 mg Etanercept . MTX tablets (escalated from 7.5 mg/week to a maximum of 20 mg/week over the first 8 weeks of the trial) or placebo tablets were given once a week on the same day as the injection of placebo or Etanercept doses, respectively. - Study IV evaluated 682 adult patients with active RA of 6 months to 20 years duration (mean of 7 years) who had an inadequate response to at least one DMARD other than MTX. Forty-three percent of patients had previously received MTX for a mean of 2 years prior to the trial at a mean dose of 12.9 mg. Patients were excluded from this study if MTX had been discontinued for lack of efficacy or for safety considerations. The patient baseline characteristics were similar to those of patients in Study I. Patients were randomized to MTX alone (7.5 to 20 mg weekly, dose escalated as described for Study III; median dose 20 mg), Etanercept alone (25 mg twice weekly), or the combination of Etanercept and MTX initiated concurrently (at the same doses as above). The study evaluated ACR response, Sharp radiographic score, and safety. Clinical Response - A higher percentage of patients treated with Etanercept and Etanercept in combination with MTX achieved ACR 20, ACR 50, and ACR 70 responses and Major Clinical Responses than in the comparison groups. The results of Studies I, II, and III are summarized in Table 6. The results of Study IV are summarized in Table 7. - The time course for ACR 20 response rates for patients receiving placebo or 25 mg Etanercept in Studies I and II is summarized in Figure 1. The time course of responses to Etanercept in Study III was similar. - Among patients receiving Etanercept , the clinical responses generally appeared within 1 to 2 weeks after initiation of therapy and nearly always occurred by 3 months. A dose response was seen in Studies I and III: 25 mg Etanercept was more effective than 10 mg (10 mg was not evaluated in Study II). Etanercept was significantly better than placebo in all components of the ACR criteria as well as other measures of RA disease activity not included in the ACR response criteria, such as morning stiffness. - In Study III, ACR response rates and improvement in all the individual ACR response criteria were maintained through 24 months of Etanercept therapy. Over the 2‑year study, 23% of Etanercept patients achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6‑month period. - The results of the components of the ACR response criteria for Study I are shown in Table 8. Similar results were observed for Etanercept ‑treated patients in Studies II and III. - After discontinuation of Etanercept , symptoms of arthritis generally returned within a month. Reintroduction of treatment with Etanercept after discontinuations of up to 18 months resulted in the same magnitudes of response as in patients who received Etanercept without interruption of therapy, based on results of open‑label studies. - Continued durable responses were seen for over 60 months in open‑label extension treatment trials when patients received Etanercept without interruption. A substantial number of patients who initially received concomitant MTX or corticosteroids were able to reduce their doses or discontinue these concomitant therapies while maintaining their clinical responses. Physical Function Response - In Studies I, II, and III, physical function and disability were assessed using the Health Assessment Questionnaire (HAQ). Additionally, in Study III, patients were administered the SF‑36 Health Survey. In Studies I and II, patients treated with 25 mg Etanercept twice weekly showed greater improvement from baseline in the HAQ score beginning in month 1 through month 6 in comparison to placebo (p < 0.001) for the HAQ disability domain (where 0 = none and 3 = severe). In Study I, the mean improvement in the HAQ score from baseline to month 6 was 0.6 (from 1.6 to 1.0) for the 25 mg Etanercept group and 0 (from 1.7 to 1.7) for the placebo group. In Study II, the mean improvement from baseline to month 6 was 0.6 (from 1.5 to 0.9) for the Etanercept /MTX group and 0.2 (from 1.3 to 1.2) for the placebo/MTX group. In Study III, the mean improvement in the HAQ score from baseline to month 6 was 0.7 (from 1.5 to 0.7) for 25 mg Etanercept twice weekly. All subdomains of the HAQ in Studies I and III were improved in patients treated with Etanercept . - In Study III, patients treated with 25 mg Etanercept twice weekly showed greater improvement from baseline in SF‑36 physical component summary score compared to Etanercept 10 mg twice weekly and no worsening in the SF‑36 mental component summary score. In open‑label Etanercept studies, improvements in physical function and disability measures have been maintained for up to 4 years. - In Study IV, median HAQ scores improved from baseline levels of 1.8, 1.8, and 1.8 to 1.1, 1.0, and 0.6 at 12 months in the MTX, Etanercept , and Etanercept /MTX combination treatment groups, respectively (combination versus both MTX and Etanercept , p < 0.01). Twenty-nine percent of patients in the MTX alone treatment group had an improvement of HAQ of at least 1 unit versus 40% and 51% in the Etanercept alone and the Etanercept /MTX combination treatment groups, respectively. Radiographic Response - In Study III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and joint space narrowing (JSN) score. Radiographs of hands/wrists and forefeet were obtained at baseline, 6 months, 12 months, and 24 months and scored by readers who were unaware of treatment group. The results are shown in Table 9. A significant difference for change in erosion score was observed at 6 months and maintained at 12 months. - Patients continued on the therapy to which they were randomized for the second year of Study III. Seventy-two percent of patients had x-rays obtained at 24 months. Compared to the patients in the MTX group, greater inhibition of progression in TSS and erosion score was seen in the 25 mg Etanercept group, and, in addition, less progression was noted in the JSN score. - In the open-label extension of Study III, 48% of the original patients treated with 25 mg Etanercept have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage, as measured by the TSS, and 55% of them had no progression of structural damage. Patients originally treated with MTX had further reduction in radiographic progression once they began treatment with Etanercept . - In Study IV, less radiographic progression (TSS) was observed with Etanercept in combination with MTX compared with Etanercept alone or MTX alone at month 12 (Table 10). In the MTX treatment group, 55% of patients experienced no radiographic progression (TSS change ≤ 0.0) at 12 months compared to 63% and 76% in the Etanercept alone and the Etanercept /MTX combination treatment groups, respectively. Once Weekly Dosing - The safety and efficacy of 50 mg Etanercept (two 25 mg SC injections) administered once weekly were evaluated in a double‑blind, placebo‑controlled study of 420 patients with active RA. Fifty‑three patients received placebo, 214 patients received 50 mg Etanercept once weekly, and 153 patients received 25 mg Etanercept twice weekly. The safety and efficacy profiles of the two Etanercept treatment groups were similar. ## Polyarticular Juvenile Idiopathic Arthritis (JIA) - The safety and efficacy of Etanercept were assessed in a 2-part study in 69 children with polyarticular JIA who had a variety of JIA onset types. Patients ages 2 to 17 years with moderately to severely active polyarticular JIA refractory to or intolerant of MTX were enrolled; patients remained on a stable dose of a single nonsteroidal anti-inflammatory drug and/or prednisone (≤ 0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received 0.4 mg/kg (maximum 25 mg per dose) Etanercept SC twice weekly. In part 2, patients with a clinical response at day 90 were randomized to remain on Etanercept or receive placebo for 4 months and assessed for disease flare. Responses were measured using the JIA Definition of Improvement (DOI), defined as ≥ 30% improvement in at least three of six and ≥ 30% worsening in no more than one of the six JIA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment, and ESR. Disease flare was defined as a ≥ 30% worsening in three of the six JIA core set criteria and ≥ 30% improvement in not more than one of the six JIA core set criteria and a minimum of two active joints. - In part 1 of the study, 51 of 69 (74%) patients demonstrated a clinical response and entered part 2. In part 2, 6 of 25 (24%) patients remaining on Etanercept experienced a disease flare compared to 20 of 26 (77%) patients receiving placebo (p = 0.007). From the start of part 2, the median time to flare was ≥ 116 days for patients who received Etanercept and 28 days for patients who received placebo. Each component of the JIA core set criteria worsened in the arm that received placebo and remained stable or improved in the arm that continued on Etanercept . The data suggested the possibility of a higher flare rate among those patients with a higher baseline ESR. Of patients who demonstrated a clinical response at 90 days and entered part 2 of the study, some of the patients remaining on Etanercept continued to improve from month 3 through month 7, while those who received placebo did not improve. - The majority of JIA patients who developed a disease flare in part 2 and reintroduced Etanercept treatment up to 4 months after discontinuation re-responded to Etanercept therapy in open-label studies. Most of the responding patients who continued Etanercept therapy without interruption have maintained responses for up to 48 months. - Studies have not been done in patients with polyarticular JIA to assess the effects of continued Etanercept therapy in patients who do not respond within 3 months of initiating Etanercept therapy, or to assess the combination of Etanercept with MTX. ## Psoriatic Arthritis - The safety and efficacy of Etanercept were assessed in a randomized, double-blind, placebo-controlled study in 205 patients with PsA. Patients were between 18 and 70 years of age and had active PsA (≥ 3 swollen joints and ≥ 3 tender joints) in one or more of the following forms: (1) distal interphalangeal (DIP) involvement (N = 104); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis; N = 173); (3) arthritis mutilans (N = 3); (4) asymmetric psoriatic arthritis (N = 81); or (5) ankylosing spondylitis-like (N = 7). Patients also had plaque psoriasis with a qualifying target lesion ≥ 2 cm in diameter. Patients on MTX therapy at enrollment (stable for ≥ 2 months) could continue at a stable dose of ≤ 25 mg/week MTX. Doses of 25 mg Etanercept or placebo were administered SC twice a week during the initial 6-month double-blind period of the study. Patients continued to receive blinded therapy in an up to 6-month maintenance period until all patients had completed the controlled period. Following this, patients received open-label 25 mg Etanercept twice a week in a 12-month extension period. - Compared to placebo, treatment with Etanercept resulted in significant improvements in measures of disease activity (Table 11). - Among patients with PsA who received Etanercept , the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. At 6 months, the ACR 20/50/70 responses were achieved by 50%, 37%, and 9%, respectively, of patients receiving Etanercept , compared to 13%, 4%, and 1%, respectively, of patients receiving placebo. Similar responses were seen in patients with each of the subtypes of PsA, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. The results of this study were similar to those seen in an earlier single-center, randomized, placebo-controlled study of 60 patients with PsA. - The skin lesions of psoriasis were also improved with Etanercept , relative to placebo, as measured by percentages of patients achieving improvements in the Psoriasis Area and Severity Index (PASI). Responses increased over time, and at 6 months, the proportions of patients achieving a 50% or 75% improvement in the PASI were 47% and 23%, respectively, in the Etanercept group (N = 66), compared to 18% and 3%, respectively, in the placebo group (N = 62). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. Radiographic Response - Radiographic changes were also assessed in the PsA study. Radiographs of hands and wrists were obtained at baseline and months 6, 12, and 24. A modified Total Sharp Score (TSS), which included distal interphalangeal joints (ie, not identical to the modified TSS used for RA) was used by readers blinded to treatment group to assess the radiographs. Some radiographic features specific to PsA (eg, pencil-and-cup deformity, joint space widening, gross osteolysis, and ankylosis) were included in the scoring system, but others (eg, phalangeal tuft resorption, juxta-articular and shaft periostitis) were not. - Most patients showed little or no change in the modified TSS during this 24-month study (median change of 0 in both patients who initially received Etanercept or placebo). More placebo-treated patients experienced larger magnitudes of radiographic worsening (increased TSS) compared to Etanercept treatment during the controlled period of the study. At 12 months, in an exploratory analysis, 12% (12 of 104) of placebo patients compared to none of the 101 Etanercept -treated patients had increases of 3 points or more in TSS. Inhibition of radiographic progression was maintained in patients who continued on Etanercept during the second year. Of the patients with 1-year and 2-year x-rays, 3% (2 of 71) had increases of 3 points or more in TSS at 1 and 2 years. Physical Function Response - In the PsA study, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 25 mg Etanercept twice weekly showed greater improvement from baseline in the HAQ-DI score (mean decreases of 54% at both months 3 and 6) in comparison to placebo (mean decreases of 6% at both months 3 and 6) (p < 0.001). At months 3 and 6, patients treated with Etanercept showed greater improvement from baseline in the SF-36 physical component summary score compared to patients treated with placebo, and no worsening in the SF-36 mental component summary score. Improvements in physical function and disability measures were maintained for up to 2 years through the open-label portion of the study. ## Ankylosing Spondylitis - The safety and efficacy of Etanercept were assessed in a randomized, double-blind, placebo-controlled study in 277 patients with active AS. Patients were between 18 and 70 years of age and had AS as defined by the modified New York Criteria for Ankylosing Spondylitis. Patients were to have evidence of active disease based on values of ≥ 30 on a 0-100 unit Visual Analog Scale (VAS) for the average of morning stiffness duration and intensity, and two of the following three other parameters: a) patient global assessment, b) average of nocturnal and total back pain, and c) the average score on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients with complete ankylosis of the spine were excluded from study participation. Patients taking hydroxychloroquine, sulfasalazine, methotrexate, or prednisone (≤ 10 mg/day) could continue these drugs at stable doses for the duration of the study. Doses of 25 mg Etanercept or placebo were administered SC twice a week for 6 months. The primary measure of efficacy was a 20% improvement in the Assessment in Ankylosing Spondylitis (ASAS) response criteria. Compared to placebo, treatment with Etanercept resulted in improvements in the ASAS and other measures of disease activity (Figure 2 and Table 12). - At 12 weeks, the ASAS 20/50/70 responses were achieved by 60%, 45%, and 29%, respectively, of patients receiving Etanercept , compared to 27%, 13%, and 7%, respectively, of patients receiving placebo (p ≤ 0.0001, Etanercept vs placebo). Similar responses were seen at week 24. Responses were similar between those patients receiving concomitant therapies at baseline and those who were not. The results of this study were similar to those seen in a single-center, randomized, placebo-controlled study of 40 patients and a multicenter, randomized, placebo-controlled study of 84 patients with AS. ## Plaque Psoriasis - The safety and efficacy of Etanercept were assessed in two randomized, double-blind, placebo-controlled studies in adults with chronic stable PsO involving ≥ 10% of the body surface area, a minimum Psoriasis Area and Severity Index (PASI) score of 10 and who had received or were candidates for systemic antipsoriatic therapy or phototherapy. Patients with guttate, erythrodermic, or pustular psoriasis and patients with severe infections within 4 weeks of screening were excluded from study. No concomitant major antipsoriatic therapies were allowed during the study. Study I evaluated 672 patients who received placebo or Etanercept SC at doses of 25 mg once a week, 25 mg twice a week, or 50 mg twice a week for 3 months. After 3 months, patients continued on blinded treatments for an additional 3 months during which time patients originally randomized to placebo began treatment with blinded Etanercept at 25 mg twice weekly (designated as placebo/Etanercept in Table 13); patients originally randomized to Etanercept continued on the originally randomized dose (designated as Etanercept /Etanercept groups in Table 13). - Study II evaluated 611 patients who received placebo or Etanercept SC at doses of 25 mg or 50 mg twice a week for 3 months. After 3 months of randomized, blinded treatment, patients in all three arms began receiving open-label Etanercept at 25 mg twice weekly for 9 additional months. - Response to treatment in both studies was assessed after 3 months of therapy and was defined as the proportion of patients who achieved a reduction in PASI score of at least 75% from baseline. The PASI is a composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of psoriatic changes within the affected regions (induration, erythema and scaling). - Other evaluated outcomes included the proportion of patients who achieved a score of “clear” or “minimal” by the Static Physician Global Assessment (sPGA) and the proportion of patients with a reduction of PASI of at least 50% from baseline. The sPGA is a 6-category scale ranging from “5 = severe” to “0 = none” indicating the physician’s overall assessment of the PsO severity focusing on induration, erythema and scaling. Treatment success of “clear” or “minimal” consisted of none or minimal elevation in plaque, up to faint red coloration in erythema and none or minimal fine scale over < 5% of the plaque. - Patients in all treatment groups and in both studies had a median baseline PASI score ranging from 15 to 17, and the percentage of patients with baseline sPGA classifications ranged from 54% to 66% for moderate, 17% to 26% for marked and 1% to 5% for severe. Across all treatment groups, the percentage of patients who previously received systemic therapy for PsO ranged from 61% to 65% in Study I and 71% to 75% in Study II, and those who previously received phototherapy ranged from 44% to 50% in Study I and 72% to 73% in Study II. - More patients randomized to Etanercept than placebo achieved at least a 75% reduction from baseline PASI score (PASI 75) with a dose response relationship across doses of 25 mg once a week, 25 mg twice a week, and 50 mg twice a week (Tables 13 and 14). The individual components of the PASI (induration, erythema and scaling) contributed comparably to the overall treatment-associated improvement in PASI. - Among PASI 75 achievers in both studies, the median time to PASI 50 and PASI 75 was approximately 1 month and approximately 2 months, respectively, after the start of therapy with either 25 or 50 mg twice a week. - In Study I, patients who achieved PASI 75 at month 6 were entered into a study drug withdrawal and retreatment period. Following withdrawal of study drug, these patients had a median duration of PASI 75 of between 1 and 2 months. - In Study I, among patients who were PASI 75 responders at 3 months, retreatment with their original blinded Etanercept dose after discontinuation of up to 5 months resulted in a similar proportion of responders as in the initial double-blind portion of the study. - In Study II, most patients initially randomized to 50 mg twice a week continued in the study after month 3 and had their Etanercept dose decreased to 25 mg twice a week. Of the 91 patients who were PASI 75 responders at month 3, 70 (77%) maintained their PASI 75 response at month 6. # How Supplied - Administration of one 50 mg Etanercept prefilled syringe or one Etanercept SureClick autoinjector provides a dose equivalent to two 25 mg Etanercept prefilled syringes or two multiple-use vials of lyophilized Etanercept , when vials are reconstituted and administered as recommended. ## Etanercept Single-use Prefilled Syringe and Etanercept Single-use Prefilled SureClick Autoinjector - Each Etanercept single-use prefilled syringe and Etanercept single-use prefilled SureClick autoinjector contains 50 mg/mL of etanercept in a single-dose syringe with a 27-gauge, ½-inch needle. ## Etanercept Multiple-use Vial (Recommended for Weight-based Dosing) - Etanercept multiple-use vial is supplied in a carton containing four dose trays. Each dose tray contains one 25 mg vial of etanercept, one diluent syringe (1 mL Sterile Bacteriostatic Water for Injection, USP, containing 0.9% benzyl alcohol), one 27-gauge ½-inch needle, one vial adapter, and one plunger. Each carton contains four “Mixing Date:” stickers. ## Storage ## Etanercept Single-use Prefilled Syringe and Etanercept Single-use Prefilled SureClick Autoinjector - Etanercept should be refrigerated at 36°F to 46°F (2°C to 8°C). Do not use Etanercept beyond the expiration date stamped on the carton or barrel label. DO NOT SHAKE. Store Etanercept in the original carton to protect from light or physical damage. - For convenience, storage of individual syringes or autoinjectors at room temperature for a maximum single period of 14 days is permissible, with protection from light and sources of heat. Once a syringe or autoinjector has been stored at room temperature, it should not be placed back into the refrigerator. If not used within 14 days at room temperature, the syringe or autoinjector should be discarded. Do not store Etanercept in extreme heat or cold. DO NOT FREEZE. Keep out of the reach of children. ## Etanercept Multiple-use Vial (Recommended for Weight-based Dosing) - Etanercept should be refrigerated at 36°F to 46°F (2°C to 8°C). Do not use Etanercept beyond the expiration date stamped on the dose tray. DO NOT SHAKE. Store Etanercept in the original carton to protect from light or physical damage. For convenience, storage of an individual dose tray containing Etanercept multi-use vial and diluent syringe at room temperature for a maximum single period of 14 days is permissible, with protection from light, sources of heat, and humidity. Once the dose tray has been stored at room temperature, it should not be placed back into the refrigerator. If not used within 14 days at room temperature, the dose tray should be discarded. Once a vial has been reconstituted, the solution must be used immediately or may be refrigerated for up to14 days. Do not store Etanercept in extreme heat or cold. DO NOT FREEZE. Keep out of the reach of children. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ## Patient Counseling - Patients should be advised of the potential benefits and risks of Etanercept . Physicians should instruct their patients to read the Medication Guide before starting Etanercept therapy and to reread each time the prescription is renewed. Infections - Inform patients that Etanercept may lower the ability of their immune system to fight infections. Advise patients of the importance of contacting their doctor if they develop any symptoms of infection, tuberculosis or reactivation of hepatitis B virus infections. Other Medical Conditions - Advise patients to report any signs of new or worsening medical conditions, such as central nervous system demyelinating disorders, heart failure or autoimmune disorders, such as lupus-like syndrome or autoimmune hepatitis. Counsel about the risk of lymphoma and other malignancies while receiving Etanercept . Advise patients to report any symptoms suggestive of a pancytopenia, such as bruising, bleeding, persistent fever or pallor. Allergic Reactions - Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the following components contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex: the needle cover of the prefilled syringe and the needle cover within the needle cap of the SureClick autoinjector. ## Administration of Etanercept - If a patient or caregiver is to administer Etanercept , the patient or caregiver should be instructed in injection techniques and how to measure and administer the correct dose. The first injection should be performed under the supervision of a qualified healthcare professional. The patient’s or caregiver’s ability to inject subcutaneously should be assessed. Patients and caregivers should be instructed in the technique, as well as proper syringe and needle disposal, and be cautioned against reuse of needles and syringes. - A puncture-resistant container for disposal of needles, syringes and autoinjectors should be used. If the product is intended for multiple use, additional syringes, needles and alcohol swabs will be required. - Patients can be advised to call 1-888-4Etanercept (1-888-436-2735) or visit www.Etanercept .com for more information about Etanercept . # Precautions with Alcohol - In a study of 48 hospitalized patients treated with Etanercept or placebo for moderate to severe alcoholic hepatitis, the mortality rate in patients treated with Etanercept was similar to patients treated with placebo at 1 month but significantly higher after 6 months. Physicians should use caution when using Etanercept in patients with moderate to severe alcoholic hepatitis. # Brand Names - ENBREL # Look-Alike Drug Names - Etanercept - Levbid # Drug Shortage Status # Price	Etanercept Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, 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 Etanercept is an antirheumatic drug that is FDA approved for the treatment of rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis and plaque psoriasis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include injection site reaction, rhinitis and upper respiratory infection. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### General Information ### Adult Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Patients - Dosing informatinon - MTX, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics may be continued during treatment with Etanercept . - Recommended dosage: 50 mg twice weekly - Doses higher than 50 mg per week are not recommended. ### Adult Plaque Psoriasis Patients - Dosing informatinon - Recommended starting dose: 50 mg twice weekly , - Starting doses of 25 mg or 50 mg per week were shown to be efficacious. The proportion of responders was related to Etanercept dosage ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Etanercept in adult patients. ### Non–Guideline-Supported Use ### Behcet's syndrome - Dosing information - 25 mg twice weekly for 4 weeks[1] ### Bone metastasis - Pain from metastases - Dosing information - 25 mg[2] ### Crohn's disease - Dosing information - 25 mg SC twice weekly[3] ### Hemophagocytic lymphohistiocytosis - Dosing information - Twice weekly injections (0.4 mg/kg)[4] ### Hidradenitis suppurativa - Dosing information - 25 mg twice weekly [5] ### Langerhans cell histiocytosis - Dosing information - 0.4 mg/kg SC twice weekly[6] ### Myelosclerosis with myeloid metaplasia - Dosing information - 25 mg twice weekly 11877307 - 25 mg twice weekly subQ for at least 4 weeks[7] ### Nephrotic syndrome - Dosing information - 25-mg SC injections twice weekly[8] ### Pemphigoid - Dosing information - 25 mg subQ twice weekly [9] ### Sarcoidosis - Dosing information - 25 mg twice weekly[10] ### Sjögren's syndrome - Dosing information - 25 mg twice per week for 12 weeks[11] ### TNF receptor-associated periodic fever syndrome (TRAPS) - Dosing information - 25 mg (adults) or 0.4 mg/kg (children) twice weekly[12] ### Uveitis - Dosing information - 25 mg twice a week for 24 weeks[13] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### JIA Patients - Dosing informatinon - In JIA patients, glucocorticoids, NSAIDs, or analgesics may be continued during treatment with Etanercept . Higher doses of Etanercept have not been studied in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - There is limited information regarding Off-Label Guideline-Supported Use of Etanercept in pediatric patients. ### Non–Guideline-Supported Use ### Graft versus host disease - Dosing information - 0.4 mg/kg SC twice weekly [14] # Contraindications - Etanercept should not be administered to patients with sepsis. # Warnings ## Serious Infections - Patients treated with Etanercept are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. - Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, and Tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease. - Treatment with Etanercept should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients: - With chronic or recurrent infection; - Who have been exposed to Tuberculosis; - With a history of an opportunistic infection; - Who have resided or traveled in areas of endemic Tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or - With underlying conditions that may predispose them to infection, such as advanced or poorly controlled diabetes. - Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Etanercept. - Etanercept should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with Etanercept should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated. Tuberculosis - Cases of reactivation of Tuberculosis or new Tuberculosis infections have been observed in patients receiving Etanercept , including patients who have previously received treatment for latent or active Tuberculosis. Data from clinical trials and preclinical studies suggest that the risk of reactivation of latent Tuberculosis infection is lower with Etanercept than with TNF-blocking monoclonal antibodies. Nonetheless, postmarketing cases of Tuberculosis reactivation have been reported for TNF blockers, including Etanercept . - Tuberculosis has developed in patients who tested negative for latent Tuberculosis prior to initiation of therapy. Patients should be evaluated for Tuberculosis risk factors and tested for latent infection prior to initiating Etanercept and periodically during therapy. Tests for latent Tuberculosis infection may be falsely negative while on therapy with Etanercept . - Treatment of latent Tuberculosis infection prior to therapy with TNF-blocking agents has been shown to reduce the risk of Tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent Tuberculosis is needed prior to initiating Etanercept , even for patients previously vaccinated with Bacille Calmette-Guerin (BCG). - Anti-Tuberculosis therapy should also be considered prior to initiation of Etanercept in patients with a past history of latent or active Tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent Tuberculosis but having risk factors for Tuberculosis infection. Consultation with a physician with expertise in the treatment of Tuberculosis is recommended to aid in the decision whether initiating anti-Tuberculosis therapy is appropriate for an individual patient. - Tuberculosis should be strongly considered in patients who develop a new infection during Etanercept treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of Tuberculosis, or who have had close contact with a person with active Tuberculosis. Invasive Fungal Infections - Cases of serious and sometimes fatal fungal infections, including histoplasmosis, have been reported with TNF blockers, including Etanercept . For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric anti-fungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric anti-fungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of anti-fungal therapy. In 38 Etanercept clinical trials and 4 cohort studies in all approved indications representing 27,169 patient-years of exposure (17,696 patients) from the United States and Canada, no histoplasmosis infections were reported among patients treated with Etanercept . ## Neurologic Events - Treatment with TNF-blocking agents, including Etanercept , has been associated with rare (< 0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barré syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with Etanercept therapy. Prescribers should exercise caution in considering the use of Etanercept in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders. ## Malignancies Lymphomas - In the controlled portions of clinical trials of TNF‑blocking agents, more cases of lymphoma have been observed among patients receiving a TNF blocker compared to control patients. During the controlled portions of Etanercept trials in adult patients with RA, AS, and PsA, 2 Lymphomas were observed among 3306 Etanercept ‑treated patients versus 0 among 1521 control patients (duration of controlled treatment ranged from 3 to 36 months). - Among 6543 adult rheumatology (RA, PsA, AS) patients treated with Etanercept in controlled and uncontrolled portions of clinical trials, representing approximately 12,845 patient‑years of therapy, the observed rate of lymphoma was 0.10 cases per 100 patient‑years. This was 3‑fold higher than the rate of lymphoma expected in the general U.S. population based on the Surveillance, Epidemiology, and End Results (SEER) Database. An increased rate of lymphoma up to several-fold has been reported in the RA patient population, and may be further increased in patients with more severe disease activity. - Among 4410 adult PsO patients treated with Etanercept in clinical trials up to 36 months, representing approximately 4278 patient‑years of therapy, the observed rate of lymphoma was 0.05 cases per 100 patient‑years, which is comparable to the rate in the general population. No cases were observed in Etanercept - or placebo-treated patients during the controlled portions of these trials. Leukemia - Cases of acute and chronic Leukemia have been reported in association with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF-blocker therapy, patients with rheumatoid arthritis may be at higher risk (approximately 2-fold) than the general population for the development of leukemia. - During the controlled portions of Etanercept trials, 2 cases of Leukemia were observed among 5445 (0.06 cases per 100 patient-years) Etanercept -treated patients versus 0 among 2890 (0%) control patients (duration of controlled treatment ranged from 3 to 48 months). - Among 15,401 patients treated with Etanercept in controlled and open portions of clinical trials representing approximately 23,325 patient-years of therapy, the observed rate of Leukemia was 0.03 cases per 100 patient-years. Other Malignancies - Information is available from 10,953 adult patients with 17,123 patient-years and 696 pediatric patients with 1282 patient-years of experience across 45 Etanercept clinical studies. - For malignancies other than lymphoma and non-melanoma skin cancer, there was no difference in exposure-adjusted rates between the Etanercept and control arms in the controlled portions of clinical studies for all indications. Analysis of the malignancy rate in combined controlled and uncontrolled portions of studies has demonstrated that types and rates are similar to what is expected in the general U.S. population based on the SEER database and suggests no increase in rates over time. Whether treatment with Etanercept might influence the development and course of malignancies in adults is unknown. Melanoma and Non-melanoma skin cancer (NMSC) - Melanoma and non-melanoma skin cancer has been reported in patients treated with TNF antagonists including etanercept. - Among 15,401 patients treated with Etanercept in controlled and open portions of clinical trials representing approximately 23,325 patient-years of therapy, the observed rate of melanoma was 0.043 cases per 100 patient-years. - Among 3306 adult rheumatology (RA, PsA, AS) patients treated with Etanercept in controlled clinical trials representing approximately 2669 patient‑years of therapy, the observed rate of NMSC was 0.41 cases per 100 patient‑years vs 0.37 cases per 100 patient-years among 1521 control-treated patients representing 1077 patient-years. Among 1245 adult psoriasis patients treated with Etanercept in controlled clinical trials, representing approximately 283 patient‑years of therapy, the observed rate of NMSC was 3.54 cases per 100 patient-years vs 1.28 cases per 100 patient-years among 720 control-treated patients representing 156 patient-years. - Postmarketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with Etanercept . - Periodic skin examinations should be considered for all patients at increased risk for skin cancer. Pediatric Patients - Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy at ≤ 18 years of age), including Etanercept . Approximately half the cases were Lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports. - In clinical trials of 1140 pediatric patients representing 1927.2 patient-years of therapy, no malignancies, including lymphoma or NMSC, have been reported. Postmarketing Use - In global postmarketing adult and pediatric use, lymphoma and other malignancies have been reported. ## Patients With Heart Failure - Two clinical trials evaluating the use of Etanercept in the treatment of heart failure were terminated early due to lack of efficacy. One of these studies suggested higher mortality in Etanercept -treated patients compared to placebo. There have been postmarketing reports of worsening of congestive heart failure (CHF), with and without identifiable precipitating factors, in patients taking Etanercept . There have also been rare (< 0.1%) reports of new onset CHF, including CHF in patients without known preexisting cardiovascular disease. Some of these patients have been under 50 years of age. Physicians should exercise caution when using Etanercept in patients who also have heart failure, and monitor patients carefully. ## Hematologic Events - Rare (< 0.1%) reports of pancytopenia, including very rare (< 0.01%) reports of aplastic anemia, some with a fatal outcome, have been reported in patients treated with Etanercept . The causal relationship to Etanercept therapy remains unclear. Although no high-risk group has been identified, caution should be exercised in patients being treated with Etanercept who have a previous history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (eg, persistent fever, bruising, bleeding, pallor) while on Etanercept . Discontinuation of Etanercept therapy should be considered in patients with confirmed significant hematologic abnormalities. - Two percent of patients treated concurrently with Etanercept and Anakinra developed neutropenia (ANC < 1 x 109/L). While neutropenic, one patient developed cellulitis that resolved with antibiotic therapy. ## Hepatitis B Reactivation - Reactivation of hepatitis B in patients who were previously infected with the hepatitis B virus (HBV) and had received concomitant TNF-blocking agents, including very rare cases (< 0.01%) with Etanercept , has been reported. In some instances, hepatitis B reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to hepatitis B reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF-blocker therapy. Prescribers should exercise caution in prescribing TNF blockers in patients previously infected with HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF-blocker therapy to prevent HBV reactivation. Patients previously infected with HBV and require treatment with Etanercept should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, consideration should be given to stopping Etanercept and initiating anti-viral therapy with appropriate supportive treatment. The safety of resuming Etanercept therapy after HBV reactivation is controlled is not known. Therefore, prescribers should weigh the risks and benefits when considering resumption of therapy in this situation. ## Allergic Reactions - Allergic reactions associated with administration of Etanercept during clinical trials have been reported in < 2% of patients. If an anaphylactic reaction or other serious allergic reaction occurs, administration of Etanercept should be discontinued immediately and appropriate therapy initiated. - Caution: The following components contain dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex: the needle cover of the prefilled syringe and the needle cover within the needle cap of the SureClick autoinjector. ## Immunizations - Live vaccines should not be given concurrently with Etanercept . It is recommended that pediatric patients, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines prior to initiating Etanercept therapy ## Autoimmunity - Treatment with Etanercept may result in the formation of autoantibodies and, rarely (< 0.1%), in the development of a lupus-like syndrome or autoimmune hepatitis, which may resolve following withdrawal of Etanercept . If a patient develops symptoms and findings suggestive of a lupus-like syndrome or autoimmune hepatitis following treatment with Etanercept , treatment should be discontinued and the patient should be carefully evaluated. ## Immunosuppression - TNF mediates inflammation and modulates cellular immune responses. TNF-blocking agents, including Etanercept , affect host defenses against infections. The effect of TNF inhibition on the development and course of malignancies is not fully understood. In a study of 49 patients with RA treated with Etanercept , there was no evidence of depression of delayed‑type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector cell populations ## Use in Wegener’s granulomatosis Patients - The use of Etanercept in patients with Wegener’s granulomatosis receiving immunosuppressive agents is not recommended. In a study of patients with Wegener’s granulomatosis, the addition of Etanercept to standard therapy (including cyclophosphamide) was associated with a higher incidence of non-cutaneous solid malignancies and was not associated with improved clinical outcomes when compared with standard therapy alone ## Use with Anakinra or Abatacept - Use of Etanercept with Anakinra or Abatacept is not recommended. ## Use in Patients with Moderate to Severe Alcoholic Hepatitis - In a study of 48 hospitalized patients treated with Etanercept or placebo for moderate to severe alcoholic hepatitis, the mortality rate in patients treated with Etanercept was similar to patients treated with placebo at 1 month but significantly higher after 6 months. Physicians should use caution when using Etanercept in patients with moderate to severe alcoholic hepatitis. # Adverse Reactions ## Clinical Trials Experience Adverse Reactions in Adult Patients with Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, or Plaque Psoriasis - The data described below reflect exposure to Etanercept in 2219 adult patients with RA followed for up to 80 months, in 182 patients with PsA for up to 24 months, in 138 patients with AS for up to 6 months, and in 1204 adult patients with PsO for up to 18 months. - In controlled trials, the proportion of Etanercept ‑treated patients who discontinued treatment due to adverse events was approximately 4% in the indications studied. - 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 predict the rates observed in clinical practice. Infections - Infections, including viral, bacterial, and fungal infections, have been observed in adult and pediatric patients. Infections have been noted in all body systems and have been reported in patients receiving Etanercept alone or in combination with other immunosuppressive agents. - In controlled portions of trials, the types and severity of infection were similar between Etanercept and the respective control group (placebo or MTX for RA and PsA patients) in RA, PsA, AS and PsO patients. Rates of infections in RA and PsO patients are provided in Table 3 and Table 4, respectively. Infections consisted primarily of upper respiratory tract infection, sinusitis and influenza. - In controlled portions of trials in RA, PsA, AS and PsO, the rates of serious infection were similar (0.8% in placebo, 3.6% in MTX, and 1.4% in Etanercept /Etanercept + MTX‑treated groups). In clinical trials in rheumatologic indications, serious infections experienced by patients have included, but are not limited to, pneumonia, cellulitis, septic arthritis, bronchitis, gastroenteritis, pyelonephritis, sepsis, abscess and osteomyelitis. In clinical trials in PsO, serious infections experienced by patients have included, but are not limited to, pneumonia, cellulitis, gastroenteritis, abscess and osteomyelitis. The rate of serious infections was not increased in open‑label extension trials and was similar to that observed in Etanercept ‑ and placebo‑treated patients from controlled trials. - In 66 global clinical trials of 17,505 patients (21,015 patient-years of therapy), tuberculosis was observed in approximately 0.02% of patients. In 17,696 patients (27,169 patient-years of therapy) from 38 clinical trials and 4 cohort studies in the U.S. and Canada, tuberculosis was observed in approximately 0.006% of patients. These studies include reports of pulmonary and extrapulmonary tuberculosis Injection Site Reactions - In placebo-controlled trials in rheumatologic indications, approximately 37% of patients treated with Etanercept developed injection site reactions. In controlled trials in patients with PsO, 15% of patients treated with Etanercept developed injection site reactions during the first 3 months of treatment. All injection site reactions were described as mild to moderate (erythema, itching, pain, swelling, bleeding, bruising) and generally did not necessitate drug discontinuation. Injection site reactions generally occurred in the first month and subsequently decreased in frequency. The mean duration of injection site reactions was 3 to 5 days. Seven percent of patients experienced redness at a previous injection site when subsequent injections were given. Immunogenicity - Patients with RA, PsA, AS or PsO were tested at multiple time points for antibodies to etanercept. Antibodies to the TNF receptor portion or other protein components of the Etanercept drug product were detected at least once in sera of approximately 6% of adult patients with RA, PsA, AS or PsO. These antibodies were all non-neutralizing. Results from JIA patients were similar to those seen in adult RA patients treated with Etanercept . - In PsO studies that evaluated the exposure of etanercept for up to 120 weeks, the percentage of patients testing positive at the assessed time points of 24, 48, 72 and 96 weeks ranged from 3.6%-8.7% and were all non-neutralizing. The percentage of patients testing positive increased with an increase in the duration of study; however, the clinical significance of this finding is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed. The immunogenicity data of Etanercept beyond 120 weeks of exposure are unknown. - The data reflect the percentage of patients whose test results were considered positive for antibodies to etanercept in an ELISA assay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of any antibody positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to etanercept with the incidence of antibodies to other products may be misleading. Autoantibodies - Patients with RA had serum samples tested for autoantibodies at multiple time points. In RA Studies I and II, the percentage of patients evaluated for antinuclear antibodies (ANA) who developed new positive ANA (titer ≥ 1:40) was higher in patients treated with Etanercept (11%) than in placebo‑treated patients (5%). The percentage of patients who developed new positive anti‑double‑stranded DNA antibodies was also higher by radioimmunoassay (15% of patients treated with Etanercept compared to 4% of placebo‑treated patients) and by Crithidia luciliae assay (3% of patients treated with Etanercept compared to none of placebo‑treated patients). The proportion of patients treated with Etanercept who developed anticardiolipin antibodies was similarly increased compared to placebo‑treated patients. In RA Study III, no pattern of increased autoantibody development was seen in Etanercept patients compared to MTX patients. Other Adverse Reactions - Table 3 summarizes adverse reactions reported in adult RA patients. The types of adverse reactions seen in patients with PsA or AS were similar to the types of adverse reactions seen in patients with RA. - In placebo-controlled PsO trials, the percentages of patients reporting adverse reactions in the 50 mg twice a week dose group were similar to those observed in the 25 mg twice a week dose group or placebo group. - Table 4 summarizes adverse reactions reported in adult PsO patients from Studies I and II. Adverse Reactions in Pediatric Patients - In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients. The types of infections reported in pediatric patients were generally mild and consistent with those commonly seen in the general pediatric population. Two JIA patients developed varicella infection and signs and symptoms of aseptic meningitis, which resolved without sequelae. In open-label clinical studies of children with JIA, adverse reactions reported in those ages 2 to 4 years were similar to adverse reactions reported in older children. ## Postmarketing Experience - Adverse reactions have been reported during post approval use of Etanercept in adults and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Etanercept exposure. Adverse reactions are listed by body system below: - Opportunistic infections, including atypical mycobacterial infection, herpes zoster, aspergillosis and Pneumocystis jiroveci pneumonia, and protozoal infections have also been reported in postmarketing use. # Drug Interactions - Specific drug interaction studies have not been conducted with Etanercept . ## Vaccines - Most PsA patients receiving Etanercept were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine, but titers in aggregate were moderately lower and fewer patients had 2-fold rises in titers compared to patients not receiving Etanercept . The clinical significance of this is unknown. Patients receiving Etanercept may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving Etanercept. - Patients with a significant exposure to varicella virus should temporarily discontinue Etanercept therapy and be considered for prophylactic treatment with varicella zoster immune globulin. ## Immune-Modulating Biologic Products - In a study in which patients with active RA were treated for up to 24 weeks with concurrent Etanercept and anakinra therapy, a 7% rate of serious infections was observed, which was higher than that observed with Etanercept alone (0%) and did not result in higher ACR response rates compared to Etanercept alone. The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure. Two percent of patients treated concurrently with Etanercept and anakinra developed neutropenia (ANC < 1 x 109/L). - In clinical studies, concurrent administration of abatacept and Etanercept resulted in increased incidences of serious adverse events, including infections, and did not demonstrate increased clinical benefit. ## Cyclophosphamide - The use of Etanercept in patients receiving concurrent cyclophosphamide therapy is not recommended. ## Sulfasalazine - Patients in a clinical study who were on established therapy with sulfasalazine, to which Etanercept was added, were noted to develop a mild decrease in mean neutrophil counts in comparison to groups treated with either Etanercept or sulfasalazine alone. The clinical significance of this observation is unknown. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): B Pregnancy Surveillance Program - There is a Pregnancy Surveillance Program that monitors outcomes in women exposed to Etanercept during pregnancy. Women who become pregnant during Etanercept treatment are encouraged to enroll. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Risk Summary - There are no adequate and well controlled studies in pregnant women. Based on limited data, etanercept concentration in cord blood at the time of delivery showed that etanercept crossed the placenta in small amounts. - Developmental toxicity studies have been performed in rats and rabbits at doses ranging from 60‑ to 100‑fold higher than the human dose and have revealed no evidence of harm to the fetus due to Etanercept . Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Human Data - Three case reports showed that cord blood levels of etanercept at delivery in infants, born to mothers administered etanercept during pregnancy, were between 3 and 32% of the maternal serum level. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etanercept in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Etanercept during labor and delivery. ### Nursing Mothers - Limited data from published literature show that etanercept is present in low levels in human milk and minimally absorbed by a breastfed infant. Caution should be exercised when Etanercept is administered to a nursing woman. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for Etanercept and any potential adverse effects on the breastfed child from the drug or from the underlying maternal condition. - Women who choose to continue Etanercept treatment while nursing are encouraged to enroll in Amgen’s Lactation Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. ### Pediatric Use - Etanercept has not been studied in children < 2 years of age with JIA. The safety and efficacy of Etanercept in pediatric patients with PsO have not been studied. Rare (< 0.1%) cases of IBD have been reported in JIA patients receiving Etanercept , which is not effective for the treatment of IBD. - The clinical significance of infant exposure to Etanercept in utero is unknown. The safety of administering live or live-attenuated vaccines in exposed infants is unknown. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to exposed infants. ### Geriatic Use - A total of 480 RA patients ages 65 years or older have been studied in clinical trials. In PsO randomized clinical trials, a total of 138 out of 1965 patients treated with Etanercept or placebo were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but the number of geriatric PsO patients is too small to determine whether they respond differently from younger patients. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly. ### Gender There is no FDA guidance on the use of Etanercept with respect to specific gender populations. ### Race There is no FDA guidance on the use of Etanercept with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Etanercept in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Etanercept in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Etanercept in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Etanercept in patients who are immunocompromised. ### Use in Diabetics - There have been reports of hypoglycemia following initiation of Etanercept therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients. # Administration and Monitoring ### Administration - Etanercept is intended for use under the guidance and supervision of a physician. Patients may self-inject when deemed appropriate and if they receive medical follow-up, as necessary. Patients should not self-administer until they receive proper training in how to prepare and administer the correct dose. - The Etanercept (etanercept) “Instructions for Use” insert for each presentation contains more detailed instructions on the preparation of Etanercept . Preparation of Etanercept Using the Single-use Prefilled Syringe or Single-use Prefilled SureClick Autoinjector - For a more comfortable injection, leave Etanercept at room temperature for about 15 to 30 minutes before injecting. DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature. - Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. There may be small white particles of protein in the solution. This is not unusual for proteinaceous solutions. The solution should not be used if discolored or cloudy, or if foreign particulate matter is present. When using the Etanercept single-use prefilled syringe, check to see if the amount of liquid in the prefilled syringe falls between the two purple fill level indicator lines on the syringe. If the syringe does not have the right amount of liquid, DO NOT USE THAT SYRINGE. Preparation of Etanercept Using the Multiple-use Vial - Etanercept should be reconstituted aseptically with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol), giving a solution of 1.0 mL containing 25 mg of Etanercept. - A vial adapter is supplied for use when reconstituting the lyophilized powder. However, the vial adapter should not be used if multiple doses are going to be withdrawn from the vial. If the vial will be used for multiple doses, a 25‑gauge needle should be used for reconstituting and withdrawing Etanercept , and the supplied “Mixing Date:” sticker should be attached to the vial and the date of reconstitution entered. Reconstituted solution must be refrigerated at 36°F to 46°F (2°C to 8°C) and used within 14 days. Discard reconstituted solution after 14 days because product stability and sterility cannot be assured after 14 days. DO NOT store reconstituted Etanercept solution at room temperature. - For a more comfortable injection, leave the Etanercept dose tray at room temperature for about 15 to 30 minutes before injecting. - If using the vial adapter, twist the vial adapter onto the diluent syringe. Then, place the vial adapter over the Etanercept vial and insert the vial adapter into the vial stopper. Push down on the plunger to inject the diluent into the Etanercept vial. If using a 25‑gauge needle to reconstitute and withdraw Etanercept , the diluent should be injected very slowly into the Etanercept vial. It is normal for some foaming to occur. Keeping the diluent syringe in place, gently swirl the contents of the Etanercept vial during dissolution. To avoid excessive foaming, do not shake or vigorously agitate. - Generally, dissolution of Etanercept takes less than 10 minutes. Do not use the solution if discolored or cloudy, or if particulate matter remains. - Withdraw the correct dose of reconstituted solution into the syringe. Some foam or bubbles may remain in the vial. Remove the syringe from the vial adapter or remove the 25‑gauge needle from the syringe. Attach a 27‑gauge needle to inject Etanercept . The contents of one vial of Etanercept solution should not be mixed with, or transferred into, the contents of another vial of Etanercept . No other medications should be added to solutions containing Etanercept , and do not reconstitute Etanercept with other diluents. Do not filter reconstituted solution during preparation or administration. ### Monitoring - Prior to initiating Etanercept and periodically during therapy, patients should be evaluated for active tuberculosis and tested for latent infection # IV Compatibility - There is limited information about the IV Compatibility. # Overdosage - Toxicology studies have been performed in monkeys at doses up to 30 times the human dose with no evidence of dose-limiting toxicities. No dose-limiting toxicities have been observed during clinical trials of Etanercept . Single IV doses up to 60 mg/m2 (approximately twice the recommended dose) have been administered to healthy volunteers in an endotoxemia study without evidence of dose-limiting toxicities. # Pharmacology ## Mechanism of Action - TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. It plays an important role in the inflammatory processes of RA, polyarticular JIA, PsA, and AS and the resulting joint pathology. In addition, TNF plays a role in the inflammatory process of PsO. Elevated levels of TNF are found in involved tissues and fluids of patients with RA, JIA, PsA, AS, and PsO. - Two distinct receptors for TNF (TNFRs), a 55 kilodalton protein (p55) and a 75 kilodalton protein (p75), exist naturally as monomeric molecules on cell surfaces and in soluble forms. Biological activity of TNF is dependent upon binding to either cell surface TNFR. - Etanercept is a dimeric soluble form of the p75 TNF receptor that can bind TNF molecules. Etanercept inhibits binding of TNF-α and TNF-β (lymphotoxin alpha [LT-α]) to cell surface TNFRs, rendering TNF biologically inactive. In in vitro studies, large complexes of etanercept with TNF-α were not detected and cells expressing transmembrane TNF (that binds Etanercept ) are not lysed in the presence or absence of complement. ## Structure - Etanercept (etanercept) is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. The Fc component of etanercept contains the CH2 domain, the CH3 domain and hinge region, but not the CH1 domain of IgG1. Etanercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. - The solution of Etanercept in the single-use prefilled syringe and the single-use prefilled SureClick autoinjector is clear and colorless, sterile, preservative-free, and is formulated at pH 6.3 ± 0.2. - Etanercept is also supplied in a multiple-use vial as a sterile, white, preservative-free, lyophilized powder. Reconstitution with 1 mL of the supplied Sterile Bacteriostatic Water for Injection, USP (containing 0.9% benzyl alcohol) yields a multiple-use, clear, and colorless solution with a pH of 7.4 ± 0.3. ## Pharmacodynamics - Etanercept can modulate biological responses that are induced or regulated by TNF, including expression of adhesion molecules responsible for leukocyte migration (eg, E-selectin, and to a lesser extent, intercellular adhesion molecule-1 [ICAM-1]), serum levels of cytokines (eg, IL-6), and serum levels of matrix metalloproteinase-3 (MMP-3 or stromelysin). Etanercept has been shown to affect several animal models of inflammation, including murine collagen-induced arthritis. ## Pharmacokinetics - After administration of 25 mg of Etanercept by a single SC injection to 25 patients with RA, a mean ± standard deviation half‑life of 102 ± 30 hours was observed with a clearance of 160 ± 80 mL/hr. A maximum serum concentration (Cmax) of 1.1 ± 0.6 mcg/mL and time to Cmax of 69 ± 34 hours was observed in these patients following a single 25 mg dose. After 6 months of twice weekly 25 mg doses in these same RA patients, the mean Cmax was 2.4 ± 1.0 mcg/mL (N = 23). Patients exhibited a 2‑ to 7‑fold increase in peak serum concentrations and approximately 4‑fold increase in AUC0‑72 hr (range 1- to 17-fold) with repeated dosing. Serum concentrations in patients with RA have not been measured for periods of dosing that exceed 6 months. - In another study, serum concentration profiles at steady state were comparable among patients with RA treated with 50 mg Etanercept once weekly and those treated with 25 mg Etanercept twice weekly. The mean (± standard deviation) Cmax, Cmin, and partial AUC were 2.4 ± 1.5 mcg/mL, 1.2 ± 0.7 mcg/mL, and 297 ± 166 mcg•h/mL, respectively, for patients treated with 50 mg Etanercept once weekly (N = 21); and 2.6 ± 1.2 mcg/mL, 1.4 ± 0.7 mcg/mL, and 316 ± 135 mcg•h/mL for patients treated with 25 mg Etanercept twice weekly (N = 16). - Patients with JIA (ages 4 to 17 years) were administered 0.4 mg/kg of Etanercept twice weekly (up to a maximum dose of 50 mg per week) for up to 18 weeks. The mean serum concentration after repeated SC dosing was 2.1 mcg/mL, with a range of 0.7 to 4.3 mcg/mL. Limited data suggest that the clearance of etanercept is reduced slightly in children ages 4 to 8 years. Population pharmacokinetic analyses predict that the pharmacokinetic differences between the regimens of 0.4 mg/kg twice weekly and 0.8 mg/kg once weekly in JIA patients are of the same magnitude as the differences observed between twice weekly and weekly regimens in adult RA patients. In clinical studies with Etanercept , pharmacokinetic parameters were not different between men and women and did not vary with age in adult patients. The pharmacokinetics of etanercept were unaltered by concomitant MTX in RA patients. No formal pharmacokinetic studies have been conducted to examine the effects of renal or hepatic impairment on etanercept disposition. ## Nonclinical Toxicology ## Carcinogenesis, Mutagenesis, Impairment of Fertility - Long-term animal studies have not been conducted to evaluate the carcinogenic potential of etanercept or its effect on fertility. Mutagenesis studies were conducted in vitro and in vivo, and no evidence of mutagenic activity was observed. # Clinical Studies ## Adult Rheumatoid Arthritis - The safety and efficacy of Etanercept were assessed in four randomized, double-blind, controlled studies. The results of all four trials were expressed in percentage of patients with improvement in RA using ACR response criteria. - Study I evaluated 234 patients with active RA who were ≥ 18 years old, had failed therapy with at least one but no more than four disease-modifying antirheumatic drugs (DMARDs) (eg, hydroxychloroquine, oral or injectable gold, MTX, azathioprine, D-penicillamine, sulfasalazine), and had ≥ 12 tender joints, ≥ 10 swollen joints, and either erythrocyte sedimentation rate (ESR) ≥ 28 mm/hr, C-reactive protein (CRP) > 2.0 mg/dL, or morning stiffness for ≥ 45 minutes. Doses of 10 mg or 25 mg Etanercept or placebo were administered SC twice a week for 6 consecutive months. - Study II evaluated 89 patients and had similar inclusion criteria to Study I except that patients in Study II had additionally received MTX for at least 6 months with a stable dose (12.5 to 25 mg/week) for at least 4 weeks and they had at least 6 tender or painful joints. Patients in Study II received a dose of 25 mg Etanercept or placebo SC twice a week for 6 months in addition to their stable MTX dose. - Study III compared the efficacy of Etanercept to MTX in patients with active RA. This study evaluated 632 patients who were ≥ 18 years old with early (≤ 3 years disease duration) active RA, had never received treatment with MTX, and had ≥ 12 tender joints, ≥ 10 swollen joints, and either ESR ≥ 28 mm/hr, CRP > 2.0 mg/dL, or morning stiffness for ≥ 45 minutes. Doses of 10 mg or 25 mg Etanercept were administered SC twice a week for 12 consecutive months. The study was unblinded after all patients had completed at least 12 months (and a median of 17.3 months) of therapy. The majority of patients remained in the study on the treatment to which they were randomized through 2 years, after which they entered an extension study and received open-label 25 mg Etanercept . MTX tablets (escalated from 7.5 mg/week to a maximum of 20 mg/week over the first 8 weeks of the trial) or placebo tablets were given once a week on the same day as the injection of placebo or Etanercept doses, respectively. - Study IV evaluated 682 adult patients with active RA of 6 months to 20 years duration (mean of 7 years) who had an inadequate response to at least one DMARD other than MTX. Forty-three percent of patients had previously received MTX for a mean of 2 years prior to the trial at a mean dose of 12.9 mg. Patients were excluded from this study if MTX had been discontinued for lack of efficacy or for safety considerations. The patient baseline characteristics were similar to those of patients in Study I. Patients were randomized to MTX alone (7.5 to 20 mg weekly, dose escalated as described for Study III; median dose 20 mg), Etanercept alone (25 mg twice weekly), or the combination of Etanercept and MTX initiated concurrently (at the same doses as above). The study evaluated ACR response, Sharp radiographic score, and safety. Clinical Response - A higher percentage of patients treated with Etanercept and Etanercept in combination with MTX achieved ACR 20, ACR 50, and ACR 70 responses and Major Clinical Responses than in the comparison groups. The results of Studies I, II, and III are summarized in Table 6. The results of Study IV are summarized in Table 7. - The time course for ACR 20 response rates for patients receiving placebo or 25 mg Etanercept in Studies I and II is summarized in Figure 1. The time course of responses to Etanercept in Study III was similar. - Among patients receiving Etanercept , the clinical responses generally appeared within 1 to 2 weeks after initiation of therapy and nearly always occurred by 3 months. A dose response was seen in Studies I and III: 25 mg Etanercept was more effective than 10 mg (10 mg was not evaluated in Study II). Etanercept was significantly better than placebo in all components of the ACR criteria as well as other measures of RA disease activity not included in the ACR response criteria, such as morning stiffness. - In Study III, ACR response rates and improvement in all the individual ACR response criteria were maintained through 24 months of Etanercept therapy. Over the 2‑year study, 23% of Etanercept patients achieved a major clinical response, defined as maintenance of an ACR 70 response over a 6‑month period. - The results of the components of the ACR response criteria for Study I are shown in Table 8. Similar results were observed for Etanercept ‑treated patients in Studies II and III. - After discontinuation of Etanercept , symptoms of arthritis generally returned within a month. Reintroduction of treatment with Etanercept after discontinuations of up to 18 months resulted in the same magnitudes of response as in patients who received Etanercept without interruption of therapy, based on results of open‑label studies. - Continued durable responses were seen for over 60 months in open‑label extension treatment trials when patients received Etanercept without interruption. A substantial number of patients who initially received concomitant MTX or corticosteroids were able to reduce their doses or discontinue these concomitant therapies while maintaining their clinical responses. Physical Function Response - In Studies I, II, and III, physical function and disability were assessed using the Health Assessment Questionnaire (HAQ). Additionally, in Study III, patients were administered the SF‑36 Health Survey. In Studies I and II, patients treated with 25 mg Etanercept twice weekly showed greater improvement from baseline in the HAQ score beginning in month 1 through month 6 in comparison to placebo (p < 0.001) for the HAQ disability domain (where 0 = none and 3 = severe). In Study I, the mean improvement in the HAQ score from baseline to month 6 was 0.6 (from 1.6 to 1.0) for the 25 mg Etanercept group and 0 (from 1.7 to 1.7) for the placebo group. In Study II, the mean improvement from baseline to month 6 was 0.6 (from 1.5 to 0.9) for the Etanercept /MTX group and 0.2 (from 1.3 to 1.2) for the placebo/MTX group. In Study III, the mean improvement in the HAQ score from baseline to month 6 was 0.7 (from 1.5 to 0.7) for 25 mg Etanercept twice weekly. All subdomains of the HAQ in Studies I and III were improved in patients treated with Etanercept . - In Study III, patients treated with 25 mg Etanercept twice weekly showed greater improvement from baseline in SF‑36 physical component summary score compared to Etanercept 10 mg twice weekly and no worsening in the SF‑36 mental component summary score. In open‑label Etanercept studies, improvements in physical function and disability measures have been maintained for up to 4 years. - In Study IV, median HAQ scores improved from baseline levels of 1.8, 1.8, and 1.8 to 1.1, 1.0, and 0.6 at 12 months in the MTX, Etanercept , and Etanercept /MTX combination treatment groups, respectively (combination versus both MTX and Etanercept , p < 0.01). Twenty-nine percent of patients in the MTX alone treatment group had an improvement of HAQ of at least 1 unit versus 40% and 51% in the Etanercept alone and the Etanercept /MTX combination treatment groups, respectively. Radiographic Response - In Study III, structural joint damage was assessed radiographically and expressed as change in Total Sharp Score (TSS) and its components, the erosion score and joint space narrowing (JSN) score. Radiographs of hands/wrists and forefeet were obtained at baseline, 6 months, 12 months, and 24 months and scored by readers who were unaware of treatment group. The results are shown in Table 9. A significant difference for change in erosion score was observed at 6 months and maintained at 12 months. - Patients continued on the therapy to which they were randomized for the second year of Study III. Seventy-two percent of patients had x-rays obtained at 24 months. Compared to the patients in the MTX group, greater inhibition of progression in TSS and erosion score was seen in the 25 mg Etanercept group, and, in addition, less progression was noted in the JSN score. - In the open-label extension of Study III, 48% of the original patients treated with 25 mg Etanercept have been evaluated radiographically at 5 years. Patients had continued inhibition of structural damage, as measured by the TSS, and 55% of them had no progression of structural damage. Patients originally treated with MTX had further reduction in radiographic progression once they began treatment with Etanercept . - In Study IV, less radiographic progression (TSS) was observed with Etanercept in combination with MTX compared with Etanercept alone or MTX alone at month 12 (Table 10). In the MTX treatment group, 55% of patients experienced no radiographic progression (TSS change ≤ 0.0) at 12 months compared to 63% and 76% in the Etanercept alone and the Etanercept /MTX combination treatment groups, respectively. Once Weekly Dosing - The safety and efficacy of 50 mg Etanercept (two 25 mg SC injections) administered once weekly were evaluated in a double‑blind, placebo‑controlled study of 420 patients with active RA. Fifty‑three patients received placebo, 214 patients received 50 mg Etanercept once weekly, and 153 patients received 25 mg Etanercept twice weekly. The safety and efficacy profiles of the two Etanercept treatment groups were similar. ## Polyarticular Juvenile Idiopathic Arthritis (JIA) - The safety and efficacy of Etanercept were assessed in a 2-part study in 69 children with polyarticular JIA who had a variety of JIA onset types. Patients ages 2 to 17 years with moderately to severely active polyarticular JIA refractory to or intolerant of MTX were enrolled; patients remained on a stable dose of a single nonsteroidal anti-inflammatory drug and/or prednisone (≤ 0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received 0.4 mg/kg (maximum 25 mg per dose) Etanercept SC twice weekly. In part 2, patients with a clinical response at day 90 were randomized to remain on Etanercept or receive placebo for 4 months and assessed for disease flare. Responses were measured using the JIA Definition of Improvement (DOI), defined as ≥ 30% improvement in at least three of six and ≥ 30% worsening in no more than one of the six JIA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment, and ESR. Disease flare was defined as a ≥ 30% worsening in three of the six JIA core set criteria and ≥ 30% improvement in not more than one of the six JIA core set criteria and a minimum of two active joints. - In part 1 of the study, 51 of 69 (74%) patients demonstrated a clinical response and entered part 2. In part 2, 6 of 25 (24%) patients remaining on Etanercept experienced a disease flare compared to 20 of 26 (77%) patients receiving placebo (p = 0.007). From the start of part 2, the median time to flare was ≥ 116 days for patients who received Etanercept and 28 days for patients who received placebo. Each component of the JIA core set criteria worsened in the arm that received placebo and remained stable or improved in the arm that continued on Etanercept . The data suggested the possibility of a higher flare rate among those patients with a higher baseline ESR. Of patients who demonstrated a clinical response at 90 days and entered part 2 of the study, some of the patients remaining on Etanercept continued to improve from month 3 through month 7, while those who received placebo did not improve. - The majority of JIA patients who developed a disease flare in part 2 and reintroduced Etanercept treatment up to 4 months after discontinuation re-responded to Etanercept therapy in open-label studies. Most of the responding patients who continued Etanercept therapy without interruption have maintained responses for up to 48 months. - Studies have not been done in patients with polyarticular JIA to assess the effects of continued Etanercept therapy in patients who do not respond within 3 months of initiating Etanercept therapy, or to assess the combination of Etanercept with MTX. ## Psoriatic Arthritis - The safety and efficacy of Etanercept were assessed in a randomized, double-blind, placebo-controlled study in 205 patients with PsA. Patients were between 18 and 70 years of age and had active PsA (≥ 3 swollen joints and ≥ 3 tender joints) in one or more of the following forms: (1) distal interphalangeal (DIP) involvement (N = 104); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis; N = 173); (3) arthritis mutilans (N = 3); (4) asymmetric psoriatic arthritis (N = 81); or (5) ankylosing spondylitis-like (N = 7). Patients also had plaque psoriasis with a qualifying target lesion ≥ 2 cm in diameter. Patients on MTX therapy at enrollment (stable for ≥ 2 months) could continue at a stable dose of ≤ 25 mg/week MTX. Doses of 25 mg Etanercept or placebo were administered SC twice a week during the initial 6-month double-blind period of the study. Patients continued to receive blinded therapy in an up to 6-month maintenance period until all patients had completed the controlled period. Following this, patients received open-label 25 mg Etanercept twice a week in a 12-month extension period. - Compared to placebo, treatment with Etanercept resulted in significant improvements in measures of disease activity (Table 11). - Among patients with PsA who received Etanercept , the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. At 6 months, the ACR 20/50/70 responses were achieved by 50%, 37%, and 9%, respectively, of patients receiving Etanercept , compared to 13%, 4%, and 1%, respectively, of patients receiving placebo. Similar responses were seen in patients with each of the subtypes of PsA, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes. The results of this study were similar to those seen in an earlier single-center, randomized, placebo-controlled study of 60 patients with PsA. - The skin lesions of psoriasis were also improved with Etanercept , relative to placebo, as measured by percentages of patients achieving improvements in the Psoriasis Area and Severity Index (PASI). Responses increased over time, and at 6 months, the proportions of patients achieving a 50% or 75% improvement in the PASI were 47% and 23%, respectively, in the Etanercept group (N = 66), compared to 18% and 3%, respectively, in the placebo group (N = 62). Responses were similar in patients who were or were not receiving concomitant MTX therapy at baseline. Radiographic Response - Radiographic changes were also assessed in the PsA study. Radiographs of hands and wrists were obtained at baseline and months 6, 12, and 24. A modified Total Sharp Score (TSS), which included distal interphalangeal joints (ie, not identical to the modified TSS used for RA) was used by readers blinded to treatment group to assess the radiographs. Some radiographic features specific to PsA (eg, pencil-and-cup deformity, joint space widening, gross osteolysis, and ankylosis) were included in the scoring system, but others (eg, phalangeal tuft resorption, juxta-articular and shaft periostitis) were not. - Most patients showed little or no change in the modified TSS during this 24-month study (median change of 0 in both patients who initially received Etanercept or placebo). More placebo-treated patients experienced larger magnitudes of radiographic worsening (increased TSS) compared to Etanercept treatment during the controlled period of the study. At 12 months, in an exploratory analysis, 12% (12 of 104) of placebo patients compared to none of the 101 Etanercept -treated patients had increases of 3 points or more in TSS. Inhibition of radiographic progression was maintained in patients who continued on Etanercept during the second year. Of the patients with 1-year and 2-year x-rays, 3% (2 of 71) had increases of 3 points or more in TSS at 1 and 2 years. Physical Function Response - In the PsA study, physical function and disability were assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. Patients treated with 25 mg Etanercept twice weekly showed greater improvement from baseline in the HAQ-DI score (mean decreases of 54% at both months 3 and 6) in comparison to placebo (mean decreases of 6% at both months 3 and 6) (p < 0.001). At months 3 and 6, patients treated with Etanercept showed greater improvement from baseline in the SF-36 physical component summary score compared to patients treated with placebo, and no worsening in the SF-36 mental component summary score. Improvements in physical function and disability measures were maintained for up to 2 years through the open-label portion of the study. ## Ankylosing Spondylitis - The safety and efficacy of Etanercept were assessed in a randomized, double-blind, placebo-controlled study in 277 patients with active AS. Patients were between 18 and 70 years of age and had AS as defined by the modified New York Criteria for Ankylosing Spondylitis. Patients were to have evidence of active disease based on values of ≥ 30 on a 0-100 unit Visual Analog Scale (VAS) for the average of morning stiffness duration and intensity, and two of the following three other parameters: a) patient global assessment, b) average of nocturnal and total back pain, and c) the average score on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients with complete ankylosis of the spine were excluded from study participation. Patients taking hydroxychloroquine, sulfasalazine, methotrexate, or prednisone (≤ 10 mg/day) could continue these drugs at stable doses for the duration of the study. Doses of 25 mg Etanercept or placebo were administered SC twice a week for 6 months. The primary measure of efficacy was a 20% improvement in the Assessment in Ankylosing Spondylitis (ASAS) response criteria. Compared to placebo, treatment with Etanercept resulted in improvements in the ASAS and other measures of disease activity (Figure 2 and Table 12). - At 12 weeks, the ASAS 20/50/70 responses were achieved by 60%, 45%, and 29%, respectively, of patients receiving Etanercept , compared to 27%, 13%, and 7%, respectively, of patients receiving placebo (p ≤ 0.0001, Etanercept vs placebo). Similar responses were seen at week 24. Responses were similar between those patients receiving concomitant therapies at baseline and those who were not. The results of this study were similar to those seen in a single-center, randomized, placebo-controlled study of 40 patients and a multicenter, randomized, placebo-controlled study of 84 patients with AS. ## Plaque Psoriasis - The safety and efficacy of Etanercept were assessed in two randomized, double-blind, placebo-controlled studies in adults with chronic stable PsO involving ≥ 10% of the body surface area, a minimum Psoriasis Area and Severity Index (PASI) score of 10 and who had received or were candidates for systemic antipsoriatic therapy or phototherapy. Patients with guttate, erythrodermic, or pustular psoriasis and patients with severe infections within 4 weeks of screening were excluded from study. No concomitant major antipsoriatic therapies were allowed during the study. Study I evaluated 672 patients who received placebo or Etanercept SC at doses of 25 mg once a week, 25 mg twice a week, or 50 mg twice a week for 3 months. After 3 months, patients continued on blinded treatments for an additional 3 months during which time patients originally randomized to placebo began treatment with blinded Etanercept at 25 mg twice weekly (designated as placebo/Etanercept in Table 13); patients originally randomized to Etanercept continued on the originally randomized dose (designated as Etanercept /Etanercept groups in Table 13). - Study II evaluated 611 patients who received placebo or Etanercept SC at doses of 25 mg or 50 mg twice a week for 3 months. After 3 months of randomized, blinded treatment, patients in all three arms began receiving open-label Etanercept at 25 mg twice weekly for 9 additional months. - Response to treatment in both studies was assessed after 3 months of therapy and was defined as the proportion of patients who achieved a reduction in PASI score of at least 75% from baseline. The PASI is a composite score that takes into consideration both the fraction of body surface area affected and the nature and severity of psoriatic changes within the affected regions (induration, erythema and scaling). - Other evaluated outcomes included the proportion of patients who achieved a score of “clear” or “minimal” by the Static Physician Global Assessment (sPGA) and the proportion of patients with a reduction of PASI of at least 50% from baseline. The sPGA is a 6-category scale ranging from “5 = severe” to “0 = none” indicating the physician’s overall assessment of the PsO severity focusing on induration, erythema and scaling. Treatment success of “clear” or “minimal” consisted of none or minimal elevation in plaque, up to faint red coloration in erythema and none or minimal fine scale over < 5% of the plaque. - Patients in all treatment groups and in both studies had a median baseline PASI score ranging from 15 to 17, and the percentage of patients with baseline sPGA classifications ranged from 54% to 66% for moderate, 17% to 26% for marked and 1% to 5% for severe. Across all treatment groups, the percentage of patients who previously received systemic therapy for PsO ranged from 61% to 65% in Study I and 71% to 75% in Study II, and those who previously received phototherapy ranged from 44% to 50% in Study I and 72% to 73% in Study II. - More patients randomized to Etanercept than placebo achieved at least a 75% reduction from baseline PASI score (PASI 75) with a dose response relationship across doses of 25 mg once a week, 25 mg twice a week, and 50 mg twice a week (Tables 13 and 14). The individual components of the PASI (induration, erythema and scaling) contributed comparably to the overall treatment-associated improvement in PASI. - Among PASI 75 achievers in both studies, the median time to PASI 50 and PASI 75 was approximately 1 month and approximately 2 months, respectively, after the start of therapy with either 25 or 50 mg twice a week. - In Study I, patients who achieved PASI 75 at month 6 were entered into a study drug withdrawal and retreatment period. Following withdrawal of study drug, these patients had a median duration of PASI 75 of between 1 and 2 months. - In Study I, among patients who were PASI 75 responders at 3 months, retreatment with their original blinded Etanercept dose after discontinuation of up to 5 months resulted in a similar proportion of responders as in the initial double-blind portion of the study. - In Study II, most patients initially randomized to 50 mg twice a week continued in the study after month 3 and had their Etanercept dose decreased to 25 mg twice a week. Of the 91 patients who were PASI 75 responders at month 3, 70 (77%) maintained their PASI 75 response at month 6. # How Supplied - Administration of one 50 mg Etanercept prefilled syringe or one Etanercept SureClick autoinjector provides a dose equivalent to two 25 mg Etanercept prefilled syringes or two multiple-use vials of lyophilized Etanercept , when vials are reconstituted and administered as recommended. ## Etanercept Single-use Prefilled Syringe and Etanercept Single-use Prefilled SureClick Autoinjector - Each Etanercept single-use prefilled syringe and Etanercept single-use prefilled SureClick autoinjector contains 50 mg/mL of etanercept in a single-dose syringe with a 27-gauge, ½-inch needle. ## Etanercept Multiple-use Vial (Recommended for Weight-based Dosing) - Etanercept multiple-use vial is supplied in a carton containing four dose trays. Each dose tray contains one 25 mg vial of etanercept, one diluent syringe (1 mL Sterile Bacteriostatic Water for Injection, USP, containing 0.9% benzyl alcohol), one 27-gauge ½-inch needle, one vial adapter, and one plunger. Each carton contains four “Mixing Date:” stickers. ## Storage ## Etanercept Single-use Prefilled Syringe and Etanercept Single-use Prefilled SureClick Autoinjector - Etanercept should be refrigerated at 36°F to 46°F (2°C to 8°C). Do not use Etanercept beyond the expiration date stamped on the carton or barrel label. DO NOT SHAKE. Store Etanercept in the original carton to protect from light or physical damage. - For convenience, storage of individual syringes or autoinjectors at room temperature for a maximum single period of 14 days is permissible, with protection from light and sources of heat. Once a syringe or autoinjector has been stored at room temperature, it should not be placed back into the refrigerator. If not used within 14 days at room temperature, the syringe or autoinjector should be discarded. Do not store Etanercept in extreme heat or cold. DO NOT FREEZE. Keep out of the reach of children. ## Etanercept Multiple-use Vial (Recommended for Weight-based Dosing) - Etanercept should be refrigerated at 36°F to 46°F (2°C to 8°C). Do not use Etanercept beyond the expiration date stamped on the dose tray. DO NOT SHAKE. Store Etanercept in the original carton to protect from light or physical damage. For convenience, storage of an individual dose tray containing Etanercept multi-use vial and diluent syringe at room temperature for a maximum single period of 14 days is permissible, with protection from light, sources of heat, and humidity. Once the dose tray has been stored at room temperature, it should not be placed back into the refrigerator. If not used within 14 days at room temperature, the dose tray should be discarded. Once a vial has been reconstituted, the solution must be used immediately or may be refrigerated for up to14 days. Do not store Etanercept in extreme heat or cold. DO NOT FREEZE. Keep out of the reach of children. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information ## Patient Counseling - Patients should be advised of the potential benefits and risks of Etanercept . Physicians should instruct their patients to read the Medication Guide before starting Etanercept therapy and to reread each time the prescription is renewed. Infections - Inform patients that Etanercept may lower the ability of their immune system to fight infections. Advise patients of the importance of contacting their doctor if they develop any symptoms of infection, tuberculosis or reactivation of hepatitis B virus infections. Other Medical Conditions - Advise patients to report any signs of new or worsening medical conditions, such as central nervous system demyelinating disorders, heart failure or autoimmune disorders, such as lupus-like syndrome or autoimmune hepatitis. Counsel about the risk of lymphoma and other malignancies while receiving Etanercept . Advise patients to report any symptoms suggestive of a pancytopenia, such as bruising, bleeding, persistent fever or pallor. Allergic Reactions - Advise patients to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the following components contain dry natural rubber (a derivative of latex) that may cause allergic reactions in individuals sensitive to latex: the needle cover of the prefilled syringe and the needle cover within the needle cap of the SureClick autoinjector. ## Administration of Etanercept - If a patient or caregiver is to administer Etanercept , the patient or caregiver should be instructed in injection techniques and how to measure and administer the correct dose. The first injection should be performed under the supervision of a qualified healthcare professional. The patient’s or caregiver’s ability to inject subcutaneously should be assessed. Patients and caregivers should be instructed in the technique, as well as proper syringe and needle disposal, and be cautioned against reuse of needles and syringes. - A puncture-resistant container for disposal of needles, syringes and autoinjectors should be used. If the product is intended for multiple use, additional syringes, needles and alcohol swabs will be required. - Patients can be advised to call 1-888-4Etanercept (1-888-436-2735) or visit www.Etanercept .com for more information about Etanercept . # Precautions with Alcohol - In a study of 48 hospitalized patients treated with Etanercept or placebo for moderate to severe alcoholic hepatitis, the mortality rate in patients treated with Etanercept was similar to patients treated with placebo at 1 month but significantly higher after 6 months. Physicians should use caution when using Etanercept in patients with moderate to severe alcoholic hepatitis. # Brand Names - ENBREL # Look-Alike Drug Names - Etanercept - Levbid[15] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Enbrel
15a158c49c27462fb1f93b88434ef7c328746b9c	wikidoc	Endostatin	Endostatin Endostatin is a naturally-occurring 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin Endostatin is a broad spectrum angiogenesis inhibitor and may interfere with the pro-angiogenic action of growth factors such as basic fibroblast growth factor (bFGF/FGF-2) and vascular endothelial growth factor (VEGF). # Research Endostatin is currently being studied as part of cancer research. ## Phase I In a Phase I clinical trial of Endostatin of the 19 patients treated, 12 were switched out of the trial by their physicians due to continued progression of their disease. Two patients continued to be treated, and the remaining patients withdrew on their own. The trial, designed primarily to demonstrate safety, indeed showed that the drug was safe and well-tolerated. ## Phase II In a Phase II clinical trial of Endostatin forty two patients with pancreatic endocrine tumors or carcinoid tumors were treated. Of the 40 patients which could be evaluated for a radiologic response, none experienced partial response to therapy, as defined by World Health Organization criteria. The conclusion from the trial was that "Treatment with Endostatin did not result in significant tumor regression in patients with advanced neuroendocrine tumors."	Endostatin Endostatin is a naturally-occurring 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin Endostatin is a broad spectrum angiogenesis inhibitor and may interfere with the pro-angiogenic action of growth factors such as basic fibroblast growth factor (bFGF/FGF-2) and vascular endothelial growth factor (VEGF).[1] # Research Endostatin is currently being studied as part of cancer research. ## Phase I In a Phase I clinical trial of Endostatin of the 19 patients treated, 12 were switched out of the trial by their physicians due to continued progression of their disease.[2] Two patients continued to be treated, and the remaining patients withdrew on their own. The trial, designed primarily to demonstrate safety, indeed showed that the drug was safe and well-tolerated. ## Phase II In a Phase II clinical trial of Endostatin forty two patients with pancreatic endocrine tumors or carcinoid tumors were treated.[3] Of the 40 patients which could be evaluated for a radiologic response, none experienced partial response to therapy, as defined by World Health Organization criteria. The conclusion from the trial was that "Treatment with Endostatin did not result in significant tumor regression in patients with advanced neuroendocrine tumors."	https://www.wikidoc.org/index.php/Endostatin
400623312863ddb0db82bc6abdeade3afdd50847	wikidoc	Endothelin	Endothelin Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute to high blood pressure (hypertension), heart disease, and potentially other diseases. Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis. Endothelins are implicated in vascular diseases of several organ systems, including the heart, lungs, kidneys, and brain. As of 2018, endothelins remain under extensive basic and clinical research to define their roles in several organ systems. # Etymology Endothelins derived the name from their isolation in cultured endothelial cells. # Isoforms There are three isoforms of the peptide (identified as ET-1, -2, -3) with varying regions of expression and binding to at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC. # Antagonists Earliest antagonists discovered for ETA were BQ123, and for ETB, BQ788. An ETA-selective antagonist, ambrisentan was approved for treatment of pulmonary arterial hypertension in 2007, followed by a more selective ETA antagonist, sitaxentan, which was later withdrawn due to potentially lethal effects in the liver. Bosentan was a precursor to macitentan, which was approved in 2013. # Physiological effects Endothelins are the most potent vasoconstrictors known. Overproduction of endothelin in the lungs may cause pulmonary hypertension, which was treatable in preliminary research by bosentan, sitaxentan or ambrisentan. Endothelins have involvement in cardiovascular function, fluid-electrolyte homeostasis, and neuronal mechanisms across diverse cell types. Endothelin receptors are present in the three pituitary lobes which display increased metabolic activity when exposed to endothelin-1 in the blood or ventricular system. ET-1 contributes to the vascular dysfunction associated with cardiovascular disease, particularly atherosclerosis and hypertension. The ETA receptor for ET-1 is primarily located on vascular smooth muscle cells, mediating vasoconstriction, whereas the ETB receptor for ET-1 is primarily located on endothelial cells, causing vasodilation due to nitric oxide release. The binding of platelets to the endothelial cell receptor LOX-1 causes a release of endothelin, which induces endothelial dysfunction. # Disease involvement The ubiquitous distribution of endothelin peptides and receptors implicates involvement in a wide variety of physiological and pathological processes among different organ systems. Among numerous diseases potentially occurring from endothelin dysregulation are: - several types of cancer - cerebral vasospasm following subarachnoid hemorrhage - arterial hypertension, pulmonary hypertension, and other cardiovascular disorders - pain mediation - cardiac hypertrophy and heart failure - Dengue haemorrhagic fever - Type II diabetes - some cases of Hirschsprung disease In insulin resistance the high levels of blood insulin results in increased production and activity of ET-1, which promotes vasoconstriction and elevates blood pressure. ET-1 impairs glucose uptake in the skeletal muscles of insulin resistant subjects, thereby worsening insulin resistance. In preliminary research, injection of endothelin-1 into a lateral cerebral ventricle was shown to potently stimulate glucose metabolism in specified interconnected circuits of the brain, and to induce convulsions, indicating its potential for diverse neural effects in conditions such as epilepsy. Receptors for endothelin-1 exist in brain neurons, indicating a potential role in neural functions. # Gene regulation The endothelium regulates local vascular tone and integrity through the coordinated release of vasoactive molecules. Secretion of endothelin-1 (ET-1)1 from the endothelium signals vasoconstriction and influences local cellular growth and survival. ET-1 has been implicated in the development and progression of vascular disorders such as atherosclerosis and hypertension. Endothelial cells upregulate ET-1 in response to hypoxia, oxidized LDL, pro-inflammatory cytokines, and bacterial toxins. Initial studies on the ET-1 promoter provided some of the earliest mechanistic insight into endothelial-specific gene regulation. Numerous studies have since provided valuable insight into ET-1 promoter regulation under basal and activated cellular states. The ET-1 mRNA is labile with a half-life of less than an hour. Together, the combined actions of ET-1 transcription and rapid mRNA turnover allow for stringent control over its expression. It has previously been shown that ET-1 mRNA is selectively stabilized in response to cellular activation by Escherichia coli O157:H7-derived verotoxins, suggesting ET-1 is regulated by post-transcriptional mechanisms. Regulatory elements modulating mRNA half-life are often found within 3'-untranslated regions (3'-UTR). The 1.1-kb 3'-UTR of human ET-1 accounts for over 50% of the transcript length and features long tracts of highly conserved sequences including an AU-rich region. Some 3'-UTR AU-rich elements (AREs) play important regulatory roles in cytokine and proto-oncogene expression by influencing half-life under basal conditions and in response to cellular activation. Several RNA-binding proteins with affinities for AREs have been characterized including AUF1 (hnRNPD), the ELAV family (HuR, HuB, HuC, HuD), tristetraprolin, TIA/TIAR, HSP70, and others. Although specific mechanisms directing ARE activity have not been fully elucidated, current models suggest ARE-binding proteins target specific mRNAs to cellular pathways that influence 3'-polyadenylate tail and 5'-cap metabolism. Recent studies have revealed a functional link between AUF1, heat shock proteins and the ubiquitin-proteasome network. Proteasome inhibition by chemical inhibition or heat shock was shown to stabilize a model ARE-containing mRNA whereas promotion of cellular ubiquitination pathways was shown to accelerate ARE mRNA turnover. Studies with in vitro proteasome preparations suggest that the proteasome itself may possess ARE-specific RNA destabilizing activity. The ARE-binding protein AUF1 has been linked to the ubiquitin-proteasome pathway. AUF1 mRNA destabilizing activity has been positively correlated with its level of polyubiquitination and has been shown to interact with a member of the E2 ubiquitin-conjugating protein family. Furthermore, under conditions of cellular heat shock AUF1 associates with heat shock protein 70 (HSP70), which itself possesses ARE binding activity. The ET-1 transcript is constitutively destabilized by its 3'-UTR through two destabilizing elements, DE1 and DE2. DE1 functions through a conserved ARE by the AUF1-proteasome pathway and is regulated by the heat shock pathway.	Endothelin Endothelins are peptides with receptors and effects in many body organs.[1][2] Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute to high blood pressure (hypertension), heart disease, and potentially other diseases.[1][3] Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis. Endothelins are implicated in vascular diseases of several organ systems, including the heart, lungs, kidneys, and brain.[4][5] As of 2018, endothelins remain under extensive basic and clinical research to define their roles in several organ systems.[1][6][7][8] # Etymology Endothelins derived the name from their isolation in cultured endothelial cells.[1][9] # Isoforms There are three isoforms of the peptide (identified as ET-1, -2, -3) with varying regions of expression and binding to at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC.[1][10] # Antagonists Earliest antagonists discovered for ETA were BQ123, and for ETB, BQ788.[9] An ETA-selective antagonist, ambrisentan was approved for treatment of pulmonary arterial hypertension in 2007, followed by a more selective ETA antagonist, sitaxentan, which was later withdrawn due to potentially lethal effects in the liver.[1] Bosentan was a precursor to macitentan, which was approved in 2013.[1] # Physiological effects Endothelins are the most potent vasoconstrictors known.[1][11] Overproduction of endothelin in the lungs may cause pulmonary hypertension, which was treatable in preliminary research by bosentan, sitaxentan or ambrisentan.[1] Endothelins have involvement in cardiovascular function, fluid-electrolyte homeostasis, and neuronal mechanisms across diverse cell types.[1] Endothelin receptors are present in the three pituitary lobes[12] which display increased metabolic activity when exposed to endothelin-1 in the blood or ventricular system.[13] ET-1 contributes to the vascular dysfunction associated with cardiovascular disease, particularly atherosclerosis and hypertension.[14] The ETA receptor for ET-1 is primarily located on vascular smooth muscle cells, mediating vasoconstriction, whereas the ETB receptor for ET-1 is primarily located on endothelial cells, causing vasodilation due to nitric oxide release.[14] The binding of platelets to the endothelial cell receptor LOX-1 causes a release of endothelin, which induces endothelial dysfunction.[15] # Disease involvement The ubiquitous distribution of endothelin peptides and receptors implicates involvement in a wide variety of physiological and pathological processes among different organ systems.[1] Among numerous diseases potentially occurring from endothelin dysregulation are: - several types of cancer[16][17] - cerebral vasospasm following subarachnoid hemorrhage[18] - arterial hypertension, pulmonary hypertension, and other cardiovascular disorders[17] - pain mediation[19] - cardiac hypertrophy and heart failure[17] - Dengue haemorrhagic fever - Type II diabetes - some cases of Hirschsprung disease In insulin resistance the high levels of blood insulin results in increased production and activity of ET-1, which promotes vasoconstriction and elevates blood pressure.[20] ET-1 impairs glucose uptake in the skeletal muscles of insulin resistant subjects, thereby worsening insulin resistance.[21] In preliminary research, injection of endothelin-1 into a lateral cerebral ventricle was shown to potently stimulate glucose metabolism in specified interconnected circuits of the brain, and to induce convulsions, indicating its potential for diverse neural effects in conditions such as epilepsy.[22] Receptors for endothelin-1 exist in brain neurons, indicating a potential role in neural functions.[17] # Gene regulation The endothelium regulates local vascular tone and integrity through the coordinated release of vasoactive molecules. Secretion of endothelin-1 (ET-1)1 from the endothelium signals vasoconstriction and influences local cellular growth and survival. ET-1 has been implicated in the development and progression of vascular disorders such as atherosclerosis and hypertension. Endothelial cells upregulate ET-1 in response to hypoxia, oxidized LDL, pro-inflammatory cytokines, and bacterial toxins. Initial studies on the ET-1 promoter provided some of the earliest mechanistic insight into endothelial-specific gene regulation. Numerous studies have since provided valuable insight into ET-1 promoter regulation under basal and activated cellular states. The ET-1 mRNA is labile with a half-life of less than an hour. Together, the combined actions of ET-1 transcription and rapid mRNA turnover allow for stringent control over its expression. It has previously been shown that ET-1 mRNA is selectively stabilized in response to cellular activation by Escherichia coli O157:H7-derived verotoxins, suggesting ET-1 is regulated by post-transcriptional mechanisms. Regulatory elements modulating mRNA half-life are often found within 3'-untranslated regions (3'-UTR). The 1.1-kb 3'-UTR of human ET-1 accounts for over 50% of the transcript length and features long tracts of highly conserved sequences including an AU-rich region. Some 3'-UTR AU-rich elements (AREs) play important regulatory roles in cytokine and proto-oncogene expression by influencing half-life under basal conditions and in response to cellular activation. Several RNA-binding proteins with affinities for AREs have been characterized including AUF1 (hnRNPD), the ELAV family (HuR, HuB, HuC, HuD), tristetraprolin, TIA/TIAR, HSP70, and others. Although specific mechanisms directing ARE activity have not been fully elucidated, current models suggest ARE-binding proteins target specific mRNAs to cellular pathways that influence 3'-polyadenylate tail and 5'-cap metabolism. Recent studies have revealed a functional link between AUF1, heat shock proteins and the ubiquitin-proteasome network. Proteasome inhibition by chemical inhibition or heat shock was shown to stabilize a model ARE-containing mRNA whereas promotion of cellular ubiquitination pathways was shown to accelerate ARE mRNA turnover. Studies with in vitro proteasome preparations suggest that the proteasome itself may possess ARE-specific RNA destabilizing activity. The ARE-binding protein AUF1 has been linked to the ubiquitin-proteasome pathway. AUF1 mRNA destabilizing activity has been positively correlated with its level of polyubiquitination and has been shown to interact with a member of the E2 ubiquitin-conjugating protein family. Furthermore, under conditions of cellular heat shock AUF1 associates with heat shock protein 70 (HSP70), which itself possesses ARE binding activity. The ET-1 transcript is constitutively destabilized by its 3'-UTR through two destabilizing elements, DE1 and DE2. DE1 functions through a conserved ARE by the AUF1-proteasome pathway and is regulated by the heat shock pathway.[23]	https://www.wikidoc.org/index.php/Endothelin
b1a817204c744b7f9973c57561af4ace011b2c99	wikidoc	Intubation	Intubation Synonyms and keywords: Intubate, Endotracheal intubation, Tracheal intubation # Overview Intubation (sometimes entubation) is a medical procedure involving the insertion of a tube into the body. Patients are generally anesthetized beforehand. Examples include tracheal intubation, and the balloon tamponade with a Sengstaken-Blakemore tube (a tube into the gastrointestinal tract). The most common intubation is tracheal intubation. The most common route for tracheal intubation is orotracheal where an endotracheal tube is passed from the oropharynx to the trachea. A bulb is then inflated near the distal tip of the tube to help secure it in place and protect the airway from blood, gastric contents and other secretions. Removal of the tube is referred to as extubation of the trachea. # Types Intubation can exist in various forms. The following are some types of intubation that can occur: - Endotracheal intubation- This is broad term that encompasses a tube going from the oropharynx to the trachea. This can be further subdivided into two other categories such as Nasotracheal intubation and Orotracheal intubation. Orotracheal intubation- This is a type of intubation in which the tube goes in through the oral cavity to the trachea. Nasotracheal intubation- This is a type of intubation in which the tube goes in through the nasal cavity to the trachea. - Orotracheal intubation- This is a type of intubation in which the tube goes in through the oral cavity to the trachea. - Nasotracheal intubation- This is a type of intubation in which the tube goes in through the nasal cavity to the trachea. - Orogastric intubation - Nasogastric intubation - Fiberoptic intubation - Surgical Airway Tracheostomy Cricothyroidotomy - Tracheostomy - Cricothyroidotomy # Historical Perspective ## BC - 3600 BC- The earliest known depiction of a tracheotomy is found on two Egyptian tablets dating back to around 3600 BC. - 2000 BC- Tracheotomy was described in the Rigveda, a Sanskrit text of ayurvedic medicine written around 2000 BC in ancient India. - 1550 BC- The 110-page Ebers Papyrus, an Egyptian medical papyrus which dates to roughly 1550 BC, also makes reference to the tracheotomy. - 400 BC- The Sushruta Samhita from around 400 BC is another text from the Indian subcontinent on ayurvedic medicine and surgery that mentions tracheotomy. - 124–40 BC- Asclepiades of Bithynia (c. 124–40 BC) is often credited as being the first physician to perform a non-emergency tracheotomy. ## 1st Century - 129–199 AD- Galen of Pergamon (AD 129–199) clarified the anatomy of the trachea and was the first to demonstrate that the larynx generates the voice. In one of his experiments, Galen used bellows to inflate the lungs of a dead animal. ## 9th Century - 1025- Ibn Sīnā (980–1037) described the use of tracheal intubation to facilitate breathing in 1025 in his 14-volume medical encyclopedia, The Canon of Medicine. - 1092–1162- In the 12th century medical textbook Al-Taisir, Ibn Zuhr (1092–1162)—also known as Avenzoar—of Al-Andalus provided a correct description of the tracheotomy operation. ## 14th Century - 1543- The first detailed descriptions of tracheal intubation and subsequent artificial respiration of animals were from Andreas Vesalius (1514–1564) of Brussels. In his landmark book published in 1543, De humani corporis fabrica, he described an experiment in which he passed a reed into the trachea of a dying animal whose thorax had been opened and maintained ventilation by blowing into the reed intermittently. The next known report on tracheal intubation and subsequent artificial respiration of animals is when Andreas Vesalius pointed out that the technique could be life-saving. This report remained unnoticed for more than 250 years. - 1546- Antonio Musa Brassavola (1490–1554) of Ferrara successfully treated a patient suffering from peritonsillar abscess by tracheotomy. Brassavola published his account in 1546; this operation has been identified as the first recorded successful tracheotomy, despite the many previous references to this operation. ## 15th Century - 1620- In 1620 the French surgeon Nicholas Habicot (1550–1624) published a report of four successful tracheotomies. ## 16th Century - 1533–1619- Towards the end of the 16th century, Hieronymus Fabricius described a useful technique for tracheotomy in his writings, although he had never actually performed the operation himself. - 1714- In 1714, anatomist Georg Detharding (1671–1747) of the University of Rostock performed a tracheotomy on a drowning victim. ## 19th Century - In 1805, Philip Bozzini used a device he invented and called the lichtleiter (or light-guiding instrument) to examine the human urinary bladder, rectum and pharynx. The practice of gastric endoscopy in humans was pioneered by U.S. Army surgeon William Beaumont - in 1822 with the cooperation of his patient Alexis St. Martin, a victim of an accidental gunshot wound to the stomach. - In 1853, Antoine Jean Desormeaux of France examined the human bladder using a device he invented and called the endoscope (this was the first time this term was applied to this practice). - In 1868, Adolph Kussmaul of Germany performed the first esophagogastroduodenoscopy on a living human. The subject was a sword-swallower, who swallowed a metal tube with a length of 47 centimeters and a diameter of 13 millimeters. - In 1869, the German surgeon Friedrich Trendelenburg documented successful human tracheotomy for administration of general anesthesia. - In 1878, the Scottish surgeon William Macewen performed the first orotracheal intubation. - In 1878, Maximilian Nitze and Josef Leiter invented the cystourethroscope and - in 1881, Jan Mikulicz-Radecki created the first rigid gastroscope for practical applications. - On 23 April 1895, Alfred Kirstein performed the first direct laryngoscopy in Berlin, Germany, using an esophagoscope he had modified for this purpose. ## 20th Century - In 1919's, German otolaryngologist Dr. Franz Kuhn developed a flexometallic tube that resisted kinking and could be shaped to the patient's upper airway anatomy. Like O'Dwyer's tubes, it was inserted using blind digital technique. The patients were intubated awake and the hypopharynx was sealed with oiled gauze packing. - During World War I, Sir Ivan Magill and Robert Macintosh achieved significant advances in techniques for tracheal intubation. The Magill curve of an endotracheal tube and the Magill forceps for positioning the tube during nasotracheal intubation are named after Magill, while the most widely used curved laryngoscope blade is named after Macintosh. - In 1937, Leech introduced a "pharyngeal bub gasway" with a noninflatable cuff that fit snug into the hypopharynx. - In 1932, Rudolph Schindler of Germany introduced the first semi-flexible gastroscope. This device had numerous lenses positioned throughout the tube and a miniature light bulb at the distal tip. The tube of this device was 75 centimeters in length and 11 millimeters in diameter, and the distal portion was capable of a certain degree of flexion. - In 1939 to 1945, During World War II the shift of mask airways to tracheal intubations occured for most surgical procedures. - Between 1945 and 1952, optical engineers (notably Karl Storz of Germany, Harold Hopkins of England, and Mutsuo Sugiura of the Japanese Olympus Corporation) built upon this early work, leading to the development of the first gastrocamera. - In 1951, Succinylcholine helped dominate the area of tracheal intubation as it was faster and muscle relaxation was easier to achieve. - In 1964, Fernando Alves Martins of Portugal applied optical fiber technology to one of these early gastrocameras to produce the first gastrocamera with a flexible fiberscope. Initially used in esophagogastroduodenoscopy (EGD), newer devices were developed in the early 1970s for use in bronchoscopy, rhinoscopy, and laryngoscopy. - By the mid-1980s, the flexible fiberoptic bronchoscope had become an indispensable instrument within the pulmonology and anesthesia communities. ## 21st Century - The Digital Revolution has brought newer technology to the art and science of tracheal intubation. Several manufacturers have developed video laryngoscopes which employ digital technology such as the CMOS active pixel sensor (CMOS APS) to generate a view of the glottis so that the trachea may be intubated. The Glidescope video laryngoscope is one example of such a device. # Indication A definitive airway (orotracheal, nasotracheal, cricothyrotomy, or tracheotomy) is indicated under any of the following circumstances: Failure to maintain airway tone - Stab wound to neck with expanding hematoma - Swelling of upper airway as in anaphylaxis or infection - Facial or neck trauma with oropharyngeal bleeding Decreased consciousness and loss of airway reflexes - Comatose or intoxicated patients with a depressed level of consciousness who are unable to protect their airways. This is commonly defined as those subjects with a Glasgow Coma Scale ≤ 8. In such cases, the throat muscles may lose their tone so that the hypopharynx becomes obstructed, impeding the free flow of air into the lungs. Furthermore, protective airway reflexes such as coughing and swallowing, which serve to protect the airways against aspiration of secretions and foreign bodies, may be absent. With tracheal intubation, airway patency is restored and the lower airways can be protected from aspiration - Cervical spine fracture with concern for edema and loss of airway patency - Intracranial hemorrhage with altered mental status and need for close blood pressure control - Failure to protect airway against aspiration - Decreased consciousness that leads to regurgitation of vomit, secretions, or blood Failure to ventilate - Requirement for mechanical ventilation, including cardiopulmonary resuscitation and general anesthesia. In such situations, spontaneous ventilation may be decreased or absent due to the effect of injury, disease, anesthetic agents, opioids, or neuromuscular-blocking drugs. To enable mechanical ventilation, an endotracheal tube is often used, although there are alternative devices such as the laryngeal mask airway or the CPAP mask. - Diagnostic or therapeutic manipulation of the airway (such as bronchoscopy, laser therapy or stenting of the bronchi) - Persistent or recurrent airway obstruction - Prolonged respiratory effort that results in fatigue or failure, as in status asthmaticus or severe COPD Failure to oxygenate (ie, transport oxygen to pulmonary capillary blood) - Apnea or hypoventilation (e.g., closed head injury, intoxication or poisoning, cervical spine injury, flail chest) - Septic shock with high minute-ventilation and poor peripheral perfusion - End result of failure to maintain and protect airway or failure to ventilate - Diffuse pulmonary edema - Large pneumonia or air-space disease - acute respiratory distress syndrome (ARDS), - Near-drowning - Pulmonary embolism - Cyanide toxicity, carbon monoxide toxicity, methemoglobinemia # Contraindications ## Absolute - Total upper airway obstruction, which requires a surgical airway - Total loss of facial/oropharyngeal landmarks, which requires a surgical airway ## Relative Anticipated "difficult" airway, in which endotracheal intubation may be unsuccessful, resulting in reliance on successful bag-valve-mask (BVM) ventilation to keep an unconscious patient alive - In this scenario, techniques for awake intubation and difficult airway adjuncts can be used. - Multiple methods can be used to evaluate the airway and the risk of difficult intubation (eg, LEMON rule, 3-3-2, Mallampati class, McCormack and Lehane grade). Please refer to the Difficult Airway Assessment section below for details. The "crash" airway, in which the patient is in an arrest situation, unconscious and apneic - In this scenario, the patient is already unconscious and may be flaccid; further, no time is available for preoxygenation, pretreatment, or induction and paralysis. - BVM ventilation, intubation, or both should be performed immediately without medications. # Equipment Equipment includes the following: - Laryngoscope Laryngoscope handle, No. 3 Macintosh (curved) blade, and No. 3 Miller (straight) blade. Confirm that light source is functional prior to intubation. A 2010 study demonstrated that single-use metal laryngoscope blades resulted in a lower failed intubation rate than did reusable metal blades.null 13 - Confirm that light source is functional prior to intubation. - A 2010 study demonstrated that single-use metal laryngoscope blades resulted in a lower failed intubation rate than did reusable metal blades.null 13 - Endotracheal (ET) tube - Stylet - Syringe, 10 mL (to inflate ET tube balloon) - Suction catheter (eg, Yankauer) - Carbon dioxide detector (eg, Easycap) - Oral and nasal airways - Ambu bag and mask attached to oxygen source - Nasal cannula ## Laryngoscopes The vast majority of "noninvasive" tracheal intubations involve the use of a viewing instrument or "scope" of one type or another. Since its introduction by Kirstein in 1895, the most common device used for this purpose has been the conventional laryngoscope. Today, the typical conventional laryngoscope consists of a handle, usually containing batteries, and a set of interchangeable blades. Two basic styles of laryngoscope blade are commercially available: the straight blade and the curved blade. The Macintosh blade is the most widely used of the curved laryngoscope blades, while the Miller blade is the most popular style of straight blade. There are many other styles of straight and curved blades, with accessories such as mirrors for enlarging the field of view and even ports for the administration of oxygen. These specialty blades are primarily designed for use by anesthetists, most commonly in the operating room. Besides the conventional laryngoscopes, many devices have been developed as alternatives to direct laryngoscopy. These include a number of indirect fiberoptic viewing laryngoscopes such as the flexible fiberoptic bronchoscope, Bullard scope, UpsherScope, and the WuScope. These devices are widely employed for tracheal intubation, especially in the setting of the difficult intubation (see below). Several types of video laryngoscopes are also currently available (e.g., Glidescope, McGrath laryngoscope, Daiken Medical Coopdech C-scope vlp-100, the Storz C-Mac, Pentax AWS and the Berci DCI). Other noninvasive devices which are commonly employed for tracheal intubation are the laryngeal mask airway (used as a guide for tracheal tube placement), the lighted stylet, and the AirTraq. Due to the widespread availability of such devices, the technique of blind digital intubation of the trachea is rarely practiced today, though it may still be useful in emergency situations under austere conditions such as natural or man-made disasters. ## Stylets A stylet is a malleable metal wire which can be inserted into the endotracheal tube to make the tube conform better to the laryngopharyngeal anatomy of the specific individual, thus facilitating its insertion. It is commonly employed under circumstances of difficult laryngoscopy. The Eschmann stylet or gum elastic bougie is a specialized type of stylet, which can also be used for difficult laryngoscopy or for removal and replacement of tracheal tubes without the need for laryngoscopy. ## Tracheal Tubes Most tracheal tubes today are constructed of polyvinyl chloride, but specialty tubes constructed of silicone rubber, latex rubber, or stainless steel are also widely available. Most tubes have an inflatable cuff to seal the trachea and bronchial tree against air leakage and aspiration of gastric contents, blood, secretions, and other fluids. Uncuffed tubes are also available, though their use is limited mostly to pediatric patients (in small children, the cricoid cartilage, the narrowest portion of the pediatric airway, often provides an adequate seal for mechanical ventilation). The "armored endotracheal tube" is a cuffed, wire-reinforced, silicone rubber tube which is quite flexible but yet difficult to compress or kink. This can make it useful for situations in which the trachea is anticipated to remain intubated for a prolonged duration, or if the neck is to remain flexed during surgery. Polyvinyl chloride tubes are relatively stiff in comparison. Preformed tubes (such as the oral and nasal RAE tubes, named after the inventors Ring, Adair and Elwyn) are also widely available for special applications. These may also be constructed of polyvinyl chloride or wire-reinforced silicone rubber. Other tubes (such as the Bivona® Fome-Cuf® tube) are designed specifcally for use in laser surgery in and around the airway. Various types of double-lumen endotracheal tubes have been developed (Carlens, Robertshaw, etc.) for ventilating each lung independently—this is useful during pulmonary and other thoracic operations. ## Observational Methods to Confirm Tube Placement - Direct visualization of the tube passing through the vocal cords - Clear and equal bilateral breath sounds on auscultation of the chest - Absent sounds on auscultation of the epigastrium - Equal bilateral chest rise with ventilation - Fogging of the tube - An absence of stomach contents in the tube ## Instruments to Confirm Tube Placement No single method for confirming tracheal tube placement has been shown to be 100% reliable. Accordingly, the use of multiple methods to confirm correct tube placement is now widely considered to be the standard of care. At least one of the methods utilized should be an instrument. Waveform capnography has emerged as the gold standard for the confirmation of correct tube placement and maintenance of the tube once it is in place. Other methods include: - Colorimetric end tidal carbon dioxide detector - Self-inflating esophageal bulb - Pulse oximetry (important limitations include a significant delay in the decrease in oxygen saturation, especially if subject has been pre-oxygenated) - Esophageal Detection Device # Predicting Ease of Intubation - Look externally (history of craniofacial traumas/previous surgery) - Evaluate 3,3,2 - three of the subject's fingers should be able to fit into his/her mouth when open, three fingers should comfortably fit between the chin and the throat, and two fingers in the thyromental distance (distance from thyroid cartilage to chin) - Mallampati score - Obstructions (stridorous breath sounds, wheezing, etc.) - Neck mobility (can subject tilt head back and then forward to touch chest) - Cormack-Lehane grading system (according to the percentage of glottic opening on laryngoscopy) # Preprocedure ## Anesthesia Rapid sequence intubation (RSI) is predicated on the administration of medications in a specific sequence. The two phases of medication administration are induction and paralysis. In general, preoxygenation is carried out while medications are being drawn up. ## Preoxygenation Preoxygenation with high-flow oxygen via a nonrebreather mask for 3-5 minutes leading up to intubation results in supersaturation of oxygen in the alveoli by way of displacement of nitrogen (nitrogen washout). This allows the patient to maintain blood oxygen saturation during the apneic period of paralysis and allows the physician more time to successfully intubate. In healthy adult volunteers who have been preoxygenated for 3-5 minutes, the average time to desaturation (oxygen saturation <90%) is approximately 8 minutes. This time is significantly shorter in patients who are critically ill and have a much higher metabolic demand for oxygen. null 1 Use the least assistance necessary to obtain good oxygen saturation and adequate preoxygenation (see Technique section below). - High-flow oxygen via nonrebreather mask may be appropriate for a patient with good respiratory effort. - High-flow oxygen via well-fitting bag-valve-mask (BVM) without additional positive pressure (ie, squeezing the bag) may be needed for those with more respiratory compromise. - High-flow oxygen via BVM with positive pressure assistance (squeezing the bag) is used only when necessary. ## Apneic oxygenation Because pulmonary blood flow is still occurring during the apneic period of ETT placement, oxygen is continually being diffused out of the alveoli epithelium at 250 mL/min and into the capillary endothelium and attaching itself to circulating hemoglobin. Despite no ventilations (RSI dictates this in assuming full stomachs unless oxygen saturations are low) after the patient is paralyzed, there is actual flow and movement of oxygen down these concentration gradients as the alveoli are somewhat subatmospheric and a mass flow of gas (oxygen) flows from the airways into the alveoli. By applying an NC at 15 L/min (noxious and otherwise not tolerable in the awake patient) proximal airways can come close to a FiO2 of 1.0 and serve to replace the alveoli oxygen. null 14 Taha et al have shown that apneic oxygenation via an NC during RSI in comparison to those without this technique desaturated in 6 minutes compared with 3.65 minutes. null 15 ## Pretreatment Pretreatment agents may be used to mitigate the physiologic response to laryngoscopy and induction and paralysis, which may be undesirable in certain clinical situations. Note though clinical dogma has supported their use in the past, evidence in the literature is deficient in this area and because of this, these are mentioned from a historical perspective. Pretreatment medications are typically administered 2-3 minutes prior to induction and paralysis. These medications can be remembered by using the mnemonic LOAD (ie, Lidocaine, Opioid analgesic, Atropine, Defasciculating agents). - Lidocaine (1.5 mg/kg IV) may suppress the cough or gag reflex experienced during laryngoscopy and has been considered to play a role in blunting increases in mean arterial pressure (MAP), heart rate (HR), and intracranial pressure (ICP). For this reason, it is commonly administered to patients with suspected intracranial hemorrhage, tumor, or any other process that may result in increased ICP, and it may be considered as part of RSI for patients in whom increased MAP could be harmful (eg, leaking aortic aneurysm). However, studies do not consistently demonstrate the effectiveness of lidocaine for these indications in patients in the emergency department (ED), and, based on this lack of evidence, a statement regarding its absolute indication cannot be made. , , , , , , , , , ] - Opioid analgesic (fentanyl 3 mcg/kg IV) mitigates the physiologic increase in sympathetic tone associated with direct laryngoscopy (ie, blunts increases in blood pressure, heart rate, and mean arterial pressure). One author recommends this in patients with suspected high ICP, , , ] though some data also suggest that these agents may increase ICP. , , , , , ] Opioid analgesics may also be useful in patients with an aortic emergency (eg, aortic dissection or leaking aortic aneurysm) in whom blood pressure spikes should be avoided. At this time, no conclusive evidence supports the use of opioids in RSI. - Atropine (0.02 mg/kg IV) may decrease the incidence of bradydysrhythmia associated with direct laryngoscopy (stimulation of parasympathetic receptors in the laryngopharynx) and administration of succinylcholine (direct stimulation of cardiac muscarinic receptors). Previous recommendations indicated that all children younger than 10 years receive atropine prior to intubation, but this has fallen out of favor because of the lack of supporting data. Even if bradydysrhythmias occur, they are usually self-limited and clinically nonrelevant. However, atropine should be available in case a clinically significant decrease in heart rate occurs. Because of the increase in cardiac vagal tone, atropine can be considered for use in children younger than 1 year and should at least be at the bedside in this age group. , ] - Some evidence indicates that bradycardia can occur equally with or without atropine during intubation. , ] Atropine can also be used in adolescents and adults for symptomatic bradycardia. - A "defasciculating" dose of a nondepolarizing agent may reduce the duration and intensity of muscle fasciculations observed with the administration of succinylcholine (due to the stimulation of nicotinic acetylcholine receptors). The recommended dose is 10% of the paralyzing dose (eg, 0.01 mg/kg for vecuronium). Equivocal studies suggest such pretreatment may help reduce increases in intracranial pressure related to the procedure. - The crux of RSI is to take the awake patient, with an assumed full stomach, and very quickly induce a state of unconsciousness and paralysis and securing the airway. This is done without positive pressure ventilation, if possible. ## Induction Induction agents provide a rapid loss of consciousness that facilitates ease of intubation and avoids psychic harm to the patient. - Etomidate (Amidate) (0.3 mg/kg IV) - Rapid onset, short duration, cerebroprotective, and not associated with significant drop in blood pressure; hemodynamically neutral compared with other agents, such as sodium thiopental. Induces a transient decrease in cortisol levels as high as 86% in some studies. However, properly powered prospective studies are needed to validate this more theoretical phenomenon. Note cortisol levels are affected by severe illness independently of the induction agent used. Critical illness‒related corticosteroid insufficiency occurs in 10-20% of critically ill medical patients and as high as 60% in severe sepsis and septic shock. , ] Most common agent used in the United States. - Ketamine (Ketalar) (1-2 mg/kg IV) - "Dissociative" state, analgesic properties, bronchodilator, may decrease rather than increase intracranial pressure. Consider for patients with asthma or anaphylactic shock; possibly avoid in patients with suspected or known aortic dissection or abdominal aortic aneurysm and in patients with acute myocardial infarction. The general teaching has also been to avoid use of ketamine in patients in whom increased ICP is a concern; in particular, trauma patients with evidence of head injury. However, a review of recent literature supports its use in this scenario as the hemodynamic stimulation induced by ketamine may, in fact, improve cerebral perfusion and prevent secondary penumbra ischemia. Furthermore, in the laboratory, ketamine seems to have neuroprotective properties. , , ]Because of its positive hemodynamic effects and etomidate’s known tendency to transiently decrease cortisol levels, ketamine is being used more frequently as an induction agent. - Propofol (Diprivan) (2 mg/kg IV) - Rapid onset, short duration, cerebral protective. However, propofol is a myocardial depressant and also decreases systemic vascular resistance. - Midazolam (Versed) (0.3 mg/kg IV) - Slower onset (2-3 min without opioid pretreatment) and longer duration (up to several hours) than etomidate. A study by Sagarin et al from a national airway registry demonstrated that midazolam is usually underdosed when used for RSI, presumably because of the concern for hypotension. null 3 Note that the induction dose is about 20 mg for a 70-kg person. Use of midazolam as an induction agent is not recommended because of its delayed time to induction, predilection for hypotension at induction doses, and prolonged duration of action. ## Paralysis Paralyzing agents provide neuromuscular blockade and are administered immediately after the induction agent. Neuromuscular blockade does not provide sedation, analgesia, or amnesia; thus, administering a potent induction agent is important. - Depolarizing neuromuscular blocker (eg, succinylcholine at 2 mg/kg IV or 4 mg/kg IM): Rapid onset (45-60 sec) and shortest duration of action (8-10 min). Should be used with caution in patients with known or suspectedhyperkalemia and those with chronic neuromuscular disease. - Zink's 1995 prospective study of 100 patients in the ED undergoing RSI did not find a change in serum potassium level from before to after RSI with succinylcholine. Exclusion criteria were minimal; a limitation was that postintubation potassium level was checked at only 1 time interval (5 min). - Nondepolarizing neuromuscular blocker (NMB) (eg, rocuronium at 1-1.2 mg/kg IV): Slightly longer onset of action (60-75 sec) than succinylcholine and longer duration of action (30-60 min). Use with caution in patients in whom difficult intubation is possible. Does not result in muscle depolarization or defasciculation and does not exacerbate hyperkalemia. Sugammadex is a new NMB reversal agent that has been shown to be safe and effective for reversal of neuromuscular blockade induced by nondepolarizing agents. Reversal occurs at 1.5 minutes with a dose of 16 mg/kg and at 3 minutes with a dose of 4 mg/kg. It has been shown to induce full reversal of such agents faster than succinylcholine’s normal metabolic breakdown and for the first time in over 50 years offers a safe alternative and viable option for emergent RSI. # Procedure In cases of trauma in which cervical spine injury is suspected and not yet ruled out, intubation must be performed without movement of the head. Immobilization is best provided by an experienced assistant. In cases in which cervical injury is not a concern, proper head positioning greatly improves visualization. - In the neutral position, the oral, pharyngeal, and laryngeal axes are not aligned to permit adequate visualization of the glottic opening (see images below). Proper alignment of the axes for tracheal intubation. - Three-axis theory. OA is oral axis, PA is pharyngeal axis, and LA is laryngeal axis. Used with permission from Springer Publishing Company. - Place the patient in the sniffing position for adequate visualization; flex the neck and extend the head. This position helps to align the axes and facilitates visualization of the glottic opening. - Studies have shown that simple head extension alone (without neck flexion) was as effective as the sniffing position in facilitating endotracheal intubation. ## Difficult Airway Assessment Several methods exist to quickly assess the probability of success during tracheal intubation. One tool for rapid assessment is the LEMON law, as described below. A patient in extremis may not be able to cooperate with all the sections of the LEMON assessment. ## L: Look externally Assessing the difficulty of an airway based on external physical features is not sensitive (not all patients who have a difficult airway appear to have a difficult airway prior to intubation) but is quite specific (most patients who appear to have a difficult airway do indeed have a difficult airway). Physical features such as a small mandible, large tongue, and short bull neck are all red flags for a difficult airway. ## E: Evaluate the 3-3-2 rule The chance for success is increased if the patient is able to insert 3 of his or her own fingers between the teeth, can accommodate 3 finger breadths between the hyoid bone and the mentum, and is able to fit 2 finger breadths between the hyoid bone and the thyroid cartilage. ## M: Mallampati classification The Mallampati assessment is ideally performed when the patient is seated with the mouth open and the tongue protruding without phonating. In many patients intubated for emergent indications, this type of assessment is not possible. A crude assessment can be performed with the patient in the supine position to gain an appreciation of the size of the mouth opening and the likelihood that the tongue and oropharynx may be factors in successful intubation. ## O: Obstruction Obstruction of the upper airway is a marker for a difficult airway. Three signs of upper airway obstruction are difficulty swallowing secretions (secondary to pain or obstruction), stridor (an ominous sign which occurs when < 10% of normal caliber of airway circumference is clear), and a muffled (hot-potato) voice. ## N: Neck mobility The inability to move the neck affects optimal visualization of the glottis during direct laryngoscopy. Cervical spine immobilization in trauma (with a C-collar) can compromise normal mobility, as can intrinsic cervical spine immobility due to medical conditions such as ankylosing spondylitis or rheumatoid arthritis. ## Preparation - Confirm that intubation equipment is functional. - Assess the patient for difficult airway (see Difficult Airway Assessment section below for recommended method). If the patient meets criteria for difficult airway, rapid sequence intubation (RSI) may be inappropriate. Nonparalysis procedures may be an alternative. The assistance of anesthesia personnel may be warranted. - Establish intravenous access. - Draw up essential drugs and determine sequence of administration (induction agent immediately followed by paralytic agent). - Review possible contraindications to medications. - Attach necessary monitoring equipment. - Check endotracheal (ET) tube cuff for leak. - Ensure functioning light bulb on laryngoscope blade. ## Preoxygenation Administer 100% oxygen via a nonrebreather mask for 3 minutes for nitrogen washout. This is done without positive pressure ventilation using a tight seal. Though rarely possible in the emergent situation, the patient can take 8 vital capacity (as deep as possible) breaths of 100% oxygen. Studies have shown this can prevent apnea-induced desaturation for 3-5 minutes. null 45 Assist ventilation with bag-valve-mask (BVM) system only if needed to obtain oxygen saturation =90%. ## Pretreatment Consider administration of drugs to mitigate the adverse effects associated with intubation. See Anesthesia for more information. ## Paralysis with induction Administer a rapidly-acting induction agent to produce loss of consciousness. Administer a neuromuscular blocking agent immediately after the induction agent. These medications should be administered as an intravenous push. ## Protection and positioning Though clinical dogma dictates that the Sellick maneuver (firm pressure over the cricoid cartilage to compress the proximal esophagus) be initiated to prevent regurgitation of gastric contents, literature is lacking in support of this technique and in fact may impede laryngeal view. Initiate this maneuver upon observing the beginning of unconsciousness. Maintain pressure throughout intubation sequence until the position of the ET tube is verified. Note that proper laryngeal view has been shown to be best accomplished by the bimanual method and should be used if the Sellick maneuver fails to show the vocal cords. Classical teaching dictates that cricoid pressure decreases the risk of gastric regurgitation into the lungs. However, in a study by Smith et al, the esophagus was partially lateral to the trachea in more than 50% of the subjects. null 46 Also, in an ultrasound study, 29 of 33 esophagi were partially displaced to the left of the trachea. null 47 In a meta-analysis, Butler and Sen showed that little evidence supports the notion that cricoid pressure decreases the risk of aspiration in RSI. null 9 ## Placement with proof Visualize the ET tube passing through the vocal cords. Confirm tube placement. - Observe color change on a qualitative end-tidal carbon dioxide device or utilize a continuous end-tidal carbon dioxide (ET-CO2) monitor. - Use the 5-point auscultation method: Listen over each lateral lung field, the left axilla, and the left supraclavicular region for good breath sounds. No air movement should occur over the stomach. - Two pilot studies have shown that ultrasonography can reliably detect passage of a tracheal tube into either the trachea or esophagus without inadvertent ventilation of the stomach. , ] See the image panel below. Left panel: Bedside ultrasound of anterior neck for proper detection of the endotracheal tube before positive-pressure ventilation is applied. Middle panel: Proper placement of the endotracheal tube in the trachea as the esophagus is normally not visualized. Right panel: Misplacement of the endotracheal tube in the left-sided esophagus. Used with permission from Springer Publishing Company. # Postprocedure ## Postintubation management Secure the ET tube into place. Initiate mechanical ventilation. Obtain a chest radiograph. - Assess pulmonary status. - Note this modality does not confirm placement; rather, it assesses the height above the carina. - Ensure that mainstem intubation has not occurred. Administer appropriate analgesic and sedative agents for patient comfort, to decrease O2 demand, and to decrease ICP. ## Video-assisted laryngoscopy (VAL) VAL offers the advantage of abandoning the need for alignment of the optical axes in the mouth, pharynx, and larynx in order to visualize the entrance of the glottis and therefore is more effective. Unfortunately, standard ETTI via DL, performed by untrained medical personnel and those who perform it only occasionally, carries a high risk of failure. In several studies looking at the success rate of ETTI via DL performed by medical support staff, medical students, and novice anesthesia residents, the initial success rate varied between 35% and 65%. It has been shown that in order to improve the success rate of DL to over 90%, one would require about 47-56 intubations. null 49 In stark contrast, VAL has been shown to be easily learned and highly successful with minimal training necessary. A prospective trial compared 37 novice residents in VAL versus DL and found that the former yielded a 14% higher success rate and 14% fewer esophageal intubations. null 50 Nouruzi-Sedeh et al evaluated medical personnel with no prior experience in ETTI (paramedic students, nurses, and medical students) and after a brief didactic/manikin session compared their laryngoscopy skills in the operating room between VAL and DL. As in many other similar studies, they showed that VAL led to a significantly higher success rate (93%) compared with DL (51%) in nonphysicians with no prior laryngoscopy experience. Subjects were also noted to have a dramatic improvement after only five ETTIs; they neared a 100% success rate using VAL. null 51 A meta-analysis looked at VAL compared with DL in 17 trials with 1,998 patients. The pooled relative risk for nondifficult intubations was 1.5 and for difficult intubations was 3.5; the authors concluded that VAL improves glottic visualization, particularly in patients with potentially difficult airways. null 52 Set up for video-assisted laryngoscopy. Used with permission from Springer Publishing Company. Video demonstration of the ease of video-assisted laryngoscopy in aligning the oral, pharyngeal, and laryngeal airway axis and glottic view. Used with permission from Springer Publishing Company. Glottic view via video-assisted laryngoscopy. Used with permission from Springer Publishing Company. # Tracheal Tube Maintenance The tube is secured in place with tape or an endotracheal tube holder. A cervical collar is sometimes used to prevent motion of the airway. Tube placement should be confirmed after each physical move of the patient and after any unexplained change in his/her clinical status. Continuous pulse oximetry and continuous waveform capnography are often used to monitor the tube's correct placement. The cuff pressure must be monitored carefully in order to avoid complications from over-inflation, which can include tracheomalacia, tracheoesophageal fistula, or even frank rupture of the trachea. Many of the complications of over-inflated cuffs can be traced to excessive cuff pressure causing ischemia of the tracheal mucosa. An excessive leak can sometimes be corrected through the placement of a larger (0.5 mm larger in internal diameter) endotracheal tube, and in difficult-to-ventilate pediatric patients children it is often necessary to use cuffed tubes to allow for high pressure ventilation if the leak is too great to overcome with the ventilator. # Special Situations ## Emergency Intubation Personnel experienced in direct laryngoscopy are not always immediately available in certain settings that require emergency tracheal intubation. For this reason, specialized devices have been designed to act as bridges to a definitive airway. Such devices include the laryngeal mask airway, cuffed oropharyngeal airway, and the Combitube. Other devices such as rigid stylets, the lightwand (a blind technique) and indirect fiberoptic rigid stylets, such as the Bullard scope, Upsher scope, and the WuScope can also be used as alternatives to direct laryngoscopy. Each of these devices have its own unique set of benefits and drawbacks, and none of them is effective under all circumstances. ## Difficult Intubation Many individuals have unusual airway anatomy, such as those who have limited range of motion of the cervical spine or temporomandibular joint, or who have oropharyngeal tumors, hematomas, angioedema, micrognathia, retrognathia, or excess adipose tissue of the face and neck. Using conventional laryngoscopic techniques, intubation of the trachea can be difficult in such people. Use of the flexible fiberoptic bronchoscope and similar devices has become among the preferred techniques in the management of such cases. Among the drawbacks of these devices are their high cost of purchase, maintenance and repair. Another drawback is that intubation with one of these devices can take considerably longer than that achieved using conventional laryngoscopy; this limits their use somewhat in urgent and emergent situations. ## Rapid Sequence Intubation Rapid-sequence intubation (RSI) refers to the method of sedation and paralysis prior to tracheal intubation. This technique is quicker than the process normally used to induce a state of general anesthesia. One important difference between RSI and routine tracheal intubation is that the practitoner does not ventilate the lungs after administration of a rapid-acting neuromuscular blocking agent. Another key feature of RSI is the application of manual pressure to the cricoid cartilage (this is referred to as the Sellick maneuver) prior to instrumentation of the airway and intubation of the trachea. RSI involves pre-oxygenating the patient with a tightly-fitting oxygen mask, followed by the sequential administration of pre-determined doses of a hypnotic drug and a rapid-acting neuromuscular blocker. Hypnotics used include thiopental, propofol and etomidate. Neuromuscular-blocking drugs used include suxamethonium (sometimes with a defasciculating dose of vecuronium) and rocuronium. Other drugs may be used in a "modified" RSI. When performing endotracheal intubation, there are several adjunct medications available. No adjunctive medications, when given for their respective indications, have been proven to improve outcomes. Opioids such as alfentanil or fentanyl may be given to attenuate the responses to the intubation process (tachycardia and raised intracranial pressure). This is supposed to have advantages in patients with ischemic heart disease and those with intra-cerebral hemorrhage (e.g. after traumatic head injury or stroke). Lidocaine is also theorized to blunt a rise in intracranial pressure during laryngoscopy, although this remains controversial and its use varies greatly. Atropine may be used to prevent a reflex bradycardia from vagal stimulation during laryngoscopy, especially in young children and infants. This procedure is usually performed by an anesthesiologist or CRNAs (certified registered nurse anesthetists) in surgery, by respiratory therapists in multiple settings, and by medical personnel in the emergency department. It may also be performed in the prehospital setting by persons trained to the EMT-Intermediate or paramedic level, including flight medics and flight nurses. Another alternative is intubation of the awake patient under local anesthesia using a flexible endoscope or by other means (e.g., using a video laryngoscope). This technique is preferred if difficulties are anticipated, as it allows the patient to breathe spontaneously throughout the procedure, thus ensuring ventilation and oxygenation even in the event of a failed intubation. Some alternatives to intubation are - Tracheotomy - a surgical technique, typically for patients who require long-term respiratory support - Cricothyrotomy - an emergency technique used when intubation is unsuccessful and tracheotomy is not an option. Because the life of a patient can depend on the success of an intubation, it is important to assess possible obstacles beforehand. The ease of intubation is difficult to predict. One score to assess anatomical difficulties is the Mallampati score, which is determined by looking at the anatomy of the mouth and based on the visibility of the base of uvula, faucial pillars and the soft palate. It should however be noted that no single score or combination of scores can be trusted to detect all patients who are difficult to intubate. Therefore, persons performing intubation must be familiar with alternative techniques of securing the airways. ## Pediatric Patients Most of the general principles of anesthesia can be applied to children, but there are some significant anatomical and physiological differences between children and adults that can cause problems, especially in neonates and children weighing less than 15 kg. For infants and young children, oral intubation is easier than nasal. Nasal route carries risk of dislodgement of adenoid tissue and epistaxis, but advantages include good fixation of tube. Because of good fixation, nasal route is preferable to oral route in children undergoing intensive care and requiring prolonged intubation. The position of the tube is checked by auscultation (equal air entry on each side and, in long-term intubation, by chest X-ray). Because the airway of a child is narrow, a small amount of oedema can produce severe obstruction. Edema can easily be caused by forcing in a tracheal tube that is too tight. (If length of the tube is suspected to be large, immediate changing it to the smaller size is suggestible.) The appropriate length for the endotracheal tube can be estimated by doubling the distance from the corner of the child's mouth to the ear canal. The tip of the tube should be at midtrachea, between the clavicles on an AP chest X-ray. The correct diameter of the tube is that which results in a small leak at a pressure of about 25 cm of water. The appropriate inner diameter for the endotracheal tube is roughly the same diameter as the child's little finger. For normally nourished children 2 years of age and older, the internal diameter of the tube can be calculated using the following formula: - Internal diameter of tube (mm) = (patient's age in years + 16) / 4 For neonates, 3 mm internal diameter is accepted while for premature infants 2.5 mm internal diameter is more appropriate. # Complications - Esophageal intubation - Iatrogenic induction of an obstructive airway - Right mainstem intubation - Pneumothorax - Dental trauma - Postintubation pneumonia - Vocal cord avulsion - Failure to intubate - Hypotension - Aspiration Tracheal intubation is potentially a very dangerous invasive procedure that requires a great deal of clinical experience to master. When performed improperly (e.g., unrecognized esophageal intubation), the associated complications may rapidly lead to the patient's death. Consequently, in recent editions of its Guidelines for Cardiopulmonary Resuscitation the American Heart Association has de-emphasized the role of tracheal intubation in advanced airway maintenance, in favor of more basic techniques like bag-valve-mask ventilation. Despite these concerns, tracheal intubation is still considered the definitive technique for airway management, as it allows the most reliable means of oxygenation and ventilation, while providing the highest level of protection against vomitus and regurgitation. Although the conventional laryngoscope has proven effective across a wide variety of settings and patients, its use and misuse can result in serious complications (e.g., trauma to oropharyngeal and dental structures). Newer technologies such as flexible fiberoptic laryngoscopy have fared better in reducing the incidence of such complications, though the most common cause of intubation trauma remains a lack of skill on the part of the laryngoscopist. # Related Chapters - Bronchoscopy - Cricothyrotomy - Jet ventilation - Mechanical ventilation - Positive end-expiratory pressure - Positive pressure ventilation - Tracheobronchial injury - Tracheotomy	Intubation Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Umar Ahmad, M.D.[2] Synonyms and keywords: Intubate, Endotracheal intubation, Tracheal intubation # Overview Intubation (sometimes entubation) is a medical procedure involving the insertion of a tube into the body. Patients are generally anesthetized beforehand. Examples include tracheal intubation, and the balloon tamponade with a Sengstaken-Blakemore tube (a tube into the gastrointestinal tract). The most common intubation is tracheal intubation. The most common route for tracheal intubation is orotracheal where an endotracheal tube is passed from the oropharynx to the trachea. A bulb is then inflated near the distal tip of the tube to help secure it in place and protect the airway from blood, gastric contents and other secretions. Removal of the tube is referred to as extubation of the trachea. # Types Intubation can exist in various forms. The following are some types of intubation that can occur: - Endotracheal intubation- This is broad term that encompasses a tube going from the oropharynx to the trachea. This can be further subdivided into two other categories such as Nasotracheal intubation and Orotracheal intubation. Orotracheal intubation- This is a type of intubation in which the tube goes in through the oral cavity to the trachea. Nasotracheal intubation- This is a type of intubation in which the tube goes in through the nasal cavity to the trachea. - Orotracheal intubation- This is a type of intubation in which the tube goes in through the oral cavity to the trachea. - Nasotracheal intubation- This is a type of intubation in which the tube goes in through the nasal cavity to the trachea. - Orogastric intubation - Nasogastric intubation - Fiberoptic intubation - Surgical Airway Tracheostomy Cricothyroidotomy - Tracheostomy - Cricothyroidotomy # Historical Perspective ## BC - 3600 BC- The earliest known depiction of a tracheotomy is found on two Egyptian tablets dating back to around 3600 BC. - 2000 BC- Tracheotomy was described in the Rigveda, a Sanskrit text of ayurvedic medicine written around 2000 BC in ancient India. - 1550 BC- The 110-page Ebers Papyrus, an Egyptian medical papyrus which dates to roughly 1550 BC, also makes reference to the tracheotomy. - 400 BC- The Sushruta Samhita from around 400 BC is another text from the Indian subcontinent on ayurvedic medicine and surgery that mentions tracheotomy. - 124–40 BC- Asclepiades of Bithynia (c. 124–40 BC) is often credited as being the first physician to perform a non-emergency tracheotomy. ## 1st Century - 129–199 AD- Galen of Pergamon (AD 129–199) clarified the anatomy of the trachea and was the first to demonstrate that the larynx generates the voice. In one of his experiments, Galen used bellows to inflate the lungs of a dead animal. ## 9th Century - 1025- Ibn Sīnā (980–1037) described the use of tracheal intubation to facilitate breathing in 1025 in his 14-volume medical encyclopedia, The Canon of Medicine. - 1092–1162- In the 12th century medical textbook Al-Taisir, Ibn Zuhr (1092–1162)—also known as Avenzoar—of Al-Andalus provided a correct description of the tracheotomy operation. ## 14th Century - 1543- The first detailed descriptions of tracheal intubation and subsequent artificial respiration of animals were from Andreas Vesalius (1514–1564) of Brussels. In his landmark book published in 1543, De humani corporis fabrica, he described an experiment in which he passed a reed into the trachea of a dying animal whose thorax had been opened and maintained ventilation by blowing into the reed intermittently. The next known report on tracheal intubation and subsequent artificial respiration of animals is when Andreas Vesalius pointed out that the technique could be life-saving. This report remained unnoticed for more than 250 years. - 1546- Antonio Musa Brassavola (1490–1554) of Ferrara successfully treated a patient suffering from peritonsillar abscess by tracheotomy. Brassavola published his account in 1546; this operation has been identified as the first recorded successful tracheotomy, despite the many previous references to this operation. ## 15th Century - 1620- In 1620 the French surgeon Nicholas Habicot (1550–1624) published a report of four successful tracheotomies. ## 16th Century - 1533–1619- Towards the end of the 16th century, Hieronymus Fabricius described a useful technique for tracheotomy in his writings, although he had never actually performed the operation himself. - 1714- In 1714, anatomist Georg Detharding (1671–1747) of the University of Rostock performed a tracheotomy on a drowning victim. ## 19th Century - In 1805, Philip Bozzini used a device he invented and called the lichtleiter (or light-guiding instrument) to examine the human urinary bladder, rectum and pharynx. The practice of gastric endoscopy in humans was pioneered by U.S. Army surgeon William Beaumont - in 1822 with the cooperation of his patient Alexis St. Martin, a victim of an accidental gunshot wound to the stomach.[1] - In 1853, Antoine Jean Desormeaux of France examined the human bladder using a device he invented and called the endoscope (this was the first time this term was applied to this practice). - In 1868, Adolph Kussmaul of Germany performed the first esophagogastroduodenoscopy on a living human. The subject was a sword-swallower, who swallowed a metal tube with a length of 47 centimeters and a diameter of 13 millimeters. - In 1869, the German surgeon Friedrich Trendelenburg documented successful human tracheotomy for administration of general anesthesia. - In 1878, the Scottish surgeon William Macewen performed the first orotracheal intubation. - In 1878, Maximilian Nitze and Josef Leiter invented the cystourethroscope and - in 1881, Jan Mikulicz-Radecki created the first rigid gastroscope for practical applications. - On 23 April 1895, Alfred Kirstein performed the first direct laryngoscopy in Berlin, Germany, using an esophagoscope he had modified for this purpose.[2] ## 20th Century - In 1919's, German otolaryngologist Dr. Franz Kuhn developed a flexometallic tube that resisted kinking and could be shaped to the patient's upper airway anatomy. Like O'Dwyer's tubes, it was inserted using blind digital technique. The patients were intubated awake and the hypopharynx was sealed with oiled gauze packing. - During World War I, Sir Ivan Magill and Robert Macintosh achieved significant advances in techniques for tracheal intubation. The Magill curve of an endotracheal tube and the Magill forceps for positioning the tube during nasotracheal intubation are named after Magill, while the most widely used curved laryngoscope blade is named after Macintosh. - In 1937, Leech introduced a "pharyngeal bub gasway" with a noninflatable cuff that fit snug into the hypopharynx. - In 1932, Rudolph Schindler of Germany introduced the first semi-flexible gastroscope. This device had numerous lenses positioned throughout the tube and a miniature light bulb at the distal tip. The tube of this device was 75 centimeters in length and 11 millimeters in diameter, and the distal portion was capable of a certain degree of flexion. - In 1939 to 1945, During World War II the shift of mask airways to tracheal intubations occured for most surgical procedures. - Between 1945 and 1952, optical engineers (notably Karl Storz of Germany, Harold Hopkins of England, and Mutsuo Sugiura of the Japanese Olympus Corporation) built upon this early work, leading to the development of the first gastrocamera. - In 1951, Succinylcholine helped dominate the area of tracheal intubation as it was faster and muscle relaxation was easier to achieve. - In 1964, Fernando Alves Martins of Portugal applied optical fiber technology to one of these early gastrocameras to produce the first gastrocamera with a flexible fiberscope. Initially used in esophagogastroduodenoscopy (EGD), newer devices were developed in the early 1970s for use in bronchoscopy, rhinoscopy, and laryngoscopy. - By the mid-1980s, the flexible fiberoptic bronchoscope had become an indispensable instrument within the pulmonology and anesthesia communities. ## 21st Century - The Digital Revolution has brought newer technology to the art and science of tracheal intubation. Several manufacturers have developed video laryngoscopes which employ digital technology such as the CMOS active pixel sensor (CMOS APS) to generate a view of the glottis so that the trachea may be intubated. The Glidescope video laryngoscope is one example of such a device. # Indication A definitive airway (orotracheal, nasotracheal, cricothyrotomy, or tracheotomy) is indicated under any of the following circumstances: Failure to maintain airway tone - Stab wound to neck with expanding hematoma - Swelling of upper airway as in anaphylaxis or infection - Facial or neck trauma with oropharyngeal bleeding Decreased consciousness and loss of airway reflexes - Comatose or intoxicated patients with a depressed level of consciousness who are unable to protect their airways. This is commonly defined as those subjects with a Glasgow Coma Scale ≤ 8. In such cases, the throat muscles may lose their tone so that the hypopharynx becomes obstructed, impeding the free flow of air into the lungs. Furthermore, protective airway reflexes such as coughing and swallowing, which serve to protect the airways against aspiration of secretions and foreign bodies, may be absent. With tracheal intubation, airway patency is restored and the lower airways can be protected from aspiration - Cervical spine fracture with concern for edema and loss of airway patency - Intracranial hemorrhage with altered mental status and need for close blood pressure control - Failure to protect airway against aspiration - Decreased consciousness that leads to regurgitation of vomit, secretions, or blood Failure to ventilate - Requirement for mechanical ventilation, including cardiopulmonary resuscitation and general anesthesia. In such situations, spontaneous ventilation may be decreased or absent due to the effect of injury, disease, anesthetic agents, opioids, or neuromuscular-blocking drugs. To enable mechanical ventilation, an endotracheal tube is often used, although there are alternative devices such as the laryngeal mask airway or the CPAP mask. - Diagnostic or therapeutic manipulation of the airway (such as bronchoscopy, laser therapy or stenting of the bronchi) - Persistent or recurrent airway obstruction - Prolonged respiratory effort that results in fatigue or failure, as in status asthmaticus or severe COPD Failure to oxygenate (ie, transport oxygen to pulmonary capillary blood) - Apnea or hypoventilation (e.g., closed head injury, intoxication or poisoning, cervical spine injury, flail chest) - Septic shock with high minute-ventilation and poor peripheral perfusion - End result of failure to maintain and protect airway or failure to ventilate - Diffuse pulmonary edema - Large pneumonia or air-space disease - acute respiratory distress syndrome (ARDS), - Near-drowning - Pulmonary embolism - Cyanide toxicity, carbon monoxide toxicity, methemoglobinemia # Contraindications ## Absolute - Total upper airway obstruction, which requires a surgical airway - Total loss of facial/oropharyngeal landmarks, which requires a surgical airway ## Relative Anticipated "difficult" airway, in which endotracheal intubation may be unsuccessful, resulting in reliance on successful bag-valve-mask (BVM) ventilation to keep an unconscious patient alive - In this scenario, techniques for awake intubation and difficult airway adjuncts can be used. - Multiple methods can be used to evaluate the airway and the risk of difficult intubation (eg, LEMON rule, 3-3-2, Mallampati class, McCormack and Lehane grade). Please refer to the Difficult Airway Assessment section below for details. The "crash" airway, in which the patient is in an arrest situation, unconscious and apneic - In this scenario, the patient is already unconscious and may be flaccid; further, no time is available for preoxygenation, pretreatment, or induction and paralysis. - BVM ventilation, intubation, or both should be performed immediately without medications. # Equipment Equipment includes the following: - Laryngoscope Laryngoscope handle, No. 3 Macintosh (curved) blade, and No. 3 Miller (straight) blade. Confirm that light source is functional prior to intubation. A 2010 study demonstrated that single-use metal laryngoscope blades resulted in a lower failed intubation rate than did reusable metal blades.null 13 - Confirm that light source is functional prior to intubation. - A 2010 study demonstrated that single-use metal laryngoscope blades resulted in a lower failed intubation rate than did reusable metal blades.null 13 - Endotracheal (ET) tube - Stylet - Syringe, 10 mL (to inflate ET tube balloon) - Suction catheter (eg, Yankauer) - Carbon dioxide detector (eg, Easycap) - Oral and nasal airways - Ambu bag and mask attached to oxygen source - Nasal cannula ## Laryngoscopes The vast majority of "noninvasive" tracheal intubations involve the use of a viewing instrument or "scope" of one type or another. Since its introduction by Kirstein in 1895, the most common device used for this purpose has been the conventional laryngoscope. Today, the typical conventional laryngoscope consists of a handle, usually containing batteries, and a set of interchangeable blades. Two basic styles of laryngoscope blade are commercially available: the straight blade and the curved blade. The Macintosh blade is the most widely used of the curved laryngoscope blades, while the Miller blade is the most popular style of straight blade. There are many other styles of straight and curved blades, with accessories such as mirrors for enlarging the field of view and even ports for the administration of oxygen. These specialty blades are primarily designed for use by anesthetists, most commonly in the operating room. Besides the conventional laryngoscopes, many devices have been developed as alternatives to direct laryngoscopy. These include a number of indirect fiberoptic viewing laryngoscopes such as the flexible fiberoptic bronchoscope, Bullard scope, UpsherScope,[3] and the WuScope. These devices are widely employed for tracheal intubation, especially in the setting of the difficult intubation (see below). Several types of video laryngoscopes are also currently available (e.g., Glidescope, McGrath laryngoscope, Daiken Medical Coopdech C-scope vlp-100, the Storz C-Mac, Pentax AWS and the Berci DCI). Other noninvasive devices which are commonly employed for tracheal intubation are the laryngeal mask airway (used as a guide for tracheal tube placement), the lighted stylet, and the AirTraq. Due to the widespread availability of such devices, the technique of blind digital intubation of the trachea is rarely practiced today, though it may still be useful in emergency situations under austere conditions such as natural or man-made disasters. ## Stylets A stylet is a malleable metal wire which can be inserted into the endotracheal tube to make the tube conform better to the laryngopharyngeal anatomy of the specific individual, thus facilitating its insertion. It is commonly employed under circumstances of difficult laryngoscopy. The Eschmann stylet or gum elastic bougie is a specialized type of stylet, which can also be used for difficult laryngoscopy or for removal and replacement of tracheal tubes without the need for laryngoscopy. ## Tracheal Tubes Most tracheal tubes today are constructed of polyvinyl chloride, but specialty tubes constructed of silicone rubber, latex rubber, or stainless steel are also widely available. Most tubes have an inflatable cuff to seal the trachea and bronchial tree against air leakage and aspiration of gastric contents, blood, secretions, and other fluids. Uncuffed tubes are also available, though their use is limited mostly to pediatric patients (in small children, the cricoid cartilage, the narrowest portion of the pediatric airway, often provides an adequate seal for mechanical ventilation). The "armored endotracheal tube" is a cuffed, wire-reinforced, silicone rubber tube which is quite flexible but yet difficult to compress or kink. This can make it useful for situations in which the trachea is anticipated to remain intubated for a prolonged duration, or if the neck is to remain flexed during surgery. Polyvinyl chloride tubes are relatively stiff in comparison. Preformed tubes (such as the oral and nasal RAE tubes, named after the inventors Ring, Adair and Elwyn) are also widely available for special applications. These may also be constructed of polyvinyl chloride or wire-reinforced silicone rubber. Other tubes (such as the Bivona® Fome-Cuf® tube) are designed specifcally for use in laser surgery in and around the airway. Various types of double-lumen endotracheal tubes have been developed (Carlens, Robertshaw, etc.) for ventilating each lung independently—this is useful during pulmonary and other thoracic operations. ## Observational Methods to Confirm Tube Placement - Direct visualization of the tube passing through the vocal cords - Clear and equal bilateral breath sounds on auscultation of the chest - Absent sounds on auscultation of the epigastrium - Equal bilateral chest rise with ventilation - Fogging of the tube - An absence of stomach contents in the tube ## Instruments to Confirm Tube Placement No single method for confirming tracheal tube placement has been shown to be 100% reliable. Accordingly, the use of multiple methods to confirm correct tube placement is now widely considered to be the standard of care. At least one of the methods utilized should be an instrument. Waveform capnography has emerged as the gold standard for the confirmation of correct tube placement and maintenance of the tube once it is in place. Other methods include: - Colorimetric end tidal carbon dioxide detector - Self-inflating esophageal bulb - Pulse oximetry (important limitations include a significant delay in the decrease in oxygen saturation, especially if subject has been pre-oxygenated) - Esophageal Detection Device[4] # Predicting Ease of Intubation - Look externally (history of craniofacial traumas/previous surgery) - Evaluate 3,3,2 - three of the subject's fingers should be able to fit into his/her mouth when open, three fingers should comfortably fit between the chin and the throat, and two fingers in the thyromental distance (distance from thyroid cartilage to chin) - Mallampati score - Obstructions (stridorous breath sounds, wheezing, etc.) - Neck mobility (can subject tilt head back and then forward to touch chest) - Cormack-Lehane grading system (according to the percentage of glottic opening on laryngoscopy) # Preprocedure ## Anesthesia Rapid sequence intubation (RSI) is predicated on the administration of medications in a specific sequence. The two phases of medication administration are induction and paralysis. In general, preoxygenation is carried out while medications are being drawn up. ## Preoxygenation Preoxygenation with high-flow oxygen via a nonrebreather mask for 3-5 minutes leading up to intubation results in supersaturation of oxygen in the alveoli by way of displacement of nitrogen (nitrogen washout). This allows the patient to maintain blood oxygen saturation during the apneic period of paralysis and allows the physician more time to successfully intubate. In healthy adult volunteers who have been preoxygenated for 3-5 minutes, the average time to desaturation (oxygen saturation <90%) is approximately 8 minutes. This time is significantly shorter in patients who are critically ill and have a much higher metabolic demand for oxygen. null 1 Use the least assistance necessary to obtain good oxygen saturation and adequate preoxygenation (see Technique section below). - High-flow oxygen via nonrebreather mask may be appropriate for a patient with good respiratory effort. - High-flow oxygen via well-fitting bag-valve-mask (BVM) without additional positive pressure (ie, squeezing the bag) may be needed for those with more respiratory compromise. - High-flow oxygen via BVM with positive pressure assistance (squeezing the bag) is used only when necessary. ## Apneic oxygenation Because pulmonary blood flow is still occurring during the apneic period of ETT placement, oxygen is continually being diffused out of the alveoli epithelium at 250 mL/min and into the capillary endothelium and attaching itself to circulating hemoglobin. Despite no ventilations (RSI dictates this in assuming full stomachs unless oxygen saturations are low) after the patient is paralyzed, there is actual flow and movement of oxygen down these concentration gradients as the alveoli are somewhat subatmospheric and a mass flow of gas (oxygen) flows from the airways into the alveoli. By applying an NC at 15 L/min (noxious and otherwise not tolerable in the awake patient) proximal airways can come close to a FiO2 of 1.0 and serve to replace the alveoli oxygen. null 14 Taha et al have shown that apneic oxygenation via an NC during RSI in comparison to those without this technique desaturated in 6 minutes compared with 3.65 minutes. null 15 ## Pretreatment Pretreatment agents may be used to mitigate the physiologic response to laryngoscopy and induction and paralysis, which may be undesirable in certain clinical situations. Note though clinical dogma has supported their use in the past, evidence in the literature is deficient in this area and because of this, these are mentioned from a historical perspective. Pretreatment medications are typically administered 2-3 minutes prior to induction and paralysis. These medications can be remembered by using the mnemonic LOAD (ie, Lidocaine, Opioid analgesic, Atropine, Defasciculating agents). - Lidocaine (1.5 mg/kg IV) may suppress the cough or gag reflex experienced during laryngoscopy and has been considered to play a role in blunting increases in mean arterial pressure (MAP), heart rate (HR), and intracranial pressure (ICP). For this reason, it is commonly administered to patients with suspected intracranial hemorrhage, tumor, or any other process that may result in increased ICP, and it may be considered as part of RSI for patients in whom increased MAP could be harmful (eg, leaking aortic aneurysm). However, studies do not consistently demonstrate the effectiveness of lidocaine for these indications in patients in the emergency department (ED), and, based on this lack of evidence, a statement regarding its absolute indication cannot be made. [[null 16], [null 17], [null 18], [null 19], [null 20], [null 21], [null 22], [null 23], [null 24], [null 8]] - Opioid analgesic (fentanyl 3 mcg/kg IV) mitigates the physiologic increase in sympathetic tone associated with direct laryngoscopy (ie, blunts increases in blood pressure, heart rate, and mean arterial pressure). One author recommends this in patients with suspected high ICP, [[null 25], [null 26], [null 27]] though some data also suggest that these agents may increase ICP. [[null 28], [null 29], [null 30], [null 31], [null 32], [null 33]] Opioid analgesics may also be useful in patients with an aortic emergency (eg, aortic dissection or leaking aortic aneurysm) in whom blood pressure spikes should be avoided. At this time, no conclusive evidence supports the use of opioids in RSI. - Atropine (0.02 mg/kg IV) may decrease the incidence of bradydysrhythmia associated with direct laryngoscopy (stimulation of parasympathetic receptors in the laryngopharynx) and administration of succinylcholine (direct stimulation of cardiac muscarinic receptors). Previous recommendations indicated that all children younger than 10 years receive atropine prior to intubation, but this has fallen out of favor because of the lack of supporting data. Even if bradydysrhythmias occur, they are usually self-limited and clinically nonrelevant. However, atropine should be available in case a clinically significant decrease in heart rate occurs. Because of the increase in cardiac vagal tone, atropine can be considered for use in children younger than 1 year and should at least be at the bedside in this age group. [[null 34], [null 35]] - Some evidence indicates that bradycardia can occur equally with or without atropine during intubation. [[null 36], [null 34]] Atropine can also be used in adolescents and adults for symptomatic bradycardia. - A "defasciculating" dose of a nondepolarizing agent may reduce the duration and intensity of muscle fasciculations observed with the administration of succinylcholine (due to the stimulation of nicotinic acetylcholine receptors). The recommended dose is 10% of the paralyzing dose (eg, 0.01 mg/kg for vecuronium). Equivocal studies suggest such pretreatment may help reduce increases in intracranial pressure related to the procedure. - The crux of RSI is to take the awake patient, with an assumed full stomach, and very quickly induce a state of unconsciousness and paralysis and securing the airway. This is done without positive pressure ventilation, if possible. ## Induction Induction agents provide a rapid loss of consciousness that facilitates ease of intubation and avoids psychic harm to the patient. - Etomidate (Amidate) (0.3 mg/kg IV) - Rapid onset, short duration, cerebroprotective, and not associated with significant drop in blood pressure; hemodynamically neutral compared with other agents, such as sodium thiopental. Induces a transient decrease in cortisol levels as high as 86% in some studies. However, properly powered prospective studies are needed to validate this more theoretical phenomenon. Note cortisol levels are affected by severe illness independently of the induction agent used. Critical illness‒related corticosteroid insufficiency occurs in 10-20% of critically ill medical patients and as high as 60% in severe sepsis and septic shock. [[null 37], [null 38]] Most common agent used in the United States. - Ketamine (Ketalar) (1-2 mg/kg IV) - "Dissociative" state, analgesic properties, bronchodilator, may decrease rather than increase intracranial pressure. Consider for patients with asthma or anaphylactic shock; possibly avoid in patients with suspected or known aortic dissection or abdominal aortic aneurysm and in patients with acute myocardial infarction. The general teaching has also been to avoid use of ketamine in patients in whom increased ICP is a concern; in particular, trauma patients with evidence of head injury. However, a review of recent literature supports its use in this scenario as the hemodynamic stimulation induced by ketamine may, in fact, improve cerebral perfusion and prevent secondary penumbra ischemia. Furthermore, in the laboratory, ketamine seems to have neuroprotective properties. [[null 39], [null 40], [null 41]]Because of its positive hemodynamic effects and etomidate’s known tendency to transiently decrease cortisol levels, ketamine is being used more frequently as an induction agent. - Propofol (Diprivan) (2 mg/kg IV) - Rapid onset, short duration, cerebral protective. However, propofol is a myocardial depressant and also decreases systemic vascular resistance. - Midazolam (Versed) (0.3 mg/kg IV) - Slower onset (2-3 min without opioid pretreatment) and longer duration (up to several hours) than etomidate. A study by Sagarin et al from a national airway registry demonstrated that midazolam is usually underdosed when used for RSI, presumably because of the concern for hypotension. null 3 Note that the induction dose is about 20 mg for a 70-kg person. Use of midazolam as an induction agent is not recommended because of its delayed time to induction, predilection for hypotension at induction doses, and prolonged duration of action. ## Paralysis Paralyzing agents provide neuromuscular blockade and are administered immediately after the induction agent. Neuromuscular blockade does not provide sedation, analgesia, or amnesia; thus, administering a potent induction agent is important. - Depolarizing neuromuscular blocker (eg, succinylcholine [Anectine] at 2 mg/kg IV or 4 mg/kg IM): Rapid onset (45-60 sec) and shortest duration of action (8-10 min). Should be used with caution in patients with known or suspectedhyperkalemia and those with chronic neuromuscular disease. - Zink's 1995 prospective study of 100 patients in the ED undergoing RSI did not find a change in serum potassium level from before to after RSI with succinylcholine. Exclusion criteria were minimal; a limitation was that postintubation potassium level was checked at only 1 time interval (5 min). - Nondepolarizing neuromuscular blocker (NMB) (eg, rocuronium [Zemuron] at 1-1.2 mg/kg IV): Slightly longer onset of action (60-75 sec) than succinylcholine and longer duration of action (30-60 min). Use with caution in patients in whom difficult intubation is possible. Does not result in muscle depolarization or defasciculation and does not exacerbate hyperkalemia. Sugammadex is a new NMB reversal agent that has been shown to be safe and effective for reversal of neuromuscular blockade induced by nondepolarizing agents. Reversal occurs at 1.5 minutes with a dose of 16 mg/kg and at 3 minutes with a dose of 4 mg/kg. It has been shown to induce full reversal of such agents faster than succinylcholine’s normal metabolic breakdown and for the first time in over 50 years offers a safe alternative and viable option for emergent RSI. # Procedure In cases of trauma in which cervical spine injury is suspected and not yet ruled out, intubation must be performed without movement of the head. Immobilization is best provided by an experienced assistant. In cases in which cervical injury is not a concern, proper head positioning greatly improves visualization. - In the neutral position, the oral, pharyngeal, and laryngeal axes are not aligned to permit adequate visualization of the glottic opening (see images below). Proper alignment of the axes for tracheal intubation. - Three-axis theory. OA is oral axis, PA is pharyngeal axis, and LA is laryngeal axis. Used with permission from Springer Publishing Company. - Place the patient in the sniffing position for adequate visualization; flex the neck and extend the head. This position helps to align the axes and facilitates visualization of the glottic opening. - Studies have shown that simple head extension alone (without neck flexion) was as effective as the sniffing position in facilitating endotracheal intubation. ## Difficult Airway Assessment Several methods exist to quickly assess the probability of success during tracheal intubation. One tool for rapid assessment is the LEMON law, as described below. A patient in extremis may not be able to cooperate with all the sections of the LEMON assessment. ## L: Look externally Assessing the difficulty of an airway based on external physical features is not sensitive (not all patients who have a difficult airway appear to have a difficult airway prior to intubation) but is quite specific (most patients who appear to have a difficult airway do indeed have a difficult airway). Physical features such as a small mandible, large tongue, and short bull neck are all red flags for a difficult airway. ## E: Evaluate the 3-3-2 rule The chance for success is increased if the patient is able to insert 3 of his or her own fingers between the teeth, can accommodate 3 finger breadths between the hyoid bone and the mentum, and is able to fit 2 finger breadths between the hyoid bone and the thyroid cartilage. ## M: Mallampati classification The Mallampati assessment is ideally performed when the patient is seated with the mouth open and the tongue protruding without phonating. In many patients intubated for emergent indications, this type of assessment is not possible. A crude assessment can be performed with the patient in the supine position to gain an appreciation of the size of the mouth opening and the likelihood that the tongue and oropharynx may be factors in successful intubation. ## O: Obstruction Obstruction of the upper airway is a marker for a difficult airway. Three signs of upper airway obstruction are difficulty swallowing secretions (secondary to pain or obstruction), stridor (an ominous sign which occurs when < 10% of normal caliber of airway circumference is clear), and a muffled (hot-potato) voice. ## N: Neck mobility The inability to move the neck affects optimal visualization of the glottis during direct laryngoscopy. Cervical spine immobilization in trauma (with a C-collar) can compromise normal mobility, as can intrinsic cervical spine immobility due to medical conditions such as ankylosing spondylitis or rheumatoid arthritis. ## Preparation - Confirm that intubation equipment is functional. - Assess the patient for difficult airway (see Difficult Airway Assessment section below for recommended method). If the patient meets criteria for difficult airway, rapid sequence intubation (RSI) may be inappropriate. Nonparalysis procedures may be an alternative. The assistance of anesthesia personnel may be warranted. - Establish intravenous access. - Draw up essential drugs and determine sequence of administration (induction agent immediately followed by paralytic agent). - Review possible contraindications to medications. - Attach necessary monitoring equipment. - Check endotracheal (ET) tube cuff for leak. - Ensure functioning light bulb on laryngoscope blade. ## Preoxygenation Administer 100% oxygen via a nonrebreather mask for 3 minutes for nitrogen washout. This is done without positive pressure ventilation using a tight seal. Though rarely possible in the emergent situation, the patient can take 8 vital capacity (as deep as possible) breaths of 100% oxygen. Studies have shown this can prevent apnea-induced desaturation for 3-5 minutes. null 45 Assist ventilation with bag-valve-mask (BVM) system only if needed to obtain oxygen saturation =90%. ## Pretreatment Consider administration of drugs to mitigate the adverse effects associated with intubation. See Anesthesia for more information. ## Paralysis with induction Administer a rapidly-acting induction agent to produce loss of consciousness. Administer a neuromuscular blocking agent immediately after the induction agent. These medications should be administered as an intravenous push. ## Protection and positioning Though clinical dogma dictates that the Sellick maneuver (firm pressure over the cricoid cartilage to compress the proximal esophagus) be initiated to prevent regurgitation of gastric contents, literature is lacking in support of this technique and in fact may impede laryngeal view. Initiate this maneuver upon observing the beginning of unconsciousness. Maintain pressure throughout intubation sequence until the position of the ET tube is verified. Note that proper laryngeal view has been shown to be best accomplished by the bimanual method and should be used if the Sellick maneuver fails to show the vocal cords. Classical teaching dictates that cricoid pressure decreases the risk of gastric regurgitation into the lungs. However, in a study by Smith et al, the esophagus was partially lateral to the trachea in more than 50% of the subjects. null 46 Also, in an ultrasound study, 29 of 33 esophagi were partially displaced to the left of the trachea. null 47 In a meta-analysis, Butler and Sen showed that little evidence supports the notion that cricoid pressure decreases the risk of aspiration in RSI. null 9 ## Placement with proof Visualize the ET tube passing through the vocal cords. Confirm tube placement. - Observe color change on a qualitative end-tidal carbon dioxide device or utilize a continuous end-tidal carbon dioxide (ET-CO2) monitor. - Use the 5-point auscultation method: Listen over each lateral lung field, the left axilla, and the left supraclavicular region for good breath sounds. No air movement should occur over the stomach. - Two pilot studies have shown that ultrasonography can reliably detect passage of a tracheal tube into either the trachea or esophagus without inadvertent ventilation of the stomach. [[null 47], [null 48]] See the image panel below. Left panel: Bedside ultrasound of anterior neck for proper detection of the endotracheal tube before positive-pressure ventilation is applied. Middle panel: Proper placement of the endotracheal tube in the trachea as the esophagus is normally not visualized. Right panel: Misplacement of the endotracheal tube in the left-sided esophagus. Used with permission from Springer Publishing Company. # Postprocedure ## Postintubation management Secure the ET tube into place. Initiate mechanical ventilation. Obtain a chest radiograph. - Assess pulmonary status. - Note this modality does not confirm placement; rather, it assesses the height above the carina. - Ensure that mainstem intubation has not occurred. Administer appropriate analgesic and sedative agents for patient comfort, to decrease O2 demand, and to decrease ICP. ## Video-assisted laryngoscopy (VAL) VAL offers the advantage of abandoning the need for alignment of the optical axes in the mouth, pharynx, and larynx in order to visualize the entrance of the glottis and therefore is more effective. Unfortunately, standard ETTI via DL, performed by untrained medical personnel and those who perform it only occasionally, carries a high risk of failure. In several studies looking at the success rate of ETTI via DL performed by medical support staff, medical students, and novice anesthesia residents, the initial success rate varied between 35% and 65%. It has been shown that in order to improve the success rate of DL to over 90%, one would require about 47-56 intubations. null 49 In stark contrast, VAL has been shown to be easily learned and highly successful with minimal training necessary. A prospective trial compared 37 novice residents in VAL versus DL and found that the former yielded a 14% higher success rate and 14% fewer esophageal intubations. null 50 Nouruzi-Sedeh et al evaluated medical personnel with no prior experience in ETTI (paramedic students, nurses, and medical students) and after a brief didactic/manikin session compared their laryngoscopy skills in the operating room between VAL and DL. As in many other similar studies, they showed that VAL led to a significantly higher success rate (93%) compared with DL (51%) in nonphysicians with no prior laryngoscopy experience. Subjects were also noted to have a dramatic improvement after only five ETTIs; they neared a 100% success rate using VAL. null 51 A meta-analysis looked at VAL compared with DL in 17 trials with 1,998 patients. The pooled relative risk for nondifficult intubations was 1.5 and for difficult intubations was 3.5; the authors concluded that VAL improves glottic visualization, particularly in patients with potentially difficult airways. null 52 Set up for video-assisted laryngoscopy. Used with permission from Springer Publishing Company. Video demonstration of the ease of video-assisted laryngoscopy in aligning the oral, pharyngeal, and laryngeal airway axis and glottic view. Used with permission from Springer Publishing Company. Glottic view via video-assisted laryngoscopy. Used with permission from Springer Publishing Company. # Tracheal Tube Maintenance The tube is secured in place with tape or an endotracheal tube holder. A cervical collar is sometimes used to prevent motion of the airway. Tube placement should be confirmed after each physical move of the patient and after any unexplained change in his/her clinical status. Continuous pulse oximetry and continuous waveform capnography are often used to monitor the tube's correct placement. The cuff pressure must be monitored carefully in order to avoid complications from over-inflation, which can include tracheomalacia, tracheoesophageal fistula, or even frank rupture of the trachea. Many of the complications of over-inflated cuffs can be traced to excessive cuff pressure causing ischemia of the tracheal mucosa.[5] An excessive leak can sometimes be corrected through the placement of a larger (0.5 mm larger in internal diameter) endotracheal tube, and in difficult-to-ventilate pediatric patients children it is often necessary to use cuffed tubes to allow for high pressure ventilation if the leak is too great to overcome with the ventilator.[6] # Special Situations ## Emergency Intubation Personnel experienced in direct laryngoscopy are not always immediately available in certain settings that require emergency tracheal intubation. For this reason, specialized devices have been designed to act as bridges to a definitive airway. Such devices include the laryngeal mask airway, cuffed oropharyngeal airway, and the Combitube.[7] Other devices such as rigid stylets, the lightwand (a blind technique) and indirect fiberoptic rigid stylets, such as the Bullard scope, Upsher scope, and the WuScope can also be used as alternatives to direct laryngoscopy. Each of these devices have its own unique set of benefits and drawbacks, and none of them is effective under all circumstances. ## Difficult Intubation Many individuals have unusual airway anatomy, such as those who have limited range of motion of the cervical spine or temporomandibular joint, or who have oropharyngeal tumors, hematomas, angioedema, micrognathia, retrognathia, or excess adipose tissue of the face and neck. Using conventional laryngoscopic techniques, intubation of the trachea can be difficult in such people. Use of the flexible fiberoptic bronchoscope and similar devices has become among the preferred techniques in the management of such cases. Among the drawbacks of these devices are their high cost of purchase, maintenance and repair.[8][9] Another drawback is that intubation with one of these devices can take considerably longer than that achieved using conventional laryngoscopy; this limits their use somewhat in urgent and emergent situations. ## Rapid Sequence Intubation Rapid-sequence intubation (RSI) refers to the method of sedation and paralysis prior to tracheal intubation. This technique is quicker than the process normally used to induce a state of general anesthesia. One important difference between RSI and routine tracheal intubation is that the practitoner does not ventilate the lungs after administration of a rapid-acting neuromuscular blocking agent. Another key feature of RSI is the application of manual pressure to the cricoid cartilage (this is referred to as the Sellick maneuver) prior to instrumentation of the airway and intubation of the trachea. RSI involves pre-oxygenating the patient with a tightly-fitting oxygen mask, followed by the sequential administration of pre-determined doses of a hypnotic drug and a rapid-acting neuromuscular blocker. Hypnotics used include thiopental, propofol and etomidate. Neuromuscular-blocking drugs used include suxamethonium (sometimes with a defasciculating dose of vecuronium) and rocuronium.[1] Other drugs may be used in a "modified" RSI. When performing endotracheal intubation, there are several adjunct medications available. No adjunctive medications, when given for their respective indications, have been proven to improve outcomes.[2] Opioids such as alfentanil or fentanyl may be given to attenuate the responses to the intubation process (tachycardia and raised intracranial pressure). This is supposed to have advantages in patients with ischemic heart disease and those with intra-cerebral hemorrhage (e.g. after traumatic head injury or stroke). Lidocaine is also theorized to blunt a rise in intracranial pressure during laryngoscopy, although this remains controversial and its use varies greatly. Atropine may be used to prevent a reflex bradycardia from vagal stimulation during laryngoscopy, especially in young children and infants. This procedure is usually performed by an anesthesiologist or CRNAs (certified registered nurse anesthetists) in surgery, by respiratory therapists in multiple settings, and by medical personnel in the emergency department. It may also be performed in the prehospital setting[1] by persons trained to the EMT-Intermediate or paramedic level, including flight medics and flight nurses. Another alternative is intubation of the awake patient under local anesthesia using a flexible endoscope or by other means (e.g., using a video laryngoscope). This technique is preferred if difficulties are anticipated, as it allows the patient to breathe spontaneously throughout the procedure, thus ensuring ventilation and oxygenation even in the event of a failed intubation. Some alternatives to intubation are - Tracheotomy - a surgical technique, typically for patients who require long-term respiratory support - Cricothyrotomy - an emergency technique used when intubation is unsuccessful and tracheotomy is not an option. Because the life of a patient can depend on the success of an intubation, it is important to assess possible obstacles beforehand. The ease of intubation is difficult to predict. One score to assess anatomical difficulties is the Mallampati score,[10] which is determined by looking at the anatomy of the mouth and based on the visibility of the base of uvula, faucial pillars and the soft palate. It should however be noted that no single score or combination of scores can be trusted to detect all patients who are difficult to intubate. Therefore, persons performing intubation must be familiar with alternative techniques of securing the airways. ## Pediatric Patients Most of the general principles of anesthesia can be applied to children, but there are some significant anatomical and physiological differences between children and adults that can cause problems, especially in neonates and children weighing less than 15 kg. For infants and young children, oral intubation is easier than nasal. Nasal route carries risk of dislodgement of adenoid tissue and epistaxis, but advantages include good fixation of tube. Because of good fixation, nasal route is preferable to oral route in children undergoing intensive care and requiring prolonged intubation. The position of the tube is checked by auscultation (equal air entry on each side and, in long-term intubation, by chest X-ray). Because the airway of a child is narrow, a small amount of oedema can produce severe obstruction. Edema can easily be caused by forcing in a tracheal tube that is too tight. (If length of the tube is suspected to be large, immediate changing it to the smaller size is suggestible.) The appropriate length for the endotracheal tube can be estimated by doubling the distance from the corner of the child's mouth to the ear canal. The tip of the tube should be at midtrachea, between the clavicles on an AP chest X-ray. The correct diameter of the tube is that which results in a small leak at a pressure of about 25 cm of water. The appropriate inner diameter for the endotracheal tube is roughly the same diameter as the child's little finger. For normally nourished children 2 years of age and older, the internal diameter of the tube can be calculated using the following formula: - Internal diameter of tube (mm) = (patient's age in years + 16) / 4 For neonates, 3 mm internal diameter is accepted while for premature infants 2.5 mm internal diameter is more appropriate. # Complications - Esophageal intubation - Iatrogenic induction of an obstructive airway - Right mainstem intubation - Pneumothorax - Dental trauma - Postintubation pneumonia - Vocal cord avulsion - Failure to intubate - Hypotension - Aspiration Tracheal intubation is potentially a very dangerous invasive procedure that requires a great deal of clinical experience to master.[11] When performed improperly (e.g., unrecognized esophageal intubation), the associated complications may rapidly lead to the patient's death.[12] Consequently, in recent editions of its Guidelines for Cardiopulmonary Resuscitation the American Heart Association has de-emphasized the role of tracheal intubation in advanced airway maintenance, in favor of more basic techniques like bag-valve-mask ventilation.[13] Despite these concerns, tracheal intubation is still considered the definitive technique for airway management, as it allows the most reliable means of oxygenation and ventilation, while providing the highest level of protection against vomitus and regurgitation. Although the conventional laryngoscope has proven effective across a wide variety of settings and patients, its use and misuse can result in serious complications (e.g., trauma to oropharyngeal and dental structures). Newer technologies such as flexible fiberoptic laryngoscopy have fared better in reducing the incidence of such complications, though the most common cause of intubation trauma remains a lack of skill on the part of the laryngoscopist. # Related Chapters - Bronchoscopy - Cricothyrotomy - Jet ventilation - Mechanical ventilation - Positive end-expiratory pressure - Positive pressure ventilation - Tracheobronchial injury - Tracheotomy # External Links - Videos of direct laryngoscopy recorded with the Airway Cam (TM) imaging system, a head mounted camera system that captures the perspective of the operator. - Airway devices for intubation	https://www.wikidoc.org/index.php/Endotracheal_intubation
54b947ca93d54fb73275f5521e2aa748a1854f1a	wikidoc	Enkephalin	Enkephalin An enkephalin (occasionally spelled encephalin) is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin have been found, one containing leucine ("leu"), and the other containing methionine ("met"). Both are products of the proenkephalin gene. - Met-enkephalin is Tyr-Gly-Gly-Phe-Met. - Leu-enkephalin has Tyr-Gly-Gly-Phe-Leu. # Endogenous opioid peptides There are three well-characterized families of opioid peptides produced by the body: enkephalins, B-endorphin, and dynorphins. The met-enkephalin peptide sequence is coded for by the enkephalin gene; the leu-enkephalin peptide sequence is coded for by both the enkephalin gene and the dynorphin gene. The proopiomelanocortin gene (POMC) also contains the met-enkephalin sequence on the N-terminus of beta-endorphin, but the endorphin peptide is not processed into enkephalin. # Effects on Stress Enkephalin is also considered a neuropeptide, which in the human body performs as an important signaling molecule in the brain. Enkephalins are found in high concentration in the brain as well as in the cells of adrenal medulla. In response to pain, norepinephrine, a hormone that is activated in fight-or-flight response is released along with endorphins. It has been shown that this polypeptide is linked to brain functioning during a stressful response, especially in the hippocampus and prefrontal cortex regions. During a stress response, several Met-enkephalin analogs had increased activity in the hippocampus, while Leu-enkephalin analogs as well as somatostatins were downregulated during stress. This observation leads to a conclusion that stressors impact neuropeptides, and that their action is localized to a specific brain region. # Enkephalin receptor The receptors for enkephalin are the delta opioid receptors and mu opioid receptors. Opioid receptors are a group of G-protein-coupled receptors, with other opioids as ligands as well. The other endogenous opioids are dynorphins (that bind to kappa receptors), endorphins (mu receptors), endomorphins, and nociceptin/orphanin FQ. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs).	Enkephalin An enkephalin (occasionally spelled encephalin) is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin have been found, one containing leucine ("leu"), and the other containing methionine ("met"). Both are products of the proenkephalin gene.[2] - Met-enkephalin is Tyr-Gly-Gly-Phe-Met. - Leu-enkephalin has Tyr-Gly-Gly-Phe-Leu. # Endogenous opioid peptides There are three well-characterized families of opioid peptides produced by the body: enkephalins, B-endorphin, and dynorphins. The met-enkephalin peptide sequence is coded for by the enkephalin gene; the leu-enkephalin peptide sequence is coded for by both the enkephalin gene and the dynorphin gene.[3] The proopiomelanocortin gene (POMC) also contains the met-enkephalin sequence on the N-terminus of beta-endorphin, but the endorphin peptide is not processed into enkephalin. # Effects on Stress Enkephalin is also considered a neuropeptide, which in the human body performs as an important signaling molecule in the brain. Enkephalins are found in high concentration in the brain as well as in the cells of adrenal medulla. In response to pain, norepinephrine, a hormone that is activated in fight-or-flight response is released along with endorphins.[4] It has been shown that this polypeptide is linked to brain functioning during a stressful response, especially in the hippocampus and prefrontal cortex regions. During a stress response, several Met-enkephalin analogs had increased activity in the hippocampus, while Leu-enkephalin analogs as well as somatostatins were downregulated during stress. This observation leads to a conclusion that stressors impact neuropeptides, and that their action is localized to a specific brain region.[5] # Enkephalin receptor The receptors for enkephalin are the delta opioid receptors and mu opioid receptors. Opioid receptors are a group of G-protein-coupled receptors, with other opioids as ligands as well. The other endogenous opioids are dynorphins (that bind to kappa receptors), endorphins (mu receptors), endomorphins, and nociceptin/orphanin FQ. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs).	https://www.wikidoc.org/index.php/Enkephalin
389bbdd1edc228c7eb0c53e2baf05d3516aa3764	wikidoc	Entacapone	Entacapone # 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 Entacapone is a Catechol-O-Methyltransferase Inhibitor that is FDA approved for the treatment of Parkinson’s Disease as an adjunct to levodopa and carbidopa therapy. Common adverse reactions include Dyskinesia, Urine Discoloration, Nausea, Diarrhea, abdominal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Entacapone Tablets are indicated as an adjunct to levodopa and carbidopa to treat patients with idiopathic Parkinson’s Disease who experience the signs and symptoms of end-of-dose "wearing-off" . - Entacapone Tablets’ effectiveness has not been systematically evaluated in patients with idiopathic Parkinson’s Disease who do not experience end-of-dose "wearing-off". ### Dosage - The recommended dose of Entacapone Tablets is one 200 mg tablet administered concomitantly with each levodopa and carbidopa dose to a maximum of 8 times daily (200 mg x 8 = 1,600 mg per day). Clinical experience with daily doses above 1,600 mg is limited. - Entacapone Tablets should always be administered in association with levodopa and carbidopa. Entacapone has no antiparkinsonian effect of its own. - In clinical trials, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa had been greater than or equal to 800 mg or if patients had moderate or severe dyskinesias before beginning treatment. - To optimize an individual patient’s response, reductions in daily levodopa dose or extending the interval between doses may be necessary. In clinical trials, the average reduction in daily levodopa dose was about 25% in those patients requiring a levodopa dose reduction. (More than 58% of patients with levodopa doses above 800 mg daily required such a reduction.) - Entacapone Tablets can be combined with both the immediate and sustained-release formulations of levodopa and carbidopa. - Entacapone Tablets may be taken with or without food . - Patients with hepatic impairment should be treated with caution. The AUC and Cmax of entacapone approximately doubled in patients with documented liver disease, compared to controls. However, these studies were conducted with single-dose entacapone without levodopa and dopa decarboxylase inhibitor coadministration, and therefore the effects of liver disease on the kinetics of chronically administered entacapone have not been evaluated . - Rapid withdrawal or abrupt reduction in the Entacapone Tablets dose could lead to emergence of signs and symptoms of Parkinson’s Disease, and may lead to Hyperpyrexia and Confusion, a symptom complex resembling the neuroleptic malignant syndrome. This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. If a decision is made to discontinue treatment with Entacapone Tablets, patients should be monitored closely and other dopaminergic treatments should be adjusted as needed. Although tapering Entacapone Tablets have not been systematically evaluated, it seems prudent to withdraw patients slowly if the decision to discontinue treatment is made. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Entacapone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Entacapone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Entacapone in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Entacapone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Entacapone in pediatric patients. # Contraindications - Entacapone Tablets are contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. # Warnings - Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of Entacapone Tablets and a non-selective MAO inhibitor (e.g., phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. For this reason, patients should ordinarily not be treated concomitantly with Entacapone Tablets and a non-selective MAO inhibitor. - Entacapone can be taken concomitantly with a selective MAO-B inhibitor (e.g., selegiline). - When a single 400 mg dose of entacapone was given together with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa and dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and epinephrine, respectively. - Therefore, drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure. - Ventricular tachycardia was noted in one 32-year-old healthy male volunteer in an interaction study after epinephrine infusion and oral entacapone administration. Treatment with propranolol was required. A causal relationship to entacapone administration appears probable but cannot be attributed with certainty. ### Precautions - Dopaminergic therapy in Parkinson’s Disease patients has been associated with orthostatic hypotension. Entacapone enhances levodopa bioavailability and, therefore, might be expected to increase the occurrence of orthostatic hypotension. In Entacapone Tablets clinical trials, however, no differences from placebo were seen for measured orthostasis or symptoms of orthostasis. Orthostatic hypotension was documented at least once in 2.7% and 3.0% of the patients treated with 200 mg Entacapone Tablets and placebo, respectively. A total of 4.3% and 4.0% of the patients treated with 200 mg Entacapone Tablets and placebo, respectively, reported orthostatic symptoms at some time during their treatment and also had at least one episode of orthostatic hypotension documented (however, the episode of orthostatic symptoms itself was not accompanied by vital sign measurements). Neither baseline treatment with dopamine agonists or selegiline, nor the presence of orthostasis at baseline, increased the risk of orthostatic hypotension in patients treated with Entacapone Tablets compared to patients on placebo. - In the large controlled trials, approximately 1.2% and 0.8% of 200 mg entacapone and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in both treatment groups who had an episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement). - In clinical trials, diarrhea developed in 60 of 603 (10.0%) and 16 of 400 (4.0%) of patients treated with 200 mg Entacapone Tablets and placebo, respectively. In patients treated with Entacapone Tablets, diarrhea was generally mild to moderate in severity (8.6%) but was regarded as severe in 1.3%. Diarrhea resulted in withdrawal in 10 of 603 (1.7%) patients, 7 (1.2%) with mild and moderate diarrhea and 3 (0.5%) with severe diarrhea. Diarrhea generally resolved after discontinuation of Entacapone Tablets. Two patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 weeks to 12 weeks after entacapone is started, but it may appear as early as the first week and as late as many months after the initiation of treatment. Diarrhea may be associated with weight loss, dehydration, and hypokalemia. - Postmarketing experience has shown that diarrhea may be a sign of drug-induced microscopic colitis, primarily lymphocytic colitis. In these cases diarrhea has usually been moderate to severe, watery, and non-bloody, at times associated with dehydration, abdominal pain, weight loss, and hypokalemia. In the majority of cases, diarrhea and other colitis-related symptoms resolved or significantly improved when Entacapone Tablets treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of Entacapone Tablets but recurred after retreatment with Entacapone Tablets. - If prolonged diarrhea is suspected to be related to Entacapone Tablets, the drug should be discontinued and appropriate medical therapy considered. If the cause of prolonged diarrhea remains unclear or continues after stopping entacapone, then further diagnostic investigations including colonoscopy and biopsies should be considered. - Dopaminergic therapy in Parkinson’s Disease patients has been associated with hallucinations. In clinical trials, hallucinations developed in approximately 4.0% of patients treated with 200 mg Entacapone Tablets or placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.8% and 0% of patients treated with 200 mg Entacapone Tablets and placebo, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the 200 mg Entacapone Tablets and placebo groups, respectively. - Entacapone Tablets may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. The rates of withdrawal for dyskinesia were 1.5% and 0.8% for 200 mg Entacapone Tablets and placebo, respectively. - The events listed below are rare events known to be associated with the use of drugs that increase dopaminergic activity, although they are most often associated with the use of direct dopamine agonists. - Cases of severe rhabdomyolysis have been reported with Entacapone Tablets use. The complicated nature of these cases makes it impossible to determine what role, if any, Entacapone Tablets played in their pathogenesis. Severe prolonged motor activity including dyskinesia may account for rhabdomyolysis. One case, however, included fever and alteration of consciousness. It is therefore possible that the rhabdomyolysis may be a result of the syndrome described in Hyperpyrexia and Confusion. - Cases of a symptom complex resembling the neuroleptic malignant syndrome characterized by elevated temperature, muscular rigidity, altered consciousness, and elevated CPK have been reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs. Several cases with similar signs and symptoms have been reported in association with Entacapone Tablets therapy, although no information about dose manipulation is available. The complicated nature of these cases makes it difficult to determine what role, if any, Entacapone Tablets may have played in their pathogenesis. No cases have been reported following the abrupt withdrawal or dose reduction of entacapone treatment during clinical studies. - Prescribers should exercise caution when discontinuing entacapone treatment. When considered necessary, withdrawal should proceed slowly. If a decision is made to discontinue treatment with Entacapone Tablets, recommendations include monitoring the patient closely and adjusting other dopaminergic treatments as needed. This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. Tapering Entacapone Tablets has not been systematically evaluated. - Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. These complications may resolve when the drug is discontinued, but complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived drugs (e.g., entacapone) that increase dopaminergic activity can cause them is unknown. It should be noted that the expected incidence of fibrotic complications is so low that even if entacapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that it would have been detected in a cohort of the size exposed to entacapone. Four cases of pulmonary fibrosis were reported during clinical development of entacapone; three of these patients were also treated with pergolide and one with bromocriptine. The duration of treatment with entacapone ranged from 7 months to 17 months. - Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. - For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Entacapone Tablets for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists). - In a 1 year toxicity study, entacapone (plasma exposure 20 times that in humans receiving the maximum recommended daily dose of 1,600 mg) caused an increased incidence in male rats of nephrotoxicity that was characterized by regenerative tubules, thickening of basement membranes, infiltration of mononuclear cells and tubular protein casts. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although this toxicity could represent a species-specific effect, there is not yet evidence that this is so. - Patients with hepatic impairment should be treated with caution. The AUC and Cmax of entacapone approximately doubled in patients with documented liver disease compared to controls. - Entacapone Tablets is a chelator of iron. The impact of entacapone on the body’s iron stores is unknown; however, a tendency towards decreasing serum iron concentrations was noted in clinical trials. In a controlled clinical study serum ferritin levels (as marker of iron deficiency and subclinical anemia) were not changed with entacapone compared to placebo after one year of treatment and there was no difference in rates of anemia or decreased hemoglobin levels. # Adverse Reactions ## Clinical Trials Experience - During the pre-marketing development of entacapone, 1,450 patients with Parkinson’s Disease were treated with entacapone. Included were patients with fluctuating symptoms, as well as those with stable responses to levodopa therapy. All patients received concomitant treatment with levodopa preparations, however, and were similar in other clinical aspects. The most commonly observed adverse events (greater than 5%) in the double-blind, placebo-controlled trials (N=1,003) associated with the use of Entacapone Tablets and not seen at an equivalent frequency among the placebo-treated patients were: dyskinesia and hyperkinesia, nausea, urine discoloration, diarrhea, and abdominal pain. - Approximately 14% of the 603 patients given entacapone in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared to 9% of the 400 patients who received placebo. The most frequent causes of discontinuation in decreasing order are: psychiatric reasons (2% vs. 1%), diarrhea (2% vs. 0%), dyskinesia and hyperkinesia (2% vs. 1%), nausea (2% vs. 1%), abdominal pain (1% vs. 0%), and aggravation of Parkinson’s Disease symptoms (1% vs. 1%). - Table 4 lists treatment emergent adverse events that occurred in at least 1% of patients treated with entacapone participating in the double-blind, placebo-controlled studies and that were numerically more common in the entacapone group, compared to placebo. In these studies, either entacapone or placebo was added to levodopa and carbidopa (or levodopa and benserazide). Table 4 Summary of Patients With Adverse Events After Start of Trial Drug Administration At Least 1% in Entacapone Tablet Group and Greater than Placebo - The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures do, however, provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse events observed in the population studied. - No differences were noted in the rate of adverse events attributable to entacapone by age or gender. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Entacapone in the drug label. # Drug Interactions - In vitro studies of human CYP enzymes showed that entacapone inhibited the CYP enzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A only at very high concentrations (IC50 from 200 microM to over 1,000 microM; an oral 200 mg dose achieves a highest level of approximately 5 microM in people); these enzymes would therefore not be expected to be inhibited in clinical use. - Entacapone is highly protein bound (98%). In vitro studies have shown no binding displacement between entacapone and other highly bound drugs, such as warfarin, salicylic acid, phenylbutazone, and diazepam. - When a single 400 mg dose of entacapone was given together with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa and dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and epinephrine, respectively. - Therefore, drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure. - Ventricular tachycardia was noted in one 32-year-old healthy male volunteer in an interaction study after epinephrine infusion and oral entacapone administration. Treatment with propranolol was required. A causal relationship to entacapone administration appears probable but cannot be attributed with certainty. - Levodopa is known to depress prolactin secretion and increase growth hormone levels. Treatment with entacapone coadministered with levodopa and dopa decarboxylase inhibitor does not change these effects. - See WARNINGS regarding concomitant use of Entacapone Tablets and non-selective MAO inhibitors. - No interaction was noted with the MAO-B inhibitor selegiline in two multiple-dose interaction studies when entacapone was coadministered with a levodopa and dopa decarboxylase inhibitor (n=29). More than 600 Parkinson’s Disease patients in clinical trials have used selegiline in combination with entacapone and levodopa and dopa decarboxylase inhibitor. - As most entacapone excretion is via the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase are given concurrently with entacapone. These include probenecid, cholestyramine, and some antibiotics (e.g., erythromycin, rifampicin, ampicillin and chloramphenicol). - No interaction with the tricyclic antidepressant imipramine was shown in a single-dose study with entacapone without coadministered levodopa and dopa-decarboxylase inhibitor. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Pregnancy Category - In embryofetal development studies, entacapone was administered to pregnant animals throughout organogenesis at doses of up to 1,000 mg per kg per day in rats and 300 mg per kg per day in rabbits. Increased incidences of fetal variations were evident in litters from rats treated with the highest dose, in the absence of overt signs of maternal toxicity. The maternal plasma drug exposure (AUC) associated with this dose was approximately 34 times the estimated plasma exposure in humans receiving the maximum recommended daily dose (MRDD) of 1,600 mg. Increased frequencies of abortions and late and total resorptions and decreased fetal weights were observed in the litters of rabbits treated with maternotoxic doses of 100 mg per kg per day (plasma AUCs 0.4 times those in humans receiving the MRDD) or greater. There was no evidence of teratogenicity in these studies. - However, when entacapone was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies (macrophthalmia, microphthalmia, anophthalmia) was observed in the litters of dams treated with doses of 160 mg per kg per day (plasma AUCs 7 times those in humans receiving the MRDD) or greater, in the absence of maternotoxicity. Administration of up to 700 mg per kg per day (plasma AUCs 28 times those in humans receiving the MRDD) to female rats during the latter part of gestation and throughout lactation, produced no evidence of developmental impairment in the offspring. - Entacapone is always given concomitantly with levodopa and carbidopa, which is known to cause visceral and skeletal malformations in rabbits. The teratogenic potential of entacapone in combination with levodopa and carbidopa was not assessed in animals. - There is no experience from clinical studies regarding the use of Entacapone Tablets in pregnant women. Therefore, Entacapone Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Entacapone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Entacapone during labor and delivery. ### Nursing Mothers - In animal studies, entacapone was excreted into maternal rat milk. - It is not known whether entacapone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when entacapone is administered to a nursing woman. ### Pediatric Use - There is no identified potential use of entacapone in pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Entacapone with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Entacapone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Entacapone with respect to specific racial populations. ### Renal Impairment - In a 1 year toxicity study, entacapone (plasma exposure 20 times that in humans receiving the maximum recommended daily dose of 1,600 mg) caused an increased incidence in male rats of nephrotoxicity that was characterized by regenerative tubules, thickening of basement membranes, infiltration of mononuclear cells and tubular protein casts. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although this toxicity could represent a species-specific effect, there is not yet evidence that this is so. ### Hepatic Impairment - Patients with hepatic impairment should be treated with caution. The AUC and Cmax of entacapone approximately doubled in patients with documented liver disease compared to controls. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Entacapone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Entacapone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Entacapone in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Entacapone in the drug label. # Overdosage - COMT inhibition by entacapone treatment is dose-dependent. A massive overdose of Entacapone Tablets may theoretically produce a 100% inhibition of the COMT enzyme in people, thereby preventing the metabolism of endogenous and exogenous catechols. - The highest single dose of entacapone administered to humans was 800 mg, resulting in a plasma concentration of 14.1 mcg per mL. The highest daily dose given to humans was 2,400 mg, administered in one study as 400 mg six times daily with levodopa and carbidopa for 14 days in 15 Parkinson’s Disease patients, and in another study as 800 mg three times daily for 7 days in 8 healthy volunteers. At this daily dose, the peak plasma concentrations of entacapone averaged 2.0 mcg per mL (at 45 min., compared to 1.0 mcg per mL and 1.2 mcg per mL with 200 mg entacapone at 45 min.). Abdominal pain and loose stools were the most commonly observed adverse events during this study. Daily doses as high as 2,000 mg Entacapone Tablet have been administered as 200 mg 10 times daily with levodopa and carbidopa or levodopa and benserazide for at least 1 year in 10 patients, for at least 2 years in 8 patients and for at least 3 years in 7 patients. Overall, however, clinical experience with daily doses above 1,600 mg is limited. - The range of lethal plasma concentrations of entacapone based on animal data was 80 mcg per mL to 130 mcg per mL in mice. Respiratory difficulties, ataxia, hypoactivity, and convulsions were observed in mice after high oral (gavage) doses. - Management of Entacapone Tablets overdose is symptomatic; there is no known antidote to Entacapone Tablets. Hospitalization is advised, and general supportive care is indicated. There is no experience with hemodialysis or hemoperfusion, but these procedures are unlikely to be of benefit, because Entacapone Tablets are highly bound to plasma proteins. An immediate gastric lavage and repeated doses of charcoal over time may hasten the elimination of Entacapone Tablet by decreasing its absorption and reabsorption from the GI tract. The adequacy of the respiratory and circulatory systems should be carefully monitored and appropriate supportive measures employed. The possibility of drug interactions, especially with catechol-structured drugs, should be borne in mind. # Pharmacology ## Mechanism of Action - Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). - In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells, and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery. - The mechanism of action of entacapone is believed to be through its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson’s Disease. The higher levodopa levels also lead to increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. - In animals, while entacapone enters the CNS to a minimal extent, it has been shown to inhibit central COMT activity. In humans, entacapone inhibits the COMT enzyme in peripheral tissues. The effects of entacapone on central COMT activity in humans have not been studied. ## Structure - Entacapone is an inhibitor of catechol-O-methyltransferase (COMT), used in the treatment of Parkinson’s Disease as an adjunct to levodopa and carbidopa therapy. It is a nitrocatechol-structured compound with a relative molecular mass of 305.29. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is C14H15N3O5 and its structural formula is: ## Pharmacodynamics - COMT Activity in Erythrocytes: Studies in healthy volunteers have shown that entacapone reversibly inhibits human erythrocyte catechol-O-methyltransferase (COMT) activity after oral administration. There was a linear correlation between entacapone dose and erythrocyte COMT inhibition, the maximum inhibition being 82% following an 800 mg single dose. With a 200 mg single dose of entacapone, maximum inhibition of erythrocyte COMT activity is on average 65% with a return to baseline level within 8 hours. ## Pharmacokinetics - When 200 mg entacapone is administered together with levodopa and carbidopa, it increases the area under the curve (AUC) of levodopa by approximately 35% and the elimination half-life of levodopa is prolonged from 1.3 h to 2.4 h. In general, the average peak levodopa plasma concentration and the time of its occurrence (Tmax of 1 hour) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. Studies in Parkinson’s Disease patients suggest that the maximal effect occurs with 200 mg entacapone. Plasma levels of 3-OMD are markedly and dose-dependently decreased by entacapone when given with levodopa and carbidopa. - Entacapone pharmacokinetics are linear over the dose range of 5 mg to 800 mg, and are independent of levodopa and carbidopa coadministration. The elimination of entacapone is biphasic, with an elimination half-life of 0.4 h to 0.7 h based on the β-phase and 2.4 h based on the γ-phase. The γ-phase accounts for approximately 10% of the total AUC. The total body clearance after i.v. administration is 850 mL per min. After a single 200 mg dose of Entacapone Tablets, the Cmax is approximately 1.2 mcg per mL. - Entacapone is rapidly absorbed, with a Tmax of approximately 1 hour. The absolute bioavailability following oral administration is 35%. Food does not affect the pharmacokinetics of entacapone. - The volume of distribution of entacapone at steady state after i.v. injection is small (20 L). Entacapone does not distribute widely into tissues due to its high plasma protein binding. Based on in vitro studies, the plasma protein binding of entacapone is 98% over the concentration range of 0.4 mcg per mL to 50 mcg per mL. Entacapone binds mainly to serum albumin. - Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. The main metabolic pathway is isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer; the glucuronide conjugate is inactive. After oral administration of a 14C-labeled dose of entacapone, 10% of labeled parent and metabolite is excreted in urine and 90% in feces. - Entacapone pharmacokinetics are independent of age. No formal gender studies have been conducted. Racial representation in clinical trials was largely limited to Caucasians (there were only 4 blacks in one US trial and no Asians in any of the clinical trials); no conclusions can therefore be reached about the effect of entacapone on groups other than Caucasian. - A single 200 mg dose of entacapone, without levodopa and dopa decarboxylase inhibitor coadministration, showed approximately twofold higher AUC and Cmax values in patients with a history of alcoholism and hepatic impairment (n=10) compared to normal subjects (n=10). All patients had biopsy-proven liver cirrhosis caused by alcohol. According to Child-Pugh grading 7 patients with liver disease had mild hepatic impairment and 3 patients had moderate hepatic impairment. As only about 10% of the entacapone dose is excreted in urine as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug. Consequently, entacapone should be administered with care to patients with biliary obstruction. - The pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose, without levodopa and dopa decarboxylase inhibitor coadministration, in a specific renal impairment study. There were three groups: normal subjects (n=7; creatinine clearance greater than 1.12 mL per sec per 1.73 m2), moderate impairment (n=10; creatinine clearance ranging from 0.60 mL per sec per 1.73 m2 to 0.89 mL per sec per 1.73 m2), and severe impairment (n=7; creatinine clearance ranging from 0.20 mL per sec per 1.73 m2 to 0.44 mL per sec per 1.73 m2). No important effects of renal function on the pharmacokinetics of entacapone were found. ## Nonclinical Toxicology - Two-year carcinogenicity studies of entacapone were conducted in mice and rats. Rats were treated once daily by oral gavage with entacapone doses of 20 mg per kg, 90 mg per kg, or 400 mg per kg. An increased incidence of renal tubular adenomas and carcinomas was found in male rats treated with the highest dose of entacapone. Plasma exposures (AUC) associated with this dose were approximately 20 times higher than estimated plasma exposures of humans receiving the maximum recommended daily dose of entacapone (MRDD = 1,600 mg). Mice were treated once daily by oral gavage with doses of 20 mg per kg, 100 mg per kg or 600 mg per kg of entacapone (0.05, 0.3, and 2 times the MRDD for humans on a mg per m2 basis). Because of a high incidence of premature mortality in mice receiving the highest dose of entacapone, the mouse study is not an adequate assessment of carcinogenicity. Although no treatment related tumors were observed in animals receiving the lower doses, the carcinogenic potential of entacapone has not been fully evaluated. The carcinogenic potential of entacapone administered in combination with levodopa and carbidopa has not been evaluated. - Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma and thymidine kinase assay in the presence and absence of metabolic activation, and was clastogenic in cultured human lymphocytes in the presence of metabolic activation. Entacapone, either alone or in combination with levodopa and carbidopa, was not clastogenic in the in vivo mouse micronucleus test or mutagenic in the bacterial reverse mutation assay (Ames test). - Entacapone did not impair fertility or general reproductive performance in rats treated with up to 700 mg per kg per day (plasma AUCs 28 times those in humans receiving the MRDD). Delayed mating, but no fertility impairment, was evident in female rats treated with 700 mg per kg per day of entacapone. # Clinical Studies - The effectiveness of Entacapone Tablets as an adjunct to levodopa in the treatment of Parkinson’s Disease was established in three 24-week multicenter, randomized, double-blind placebo-controlled trials in patients with Parkinson’s Disease. In two of these trials, the patients’ disease was "fluctuating", i.e., was characterized by documented periods of "On" (periods of relatively good functioning) and "Off" (periods of relatively poor functioning), despite optimum levodopa therapy. There was also a withdrawal period following 6 months of treatment. In the third trial patients were not required to have been experiencing fluctuations. Prior to the controlled part of the trials, patients were stabilized on levodopa for 2 weeks to 4 weeks. Entacapone has not been systematically evaluated in patients who do not experience fluctuations. - In the first two studies to be described, patients were randomized to receive placebo or entacapone 200 mg administered concomitantly with each dose of levodopa and carbidopa (up to 10 times daily, but averaging 4 doses to 6 doses per day). The formal double-blind portion of both trials was 6 months long. Patients recorded the time spent in the "On" and "Off" states in home diaries periodically throughout the duration of the trial. In one study, conducted in the Nordic countries, the primary outcome measure was the total mean time spent in the "On" state during an 18-hour diary recorded day (6 AM to midnight). In the other study, the primary outcome measure was the proportion of awake time spent over 24 hours in the "On" state. - In addition to the primary outcome measure, the amount of time spent in the "Off" state was evaluated, and patients were also evaluated by subparts of the Unified Parkinson’s Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to assess mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Part V and VI); an investigator’s and patient’s global assessment of clinical condition, a 7-point subjective scale designed to assess global functioning in Parkinson’s Disease; and the change in daily levodopa and carbidopa dose. - In one of the studies, 171 patients were randomized in 16 centers in Finland, Norway, Sweden, and Denmark (Nordic study), all of whom received concomitant levodopa plus dopa-decarboxylase inhibitor (either levodopa and carbidopa or levodopa and benserazide). In the second trial, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant levodopa and carbidopa. - The following tables display the results of these two trials: - Effects on "On" time did not differ by age, sex, weight, disease severity at baseline, levodopa dose and concurrent treatment with dopamine agonists or selegiline. - Withdrawal of entacapone: In the North American study, abrupt withdrawal of entacapone, without alteration of the dose of levodopa and carbidopa, resulted in a significant worsening of fluctuations, compared to placebo. In some cases, symptoms were slightly worse than at baseline, but returned to approximately baseline severity within two weeks following levodopa dose increase on average by 80 mg. In the Nordic study, similarly, a significant worsening of parkinsonian symptoms was observed after entacapone withdrawal, as assessed two weeks after drug withdrawal. At this phase, the symptoms were approximately at baseline severity following levodopa dose increase by about 50 mg. - In the third placebo controlled trial, a total of 301 patients were randomized in 32 centers in Germany and Austria. In this trial, as in the other two trials, entacapone 200 mg was administered with each dose of levodopa and dopa decarboxylase inhibitor (up to 10 times daily) and UPDRS Parts II and III and total daily "On" time were the primary measures of effectiveness. The following results were seen for the primary measures, as well as for some secondary measures: # How Supplied - Entacapone Tablets are supplied as 200 mg film-coated tablets for oral administration. The oval-shaped tablets are brownish-orange, unscored and embossed “EN1” over “200” on one side. Tablets are provided in HDPE containers as follows: - Bottle of 100 tablets NDC 0378-9080-01 ## Storage - Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL – 200 mg NDC 0378-9080-01 Entacapone Tablets 200 mg Rx only 100 Tablets Each tablet contains: Entacapone 200 mg Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Usual Adult Dosage: See package insert for dosage information. ### Ingredients and Appearance # Patient Counseling Information - Patients should be instructed to take Entacapone Tablets only as prescribed. - Patients should be informed that hallucinations can occur. - Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sweating. Hypotension may occur more frequently during initial therapy. Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods, and especially at the initiation of treatment with Entacapone Tablets. - Patients should be advised that they should neither drive a car nor operate other complex machinery until they have gained sufficient experience on Entacapone Tablets to gauge whether or not it affects their mental and/or motor performance adversely. Because of the possible additive sedative effects, caution should be used when patients are taking other CNS depressants in combination with Entacapone Tablets. - Patients should be informed that nausea may occur, especially at the initiation of treatment with Entacapone Tablets. - Patients should be informed that diarrhea may occur with Entacapone Tablets and it may have a delayed onset. Sometimes prolonged diarrhea may be caused by colitis (inflammation of the large intestine). Patients with diarrhea should drink fluids to maintain adequate hydration and monitor for weight loss. If diarrhea associated with Entacapone Tablets is prolonged, discontinuing the drug is expected to lead to resolution, if diarrhea continues after stopping entacapone, further diagnostic investigations may be needed. - Patients should be advised of the possibility of an increase in dyskinesia. - Patients should be advised that treatment with entacapone may cause a change in the color of their urine (a brownish orange discoloration) that is not clinically relevant. In controlled trials, 10% of patients treated with Entacapone Tablets reported urine discoloration compared to 0% of placebo patients. - Although Entacapone Tablets has not been shown to be teratogenic in animals, it is always given in conjunction with levodopa and carbidopa, which is known to cause visceral and skeletal malformations in the rabbit. Accordingly, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy (see PRECAUTIONS, PREGNANCY). - Entacapone is excreted into maternal milk in rats. Because of the possibility that entacapone may be excreted into human maternal milk, patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant. - There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease, including Entacapone Tablets. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Entacapone Tablets. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Entacapone Tablets. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Entacapone Tablets. # Precautions with Alcohol - Alcohol-Entacapone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Comtan® # Look-Alike Drug Names There is limited information regarding Entacapone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Entacapone 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 Entacapone is a Catechol-O-Methyltransferase Inhibitor that is FDA approved for the treatment of Parkinson’s Disease as an adjunct to levodopa and carbidopa therapy. Common adverse reactions include Dyskinesia, Urine Discoloration, Nausea, Diarrhea, abdominal pain. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - Entacapone Tablets are indicated as an adjunct to levodopa and carbidopa to treat patients with idiopathic Parkinson’s Disease who experience the signs and symptoms of end-of-dose "wearing-off" . - Entacapone Tablets’ effectiveness has not been systematically evaluated in patients with idiopathic Parkinson’s Disease who do not experience end-of-dose "wearing-off". ### Dosage - The recommended dose of Entacapone Tablets is one 200 mg tablet administered concomitantly with each levodopa and carbidopa dose to a maximum of 8 times daily (200 mg x 8 = 1,600 mg per day). Clinical experience with daily doses above 1,600 mg is limited. - Entacapone Tablets should always be administered in association with levodopa and carbidopa. Entacapone has no antiparkinsonian effect of its own. - In clinical trials, the majority of patients required a decrease in daily levodopa dose if their daily dose of levodopa had been greater than or equal to 800 mg or if patients had moderate or severe dyskinesias before beginning treatment. - To optimize an individual patient’s response, reductions in daily levodopa dose or extending the interval between doses may be necessary. In clinical trials, the average reduction in daily levodopa dose was about 25% in those patients requiring a levodopa dose reduction. (More than 58% of patients with levodopa doses above 800 mg daily required such a reduction.) - Entacapone Tablets can be combined with both the immediate and sustained-release formulations of levodopa and carbidopa. - Entacapone Tablets may be taken with or without food . - Patients with hepatic impairment should be treated with caution. The AUC and Cmax of entacapone approximately doubled in patients with documented liver disease, compared to controls. However, these studies were conducted with single-dose entacapone without levodopa and dopa decarboxylase inhibitor coadministration, and therefore the effects of liver disease on the kinetics of chronically administered entacapone have not been evaluated . - Rapid withdrawal or abrupt reduction in the Entacapone Tablets dose could lead to emergence of signs and symptoms of Parkinson’s Disease, and may lead to Hyperpyrexia and Confusion, a symptom complex resembling the neuroleptic malignant syndrome. This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. If a decision is made to discontinue treatment with Entacapone Tablets, patients should be monitored closely and other dopaminergic treatments should be adjusted as needed. Although tapering Entacapone Tablets have not been systematically evaluated, it seems prudent to withdraw patients slowly if the decision to discontinue treatment is made. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Entacapone in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Entacapone in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Entacapone in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Entacapone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Entacapone in pediatric patients. # Contraindications - Entacapone Tablets are contraindicated in patients who have demonstrated hypersensitivity to the drug or its ingredients. # Warnings - Monoamine oxidase (MAO) and COMT are the two major enzyme systems involved in the metabolism of catecholamines. It is theoretically possible, therefore, that the combination of Entacapone Tablets and a non-selective MAO inhibitor (e.g., phenelzine and tranylcypromine) would result in inhibition of the majority of the pathways responsible for normal catecholamine metabolism. For this reason, patients should ordinarily not be treated concomitantly with Entacapone Tablets and a non-selective MAO inhibitor. - Entacapone can be taken concomitantly with a selective MAO-B inhibitor (e.g., selegiline). - When a single 400 mg dose of entacapone was given together with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa and dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and epinephrine, respectively. - Therefore, drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure. - Ventricular tachycardia was noted in one 32-year-old healthy male volunteer in an interaction study after epinephrine infusion and oral entacapone administration. Treatment with propranolol was required. A causal relationship to entacapone administration appears probable but cannot be attributed with certainty. ### Precautions - Dopaminergic therapy in Parkinson’s Disease patients has been associated with orthostatic hypotension. Entacapone enhances levodopa bioavailability and, therefore, might be expected to increase the occurrence of orthostatic hypotension. In Entacapone Tablets clinical trials, however, no differences from placebo were seen for measured orthostasis or symptoms of orthostasis. Orthostatic hypotension was documented at least once in 2.7% and 3.0% of the patients treated with 200 mg Entacapone Tablets and placebo, respectively. A total of 4.3% and 4.0% of the patients treated with 200 mg Entacapone Tablets and placebo, respectively, reported orthostatic symptoms at some time during their treatment and also had at least one episode of orthostatic hypotension documented (however, the episode of orthostatic symptoms itself was not accompanied by vital sign measurements). Neither baseline treatment with dopamine agonists or selegiline, nor the presence of orthostasis at baseline, increased the risk of orthostatic hypotension in patients treated with Entacapone Tablets compared to patients on placebo. - In the large controlled trials, approximately 1.2% and 0.8% of 200 mg entacapone and placebo patients, respectively, reported at least one episode of syncope. Reports of syncope were generally more frequent in patients in both treatment groups who had an episode of documented hypotension (although the episodes of syncope, obtained by history, were themselves not documented with vital sign measurement). - In clinical trials, diarrhea developed in 60 of 603 (10.0%) and 16 of 400 (4.0%) of patients treated with 200 mg Entacapone Tablets and placebo, respectively. In patients treated with Entacapone Tablets, diarrhea was generally mild to moderate in severity (8.6%) but was regarded as severe in 1.3%. Diarrhea resulted in withdrawal in 10 of 603 (1.7%) patients, 7 (1.2%) with mild and moderate diarrhea and 3 (0.5%) with severe diarrhea. Diarrhea generally resolved after discontinuation of Entacapone Tablets. Two patients with diarrhea were hospitalized. Typically, diarrhea presents within 4 weeks to 12 weeks after entacapone is started, but it may appear as early as the first week and as late as many months after the initiation of treatment. Diarrhea may be associated with weight loss, dehydration, and hypokalemia. - Postmarketing experience has shown that diarrhea may be a sign of drug-induced microscopic colitis, primarily lymphocytic colitis. In these cases diarrhea has usually been moderate to severe, watery, and non-bloody, at times associated with dehydration, abdominal pain, weight loss, and hypokalemia. In the majority of cases, diarrhea and other colitis-related symptoms resolved or significantly improved when Entacapone Tablets treatment was stopped. In some patients with biopsy confirmed colitis, diarrhea had resolved or significantly improved after discontinuation of Entacapone Tablets but recurred after retreatment with Entacapone Tablets. - If prolonged diarrhea is suspected to be related to Entacapone Tablets, the drug should be discontinued and appropriate medical therapy considered. If the cause of prolonged diarrhea remains unclear or continues after stopping entacapone, then further diagnostic investigations including colonoscopy and biopsies should be considered. - Dopaminergic therapy in Parkinson’s Disease patients has been associated with hallucinations. In clinical trials, hallucinations developed in approximately 4.0% of patients treated with 200 mg Entacapone Tablets or placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 0.8% and 0% of patients treated with 200 mg Entacapone Tablets and placebo, respectively. Hallucinations led to hospitalization in 1.0% and 0.3% of patients in the 200 mg Entacapone Tablets and placebo groups, respectively. - Entacapone Tablets may potentiate the dopaminergic side effects of levodopa and may cause and/or exacerbate preexisting dyskinesia. Although decreasing the dose of levodopa may ameliorate this side effect, many patients in controlled trials continued to experience frequent dyskinesias despite a reduction in their dose of levodopa. The rates of withdrawal for dyskinesia were 1.5% and 0.8% for 200 mg Entacapone Tablets and placebo, respectively. - The events listed below are rare events known to be associated with the use of drugs that increase dopaminergic activity, although they are most often associated with the use of direct dopamine agonists. - Cases of severe rhabdomyolysis have been reported with Entacapone Tablets use. The complicated nature of these cases makes it impossible to determine what role, if any, Entacapone Tablets played in their pathogenesis. Severe prolonged motor activity including dyskinesia may account for rhabdomyolysis. One case, however, included fever and alteration of consciousness. It is therefore possible that the rhabdomyolysis may be a result of the syndrome described in Hyperpyrexia and Confusion. - Cases of a symptom complex resembling the neuroleptic malignant syndrome characterized by elevated temperature, muscular rigidity, altered consciousness, and elevated CPK have been reported in association with the rapid dose reduction or withdrawal of other dopaminergic drugs. Several cases with similar signs and symptoms have been reported in association with Entacapone Tablets therapy, although no information about dose manipulation is available. The complicated nature of these cases makes it difficult to determine what role, if any, Entacapone Tablets may have played in their pathogenesis. No cases have been reported following the abrupt withdrawal or dose reduction of entacapone treatment during clinical studies. - Prescribers should exercise caution when discontinuing entacapone treatment. When considered necessary, withdrawal should proceed slowly. If a decision is made to discontinue treatment with Entacapone Tablets, recommendations include monitoring the patient closely and adjusting other dopaminergic treatments as needed. This syndrome should be considered in the differential diagnosis for any patient who develops a high fever or severe rigidity. Tapering Entacapone Tablets has not been systematically evaluated. - Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening have been reported in some patients treated with ergot derived dopaminergic agents. These complications may resolve when the drug is discontinued, but complete resolution does not always occur. Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot derived drugs (e.g., entacapone) that increase dopaminergic activity can cause them is unknown. It should be noted that the expected incidence of fibrotic complications is so low that even if entacapone caused these complications at rates similar to those attributable to other dopaminergic therapies, it is unlikely that it would have been detected in a cohort of the size exposed to entacapone. Four cases of pulmonary fibrosis were reported during clinical development of entacapone; three of these patients were also treated with pergolide and one with bromocriptine. The duration of treatment with entacapone ranged from 7 months to 17 months. - Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. - For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Entacapone Tablets for any indication. Ideally, periodic skin examination should be performed by appropriately qualified individuals (e.g., dermatologists). - In a 1 year toxicity study, entacapone (plasma exposure 20 times that in humans receiving the maximum recommended daily dose of 1,600 mg) caused an increased incidence in male rats of nephrotoxicity that was characterized by regenerative tubules, thickening of basement membranes, infiltration of mononuclear cells and tubular protein casts. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although this toxicity could represent a species-specific effect, there is not yet evidence that this is so. - Patients with hepatic impairment should be treated with caution. The AUC and Cmax of entacapone approximately doubled in patients with documented liver disease compared to controls. - Entacapone Tablets is a chelator of iron. The impact of entacapone on the body’s iron stores is unknown; however, a tendency towards decreasing serum iron concentrations was noted in clinical trials. In a controlled clinical study serum ferritin levels (as marker of iron deficiency and subclinical anemia) were not changed with entacapone compared to placebo after one year of treatment and there was no difference in rates of anemia or decreased hemoglobin levels. # Adverse Reactions ## Clinical Trials Experience - During the pre-marketing development of entacapone, 1,450 patients with Parkinson’s Disease were treated with entacapone. Included were patients with fluctuating symptoms, as well as those with stable responses to levodopa therapy. All patients received concomitant treatment with levodopa preparations, however, and were similar in other clinical aspects. The most commonly observed adverse events (greater than 5%) in the double-blind, placebo-controlled trials (N=1,003) associated with the use of Entacapone Tablets and not seen at an equivalent frequency among the placebo-treated patients were: dyskinesia and hyperkinesia, nausea, urine discoloration, diarrhea, and abdominal pain. - Approximately 14% of the 603 patients given entacapone in the double-blind, placebo-controlled trials discontinued treatment due to adverse events compared to 9% of the 400 patients who received placebo. The most frequent causes of discontinuation in decreasing order are: psychiatric reasons (2% vs. 1%), diarrhea (2% vs. 0%), dyskinesia and hyperkinesia (2% vs. 1%), nausea (2% vs. 1%), abdominal pain (1% vs. 0%), and aggravation of Parkinson’s Disease symptoms (1% vs. 1%). - Table 4 lists treatment emergent adverse events that occurred in at least 1% of patients treated with entacapone participating in the double-blind, placebo-controlled studies and that were numerically more common in the entacapone group, compared to placebo. In these studies, either entacapone or placebo was added to levodopa and carbidopa (or levodopa and benserazide). Table 4 Summary of Patients With Adverse Events After Start of Trial Drug Administration At Least 1% in Entacapone Tablet Group and Greater than Placebo - The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures do, however, provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse events observed in the population studied. - No differences were noted in the rate of adverse events attributable to entacapone by age or gender. ## Postmarketing Experience There is limited information regarding Postmarketing Experience of Entacapone in the drug label. # Drug Interactions - In vitro studies of human CYP enzymes showed that entacapone inhibited the CYP enzymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A only at very high concentrations (IC50 from 200 microM to over 1,000 microM; an oral 200 mg dose achieves a highest level of approximately 5 microM in people); these enzymes would therefore not be expected to be inhibited in clinical use. - Entacapone is highly protein bound (98%). In vitro studies have shown no binding displacement between entacapone and other highly bound drugs, such as warfarin, salicylic acid, phenylbutazone, and diazepam. - When a single 400 mg dose of entacapone was given together with intravenous isoprenaline (isoproterenol) and epinephrine without coadministered levodopa and dopa decarboxylase inhibitor, the overall mean maximal changes in heart rate during infusion were about 50% and 80% higher than with placebo, for isoprenaline and epinephrine, respectively. - Therefore, drugs known to be metabolized by COMT, such as isoproterenol, epinephrine, norepinephrine, dopamine, dobutamine, alpha-methyldopa, apomorphine, isoetherine, and bitolterol should be administered with caution in patients receiving entacapone regardless of the route of administration (including inhalation), as their interaction may result in increased heart rates, possibly arrhythmias, and excessive changes in blood pressure. - Ventricular tachycardia was noted in one 32-year-old healthy male volunteer in an interaction study after epinephrine infusion and oral entacapone administration. Treatment with propranolol was required. A causal relationship to entacapone administration appears probable but cannot be attributed with certainty. - Levodopa is known to depress prolactin secretion and increase growth hormone levels. Treatment with entacapone coadministered with levodopa and dopa decarboxylase inhibitor does not change these effects. - See WARNINGS regarding concomitant use of Entacapone Tablets and non-selective MAO inhibitors. - No interaction was noted with the MAO-B inhibitor selegiline in two multiple-dose interaction studies when entacapone was coadministered with a levodopa and dopa decarboxylase inhibitor (n=29). More than 600 Parkinson’s Disease patients in clinical trials have used selegiline in combination with entacapone and levodopa and dopa decarboxylase inhibitor. - As most entacapone excretion is via the bile, caution should be exercised when drugs known to interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase are given concurrently with entacapone. These include probenecid, cholestyramine, and some antibiotics (e.g., erythromycin, rifampicin, ampicillin and chloramphenicol). - No interaction with the tricyclic antidepressant imipramine was shown in a single-dose study with entacapone without coadministered levodopa and dopa-decarboxylase inhibitor. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - Pregnancy Category - In embryofetal development studies, entacapone was administered to pregnant animals throughout organogenesis at doses of up to 1,000 mg per kg per day in rats and 300 mg per kg per day in rabbits. Increased incidences of fetal variations were evident in litters from rats treated with the highest dose, in the absence of overt signs of maternal toxicity. The maternal plasma drug exposure (AUC) associated with this dose was approximately 34 times the estimated plasma exposure in humans receiving the maximum recommended daily dose (MRDD) of 1,600 mg. Increased frequencies of abortions and late and total resorptions and decreased fetal weights were observed in the litters of rabbits treated with maternotoxic doses of 100 mg per kg per day (plasma AUCs 0.4 times those in humans receiving the MRDD) or greater. There was no evidence of teratogenicity in these studies. - However, when entacapone was administered to female rats prior to mating and during early gestation, an increased incidence of fetal eye anomalies (macrophthalmia, microphthalmia, anophthalmia) was observed in the litters of dams treated with doses of 160 mg per kg per day (plasma AUCs 7 times those in humans receiving the MRDD) or greater, in the absence of maternotoxicity. Administration of up to 700 mg per kg per day (plasma AUCs 28 times those in humans receiving the MRDD) to female rats during the latter part of gestation and throughout lactation, produced no evidence of developmental impairment in the offspring. - Entacapone is always given concomitantly with levodopa and carbidopa, which is known to cause visceral and skeletal malformations in rabbits. The teratogenic potential of entacapone in combination with levodopa and carbidopa was not assessed in animals. - There is no experience from clinical studies regarding the use of Entacapone Tablets in pregnant women. Therefore, Entacapone Tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Entacapone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Entacapone during labor and delivery. ### Nursing Mothers - In animal studies, entacapone was excreted into maternal rat milk. - It is not known whether entacapone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when entacapone is administered to a nursing woman. ### Pediatric Use - There is no identified potential use of entacapone in pediatric patients. ### Geriatic Use There is no FDA guidance on the use of Entacapone with respect to geriatric patients. ### Gender There is no FDA guidance on the use of Entacapone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Entacapone with respect to specific racial populations. ### Renal Impairment - In a 1 year toxicity study, entacapone (plasma exposure 20 times that in humans receiving the maximum recommended daily dose of 1,600 mg) caused an increased incidence in male rats of nephrotoxicity that was characterized by regenerative tubules, thickening of basement membranes, infiltration of mononuclear cells and tubular protein casts. These effects were not associated with changes in clinical chemistry parameters, and there is no established method for monitoring for the possible occurrence of these lesions in humans. Although this toxicity could represent a species-specific effect, there is not yet evidence that this is so. ### Hepatic Impairment - Patients with hepatic impairment should be treated with caution. The AUC and Cmax of entacapone approximately doubled in patients with documented liver disease compared to controls. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Entacapone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Entacapone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Entacapone in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Entacapone in the drug label. # Overdosage - COMT inhibition by entacapone treatment is dose-dependent. A massive overdose of Entacapone Tablets may theoretically produce a 100% inhibition of the COMT enzyme in people, thereby preventing the metabolism of endogenous and exogenous catechols. - The highest single dose of entacapone administered to humans was 800 mg, resulting in a plasma concentration of 14.1 mcg per mL. The highest daily dose given to humans was 2,400 mg, administered in one study as 400 mg six times daily with levodopa and carbidopa for 14 days in 15 Parkinson’s Disease patients, and in another study as 800 mg three times daily for 7 days in 8 healthy volunteers. At this daily dose, the peak plasma concentrations of entacapone averaged 2.0 mcg per mL (at 45 min., compared to 1.0 mcg per mL and 1.2 mcg per mL with 200 mg entacapone at 45 min.). Abdominal pain and loose stools were the most commonly observed adverse events during this study. Daily doses as high as 2,000 mg Entacapone Tablet have been administered as 200 mg 10 times daily with levodopa and carbidopa or levodopa and benserazide for at least 1 year in 10 patients, for at least 2 years in 8 patients and for at least 3 years in 7 patients. Overall, however, clinical experience with daily doses above 1,600 mg is limited. - The range of lethal plasma concentrations of entacapone based on animal data was 80 mcg per mL to 130 mcg per mL in mice. Respiratory difficulties, ataxia, hypoactivity, and convulsions were observed in mice after high oral (gavage) doses. - Management of Entacapone Tablets overdose is symptomatic; there is no known antidote to Entacapone Tablets. Hospitalization is advised, and general supportive care is indicated. There is no experience with hemodialysis or hemoperfusion, but these procedures are unlikely to be of benefit, because Entacapone Tablets are highly bound to plasma proteins. An immediate gastric lavage and repeated doses of charcoal over time may hasten the elimination of Entacapone Tablet by decreasing its absorption and reabsorption from the GI tract. The adequacy of the respiratory and circulatory systems should be carefully monitored and appropriate supportive measures employed. The possibility of drug interactions, especially with catechol-structured drugs, should be borne in mind. # Pharmacology ## Mechanism of Action - Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). - In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells, and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery. - The mechanism of action of entacapone is believed to be through its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson’s Disease. The higher levodopa levels also lead to increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. - In animals, while entacapone enters the CNS to a minimal extent, it has been shown to inhibit central COMT activity. In humans, entacapone inhibits the COMT enzyme in peripheral tissues. The effects of entacapone on central COMT activity in humans have not been studied. ## Structure - Entacapone is an inhibitor of catechol-O-methyltransferase (COMT), used in the treatment of Parkinson’s Disease as an adjunct to levodopa and carbidopa therapy. It is a nitrocatechol-structured compound with a relative molecular mass of 305.29. The chemical name of entacapone is (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide. Its empirical formula is C14H15N3O5 and its structural formula is: ## Pharmacodynamics - COMT Activity in Erythrocytes: Studies in healthy volunteers have shown that entacapone reversibly inhibits human erythrocyte catechol-O-methyltransferase (COMT) activity after oral administration. There was a linear correlation between entacapone dose and erythrocyte COMT inhibition, the maximum inhibition being 82% following an 800 mg single dose. With a 200 mg single dose of entacapone, maximum inhibition of erythrocyte COMT activity is on average 65% with a return to baseline level within 8 hours. ## Pharmacokinetics - When 200 mg entacapone is administered together with levodopa and carbidopa, it increases the area under the curve (AUC) of levodopa by approximately 35% and the elimination half-life of levodopa is prolonged from 1.3 h to 2.4 h. In general, the average peak levodopa plasma concentration and the time of its occurrence (Tmax of 1 hour) are unaffected. The onset of effect occurs after the first administration and is maintained during long-term treatment. Studies in Parkinson’s Disease patients suggest that the maximal effect occurs with 200 mg entacapone. Plasma levels of 3-OMD are markedly and dose-dependently decreased by entacapone when given with levodopa and carbidopa. - Entacapone pharmacokinetics are linear over the dose range of 5 mg to 800 mg, and are independent of levodopa and carbidopa coadministration. The elimination of entacapone is biphasic, with an elimination half-life of 0.4 h to 0.7 h based on the β-phase and 2.4 h based on the γ-phase. The γ-phase accounts for approximately 10% of the total AUC. The total body clearance after i.v. administration is 850 mL per min. After a single 200 mg dose of Entacapone Tablets, the Cmax is approximately 1.2 mcg per mL. - Entacapone is rapidly absorbed, with a Tmax of approximately 1 hour. The absolute bioavailability following oral administration is 35%. Food does not affect the pharmacokinetics of entacapone. - The volume of distribution of entacapone at steady state after i.v. injection is small (20 L). Entacapone does not distribute widely into tissues due to its high plasma protein binding. Based on in vitro studies, the plasma protein binding of entacapone is 98% over the concentration range of 0.4 mcg per mL to 50 mcg per mL. Entacapone binds mainly to serum albumin. - Entacapone is almost completely metabolized prior to excretion, with only a very small amount (0.2% of dose) found unchanged in urine. The main metabolic pathway is isomerization to the cis-isomer, followed by direct glucuronidation of the parent and cis-isomer; the glucuronide conjugate is inactive. After oral administration of a 14C-labeled dose of entacapone, 10% of labeled parent and metabolite is excreted in urine and 90% in feces. - Entacapone pharmacokinetics are independent of age. No formal gender studies have been conducted. Racial representation in clinical trials was largely limited to Caucasians (there were only 4 blacks in one US trial and no Asians in any of the clinical trials); no conclusions can therefore be reached about the effect of entacapone on groups other than Caucasian. - A single 200 mg dose of entacapone, without levodopa and dopa decarboxylase inhibitor coadministration, showed approximately twofold higher AUC and Cmax values in patients with a history of alcoholism and hepatic impairment (n=10) compared to normal subjects (n=10). All patients had biopsy-proven liver cirrhosis caused by alcohol. According to Child-Pugh grading 7 patients with liver disease had mild hepatic impairment and 3 patients had moderate hepatic impairment. As only about 10% of the entacapone dose is excreted in urine as parent compound and conjugated glucuronide, biliary excretion appears to be the major route of excretion of this drug. Consequently, entacapone should be administered with care to patients with biliary obstruction. - The pharmacokinetics of entacapone have been investigated after a single 200 mg entacapone dose, without levodopa and dopa decarboxylase inhibitor coadministration, in a specific renal impairment study. There were three groups: normal subjects (n=7; creatinine clearance greater than 1.12 mL per sec per 1.73 m2), moderate impairment (n=10; creatinine clearance ranging from 0.60 mL per sec per 1.73 m2 to 0.89 mL per sec per 1.73 m2), and severe impairment (n=7; creatinine clearance ranging from 0.20 mL per sec per 1.73 m2 to 0.44 mL per sec per 1.73 m2). No important effects of renal function on the pharmacokinetics of entacapone were found. ## Nonclinical Toxicology - Two-year carcinogenicity studies of entacapone were conducted in mice and rats. Rats were treated once daily by oral gavage with entacapone doses of 20 mg per kg, 90 mg per kg, or 400 mg per kg. An increased incidence of renal tubular adenomas and carcinomas was found in male rats treated with the highest dose of entacapone. Plasma exposures (AUC) associated with this dose were approximately 20 times higher than estimated plasma exposures of humans receiving the maximum recommended daily dose of entacapone (MRDD = 1,600 mg). Mice were treated once daily by oral gavage with doses of 20 mg per kg, 100 mg per kg or 600 mg per kg of entacapone (0.05, 0.3, and 2 times the MRDD for humans on a mg per m2 basis). Because of a high incidence of premature mortality in mice receiving the highest dose of entacapone, the mouse study is not an adequate assessment of carcinogenicity. Although no treatment related tumors were observed in animals receiving the lower doses, the carcinogenic potential of entacapone has not been fully evaluated. The carcinogenic potential of entacapone administered in combination with levodopa and carbidopa has not been evaluated. - Entacapone was mutagenic and clastogenic in the in vitro mouse lymphoma and thymidine kinase assay in the presence and absence of metabolic activation, and was clastogenic in cultured human lymphocytes in the presence of metabolic activation. Entacapone, either alone or in combination with levodopa and carbidopa, was not clastogenic in the in vivo mouse micronucleus test or mutagenic in the bacterial reverse mutation assay (Ames test). - Entacapone did not impair fertility or general reproductive performance in rats treated with up to 700 mg per kg per day (plasma AUCs 28 times those in humans receiving the MRDD). Delayed mating, but no fertility impairment, was evident in female rats treated with 700 mg per kg per day of entacapone. # Clinical Studies - The effectiveness of Entacapone Tablets as an adjunct to levodopa in the treatment of Parkinson’s Disease was established in three 24-week multicenter, randomized, double-blind placebo-controlled trials in patients with Parkinson’s Disease. In two of these trials, the patients’ disease was "fluctuating", i.e., was characterized by documented periods of "On" (periods of relatively good functioning) and "Off" (periods of relatively poor functioning), despite optimum levodopa therapy. There was also a withdrawal period following 6 months of treatment. In the third trial patients were not required to have been experiencing fluctuations. Prior to the controlled part of the trials, patients were stabilized on levodopa for 2 weeks to 4 weeks. Entacapone has not been systematically evaluated in patients who do not experience fluctuations. - In the first two studies to be described, patients were randomized to receive placebo or entacapone 200 mg administered concomitantly with each dose of levodopa and carbidopa (up to 10 times daily, but averaging 4 doses to 6 doses per day). The formal double-blind portion of both trials was 6 months long. Patients recorded the time spent in the "On" and "Off" states in home diaries periodically throughout the duration of the trial. In one study, conducted in the Nordic countries, the primary outcome measure was the total mean time spent in the "On" state during an 18-hour diary recorded day (6 AM to midnight). In the other study, the primary outcome measure was the proportion of awake time spent over 24 hours in the "On" state. - In addition to the primary outcome measure, the amount of time spent in the "Off" state was evaluated, and patients were also evaluated by subparts of the Unified Parkinson’s Disease Rating Scale (UPDRS), a frequently used multi-item rating scale intended to assess mentation (Part I), activities of daily living (Part II), motor function (Part III), complications of therapy (Part IV), and disease staging (Part V and VI); an investigator’s and patient’s global assessment of clinical condition, a 7-point subjective scale designed to assess global functioning in Parkinson’s Disease; and the change in daily levodopa and carbidopa dose. - In one of the studies, 171 patients were randomized in 16 centers in Finland, Norway, Sweden, and Denmark (Nordic study), all of whom received concomitant levodopa plus dopa-decarboxylase inhibitor (either levodopa and carbidopa or levodopa and benserazide). In the second trial, 205 patients were randomized in 17 centers in North America (US and Canada); all patients received concomitant levodopa and carbidopa. - The following tables display the results of these two trials: - Effects on "On" time did not differ by age, sex, weight, disease severity at baseline, levodopa dose and concurrent treatment with dopamine agonists or selegiline. - Withdrawal of entacapone: In the North American study, abrupt withdrawal of entacapone, without alteration of the dose of levodopa and carbidopa, resulted in a significant worsening of fluctuations, compared to placebo. In some cases, symptoms were slightly worse than at baseline, but returned to approximately baseline severity within two weeks following levodopa dose increase on average by 80 mg. In the Nordic study, similarly, a significant worsening of parkinsonian symptoms was observed after entacapone withdrawal, as assessed two weeks after drug withdrawal. At this phase, the symptoms were approximately at baseline severity following levodopa dose increase by about 50 mg. - In the third placebo controlled trial, a total of 301 patients were randomized in 32 centers in Germany and Austria. In this trial, as in the other two trials, entacapone 200 mg was administered with each dose of levodopa and dopa decarboxylase inhibitor (up to 10 times daily) and UPDRS Parts II and III and total daily "On" time were the primary measures of effectiveness. The following results were seen for the primary measures, as well as for some secondary measures: # How Supplied - Entacapone Tablets are supplied as 200 mg film-coated tablets for oral administration. The oval-shaped tablets are brownish-orange, unscored and embossed “EN1” over “200” on one side. Tablets are provided in HDPE containers as follows: - Bottle of 100 tablets NDC 0378-9080-01 ## Storage - Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL – 200 mg NDC 0378-9080-01 Entacapone Tablets 200 mg Rx only 100 Tablets Each tablet contains: Entacapone 200 mg Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Usual Adult Dosage: See package insert for dosage information. ### Ingredients and Appearance # Patient Counseling Information - Patients should be instructed to take Entacapone Tablets only as prescribed. - Patients should be informed that hallucinations can occur. - Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sweating. Hypotension may occur more frequently during initial therapy. Accordingly, patients should be cautioned against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods, and especially at the initiation of treatment with Entacapone Tablets. - Patients should be advised that they should neither drive a car nor operate other complex machinery until they have gained sufficient experience on Entacapone Tablets to gauge whether or not it affects their mental and/or motor performance adversely. Because of the possible additive sedative effects, caution should be used when patients are taking other CNS depressants in combination with Entacapone Tablets. - Patients should be informed that nausea may occur, especially at the initiation of treatment with Entacapone Tablets. - Patients should be informed that diarrhea may occur with Entacapone Tablets and it may have a delayed onset. Sometimes prolonged diarrhea may be caused by colitis (inflammation of the large intestine). Patients with diarrhea should drink fluids to maintain adequate hydration and monitor for weight loss. If diarrhea associated with Entacapone Tablets is prolonged, discontinuing the drug is expected to lead to resolution, if diarrhea continues after stopping entacapone, further diagnostic investigations may be needed. - Patients should be advised of the possibility of an increase in dyskinesia. - Patients should be advised that treatment with entacapone may cause a change in the color of their urine (a brownish orange discoloration) that is not clinically relevant. In controlled trials, 10% of patients treated with Entacapone Tablets reported urine discoloration compared to 0% of placebo patients. - Although Entacapone Tablets has not been shown to be teratogenic in animals, it is always given in conjunction with levodopa and carbidopa, which is known to cause visceral and skeletal malformations in the rabbit. Accordingly, patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy (see PRECAUTIONS, PREGNANCY). - Entacapone is excreted into maternal milk in rats. Because of the possibility that entacapone may be excreted into human maternal milk, patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant. - There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease, including Entacapone Tablets. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Entacapone Tablets. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Entacapone Tablets. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Entacapone Tablets. # Precautions with Alcohol - Alcohol-Entacapone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Comtan®[1] # Look-Alike Drug Names There is limited information regarding Entacapone Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Entacapone
5994ea98b61b1f80d9e24d36a7fb19b17a80c623	wikidoc	Enterocyte	Enterocyte # Overview Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal lumen. The cells also have a secretory role. # Functions The major functions of enterocytes include: - Ion uptake, including sodium, calcium, magnesium, and iron. This typically occurs through active transport. - Water uptake. This follows the osmotic gradient established by Na+/K+ ATPase on the basolateral surface. This can occur transcellularly or paracellularly. - Sugar uptake. Polysaccharidases and disaccharidases in the glycocalyx break down large sugar molecules, which are then absorbed. Glucose crosses the apical membrane of the enterocyte using the Na+ dependent glucose transporter. It moves through the cytosol (cytoplasm) and exits the enterocyte via the basolateral membrane (into the blood capillary) using GLUT-2 (SLC2A2). Galactose uses the same transport system. Fructose, on the other hand, crosses the apical membrane of the enterocyte, using GLUT-5 (SLC2A5). It is thought to cross into the blood capillary using one of the other GLUT transporters. - Peptide and amino acid uptake. Peptidases in the glycocalyx cleave proteins to amino acids or small peptides. Enteropeptidase is responsible for activating pancreatic trypsinogen into trypsin, which activates other pancreatic zymogens. - Lipid uptake. Lipids are broken down by pancreatic lipase and bile, and then diffuse into the enterocytes. Smaller lipids are transported into intestinal capillaries, while larger lipids are processed by the Golgi and smooth endoplasmic reticulum into lipoprotein chylomicra and exocytozed into lacteals. - Vitamin uptake. Receptors bind to the ]-gastric intrinsic factor complex and are taken into the cell. - Resorption of unconjugated bile salts. Bile that was released and not used in emulsification of lipids are reabsorbed in the ileum. Also known as the enterohepatic circulation. - Secretion of immunoglobulins. IgA from plasma cells in the mucosa are absorbed through receptor mediated endocytosis on the basolateral surface and released as a receptor-IgA complex into the intestinal lumen. The receptor component confers additional stability to the molecule. # Pathology Dietary fructose intolerance occurs when there is a deficiency in the amount of fructose carrier. Lactose intolerance is the most common problem of carbohydrate digestion and is created by an insufficient amount of lactase (a disaccharidase) enzyme, which is used to break down the sugar. As a result of this deficiency, undigested lactose cannot be absorbed and is instead passed on to the colonic bacteria, which metabolize the lactose. The bacteria release gas and metabolic products that enhance colonic motility. Problems with the gastric intrinsic factor or its receptor can result in pernicious anemia.	Enterocyte Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal lumen. The cells also have a secretory role. # Functions The major functions of enterocytes include[1]: - Ion uptake, including sodium, calcium, magnesium, and iron. This typically occurs through active transport. - Water uptake. This follows the osmotic gradient established by Na+/K+ ATPase on the basolateral surface. This can occur transcellularly or paracellularly. - Sugar uptake. Polysaccharidases and disaccharidases in the glycocalyx break down large sugar molecules, which are then absorbed. Glucose crosses the apical membrane of the enterocyte using the Na+ dependent glucose transporter. It moves through the cytosol (cytoplasm) and exits the enterocyte via the basolateral membrane (into the blood capillary) using GLUT-2 (SLC2A2). Galactose uses the same transport system. Fructose, on the other hand, crosses the apical membrane of the enterocyte, using GLUT-5 (SLC2A5). It is thought to cross into the blood capillary using one of the other GLUT transporters. - Peptide and amino acid uptake. Peptidases in the glycocalyx cleave proteins to amino acids or small peptides. Enteropeptidase is responsible for activating pancreatic trypsinogen into trypsin, which activates other pancreatic zymogens. - Lipid uptake. Lipids are broken down by pancreatic lipase and bile, and then diffuse into the enterocytes. Smaller lipids are transported into intestinal capillaries, while larger lipids are processed by the Golgi and smooth endoplasmic reticulum into lipoprotein chylomicra and exocytozed into lacteals. - Vitamin uptake. Receptors bind to the [[vitamin B12\|vitamin BTemplate:Ssub]]-gastric intrinsic factor complex and are taken into the cell. - Resorption of unconjugated bile salts. Bile that was released and not used in emulsification of lipids are reabsorbed in the ileum. Also known as the enterohepatic circulation. - Secretion of immunoglobulins. IgA from plasma cells in the mucosa are absorbed through receptor mediated endocytosis on the basolateral surface and released as a receptor-IgA complex into the intestinal lumen. The receptor component confers additional stability to the molecule. # Pathology Dietary fructose intolerance occurs when there is a deficiency in the amount of fructose carrier. Lactose intolerance is the most common problem of carbohydrate digestion and is created by an insufficient amount of lactase (a disaccharidase) enzyme, which is used to break down the sugar. As a result of this deficiency, undigested lactose cannot be absorbed and is instead passed on to the colonic bacteria, which metabolize the lactose. The bacteria release gas and metabolic products that enhance colonic motility. Problems with the gastric intrinsic factor or its receptor can result in pernicious anemia.	https://www.wikidoc.org/index.php/Enterocyte
718320a606f3f786ed6f5054467380505f94bc06	wikidoc	Germ layer	Germ layer # Overview A germ layer is a collection of cells, formed during animal embryogenesis. Germ layers are only really pronounced in the vertebrates. However, all animals more complex than sponges (eumetazoans and agnotozoans) produce two or three primary tissue layers (sometimes called primary germ layers). Animals with radial symmetry, like cnidarians, produce two called ectoderm and endoderm, making them diploblastic. Animals with bilateral symmetry produce a third layer in-between called mesoderm, making them triploblastic. Germ layers will eventually give rise to all of an animal’s tissues and organs through a process called organogenesis. # Germ layers Caspar Friedrich Wolff observed organization of the early embryo in leaf-like layers. Later, Heinz Christian Pander discovered germ layers while studying chick embryos. Among animals, sponges show the simplest organization, having a single germ layer. Although they have differentiated cells (e.g. collar cells), they lack true tissue coordination. Diploblastic animals, Cnidaria and ctenophores, show an increase in complexity, having two germ layers, the endoderm and ectoderm. Diploblastic animals are organized into recognisable tissues. All higher animals (from flatworms to man) are triploblastic, having in addition a mesoderm. Triploblastic animals develop recognisable organs. ## Development Fertilization leads to the formation of a zygote. During the next stage, cleavage, mitotic cell divisions transform the zygote into a tiny ball of cells called a blastula. This early embryonic form undergoes a massive reorganization called gastrulation forming a gastrula with either two or three layers (the germ layers). In all vertebrates, these are the forerunners of all adult tissues and organs. The appearance of the archenteron marks the onset of gastrulation. In humans, after about three days, the zygote has formed a solid mass of cells by mitotic division, called a morula. This then changes to a blastocyst, consisting of an outer layer called a trophoblast, and an inner cell mass called the embryoblast. Filled with uterine fluid, the blastocyst breaks out of the zona pellucida undergoes implantation. The inner cell mass initially has two layers: the hypoblast and epiblast. At the end of the second week, a primitive streak appears. The epiblast in this region moves towards the primitive streak, dive down into it, and form a new layer, called the endoderm, pushing the hypoblast out of the way (this goes on to form the amnion.) The epiblast keeps moving and forms a second layer, the mesoderm. The top layer is now called the ectoderm. ## Endoderm The endoderm is one of the germ layers formed during animal embryogenesis. Cells migrating inward along the archenteron form the inner layer of the gastrula, which develops into the endoderm. The endoderm consists at first of flattened cells, which subsequently become columnar. It forms the epithelial lining of the whole of the digestive tube excepting part of the mouth and pharynx and the terminal part of the rectum (which are lined by involutions of the ectoderm). The lining cells of all the glands which open into the digestive tube, including those of the liver and pancreas, the epithelium of the auditory tube and tympanic cavity, of the trachea, bronchi, and air cells of the lungs, of the urinary bladder and part of the urethra, and that which lines the follicles of the thyroid gland and thymus are also formed by this layer. The endoderm forms: stomach, colon, liver, pancreas, urinary bladder; lining of urethra, epithelial parts of trachea, lungs, pharynx, thyroid, parathyroid, intestine. ## Mesoderm The mesoderm germ layer forms in the embryos of animals more complex than cnidarians, making them triploblastic. During gastrulation, some of the cells migrating inward contribute to the mesoderm, an additional layer between the endoderm and the ectoderm. This key innovation evolved hundreds of millions of years ago and led to the evolution of nearly all large, complex animals. The formation of a mesoderm led to the formation of a coelom. Organs formed inside a coelom can freely move, grow, and develop independently of the body wall while fluid cushions protect them from shocks. The mesoderm forms: skeletal muscle, skeleton, dermis of skin, crystal lens of the eye, connective tissue, urogenital system, heart, blood (lymph cells), and spleen. ## Ectoderm The ectoderm is the start of a tissue that covers the body surfaces. It emerges first and forms from the outermost of the germ layers. The ectoderm forms: Central nervous system, retina and cornea (but not crystal lens), cranial and sensory, ganglia and nerves, pigment cells, head connective tissue, epidermis, hair, mammary glands. ## Neural crest Due to the great importance of the neural crest it has been referred to as the fourth germ layer. It is, however, derived from the ectoderm.	Germ layer Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview A germ layer is a collection of cells, formed during animal embryogenesis. Germ layers are only really pronounced in the vertebrates. However, all animals more complex than sponges (eumetazoans and agnotozoans) produce two or three primary tissue layers (sometimes called primary germ layers). Animals with radial symmetry, like cnidarians, produce two called ectoderm and endoderm, making them diploblastic. Animals with bilateral symmetry produce a third layer in-between called mesoderm, making them triploblastic. Germ layers will eventually give rise to all of an animal’s tissues and organs through a process called organogenesis. # Germ layers Caspar Friedrich Wolff observed organization of the early embryo in leaf-like layers. Later, Heinz Christian Pander discovered germ layers while studying chick embryos. Among animals, sponges show the simplest organization, having a single germ layer. Although they have differentiated cells (e.g. collar cells), they lack true tissue coordination. Diploblastic animals, Cnidaria and ctenophores, show an increase in complexity, having two germ layers, the endoderm and ectoderm. Diploblastic animals are organized into recognisable tissues. All higher animals (from flatworms to man) are triploblastic, having in addition a mesoderm. Triploblastic animals develop recognisable organs. ## Development Fertilization leads to the formation of a zygote. During the next stage, cleavage, mitotic cell divisions transform the zygote into a tiny ball of cells called a blastula. This early embryonic form undergoes a massive reorganization called gastrulation forming a gastrula with either two or three layers (the germ layers). In all vertebrates, these are the forerunners of all adult tissues and organs. The appearance of the archenteron marks the onset of gastrulation. In humans, after about three days, the zygote has formed a solid mass of cells by mitotic division, called a morula. This then changes to a blastocyst, consisting of an outer layer called a trophoblast, and an inner cell mass called the embryoblast. Filled with uterine fluid, the blastocyst breaks out of the zona pellucida undergoes implantation. The inner cell mass initially has two layers: the hypoblast and epiblast. At the end of the second week, a primitive streak appears. The epiblast in this region moves towards the primitive streak, dive down into it, and form a new layer, called the endoderm, pushing the hypoblast out of the way (this goes on to form the amnion.) The epiblast keeps moving and forms a second layer, the mesoderm. The top layer is now called the ectoderm. ## Endoderm The endoderm is one of the germ layers formed during animal embryogenesis. Cells migrating inward along the archenteron form the inner layer of the gastrula, which develops into the endoderm. The endoderm consists at first of flattened cells, which subsequently become columnar. It forms the epithelial lining of the whole of the digestive tube excepting part of the mouth and pharynx and the terminal part of the rectum (which are lined by involutions of the ectoderm). The lining cells of all the glands which open into the digestive tube, including those of the liver and pancreas, the epithelium of the auditory tube and tympanic cavity, of the trachea, bronchi, and air cells of the lungs, of the urinary bladder and part of the urethra, and that which lines the follicles of the thyroid gland and thymus are also formed by this layer. The endoderm forms: stomach, colon, liver, pancreas, urinary bladder; lining of urethra, epithelial parts of trachea, lungs, pharynx, thyroid, parathyroid, intestine. ## Mesoderm The mesoderm germ layer forms in the embryos of animals more complex than cnidarians, making them triploblastic. During gastrulation, some of the cells migrating inward contribute to the mesoderm, an additional layer between the endoderm and the ectoderm. This key innovation evolved hundreds of millions of years ago and led to the evolution of nearly all large, complex animals. The formation of a mesoderm led to the formation of a coelom. Organs formed inside a coelom can freely move, grow, and develop independently of the body wall while fluid cushions protect them from shocks. The mesoderm forms: skeletal muscle, skeleton, dermis of skin, crystal lens of the eye, connective tissue, urogenital system, heart, blood (lymph cells), and spleen. ## Ectoderm The ectoderm is the start of a tissue that covers the body surfaces. It emerges first and forms from the outermost of the germ layers. The ectoderm forms: Central nervous system, retina and cornea (but not crystal lens), cranial and sensory, ganglia and nerves, pigment cells, head connective tissue, epidermis, hair, mammary glands. ## Neural crest Due to the great importance of the neural crest it has been referred to as the fourth germ layer. It is, however, derived from the ectoderm.	https://www.wikidoc.org/index.php/Entoderm
cdbb04626c36b36aff46c20de602844d148410fb	wikidoc	Glial cell	Glial cell File:Neuroglia.png Glial cells, commonly called neuroglia or simply glia (greek for "glue"), are non-neuronal cells that provide support and nutrition, maintain homeostasis, form myelin, and participate in signal transmission in the nervous system. In the human brain, glia are estimated to outnumber neurons by about 10 to 1. Glial cells provide support and protection for neurons, the other main type of cell in the central nervous system. They are thus known as the "glue" of the nervous system. The four main functions of glial cells are to surround neurons and hold them in place, to supply nutrients and oxygen to neurons, to insulate one neuron from another, and to destroy pathogens and remove dead neurons. # Function of the glial cell Some glia function primarily as physical support for neurons. Others regulate the internal environment of the brain, especially the fluid surrounding neurons and their synapses, and provide nutrition to nerve cells. Glia have important developmental roles, guiding migration of neurons in early development, and producing molecules that modify the growth of axons and dendrites. Recent findings in the hippocampus and cerebellum have indicated that glia are also active participants in synaptic transmission, regulating clearance of neurotransmitter from the synaptic cleft, releasing factors such as ATP which modulate presynaptic function, and even releasing neurotransmitters themselves. Unlike the neuron, which is amitotic, glia are capable of mitosis. Traditionally glia had been thought to lack certain features of neurons. For example, glia were not believed to have chemical synapses or to release neurotransmitters. They were considered to be the passive bystanders of neural transmission. However, recent studies disproved this. For example, astrocytes are crucial in clearance of neurotransmitter from within the synaptic cleft, which provides distinction between arrival of action potentials and prevents toxic build up of certain neurotransmitters such as glutamate (excitotoxicity). Furthermore, at least in vitro, astrocytes can release neurotransmitter glutamate in response to certain stimulation. Another unique type of glia, the oligodendrocyte precursor cells or OPCs, have very well defined and functional synapses from at least two major groups of neurons. The only notable differences between neurons and glia, by modern scrutiny, are the ability to generate action potentials and the polarity of neurons, namely the axons and dendrites which glia lack. It is inappropriate nowadays to consider glia as 'glue' in the nervous system as the name implies but more of a partner to neurons. They are also crucial in the development of the nervous system and in processes such as synaptic plasticity and synaptogenesis. Glia have a role in the regulation of repair of neurons after injury. In the CNS glia suppress repair. Astrocytes enlarge and proliferate to form a scar and produce myelin and inhibitory molecules that inhibit regrowth of a damaged or severed axon. In the PNS Schwann cells promote repair. After axon injury Schwann cells regress to an earlier developmental state to encourage regrowth of the axon. This difference between PNS and CNS raises hopes for the regeneration of nervous tissue in the CNS, for example a spinal cord injury or severance. # Types of glia ## Microglia Microglia are specialized macrophages capable of phagocytosis that protect neurons of the central nervous system. Though not technically glia because they are derived from hemopoietic precursors rather than ectodermal tissue, they are commonly categorized as such because of their supportive role to neurons. These cells comprise approximately 15% of the total cells of the central nervous system. They are found in all regions of the brain and spinal cord. Microglial cells are small relative to macroglial cells, with changing shapes and oblong nuclei. They are mobile within the brain and multiply when the brain is damaged. In the healthy central nervous system, microglia processes constantly sample all aspects of their environment (neurons, macroglia and blood vessels). ## Macroglia # Capacity to divide Glia retain the ability to undergo cell division in adulthood, while most neurons cannot. The view is based on the general deficiency of the mature nervous system in replacing neurons after an insult or injury, such as a stroke or trauma, while very often there is a profound proliferation of glia, or gliosis near or at the site of damage. However, detailed studies found no evidence that 'mature' glia, such as astrocytes or oligodendrocytes, retain the ability of mitosis. Only the resident oligodendrocyte precursor cells seem to keep this ability after the nervous system matures. On the other hand, there are a few regions in the mature nervous system, such as the dentate gyrus of the hippocampus and the subventricular zone, where generation of new neurons can be observed. # Embryological development Most glia are derived from ectodermal tissue of the developing embryo, particularly the neural tube and crest. The exception is microglia, which are derived from hemopoietic stem cells. In the adult, microglia are largely a self-renewing population and are distinct from macrophages and monocytes which infiltrate the injured and diseased CNS. In the central nervous system, glia develop from the ventricular zone of the neural tube. These glia include the oligodendrocytes, ependymal cells, and astrocytes. In the peripheral nervous system, glia derive from the neural crest. These PNS glia include Schwann cells in nerves and satellite cells in ganglia. # History Glia were discovered in 1856 by the pathologist Rudolf Virchow in his search for a 'connective tissue' in the brain. The human brain contains about ten times more glial cells than neurons. Following its discovery in the late 19th century, this fact underwent significant media distortion, emerging as the famous myth claiming that "we are using only 10% of our brain". The role of glial cells as managers of communications in the synapse gap, thus modifying learning pace, has been discovered only very recently (2004). # Additional images - Oligodendrocyte - Section of central canal of medulla spinalis, showing ependymal and neuroglial cells. - Transverse section of a cerebellar folium.	Glial cell Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] File:Neuroglia.png Glial cells, commonly called neuroglia or simply glia (greek for "glue"), are non-neuronal cells that provide support and nutrition, maintain homeostasis, form myelin, and participate in signal transmission in the nervous system. In the human brain, glia are estimated to outnumber neurons by about 10 to 1.[1] Glial cells provide support and protection for neurons, the other main type of cell in the central nervous system. They are thus known as the "glue" of the nervous system. The four main functions of glial cells are to surround neurons and hold them in place, to supply nutrients and oxygen to neurons, to insulate one neuron from another, and to destroy pathogens and remove dead neurons. # Function of the glial cell Some glia function primarily as physical support for neurons. Others regulate the internal environment of the brain, especially the fluid surrounding neurons and their synapses, and provide nutrition to nerve cells. Glia have important developmental roles, guiding migration of neurons in early development, and producing molecules that modify the growth of axons and dendrites. Recent findings in the hippocampus and cerebellum have indicated that glia are also active participants in synaptic transmission, regulating clearance of neurotransmitter from the synaptic cleft, releasing factors such as ATP which modulate presynaptic function, and even releasing neurotransmitters themselves. Unlike the neuron, which is amitotic, glia are capable of mitosis. Traditionally glia had been thought to lack certain features of neurons. For example, glia were not believed to have chemical synapses or to release neurotransmitters. They were considered to be the passive bystanders of neural transmission. However, recent studies disproved this. For example, astrocytes are crucial in clearance of neurotransmitter from within the synaptic cleft, which provides distinction between arrival of action potentials and prevents toxic build up of certain neurotransmitters such as glutamate (excitotoxicity). Furthermore, at least in vitro, astrocytes can release neurotransmitter glutamate in response to certain stimulation. Another unique type of glia, the oligodendrocyte precursor cells or OPCs, have very well defined and functional synapses from at least two major groups of neurons. The only notable differences between neurons and glia, by modern scrutiny, are the ability to generate action potentials and the polarity of neurons, namely the axons and dendrites which glia lack. It is inappropriate nowadays to consider glia as 'glue' in the nervous system as the name implies but more of a partner to neurons. They are also crucial in the development of the nervous system and in processes such as synaptic plasticity and synaptogenesis. Glia have a role in the regulation of repair of neurons after injury. In the CNS glia suppress repair. Astrocytes enlarge and proliferate to form a scar and produce myelin and inhibitory molecules that inhibit regrowth of a damaged or severed axon. In the PNS Schwann cells promote repair. After axon injury Schwann cells regress to an earlier developmental state to encourage regrowth of the axon. This difference between PNS and CNS raises hopes for the regeneration of nervous tissue in the CNS, for example a spinal cord injury or severance. # Types of glia ## Microglia Microglia are specialized macrophages capable of phagocytosis that protect neurons of the central nervous system. Though not technically glia because they are derived from hemopoietic precursors rather than ectodermal tissue, they are commonly categorized as such because of their supportive role to neurons. These cells comprise approximately 15% of the total cells of the central nervous system. They are found in all regions of the brain and spinal cord. Microglial cells are small relative to macroglial cells, with changing shapes and oblong nuclei. They are mobile within the brain and multiply when the brain is damaged. In the healthy central nervous system, microglia processes constantly sample all aspects of their environment (neurons, macroglia and blood vessels). ## Macroglia # Capacity to divide Glia retain the ability to undergo cell division in adulthood, while most neurons cannot. The view is based on the general deficiency of the mature nervous system in replacing neurons after an insult or injury, such as a stroke or trauma, while very often there is a profound proliferation of glia, or gliosis near or at the site of damage. However, detailed studies found no evidence that 'mature' glia, such as astrocytes or oligodendrocytes, retain the ability of mitosis. Only the resident oligodendrocyte precursor cells seem to keep this ability after the nervous system matures. On the other hand, there are a few regions in the mature nervous system, such as the dentate gyrus of the hippocampus and the subventricular zone, where generation of new neurons can be observed. # Embryological development Most glia are derived from ectodermal tissue of the developing embryo, particularly the neural tube and crest. The exception is microglia, which are derived from hemopoietic stem cells. In the adult, microglia are largely a self-renewing population and are distinct from macrophages and monocytes which infiltrate the injured and diseased CNS. In the central nervous system, glia develop from the ventricular zone of the neural tube. These glia include the oligodendrocytes, ependymal cells, and astrocytes. In the peripheral nervous system, glia derive from the neural crest. These PNS glia include Schwann cells in nerves and satellite cells in ganglia. # History Glia were discovered in 1856 by the pathologist Rudolf Virchow in his search for a 'connective tissue' in the brain. The human brain contains about ten times more glial cells than neurons. [1] Following its discovery in the late 19th century, this fact underwent significant media distortion, emerging as the famous myth claiming that "we are using only 10% of our brain". The role of glial cells as managers of communications in the synapse gap, thus modifying learning pace, has been discovered only very recently (2004). # Additional images - Oligodendrocyte - Section of central canal of medulla spinalis, showing ependymal and neuroglial cells. - Transverse section of a cerebellar folium.	https://www.wikidoc.org/index.php/Ependymal_cell
1de164485e249ac677450ed0f83feb733d3462f7	wikidoc	Epicardial	Epicardial Epicardial is a term used by some cardiac surgeons meaning " on the outside of the cardiac muscle". # Pathological Findings Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology - Epicardial Scarring: Gross, marked thickening of epicardium, sugar-coated appearance cause unknown - Epicardial Scarring: Gross, marked thickening of epicardium, sugar-coated appearance - Epicardial petechiae: Gross, an excellent example of infarct heart with petechiae. - Heart: Soldiers Patch: Gross, natural color, large area of epicardial fibrosis over mid-portion of left ventricle. - Disseminated intravascular coagulation; External surface of the heart showing epicardial petechiae - Cardiac rhabdomyoma: Note the multiple, minute tumors studding the epicardial surface. This pattern of involvement is typical in patients with tuberous sclerosis. - Granular cell tumor: Localized epicardial tumor: Note the cut surface of circumscribed white tumor on the epicardial surface and the underlying right ventricular trabeculations. - Granular cell tumor: Localized epicardial tumor (arrowheads) overlying the left main coronary artery close to its takeoff. Note aorta (AO) posterior to the pulmonary artery (PA). - Bronchogenic cyst: This example was removed from the epicardial surface of a 13-year-old. - Liposarcoma, Heart: Gross specimen demonstrates the posterior wall of the heart studded with multiple epicardial nodules over the right and left ventricles. - Acute myocardial infarction with epicardial fibrin - The heart in Leukemia: Note the biventricular, predominantly subepicardial diffuse infiltrates. The patient was a 45-year-old man with acute myelogenous leukemia who died with disseminated disease.	Epicardial Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Epicardial is a term used by some cardiac surgeons meaning " on the outside of the cardiac muscle". # Pathological Findings Image courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology - Epicardial Scarring: Gross, marked thickening of epicardium, sugar-coated appearance cause unknown - Epicardial Scarring: Gross, marked thickening of epicardium, sugar-coated appearance - Epicardial petechiae: Gross, an excellent example of infarct heart with petechiae. - Heart: Soldiers Patch: Gross, natural color, large area of epicardial fibrosis over mid-portion of left ventricle. - Disseminated intravascular coagulation; External surface of the heart showing epicardial petechiae - Cardiac rhabdomyoma: Note the multiple, minute tumors studding the epicardial surface. This pattern of involvement is typical in patients with tuberous sclerosis. - Granular cell tumor: Localized epicardial tumor: Note the cut surface of circumscribed white tumor on the epicardial surface and the underlying right ventricular trabeculations. - Granular cell tumor: Localized epicardial tumor (arrowheads) overlying the left main coronary artery close to its takeoff. Note aorta (AO) posterior to the pulmonary artery (PA). - Bronchogenic cyst: This example was removed from the epicardial surface of a 13-year-old. - Liposarcoma, Heart: Gross specimen demonstrates the posterior wall of the heart studded with multiple epicardial nodules over the right and left ventricles. - Acute myocardial infarction with epicardial fibrin - The heart in Leukemia: Note the biventricular, predominantly subepicardial diffuse infiltrates. The patient was a 45-year-old man with acute myelogenous leukemia who died with disseminated disease.	https://www.wikidoc.org/index.php/Epicardial
3543478c85e034dced0be9164710ce5bdc8c5115	wikidoc	Epicardium	Epicardium # Overview Epicardium describes the outer layer of heart tissue (from Greek; epi- outer, cardium heart). When considered as a part of the pericardium, it is the inner layer, or visceral pericardium. Its largest constituent is connective tissue and functions as a protective layer. The visceral pericardium apparently produces the pericardial fluid, which lubricates motion between the inner and outer layers of the pericardium. During ventricular contraction, the wave of depolarization moves from endocardial to epicardial surface.	Epicardium Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Epicardium describes the outer layer of heart tissue (from Greek; epi- outer, cardium heart). When considered as a part of the pericardium, it is the inner layer, or visceral pericardium. Its largest constituent is connective tissue and functions as a protective layer. The visceral pericardium apparently produces the pericardial fluid, which lubricates motion between the inner and outer layers of the pericardium. During ventricular contraction, the wave of depolarization moves from endocardial to epicardial surface. # External links - Histology at University of Southern California cv/c_63 - http://sprojects.mmi.mcgill.ca/embryology/cvs/heart_tube.html - Template:UMichAtlas - "MRI of chest, lateral view" it:Epicardio nl:Epicard Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Epicardium
ff6d349d60e7e7a391ec2415475253a73c5f25bc	wikidoc	Epididymis	Epididymis The epididymis is part of the human male reproductive system and is present in all male mammals. It is a narrow, tightly-coiled tube connecting the efferent ducts from the rear of each testicle to its vas deferens. # Regions The epididymis can be divided into three main regions - the head (caput) - the body (corpus) - the tail (cauda) # Role in storage of sperm and ejaculation Spermatozoa formed in the testis enter the caput epididymis, progress to the corpus, and finally reach the cauda region, where they are stored. Sperm entering the caput epididymis are incomplete - they lack the ability to swim forward (motility) and to fertilize an egg. During their transit in the epididymis, sperm undergo maturation processes necessary for them to acquire these functions. Final maturation is completed in the female reproductive tract (capacitation). During ejaculation, sperm flow from the lower portion of the epididymis (which functions as a storage reservoir). They are packed so tightly that they are unable to swim, but are transported via the peristaltic action of muscle layers within the vas deferens, and are mixed with the diluting fluids of the seminal vesicles and other accessory glands prior to ejaculation (forming semen). The epididymis is one of only two regions of the body to have stereocilia (the inner ear being the other.) # Pathology An inflammation of the epididymis is called epididymitis. It is a swollen blood vessel from the testicle that appears or feels like an enlarged epididymis. # Embryology and vestigial structures A Gartner's duct is a homologous remnant in the female. Embryologically, the epididymis is derived from tissue that once formed the mesonephros, a primitive kidney found in many aquatic vertebrates. Persistence of the cranial end of the mesonephric duct will leave behind a remnant called the appendix of the epididymis. Additionally, some mesonephric tubules can persist as the paradidymis, a small body caudal to the efferent ductules. # Additional images - Male reproductive system. - Testis - Schematic drawing of a cross-section through the vaginal process. - Microscopic shot.	Epididymis Template:Infobox Anatomy Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] The epididymis is part of the human male reproductive system and is present in all male mammals. It is a narrow, tightly-coiled tube connecting the efferent ducts from the rear of each testicle to its vas deferens. # Regions The epididymis can be divided into three main regions - the head (caput) - the body (corpus) - the tail (cauda) # Role in storage of sperm and ejaculation Spermatozoa formed in the testis enter the caput epididymis, progress to the corpus, and finally reach the cauda region, where they are stored. Sperm entering the caput epididymis are incomplete - they lack the ability to swim forward (motility) and to fertilize an egg. During their transit in the epididymis, sperm undergo maturation processes necessary for them to acquire these functions.[1] Final maturation is completed in the female reproductive tract (capacitation). During ejaculation, sperm flow from the lower portion of the epididymis (which functions as a storage reservoir). They are packed so tightly that they are unable to swim, but are transported via the peristaltic action of muscle layers within the vas deferens, and are mixed with the diluting fluids of the seminal vesicles and other accessory glands prior to ejaculation (forming semen). The epididymis is one of only two regions of the body to have stereocilia (the inner ear being the other.)[2] # Pathology An inflammation of the epididymis is called epididymitis. It is a swollen blood vessel from the testicle that appears or feels like an enlarged epididymis. # Embryology and vestigial structures A Gartner's duct is a homologous remnant in the female. Embryologically, the epididymis is derived from tissue that once formed the mesonephros, a primitive kidney found in many aquatic vertebrates. Persistence of the cranial end of the mesonephric duct will leave behind a remnant called the appendix of the epididymis. Additionally, some mesonephric tubules can persist as the paradidymis, a small body caudal to the efferent ductules. # Additional images - Male reproductive system. - Testis - Schematic drawing of a cross-section through the vaginal process. - Microscopic shot.	https://www.wikidoc.org/index.php/Epididymides
53cc19c053800b81b374201880234870ace49f3a	wikidoc	Epigenomes	Epigenomes Inside each eukaryote nucleus is genetic material (DNA) surrounded by protective and regulatory proteins. These protective and regulatory proteins and the dynamic changes to them that occur during the course of a eukaryote's existence are the epigenome. An epigenome consists of a record of the chemical changes to the DNA and histone proteins of an organism that can be passed down to an organism's offspring via transgenerational epigenetic inheritance, where changes to the epigenome can result in changes to the structure of chromatin and changes to the function of the genome. Unlike the underlying genome which is largely static within an individual, the epigenome can be dynamically altered by environmental conditions. # Evolution Evolution, the accumulation of change, while broadly applicable to anything which accumulates changes, is often thought of as gradual change or a series of changes, such as changes in the genetic composition of a population over successive generations. # Lamarckism Lamarckism (or Lamarckian inheritance) is the idea that an organism can pass on characteristics that it acquired during its lifetime to its offspring (also known as heritability of acquired characteristics or soft inheritance). It is named after the French biologist Jean-Baptiste Lamarck (1744–1829), who incorporated the action of soft inheritance into his evolutionary theories. After Erasmus Darwin wrote Zoonomia suggesting "that all warm-blooded animals have arisen ... with the power of acquiring new parts" in response to stimuli, with each round of "improvements" being inherited by successive generations", Jean-Baptiste Lamarck repeated in his Philosophie Zoologique of 1809 the folk wisdom that characteristics which were "needed" were acquired (or diminished) during the lifetime of an organism then passed on to the offspring. Neo-Lamarckism is a theory of inheritance based on a modification and extension of Lamarckism, essentially maintaining the principle that genetic changes can be influenced and directed by environmental factors. # Epigenetics Epigenetics is the study of genome or epigenome changes resulting from external rather than genetic influences. "Epigenetic mechanisms are affected by several factors and processes including development in utero and in childhood, environmental chemicals, drugs and pharmaceuticals, aging, and diet. DNA methylation is what occurs when methyl groups, an epigenetic factor found in some dietary sources, can tag DNA and activate or repress genes. Histones are proteins around which DNA can wind for compaction and gene regulation. Histone modification occurs when the binding of epigenetic factors to histone "tails"; alters the extent to which DNA is wrapped around histones and the availability of genes in the DNA to be activated. All of these factors and processes can have an effect on people's health and influence their health possibly resulting in cancer, autoimmune disease, mental disorders, or diabetes among other illnesses." # Epigenomic theory Def. a chemical entity anterior to, after, at, besides, near to, on, outer to, over, related to, or upon another chemical is called an epi (or epi-) chemical. Def. the "complete genetic information ... of an organism" is called a genome. Here's a theoretical definition: Def. a chemical entity anterior to, after, at, besides, near to, on, outer to, over, related to, or upon the complete genetic information of an organism is called an epi (or epi-) genome, or epigenome. # Genomes The genome is the entirety of an organism's hereditary information. In humans, it is encoded in DNA. The genome includes both the genes and the non-coding sequences of the DNA. Homo sapiens estimated genome size 3.2 billion bp. Genetic information is encoded as a sequence of nucleobases: adenine (A), cytosine (C), guanine (G), and thymine (T). # Deoxyribonucleic acid molecules Deoxyribonucleic acid (DNA) is composed of nucleobases (the sequence of which is the genome), deoxyribose (a sugar), and phosphate groups. Each nucleobase is attached to one deoxyribose molecule and one (PO4) phosphate molecule to form a chain of nucleotides (nucleobase + deoxyribose + phosphate) for a haploid genome. A linking of nucleobases may occur without the phosphate or the deoxyribose. The phosphate and the sugar are part of the epigenome. DNA often occurs as a double helix. The linking between one nitrogenous nucleobase of a DNA molecule and another nitrogenous nucleobase of a second DNA molecule is via hydrogen bonds. Each hydrogen bond (the electromagnetic attractive interaction of a hydrogen atom and an electronegative atom, such as nitrogen or oxygen of a nucleobase) is part of the epigenome. The structure a DNA molecule shown in the top image on the left depends on its environment. In aqueous environments, including the majority of DNA in a cell, B-DNA is the most common structure. The A-DNA structure dominates in dehydrated samples and is similar to the double-stranded RNA and DNA/RNA hybrids. Z-DNA is a rarer structure found in DNA bound to certain proteins. # Nucleosomes DNA packaging in eukaryotes consists of "DNA wound in sequence around four histone protein cores. Nucleosomes form the fundamental repeating units of eukaryotic chromatin. The nucleosome core particle consists of approximately 147 base pairs of DNA wrapped in 1.67 left-handed superhelical turns around a histone octamer consisting of 2 copies each of the core histones H2A, H2B, H3, and H4. Core particles are connected by stretches of "linker DNA", which can be up to about 80 bp long. # Histones Histone deacetylases (HDAC) ( EC number 3.5.1) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. Histone deacetylase action is opposite to that of histone acetyltransferase. # Chromatin Chromatin, or the Chromatin network, is a complex of macromolecules found in cells, consisting of DNA, protein, and RNA. DNA which codes genes that are actively transcribed ("turned on") is more loosely packaged and associated with RNA polymerases (referred to as euchromatin) while that DNA which codes inactive genes ("turned off") is more condensed and associated with structural proteins (heterochromatin). Polycomb-group proteins play a role in regulating genes through modulation of chromatin structure. # Euchromatin Def. "uncoiled dispersed threads of chromosomal material that occurs during interphase" is called euchromatin. The structure of euchromatin is reminiscent of an unfolded set of beads along a string, wherein those beads represent nucleosomes. The presence of methylated lysine 4 on the histone tails may act as a general marker for euchromatin. One example of constitutive euchromatin that is 'always turned on' is housekeeping genes, which code for the proteins needed for basic functions of cell survival. # Heterochromatin Heterochromatin mainly consists of genetically inactive satellite sequences, and many genes are repressed to various extents, although some cannot be expressed in euchromatin at all. Both centromeres and telomeres are heterochromatic, as is the Barr body of the second, inactivated X-chromosome in a female. # Constitutive heterochromatin Sections of DNA that occur particularly at the centromeres and telomeres often consisting of repetitive DNA that is largely transcriptionally silent are constitutive heterochromatin. Regions of DNA that exist as constitutive heterochromatin are the same for all cells of a given species. All human chromosomes 1, 9, 16, and the Y-chromosome contain large regions of constitutive heterochromatin. In most organisms, constitutive heterochromatin occurs around the chromosome centromere and near telomeres. # Facultative heterochromatin Genes that are silenced through a mechanism such as histone methylation or siRNA through RNAi produce facultative heterochromatin. The regions of DNA packaged in facultative heterochromatin are not consistent between the cell types within a species, and thus a sequence in one cell that is packaged in facultative heterochromatin (and the genes within poorly expressed) may be packaged in euchromatin in another cell (and the genes within no longer silenced). An example of facultative heterochromatin is X-chromosome inactivation in female mammals such as the cat in the image on the right: one X chromosome is packaged as facultative heterochromatin and silenced, while the other X chromosome is packaged as euchromatin and expressed. The black and orange alleles of a fur coloration gene reside on the X chromosome. For any given patch of fur, the inactivation of an X chromosome that carries one gene results in the fur color of the other, active gene. # Centric heterochromatin Centric heterochromatin, a variety of heterochromatin, is a tightly packed form of DNA that is a constituent in the formation of active centromeres in most higher-order organisms; the domain exists on both mitotic and interphase chromosomes. Centric heterochromatin is usually formed on alpha satellite DNA in humans; however, there have been cases where centric heterochromatin and centromeres have formed on originally euchromatin domains lacking alpha satellite DNA; this usually happens as a result of a chromosome breakage event and the formed centromere is called a neocentromere. Centric heterochromatin domains are flanked by pericentric heterochromatin. # Acetyl groups Acetylation (or in IUPAC nomenclature ethanoylation) describes a reaction that introduces an acetyl functional group into a chemical compound. (Deacetylation is the removal of the acetyl group.) In histone acetylation and deacetylation, histone proteins are acetylated and deacetylated on lysine residues in the N-terminal tail as part of gene regulation. Typically, these reactions are catalyzed by enzymes with histone acetyltransferase (HAT) or histone deacetylase (HDAC) activity, although HATs and HDACs can modify the acetylation status of non-histone proteins as well. There are "nearly 50,000 acetylated sites in the human genome that correlate with active transcription start sites and CpG islands and tend to cluster within gene-rich loci." "ysine acetylation almost always correlates with chromatin accessibility and transcriptional activity". # Acyl groups # Adenyl groups Adenylylation, more commonly known as AMPylation, is a process in which an adenosine monophosphate (AMP) molecule is covalently attached to the amino acid side chain of a protein. This covalent addition of AMP to a hydroxyl side chain of the protein is a posttranslational modification. # Amidal groups # Aminal groups # Carbamyl groups # Carboxyl groups # Citrulinyl groups # Desmosinal groups Desmosine in urine, plasma or sputum samples can be a marker for elastin breakdown due to high elastase activity related to certain diseases. # Detyrosinal groups # Diphthal groups # Disulfidyl groups # Flavinal groups # Formyl groups # Glutamyl groups # Glycyl groups # Glycosyl groups # Hydroxyl groups # Imidazolinonal groups The property of photoconversion in Kaede is contributed by the tripeptide, His62-Tyr63-Gly64, that acts as a green chromophore that can be converted to red. Once Kaede is synthesized, a chromophore, 4-(p-hydroxybenzylidene)-5-imidazolinone, derived from the tripeptide mediates green fluorescence in Kaede. When exposed to UV, Kaede protein undergoes un conventional cleavage between the amide nitrogen and the α carbon (Cα) at His62 via a formal β-elimination reaction. Followed by the formation of a double bond between His62-Cα and –Cβ, the π-conjugation is extended to the imidazole ring of His62. A new chromophore, 2--4-(p-hydroxybenzylidene)-5-imidazolinone, is formed with the red-emitting property. GFP has a beta barrel structure consisting of eleven β-strands with a pleated sheet arrangement, with an alpha helix containing the covalently bonded chromophore 4-(p-hydroxybenzylidene)imidazolidin-5-one (HBI) running through the center. Five shorter alpha helices form caps on the ends of the structure. The beta barrel structure is a nearly perfect cylinder, 42Å long and 24Å in diameter (some studies have reported a diameter of 30Å), creating what is referred to as a "β-can" formation, which is unique to the GFP-like family. HBI, the spontaneously modified form of the tripeptide Ser65–Tyr66–Gly67, is nonfluorescent in the absence of the properly folded GFP scaffold and exists mainly in the un-ionized phenol form in wtGFP. Inward-facing sidechains of the barrel induce specific cyclization reactions in Ser65–Tyr66–Gly67 that induce ionization of HBI to the phenolate form and chromophore formation. This process of post-translational modification is referred to as maturation. The hydrogen-bonding network and electron-stacking interactions with these sidechains influence the color, intensity and photostability of GFP and its numerous derivatives. The tightly packed nature of the barrel excludes solvent molecules, protecting the chromophore fluorescence from quenching by water. In addition to the auto-cyclization of the Ser65-Tyr66-Gly67, a 1,2-dehydrogenation reaction occurs at the Tyr66 residue. Besides the three residues that form the chromophore, residues such as Gln94, Arg96, His148, Thr203, and Glu222 all act as stabilizers. The residues of Gln94, Arg96, and His148 are able to stabilize by delocalizing the chromophore charge. Arg96 is the most important stabilizing residue due to the fact that it prompts the necessary structural realignments that are necessary from the HBI ring to occur. Any mutation to the Arg96 residue would result in a decrease in the development rate of the chromophore because proper electrostatic and steric interactions would be lost. Tyr66 is the recipient of hydrogen bonds and does not ionize in order to produce favorable electrostatics. # Iminal groups # Mannosyl groups # Methyl groups Methylation is "the addition of a methyl group replacing a hydrogen atom. DNA methylation in vertebrates typically occurs at CpG sites (cytosine-phosphate-guanine sites, that is, where a cytosine is directly followed by a guanine in the DNA sequence). This methylation results in the conversion of the cytosine to 5-methylcytosine. The formation of Me-CpG is catalyzed by the enzyme DNA methyltransferase. Human DNA has about 80%-90% of CpG sites methylated, but there are certain areas, known as CpG islands, that are GC-rich (made up of about 65% CG residues), wherein none are methylated. These are associated with the promoters of 56% of mammalian genes, including all ubiquitously expressed genes. One to two percent of the human genome are CpG clusters, and there is an inverse relationship between CpG methylation and transcriptional activity. "Non-CpG methylation (CNG and CNN) ... has been observed at a low frequency in the early mouse embryo" Protein methylation typically takes place on arginine or lysine amino acid residues in the protein sequence. Arginine can be methylated once (monomethylated arginine) or twice, with either both methyl groups on one terminal nitrogen (asymmetric dimethylated arginine) or one on both nitrogens (symmetric dimethylated arginine) by peptidylarginine methyltransferases (PRMTs). Lysine can be methylated once, twice or three times by lysine methyltransferases. Protein methylation has been most-studied in the histones. The transfer of methyl groups from S-adenosyl methionine to histones is catalyzed by enzymes known as histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression. # Myristoyl groups # Palmitoyl groups # Phosphoryl groups Phosphorylation is the addition of a phosphate (PO43-) group to a protein or other organic molecule. Kinases phosphorylate proteins and phosphatases dephosphorylate proteins. Reversible phosphorylation of proteins is an important regulatory mechanism that occurs in both prokaryotic and eukaryotic organisms. Phosphoryl groups attach to histones at serine and threonine sites. # Porphyl groups # Prenyl groups # Ribosyl groups ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. # Succinimidal groups # Sulfal groups # Sulfiliminal groups Sulfilimine bonds stabilize collagen IV strands found in the extracellular matrix and arose at least 500 mya. These bonds covalently connect hydroxylysine and methionine residues of adjacent polypeptide strands to form a larger collagen trimer. # Sumoyl groups # Topaquinyl groups # Tryptophanyl groups Tryptophan tryptophylquinone (TTQ) is an enzyme cofactor, generated by posttranslational modification of amino acids within the protein. Methylamine dehydrogenase (MADH), an amine dehydrogenase, requires TTQ for its catalytic function. # Tyrosylquinonal groups # Ubiquityl groups "The core histones that make up the nucleosome are subject to ... modifications, including ubiquitination primarily at specific positions within the amino-terminal histone tails." # Hypotheses - The epigenome around A1BG is opened as if for any gene rather than a specific promoter, enhancer, or other transcription related factor. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff.	Epigenomes Editor-In-Chief: Henry A. Hoff Inside each eukaryote nucleus is genetic material (DNA) surrounded by protective and regulatory proteins. These protective and regulatory proteins and the dynamic changes to them that occur during the course of a eukaryote's existence are the epigenome. An epigenome consists of a record of the chemical changes to the DNA and histone proteins of an organism that can be passed down to an organism's offspring via transgenerational epigenetic inheritance, where changes to the epigenome can result in changes to the structure of chromatin and changes to the function of the genome.[1] Unlike the underlying genome which is largely static within an individual, the epigenome can be dynamically altered by environmental conditions.[2] # Evolution Evolution, the accumulation of change, while broadly applicable to anything which accumulates changes, is often thought of as gradual change or a series of changes, such as changes in the genetic composition of a population over successive generations. # Lamarckism Lamarckism (or Lamarckian inheritance) is the idea that an organism can pass on characteristics that it acquired during its lifetime to its offspring (also known as heritability of acquired characteristics or soft inheritance). It is named after the French biologist Jean-Baptiste Lamarck (1744–1829), who incorporated the action of soft inheritance into his evolutionary theories. After Erasmus Darwin wrote Zoonomia suggesting "that all warm-blooded animals have arisen ... with the power of acquiring new parts" in response to stimuli, with each round of "improvements" being inherited by successive generations",[3] Jean-Baptiste Lamarck repeated in his Philosophie Zoologique of 1809 the folk wisdom that characteristics which were "needed" were acquired (or diminished) during the lifetime of an organism then passed on to the offspring. Neo-Lamarckism is a theory of inheritance based on a modification and extension of Lamarckism, essentially maintaining the principle that genetic changes can be influenced and directed by environmental factors. # Epigenetics Epigenetics is the study of genome or epigenome changes resulting from external rather than genetic influences. "Epigenetic mechanisms are affected by several factors and processes including development in utero and in childhood, environmental chemicals, drugs and pharmaceuticals, aging, and diet. DNA methylation is what occurs when methyl groups, an epigenetic factor found in some dietary sources, can tag DNA and activate or repress genes. Histones are proteins around which DNA can wind for compaction and gene regulation. Histone modification occurs when the binding of epigenetic factors to histone "tails"; alters the extent to which DNA is wrapped around histones and the availability of genes in the DNA to be activated. All of these factors and processes can have an effect on people's health and influence their health possibly resulting in cancer, autoimmune disease, mental disorders, or diabetes among other illnesses."[4] # Epigenomic theory Def. a chemical entity anterior to, after, at, besides, near to, on, outer to, over, related to, or upon another chemical is called an epi (or epi-) chemical. Def. the "complete genetic information ... of an organism"[5] is called a genome. Here's a theoretical definition: Def. a chemical entity anterior to, after, at, besides, near to, on, outer to, over, related to, or upon the complete genetic information of an organism is called an epi (or epi-) genome, or epigenome. # Genomes The genome is the entirety of an organism's hereditary information. In humans, it is encoded in DNA. The genome includes both the genes and the non-coding sequences of the DNA.[6] Homo sapiens estimated genome size [is] 3.2 billion bp.[7] Genetic information is encoded as a sequence of nucleobases: adenine (A), cytosine (C), guanine (G), and thymine (T). # Deoxyribonucleic acid molecules Deoxyribonucleic acid (DNA) is composed of nucleobases (the sequence of which is the genome), deoxyribose (a sugar), and phosphate groups. Each nucleobase is attached to one deoxyribose molecule and one (PO4) phosphate molecule to form a chain of nucleotides (nucleobase + deoxyribose + phosphate) for a haploid genome. A linking of nucleobases may occur without the phosphate or the deoxyribose. The phosphate and the sugar are part of the epigenome. DNA often occurs as a double helix. The linking between one nitrogenous nucleobase of a DNA molecule and another nitrogenous nucleobase of a second DNA molecule is via hydrogen bonds. Each hydrogen bond (the electromagnetic attractive interaction of a hydrogen atom and an electronegative atom, such as nitrogen or oxygen of a nucleobase) is part of the epigenome. The structure a DNA molecule shown in the top image on the left depends on its environment. In aqueous environments, including the majority of DNA in a cell, B-DNA is the most common structure. The A-DNA structure dominates in dehydrated samples and is similar to the double-stranded RNA and DNA/RNA hybrids. Z-DNA is a rarer structure found in DNA bound to certain proteins. # Nucleosomes DNA packaging in eukaryotes consists of "DNA wound in sequence around four histone protein cores.[10] Nucleosomes form the fundamental repeating units of eukaryotic chromatin.[11] The nucleosome core particle consists of approximately 147 base pairs of DNA wrapped in 1.67 left-handed superhelical turns around a histone octamer consisting of 2 copies each of the core histones H2A, H2B, H3, and H4.[12] Core particles are connected by stretches of "linker DNA", which can be up to about 80 bp long. # Histones Histone deacetylases (HDAC) ([Enzyme Commission number] EC number 3.5.1) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. Histone deacetylase action is opposite to that of histone acetyltransferase. # Chromatin Chromatin, or the Chromatin network, is a complex of macromolecules found in cells, consisting of DNA, protein, and RNA.[13] DNA which codes genes that are actively transcribed ("turned on") is more loosely packaged and associated with RNA polymerases (referred to as euchromatin) while that DNA which codes inactive genes ("turned off") is more condensed and associated with structural proteins (heterochromatin).[14][15] Polycomb-group proteins play a role in regulating genes through modulation of chromatin structure.[16] # Euchromatin Def. "uncoiled dispersed threads of chromosomal material that occurs during interphase"[17] is called euchromatin. The structure of euchromatin is reminiscent of an unfolded set of beads along a string, wherein those beads represent nucleosomes. The presence of methylated lysine 4 on the histone tails may act as a general marker for euchromatin. One example of constitutive euchromatin that is 'always turned on' is housekeeping genes, which code for the proteins needed for basic functions of cell survival. # Heterochromatin Heterochromatin mainly consists of genetically inactive satellite sequences,[18] and many genes are repressed to various extents, although some cannot be expressed in euchromatin at all.[19] Both centromeres and telomeres are heterochromatic, as is the Barr body of the second, inactivated X-chromosome in a female. # Constitutive heterochromatin Sections of DNA that occur particularly at the centromeres and telomeres often consisting of repetitive DNA that is largely transcriptionally silent are constitutive heterochromatin. Regions of DNA that exist as constitutive heterochromatin are the same for all cells of a given species. All human chromosomes 1, 9, 16, and the Y-chromosome contain large regions of constitutive heterochromatin. In most organisms, constitutive heterochromatin occurs around the chromosome centromere and near telomeres. # Facultative heterochromatin Genes that are silenced through a mechanism such as histone methylation or siRNA through RNAi produce facultative heterochromatin. The regions of DNA packaged in facultative heterochromatin are not consistent between the cell types within a species, and thus a sequence in one cell that is packaged in facultative heterochromatin (and the genes within poorly expressed) may be packaged in euchromatin in another cell (and the genes within no longer silenced). An example of facultative heterochromatin is X-chromosome inactivation in female mammals such as the cat in the image on the right: one X chromosome is packaged as facultative heterochromatin and silenced, while the other X chromosome is packaged as euchromatin and expressed. The black and orange alleles of a fur coloration gene reside on the X chromosome. For any given patch of fur, the inactivation of an X chromosome that carries one gene results in the fur color of the other, active gene. # Centric heterochromatin Centric heterochromatin, a variety of heterochromatin, is a tightly packed form of DNA that is a constituent in the formation of active centromeres in most higher-order organisms; the domain exists on both mitotic and interphase chromosomes.[21] Centric heterochromatin is usually formed on alpha satellite DNA in humans; however, there have been cases where centric heterochromatin and centromeres have formed on originally euchromatin domains lacking alpha satellite DNA; this usually happens as a result of a chromosome breakage event and the formed centromere is called a neocentromere.[21] Centric heterochromatin domains are flanked by pericentric heterochromatin.[21] # Acetyl groups Acetylation (or in IUPAC nomenclature ethanoylation) describes a reaction that introduces an acetyl functional group into a chemical compound. (Deacetylation is the removal of the acetyl group.) In histone acetylation and deacetylation, histone proteins are acetylated and deacetylated on lysine residues in the N-terminal tail as part of gene regulation. Typically, these reactions are catalyzed by enzymes with histone acetyltransferase (HAT) or histone deacetylase (HDAC) activity, although HATs and HDACs can modify the acetylation status of non-histone proteins as well.[22] There are "nearly 50,000 acetylated sites [punctate sites of modified histones] in the human genome that correlate with active transcription start sites and CpG islands and tend to cluster within gene-rich loci."[1] "[L]ysine acetylation almost always correlates with chromatin accessibility and transcriptional activity".[1] # Acyl groups # Adenyl groups Adenylylation,[23][24] more commonly known as AMPylation, is a process in which an adenosine monophosphate (AMP) molecule is covalently attached to the amino acid side chain of a protein.[25] This covalent addition of AMP to a hydroxyl side chain of the protein is a posttranslational modification.[26] # Amidal groups # Aminal groups # Carbamyl groups # Carboxyl groups # Citrulinyl groups # Desmosinal groups Desmosine in urine, plasma or sputum samples can be a marker for elastin breakdown due to high elastase activity related to certain diseases.[27][28] # Detyrosinal groups # Diphthal groups # Disulfidyl groups # Flavinal groups # Formyl groups # Glutamyl groups # Glycyl groups # Glycosyl groups # Hydroxyl groups # Imidazolinonal groups The property of photoconversion in Kaede is contributed by the tripeptide, His62-Tyr63-Gly64, that acts as a green chromophore that can be converted to red.[29] Once Kaede is synthesized, a chromophore, 4-(p-hydroxybenzylidene)-5-imidazolinone, derived from the tripeptide mediates green fluorescence in Kaede. When exposed to UV, Kaede protein undergoes un conventional cleavage between the amide nitrogen and the α carbon (Cα) at His62 via a formal β-elimination reaction. Followed by the formation of a double bond between His62-Cα and –Cβ, the π-conjugation is extended to the imidazole ring of His62. A new chromophore, 2-[(1E)-2-(5-imidazolyl)ethenyl]-4-(p-hydroxybenzylidene)-5-imidazolinone, is formed with the red-emitting property. GFP has a beta barrel structure consisting of eleven β-strands with a pleated sheet arrangement, with an alpha helix containing the covalently bonded chromophore 4-(p-hydroxybenzylidene)imidazolidin-5-one (HBI) running through the center.[30][31][32] Five shorter alpha helices form caps on the ends of the structure. The beta barrel structure is a nearly perfect cylinder, 42Å long and 24Å in diameter (some studies have reported a diameter of 30Å[33]),[31] creating what is referred to as a "β-can" formation, which is unique to the GFP-like family.[32] HBI, the spontaneously modified form of the tripeptide Ser65–Tyr66–Gly67, is nonfluorescent in the absence of the properly folded GFP scaffold and exists mainly in the un-ionized phenol form in wtGFP.[34] Inward-facing sidechains of the barrel induce specific cyclization reactions in Ser65–Tyr66–Gly67 that induce ionization of HBI to the phenolate form and chromophore formation. This process of post-translational modification is referred to as maturation.[35] The hydrogen-bonding network and electron-stacking interactions with these sidechains influence the color, intensity and photostability of GFP and its numerous derivatives.[36] The tightly packed nature of the barrel excludes solvent molecules, protecting the chromophore fluorescence from quenching by water. In addition to the auto-cyclization of the Ser65-Tyr66-Gly67, a 1,2-dehydrogenation reaction occurs at the Tyr66 residue.[33] Besides the three residues that form the chromophore, residues such as Gln94, Arg96, His148, Thr203, and Glu222 all act as stabilizers. The residues of Gln94, Arg96, and His148 are able to stabilize by delocalizing the chromophore charge. Arg96 is the most important stabilizing residue due to the fact that it prompts the necessary structural realignments that are necessary from the HBI ring to occur. Any mutation to the Arg96 residue would result in a decrease in the development rate of the chromophore because proper electrostatic and steric interactions would be lost. Tyr66 is the recipient of hydrogen bonds and does not ionize in order to produce favorable electrostatics.[37] # Iminal groups # Mannosyl groups # Methyl groups Methylation is "the addition of a methyl group replacing a hydrogen atom. DNA methylation in vertebrates typically occurs at CpG sites (cytosine-phosphate-guanine sites, that is, where a cytosine is directly followed by a guanine in the DNA sequence). This methylation results in the conversion of the cytosine to 5-methylcytosine. The formation of Me-CpG is catalyzed by the enzyme DNA methyltransferase. Human DNA has about 80%-90% of CpG sites methylated, but there are certain areas, known as CpG islands, that are GC-rich (made up of about 65% CG residues), wherein none are methylated. These are associated with the promoters of 56% of mammalian genes, including all ubiquitously expressed genes. One to two percent of the human genome are CpG clusters, and there is an inverse relationship between CpG methylation and transcriptional activity. "Non-CpG methylation (CNG and CNN) ... has been observed at a low frequency in the early mouse embryo"[1] Protein methylation typically takes place on arginine or lysine amino acid residues in the protein sequence.[38] Arginine can be methylated once (monomethylated arginine) or twice, with either both methyl groups on one terminal nitrogen (asymmetric dimethylated arginine) or one on both nitrogens (symmetric dimethylated arginine) by peptidylarginine methyltransferases (PRMTs). Lysine can be methylated once, twice or three times by lysine methyltransferases. Protein methylation has been most-studied in the histones. The transfer of methyl groups from S-adenosyl methionine to histones is catalyzed by enzymes known as histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.[39][40] # Myristoyl groups # Palmitoyl groups # Phosphoryl groups Phosphorylation is the addition of a phosphate (PO43-) group to a protein or other organic molecule. Kinases phosphorylate proteins and phosphatases dephosphorylate proteins. Reversible phosphorylation of proteins is an important regulatory mechanism that occurs in both prokaryotic and eukaryotic organisms.[41][42][43][44] Phosphoryl groups attach to histones at serine and threonine sites.[1] # Porphyl groups # Prenyl groups # Ribosyl groups ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein.[45][46] It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis.[47][48] # Succinimidal groups # Sulfal groups # Sulfiliminal groups Sulfilimine bonds stabilize collagen IV strands found in the extracellular matrix[49] and arose at least 500 mya.[50] These bonds covalently connect hydroxylysine and methionine residues of adjacent polypeptide strands to form a larger collagen trimer. # Sumoyl groups # Topaquinyl groups # Tryptophanyl groups Tryptophan tryptophylquinone (TTQ)[51] is an enzyme cofactor, generated by posttranslational modification of amino acids within the protein. Methylamine dehydrogenase (MADH), an amine dehydrogenase, requires TTQ for its catalytic function.[52] # Tyrosylquinonal groups # Ubiquityl groups "The core histones that make up the nucleosome are subject to ... modifications, including ubiquitination [that occurs] primarily at specific positions within the amino-terminal histone tails."[1] # Hypotheses - The epigenome around A1BG is opened as if for any gene rather than a specific promoter, enhancer, or other transcription related factor. # Acknowledgements The content on this page was first contributed by: Henry A. Hoff.	https://www.wikidoc.org/index.php/Epigenomes
f7213aa4d10aa06060a0da06c3de78b5f893e972	wikidoc	Epiglottis	Epiglottis # Overview The epiglottis is a lid-like flap of elastic cartilage tissue covered with a mucus membrane, attached to the root of the tongue. It projects obliquely upwards behind the tongue and the hyoid bone. # Anatomy and function The epiglottis guards the entrance of the glottis, the opening between the vocal folds. It is normally pointed upward, but during swallowing, elevation of the hyoid bone draws the larynx upward; as a result, the epiglottis folds down to a more horizontal position. In this manner it prevents food from going into the trachea and instead directs it to the esophagus, which is more posterior. The epiglottis is one of three large cartilaginous structures that make up the larynx (voice box). # Clinical significance ## Reflexes The glossopharyngeal nerve (CN IX) sends fibers to the upper epiglottis that contribute to the afferent limb of the gag reflex. The superior laryngeal branch of the vagus nerve (CN X) sends fibers to the lower epiglottis that contribute to the afferent limb of the cough reflex. ## Infection of the epiglottis In children, the epiglottis will occasionally become infected with Haemophilus influenzae or Streptococcus pneumoniae bacteria. Although easily treated, this condition is a medical emergency because without treatment the epiglottis may swell and block the trachea, causing massive inflammation. This condition has become rare in countries where vaccination against Haemophilus influenzae (HIB) is administered. # Additional images - Larynx - Cut through the larynx of a horse - The cartilages of the larynx. Posterior view. - Ligaments of the larynx. Posterior view. - Coronal section of larynx and upper part of trachea. - The entrance to the larynx, viewed from behind. - Muscles of larynx. Posterior view. - Muscles of larynx. Side view. Right lamina of thyroid cartilage removed. - Sagittal section of nose mouth, pharynx, and larynx.	Epiglottis # Overview Template:Infobox Anatomy The epiglottis is a lid-like flap of elastic cartilage tissue covered with a mucus membrane, attached to the root of the tongue. It projects obliquely upwards behind the tongue and the hyoid bone. # Anatomy and function The epiglottis guards the entrance of the glottis, the opening between the vocal folds. It is normally pointed upward, but during swallowing, elevation of the hyoid bone draws the larynx upward; as a result, the epiglottis folds down to a more horizontal position. In this manner it prevents food from going into the trachea and instead directs it to the esophagus, which is more posterior. The epiglottis is one of three large cartilaginous structures that make up the larynx (voice box). # Clinical significance ## Reflexes The glossopharyngeal nerve (CN IX) sends fibers to the upper epiglottis that contribute to the afferent limb of the gag reflex. The superior laryngeal branch of the vagus nerve (CN X) sends fibers to the lower epiglottis that contribute to the afferent limb of the cough reflex. [1] ## Infection of the epiglottis In children, the epiglottis will occasionally become infected with Haemophilus influenzae or Streptococcus pneumoniae bacteria. Although easily treated, this condition is a medical emergency because without treatment the epiglottis may swell and block the trachea, causing massive inflammation. This condition has become rare in countries where vaccination against Haemophilus influenzae (HIB) is administered. # Additional images - Larynx - Cut through the larynx of a horse - The cartilages of the larynx. Posterior view. - Ligaments of the larynx. Posterior view. - Coronal section of larynx and upper part of trachea. - The entrance to the larynx, viewed from behind. - Muscles of larynx. Posterior view. - Muscles of larynx. Side view. Right lamina of thyroid cartilage removed. - Sagittal section of nose mouth, pharynx, and larynx.	https://www.wikidoc.org/index.php/Epiglottic_cartilage
2adfb262b9e1880bf09a6187a5a3059b27b86fa8	wikidoc	Epiregulin	Epiregulin Epiregulin (EPR) is a protein that in humans is encoded by the EREG gene. # Structure Epiregulin consists of 46 amino acid residues. Its secondary structure contains approximately 30 percent of β-sheet in the strand. Some of the residues form loops and turns due to the hydrogen bonding. The percentage of β-sheet in epiregulin depends on the domain and the secondary structures that they occupy. The polymeric molecules of epiregulin has the formula weight of 5280.1 g/mol with a polypeptide(L), a polymer type. Structural motifs in most proteins have typical connections in an all β motif. Meaning that the polypeptide chains do not make a crossover connection or in so far as this type of connection has not been observed. Epiregulin is one of the proteins that occupies a typical connection in all β motif. Furthermore, as the structure of epiregulin forms a chain in an all β motif, it also forms β hairpin structural motif. A β hairpin is when the two adjacent anti-parallel β strands connected by a β-turn. # Function Epiregulin is a member of the epidermal growth factor family. Epiregulin can function as a ligand of epidermal growth factor receptor (EGFR), as well as a ligand of most members of the ERBB (v-erb-b2 oncogene homolog) family of tyrosine-kinase receptors. The secondary structure at the C-terminus epiregulin is different from other epidermal growth factor family ligands because of the lack of hydrogen bonds. The structural difference at the C-terminus may provide an explanation for the reduced binding affinity of epiregulin to the ERBB receptors.	Epiregulin Epiregulin (EPR) is a protein that in humans is encoded by the EREG gene.[1][2] # Structure Epiregulin consists of 46 amino acid residues. Its secondary structure contains approximately 30 percent of β-sheet in the strand.[3] Some of the residues form loops and turns due to the hydrogen bonding.[3] The percentage of β-sheet in epiregulin depends on the domain and the secondary structures that they occupy. The polymeric molecules of epiregulin has the formula weight of 5280.1 g/mol with a polypeptide(L), a polymer type.[3] Structural motifs in most proteins have typical connections in an all β motif. Meaning that the polypeptide chains do not make a crossover connection or in so far as this type of connection has not been observed. Epiregulin is one of the proteins that occupies a typical connection in all β motif. Furthermore, as the structure of epiregulin forms a chain in an all β motif, it also forms β hairpin structural motif. A β hairpin is when the two adjacent anti-parallel β strands connected by a β-turn. # Function Epiregulin is a member of the epidermal growth factor family. Epiregulin can function as a ligand of epidermal growth factor receptor (EGFR), as well as a ligand of most members of the ERBB (v-erb-b2 oncogene homolog) family of tyrosine-kinase receptors.[2] The secondary structure at the C-terminus epiregulin is different from other epidermal growth factor family ligands because of the lack of hydrogen bonds. The structural difference at the C-terminus may provide an explanation for the reduced binding affinity of epiregulin to the ERBB receptors.[3]	https://www.wikidoc.org/index.php/Epiregulin
650b8524691841271a1cc57c0c8f635d7ed764a0	wikidoc	Episiotomy	Episiotomy # Overview An episiotomy ] is a surgical incision through the perineum made to enlarge the vagina and assist childbirth. The incision can be midline or at an angle from the posterior end of the vulva, is performed under local anaesthetic (pudendal anesthesia) and is sutured closed after delivery. It is one of the most common medical procedures performed on women, and although its routine use in childbirth has steadily declined in recent decades, it is still widely practiced in Latin America. # Uses Many physicians use episiotomies because they believe that it will lessen perineal trauma, minimize postpartum pelvic floor dysfunction by reducing anal sphincter muscle damage, reduce the loss of blood at delivery, and protect against neonatal trauma. In many cases though, episiotomies cause all of these problems. Research has shown that natural tears typically are less severe. Episiotomies may be indicated if: - there is any sign of fetal distress while the baby is in the birth canal - a delivery occurs too quickly for the vagina to stretch naturally - the baby's head is too large for the opening - the baby's shoulders are stuck (When a baby's shoulders are stuck they are stuck behind bony pelvis, not soft tissue, so this indication is disputed) - it is a breech birth or forceps delivery # Controversy about common usage In various countries, routine episiotomy has been accepted medical practice for many years. Various urban legends circulate on the fact that after very rapid natural births, young doctors would still make episiotomies so as not to displease their professors. Since about the 1960s, routine episiotomies are rapidly losing popularity among obstetricians and midwives in Europe, Australia and the United States. A nationwide US population study by Weber and Meyn (2002) suggested that 31% of women having babies in U.S. hospitals received episiotomies in 1997, compared with 56% in 1979. In Latin America it's still popular, where it's done on 90% of hospital births and in most cases without the mother's consent. There, routine episiotomy is a major cause of infections, some of them fatal . Recent studies indicate that routine episiotomies should not be performed, as they may increase morbidity. Hartmann et al (2005), reviewing the literature, indicate that this procedure is not helpful for routine patients, though there are certain instances, such as a narrow birth canal and other problems as described above. Having an episiotomy may increase perineal pain in the postpartum period, resulting in trouble defecating (particularly in midline episiotomies, as demonstrated by Signorello et al 2000). In addition it may complicate sexual intercourse by making it painful and replacing erectile tissues in the vulva with fibrotic tissue. In cases where an episiotomy is indicated, a mediolateral incision may be preferable to a median (midline) incision as the latter is associated with a higher risk of injury to the anal sphincter and the rectum. (ACOG Practice Bulletin). # Informed consent Expectant mothers frequently make "birth plans" during their antenatal care, and are generally encouraged to discuss their views on episiotomy with their caregivers, or as early as possible in labour. In the final stages of delivery the midwife or obstetrician may not have time to discuss the benefits, risks and alternatives without endangering the mother or baby. However, staff restrictions or complications in labour often mean that these plans have to be altered in the course of the birth. # Avoidance Perineal massage beginning around the 34th week has been shown to reduce perineal damage by 6% (Shipman MK. Antenatal perineal massage and subsequent perineal outcomes: A Randomized trial. BrJObGyn 1997;104:787. Controlled delivery of the head that allows slow gradual stretching of the perineal tissue can help in minimising damage to the perineum. Episiotomy is almost never required. If the tissue is stretching, some studies suggest that small natural tears heal quicker and are less painful, so a tear is preferrable to an episiotomy. There are also devices which are made to stretch the perineal tissue gradually to train it in preparation for birth. One example is the "Epi-no", which consists of an inflatable balloon pumped with the same pump as a sphygmomanometer. The Epi-no device has been shown to reduce perineal damage by 50% at first births.	Episiotomy For patient information, click here Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview An episiotomy [[International Phonetic Alphabet for English\|Template:IPA]] is a surgical incision through the perineum made to enlarge the vagina and assist childbirth. The incision can be midline or at an angle from the posterior end of the vulva, is performed under local anaesthetic (pudendal anesthesia) and is sutured closed after delivery. It is one of the most common medical procedures performed on women, and although its routine use in childbirth has steadily declined in recent decades, it is still widely practiced in Latin America. # Uses Many physicians use episiotomies because they believe that it will lessen perineal trauma, minimize postpartum pelvic floor dysfunction by reducing anal sphincter muscle damage, reduce the loss of blood at delivery, and protect against neonatal trauma. In many cases though, episiotomies cause all of these problems.[citation needed] Research has shown that natural tears typically are less severe. Episiotomies may be indicated if: - there is any sign of fetal distress while the baby is in the birth canal - a delivery occurs too quickly for the vagina to stretch naturally - the baby's head is too large for the opening - the baby's shoulders are stuck (When a baby's shoulders are stuck they are stuck behind bony pelvis, not soft tissue, so this indication is disputed) - it is a breech birth or forceps delivery # Controversy about common usage In various countries, routine episiotomy has been accepted medical practice for many years. Various urban legends circulate on the fact that after very rapid natural births, young doctors would still make episiotomies so as not to displease their professors. Since about the 1960s, routine episiotomies are rapidly losing popularity among obstetricians and midwives in Europe, Australia and the United States. A nationwide US population study by Weber and Meyn (2002) suggested that 31% of women having babies in U.S. hospitals received episiotomies in 1997, compared with 56% in 1979. In Latin America it's still popular, where it's done on 90% of hospital births [2] and in most cases without the mother's consent. There, routine episiotomy is a major cause of infections, some of them fatal [3] . Recent studies indicate that routine episiotomies should not be performed, as they may increase morbidity. Hartmann et al (2005), reviewing the literature, indicate that this procedure is not helpful for routine patients, though there are certain instances, such as a narrow birth canal and other problems as described above. Having an episiotomy may increase perineal pain in the postpartum period, resulting in trouble defecating (particularly in midline episiotomies, as demonstrated by Signorello et al 2000). In addition it may complicate sexual intercourse by making it painful [4] and replacing erectile tissues in the vulva with fibrotic tissue. In cases where an episiotomy is indicated, a mediolateral incision may be preferable to a median (midline) incision as the latter is associated with a higher risk of injury to the anal sphincter and the rectum. (ACOG Practice Bulletin). # Informed consent Expectant mothers frequently make "birth plans" during their antenatal care, and are generally encouraged to discuss their views on episiotomy with their caregivers, or as early as possible in labour. In the final stages of delivery the midwife or obstetrician may not have time to discuss the benefits, risks and alternatives without endangering the mother or baby. However, staff restrictions or complications in labour often mean that these plans have to be altered in the course of the birth. # Avoidance Perineal massage beginning around the 34th week has been shown to reduce perineal damage by 6% (Shipman MK. Antenatal perineal massage and subsequent perineal outcomes: A Randomized trial. BrJObGyn 1997;104:787. Controlled delivery of the head that allows slow gradual stretching of the perineal tissue can help in minimising damage to the perineum. Episiotomy is almost never required. If the tissue is stretching, some studies suggest that small natural tears heal quicker and are less painful, so a tear is preferrable to an episiotomy. There are also devices which are made to stretch the perineal tissue gradually to train it in preparation for birth. One example is the "Epi-no", which consists of an inflatable balloon pumped with the same pump as a sphygmomanometer. The Epi-no device has been shown to reduce perineal damage by 50% at first births. [1]	https://www.wikidoc.org/index.php/Episiotomy
0fa5e9bfa9a32669d5ef98aa1e0814fbca152b99	wikidoc	Epispadias	Epispadias For patient information page, click here Steven C. Campbell, M.D., Ph.D. # Overview An epispadias is a rare type of malformation of the penis in which the urethra ends in an opening on the upper aspect (the dorsum) of the penis. An epispadias is an uncommon and partial form of a spectrum of failures of abdominal and pelvic fusion in the first months of embryogenesis. Most cases involve more severe defects, including a small and bifid phallus with bladder exstrophy or even cloacal exstrophy involving the entire perineum. Despite the similarity of name, an epispadias is not a type of hypospadias, and involves a problem with a different set of embryologic processes. The cause of this defect of early embryogenesis is unknown but does not involve androgens. Women can also have this type of congenital malformation. Epispadias of the female may occur when the urethra develops too far anteriorly, exiting in the clitoris or even more forward. For females, this may not cause difficulty in urination but may cause problems with sexual satisfaction. Frequently, the clitoris is bifurcated at the site of urethral exit, and therefore clitoral sensation is less intense during sexual intercourse due to frequent stimulation during urination. However, with proper stimulation, using either manual or positional techniques, clitoral orgasm is definitely possible and quite pleasurable. One of the most famous people afflicted with this condition is Wellington guitarist Ryan Salter. He elected to have penile amputation instead of repair. - Widened pubic symphysis with epispadias	Epispadias For patient information page, click here Template:Search infobox Steven C. Campbell, M.D., Ph.D. # Overview An epispadias is a rare type of malformation of the penis in which the urethra ends in an opening on the upper aspect (the dorsum) of the penis. An epispadias is an uncommon and partial form of a spectrum of failures of abdominal and pelvic fusion in the first months of embryogenesis. Most cases involve more severe defects, including a small and bifid phallus with bladder exstrophy or even cloacal exstrophy involving the entire perineum. Despite the similarity of name, an epispadias is not a type of hypospadias, and involves a problem with a different set of embryologic processes. The cause of this defect of early embryogenesis is unknown but does not involve androgens. Women can also have this type of congenital malformation. Epispadias of the female may occur when the urethra develops too far anteriorly, exiting in the clitoris or even more forward. For females, this may not cause difficulty in urination but may cause problems with sexual satisfaction. Frequently, the clitoris is bifurcated at the site of urethral exit, and therefore clitoral sensation is less intense during sexual intercourse due to frequent stimulation during urination. However, with proper stimulation, using either manual or positional techniques, clitoral orgasm is definitely possible and quite pleasurable. One of the most famous people afflicted with this condition is Wellington guitarist Ryan Salter. He elected to have penile amputation instead of repair. - Widened pubic symphysis with epispadias	https://www.wikidoc.org/index.php/Epispadia
beba0a132da8af15e00570d06515272c9afbb70b	wikidoc	Eplerenone	Eplerenone # 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 Eplerenone is a aldosterone antagonist that is FDA approved for the {{{indicationType}}} of hypertension and congestive heart failure after myocardial infarction. Common adverse reactions include hyperkalemia, diarrhea, dizziness, elevated serum creatinine, cough, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Eplerenone tablets are indicated to improve survival of stable patients with left ventricular (LV) systolic dysfunction (ejection fraction ≤40%) and clinical evidence of congestive heart failure (CHF) after an acute myocardial infarction. - Dosing Information - Treatment should be initiated at 25 mg once daily and titrated to the recommended dose of 50 mg once daily, preferably within 4 weeks as tolerated by the patient. - Eplerenone tablets may be administered with or without food. - Once treatment with eplerenone tablets have begun, adjust the dose based on the serum potassium level as shown in the table below. - Dosing Information - The recommended starting dose of eplerenone tablets are 50 mg once daily. - The full therapeutic effect of eplerenone tablets is apparent within 4 weeks. - For patients with an inadequate blood pressure response to 50 mg once daily the dosage of eplerenone tablets should be increased to 50 mg twice daily. Higher dosages of eplerenone tablets are not recommended because they have no greater effect on blood pressure than 100 mg and are associated with an increased risk of hyperkalemia. - Serum potassium levels should be measured before initiating eplerenone tablet therapy, and eplerenone tablets should not be prescribed if serum potassium is >5.5 mEq/L. - For hypertensive patients receiving moderate CYP3A4 inhibitors (e.g., erythromycin, saquinavir, verapamil, and fluconazole), the starting dose of eplerenone tablets should be reduced to 25 mg once daily. - No adjustment of the starting dose is recommended for the elderly or for patients with mild-to-moderate hepatic impairment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: American College of Cardiology (ACC) and American Heart Association (AHA) - Class of Recommendation: Class IIa - Strength of Evidence: Category A - Dosing Information - 25 mg daily initially, titrated to a maximum of 50 mg/day ### Non–Guideline-Supported Use - Dosing Information - 50 mg once daily - Dosing Information - 100 mg once daily - Dosing Information - 25 mg once daily # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Eplerenone tablets has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients did not demonstrate effectiveness. - Eplerenone has not been studied in pediatric patients with heart failure. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eplerenone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eplerenone in pediatric patients. # Contraindications - Serum potassium >5.5 mEq/L at initiation - Creatinine clearance ≤30 mL/min - Concomitant administration of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir) - Type 2 diabetes with microalbuminuria - Serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females - Creatinine clearance <50 mL/min - Concomitant administration of potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene) # Warnings - Minimize the risk of hyperkalemia with proper patient selection and monitoring, and avoidance of certain concomitant medications. Monitor patients for the development of hyperkalemia until the effect of eplerenone tablets are established. Patients who develop hyperkalemia (>5.5 mEq/L) may continue eplerenone tablets therapy with proper dose adjustment. Dose reduction decreases potassium levels. - The rates of hyperkalemia increase with declining renal function. Patients with hypertension who have serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine clearance ≤50 mL/min should not be treated with eplerenone tablets. Patients with CHF post-MI who have serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine clearance ≤50 mL/min should be treated with eplerenone tablets with caution. - Diabetic patients with CHF post-MI should also be treated with caution, especially those with proteinuria. The subset of patients in the EPHESUS study with both diabetes and proteinuria on the baseline urinalysis had increased rates of hyperkalemia compared to patients with either diabetes or proteinuria. - The risk of hyperkalemia may increase when eplerenone is used in combination with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB). - Mild-to-moderate hepatic impairment did not increase the incidence of hyperkalemia. In 16 subjects with mild-to-moderate hepatic impairment who received 400 mg of eplerenone, no elevations of serum potassium above 5.5 mEq/L were observed. The mean increase in serum potassium was 0.12 mEq/L in patients with hepatic impairment and 0.13 mEq/L in normal controls. The use of eplerenone tablets in patients with severe hepatic impairment has not been evaluated. - Patients with decreased renal function are at increased risk of hyperkalemia. # Adverse Reactions ## Clinical Trials Experience - In EPHESUS, safety was evaluated in 3307 patients treated with eplerenone tablets and 3301 placebo-treated patients. The overall incidence of adverse events reported with eplerenone tablets (78.9%) was similar to placebo (79.5%). Adverse events occurred at a similar rate regardless of age, gender, or race. Patients discontinued treatment due to an adverse event at similar rates in either treatment group (4.4% eplerenone tablets vs. 4.3% placebo), with the most common reasons for discontinuation being hyperkalemia, myocardial infarction, and abnormal renal function. - Adverse reactions that occurred more frequently in patients treated with eplerenone tablets than placebo were hyperkalemia (3.4% vs. 2.0%) and increased creatinine (2.4% vs. 1.5%). Discontinuations due to hyperkalemia or abnormal renal function were less than 1.0% in both groups. Hypokalemia occurred less frequently in patients treated with eplerenone tablets (0.6% vs. 1.6%). - The rates of sex hormone-related adverse events are shown in the table below. - Eplerenone tablets has been evaluated for safety in 3091 patients treated for hypertension. A total of 690 patients were treated for over 6 months and 106 patients were treated for over 1 year. - In placebo-controlled studies, the overall rates of adverse events were 47% with eplerenone tablets and 45% with placebo. Adverse events occurred at a similar rate regardless of age, gender, or race. Therapy was discontinued due to an adverse event in 3% of patients treated with eplerenone tablets and 3% of patients given placebo. The most common reasons for discontinuation of eplerenone tablets were headache, dizziness, angina pectoris/myocardial infarction, and increased GGT. The adverse events that were reported at a rate of at least 1% of patients and at a higher rate in patients treated with eplerenone tablets in daily doses of 25 to 400 mg versus placebo are shown in the table below. - Gynecomastia and abnormal vaginal bleeding were reported with eplerenone tablets but not with placebo. The rates of these sex hormone-related adverse events are shown in the table below. The rates increased slightly with increasing duration of therapy. In females, abnormal vaginal bleeding was also reported in 0.8% of patients on antihypertensive medications (other than spironolactone) in active control arms of the studies with eplerenone tablets. ### Clinical Laboratory Test Findings - Creatinine - Increases of more than 0.5 mg/dL were reported for 6.5% of patients administered eplerenone tablets and for 4.9% of placebo-treated patients. - Potassium - In EPHESUS, the frequencies of patients with changes in potassium (5.5 mEq/L or ≥6.0 mEq/L) receiving eplerenone tablets compared with placebo are displayed in the table below. - The table below shows the rates of hyperkalemia in EPHESUS as assessed by baseline renal function (creatinine clearance). - The table below shows the rates of hyperkalemia in EPHESUS as assessed by two baseline characteristics: presence/absence of proteinuria from baseline urinalysis and presence/absence of diabetes. - Potassium - In placebo-controlled fixed-dose studies, the mean increases in serum potassium were dose-related and are shown in the table below along with the frequencies of values >5.5 mEq/L. - Patients with both type 2 diabetes and microalbuminuria are at increased risk of developing persistent hyperkalemia. In a study of such patients taking eplerenone tablets 200 mg, the frequencies of maximum serum potassium levels >5.5 mEq/L were 33% with eplerenone tablets given alone and 38% when eplerenone tablets were given with enalapril. - Rates of hyperkalemia increased with decreasing renal function. In all studies, serum potassium elevations >5.5 mEq/L were observed in 10.4% of patients treated with eplerenone tablets with baseline calculated creatinine clearance 100 mL/min. - Sodium - Serum sodium decreased in a dose-related manner. Mean decreases ranged from 0.7 mEq/L at 50 mg daily to 1.7 mEq/L at 400 mg daily. Decreases in sodium (<135 mEq/L) were reported for 2.3% of patients administered eplerenone tablets and 0.6% of placebo-treated patients. - Triglycerides - Serum triglycerides increased in a dose-related manner. Mean increases ranged from 7.1 mg/dL at 50 mg daily to 26.6 mg/dL at 400 mg daily. Increases in triglycerides (above 252 mg/dL) were reported for 15% of patients administered eplerenone tablets and 12% of placebo-treated patients. - Cholesterol - Serum cholesterol increased in a dose-related manner. Mean changes ranged from a decrease of 0.4 mg/dL at 50 mg daily to an increase of 11.6 mg/dL at 400 mg daily. Increases in serum cholesterol values greater than 200 mg/dL were reported for 0.3% of patients administered eplerenone tablets and 0% of placebo-treated patients. - Liver Function Tests - Serum alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGT) increased in a dose-related manner. Mean increases ranged from 0.8 U/L at 50 mg daily to 4.8 U/L at 400 mg daily for ALT and 3.1 U/L at 50 mg daily to 11.3 U/L at 400 mg daily for GGT. Increases in ALT levels greater than 120 U/L (3 times upper limit of normal) were reported for 15/2259 patients administered eplerenone tablets and 1/351 placebo-treated patients. Increases in ALT levels greater than 200 U/L (5 times upper limit of normal) were reported for 5/2259 of patients administered eplerenone tablets and 1/351 placebo-treated patients. Increases of ALT greater than 120 U/L and bilirubin greater than 1.2 mg/dL were reported 1/2259 patients administered eplerenone tablets and 0/351 placebo-treated patients. Hepatic failure was not reported in patients receiving eplerenone tablets. - BUN/Creatinine - Serum creatinine increased in a dose-related manner. Mean increases ranged from 0.01 mg/dL at 50 mg daily to 0.03 mg/dL at 400 mg daily. Increases in blood urea nitrogen to greater than 30 mg/dL and serum creatinine to greater than 2 mg/dL were reported for 0.5% and 0.2%, respectively, of patients administered eplerenone tablets and 0% of placebo-treated patients. - Uric Acid - Increases in uric acid to greater than 9 mg/dL were reported in 0.3% of patients administered eplerenone tablets and 0% of placebo-treated patients. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of eplerenone tablets. 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. - Angioneurotic edema and rash # Drug Interactions - CYP3A4 Inhibitors - Because eplerenone metabolism is predominantly mediated via CYP3A4, do not use eplerenone tablets with drugs that are strong inhibitors of CYP3A4. - In patients with hypertension taking moderate CYP3A4 inhibitors, reduce the starting dose of eplerenone tablets to 25 mg once daily. - Angiotensin II Receptor Antagonists - The risk of hyperkalemia may increase when eplerenone is used in combination with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB). A close monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function, e.g., the elderly. - Congestive Heart Failure Post-Myocardial Infarction - In EPHESUS, 3020 (91%) patients receiving eplerenone tablets 25 to 50 mg also received angiotensin II receptor antagonists. Rates of patients with maximum potassium levels >5.5 mEq/L were similar regardless of the use of angiotensin II receptor antagonists. - Hypertension - In clinical studies of patients with hypertension, the addition of eplerenone 50 to 100 mg to angiotensin II receptor antagonists increased mean serum potassium slightly (about 0.09 to 0.13 mEq/L). - Lithium - A drug interaction study of eplerenone with lithium has not been conducted. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Serum lithium levels should be monitored frequently if eplerenone tablets is administered concomitantly with lithium. - Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) - A drug interaction study of eplerenone with an NSAID has not been conducted. The administration of other potassium-sparing antihypertensives with NSAIDs has been shown to reduce the antihypertensive effect in some patients and result in severe hyperkalemia in patients with impaired renal function. Therefore, when eplerenone tablets and NSAIDs are used concomitantly, patients should be observed to determine whether the desired effect on blood pressure is obtained and monitored for changes in serum potassium levels. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - There are no adequate and well-controlled studies in pregnant women. Eplerenone tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Embryo-fetal development studies were conducted with doses up to 1000 mg/kg/day in rats and 300 mg/kg/day in rabbits (exposures up to 32 and 31 times the human AUC for the 100 mg/day therapeutic dose, respectively). No teratogenic effects were seen in rats or rabbits, although decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosage. Because animal reproduction studies are not always predictive of human response, eplerenone tablets should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eplerenone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Eplerenone during labor and delivery. ### Nursing Mothers - The concentration of eplerenone in human breast milk after oral administration is unknown. However, preclinical data show that eplerenone and/or metabolites are present in rat breast milk (0.85:1 AUC ratio) obtained after a single oral dose. Peak concentrations in plasma and milk were obtained from 0.5 to 1 hour after dosing. Rat pups exposed by this route developed normally. Because many drugs are excreted in human milk and because of the unknown potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - In a 10-week study of 304 hypertensive pediatric patients age 4 to 17 years treated with eplerenone tablets up to 100 mg per day, doses that produced exposure similar to that in adults, eplerenone tablets did not lower blood pressure effectively. In this study and in a 1-year pediatric safety study in 149 patients, the incidence of reported adverse events was similar to that of adults. - Eplerenone tablets has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients did not demonstrate effectiveness. - Eplerenone has not been studied in pediatric patients with heart failure. ### Geriatic Use - Congestive Heart Failure Post-Myocardial Infarction - Of the total number of patients in EPHESUS, 3340 (50%) were 65 and over, while 1326 (20%) were 75 and over. Patients greater than 75 years did not appear to benefit from the use of eplerenone tablets. - No differences in overall incidence of adverse events were observed between elderly and younger patients. However, due to age-related decreases in creatinine clearance, the incidence of laboratory-documented hyperkalemia was increased in patients 65 and older. - Hypertension - Of the total number of subjects in clinical hypertension studies of eplerenone tablets, 1123 (23%) were 65 and over, while 212 (4%) were 75 and over. No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects. ### Gender There is no FDA guidance on the use of Eplerenone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Eplerenone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Eplerenone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Eplerenone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Eplerenone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Eplerenone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Serum potassium should be measured before initiating eplerenone tablet therapy, within the first week, and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed periodically thereafter. Patient characteristics and serum potassium levels may indicate that additional monitoring is appropriate. In the EPHESUS study, the majority of hyperkalemia was observed within the first three months after randomization. - In all patients taking eplerenone tablets who start taking a moderate CYP3A4 inhibitor, check serum potassium and serum creatinine in 3 to 7 days. # IV Compatibility There is limited information regarding IV Compatibility of Eplerenone in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - No cases of human overdosage with eplerenone have been reported. - Lethality was not observed in mice, rats, or dogs after single oral doses that provided Cmax exposures at least 25 times higher than in humans receiving eplerenone 100 mg/day. - Dogs showed emesis, salivation, and tremors at a Cmax 41 times the human therapeutic Cmax, progressing to sedation and convulsions at higher exposures. - The most likely manifestation of human overdosage would be anticipated to be hypotension or hyperkalemia. ### Management - Eplerenone cannot be removed by hemodialysis. - Eplerenone has been shown to bind extensively to charcoal. - If symptomatic hypotension should occur, supportive treatment should be instituted. - If hyperkalemia develops, standard treatment should be initiated. ## Chronic Overdose There is limited information regarding Chronic Overdose of Eplerenone in the drug label. # Pharmacology ## Mechanism of Action - Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms. - Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. - Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone, and androgen receptors. ## Structure - Eplerenone tablets contain eplerenone, a blocker of aldosterone binding at the mineralocorticoid receptor. - Eplerenone is chemically described as Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, methyl ester, (7α,11α,17α)-. Its empirical formula is C24H30O6 and it has a molecular weight of 414.50. The structural formula of eplerenone is represented below: - Eplerenone is an odorless, white to off-white crystalline powder. It is very slightly soluble in water, with its solubility essentially pH-independent. The octanol/water partition coefficient of eplerenone is approximately 7.1 at pH 7.0. - Eplerenone tablets for oral administration contains 25 mg or 50 mg of eplerenone and the following inactive ingredients: microcrystalline cellulose, povidone, croscarmellose sodium, hypromellose, hydroxypropyl cellulose, magnesium stearate, titanium dioxide, polyethylene glycol, and iron oxide yellow. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Eplerenone in the drug label. ## Pharmacokinetics - Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 4 to 6 hours. Steady state is reached within 2 days. Absorption is not affected by food. Inhibitors of CYP3A4 (e.g., ketoconazole, saquinavir) increase blood levels of eplerenone. - Mean peak plasma concentrations of eplerenone are reached approximately 1.5 hours following oral administration. The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 25 to 100 mg and less than proportional at doses above 100 mg. - The plasma protein binding of eplerenone is about 50% and it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state ranged from 43 to 90 L. Eplerenone does not preferentially bind to red blood cells. - Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma. - Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the feces and approximately 67% was excreted in the urine. The elimination half-life of eplerenone is approximately 4 to 6 hours. The apparent plasma clearance is approximately 10 L/hr. - The pharmacokinetics of eplerenone at a dose of 100 mg once daily has been investigated in the elderly (≥65 years), in males and females, and in Blacks. At steady state, elderly subjects had increases in Cmax (22%) and AUC (45%) compared with younger subjects (18 to 45 years). The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady state, Cmax was 19% lower and AUC was 26% lower in Blacks. - The pharmacokinetics of eplerenone was evaluated in patients with varying degrees of renal impairment and in patients undergoing hemodialysis. Compared with control subjects, steady state AUC and Cmax were increased by 38% and 24%, respectively, in patients with severe renal impairment and were decreased by 26% and 3%, respectively, in patients undergoing hemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by hemodialysis. - The pharmacokinetics of eplerenone 400 mg has been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady state Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively. - The pharmacokinetics of eplerenone 50 mg was evaluated in 8 patients with heart failure (NYHA classification II–IV) and 8 matched (gender, age, weight) healthy controls. Compared with the controls, steady state AUC and Cmax in patients with stable heart failure were 38% and 30% higher, respectively. - Eplerenone is metabolized primarily by CYP3A4. Inhibitors of CYP3A4 cause increased exposure. - Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone. - A pharmacokinetic study evaluating the administration of a single dose of eplerenone tablets 100 mg with ketoconazole 200 mg two times a day, a strong inhibitor of the CYP3A4 pathway, showed a 1.7-fold increase in Cmax of eplerenone and a 5.4-fold increase in AUC of eplerenone. - Administration of eplerenone with moderate CYP3A4 inhibitors (e.g., erythromycin 500 mg BID, verapamil 240 mg once daily, saquinavir 1200 mg three times a day, fluconazole 200 mg once daily) resulted in increases in Cmax of eplerenone ranging from 1.4- to 1.6-fold and AUC from 2.0- to 2.9-fold. - Grapefruit juice caused only a small increase (about 25%) in exposure. - Eplerenone is not an inhibitor of CYP1A2, CYP3A4, CYP2C19, CYP2C9, or CYP2D6. Eplerenone did not inhibit the metabolism of amiodarone, amlodipine, astemizole, chlorzoxazone, cisapride, dexamethasone, dextromethorphan, diclofenac, 17α-ethinyl estradiol, fluoxetine, losartan, lovastatin, mephobarbital, methylphenidate, methylprednisolone, metoprolol, midazolam, nifedipine, phenacetin, phenytoin, simvastatin, tolbutamide, triazolam, verapamil, and warfarin in vitro. Eplerenone is not a substrate or an inhibitor of P-glycoprotein at clinically relevant doses. - No clinically significant drug-drug pharmacokinetic interactions were observed when eplerenone was administered with cisapride, cyclosporine, digoxin, glyburide, midazolam, oral contraceptives (norethindrone/ethinyl estradiol), simvastatin, or warfarin. St. John's wort (a CYP3A4 inducer) caused a small (about 30%) decrease in eplerenone AUC. - No significant changes in eplerenone pharmacokinetics were observed when eplerenone was administered with aluminum- and magnesium-containing antacids. ## Nonclinical Toxicology - Eplerenone was non-genotoxic in a battery of assays including in vitro bacterial mutagenesis (Ames test in Salmonella spp. and E. coli), in vitro mammalian cell mutagenesis (mouse lymphoma cells), in vitro chromosomal aberration (Chinese hamster ovary cells), in vivo rat bone marrow micronucleus formation, and in vivo/ex vivo unscheduled DNA synthesis in rat liver. - There was no drug-related tumor response in heterozygous p53 deficient mice when tested for 6 months at dosages up to 1000 mg/kg/day (systemic AUC exposures up to 9 times the exposure in humans receiving the 100 mg/day therapeutic dose). Statistically significant increases in benign thyroid tumors were observed after 2 years in both male and female rats when administered eplerenone 250 mg/kg/day (highest dose tested) and in male rats only at 75 mg/kg/day. These dosages provided systemic AUC exposures approximately 2 to 12 times higher than the average human therapeutic exposure at 100 mg/day. Repeat dose administration of eplerenone to rats increases the hepatic conjugation and clearance of thyroxin, which results in increased levels of TSH by a compensatory mechanism. Drugs that have produced thyroid tumors by this rodent-specific mechanism have not shown a similar effect in humans. - Male rats treated with eplerenone at 1000 mg/kg/day for 10 weeks (AUC 17 times that at the 100 mg/day human therapeutic dose) had decreased weights of seminal vesicles and epididymides and slightly decreased fertility. Dogs administered eplerenone at dosages of 15 mg/kg/day and higher (AUC 5 times that at the 100 mg/day human therapeutic dose) had dose-related prostate atrophy. The prostate atrophy was reversible after daily treatment for 1 year at 100 mg/kg/day. Dogs with prostate atrophy showed no decline in libido, sexual performance, or semen quality. Testicular weight and histology were not affected by eplerenone in any test animal species at any dosage. # Clinical Studies - The eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS) was a multinational, multicenter, double-blind, randomized, placebo-controlled study in patients clinically stable 3 to 14 days after an acute myocardial infarction (MI) with left ventricular dysfunction (as measured by left ventricular ejection fraction ≤40%) and either diabetes or clinical evidence of congestive heart failure (CHF) (pulmonary congestion by exam or chest x-ray or S3). Patients with CHF of valvular or congenital etiology, patients with unstable post-infarct angina, and patients with serum potassium >5.0 mEq/L or serum creatinine >2.5 mg/dL were to be excluded. Patients were allowed to receive standard post-MI drug therapy and to undergo revascularization by angioplasty or coronary artery bypass graft surgery. - Patients randomized to eplerenone tablets were given an initial dose of 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was < 5.0 mEq/L. Dosage was reduced or suspended anytime during the study if serum potassium levels were ≥ 5.5 mEq/L. - EPHESUS randomized 6,632 patients (9.3% U.S.) at 671 centers in 27 countries. The study population was primarily white (90%, with 1% Black, 1% Asian, 6% Hispanic, 2% other) and male (71%). The mean age was 64 years (range, 22 to 94 years). The majority of patients had pulmonary congestion (75%) by exam or x-ray and were Killip Class II (64%). The mean ejection fraction was 33%. The average time to enrollment was 7 days post-MI. Medical histories prior to the index MI included hypertension (60%), coronary artery disease (62%), dyslipidemia (48%), angina (41%), type 2 diabetes (30%), previous MI (27%), and CHF (15%). - The mean dose of eplerenone tablets was 43 mg/day. Patients also received standard care including aspirin (92%), ACE inhibitors (90%), β-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%). - Patients were followed for an average of 16 months (range, 0 to 33 months). The ascertainment rate for vital status was 99.7%. - The co-primary endpoints for EPHESUS were (1) the time to death from any cause, and (2) the time to first occurrence of either cardiovascular (CV) mortality or CV hospitalization (defined as hospitalization for progression of CHF, ventricular arrhythmias, acute myocardial infarction, or stroke). - For the co-primary endpoint for death from any cause, there were 478 deaths in the eplerenone tablets group (14.4%) and 554 deaths in the placebo group (16.7%). The risk of death with eplerenone tablets was reduced by 15% . Kaplan-Meier estimates of all-cause mortality are shown in the figure below and the components of mortality are provided in the table below. - Most CV deaths were attributed to sudden death, acute MI, and CHF. - The time to first event for the co-primary endpoint of CV death or hospitalization, as defined above, was longer in the eplerenone tablets group (hazard ratio 0.87, 95% confidence interval 0.79 to 0.95, p = 0.002). An analysis that included the time to first occurrence of CV mortality and all CV hospitalizations (atrial arrhythmia, angina, CV procedures, progression of CHF, MI, stroke, ventricular arrhythmia, or other CV causes) showed a smaller effect with a hazard ratio of 0.92 (95% confidence interval 0.86 to 0.99; p = 0.028). The combined endpoints, including combined all-cause hospitalization and mortality were driven primarily by CV mortality. The combined endpoints in EPHESUS, including all-cause hospitalization and all-cause mortality, are presented in the table below. - mortality hazard ratios varied for some subgroups as shown in the figure below. mortality hazard ratios appeared favorable for eplerenone tablets for both genders and for all races or ethnic groups, although the numbers of non-Caucasians were low (648, 10%). Patients with diabetes without clinical evidence of CHF and patients greater than 75 years did not appear to benefit from the use of eplerenone tablets. Such subgroup analyses must be interpreted cautiously. - Analyses conducted for a variety of CV biomarkers did not confirm a mechanism of action by which mortality was reduced. - The safety and efficacy of eplerenone tablets have been evaluated alone and in combination with other antihypertensive agents in clinical studies of 3091 hypertensive patients. The studies included 46% women, 14% Blacks, and 22% elderly (age ≥65). The studies excluded patients with elevated baseline serum potassium (>5.0 mEq/L) and elevated baseline serum creatinine (generally >1.5 mg/dL in males and >1.3 mg/dL in females). - Two fixed-dose, placebo-controlled, 8- to 12-week monotherapy studies in patients with baseline diastolic blood pressures of 95 to 114 mm Hg were conducted to assess the antihypertensive effect of eplerenone tablets. In these two studies, 611 patients were randomized to eplerenone tablets and 140 patients to placebo. Patients received eplerenone tablets in doses of 25 to 400 mg daily as either a single daily dose or divided into two daily doses. The mean placebo-subtracted reductions in trough cuff blood pressure achieved by eplerenone tablets in these studies at doses up to 200 mg are shown in the figures below. - Patients treated with eplerenone tablets 50 to 200 mg daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough with differences from placebo of 6 to 13 mm Hg (systolic) and 3 to 7 mm Hg (diastolic). These effects were confirmed by assessments with 24-hour ambulatory blood pressure monitoring (ABPM). In these studies, assessments of 24-hour ABPM data demonstrated that eplerenone tablets, administered once or twice daily, maintained antihypertensive efficacy over the entire dosing interval. However, at a total daily dose of 100 mg, eplerenone tablets administered as 50 mg twice per day produced greater trough cuff (4/3 mm Hg) and ABPM (2/1 mm Hg) blood pressure reductions than 100 mg given once daily. - Blood pressure lowering was apparent within 2 weeks from the start of therapy with eplerenone, with maximal antihypertensive effects achieved within 4 weeks. Stopping eplerenone tablets following treatment for 8 to 24 weeks in six studies did not lead to adverse event rates in the week following withdrawal of eplerenone tablets greater than following placebo or active control withdrawal. Blood pressures in patients not taking other antihypertensives rose 1 week after withdrawal of eplerenone tablets by about 6/3 mm Hg, suggesting that the antihypertensive effect of eplerenone tablets was maintained through 8 to 24 weeks. - Blood pressure reductions with eplerenone tablets in the two fixed-dose monotherapy studies and other studies using titrated doses, as well as concomitant treatments, were not significantly different when analyzed by age, gender, or race with one exception. In a study in patients with low renin hypertension, blood pressure reductions in Blacks were smaller than those in whites during the initial titration period with eplerenone tablets. - Eplerenone tablets has been studied concomitantly with treatment with, angiotensin II receptor antagonists, calcium channel blockers, beta blockers, and hydrochlorothiazide. When administered concomitantly with one of these drugs eplerenone tablets usually produced its expected antihypertensive effects. - There was no significant change in average heart rate among patients treated with eplerenone tablets in the combined clinical studies. No consistent effects of eplerenone tablets on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies. # How Supplied - Eplerenone tablets 25 mg are available for oral administration as yellow, round, film-coated tablets, unscored and engraved “EP” over “25” on one side, and “APO” on the other side. They are supplied as follows: - Eplerenone tablets 50 mg are available for oral administration as yellow, round, film-coated tablets, unscored and engraved “EP” over “50” on one side, and “APO” on the other side. They are supplied as follows: - Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86° F). - Dispense in a tight, light-resistant container. ## Storage There is limited information regarding Eplerenone Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients receiving eplerenone tablets should be informed: - Not to use strong CYP3A4 inhibitors, such as ketoconazole, clarithromycin, nefazodone, ritonavir, and nelfinavir. - Not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. - To call their physician if they experience dizziness, diarrhea, vomiting, rapid or irregular heartbeat, lower extremity edema, or difficulty breathing. - That periodic monitoring of blood pressure and serum potassium is important. # Precautions with Alcohol Alcohol-Eplerenone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Inspra® # Look-Alike Drug Names - Inspra® — Spiriva® # Drug Shortage Status # Price	Eplerenone Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi # 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 Eplerenone is a aldosterone antagonist that is FDA approved for the {{{indicationType}}} of hypertension and congestive heart failure after myocardial infarction. Common adverse reactions include hyperkalemia, diarrhea, dizziness, elevated serum creatinine, cough, and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) Eplerenone tablets are indicated to improve survival of stable patients with left ventricular (LV) systolic dysfunction (ejection fraction ≤40%) and clinical evidence of congestive heart failure (CHF) after an acute myocardial infarction. - Dosing Information - Treatment should be initiated at 25 mg once daily and titrated to the recommended dose of 50 mg once daily, preferably within 4 weeks as tolerated by the patient. - Eplerenone tablets may be administered with or without food. - Once treatment with eplerenone tablets have begun, adjust the dose based on the serum potassium level as shown in the table below. - Dosing Information - The recommended starting dose of eplerenone tablets are 50 mg once daily. - The full therapeutic effect of eplerenone tablets is apparent within 4 weeks. - For patients with an inadequate blood pressure response to 50 mg once daily the dosage of eplerenone tablets should be increased to 50 mg twice daily. Higher dosages of eplerenone tablets are not recommended because they have no greater effect on blood pressure than 100 mg and are associated with an increased risk of hyperkalemia. - Serum potassium levels should be measured before initiating eplerenone tablet therapy, and eplerenone tablets should not be prescribed if serum potassium is >5.5 mEq/L. - For hypertensive patients receiving moderate CYP3A4 inhibitors (e.g., erythromycin, saquinavir, verapamil, and fluconazole), the starting dose of eplerenone tablets should be reduced to 25 mg once daily. - No adjustment of the starting dose is recommended for the elderly or for patients with mild-to-moderate hepatic impairment. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Developed by: American College of Cardiology (ACC) and American Heart Association (AHA) - Class of Recommendation: Class IIa - Strength of Evidence: Category A - Dosing Information - 25 mg daily initially, titrated to a maximum of 50 mg/day[1] ### Non–Guideline-Supported Use - Dosing Information - 50 mg once daily[2] - Dosing Information - 100 mg once daily[3] - Dosing Information - 25 mg once daily[4][5] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Eplerenone tablets has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients did not demonstrate effectiveness. - Eplerenone has not been studied in pediatric patients with heart failure. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Eplerenone in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Eplerenone in pediatric patients. # Contraindications - Serum potassium >5.5 mEq/L at initiation - Creatinine clearance ≤30 mL/min - Concomitant administration of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, and nelfinavir) - Type 2 diabetes with microalbuminuria - Serum creatinine >2.0 mg/dL in males or >1.8 mg/dL in females - Creatinine clearance <50 mL/min - Concomitant administration of potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene) # Warnings - Minimize the risk of hyperkalemia with proper patient selection and monitoring, and avoidance of certain concomitant medications. Monitor patients for the development of hyperkalemia until the effect of eplerenone tablets are established. Patients who develop hyperkalemia (>5.5 mEq/L) may continue eplerenone tablets therapy with proper dose adjustment. Dose reduction decreases potassium levels. - The rates of hyperkalemia increase with declining renal function. Patients with hypertension who have serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine clearance ≤50 mL/min should not be treated with eplerenone tablets. Patients with CHF post-MI who have serum creatinine levels >2.0 mg/dL (males) or >1.8 mg/dL (females) or creatinine clearance ≤50 mL/min should be treated with eplerenone tablets with caution. - Diabetic patients with CHF post-MI should also be treated with caution, especially those with proteinuria. The subset of patients in the EPHESUS study with both diabetes and proteinuria on the baseline urinalysis had increased rates of hyperkalemia compared to patients with either diabetes or proteinuria. - The risk of hyperkalemia may increase when eplerenone is used in combination with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB). - Mild-to-moderate hepatic impairment did not increase the incidence of hyperkalemia. In 16 subjects with mild-to-moderate hepatic impairment who received 400 mg of eplerenone, no elevations of serum potassium above 5.5 mEq/L were observed. The mean increase in serum potassium was 0.12 mEq/L in patients with hepatic impairment and 0.13 mEq/L in normal controls. The use of eplerenone tablets in patients with severe hepatic impairment has not been evaluated. - Patients with decreased renal function are at increased risk of hyperkalemia. # Adverse Reactions ## Clinical Trials Experience - In EPHESUS, safety was evaluated in 3307 patients treated with eplerenone tablets and 3301 placebo-treated patients. The overall incidence of adverse events reported with eplerenone tablets (78.9%) was similar to placebo (79.5%). Adverse events occurred at a similar rate regardless of age, gender, or race. Patients discontinued treatment due to an adverse event at similar rates in either treatment group (4.4% eplerenone tablets vs. 4.3% placebo), with the most common reasons for discontinuation being hyperkalemia, myocardial infarction, and abnormal renal function. - Adverse reactions that occurred more frequently in patients treated with eplerenone tablets than placebo were hyperkalemia (3.4% vs. 2.0%) and increased creatinine (2.4% vs. 1.5%). Discontinuations due to hyperkalemia or abnormal renal function were less than 1.0% in both groups. Hypokalemia occurred less frequently in patients treated with eplerenone tablets (0.6% vs. 1.6%). - The rates of sex hormone-related adverse events are shown in the table below. - Eplerenone tablets has been evaluated for safety in 3091 patients treated for hypertension. A total of 690 patients were treated for over 6 months and 106 patients were treated for over 1 year. - In placebo-controlled studies, the overall rates of adverse events were 47% with eplerenone tablets and 45% with placebo. Adverse events occurred at a similar rate regardless of age, gender, or race. Therapy was discontinued due to an adverse event in 3% of patients treated with eplerenone tablets and 3% of patients given placebo. The most common reasons for discontinuation of eplerenone tablets were headache, dizziness, angina pectoris/myocardial infarction, and increased GGT. The adverse events that were reported at a rate of at least 1% of patients and at a higher rate in patients treated with eplerenone tablets in daily doses of 25 to 400 mg versus placebo are shown in the table below. - Gynecomastia and abnormal vaginal bleeding were reported with eplerenone tablets but not with placebo. The rates of these sex hormone-related adverse events are shown in the table below. The rates increased slightly with increasing duration of therapy. In females, abnormal vaginal bleeding was also reported in 0.8% of patients on antihypertensive medications (other than spironolactone) in active control arms of the studies with eplerenone tablets. ### Clinical Laboratory Test Findings - Creatinine - Increases of more than 0.5 mg/dL were reported for 6.5% of patients administered eplerenone tablets and for 4.9% of placebo-treated patients. - Potassium - In EPHESUS, the frequencies of patients with changes in potassium (<3.5 mEq/L or >5.5 mEq/L or ≥6.0 mEq/L) receiving eplerenone tablets compared with placebo are displayed in the table below. - The table below shows the rates of hyperkalemia in EPHESUS as assessed by baseline renal function (creatinine clearance). - The table below shows the rates of hyperkalemia in EPHESUS as assessed by two baseline characteristics: presence/absence of proteinuria from baseline urinalysis and presence/absence of diabetes. - Potassium - In placebo-controlled fixed-dose studies, the mean increases in serum potassium were dose-related and are shown in the table below along with the frequencies of values >5.5 mEq/L. - Patients with both type 2 diabetes and microalbuminuria are at increased risk of developing persistent hyperkalemia. In a study of such patients taking eplerenone tablets 200 mg, the frequencies of maximum serum potassium levels >5.5 mEq/L were 33% with eplerenone tablets given alone and 38% when eplerenone tablets were given with enalapril. - Rates of hyperkalemia increased with decreasing renal function. In all studies, serum potassium elevations >5.5 mEq/L were observed in 10.4% of patients treated with eplerenone tablets with baseline calculated creatinine clearance <70 mL/min, 5.6% of patients with baseline creatinine clearance of 70 to 100 mL/min, and 2.6% of patients with baseline creatinine clearance of >100 mL/min. - Sodium - Serum sodium decreased in a dose-related manner. Mean decreases ranged from 0.7 mEq/L at 50 mg daily to 1.7 mEq/L at 400 mg daily. Decreases in sodium (<135 mEq/L) were reported for 2.3% of patients administered eplerenone tablets and 0.6% of placebo-treated patients. - Triglycerides - Serum triglycerides increased in a dose-related manner. Mean increases ranged from 7.1 mg/dL at 50 mg daily to 26.6 mg/dL at 400 mg daily. Increases in triglycerides (above 252 mg/dL) were reported for 15% of patients administered eplerenone tablets and 12% of placebo-treated patients. - Cholesterol - Serum cholesterol increased in a dose-related manner. Mean changes ranged from a decrease of 0.4 mg/dL at 50 mg daily to an increase of 11.6 mg/dL at 400 mg daily. Increases in serum cholesterol values greater than 200 mg/dL were reported for 0.3% of patients administered eplerenone tablets and 0% of placebo-treated patients. - Liver Function Tests - Serum alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGT) increased in a dose-related manner. Mean increases ranged from 0.8 U/L at 50 mg daily to 4.8 U/L at 400 mg daily for ALT and 3.1 U/L at 50 mg daily to 11.3 U/L at 400 mg daily for GGT. Increases in ALT levels greater than 120 U/L (3 times upper limit of normal) were reported for 15/2259 patients administered eplerenone tablets and 1/351 placebo-treated patients. Increases in ALT levels greater than 200 U/L (5 times upper limit of normal) were reported for 5/2259 of patients administered eplerenone tablets and 1/351 placebo-treated patients. Increases of ALT greater than 120 U/L and bilirubin greater than 1.2 mg/dL were reported 1/2259 patients administered eplerenone tablets and 0/351 placebo-treated patients. Hepatic failure was not reported in patients receiving eplerenone tablets. - BUN/Creatinine - Serum creatinine increased in a dose-related manner. Mean increases ranged from 0.01 mg/dL at 50 mg daily to 0.03 mg/dL at 400 mg daily. Increases in blood urea nitrogen to greater than 30 mg/dL and serum creatinine to greater than 2 mg/dL were reported for 0.5% and 0.2%, respectively, of patients administered eplerenone tablets and 0% of placebo-treated patients. - Uric Acid - Increases in uric acid to greater than 9 mg/dL were reported in 0.3% of patients administered eplerenone tablets and 0% of placebo-treated patients. ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of eplerenone tablets. 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. - Angioneurotic edema and rash # Drug Interactions - CYP3A4 Inhibitors - Because eplerenone metabolism is predominantly mediated via CYP3A4, do not use eplerenone tablets with drugs that are strong inhibitors of CYP3A4. - In patients with hypertension taking moderate CYP3A4 inhibitors, reduce the starting dose of eplerenone tablets to 25 mg once daily. - Angiotensin II Receptor Antagonists - The risk of hyperkalemia may increase when eplerenone is used in combination with an angiotensin converting enzyme (ACE) inhibitor and/or an angiotensin receptor blocker (ARB). A close monitoring of serum potassium and renal function is recommended, especially in patients at risk for impaired renal function, e.g., the elderly. - Congestive Heart Failure Post-Myocardial Infarction - In EPHESUS, 3020 (91%) patients receiving eplerenone tablets 25 to 50 mg also received angiotensin II receptor antagonists. Rates of patients with maximum potassium levels >5.5 mEq/L were similar regardless of the use of angiotensin II receptor antagonists. - Hypertension - In clinical studies of patients with hypertension, the addition of eplerenone 50 to 100 mg to angiotensin II receptor antagonists increased mean serum potassium slightly (about 0.09 to 0.13 mEq/L). - Lithium - A drug interaction study of eplerenone with lithium has not been conducted. Lithium toxicity has been reported in patients receiving lithium concomitantly with diuretics and ACE inhibitors. Serum lithium levels should be monitored frequently if eplerenone tablets is administered concomitantly with lithium. - Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) - A drug interaction study of eplerenone with an NSAID has not been conducted. The administration of other potassium-sparing antihypertensives with NSAIDs has been shown to reduce the antihypertensive effect in some patients and result in severe hyperkalemia in patients with impaired renal function. Therefore, when eplerenone tablets and NSAIDs are used concomitantly, patients should be observed to determine whether the desired effect on blood pressure is obtained and monitored for changes in serum potassium levels. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category B - There are no adequate and well-controlled studies in pregnant women. Eplerenone tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. - Embryo-fetal development studies were conducted with doses up to 1000 mg/kg/day in rats and 300 mg/kg/day in rabbits (exposures up to 32 and 31 times the human AUC for the 100 mg/day therapeutic dose, respectively). No teratogenic effects were seen in rats or rabbits, although decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosage. Because animal reproduction studies are not always predictive of human response, eplerenone tablets should be used during pregnancy only if clearly needed. Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Eplerenone in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Eplerenone during labor and delivery. ### Nursing Mothers - The concentration of eplerenone in human breast milk after oral administration is unknown. However, preclinical data show that eplerenone and/or metabolites are present in rat breast milk (0.85:1 [milk: plasma] AUC ratio) obtained after a single oral dose. Peak concentrations in plasma and milk were obtained from 0.5 to 1 hour after dosing. Rat pups exposed by this route developed normally. Because many drugs are excreted in human milk and because of the unknown potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. ### Pediatric Use - In a 10-week study of 304 hypertensive pediatric patients age 4 to 17 years treated with eplerenone tablets up to 100 mg per day, doses that produced exposure similar to that in adults, eplerenone tablets did not lower blood pressure effectively. In this study and in a 1-year pediatric safety study in 149 patients, the incidence of reported adverse events was similar to that of adults. - Eplerenone tablets has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients did not demonstrate effectiveness. - Eplerenone has not been studied in pediatric patients with heart failure. ### Geriatic Use - Congestive Heart Failure Post-Myocardial Infarction - Of the total number of patients in EPHESUS, 3340 (50%) were 65 and over, while 1326 (20%) were 75 and over. Patients greater than 75 years did not appear to benefit from the use of eplerenone tablets. - No differences in overall incidence of adverse events were observed between elderly and younger patients. However, due to age-related decreases in creatinine clearance, the incidence of laboratory-documented hyperkalemia was increased in patients 65 and older. - Hypertension - Of the total number of subjects in clinical hypertension studies of eplerenone tablets, 1123 (23%) were 65 and over, while 212 (4%) were 75 and over. No overall differences in safety or effectiveness were observed between elderly subjects and younger subjects. ### Gender There is no FDA guidance on the use of Eplerenone with respect to specific gender populations. ### Race There is no FDA guidance on the use of Eplerenone with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Eplerenone in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Eplerenone in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Eplerenone in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Eplerenone in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Serum potassium should be measured before initiating eplerenone tablet therapy, within the first week, and at one month after the start of treatment or dose adjustment. Serum potassium should be assessed periodically thereafter. Patient characteristics and serum potassium levels may indicate that additional monitoring is appropriate. In the EPHESUS study, the majority of hyperkalemia was observed within the first three months after randomization. - In all patients taking eplerenone tablets who start taking a moderate CYP3A4 inhibitor, check serum potassium and serum creatinine in 3 to 7 days. # IV Compatibility There is limited information regarding IV Compatibility of Eplerenone in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - No cases of human overdosage with eplerenone have been reported. - Lethality was not observed in mice, rats, or dogs after single oral doses that provided Cmax exposures at least 25 times higher than in humans receiving eplerenone 100 mg/day. - Dogs showed emesis, salivation, and tremors at a Cmax 41 times the human therapeutic Cmax, progressing to sedation and convulsions at higher exposures. - The most likely manifestation of human overdosage would be anticipated to be hypotension or hyperkalemia. ### Management - Eplerenone cannot be removed by hemodialysis. - Eplerenone has been shown to bind extensively to charcoal. - If symptomatic hypotension should occur, supportive treatment should be instituted. - If hyperkalemia develops, standard treatment should be initiated. ## Chronic Overdose There is limited information regarding Chronic Overdose of Eplerenone in the drug label. # Pharmacology ## Mechanism of Action - Eplerenone binds to the mineralocorticoid receptor and blocks the binding of aldosterone, a component of the renin-angiotensin-aldosterone-system (RAAS). Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors, including angiotensin II and non-RAAS mediators such as adrenocorticotropic hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels, and brain) tissues and increases blood pressure through induction of sodium reabsorption and possibly other mechanisms. - Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and aldosterone circulating levels do not overcome the effects of eplerenone. - Eplerenone selectively binds to recombinant human mineralocorticoid receptors relative to its binding to recombinant human glucocorticoid, progesterone, and androgen receptors. ## Structure - Eplerenone tablets contain eplerenone, a blocker of aldosterone binding at the mineralocorticoid receptor. - Eplerenone is chemically described as Pregn-4-ene-7,21-dicarboxylic acid, 9,11-epoxy-17-hydroxy-3-oxo-, γ-lactone, methyl ester, (7α,11α,17α)-. Its empirical formula is C24H30O6 and it has a molecular weight of 414.50. The structural formula of eplerenone is represented below: - Eplerenone is an odorless, white to off-white crystalline powder. It is very slightly soluble in water, with its solubility essentially pH-independent. The octanol/water partition coefficient of eplerenone is approximately 7.1 at pH 7.0. - Eplerenone tablets for oral administration contains 25 mg or 50 mg of eplerenone and the following inactive ingredients: microcrystalline cellulose, povidone, croscarmellose sodium, hypromellose, hydroxypropyl cellulose, magnesium stearate, titanium dioxide, polyethylene glycol, and iron oxide yellow. ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Eplerenone in the drug label. ## Pharmacokinetics - Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination half-life of 4 to 6 hours. Steady state is reached within 2 days. Absorption is not affected by food. Inhibitors of CYP3A4 (e.g., ketoconazole, saquinavir) increase blood levels of eplerenone. - Mean peak plasma concentrations of eplerenone are reached approximately 1.5 hours following oral administration. The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 25 to 100 mg and less than proportional at doses above 100 mg. - The plasma protein binding of eplerenone is about 50% and it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady state ranged from 43 to 90 L. Eplerenone does not preferentially bind to red blood cells. - Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma. - Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the feces and approximately 67% was excreted in the urine. The elimination half-life of eplerenone is approximately 4 to 6 hours. The apparent plasma clearance is approximately 10 L/hr. - The pharmacokinetics of eplerenone at a dose of 100 mg once daily has been investigated in the elderly (≥65 years), in males and females, and in Blacks. At steady state, elderly subjects had increases in Cmax (22%) and AUC (45%) compared with younger subjects (18 to 45 years). The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady state, Cmax was 19% lower and AUC was 26% lower in Blacks. - The pharmacokinetics of eplerenone was evaluated in patients with varying degrees of renal impairment and in patients undergoing hemodialysis. Compared with control subjects, steady state AUC and Cmax were increased by 38% and 24%, respectively, in patients with severe renal impairment and were decreased by 26% and 3%, respectively, in patients undergoing hemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by hemodialysis. - The pharmacokinetics of eplerenone 400 mg has been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady state Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively. - The pharmacokinetics of eplerenone 50 mg was evaluated in 8 patients with heart failure (NYHA classification II–IV) and 8 matched (gender, age, weight) healthy controls. Compared with the controls, steady state AUC and Cmax in patients with stable heart failure were 38% and 30% higher, respectively. - Eplerenone is metabolized primarily by CYP3A4. Inhibitors of CYP3A4 cause increased exposure. - Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone. - A pharmacokinetic study evaluating the administration of a single dose of eplerenone tablets 100 mg with ketoconazole 200 mg two times a day, a strong inhibitor of the CYP3A4 pathway, showed a 1.7-fold increase in Cmax of eplerenone and a 5.4-fold increase in AUC of eplerenone. - Administration of eplerenone with moderate CYP3A4 inhibitors (e.g., erythromycin 500 mg BID, verapamil 240 mg once daily, saquinavir 1200 mg three times a day, fluconazole 200 mg once daily) resulted in increases in Cmax of eplerenone ranging from 1.4- to 1.6-fold and AUC from 2.0- to 2.9-fold. - Grapefruit juice caused only a small increase (about 25%) in exposure. - Eplerenone is not an inhibitor of CYP1A2, CYP3A4, CYP2C19, CYP2C9, or CYP2D6. Eplerenone did not inhibit the metabolism of amiodarone, amlodipine, astemizole, chlorzoxazone, cisapride, dexamethasone, dextromethorphan, diclofenac, 17α-ethinyl estradiol, fluoxetine, losartan, lovastatin, mephobarbital, methylphenidate, methylprednisolone, metoprolol, midazolam, nifedipine, phenacetin, phenytoin, simvastatin, tolbutamide, triazolam, verapamil, and warfarin in vitro. Eplerenone is not a substrate or an inhibitor of P-glycoprotein at clinically relevant doses. - No clinically significant drug-drug pharmacokinetic interactions were observed when eplerenone was administered with cisapride, cyclosporine, digoxin, glyburide, midazolam, oral contraceptives (norethindrone/ethinyl estradiol), simvastatin, or warfarin. St. John's wort (a CYP3A4 inducer) caused a small (about 30%) decrease in eplerenone AUC. - No significant changes in eplerenone pharmacokinetics were observed when eplerenone was administered with aluminum- and magnesium-containing antacids. ## Nonclinical Toxicology - Eplerenone was non-genotoxic in a battery of assays including in vitro bacterial mutagenesis (Ames test in Salmonella spp. and E. coli), in vitro mammalian cell mutagenesis (mouse lymphoma cells), in vitro chromosomal aberration (Chinese hamster ovary cells), in vivo rat bone marrow micronucleus formation, and in vivo/ex vivo unscheduled DNA synthesis in rat liver. - There was no drug-related tumor response in heterozygous p53 deficient mice when tested for 6 months at dosages up to 1000 mg/kg/day (systemic AUC exposures up to 9 times the exposure in humans receiving the 100 mg/day therapeutic dose). Statistically significant increases in benign thyroid tumors were observed after 2 years in both male and female rats when administered eplerenone 250 mg/kg/day (highest dose tested) and in male rats only at 75 mg/kg/day. These dosages provided systemic AUC exposures approximately 2 to 12 times higher than the average human therapeutic exposure at 100 mg/day. Repeat dose administration of eplerenone to rats increases the hepatic conjugation and clearance of thyroxin, which results in increased levels of TSH by a compensatory mechanism. Drugs that have produced thyroid tumors by this rodent-specific mechanism have not shown a similar effect in humans. - Male rats treated with eplerenone at 1000 mg/kg/day for 10 weeks (AUC 17 times that at the 100 mg/day human therapeutic dose) had decreased weights of seminal vesicles and epididymides and slightly decreased fertility. Dogs administered eplerenone at dosages of 15 mg/kg/day and higher (AUC 5 times that at the 100 mg/day human therapeutic dose) had dose-related prostate atrophy. The prostate atrophy was reversible after daily treatment for 1 year at 100 mg/kg/day. Dogs with prostate atrophy showed no decline in libido, sexual performance, or semen quality. Testicular weight and histology were not affected by eplerenone in any test animal species at any dosage. # Clinical Studies - The eplerenone post-acute myocardial infarction heart failure efficacy and survival study (EPHESUS) was a multinational, multicenter, double-blind, randomized, placebo-controlled study in patients clinically stable 3 to 14 days after an acute myocardial infarction (MI) with left ventricular dysfunction (as measured by left ventricular ejection fraction [LVEF] ≤40%) and either diabetes or clinical evidence of congestive heart failure (CHF) (pulmonary congestion by exam or chest x-ray or S3). Patients with CHF of valvular or congenital etiology, patients with unstable post-infarct angina, and patients with serum potassium >5.0 mEq/L or serum creatinine >2.5 mg/dL were to be excluded. Patients were allowed to receive standard post-MI drug therapy and to undergo revascularization by angioplasty or coronary artery bypass graft surgery. - Patients randomized to eplerenone tablets were given an initial dose of 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was < 5.0 mEq/L. Dosage was reduced or suspended anytime during the study if serum potassium levels were ≥ 5.5 mEq/L. - EPHESUS randomized 6,632 patients (9.3% U.S.) at 671 centers in 27 countries. The study population was primarily white (90%, with 1% Black, 1% Asian, 6% Hispanic, 2% other) and male (71%). The mean age was 64 years (range, 22 to 94 years). The majority of patients had pulmonary congestion (75%) by exam or x-ray and were Killip Class II (64%). The mean ejection fraction was 33%. The average time to enrollment was 7 days post-MI. Medical histories prior to the index MI included hypertension (60%), coronary artery disease (62%), dyslipidemia (48%), angina (41%), type 2 diabetes (30%), previous MI (27%), and CHF (15%). - The mean dose of eplerenone tablets was 43 mg/day. Patients also received standard care including aspirin (92%), ACE inhibitors (90%), β-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%). - Patients were followed for an average of 16 months (range, 0 to 33 months). The ascertainment rate for vital status was 99.7%. - The co-primary endpoints for EPHESUS were (1) the time to death from any cause, and (2) the time to first occurrence of either cardiovascular (CV) mortality [defined as sudden cardiac death or death due to progression of congestive heart failure (CHF), stroke, or other CV causes] or CV hospitalization (defined as hospitalization for progression of CHF, ventricular arrhythmias, acute myocardial infarction, or stroke). - For the co-primary endpoint for death from any cause, there were 478 deaths in the eplerenone tablets group (14.4%) and 554 deaths in the placebo group (16.7%). The risk of death with eplerenone tablets was reduced by 15% [hazard ratio equal to 0.85 (95% confidence interval 0.75 to 0.96; p = 0.008 by log rank test)]. Kaplan-Meier estimates of all-cause mortality are shown in the figure below and the components of mortality are provided in the table below. - Most CV deaths were attributed to sudden death, acute MI, and CHF. - The time to first event for the co-primary endpoint of CV death or hospitalization, as defined above, was longer in the eplerenone tablets group (hazard ratio 0.87, 95% confidence interval 0.79 to 0.95, p = 0.002). An analysis that included the time to first occurrence of CV mortality and all CV hospitalizations (atrial arrhythmia, angina, CV procedures, progression of CHF, MI, stroke, ventricular arrhythmia, or other CV causes) showed a smaller effect with a hazard ratio of 0.92 (95% confidence interval 0.86 to 0.99; p = 0.028). The combined endpoints, including combined all-cause hospitalization and mortality were driven primarily by CV mortality. The combined endpoints in EPHESUS, including all-cause hospitalization and all-cause mortality, are presented in the table below. - mortality hazard ratios varied for some subgroups as shown in the figure below. mortality hazard ratios appeared favorable for eplerenone tablets for both genders and for all races or ethnic groups, although the numbers of non-Caucasians were low (648, 10%). Patients with diabetes without clinical evidence of CHF and patients greater than 75 years did not appear to benefit from the use of eplerenone tablets. Such subgroup analyses must be interpreted cautiously. - Analyses conducted for a variety of CV biomarkers did not confirm a mechanism of action by which mortality was reduced. - The safety and efficacy of eplerenone tablets have been evaluated alone and in combination with other antihypertensive agents in clinical studies of 3091 hypertensive patients. The studies included 46% women, 14% Blacks, and 22% elderly (age ≥65). The studies excluded patients with elevated baseline serum potassium (>5.0 mEq/L) and elevated baseline serum creatinine (generally >1.5 mg/dL in males and >1.3 mg/dL in females). - Two fixed-dose, placebo-controlled, 8- to 12-week monotherapy studies in patients with baseline diastolic blood pressures of 95 to 114 mm Hg were conducted to assess the antihypertensive effect of eplerenone tablets. In these two studies, 611 patients were randomized to eplerenone tablets and 140 patients to placebo. Patients received eplerenone tablets in doses of 25 to 400 mg daily as either a single daily dose or divided into two daily doses. The mean placebo-subtracted reductions in trough cuff blood pressure achieved by eplerenone tablets in these studies at doses up to 200 mg are shown in the figures below. - Patients treated with eplerenone tablets 50 to 200 mg daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough with differences from placebo of 6 to 13 mm Hg (systolic) and 3 to 7 mm Hg (diastolic). These effects were confirmed by assessments with 24-hour ambulatory blood pressure monitoring (ABPM). In these studies, assessments of 24-hour ABPM data demonstrated that eplerenone tablets, administered once or twice daily, maintained antihypertensive efficacy over the entire dosing interval. However, at a total daily dose of 100 mg, eplerenone tablets administered as 50 mg twice per day produced greater trough cuff (4/3 mm Hg) and ABPM (2/1 mm Hg) blood pressure reductions than 100 mg given once daily. - Blood pressure lowering was apparent within 2 weeks from the start of therapy with eplerenone, with maximal antihypertensive effects achieved within 4 weeks. Stopping eplerenone tablets following treatment for 8 to 24 weeks in six studies did not lead to adverse event rates in the week following withdrawal of eplerenone tablets greater than following placebo or active control withdrawal. Blood pressures in patients not taking other antihypertensives rose 1 week after withdrawal of eplerenone tablets by about 6/3 mm Hg, suggesting that the antihypertensive effect of eplerenone tablets was maintained through 8 to 24 weeks. - Blood pressure reductions with eplerenone tablets in the two fixed-dose monotherapy studies and other studies using titrated doses, as well as concomitant treatments, were not significantly different when analyzed by age, gender, or race with one exception. In a study in patients with low renin hypertension, blood pressure reductions in Blacks were smaller than those in whites during the initial titration period with eplerenone tablets. - Eplerenone tablets has been studied concomitantly with treatment with, angiotensin II receptor antagonists, calcium channel blockers, beta blockers, and hydrochlorothiazide. When administered concomitantly with one of these drugs eplerenone tablets usually produced its expected antihypertensive effects. - There was no significant change in average heart rate among patients treated with eplerenone tablets in the combined clinical studies. No consistent effects of eplerenone tablets on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies. # How Supplied - Eplerenone tablets 25 mg are available for oral administration as yellow, round, film-coated tablets, unscored and engraved “EP” over “25” on one side, and “APO” on the other side. They are supplied as follows: - Eplerenone tablets 50 mg are available for oral administration as yellow, round, film-coated tablets, unscored and engraved “EP” over “50” on one side, and “APO” on the other side. They are supplied as follows: - Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86° F). - Dispense in a tight, light-resistant container. ## Storage There is limited information regarding Eplerenone Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Patients receiving eplerenone tablets should be informed: - Not to use strong CYP3A4 inhibitors, such as ketoconazole, clarithromycin, nefazodone, ritonavir, and nelfinavir. - Not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. - To call their physician if they experience dizziness, diarrhea, vomiting, rapid or irregular heartbeat, lower extremity edema, or difficulty breathing. - That periodic monitoring of blood pressure and serum potassium is important. # Precautions with Alcohol Alcohol-Eplerenone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Inspra® # Look-Alike Drug Names - Inspra® — Spiriva®[6] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Eplerenone
bcda1229bc4e657ab8c20afb6b82e82f9e4170b1	wikidoc	Epoophoron	Epoophoron # Overview The epoophoron (also called organ of Rosenmüller or the parovarium) is a remnant of the Wolffian duct that can be found next to the ovary and fallopian tube. # Anatomy It may contain 10-15 transverse small ducts or tubules that lead to the Gartner’s duct (also longitudinal duct of epoophoron) that represents the caudal remnant of the Wolffian duct and passes through the broad ligament and the lateral wall of the cervix and vagina. The epoophoron is a homologue to the epididymis in the male. While the epoophoron is located in the lateral portion of the mesosalpinx and mesovarium, the paroophoron (residual remnant of that part of the Wolfian duct that forms the paradidymis in the male) lies more medially in the mesosalpinx. # Histology It has a unique histological profile. # Clinical significance Clinically the organ may give rise to a local paraovarian cyst or adenoma.	Epoophoron Template:Infobox Anatomy # Overview The epoophoron (also called organ of Rosenmüller[1][2] or the parovarium) is a remnant of the Wolffian duct that can be found next to the ovary and fallopian tube. # Anatomy It may contain 10-15 transverse small ducts or tubules that lead to the Gartner’s duct (also longitudinal duct of epoophoron) that represents the caudal remnant of the Wolffian duct and passes through the broad ligament and the lateral wall of the cervix and vagina. The epoophoron is a homologue to the epididymis in the male. While the epoophoron is located in the lateral portion of the mesosalpinx and mesovarium, the paroophoron (residual remnant of that part of the Wolfian duct that forms the paradidymis in the male) lies more medially in the mesosalpinx. # Histology It has a unique histological profile.[3][4] # Clinical significance Clinically the organ may give rise to a local paraovarian cyst or adenoma.	https://www.wikidoc.org/index.php/Epoophoron
d8123fd3d5c1b3b497369aa166535967ea8d1877	wikidoc	Epothilone	Epothilone # Overview The epothilones are a new class of cytotoxic molecules, including epothilone A, epothilone B, and epothilone D, identified as potential chemotherapy drugs. Early studies in cancer cell lines and in human cancer patients indicate superior efficacy to the taxanes. Their mechanism of action is similar to that of the taxanes, but their chemical structure is simpler and they are more soluble in water. Due to improved water solubility, cremophors (solubilizing agents used in paclitaxel which can affect cardiac function and cause severe hypersensitivity) are no longer needed in the formulation of this anticancer drug. Other undesired effects such as endotoxin-like properties where macrophages are actived to synthesize inflammatory cytokines and nitric oxide (paclitaxel) are not observed by epothilone B. Epothilones were originally identified as metabolites produced by the myxobacterium Sorangium cellulosum. # History The structure of epothilone A was determined in 1996 using x-ray crystallography. # Mechanism of action The principal mechanism of the epothilone class is inhibition of microtubule function. Microtubules are essential to cell division, and epothilones therefore stop cells from properly dividing. Epothilone B possess the same biological effects as taxol both in vitro and in cultured cells. This is due to the fact that they share the same binding site, as well as binding affinity to the microtubule. Like taxol, epothilone B binds to the αβ-tubulin heterodimer subunit. Once bound, the rate of αβ-tubulin dissociation decreases, thus stabilizing the microtubules. Furthermore, epothilone B has also been shown to induce tubulin polymerization into microtubules without the presence of GTP. This is caused by formation of microtubule bundles throughout the cytoplasm. Finally, epothilone B also causes cell cycle arrest at the G2-M transition phase, thus leading to cytotoxicity and eventually cell apoptosis. # Clinical trials Several epothilone analogs are currently undergoing clinical development for treatment of various cancers. One analog, ixabepilone, was approved by the United States Food and Drug Administration for use in the treatment of metastatic breast cancer in October 2007 after accepting the priority filing of a New Drug Application for the compound in June 2007. Epothilone B has proven to contain potent in vivo anticancer activities at tolerate dose levels in several human xenograft models. As a result, epothilone B and its various analogues are currently undergoing various clinical phases (patupilone (EPO906) - phase II trials; BMS-310704 and BMS-247550 - phase I trials). Results of a phase III trial with Ixabepilone in combination with capecitabine in metastatic breast cancer have been announced. # Organic synthesis Due to the high potency and clinical need for cancer treatments, epothilones have been the target of many total syntheses. The first group to publish the total synthesis of epothilones was S. J. Danishefsky et al. in 1996. This total synthesis of epothilone A was achieved via an intramolecular ester enolate-aldehyde condensation. Other syntheses of epothilones have been published by Nicolaou, Schinzer, Mulzer, and Carreira. In this approach, key building blocks aldehyde, glycidols, and ketoacid were constructed and coupled to olefin metathesis precursor via an aldol reaction and then an esterification coupling. Grubbs' catalyst was employed to close the bis terminal olefin of the precursor compound. The resulting compounds were cis- and tran-macrocyclic isomers with distinct stereocenters. Epoxidation of cis- and trans-olefins yield epothilone A and its analogues. The particular synthetic method determined by the laboratories of K.C Nicolaou, described the synthesis of appropriate building blocks 9, 11, and 12, derived from the retrosynthetic analysis of epothilone B (Figure 1), both diastereoisomers and the geometrical isomers at C6-C7 and C12-C13, can be obtained to give a diverse molecular product. The synthesis of required building blocks 9, 11 and 12, were obtained in a maximum of 4 steps for each building block as seen in Figure 2. With fragments 9, 11 and 12 in hand, these intermediates can then react with one another via Wittig olefination, aldol reaction, macrolactionization, and epoxidation to give the various epothilone B as seen in Figure 3. # Biosynthesis Epothilone B is a 16-membered polyketide macrolactone with a methylthiazole group connected to the macrocycle by an olefinic bond. The polyketide backbone was synthesized by type I polyketide synthase (PKS) and the thiazole ring was derived from a cysteine incorporated by a nonribosomal peptide synthetase (NRPS). In this biosythesis, both PKS and NRPS use carrier proteins, which have been post-translationally modified by phosphopantheteine groups, to join the growing chain. PKS uses coenzyme-A thioester to catalyze the reaction and modify the substrates by selectively reducing the β carbonyl to the hydroxyl (Ketoreductase, KR), the alkene (Dehydratase, DH), and the alkane (Enoyl Reductase, ER). PKS-I can also methylate the α carbon of the substrate. NRPS, on the other hand, uses amino acids activated on the enzyme as aminoacyl adenylates. Unlike PKS, epimerization, N-methylation, and heterocycle formation occurs in NRPS enzyme. Epothilone B starts with a 2-methyl-4-carboxythiazole starter unit, which was formed through the translational coupling between PKS, EPOS A (epoA) module, and NRPS, EPOS P(epoP) module. The EPOS A contains a modified β-ketoacyl-synthase (malonyl-ACP decarboxylase, KSQ), an acyltransferase (AT), an enoyl reductase (ER), and an acyl carrier protein domain (ACP). The EPOS P however, contains a heterocylization, an adenylation, an oxidase, and a thiolation domain. These domains are important because they are involved in the formation of the five-membered heterocyclic ring of the thiazole. As seen in Figure 4, the EPOS P activates the cysteine and binds the activated cysteine as an aminoacyl-S-PCP. Once the cysteine has been bound, EPOS A loads an acetate unit onto the EPOS P complex, thus initiating the formation of the thiazoline ring by intramolecular cyclodehydration. Once the 2-methylthiazole ring has been made, it is then transferred to the PKS EPOS B (epoB), EPOS C (epoC), EPOS D (epoD), EPOS E (epoE), and EPOS F (epoF) for subsequent elongation and modification to generate the olefinic bond, the 16-membered ring, and the epoxide, as seen in Figure 5. One important thing to note is the synthesis of the gem-dimethyl unit in module 7. These two dimethyls were not synthesized by two successive C-methylations. Instead one of the methyl group was derived from the propionate extender unit, while the second methyl group was integrated by a C-methyl-transferase domain.	Epothilone # Overview The epothilones are a new class of cytotoxic molecules, including epothilone A, epothilone B, and epothilone D, identified as potential chemotherapy drugs.[1] Early studies in cancer cell lines and in human cancer patients indicate superior efficacy to the taxanes. Their mechanism of action is similar to that of the taxanes, but their chemical structure is simpler and they are more soluble in water. Due to improved water solubility, cremophors (solubilizing agents used in paclitaxel which can affect cardiac function and cause severe hypersensitivity) are no longer needed in the formulation of this anticancer drug.[2] Other undesired effects such as endotoxin-like properties where macrophages are actived to synthesize inflammatory cytokines and nitric oxide (paclitaxel)[3] are not observed by epothilone B. Epothilones were originally identified as metabolites produced by the myxobacterium Sorangium cellulosum. # History The structure of epothilone A was determined in 1996 using x-ray crystallography.[4] # Mechanism of action The principal mechanism of the epothilone class is inhibition of microtubule function.[5] Microtubules are essential to cell division, and epothilones therefore stop cells from properly dividing. Epothilone B possess the same biological effects as taxol both in vitro and in cultured cells. This is due to the fact that they share the same binding site, as well as binding affinity to the microtubule. Like taxol, epothilone B binds to the αβ-tubulin heterodimer subunit. Once bound, the rate of αβ-tubulin dissociation decreases, thus stabilizing the microtubules. Furthermore, epothilone B has also been shown to induce tubulin polymerization into microtubules without the presence of GTP. This is caused by formation of microtubule bundles throughout the cytoplasm. Finally, epothilone B also causes cell cycle arrest at the G2-M transition phase, thus leading to cytotoxicity and eventually cell apoptosis.[6] # Clinical trials Several epothilone analogs are currently undergoing clinical development for treatment of various cancers. One analog, ixabepilone, was approved by the United States Food and Drug Administration for use in the treatment of metastatic breast cancer in October 2007[7] after accepting the priority filing of a New Drug Application for the compound in June 2007.[8] Epothilone B has proven to contain potent in vivo anticancer activities at tolerate dose levels in several human xenograft models.[9] As a result, epothilone B and its various analogues are currently undergoing various clinical phases (patupilone (EPO906) - phase II trials; BMS-310704 and BMS-247550 - phase I trials). Results of a phase III trial with Ixabepilone in combination with capecitabine in metastatic breast cancer have been announced.[10] # Organic synthesis Due to the high potency and clinical need for cancer treatments, epothilones have been the target of many total syntheses.[11] The first group to publish the total synthesis of epothilones was S. J. Danishefsky et al. in 1996.[6][12] This total synthesis of epothilone A was achieved via an intramolecular ester enolate-aldehyde condensation. Other syntheses of epothilones have been published by Nicolaou[13], Schinzer[14], Mulzer[15], and Carreira[16]. In this approach, key building blocks aldehyde, glycidols, and ketoacid were constructed and coupled to olefin metathesis precursor via an aldol reaction and then an esterification coupling. Grubbs' catalyst was employed to close the bis terminal olefin of the precursor compound. The resulting compounds were cis- and tran-macrocyclic isomers with distinct stereocenters. Epoxidation of cis- and trans-olefins yield epothilone A and its analogues. The particular synthetic method determined by the laboratories of K.C Nicolaou[17], described the synthesis of appropriate building blocks 9, 11, and 12, derived from the retrosynthetic analysis of epothilone B (Figure 1), both diastereoisomers and the geometrical isomers at C6-C7 and C12-C13, can be obtained to give a diverse molecular product. The synthesis of required building blocks 9, 11 and 12, were obtained in a maximum of 4 steps for each building block as seen in Figure 2. With fragments 9, 11 and 12 in hand, these intermediates can then react with one another via Wittig olefination, aldol reaction, macrolactionization, and epoxidation to give the various epothilone B as seen in Figure 3. # Biosynthesis Epothilone B is a 16-membered polyketide macrolactone with a methylthiazole group connected to the macrocycle by an olefinic bond. The polyketide backbone was synthesized by type I polyketide synthase (PKS) and the thiazole ring was derived from a cysteine incorporated by a nonribosomal peptide synthetase (NRPS). In this biosythesis, both PKS and NRPS use carrier proteins, which have been post-translationally modified by phosphopantheteine groups, to join the growing chain. PKS uses coenzyme-A thioester to catalyze the reaction and modify the substrates by selectively reducing the β carbonyl to the hydroxyl (Ketoreductase, KR), the alkene (Dehydratase, DH), and the alkane (Enoyl Reductase, ER). PKS-I can also methylate the α carbon of the substrate. NRPS, on the other hand, uses amino acids activated on the enzyme as aminoacyl adenylates. Unlike PKS, epimerization, N-methylation, and heterocycle formation occurs in NRPS enzyme.[18] Epothilone B starts with a 2-methyl-4-carboxythiazole starter unit, which was formed through the translational coupling between PKS, EPOS A (epoA) module, and NRPS, EPOS P(epoP) module. The EPOS A contains a modified β-ketoacyl-synthase (malonyl-ACP decarboxylase, KSQ), an acyltransferase (AT), an enoyl reductase (ER), and an acyl carrier protein domain (ACP). The EPOS P however, contains a heterocylization, an adenylation, an oxidase, and a thiolation domain. These domains are important because they are involved in the formation of the five-membered heterocyclic ring of the thiazole. As seen in Figure 4, the EPOS P activates the cysteine and binds the activated cysteine as an aminoacyl-S-PCP. Once the cysteine has been bound, EPOS A loads an acetate unit onto the EPOS P complex, thus initiating the formation of the thiazoline ring by intramolecular cyclodehydration.[18] Once the 2-methylthiazole ring has been made, it is then transferred to the PKS EPOS B (epoB), EPOS C (epoC), EPOS D (epoD), EPOS E (epoE), and EPOS F (epoF) for subsequent elongation and modification to generate the olefinic bond, the 16-membered ring, and the epoxide, as seen in Figure 5. One important thing to note is the synthesis of the gem-dimethyl unit in module 7. These two dimethyls were not synthesized by two successive C-methylations. Instead one of the methyl group was derived from the propionate extender unit, while the second methyl group was integrated by a C-methyl-transferase domain.[18]	https://www.wikidoc.org/index.php/Epothilone
b492c3d26623df402d6abca4d48a52fa1e95e8ef	wikidoc	Eprosartan	Eprosartan # 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 Eprosartan is an angiotensin II receptor blocker that is FDA approved for the {{{indicationType}}} of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, myalgia, dizziness, upper respiratory infection and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - May be used alone or in combination with other antihypertensives such as diuretics and calcium channel blockers. - Discontinuation of treatment with eprosartan does not lead to a rapid rebound increase in blood pressure. - Initial dosage: - 600 mg/day, in patients who are not volume depleted. - May be administered once or twice daily with total daily doses ranging from 400 - 800 mg. - There is limited experience with doses beyond 800 mg/day. - If the antihypertensive effect measured at trough using once-daily dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. - Achievement of maximum blood pressure reduction in most patients may take 2 to 3 weeks. - Elderly, Hepatically Impaired or Renally Impaired Patients - No initial dosing adjustment is generally necessary for elderly or hepatically impaired patients or those with renal impairment. - No initial dosing adjustment is generally necessary in patients with moderate and severe renal impairment, with maximum dose not exceeding 600 mg daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of eprosartan in adult patients. ### Non–Guideline-Supported Use - Dosing Information - (Dosage) - Dosing Information - (Dosage) - Dosing Information - (Dosage) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Label Guideline-Supported Use of eprosartan in children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of eprosartan in children. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Nonguideline-Supported Use of eprosartan in children. # Contraindications - Hypersensitivity to eprosartan mesylate or any of its components. - Do not co-administer aliskiren with eprosartan mesylate in diabetic patients # Warnings - 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 eprosartan mesylate as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - 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 examination to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue eprosartan, 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 eprosartan for hypotension, oliguria, and hyperkalemia. - Eprosartan mesylate has been shown to produce maternal and fetal toxicities (maternal and fetal mortality, low maternal body weight and food consumption, resorptions, abortions and litter loss) in pregnant rabbits given oral doses as low as 10 mg eprosartan/kg/day. No maternal or fetal adverse effects were observed at 3 mg/kg/day; this oral dose yielded a systemic exposure (AUC) to unbound eprosartan 0.8 times that achieved in humans given 400 mg b.i.d. No adverse effects on in utero or postnatal development and maturation of offspring were observed when eprosartan mesylate was administered to pregnant rats at oral doses up to 1000 mg eprosartan/kg/day (the 1000 mg eprosartan/kg/day dose in non-pregnant rats yielded systemic exposure to unbound eprosartan approximately 0.6 times the exposure achieved in humans given 400 mg b.i.d.). - In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of eprosartan mesylate, or the treatment should start under close medical supervision. If hypotension occurs, 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. # Adverse Reactions ## Clinical Trials Experience - Eprosartan has been evaluated for safety in more than 3,300 healthy volunteers and patients worldwide, including more than 1,460 patients treated for more than 6 months, and more than 980 patients treated for 1 year or longer. Eprosartan was well tolerated at doses up to 1200 mg daily. Most adverse events were of mild or moderate severity and did not require discontinuation of therapy. The overall incidence of adverse experiences and the incidences of specific adverse events reported with eprosartan were similar to placebo. - Adverse experiences were similar in patients regardless of age, gender, or race. - Adverse experiences were not dose-related. - In placebo-controlled clinical trials, about 4% of 1,202 patients treated with eprosartan discontinued therapy due to clinical adverse experiences, compared to 6.5% of 352 patients given placebo. - Adverse events occurring at an Incidence of 1% or more among eprosartan-treated patients. - The following table lists adverse events that occurred at an incidence of 1% or more among eprosartan-treated patients who participated in placebo-controlled trials of 8 to 13 weeks' duration, using doses of 25 mg to 400 mg twice daily, and 400 mg to 1200 mg once daily. - The overall incidence of adverse events reported with eprosartan (54.4%) was similar to placebo (52.8%). - The following adverse events were also reported at a rate of 1% or greater in patients treated with eprosartan, but were as, or more, frequent in the placebo group: - Headache - Myalgia - Dizziness - Sinusitis - Diarrhea - Bronchitis - Dependent edema - Dyspepsia - Chest pain - Facial edema was reported in 5 patients receiving eprosartan. - Angioedema has been reported with other angiotensin II antagonists. - Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. - In addition to the adverse events above, potentially important events that occurred in at least two patients/subjects exposed to eprosartan or other adverse events that occurred in <1% of patients in clinical studies are listed below. It cannot be determined whether events were causally related to eprosartan: - Alcohol intolerance - Asthenia - Substernal chest pain - Peripheral edema - Fatigue - Fever - Hot flushes - Influenza-like symptoms - Malaise - Rigors - Pain - Angina pectoris - Bradycardia - Abnormal ECG, - Extrasystoles - Atrial fibrillation - Hypotension and orthostatic hypotension - Tachycardia - Palpitations - Anorexia - Constipation - Dry mouth - Esophagitis - Flatulence - Gastritis - Gastroenteritis - Gingivitis - Nausea - Periodontitis - Toothache - Vomiting - Anemia - Purpura - Increased SGOT - Increased SGPT - Increased creatine phosphokinase - Diabetes mellitus - Glycosuria - Gout - Hypercholesterolemia - Hyperglycemia - Hyperkalemia - Hypokalemia - Hyponatremia - Arthritis - Aggravated arthritis - Arthrosis - Skeletal pain - Tendinitis - Back pain - Anxiety - Ataxia - Insomnia - Migraine - Neuritis - Nervousness - Paresthesia - Somnolence - Vertigo - Herpes simplex - Otitis externa - Otitis media - Upper respiratory tract infection - Asthma - Epistaxis - Eczema - Furunculosis - Pruritus - Rash - Maculopapular rash - Increased sweating - Conjunctivitis - Abnormal vision - Xerophthalmia - Tinnitus - Albuminuria - Cystitis - Hematuria - Micturition frequency - Polyuria - Renal calculus - Urinary incontinence - Leg cramps - Peripheral ischemia - In placebo-controlled studies, clinically important changes in standard laboratory parameters were rarely associated with administration of eprosartan. Patients were rarely withdrawn from eprosartan because of laboratory test results. - Creatinine, Blood Urea Nitrogen - Minor elevations in creatinine and in BUN occurred in 0.6% and 1.3%, respectively, of patients taking eprosartan and 0.9% and 0.3%, respectively, of patients given placebo in controlled clinical trials. Two patients were withdrawn from clinical trials for elevations in serum creatinine and BUN, and three additional patients were withdrawn for increases in serum creatinine. - Liver Function Tests - Minor elevations of ALAT, ASAT, and alkaline phosphatase occurred for comparable percentages of patients taking eprosartan or placebo in controlled clinical trials. An elevated ALAT of >3.5 x ULN occurred in 0.1% of patients taking eprosartan (one patient) and in no patient given placebo in controlled clinical trials. Four patients were withdrawn from clinical trials for an elevation in liver function tests. - Hemoglobin - A greater than 20% decrease in hemoglobin was observed in 0.1% of patients taking eprosartan (one patient) and in no patient given placebo in controlled clinical trials. Two patients were withdrawn from clinical trials for anemia. - Leukopenia - A WBC count of ≤3.0 x 103/mm3 occurred in 0.3% of patients taking eprosartan and in 0.3% of patients given placebo in controlled clinical trials. One patient was withdrawn from clinical trials for leukopenia. - Neutropenia - A neutrophil count of ≤1.5 x 103/mm3 occurred in 1.3% of patients taking eprosartan and in 1.4% of patients given placebo in controlled clinical trials. No patient was withdrawn from any clinical trial for neutropenia. - Thrombocytopenia - A platelet count of ≤100 x 109/L occurred in 0.3% of patients taking eprosartan (one patient) and in no patient given placebo in controlled clinical trials. Four patients receiving eprosartan in clinical trials were withdrawn for thrombocytopenia. In one case, thrombocytopenia was present prior to dosing with eprosartan. - Serum Potassium - A potassium value of ≥5.6 mmol/L occurred in 0.9% of patients taking eprosartan and 0.3% of patients given placebo in controlled clinical trials. One patient was withdrawn from clinical trials for hyperkalemia and three for hypokalemia. ## Postmarketing Experience There is limited data regarding adverse reactions reported from post marketing experience. # Drug Interactions - Digoxin - concomitant administration of eprosartan and digoxin had no effect on single oral-dose digoxin pharmacokinetics. - Warfarin - concomitant administration of eprosartan and warfarin had no effect on steady-state prothrombin time ratios (INR) in healthy volunteers. - Glyburide - concomitant administration of eprosartan and glyburide in diabetic patients did not affect 24-hour plasma glucose profiles. - Ranitidine - eprosartan pharmacokinetics were not affected by concomitant administration of ranitidine. - Eprosartan did not inhibit human cytochrome P450 enzymes CYP1A, 2A6, 2C9/8, 2C19, 2D6, 2E and 3A in vitro. - Eprosartan is not metabolized by the cytochrome P450 system. - Ketoconazole and fluconazole - Eprosartan steady-state concentrations were not affected by concomitant administration of ketoconazole or fluconazole, potent inhibitors of CYP3A and 2C9, respectively. - Dual Blockade of the Renin-Angiotensin System (RAS): - Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on eprosartan mesylate and other agents that affect the RAS. - Do not co-administer aliskiren with eprosartan mesylate in patients with diabetes. Avoid use of aliskiren with eprosartan mesylate in patients with renal impairment (GFR <60 ml/min). - Eprosartan has been shown to have no effect on the pharmacokinetics of digoxin and the pharmacodynamics of warfarin and glyburide. Thus, no dosing adjustments are necessary during concomitant use with these agents. Because eprosartan is not metabolized by the cytochrome P450 system, inhibitors of CYP450 enzyme would not be expected to affect its metabolism, and ketoconazole and fluconazole, potent inhibitors of CYP3A and 2C9, respectively, have been shown to have no effect on eprosartan pharmacokinetics. Ranitidine also has no effect on eprosartan pharmacokinetics. - Eprosartan (up to 400 mg b.i.d. or 800 mg q.d.) doses have been safely used concomitantly with a thiazide diuretic (hydrochlorothiazide). - Eprosartan doses of up to 300 mg b.i.d. have been safely used concomitantly with sustained-release calcium channel blockers (sustained-release nifedipine) with no clinically significant adverse interactions. - 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 eprosartan, may result in deterioration of renal function, including possible acute renal failure. - These effects are usually reversible. - Monitor renal function periodically in patients receiving eprosartan and NSAID therapy. - The antihypertensive effect of angiotensin II receptor antagonists, including eprosartan may be attenuated by NSAIDs including selective COX-2 inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Female patients of childbearing age should be told about the consequences of exposure to eprosartan during pregnancy. - Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. - 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 eprosartan mesylate as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - 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 examination to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue eprosartan, 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 eprosartan for hypotension, oliguria, and hyperkalemia. - Eprosartan mesylate has been shown to produce maternal and fetal toxicities (maternal and fetal mortality, low maternal body weight and food consumption, resorptions, abortions and litter loss) in pregnant rabbits given oral doses as low as 10 mg eprosartan/kg/day. No maternal or fetal adverse effects were observed at 3 mg/kg/day; this oral dose yielded a systemic exposure (AUC) to unbound eprosartan 0.8 times that achieved in humans given 400 mg b.i.d. No adverse effects on in utero or postnatal development and maturation of offspring were observed when eprosartan mesylate was administered to pregnant rats at oral doses up to 1000 mg eprosartan/kg/day (the 1000 mg eprosartan/kg/day dose in non-pregnant rats yielded systemic exposure to unbound eprosartan approximately 0.6 times the exposure achieved in humans given 400 mg b.i.d.). Pregnancy Category (AUS): D There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of eprosartan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Eprosartan during labor and delivery. ### Nursing Mothers - Eprosartan is excreted in animal milk; it is not known whether eprosartan 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 eprosartan, 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 - Eprosartan pharmacokinetics have not been investigated in patients younger than 18 years of age. - Neonates with a history of in utero exposure to eprosartan: - 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. ### Geriatic Use - Following single oral dose administration of eprosartan to healthy elderly men (aged 68 to 78 years), AUC, Cmax, and Tmax eprosartan values increased, on average by approximately twofold, compared to healthy young men (aged 20 to 39 years) who received the same dose. - The extent of plasma protein binding was not influenced by age. - Of the total number of patients receiving eprosartan in clinical studies, 29% (681 of 2,334) were 65 years and over, while 5% (124 of 2,334) were 75 years and over. - Based on the pooled data from randomized trials, the decrease in diastolic blood pressure and systolic blood pressure with eprosartan was slightly less in patients ≥65 years of age compared to younger patients. - In a study of only patients over the age of 65, eprosartan at 200 mg twice daily (and increased optionally up to 300 mg twice daily) decreased diastolic blood pressure on average by 3 mmHg (placebo corrected). - Adverse experiences were similar in younger and older patients. ### Gender - There was no difference in the pharmacokinetics and plasma protein binding between men and women following single oral dose administration of eprosartan. ### Race - A pooled population pharmacokinetic analysis of 442 Caucasian and 29 non-Caucasian hypertensive patients showed that oral clearance and steady-state volume of distribution were not influenced by race. ### Renal Impairment - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals treated with angiotensin II antagonists; in some patients, these changes in renal function were reversible upon discontinuation of therapy. - In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Eprosartan mesylate would be expected to behave similarly. - In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN have been reported. Similar effects have been reported with angiotensin II antagonists; in some patients, these effects were reversible upon discontinuation of therapy. ### Hepatic Impairment - Eprosartan AUC (but not Cmax) values increased, on average, by approximately 40% in men with decreased hepatic function compared to healthy men after a single 100 mg oral dose of eprosartan. Hepatic disease was defined as a documented clinical history of chronic hepatic abnormality diagnosed by liver biopsy, liver/spleen scan or clinical laboratory tests. - The extent of eprosartan plasma protein binding was not influenced by hepatic dysfunction. - No dosage adjustment is necessary for patients with hepatic impairment. ### Females of Reproductive Potential and Males - Eprosartan mesylate was not carcinogenic in dietary restricted rats or ad libitum fed mice dosed at 600 mg and 2000 mg eprosartan/kg/day, respectively, for up to 2 years. In male and female rats, the systemic exposure (AUC) to unbound eprosartan at the dose evaluated was only approximately 20% of the exposure achieved in humans given 400 mg b.i.d. In mice, the systemic exposure (AUC) to unbound eprosartan was approximately 25 times the exposure achieved in humans given 400 mg b.i.d. - Eprosartan mesylate was not mutagenic in vitro in bacteria or mammalian cells (mouse lymphoma assay). Eprosartan mesylate also did not cause structural chromosomal damage in vivo (mouse micronucleus assay). - In human peripheral lymphocytes in vitro , eprosartan mesylate was equivocal for clastogenicity with metabolic activation, and was negative without metabolic activation. In the same assay, eprosartan mesylate was positive for polyploidy with metabolic activation and equivocal for polyploidy without metabolic activation. - Eprosartan mesylate had no adverse effects on the reproductive performance of male or female rats at oral doses up to 1000 mg eprosartan/kg/day. This dose provided systemic exposure (AUC) to unbound eprosartan approximately 0.6 times the exposure achieved in humans given 400 mg b.i.d. ### Immunocompromised Patients There is no FDA guidance one the use of Eprosartan in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - Dual Blockade of the Renin-Angiotensin System: - Monitor blood pressure, renal function and electrolytes in patients on eprosartan and other agents that affect the RAS. - Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 inhibitors (COX-2 Inhibitors) - Monitor renal function periodically in patients receiving eprosartan and NSAID therapy. # IV Compatibility There is limited information regarding the compatibility of eprosartan and IV administrations. # Overdosage - Limited data are available regarding overdosage. - Appropriate symptomatic and supportive therapy should be given if overdosage should occur. - There was no mortality in rats and mice receiving oral doses of up to 3000 mg eprosartan/kg and in dogs receiving oral doses of up to 1000 mg eprosartan/kg. # Pharmacology ## Mechanism of Action - Angiotensin II (formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme ), a potent vasoconstrictor, is the principal pressor agent of the renin-angiotensin system. Angiotensin II also stimulates aldosterone synthesis and secretion by the adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth. - Eprosartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. - Eprosartan does not exhibit any partial agonist activity at the AT1 receptor. Its affinity for the AT1 receptor is 1,000 times greater than for the AT2 receptor. In vitro binding studies indicate that eprosartan is a reversible, competitive inhibitor of the AT1 receptor. - Blockade of the AT1 receptor removes the negative feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II do not overcome the effect of eprosartan on blood pressure. - Eprosartan mesylate does not inhibit kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin; whether this has clinical relevance is not known. It does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. ## Structure - Eprosartan mesylate is a non-biphenyl non-tetrazole angiotensin II receptor (AT1) antagonist. A selective non-peptide molecule, eprosartan mesylate is chemically described as the monomethanesulfonate of (E )-2-butyl-1-(p-carboxybenzyl)-α-2-thienylmethylimid-azole-5-acrylic acid. - Its empirical formula is C23H24N2O4SCH4O3S and molecular weight is 520.625. Its structural formula is: - Eprosartan mesylate is a white to off-white free-flowing crystalline powder that is insoluble in water, freely soluble in ethanol, and melts between 248°C and 250°C. - Eprosartan mesylate is available as aqueous film-coated tablets containing eprosartan mesylate equivalent to 400 mg or 600 mg eprosartan zwitterion (pink, oval, non-scored tablets or white, non-scored, capsule-shaped tablets, respectively). - Inactive Ingredients: - The 400 mg tablet contains the following: croscarmellose sodium, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, and titanium dioxide. The 600 mg tablet contains crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, and titanium dioxide. ## Pharmacodynamics - Eprosartan inhibits the pharmacologic effects of angiotensin II infusions in healthy adult men. Single oral doses of eprosartan from 10 mg to 400 mg have been shown to inhibit the vasopressor, renal vasoconstrictive and aldosterone secretory effects of infused angiotensin II with complete inhibition evident at doses of 350 mg and above. Eprosartan inhibits the pressor effects of angiotensin II infusions. A single oral dose of 350 mg of eprosartan inhibits pressor effects by approximately 100% at peak, with approximately 30% inhibition persisting for 24 hours. The absence of angiotensin II AT1 agonist activity has been demonstrated in healthy adult men. In hypertensive patients treated chronically with eprosartan, there was a twofold rise in angiotensin II plasma concentration and a twofold rise in plasma renin activity, while plasma aldosterone levels remained unchanged. Serum potassium levels also remained unchanged in these patients. - Achievement of maximal blood pressure response to a given dose in most patients may take 2 to 3 weeks of treatment. Onset of blood pressure reduction is seen within 1 to 2 hours of dosing with few instances of orthostatic hypotension. Blood pressure control is maintained with once- or twice-daily dosing over a 24-hour period. Discontinuing treatment with eprosartan does not lead to a rapid rebound increase in blood pressure. - There was no change in mean heart rate in patients treated with eprosartan in controlled clinical trials. - Eprosartan increases mean effective renal plasma flow (ERPF) in salt-replete and salt-restricted normal subjects. A dose-related increase in ERPF of 25% to 30% occurred in salt-restricted normal subjects, with the effect plateauing between the 200 mg and 400 mg doses. There was no change in ERPF in hypertensive patients and patients with renal insufficiency on normal salt diets. Eprosartan did not reduce glomerular filtration rate in patients with renal insufficiency or in patients hypertension, after 7 days and 28 days of dosing, respectively. In hypertensive patients and patients with chronic renal insufficiency, eprosartan did not change fractional excretion of sodium and potassium. - Eprosartan (1200 mg once daily for 7 days or 300 mg twice daily for 28 days) had no effect on the excretion of uric acid in healthy men, patients with essential hypertension or those with varying degrees of renal insufficiency. - There were no effects on mean levels of fasting triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol or fasting glucose. ## Pharmacokinetics - General: - Absolute bioavailability following a single 300 mg oral dose of eprosartan is approximately 13%. - Eprosartan plasma concentrations peak at 1 to 2 hours after an oral dose in the fasted state. - Administering eprosartan with food delays absorption, and causes variable changes (<25%) in Cmax and AUC values which do not appear clinically important. Plasma concentrations of eprosartan increase in a slightly less than dose-proportional manner over the 100 mg to 800 mg dose range. The mean terminal elimination half-life of eprosartan following multiple oral doses of 600 mg was approximately 20 hours. - Eprosartan does not significantly accumulate with chronic use. - Metabolism and Excretion: - Eprosartan is eliminated by biliary and renal excretion, primarily as unchanged compound. - Less than 2% of an oral dose is excreted in the urine as a glucuronide. - There are no active metabolites following oral and intravenous dosing with eprosartan in human subjects. - Eprosartan was the only drug-related compound found in the plasma and feces. Following intravenous eprosartan, about 61% of the material is recovered in the feces and about 37% in the urine. Following an oral dose of eprosartan, about 90% is recovered in the feces and about 7% in the urine. Approximately 20% of the radioactivity excreted in the urine was an acyl glucuronide of eprosartan with the remaining 80% being unchanged eprosartan. - Distribution: - Plasma protein binding of eprosartan is high (approximately 98%) and constant over the concentration range achieved with therapeutic doses. - The pooled population pharmacokinetic analysis from two Phase 3 trials of 299 men and 172 women with mild to moderate hypertension (aged 20 to 93 years) showed that eprosartan exhibited a population mean oral clearance (CL/F) for an average 60-year-old patient of 48.5 L/hr. The population mean steady-state volume of distribution (Vss/F) was 308 L. Eprosartan pharmacokinetics were not influenced by weight, race, gender or severity of hypertension at baseline. Oral clearance was shown to be a linear function of age with CL/F decreasing 0.62 L/hr for every year increase. ## Nonclinical Toxicology There is limited information regarding the nonclinical toxicology of eprosartan. # Clinical Studies - The safety and efficacy of eprosartan mesylate have been evaluated in controlled clinical trials worldwide that enrolled predominantly hypertensive patients with sitting DBP ranging from 95 mmHg to ≤115 mmHg. - There is also some experience with use of eprosartan together with other antihypertensive drugs in more severe hypertension. - The antihypertensive effects of eprosartan mesylate were demonstrated principally in five placebo-controlled trials (4 to 13 weeks' duration) including dosages of 400 mg to 1200 mg given once daily (two studies), 25 mg to 400 mg twice daily (two studies), and one study comparing total daily doses of 400 mg to 800 mg given once daily or twice daily. The five studies included 1,111 patients randomized to eprosartan and 395 patients randomized to placebo. The studies showed dose-related antihypertensive responses. - At study endpoint, patients treated with eprosartan mesylate at doses of 600 mg to 1200 mg given once daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough, with differences from placebo of approximately 5-10/3-6 mmHg. Limited experience is available with the dose of 1200 mg administered once daily. In a direct comparison of 200 mg to 400 mg b.i.d. with 400 mg to 800 mg q.d. of eprosartan mesylate, effects at trough were similar. Patients treated with eprosartan mesylate at doses of 200 mg to 400 mg given twice daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough, with differences from placebo of approximately 7-10/4-6 mmHg. - Peak (1 to 3 hours) effects were uniformly, but moderately, larger than trough effects with b.i.d. dosing, with the trough-to-peak ratio for diastolic blood pressure 65% to 80%. In the once-daily dose-response study, trough-to-peak responses of ≤50% were observed at some doses (including 1200 mg), suggesting attenuation of effect at the end of the dosing interval. The antihypertensive effect of eprosartan mesylate was similar in men and women, but was somewhat smaller in patients over 65. There were too few black subjects to determine whether their response was similar to Caucasians. In general, blacks (usually a low renin population) have had smaller responses to ACE inhibitors and angiotensin II inhibitors than caucasian populations. - Angiotensin-converting enzyme inhibitor-induced cough (a dry, persistent cough) can lead to discontinuation of ACE inhibitor therapy. In one study, patients who had previously coughed while taking an ACE inhibitor were treated with eprosartan, an ACE inhibitor (enalapril) or placebo for six weeks. The incidence of dry, persistent cough was 2.2% on eprosartan, 4.4% on placebo, and 20.5% on the ACE inhibitor; p=0.008 for the comparison of eprosartan with enalapril. In a second study comparing the incidence of cough in 259 patients treated with eprosartan to 261 patients treated with the ACE inhibitor enalapril, the incidence of dry, persistent cough in eprosartan-treated patients (1.5%) was significantly lower (p=0.018) than that observed in patients treated with the ACE inhibitor (5.4%). In addition, analysis of overall data from six double-blind clinical trials involving 1,554 patients showed an incidence of spontaneously reported cough in patients treated with eprosartan of 3.5%, similar to placebo (2.6%). # How Supplied - TEVETEN® is available as aqueous film-coated tablets as follows: - 400 mg pink, non-scored, oval tablets, debossed with “5044” on one side. - NDC 0074–3025–11 (bottles of 100) - 600 mg white, non-scored, capsule-shaped tablets, debossed with “5046” on one side. - NDC 0074–3040–11 (bottles of 100) ## Storage Store at controlled room temperature 20 to 25°C (68 to 77°F) . # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Female patients of childbearing age should be told about the consequences of exposure to eprosartan mesylate during pregnancy. - Discuss treatment options with women planning to become pregnant. - Patients should be asked to report pregnancies to their physicians as soon as possible. # Precautions with Alcohol - Some patients previously exposed to eprosartan showed signs of alcohol intolerance, however, it is not possible to confirm if eprosartan was directly involved in the adverse reaction. # Brand Names Teveten® # Look-Alike Drug Names N/A # Drug Shortage Status Drug Shortage # Price	Eprosartan Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, 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 Eprosartan is an angiotensin II receptor blocker that is FDA approved for the {{{indicationType}}} of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, myalgia, dizziness, upper respiratory infection and fatigue. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - May be used alone or in combination with other antihypertensives such as diuretics and calcium channel blockers. - Discontinuation of treatment with eprosartan does not lead to a rapid rebound increase in blood pressure. - Initial dosage: - 600 mg/day, in patients who are not volume depleted. - May be administered once or twice daily with total daily doses ranging from 400 - 800 mg. - There is limited experience with doses beyond 800 mg/day. - If the antihypertensive effect measured at trough using once-daily dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. - Achievement of maximum blood pressure reduction in most patients may take 2 to 3 weeks. - Elderly, Hepatically Impaired or Renally Impaired Patients - No initial dosing adjustment is generally necessary for elderly or hepatically impaired patients or those with renal impairment. - No initial dosing adjustment is generally necessary in patients with moderate and severe renal impairment, with maximum dose not exceeding 600 mg daily. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of eprosartan in adult patients. ### Non–Guideline-Supported Use - Dosing Information - (Dosage) - Dosing Information - (Dosage) - Dosing Information - (Dosage) # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Label Guideline-Supported Use of eprosartan in children. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of eprosartan in children. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Nonguideline-Supported Use of eprosartan in children. # Contraindications - Hypersensitivity to eprosartan mesylate or any of its components. - Do not co-administer aliskiren with eprosartan mesylate in diabetic patients # Warnings - 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 eprosartan mesylate as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - 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 examination to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue eprosartan, 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 eprosartan for hypotension, oliguria, and hyperkalemia. - Eprosartan mesylate has been shown to produce maternal and fetal toxicities (maternal and fetal mortality, low maternal body weight and food consumption, resorptions, abortions and litter loss) in pregnant rabbits given oral doses as low as 10 mg eprosartan/kg/day. No maternal or fetal adverse effects were observed at 3 mg/kg/day; this oral dose yielded a systemic exposure (AUC) to unbound eprosartan 0.8 times that achieved in humans given 400 mg b.i.d. No adverse effects on in utero or postnatal development and maturation of offspring were observed when eprosartan mesylate was administered to pregnant rats at oral doses up to 1000 mg eprosartan/kg/day (the 1000 mg eprosartan/kg/day dose in non-pregnant rats yielded systemic exposure to unbound eprosartan approximately 0.6 times the exposure achieved in humans given 400 mg b.i.d.). - In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of eprosartan mesylate, or the treatment should start under close medical supervision. If hypotension occurs, 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. # Adverse Reactions ## Clinical Trials Experience - Eprosartan has been evaluated for safety in more than 3,300 healthy volunteers and patients worldwide, including more than 1,460 patients treated for more than 6 months, and more than 980 patients treated for 1 year or longer. Eprosartan was well tolerated at doses up to 1200 mg daily. Most adverse events were of mild or moderate severity and did not require discontinuation of therapy. The overall incidence of adverse experiences and the incidences of specific adverse events reported with eprosartan were similar to placebo. - Adverse experiences were similar in patients regardless of age, gender, or race. - Adverse experiences were not dose-related. - In placebo-controlled clinical trials, about 4% of 1,202 patients treated with eprosartan discontinued therapy due to clinical adverse experiences, compared to 6.5% of 352 patients given placebo. - Adverse events occurring at an Incidence of 1% or more among eprosartan-treated patients. - The following table lists adverse events that occurred at an incidence of 1% or more among eprosartan-treated patients who participated in placebo-controlled trials of 8 to 13 weeks' duration, using doses of 25 mg to 400 mg twice daily, and 400 mg to 1200 mg once daily. - The overall incidence of adverse events reported with eprosartan (54.4%) was similar to placebo (52.8%). - The following adverse events were also reported at a rate of 1% or greater in patients treated with eprosartan, but were as, or more, frequent in the placebo group: - Headache - Myalgia - Dizziness - Sinusitis - Diarrhea - Bronchitis - Dependent edema - Dyspepsia - Chest pain - Facial edema was reported in 5 patients receiving eprosartan. - Angioedema has been reported with other angiotensin II antagonists. - Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers. - In addition to the adverse events above, potentially important events that occurred in at least two patients/subjects exposed to eprosartan or other adverse events that occurred in <1% of patients in clinical studies are listed below. It cannot be determined whether events were causally related to eprosartan: - Alcohol intolerance - Asthenia - Substernal chest pain - Peripheral edema - Fatigue - Fever - Hot flushes - Influenza-like symptoms - Malaise - Rigors - Pain - Angina pectoris - Bradycardia - Abnormal ECG, - Extrasystoles - Atrial fibrillation - Hypotension and orthostatic hypotension - Tachycardia - Palpitations - Anorexia - Constipation - Dry mouth - Esophagitis - Flatulence - Gastritis - Gastroenteritis - Gingivitis - Nausea - Periodontitis - Toothache - Vomiting - Anemia - Purpura - Increased SGOT - Increased SGPT - Increased creatine phosphokinase - Diabetes mellitus - Glycosuria - Gout - Hypercholesterolemia - Hyperglycemia - Hyperkalemia - Hypokalemia - Hyponatremia - Arthritis - Aggravated arthritis - Arthrosis - Skeletal pain - Tendinitis - Back pain - Anxiety - Ataxia - Insomnia - Migraine - Neuritis - Nervousness - Paresthesia - Somnolence - Vertigo - Herpes simplex - Otitis externa - Otitis media - Upper respiratory tract infection - Asthma - Epistaxis - Eczema - Furunculosis - Pruritus - Rash - Maculopapular rash - Increased sweating - Conjunctivitis - Abnormal vision - Xerophthalmia - Tinnitus - Albuminuria - Cystitis - Hematuria - Micturition frequency - Polyuria - Renal calculus - Urinary incontinence - Leg cramps - Peripheral ischemia - In placebo-controlled studies, clinically important changes in standard laboratory parameters were rarely associated with administration of eprosartan. Patients were rarely withdrawn from eprosartan because of laboratory test results. - Creatinine, Blood Urea Nitrogen - Minor elevations in creatinine and in BUN occurred in 0.6% and 1.3%, respectively, of patients taking eprosartan and 0.9% and 0.3%, respectively, of patients given placebo in controlled clinical trials. Two patients were withdrawn from clinical trials for elevations in serum creatinine and BUN, and three additional patients were withdrawn for increases in serum creatinine. - Liver Function Tests - Minor elevations of ALAT, ASAT, and alkaline phosphatase occurred for comparable percentages of patients taking eprosartan or placebo in controlled clinical trials. An elevated ALAT of >3.5 x ULN occurred in 0.1% of patients taking eprosartan (one patient) and in no patient given placebo in controlled clinical trials. Four patients were withdrawn from clinical trials for an elevation in liver function tests. - Hemoglobin - A greater than 20% decrease in hemoglobin was observed in 0.1% of patients taking eprosartan (one patient) and in no patient given placebo in controlled clinical trials. Two patients were withdrawn from clinical trials for anemia. - Leukopenia - A WBC count of ≤3.0 x 103/mm3 occurred in 0.3% of patients taking eprosartan and in 0.3% of patients given placebo in controlled clinical trials. One patient was withdrawn from clinical trials for leukopenia. - Neutropenia - A neutrophil count of ≤1.5 x 103/mm3 occurred in 1.3% of patients taking eprosartan and in 1.4% of patients given placebo in controlled clinical trials. No patient was withdrawn from any clinical trial for neutropenia. - Thrombocytopenia - A platelet count of ≤100 x 109/L occurred in 0.3% of patients taking eprosartan (one patient) and in no patient given placebo in controlled clinical trials. Four patients receiving eprosartan in clinical trials were withdrawn for thrombocytopenia. In one case, thrombocytopenia was present prior to dosing with eprosartan. - Serum Potassium - A potassium value of ≥5.6 mmol/L occurred in 0.9% of patients taking eprosartan and 0.3% of patients given placebo in controlled clinical trials. One patient was withdrawn from clinical trials for hyperkalemia and three for hypokalemia. ## Postmarketing Experience There is limited data regarding adverse reactions reported from post marketing experience. # Drug Interactions - Digoxin - concomitant administration of eprosartan and digoxin had no effect on single oral-dose digoxin pharmacokinetics. - Warfarin - concomitant administration of eprosartan and warfarin had no effect on steady-state prothrombin time ratios (INR) in healthy volunteers. - Glyburide - concomitant administration of eprosartan and glyburide in diabetic patients did not affect 24-hour plasma glucose profiles. - Ranitidine - eprosartan pharmacokinetics were not affected by concomitant administration of ranitidine. - Eprosartan did not inhibit human cytochrome P450 enzymes CYP1A, 2A6, 2C9/8, 2C19, 2D6, 2E and 3A in vitro. - Eprosartan is not metabolized by the cytochrome P450 system. - Ketoconazole and fluconazole - Eprosartan steady-state concentrations were not affected by concomitant administration of ketoconazole or fluconazole, potent inhibitors of CYP3A and 2C9, respectively. - Dual Blockade of the Renin-Angiotensin System (RAS): - Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on eprosartan mesylate and other agents that affect the RAS. - Do not co-administer aliskiren with eprosartan mesylate in patients with diabetes. Avoid use of aliskiren with eprosartan mesylate in patients with renal impairment (GFR <60 ml/min). - Eprosartan has been shown to have no effect on the pharmacokinetics of digoxin and the pharmacodynamics of warfarin and glyburide. Thus, no dosing adjustments are necessary during concomitant use with these agents. Because eprosartan is not metabolized by the cytochrome P450 system, inhibitors of CYP450 enzyme would not be expected to affect its metabolism, and ketoconazole and fluconazole, potent inhibitors of CYP3A and 2C9, respectively, have been shown to have no effect on eprosartan pharmacokinetics. Ranitidine also has no effect on eprosartan pharmacokinetics. - Eprosartan (up to 400 mg b.i.d. or 800 mg q.d.) doses have been safely used concomitantly with a thiazide diuretic (hydrochlorothiazide). - Eprosartan doses of up to 300 mg b.i.d. have been safely used concomitantly with sustained-release calcium channel blockers (sustained-release nifedipine) with no clinically significant adverse interactions. - 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 eprosartan, may result in deterioration of renal function, including possible acute renal failure. - These effects are usually reversible. - Monitor renal function periodically in patients receiving eprosartan and NSAID therapy. - The antihypertensive effect of angiotensin II receptor antagonists, including eprosartan may be attenuated by NSAIDs including selective COX-2 inhibitors. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): D - Female patients of childbearing age should be told about the consequences of exposure to eprosartan during pregnancy. - Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. - 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 eprosartan mesylate as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. - 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 examination to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue eprosartan, 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 eprosartan for hypotension, oliguria, and hyperkalemia. - Eprosartan mesylate has been shown to produce maternal and fetal toxicities (maternal and fetal mortality, low maternal body weight and food consumption, resorptions, abortions and litter loss) in pregnant rabbits given oral doses as low as 10 mg eprosartan/kg/day. No maternal or fetal adverse effects were observed at 3 mg/kg/day; this oral dose yielded a systemic exposure (AUC) to unbound eprosartan 0.8 times that achieved in humans given 400 mg b.i.d. No adverse effects on in utero or postnatal development and maturation of offspring were observed when eprosartan mesylate was administered to pregnant rats at oral doses up to 1000 mg eprosartan/kg/day (the 1000 mg eprosartan/kg/day dose in non-pregnant rats yielded systemic exposure to unbound eprosartan approximately 0.6 times the exposure achieved in humans given 400 mg b.i.d.). Pregnancy Category (AUS): D There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of eprosartan in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Eprosartan during labor and delivery. ### Nursing Mothers - Eprosartan is excreted in animal milk; it is not known whether eprosartan 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 eprosartan, 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 - Eprosartan pharmacokinetics have not been investigated in patients younger than 18 years of age. - Neonates with a history of in utero exposure to eprosartan: - 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. ### Geriatic Use - Following single oral dose administration of eprosartan to healthy elderly men (aged 68 to 78 years), AUC, Cmax, and Tmax eprosartan values increased, on average by approximately twofold, compared to healthy young men (aged 20 to 39 years) who received the same dose. - The extent of plasma protein binding was not influenced by age. - Of the total number of patients receiving eprosartan in clinical studies, 29% (681 of 2,334) were 65 years and over, while 5% (124 of 2,334) were 75 years and over. - Based on the pooled data from randomized trials, the decrease in diastolic blood pressure and systolic blood pressure with eprosartan was slightly less in patients ≥65 years of age compared to younger patients. - In a study of only patients over the age of 65, eprosartan at 200 mg twice daily (and increased optionally up to 300 mg twice daily) decreased diastolic blood pressure on average by 3 mmHg (placebo corrected). - Adverse experiences were similar in younger and older patients. ### Gender - There was no difference in the pharmacokinetics and plasma protein binding between men and women following single oral dose administration of eprosartan. ### Race - A pooled population pharmacokinetic analysis of 442 Caucasian and 29 non-Caucasian hypertensive patients showed that oral clearance and steady-state volume of distribution were not influenced by race. ### Renal Impairment - As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals treated with angiotensin II antagonists; in some patients, these changes in renal function were reversible upon discontinuation of therapy. - In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Eprosartan mesylate would be expected to behave similarly. - In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN have been reported. Similar effects have been reported with angiotensin II antagonists; in some patients, these effects were reversible upon discontinuation of therapy. ### Hepatic Impairment - Eprosartan AUC (but not Cmax) values increased, on average, by approximately 40% in men with decreased hepatic function compared to healthy men after a single 100 mg oral dose of eprosartan. Hepatic disease was defined as a documented clinical history of chronic hepatic abnormality diagnosed by liver biopsy, liver/spleen scan or clinical laboratory tests. - The extent of eprosartan plasma protein binding was not influenced by hepatic dysfunction. - No dosage adjustment is necessary for patients with hepatic impairment. ### Females of Reproductive Potential and Males - Eprosartan mesylate was not carcinogenic in dietary restricted rats or ad libitum fed mice dosed at 600 mg and 2000 mg eprosartan/kg/day, respectively, for up to 2 years. In male and female rats, the systemic exposure (AUC) to unbound eprosartan at the dose evaluated was only approximately 20% of the exposure achieved in humans given 400 mg b.i.d. In mice, the systemic exposure (AUC) to unbound eprosartan was approximately 25 times the exposure achieved in humans given 400 mg b.i.d. - Eprosartan mesylate was not mutagenic in vitro in bacteria or mammalian cells (mouse lymphoma assay). Eprosartan mesylate also did not cause structural chromosomal damage in vivo (mouse micronucleus assay). - In human peripheral lymphocytes in vitro , eprosartan mesylate was equivocal for clastogenicity with metabolic activation, and was negative without metabolic activation. In the same assay, eprosartan mesylate was positive for polyploidy with metabolic activation and equivocal for polyploidy without metabolic activation. - Eprosartan mesylate had no adverse effects on the reproductive performance of male or female rats at oral doses up to 1000 mg eprosartan/kg/day. This dose provided systemic exposure (AUC) to unbound eprosartan approximately 0.6 times the exposure achieved in humans given 400 mg b.i.d. ### Immunocompromised Patients There is no FDA guidance one the use of Eprosartan in patients who are immunocompromised. # Administration and Monitoring ### Administration Oral ### Monitoring - Dual Blockade of the Renin-Angiotensin System: - Monitor blood pressure, renal function and electrolytes in patients on eprosartan and other agents that affect the RAS. - Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 inhibitors (COX-2 Inhibitors) - Monitor renal function periodically in patients receiving eprosartan and NSAID therapy. # IV Compatibility There is limited information regarding the compatibility of eprosartan and IV administrations. # Overdosage - Limited data are available regarding overdosage. - Appropriate symptomatic and supportive therapy should be given if overdosage should occur. - There was no mortality in rats and mice receiving oral doses of up to 3000 mg eprosartan/kg and in dogs receiving oral doses of up to 1000 mg eprosartan/kg. # Pharmacology ## Mechanism of Action - Angiotensin II (formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme [kininase II]), a potent vasoconstrictor, is the principal pressor agent of the renin-angiotensin system. Angiotensin II also stimulates aldosterone synthesis and secretion by the adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth. - Eprosartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. - Eprosartan does not exhibit any partial agonist activity at the AT1 receptor. Its affinity for the AT1 receptor is 1,000 times greater than for the AT2 receptor. In vitro binding studies indicate that eprosartan is a reversible, competitive inhibitor of the AT1 receptor. - Blockade of the AT1 receptor removes the negative feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II do not overcome the effect of eprosartan on blood pressure. - Eprosartan mesylate does not inhibit kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin; whether this has clinical relevance is not known. It does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. ## Structure - Eprosartan mesylate is a non-biphenyl non-tetrazole angiotensin II receptor (AT1) antagonist. A selective non-peptide molecule, eprosartan mesylate is chemically described as the monomethanesulfonate of (E )-2-butyl-1-(p-carboxybenzyl)-α-2-thienylmethylimid-azole-5-acrylic acid. - Its empirical formula is C23H24N2O4S•CH4O3S and molecular weight is 520.625. Its structural formula is: - Eprosartan mesylate is a white to off-white free-flowing crystalline powder that is insoluble in water, freely soluble in ethanol, and melts between 248°C and 250°C. - Eprosartan mesylate is available as aqueous film-coated tablets containing eprosartan mesylate equivalent to 400 mg or 600 mg eprosartan zwitterion (pink, oval, non-scored tablets or white, non-scored, capsule-shaped tablets, respectively). - Inactive Ingredients: - The 400 mg tablet contains the following: croscarmellose sodium, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, and titanium dioxide. The 600 mg tablet contains crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, and titanium dioxide. ## Pharmacodynamics - Eprosartan inhibits the pharmacologic effects of angiotensin II infusions in healthy adult men. Single oral doses of eprosartan from 10 mg to 400 mg have been shown to inhibit the vasopressor, renal vasoconstrictive and aldosterone secretory effects of infused angiotensin II with complete inhibition evident at doses of 350 mg and above. Eprosartan inhibits the pressor effects of angiotensin II infusions. A single oral dose of 350 mg of eprosartan inhibits pressor effects by approximately 100% at peak, with approximately 30% inhibition persisting for 24 hours. The absence of angiotensin II AT1 agonist activity has been demonstrated in healthy adult men. In hypertensive patients treated chronically with eprosartan, there was a twofold rise in angiotensin II plasma concentration and a twofold rise in plasma renin activity, while plasma aldosterone levels remained unchanged. Serum potassium levels also remained unchanged in these patients. - Achievement of maximal blood pressure response to a given dose in most patients may take 2 to 3 weeks of treatment. Onset of blood pressure reduction is seen within 1 to 2 hours of dosing with few instances of orthostatic hypotension. Blood pressure control is maintained with once- or twice-daily dosing over a 24-hour period. Discontinuing treatment with eprosartan does not lead to a rapid rebound increase in blood pressure. - There was no change in mean heart rate in patients treated with eprosartan in controlled clinical trials. - Eprosartan increases mean effective renal plasma flow (ERPF) in salt-replete and salt-restricted normal subjects. A dose-related increase in ERPF of 25% to 30% occurred in salt-restricted normal subjects, with the effect plateauing between the 200 mg and 400 mg doses. There was no change in ERPF in hypertensive patients and patients with renal insufficiency on normal salt diets. Eprosartan did not reduce glomerular filtration rate in patients with renal insufficiency or in patients hypertension, after 7 days and 28 days of dosing, respectively. In hypertensive patients and patients with chronic renal insufficiency, eprosartan did not change fractional excretion of sodium and potassium. - Eprosartan (1200 mg once daily for 7 days or 300 mg twice daily for 28 days) had no effect on the excretion of uric acid in healthy men, patients with essential hypertension or those with varying degrees of renal insufficiency. - There were no effects on mean levels of fasting triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol or fasting glucose. ## Pharmacokinetics - General: - Absolute bioavailability following a single 300 mg oral dose of eprosartan is approximately 13%. - Eprosartan plasma concentrations peak at 1 to 2 hours after an oral dose in the fasted state. - Administering eprosartan with food delays absorption, and causes variable changes (<25%) in Cmax and AUC values which do not appear clinically important. Plasma concentrations of eprosartan increase in a slightly less than dose-proportional manner over the 100 mg to 800 mg dose range. The mean terminal elimination half-life of eprosartan following multiple oral doses of 600 mg was approximately 20 hours. - Eprosartan does not significantly accumulate with chronic use. - Metabolism and Excretion: - Eprosartan is eliminated by biliary and renal excretion, primarily as unchanged compound. - Less than 2% of an oral dose is excreted in the urine as a glucuronide. - There are no active metabolites following oral and intravenous dosing with [14C] eprosartan in human subjects. - Eprosartan was the only drug-related compound found in the plasma and feces. Following intravenous [14C] eprosartan, about 61% of the material is recovered in the feces and about 37% in the urine. Following an oral dose of [14C] eprosartan, about 90% is recovered in the feces and about 7% in the urine. Approximately 20% of the radioactivity excreted in the urine was an acyl glucuronide of eprosartan with the remaining 80% being unchanged eprosartan. - Distribution: - Plasma protein binding of eprosartan is high (approximately 98%) and constant over the concentration range achieved with therapeutic doses. - The pooled population pharmacokinetic analysis from two Phase 3 trials of 299 men and 172 women with mild to moderate hypertension (aged 20 to 93 years) showed that eprosartan exhibited a population mean oral clearance (CL/F) for an average 60-year-old patient of 48.5 L/hr. The population mean steady-state volume of distribution (Vss/F) was 308 L. Eprosartan pharmacokinetics were not influenced by weight, race, gender or severity of hypertension at baseline. Oral clearance was shown to be a linear function of age with CL/F decreasing 0.62 L/hr for every year increase. ## Nonclinical Toxicology There is limited information regarding the nonclinical toxicology of eprosartan. # Clinical Studies - The safety and efficacy of eprosartan mesylate have been evaluated in controlled clinical trials worldwide that enrolled predominantly hypertensive patients with sitting DBP ranging from 95 mmHg to ≤115 mmHg. - There is also some experience with use of eprosartan together with other antihypertensive drugs in more severe hypertension. - The antihypertensive effects of eprosartan mesylate were demonstrated principally in five placebo-controlled trials (4 to 13 weeks' duration) including dosages of 400 mg to 1200 mg given once daily (two studies), 25 mg to 400 mg twice daily (two studies), and one study comparing total daily doses of 400 mg to 800 mg given once daily or twice daily. The five studies included 1,111 patients randomized to eprosartan and 395 patients randomized to placebo. The studies showed dose-related antihypertensive responses. - At study endpoint, patients treated with eprosartan mesylate at doses of 600 mg to 1200 mg given once daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough, with differences from placebo of approximately 5-10/3-6 mmHg. Limited experience is available with the dose of 1200 mg administered once daily. In a direct comparison of 200 mg to 400 mg b.i.d. with 400 mg to 800 mg q.d. of eprosartan mesylate, effects at trough were similar. Patients treated with eprosartan mesylate at doses of 200 mg to 400 mg given twice daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough, with differences from placebo of approximately 7-10/4-6 mmHg. - Peak (1 to 3 hours) effects were uniformly, but moderately, larger than trough effects with b.i.d. dosing, with the trough-to-peak ratio for diastolic blood pressure 65% to 80%. In the once-daily dose-response study, trough-to-peak responses of ≤50% were observed at some doses (including 1200 mg), suggesting attenuation of effect at the end of the dosing interval. The antihypertensive effect of eprosartan mesylate was similar in men and women, but was somewhat smaller in patients over 65. There were too few black subjects to determine whether their response was similar to Caucasians. In general, blacks (usually a low renin population) have had smaller responses to ACE inhibitors and angiotensin II inhibitors than caucasian populations. - Angiotensin-converting enzyme inhibitor-induced cough (a dry, persistent cough) can lead to discontinuation of ACE inhibitor therapy. In one study, patients who had previously coughed while taking an ACE inhibitor were treated with eprosartan, an ACE inhibitor (enalapril) or placebo for six weeks. The incidence of dry, persistent cough was 2.2% on eprosartan, 4.4% on placebo, and 20.5% on the ACE inhibitor; p=0.008 for the comparison of eprosartan with enalapril. In a second study comparing the incidence of cough in 259 patients treated with eprosartan to 261 patients treated with the ACE inhibitor enalapril, the incidence of dry, persistent cough in eprosartan-treated patients (1.5%) was significantly lower (p=0.018) than that observed in patients treated with the ACE inhibitor (5.4%). In addition, analysis of overall data from six double-blind clinical trials involving 1,554 patients showed an incidence of spontaneously reported cough in patients treated with eprosartan of 3.5%, similar to placebo (2.6%). # How Supplied - TEVETEN® is available as aqueous film-coated tablets as follows: - 400 mg pink, non-scored, oval tablets, debossed with “5044” on one side. - NDC 0074–3025–11 (bottles of 100) - 600 mg white, non-scored, capsule-shaped tablets, debossed with “5046” on one side. - NDC 0074–3040–11 (bottles of 100) ## Storage Store at controlled room temperature 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature]. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Female patients of childbearing age should be told about the consequences of exposure to eprosartan mesylate during pregnancy. - Discuss treatment options with women planning to become pregnant. - Patients should be asked to report pregnancies to their physicians as soon as possible. # Precautions with Alcohol - Some patients previously exposed to eprosartan showed signs of alcohol intolerance, however, it is not possible to confirm if eprosartan was directly involved in the adverse reaction. # Brand Names Teveten® # Look-Alike Drug Names N/A # Drug Shortage Status Drug Shortage # Price	https://www.wikidoc.org/index.php/Eprosartan
cf143d087a73dace04107b622cea0877fa602bcc	wikidoc	Levamisole	Levamisole Levamisole, marketed as the hydrochloride salt under the trade name Ergamisol (R12564), is an anthelmintic and immunomodulator belonging to a class of synthetic imidazothiazole derivatives. It was discovered in 1966 at Belgium's Janssen Pharmaceutica, where it was prepared initially in the form of its racemate called tetramisole. The two stereoisomers of tetramisole were subsequently synthesized, and the levorotatory isomer was given the name levamisole. Levamisole was originally marketed in humans to treat parasitic worm infections. However, Levamisole was withdrawn from the U.S. and Canadian markets in 1999 and 2003, respectively, due to the risk of serious side effects and the availability of more effective replacement medications. The most serious side effect of levamisole is agranulocytosis, a severe depletion of white blood cells that leaves patients vulnerable to infection. More recently, Levamisole has been studied in combination with other forms of chemotherapy for the treatment of colon cancer, melanoma, and head and neck cancer. Currently, Levamisole remains in veterinary use as a dewormer for livestock. The medication has also been increasingly used as an adulterant in cocaine sold in the United States and Canada, resulting in serious side effects. It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system. # Medical uses Levamisole was originally used as an anthelmintic to treat worm infestations in both humans and animals. Levamisole works as a nicotinic acetylcholine receptor agonist that causes continued stimulation of the parasitic worm muscles, leading to paralysis. In countries that still permit the use of levamisole, the recommended dose for anthelmintic therapy is a single dose, with a repeated dose 7 days later if needed for a severe hookworm infection. Most current commercial preparations are intended for veterinary use as a dewormer in cattle, pigs, and sheep. However, levamisole has also recently gained prominence among aquarists as an effective treatment for Camallanus roundworm infestations in freshwater tropical fish. After being pulled from the market in the U.S. and Canada in 1999 and 2003, respectively, levamisole has been tested in combination with fluorouracil to treat colon cancer. Evidence from clinical trials support its addition to fluorouracil therapy to benefit patients with colon cancer. In some of the leukemic cell line studies, both levamisole and tetramisole showed similar effect. Levamisole has been used to treat a variety of dermatologic conditions, including skin infections, leprosy, warts, lichen planus, and aphthous ulcers. An interesting adverse side effect these reviewers reported in passing was "neurologic excitement". Later papers, from the Janssen group and others, indicate levamisole and its enantiomer, dexamisole, have some mood-elevating or antidepressant properties, although this was never a marketed use of the drug. # Adverse effects One of the more serious side effects of Levamisole is agranulocytosis, or the depletion of the white blood cells. In particular, neutrophils appear to be affected the most. This occurs in 0.08-5% of the studied populations. There have also been reports of levamisole induced necrosis syndrome in which erythematous painful papules can appear almost anywhere on skin. # Metabolism Levamisole is readily absorbed from the gastrointestinal tract and metabolized in the liver. Its time to peak plasma concentration is 1.5–2 hours. The plasma elimination half-life is fairly quick at 3–4 hours which can contribute to not detecting Levamisole intoxication. The metabolite half-life is 16 hours. Levamisole's excretion is primarily through the kidneys, with about 70% being excreted over 3 days. Only about 5% is excreted as unchanged Levamisole. Drug testing of racehorse urine has led to the revelation that among Levamisole equine metabolites are both pemoline and aminorex, stimulants that are forbidden by racing authorities. Further testing confirmed aminorex in human and canine urine, meaning that both humans and dogs also metabolize levamisole into aminorex. The possible stimulant properties of aminorex are what has caused Levamisole to be used as a cocaine adulterant which is described in more detail below. # Detection in body fluids Levamisole may be quantified in blood, plasma, or urine as a diagnostic tool in clinical poisoning situations or to aid in the medicolegal investigation of suspicious deaths involving adulterated street drugs. About 3% of an oral dose is eliminated unchanged in the 24-hour urine of humans. A post mortem blood levamisole concentration of 2.2 mg/l was present in a woman who died of a cocaine overdose. # Illicit use Levamisole has increasingly been used as a cutting agent in cocaine sold around the globe with the highest incidence being in the U.S.A . In 2008–2009, levamisole was found in 69% of cocaine samples seized by the Drug Enforcement Administration (DEA). By April 2011, the DEA reported the adulterant was found in 82% of seizures. Levamisole adds bulk and weight to powdered cocaine (whereas other adulterants produce smaller "rocks" of cocaine) and makes the drug appear purer. In a series of investigative articles for The Stranger, Brendan Kiley details other rationales for levamisole's rise as an adulterant: possible stimulant effects, a similar appearance to cocaine, and an ability to pass street purity tests. Levamisole suppresses the production of white blood cells, resulting in neutropenia and agranulocytosis. With the increasing use of levamisole as an adulterant, a number of these complications have been reported among cocaine users. Levamisole has also been linked to a risk of vasculitis, and two cases of vasculitic skin necrosis have been reported in users of cocaine adulterated with levamisole. Levamisole-tainted cocaine was linked to several high-profile deaths. Toxicology reports showed levamisole, along with cocaine, was present in DJ AM's body at the time of his death. Andrew Koppel, son of newsman Ted Koppel, was also found with levamisole in his body after his death was ruled a drug overdose. More recently it has also been suspected in the death of a Sydney teenager. In response to the dangers, The Stranger, People's Harm-Reduction Alliance and DanceSafe began producing tests to identify levamisole's presence in cocaine. The kits include a survey postcard, and one revealed its presence in a 1/4-kg block of cocaine, indicating both users and dealers were using the kits. # Chemistry The original synthesis at Janssen Pharmaceutica resulted in the preparation of a racemic mixture of two enantiomers, whose hydrochloride salt was reported to have a melting point of 264–265 °C; the free base of the racemate has a melting point of 87–89 °C. When the two enantiomers were made separately, the levorotatory (S-(−)-) enantiomer, subsequently called levamisole, was found to have a melting point of 227–229 °C as its hydrochloride salt, and 60–61.5 °C as the free base. Thus, 60 °C is entered as the value for melting point in the info box. The dextrorotatory (R-(+)-) enantiomer, subsequently called dexamisole, has a melting point of 227–227.5 °C as its hydrochloride salt, and 60–61.5 °C as the free base. # Toxicity The LD50 (intravenous, mouse) is 22 mg/kg. # Laboratory use Levamisole reversibly and noncompetitively inhibits most isoforms of alkaline phosphatase (e.g., human liver, bone, kidney, and spleen) except the intestinal and placental isoform. It is thus used as an inhibitor along with substrate to reduce background alkaline phosphatase activity in biomedical assays involving detection signal amplification by intestinal alkaline phosphatase, for example in in situ hybridization or Western blot protocols. It is used to immobilize the nematode C. elegans on glass slides for imaging and dissection. In a C. elegans behavioral assay, analyzing the time course of paralysis provides information about the neuromuscular junction. Levamisole acts as an acetylcholine receptor agonist, which leads to muscle contraction. Continuing activation leads to paralysis. The time course of paralysis provides information about the acetylcholine receptors on the muscle. For example, mutants with fewer acetylcholine receptors may paralyze slower than wild type.	Levamisole Levamisole, marketed as the hydrochloride salt under the trade name Ergamisol (R12564), is an anthelmintic and immunomodulator belonging to a class of synthetic imidazothiazole derivatives. It was discovered in 1966 at Belgium's Janssen Pharmaceutica, where it was prepared initially in the form of its racemate called tetramisole.[1] The two stereoisomers of tetramisole were subsequently synthesized, and the levorotatory isomer was given the name levamisole.[2] Levamisole was originally marketed in humans to treat parasitic worm infections. However, Levamisole was withdrawn from the U.S. and Canadian markets in 1999 and 2003, respectively, due to the risk of serious side effects and the availability of more effective replacement medications.[3][4] The most serious side effect of levamisole is agranulocytosis, a severe depletion of white blood cells that leaves patients vulnerable to infection. More recently, Levamisole has been studied in combination with other forms of chemotherapy for the treatment of colon cancer, melanoma, and head and neck cancer. Currently, Levamisole remains in veterinary use as a dewormer for livestock. The medication has also been increasingly used as an adulterant in cocaine sold in the United States and Canada, resulting in serious side effects.[5][6] It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[7] # Medical uses Levamisole was originally used as an anthelmintic to treat worm infestations in both humans and animals. Levamisole works as a nicotinic acetylcholine receptor agonist that causes continued stimulation of the parasitic worm muscles, leading to paralysis. In countries that still permit the use of levamisole, the recommended dose for anthelmintic therapy is a single dose, with a repeated dose 7 days later if needed for a severe hookworm infection.[8] Most current commercial preparations are intended for veterinary use as a dewormer in cattle, pigs, and sheep. However, levamisole has also recently gained prominence among aquarists as an effective treatment for Camallanus roundworm infestations in freshwater tropical fish.[9] After being pulled from the market in the U.S. and Canada in 1999 and 2003, respectively, levamisole has been tested in combination with fluorouracil to treat colon cancer. Evidence from clinical trials support its addition to fluorouracil therapy to benefit patients with colon cancer. In some of the leukemic cell line studies, both levamisole and tetramisole showed similar effect.[10] Levamisole has been used to treat a variety of dermatologic conditions, including skin infections, leprosy, warts, lichen planus, and aphthous ulcers.[11] An interesting adverse side effect these reviewers reported in passing was "neurologic excitement". Later papers, from the Janssen group and others, indicate levamisole and its enantiomer, dexamisole, have some mood-elevating or antidepressant properties, although this was never a marketed use of the drug.[12][13] # Adverse effects One of the more serious side effects of Levamisole is agranulocytosis, or the depletion of the white blood cells. In particular, neutrophils appear to be affected the most. This occurs in 0.08-5% of the studied populations.[14] There have also been reports of levamisole induced necrosis syndrome in which erythematous painful papules can appear almost anywhere on skin. # Metabolism Levamisole is readily absorbed from the gastrointestinal tract and metabolized in the liver. Its time to peak plasma concentration is 1.5–2 hours. The plasma elimination half-life is fairly quick at 3–4 hours which can contribute to not detecting Levamisole intoxication. The metabolite half-life is 16 hours. Levamisole's excretion is primarily through the kidneys, with about 70% being excreted over 3 days. Only about 5% is excreted as unchanged Levamisole.[15][16] Drug testing of racehorse urine has led to the revelation that among Levamisole equine metabolites are both pemoline and aminorex, stimulants that are forbidden by racing authorities.[17][18][19] Further testing confirmed aminorex in human and canine urine, meaning that both humans and dogs also metabolize levamisole into aminorex.[20] The possible stimulant properties of aminorex are what has caused Levamisole to be used as a cocaine adulterant which is described in more detail below. # Detection in body fluids Levamisole may be quantified in blood, plasma, or urine as a diagnostic tool in clinical poisoning situations or to aid in the medicolegal investigation of suspicious deaths involving adulterated street drugs. About 3% of an oral dose is eliminated unchanged in the 24-hour urine of humans. A post mortem blood levamisole concentration of 2.2 mg/l was present in a woman who died of a cocaine overdose.[21][22] # Illicit use Levamisole has increasingly been used as a cutting agent in cocaine sold around the globe with the highest incidence being in the U.S.A . In 2008–2009, levamisole was found in 69% of cocaine samples seized by the Drug Enforcement Administration (DEA).[6] By April 2011, the DEA reported the adulterant was found in 82% of seizures.[23] Levamisole adds bulk and weight to powdered cocaine (whereas other adulterants produce smaller "rocks" of cocaine) and makes the drug appear purer.[24] In a series of investigative articles for The Stranger, Brendan Kiley details other rationales for levamisole's rise as an adulterant: possible stimulant effects, a similar appearance to cocaine, and an ability to pass street purity tests.[25] Levamisole suppresses the production of white blood cells, resulting in neutropenia and agranulocytosis. With the increasing use of levamisole as an adulterant, a number of these complications have been reported among cocaine users.[6][26][27] Levamisole has also been linked to a risk of vasculitis,[28] and two cases of vasculitic skin necrosis have been reported in users of cocaine adulterated with levamisole.[29] Levamisole-tainted cocaine was linked to several high-profile deaths. Toxicology reports showed levamisole, along with cocaine, was present in DJ AM's body at the time of his death.[30] Andrew Koppel, son of newsman Ted Koppel, was also found with levamisole in his body after his death was ruled a drug overdose.[31] More recently it has also been suspected in the death of a Sydney teenager.[32] In response to the dangers, The Stranger, People's Harm-Reduction Alliance and DanceSafe began producing tests to identify levamisole's presence in cocaine. The kits include a survey postcard, and one revealed its presence in a 1/4-kg block of cocaine, indicating both users and dealers were using the kits.[33] # Chemistry The original synthesis at Janssen Pharmaceutica resulted in the preparation of a racemic mixture of two enantiomers, whose hydrochloride salt was reported to have a melting point of 264–265 °C; the free base of the racemate has a melting point of 87–89 °C. When the two enantiomers were made separately, the levorotatory (S-(−)-) enantiomer, subsequently called levamisole, was found to have a melting point of 227–229 °C as its hydrochloride salt, and 60–61.5 °C as the free base. Thus, 60 °C is entered as the value for melting point in the info box. The dextrorotatory (R-(+)-) enantiomer, subsequently called dexamisole, has a melting point of 227–227.5 °C as its hydrochloride salt, and 60–61.5 °C as the free base.[34] # Toxicity The LD50 (intravenous, mouse) is 22 mg/kg.[35] # Laboratory use Levamisole reversibly and noncompetitively inhibits most isoforms of alkaline phosphatase (e.g., human liver, bone, kidney, and spleen) except the intestinal and placental isoform.[36] It is thus used as an inhibitor along with substrate to reduce background alkaline phosphatase activity in biomedical assays involving detection signal amplification by intestinal alkaline phosphatase, for example in in situ hybridization or Western blot protocols. It is used to immobilize the nematode C. elegans on glass slides for imaging and dissection.[37] In a C. elegans behavioral assay, analyzing the time course of paralysis provides information about the neuromuscular junction. Levamisole acts as an acetylcholine receptor agonist, which leads to muscle contraction. Continuing activation leads to paralysis. The time course of paralysis provides information about the acetylcholine receptors on the muscle. For example, mutants with fewer acetylcholine receptors may paralyze slower than wild type.[38]	https://www.wikidoc.org/index.php/Ergamisol
fd3258c91a5da1023fe80b13712fffeeca40abb8	wikidoc	Eric Topol	Eric Topol Eric Topol, M.D. is a noted American cardiologist, geneticist and administrator. He is currently leads the Translational Science Institute and Genomic Medicine program at Scripps Green Hospital in La Jolla as the chief academic officer and chief of genomic medicine and translational science for Scripps Health. Before this, he was the chairman of cardiovascular medicine the Cleveland Clinic in Ohio where is widely credited with leading its cardiovascular program to the topmost position in the US. Topol gained prominence as a leading litigationist in the Vioxx lawsuit against Merck.	Eric Topol Eric Topol, M.D. is a noted American cardiologist, geneticist and administrator. He is currently leads the Translational Science Institute and Genomic Medicine program at Scripps Green Hospital in La Jolla as the chief academic officer and chief of genomic medicine and translational science for Scripps Health. Before this, he was the chairman of cardiovascular medicine [1] the Cleveland Clinic in Ohio where is widely credited [2] with leading its cardiovascular program to the topmost position in the US. Topol gained prominence as a leading litigationist in the Vioxx lawsuit against Merck.	https://www.wikidoc.org/index.php/Eric_Topol
c2e31685b36679a0b21c0fd096d2a3076bf41668	wikidoc	Esketamine	Esketamine # Overview Esketamine (also (S)-ketamine or S(+)-ketamine) (brand name Ketanest S) is a general anaesthetic and a dissociative. It is the S(+) enantiomer of the drug ketamine, a general anaesthetic. Esketamine acts primarily as a non-competitive NMDA receptor antagonist, but is also a dopamine reuptake inhibitor. As of July 2014, it is in phase II clinical trials for treatment-resistant depression (TRD). # Pharmacology Esketamine is approximately twice as potent as racemic ketamine. It is eliminated from the human body more quickly than R(−)-ketamine or racemic ketamine, although R(−)-ketamine slows its elimination. A number of studies have suggested that esketamine has a more medically useful pharmacological action than R(−)-ketamine or racemic ketamine. Esketamine inhibits dopamine transporters eight times more than R(−)-ketamine. This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients. Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly. Esketamine has an affinity for the PCP binding site of the NMDA receptor 3-4 times higher than that of R(−)-ketamine. Unlike R(−)-ketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in frontal cortex, while R(−)-ketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while R(−)-ketamine is reportedly more relaxing. However, other studies have found no difference between the isomers in the patient's level of vigilance. # Potential use as an antidepressant Johnson & Johnson is developing a nasal spray formulation of esketamine as a treatment for depression in patients that have been unresponsive to other antidepressants in the United States. As of July 2014, phase II clinical trials of intranasal esketamine sponsored by the Johnson & Johnson subsidiary Janssen Pharmaceutica are underway. Other pharmaceutical companies are also developing new antidepressant drugs that act similarly to ketamine, including Naurex's rapastinel (GLYX-13) and NRX-1074, and Cerecor's CERC-301. Although most studies suggest that esketamine is preferable for medical uses, a 2013 study found that the antidepressant effect of R(−)-ketamine lasted longer than those of S(+)-ketamine in mice.	Esketamine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Esketamine (also (S)-ketamine or S(+)-ketamine) (brand name Ketanest S) is a general anaesthetic and a dissociative. It is the S(+) enantiomer of the drug ketamine, a general anaesthetic. Esketamine acts primarily as a non-competitive NMDA receptor antagonist, but is also a dopamine reuptake inhibitor. As of July 2014, it is in phase II clinical trials for treatment-resistant depression (TRD).[1] # Pharmacology Esketamine is approximately twice as potent as racemic ketamine.[2] It is eliminated from the human body more quickly than R(−)-ketamine or racemic ketamine, although R(−)-ketamine slows its elimination.[3] A number of studies have suggested that esketamine has a more medically useful pharmacological action than R(−)-ketamine or racemic ketamine. Esketamine inhibits dopamine transporters eight times more than R(−)-ketamine.[4] This increases dopamine activity in the brain. At doses causing the same intensity of effects, esketamine is generally considered to be more pleasant by patients.[5][6] Patients also generally recover mental function more quickly after being treated with pure esketamine, which may be a result of the fact that it is cleared from their system more quickly.[2][7] Esketamine has an affinity for the PCP binding site of the NMDA receptor 3-4 times higher than that of R(−)-ketamine. Unlike R(−)-ketamine, esketamine does not bind significantly to sigma receptors. Esketamine increases glucose metabolism in frontal cortex, while R(−)-ketamine decreases glucose metabolism in the brain. This difference may be responsible for the fact that esketamine generally has a more dissociative or hallucinogenic effect while R(−)-ketamine is reportedly more relaxing.[7] However, other studies have found no difference between the isomers in the patient's level of vigilance.[5] # Potential use as an antidepressant Johnson & Johnson is developing a nasal spray formulation of esketamine as a treatment for depression in patients that have been unresponsive to other antidepressants in the United States.[1] As of July 2014, phase II clinical trials of intranasal esketamine sponsored by the Johnson & Johnson subsidiary Janssen Pharmaceutica are underway.[1][8] Other pharmaceutical companies are also developing new antidepressant drugs that act similarly to ketamine, including Naurex's rapastinel (GLYX-13) and NRX-1074, and Cerecor's CERC-301.[1] Although most studies suggest that esketamine is preferable for medical uses, a 2013 study found that the antidepressant effect of R(−)-ketamine lasted longer than those of S(+)-ketamine in mice.[9]	https://www.wikidoc.org/index.php/Esketamine
aef9bb0a5cadc459408f831e4ee7fb87f806aa97	wikidoc	Etanautine	Etanautine # Overview Etanautine, also known as diphenhydramine monoacefyllinate, is an anticholinergic used as an antiparkinsonian agent. It is a 1:1 salt of diphenhydramine with acefylline, similar to the diphenhydramine/8-chlorotheophylline combination product dimenhydrinate. As with dimenhydrinate, the stimulant effect of the acefylline counteracts the sedative effect from the diphenhydramine, resulting in an improved therapeutic profile. The 1:2 salt diphenhydramine diacefylline (with two molecules of acefylline to each molecule of diphenhydramine) is also used in medicine, under the brand name Nautamine.	Etanautine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Etanautine, also known as diphenhydramine monoacefyllinate, is an anticholinergic used as an antiparkinsonian agent. It is a 1:1 salt of diphenhydramine with acefylline, similar to the diphenhydramine/8-chlorotheophylline combination product dimenhydrinate. As with dimenhydrinate, the stimulant effect of the acefylline counteracts the sedative effect from the diphenhydramine, resulting in an improved therapeutic profile. The 1:2 salt diphenhydramine diacefylline (with two molecules of acefylline to each molecule of diphenhydramine) is also used in medicine, under the brand name Nautamine.	https://www.wikidoc.org/index.php/Etanautine
be5c111b2fdc402a8a239cec671e58d7e7c5d439	wikidoc	Ethambutol	Ethambutol # 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 Ethambutol is an anti- infective agent, antibacterial agent that is FDA approved for the treatment of pulmonary tuberculosis as an adjunct. Common adverse reactions include hyperuricemia, nausea, vomiting, mania. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - MYAMBUTOL should not be used alone, in initial treatment or in retreatment. MYAMBUTOL should be administered on a once every 24-hour basis only. Absorption is not significantly altered by administration with food. Therapy, in general, should be continued until bacteriological conversion has become permanent and maximal clinical improvement has occured. - MYAMBUTOL is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. - Initial Treatment: In patients who have not received previous antituberculous therapy, administer MYAMBUTOL 15 mg/kg (7 mg/lb) of body weight, as a single oral dose once every 24 hours. In the more recent studies, isoniazid has been administered concurrently in a single, daily, oral dose. - Retreatment: In patients who have received previous antituberculous therapyadminister MYAMBUTOL 25 mg/kg (11mg/lb) of body weight, as a single oral dose once every 24 hours. Concurrently administer at least one other antituberculous drug to which the organisms have been demonstrated to be susceptible by appropriate in vitro tests. Suitable drugs usually consist of those not previously used in the treatment of the patient. After 60 days of MYAMBUTOL administration, decrease the dose to 15 mg/kg (7 mg/lb) of body weight, and administer as a single oral dose once every 24 hours. - During the period when patient is on a daily dose of 25 mg/kg, monthly eye examinations are advised. - See Table for easy selection of proper weight-dose tablet(s). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Dosing information: - Guideline Recommendations: - Secondary Prevention: - The recommended dose of ethambutol for the prevention of recurrence (secondary prophylaxis) of disseminated Mycobacterium avium complex disease in HIV-infected patients is 15 mg/kg orally daily in combination with clarithromycin 500 mg orally twice daily (or azithromycin 500 to 600 mg orally daily as an alternative), with or without rifabutin 300 mg orally daily. - Secondary prophylaxis is indicated as lifelong therapy for individuals with documented disseminated disease. However, discontinuation of secondary prophylaxis may be considered in individuals who have completed at least 12 months of therapy, remained asymptomatic with respect to mycobacterial infection signs and symptoms, and have responded to HAART with a sustained CD4 count greater than 100/mcL for at least 6 months. Secondary prophylaxis should include a combination of clarithromycin (or azithromycin as an alternative choice) plus ethambutol with the possible addition of rifabutin. - Dosing information: - Guideline Recommendations: - The recommended dose of ethambutol for the treatment of disseminated Mycobacterium avium complex disease in HIV-infected patients is 15 mg/kg orally daily in combination with clarithromycin 500 mg orally twice daily (or azithromycin 500 to 600 mg orally daily as an alternative), with or without rifabutin 300 mg orally daily. ### HIV infection - Tuberculosis - Dosing information: - The Centers for Disease Control and Prevention (CDC), in association with the American Thoracic Society and the Infectious Diseases Society of America, recommends a 6-month treatment regimen for tuberculosis in HIV-infected patients on antiretroviral therapy. The treatment regimen consists of a 2-month initial phase of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by a continuation phase of 4 to 7 months. For patients on directly observed therapy (DOT), 5 day-a-week dosing may be used to replace 7 day-a-week dosing (AIII). Rifabutin, which has fewer problematic drug interactions, may be used interchangeably with rifampin; dose adjustments to rifabutin and antiretroviral agents may be necessary. Ethambutol may be excluded if drug susceptibility results indicate that the organisms are fully susceptible to isoniazid and rifampin. If pyrazinamide cannot be included in the initial phase due to conditions such as severe liver disease, gout, or pregnancy, the initial phase should consist of isoniazid, rifampin, and ethambutol given once daily for 2 months. If isoniazid cannot be used, a 6-month regimen of rifampin, pyrazinamide, and ethambutol may be substituted (BI). If rifampin cannot be used, treatment with isoniazid and ethambutol for 12 to 18 months, with pyrazinamide during at least the initial phase is recommended. Completion of treatment should be determined by the total number of doses taken, and not solely on duration of therapy. The following is a list of 4 different regimens of initial and continuation phases that may be used for the treatment of tuberculosis in HIV-infected patients. Strength of recommendation and quality of evidence ratings are included at the end of this protocol. - Regimen 1 - Initial Phase: - Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for 56 doses/8 weeks (AII), OR - Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for 5 days/week for 40 doses/8 weeks (AIII) - Continuation Phase: - Isoniazid and rifampin administered once daily for 126 doses/18 weeks (AII), OR - Isoniazid and rifampin administered once daily for 5 days/week for 90 doses/18 weeks (AIII), OR - Isoniazid and rifampin administered twice weekly for 36 doses/18 weeks (AII) (not recommended in HIV-infected patients with CD4+ counts less than 100 cells/milliliter) - Regimen 2 (not recommended in HIV-infected patients with CD4+ counts less than 100 cells/milliliter) - Initial Phase: - Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for at least the first 14 doses/2 weeks, followed by twice weekly dosing for 12 doses/6 weeks (BII), OR - Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for 5 days/week for 10 doses/2 weeks (AIII), followed by twice weekly dosing for 12 doses/6 weeks (BII) - Continuation Phase: - Isoniazid and rifampin administered twice weekly for 36 doses/18 weeks (BII) - Regimen 3 - Initial Phase: - Isoniazid, rifampin, pyrazinamide, and ethambutol administered 3 times weekly for 24 doses/8 weeks (BII) - Continuation Phase: - Isoniazid and rifampin administered 3 times weekly for 54 doses/18 weeks (BII) - Regimen 4Initial Phase: - Isoniazid, rifampin, and ethambutol administered once daily for 56 doses/8 weeks (CII), OR - Isoniazid, rifampin, and ethambutol administered once daily for 5 days/week for 40 doses/8 weeks (AIII) - Continuation Phase:Isoniazid and rifampin administered once daily for 217 doses/31 weeks (CII), OR - Isoniazid and rifampin administered once daily for 5 days/week for 155 doses/31 weeks (AIII), OR - Isoniazid and rifampin administered twice weekly for 62 doses/31 weeks (CII) ### Mycobacterium avium complex infection, Lung disease - Dosing information: - Guideline Recommendations: - Nodular/Bronchiectatic Disease: - An intermittent regimen including ethambutol (25 mg/kg orally), rifampin (600 mg orally), and a macrolide (azithromycin 500 to 600 mg orally OR clarithromycin 1000 mg orally), administered 3 times a week, is recommended as initial therapy for patients with nodular/bronchiectatic disease, patients with a goal of disease suppression only, or fibrocavitary patients unable to tolerate daily therapy. The 3 times a week dosing regimen is not recommended for patients with severe or previously treated disease. - Cavitary Disease: - A daily regimen including ethambutol (15 mg/kg orally), rifampin (10 mg/kg orally; maximum, 600 mg/day), and a macrolide (azithromycin 250 mg orally OR clarithromycin 1000 mg orally (or 500 mg orally twice daily)), with or without an injectable aminoglycoside (streptomycin OR amikacin), is recommended as initial therapy for patients with fibrocavitary disease or severe nodular/bronchiectatic disease. For patients weighing less than 50 kg or older than 70 years, the clarithromycin dose may be reduced to 500 mg daily (or 250 mg twice daily) if gastrointestinal intolerance occurs. - Advanced (Severe) or Previously Treated Disease: - An aggressive daily regimen including ethambutol (15 mg/kg orally), rifampin 10 mg/kg orally (maximum, 600 mg/day) OR rifabutin 150 to 300 mg orally, a macrolide (azithromycin 250 mg orally OR clarithromycin 1000 mg orally ), and an injectable aminoglycoside (streptomycin OR amikacin) is recommended as initial therapy for patients with fibrocavitary disease or severe nodular/bronchiectatic disease. For patients weighing less than 50 kg or older than 70 years, the clarithromycin dose may be reduced to 500 mg daily (or 250 mg twice daily) if gastrointestinal intolerance occurs. ### Pulmonary tuberculosis ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethambutol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - 15 to 20 mg/kg ORALLY daily, OR 50 mg/kg ORALLY twice weekly; MAX 2500 mg/dose (guideline dosing) (younger than 15 years and 40 kg or less ideal body weight) . - Initial, 15 mg/kg ORALLY once daily as combination therapy with at least one other antitubercular agent (eg, isoniazid, with or without streptomycin); patients weighing over 97 kg, dose is 1500 mg(13 years or older). - Retreatment, 25 mg/kg ORALLY once daily for 60 days, then 15 mg/kg ORALLY once daily as combination therapy with at least one of the second line antitubercular agents not previously used (eg, cycloserine, ethionamide, pyrazinamide, or viomycin; additionally, isoniazid, aminosalicylic acid, streptomycin, or other alternating drug regimens have been used); patients weighing over 99 kg, dose is 2500 mg (13 years or older). ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - Dosing Information - 15 to 25 mg/kg ORALLY daily (MAX 2.5 g/day) in combination with clarithromycin 7.5 mg/kg ORALLY twice daily (MAX 500 mg twice daily), with or without rifabutin 5 mg/kg ORALLY daily (MAX 300 mg/day). - Dosing Information - 15 to 25 mg/kg ORALLY once daily (MAX 2.5 g/day) in combination with either clarithromycin 7.5 to 15 mg/kg ORALLY twice daily (MAX 500 mg twice daily) (preferred) or azithromycin 10 to 12 mg/kg (MAX 500 mg/day) ORALLY once daily (alternative); for severe disease, add rifabutin 10 to 20 mg/kg ORALLY once daily (MAX, 300 mg/day) . ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethambutol in pediatric patients. # Contraindications - MYAMBUTOL is contraindicated in patients who are known to be hypersensitive to this drug. It is also contraindicated in patients with known optic neuritis unless clinical judgement determines that it may be used. MYAMBUTOL is contraindicated in patients who are unable to appreciate and report visual side effects or changes in vision (e.g., young children, unconscious patients). # Warnings - MYAMBUTOL may produce decreases in visual acuity which appear to be due to optic neuritis. This effect may be related to dose and duration of treatment. This effect is generally reversible when administration of the drug is discontinued promptly. However, irreversible blindness has been reported. (See PRECAUTIONS and ADVERSE REACTIONS). - Liver toxicities including fatalities have been reported (see ADVERSE REACTIONS). Baseline and periodic assessment of hepatic function should be performed. ### Precautions - MYAMBUTOL ethambutol hydrochloride is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. - Patients with decreased renal function need the dosage reduced as determined by serum levels of MYAMBUTOL, since the main path of excretion of this drug is by the kidneys. - Because this drug may have adverse effects on vision, physical examination should include ophthalmoscopy, finger perimetry and testing of color discrimination. In patients with visual defects such as cataracts, recurrent inflammatory conditions of the eye, optic neuritis, and diabetic retinopathy, the evaluation of changes in visual acuity is more difficult, and care should be taken to be sure the variations in vision are not due to the underlying disease conditions. In such patients, consideration should be given to relationship between benefits expected and possible visual deterioration since evaluation of visual changes is difficult. - As with any potent drug, baseline and periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, should be performed. # Adverse Reactions ## Clinical Trials Experience - MYAMBUTOL may produce decreases in visual acuity, including irreversable blindness, which appear o be due to optic neuritis. Optic neuropathy including optic neuritis or retrobulbar neuritis occuring in association with ethambutol therapy may be characterized by one or more of the following events: decreased visual acuity, scotoma, color blindness, and/or visual defect. These events have also been reported in the absence of a diagnosis of optic or retrobulbar neuritis. - Patients should be advised to report promptly to their physician any change of visual acuity - The change in visual acuity may be unilateral or bilateral and hence each eye must be tested separately and both eyes tested together. Testing of visual acuity should be performed before beginning MYAMBUTOL therapy and periodically during drug administration, except that it should be done monthly when a patient is on a dosage of more than 15 mg per kilogram per day. Snellen eye charts are recommeneded for testing of visual acuity. Studies have shown that there are definite fluctuations of one or two lines of the Snellen chart in the visual acuity of many tuberculous patients not receiving MYAMBUTOL. - The following table may be useful in interpreting possible changes in visual acuity attributable to MYAMBUTOL. - In general, changes in visual acuity less than those indicated under "Significant Number of Lines" and "Decrease Number of Points" may be due to chance variation, limitations of the testing method, or physiologic variability. Conversely, changes in visual acuity equaling or exceeding those under "Significant Number of LInes" and "Decrease Number of Points" indicate need for retesting and careful evaluation of the patient's visual status. If careful evaluation confirms the magnitude of visual change and fails to reveal another cause, MYAMBUTOL should be discontinued and the patient reevaluated at frequent intervals. Progressive decreases in visual acuity during therapy must be considered to be due to MYAMBUTOL. - If corrective glasses are used prior to treatment, these must be worn during visual acuity testing. During 1 to 2 years of therapy, a refractive error may develop which must be corrected in order to obtain accurate test results. Testing the visual acuity through a pinhole eliminates refractive error. Patients developing visual abnormality during MYAMBUTOL treatment may show subjective visual symptoms before, or simultaneously with, the demonstration of decreases in visual acuity, and all patients receiving MYAMBUTOL should be questioned periodically about blurred vision and other subjective eye symptoms. - Recovery of visual acuity generally occurs over a period of weeks to months after the drug has been discontinued. Some patients have received MYAMBUTOL ethambutol hydrochloride again after such recovery without recurrence of loss of visual acuity. - Other adverse reactions reported include: hypersensitivity, anaphylactic/anaphylactoid reaction, dermatitis, erythmea multiforme, pruritus, and joint pain; anorexia, nausea, vomiting, gastrointestinal upset, and abdominal pain; fever, malaise, headache, and dizziness; mental confusion, disorientation, and possible hallucinations; thrombocytopenia, leukopenia and neutropenia. Numbness and tingling of the extremities due to peripheral neuritis have been reported. - Elevated serum uric acid levels occur and precipiation of acute gout has been reported. Pulmonary infiltrates, with or without eosinophilia, also have been reported during MYAMBUTOL therapy. Liver toxicities, including fatalities, have been reported. (See WARNINGS). Since MYAMBUTOL is recommended for therapy in conjunction with one or more other antituberculous drugs, these changes may be related to the concurent therapy. Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exofoliative dermatitis), eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, pericarditis. Fever and lymphadenopathy may be present. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Ethambutol in the drug label. # Drug Interactions - The results of a study of coadministration of ethambutol (50 mg/kg) with an aluminum hydroxide containing antacid to 13 patients with tuberculosis showed a reduction of mean serum concentrations and urinary excretion of ethambutol of approximately 20% and 13%, respectively, suggesting that the oral absorption of ethambutol may be reduced by these antacid products. It is recommended to avoid concurrent administration of ethambutol with aluminum hydroxide containing antacids for at least 4 hours following ethambutol administration. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Teratogenic Effects: Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. There are reports of ophthalmic abnormalities occuring in infants born to women on antituberculous therapy that included ethambutol hydrochloride. MYAMBUTOL should be used during pregnancy only if the benefit justifies the potential risk to the fetus. - MYAMBUTOL has been shown to be teratogenic in pregnant mice and rabbits when given in high doses. When pregnant mice or rabbits were treated with high doses of ethambutol hydrochloride, fettal mortality was slightly but not significantly (P>0.05) increased. Femal rats treated with ethambutol hydrochloride displayed slight but insignificant (P>0.05) decreases in fertility and litter size. - In fetuses born of mice treated with high doses of MYAMBUTOL during pregnancy, a low incidence of cleft palate, exencephaly and abnormality of the vertebral column were observed. Minor abnormalities of the cervical vertebra were seen in the newborn of rats treated with high doses of ethambutol hydrochloride during pregnancy. Rabbits receiving high doses of MYAMBUTOL during pregnancy gave birth to two fetuses with monophthalmmia, one with a shortened right forearm accompanied by bulateral wrist-joint contracture and one with hare lip and cleft palate. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ethambutol in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Ethambutol during labor and delivery. ### Nursing Mothers - MYAMBUTOL is excreted into breast milk. The use of MYAMBUTOL should be considered only if the expected benefit to the mother outweighs the potential risk to the infant. ### Pediatric Use - MYAMBUTOL ethambutol hydrochloride is not recommended for use in pediatric patients under thirteen years of age since safe conditions have not been established. ### Geriatic Use - There are limited date on the use of ethambutol in the elderly. One study of 101 patients, 65 years and older, on multiple drug antituberculosis regimens included 94 patients on ethambutol. No differences in safety of tolerability were observed in these patients compared with that reported in adults in general. - Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender - There is no FDA guidance on the use of Ethambutol with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Ethambutol with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Ethambutol in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Ethambutol in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Ethambutol in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Ethambutol in patients who are immunocompromised. # Administration and Monitoring ### Administration - MYAMBUTOL should not be used alone, in initial treatment or in retreatment. MYAMBUTOL should be administered on a once every 24-hour basis only. Absorption is not significantly altered by administration with food. Therapy, in general, should be continued until bacteriological conversion has become permanent and maximal clinical improvement has occured. - MYAMBUTOL is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. - Initial Treatment: In patients who have not received previous antituberculous therapy, administer MYAMBUTOL 15 mg/kg (7 mg/lb) of body weight, as a single oral dose once every 24 hours. In the more recent studies, isoniazid has been administered concurrently in a single, daily, oral dose. - Retreatment: In patients who have received previous antituberculous therapy, administer MYAMBUTOL 25 mg/kg (11mg/lb) of body weight, as a single oral dose once every 24 hours. Concurrently administer at least one other antituberculous drug to which the organisms have been demonstrated to be susceptible by appropriate in vitro tests. Suitable drugs usually consist of those not previously used in the treatment of the patient. After 60 days of MYAMBUTOL administration, decrease the dose to 15 mg/kg (7 mg/lb) of body weight, and administer as a single oral dose once every 24 hours. - During the period when patient is on a daily dose of 25 mg/kg, monthly eye examinations are advised. - See Table for easy selection of proper weight-dose tablet(s). ### Monitoring - There is limited information regarding Monitoring of Ethambutol in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Ethambutol in the drug label. # Overdosage - There is limited information regarding Chronic Overdose of Ethambutol in the drug label. # Pharmacology There is limited information regarding Ethambutol Pharmacology in the drug label. ## Mechanism of Action ## Structure ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Ethambutol in the drug label. ## Pharmacokinetics - MYAMBUTOL® following a single oral dose of 25 mg/kg of body weight, attains a peak of 2 to 5 mcg/mL in serum 2 to 4 hours after administration. When the drug is administered daily for longer periods of time at this dose, serum levels are similar. The serum levels of MYAMBUTOL falls to undetectable levels by 24 hours after the last dose except in some patients with abnormal renal function. The intracellular concentrations of erythrocytes reach peak values approximately twice those of plasma and maintain this ratio throughout the 24 hours. - During the 24-hour period following oral administration of MYAMBUTOL approximately 50 percent of the initial dose is excreted unchanged in the urine, while an additional 8 to 15 percent appears in the form of metabolites. The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid. From 20 to 22 percent of the initial dose is excreted in the feces as unchanged drug. No drug accumulation has been observed with consecutive single daily doses of 25 mg/kg in patients with normal kidney function, although marked accumulation has been demonstrated in patients with renal insufficiency. - MYAMBUTOL diffuses into actively growing mycobacterium cells such as tubercle bacilli. MYAMBUTOL appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross resistance with other available antimycobacterial agents has been demonstrated. - MYAMBUTOL has been shown to be effective against strains of Mycobacterium tuberculosis but does not seem to be active against fungi, viruses, or other bacteria. Mycobacterium tuberculosis strains previously unexposed to MYAMBUTOL have been uniformly sensitive to concentrations of 8 or less mcg/mL, depending on the nature of the culture media. When MYAMBUTOL has been used alone for treatment of tuberculosis, tubercle bacilli from these patients have developed resistance of MYAMBUTOL ethambutol hydrochloride by in vitro susceptibility tests; the development of resistance has been unpredictable and appears to occur in a step-like manner. No cross resistance between MYAMBUTOL and other antituberculous drugs has been reported. MYAMBUTOL has reduced the emergence of mycobacterial resistance is isoniazid when both drugs have been used concurrently. - Any agar diffusion microbiologic assay, based upon inhibition of Mycobacterium smegmatis (ATCC 607) may be used to determine concentrations of MYAMBUTOL in serum and urine. ## Nonclinical Toxicology ANIMAL PHARMACOLOGY Toxicological studies in dogs on high prolonged doses produced evidence of myocardial damage and failure, and depigmentation of the tapetum lucidum of he eyes, the significance of which is not known. Degenerative changes in the central nervous system, apparently not dose-related, have also been noted in dogs receiving ethambutol hydrochloride over a prolonged period. In the rhesus monkey, neurological signs appeared after treatment with high doses given daily over a period of several months. These were correlated with specific serum levels of ethambutol hydrochloride and with definite neuroanatomical changes in the central nervous system. Focal interstitial carditis was also noted in monkeys which received ethambutol hydrochloride in high doses for a prolonged period. # Clinical Studies - There is limited information regarding Clinical Studies of Ethambutol in the drug label. # How Supplied - MYAMBUTOL® Ethambutol Hydrochloride Tablets USP - 100 mg - round, convex, white, film coated tablets engraved M6 on one side are supplied as follows: - NDC 68850-010-01 - Bottle of 100 - 400 mg - round, convex, white, scored, film coated tablets engraved with M to the left and 7 to the right of the score on one side are supplied as follows: - NDC 68850-012-01 - Bottle of 100 - NDC 68850-012-02 - 10 Blister-packs x 10 Tablets ## Storage - Store at controlled room temperature 20° to 25°C (68° to 77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - There is limited information regarding Patient Counseling Information of Ethambutol in the drug label. # Precautions with Alcohol - Alcohol-Ethambutol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Myambutol # Look-Alike Drug Names - A® — B® # Drug Shortage Status # Price	Ethambutol Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [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 Ethambutol is an anti- infective agent, antibacterial agent that is FDA approved for the treatment of pulmonary tuberculosis as an adjunct. Common adverse reactions include hyperuricemia, nausea, vomiting, mania. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Dosing Information - MYAMBUTOL should not be used alone, in initial treatment or in retreatment. MYAMBUTOL should be administered on a once every 24-hour basis only. Absorption is not significantly altered by administration with food. Therapy, in general, should be continued until bacteriological conversion has become permanent and maximal clinical improvement has occured. - MYAMBUTOL is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. - Initial Treatment: In patients who have not received previous antituberculous therapy, administer MYAMBUTOL 15 mg/kg (7 mg/lb) of body weight, as a single oral dose once every 24 hours. In the more recent studies, isoniazid has been administered concurrently in a single, daily, oral dose. - Retreatment: In patients who have received previous antituberculous therapyadminister MYAMBUTOL 25 mg/kg (11mg/lb) of body weight, as a single oral dose once every 24 hours. Concurrently administer at least one other antituberculous drug to which the organisms have been demonstrated to be susceptible by appropriate in vitro tests. Suitable drugs usually consist of those not previously used in the treatment of the patient. After 60 days of MYAMBUTOL administration, decrease the dose to 15 mg/kg (7 mg/lb) of body weight, and administer as a single oral dose once every 24 hours. - During the period when patient is on a daily dose of 25 mg/kg, monthly eye examinations are advised. - See Table for easy selection of proper weight-dose tablet(s). ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use - Dosing information: - Guideline Recommendations: - Secondary Prevention: - The recommended dose of ethambutol for the prevention of recurrence (secondary prophylaxis) of disseminated Mycobacterium avium complex disease in HIV-infected patients is 15 mg/kg orally daily in combination with clarithromycin 500 mg orally twice daily (or azithromycin 500 to 600 mg orally daily as an alternative), with or without rifabutin 300 mg orally daily. - Secondary prophylaxis is indicated as lifelong therapy for individuals with documented disseminated disease. However, discontinuation of secondary prophylaxis may be considered in individuals who have completed at least 12 months of therapy, remained asymptomatic with respect to mycobacterial infection signs and symptoms, and have responded to HAART with a sustained CD4 count greater than 100/mcL for at least 6 months. Secondary prophylaxis should include a combination of clarithromycin (or azithromycin as an alternative choice) plus ethambutol with the possible addition of rifabutin. - Dosing information: - Guideline Recommendations: - The recommended dose of ethambutol for the treatment of disseminated Mycobacterium avium complex disease in HIV-infected patients is 15 mg/kg orally daily in combination with clarithromycin 500 mg orally twice daily (or azithromycin 500 to 600 mg orally daily as an alternative), with or without rifabutin 300 mg orally daily. ### HIV infection - Tuberculosis - Dosing information: - The Centers for Disease Control and Prevention (CDC), in association with the American Thoracic Society and the Infectious Diseases Society of America, recommends a 6-month treatment regimen for tuberculosis in HIV-infected patients on antiretroviral therapy. The treatment regimen consists of a 2-month initial phase of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by a continuation phase of 4 to 7 months. For patients on directly observed therapy (DOT), 5 day-a-week dosing may be used to replace 7 day-a-week dosing (AIII). Rifabutin, which has fewer problematic drug interactions, may be used interchangeably with rifampin; dose adjustments to rifabutin and antiretroviral agents may be necessary. Ethambutol may be excluded if drug susceptibility results indicate that the organisms are fully susceptible to isoniazid and rifampin. If pyrazinamide cannot be included in the initial phase due to conditions such as severe liver disease, gout, or pregnancy, the initial phase should consist of isoniazid, rifampin, and ethambutol given once daily for 2 months. If isoniazid cannot be used, a 6-month regimen of rifampin, pyrazinamide, and ethambutol may be substituted (BI). If rifampin cannot be used, treatment with isoniazid and ethambutol for 12 to 18 months, with pyrazinamide during at least the initial phase is recommended. Completion of treatment should be determined by the total number of doses taken, and not solely on duration of therapy. The following is a list of 4 different regimens of initial and continuation phases that may be used for the treatment of tuberculosis in HIV-infected patients. Strength of recommendation and quality of evidence ratings are included at the end of this protocol. - Regimen 1 - Initial Phase: - Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for 56 doses/8 weeks (AII), OR - Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for 5 days/week for 40 doses/8 weeks (AIII) - Continuation Phase: - Isoniazid and rifampin administered once daily for 126 doses/18 weeks (AII), OR - Isoniazid and rifampin administered once daily for 5 days/week for 90 doses/18 weeks (AIII), OR - Isoniazid and rifampin administered twice weekly for 36 doses/18 weeks (AII) (not recommended in HIV-infected patients with CD4+ counts less than 100 cells/milliliter) - Regimen 2 (not recommended in HIV-infected patients with CD4+ counts less than 100 cells/milliliter) - Initial Phase: - Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for at least the first 14 doses/2 weeks, followed by twice weekly dosing for 12 doses/6 weeks (BII), OR - Isoniazid, rifampin, pyrazinamide, and ethambutol administered once daily for 5 days/week for 10 doses/2 weeks (AIII), followed by twice weekly dosing for 12 doses/6 weeks (BII) - Continuation Phase: - Isoniazid and rifampin administered twice weekly for 36 doses/18 weeks (BII) - Regimen 3 - Initial Phase: - Isoniazid, rifampin, pyrazinamide, and ethambutol administered 3 times weekly for 24 doses/8 weeks (BII) - Continuation Phase: - Isoniazid and rifampin administered 3 times weekly for 54 doses/18 weeks (BII) - Regimen 4Initial Phase: - Isoniazid, rifampin, and ethambutol administered once daily for 56 doses/8 weeks (CII), OR - Isoniazid, rifampin, and ethambutol administered once daily for 5 days/week for 40 doses/8 weeks (AIII) - Continuation Phase:Isoniazid and rifampin administered once daily for 217 doses/31 weeks (CII), OR - Isoniazid and rifampin administered once daily for 5 days/week for 155 doses/31 weeks (AIII), OR - Isoniazid and rifampin administered twice weekly for 62 doses/31 weeks (CII) ### Mycobacterium avium complex infection, Lung disease - Dosing information: - Guideline Recommendations: - Nodular/Bronchiectatic Disease: - An intermittent regimen including ethambutol (25 mg/kg orally), rifampin (600 mg orally), and a macrolide (azithromycin 500 to 600 mg orally OR clarithromycin 1000 mg orally), administered 3 times a week, is recommended as initial therapy for patients with nodular/bronchiectatic disease, patients with a goal of disease suppression only, or fibrocavitary patients unable to tolerate daily therapy. The 3 times a week dosing regimen is not recommended for patients with severe or previously treated disease. - Cavitary Disease: - A daily regimen including ethambutol (15 mg/kg orally), rifampin (10 mg/kg orally; maximum, 600 mg/day), and a macrolide (azithromycin 250 mg orally OR clarithromycin 1000 mg orally (or 500 mg orally twice daily)), with or without an injectable aminoglycoside (streptomycin OR amikacin), is recommended as initial therapy for patients with fibrocavitary disease or severe nodular/bronchiectatic disease. For patients weighing less than 50 kg or older than 70 years, the clarithromycin dose may be reduced to 500 mg daily (or 250 mg twice daily) if gastrointestinal intolerance occurs. - Advanced (Severe) or Previously Treated Disease: - An aggressive daily regimen including ethambutol (15 mg/kg orally), rifampin 10 mg/kg orally (maximum, 600 mg/day) OR rifabutin 150 to 300 mg orally, a macrolide (azithromycin 250 mg orally OR clarithromycin 1000 mg orally [or 500 mg orally twice daily]), and an injectable aminoglycoside (streptomycin OR amikacin) is recommended as initial therapy for patients with fibrocavitary disease or severe nodular/bronchiectatic disease. For patients weighing less than 50 kg or older than 70 years, the clarithromycin dose may be reduced to 500 mg daily (or 250 mg twice daily) if gastrointestinal intolerance occurs. ### Pulmonary tuberculosis ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethambutol in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - 15 to 20 mg/kg ORALLY daily, OR 50 mg/kg ORALLY twice weekly; MAX 2500 mg/dose (guideline dosing) (younger than 15 years and 40 kg or less ideal body weight) . - Initial, 15 mg/kg ORALLY once daily as combination therapy with at least one other antitubercular agent (eg, isoniazid, with or without streptomycin); patients weighing over 97 kg, dose is 1500 mg(13 years or older). - Retreatment, 25 mg/kg ORALLY once daily for 60 days, then 15 mg/kg ORALLY once daily as combination therapy with at least one of the second line antitubercular agents not previously used (eg, cycloserine, ethionamide, pyrazinamide, or viomycin; additionally, isoniazid, aminosalicylic acid, streptomycin, or other alternating drug regimens have been used); patients weighing over 99 kg, dose is 2500 mg (13 years or older). ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use - Dosing Information - 15 to 25 mg/kg ORALLY daily (MAX 2.5 g/day) in combination with clarithromycin 7.5 mg/kg ORALLY twice daily (MAX 500 mg twice daily), with or without rifabutin 5 mg/kg ORALLY daily (MAX 300 mg/day). - Dosing Information - 15 to 25 mg/kg ORALLY once daily (MAX 2.5 g/day) in combination with either clarithromycin 7.5 to 15 mg/kg ORALLY twice daily (MAX 500 mg twice daily) (preferred) or azithromycin 10 to 12 mg/kg (MAX 500 mg/day) ORALLY once daily (alternative); for severe disease, add rifabutin 10 to 20 mg/kg ORALLY once daily (MAX, 300 mg/day) . ### Non–Guideline-Supported Use - There is limited information regarding Off-Label Non–Guideline-Supported Use of Ethambutol in pediatric patients. # Contraindications - MYAMBUTOL is contraindicated in patients who are known to be hypersensitive to this drug. It is also contraindicated in patients with known optic neuritis unless clinical judgement determines that it may be used. MYAMBUTOL is contraindicated in patients who are unable to appreciate and report visual side effects or changes in vision (e.g., young children, unconscious patients). # Warnings - MYAMBUTOL may produce decreases in visual acuity which appear to be due to optic neuritis. This effect may be related to dose and duration of treatment. This effect is generally reversible when administration of the drug is discontinued promptly. However, irreversible blindness has been reported. (See PRECAUTIONS and ADVERSE REACTIONS). - Liver toxicities including fatalities have been reported (see ADVERSE REACTIONS). Baseline and periodic assessment of hepatic function should be performed. ### Precautions - MYAMBUTOL ethambutol hydrochloride is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. - Patients with decreased renal function need the dosage reduced as determined by serum levels of MYAMBUTOL, since the main path of excretion of this drug is by the kidneys. - Because this drug may have adverse effects on vision, physical examination should include ophthalmoscopy, finger perimetry and testing of color discrimination. In patients with visual defects such as cataracts, recurrent inflammatory conditions of the eye, optic neuritis, and diabetic retinopathy, the evaluation of changes in visual acuity is more difficult, and care should be taken to be sure the variations in vision are not due to the underlying disease conditions. In such patients, consideration should be given to relationship between benefits expected and possible visual deterioration since evaluation of visual changes is difficult. - As with any potent drug, baseline and periodic assessment of organ system functions, including renal, hepatic, and hematopoietic, should be performed. # Adverse Reactions ## Clinical Trials Experience - MYAMBUTOL may produce decreases in visual acuity, including irreversable blindness, which appear o be due to optic neuritis. Optic neuropathy including optic neuritis or retrobulbar neuritis occuring in association with ethambutol therapy may be characterized by one or more of the following events: decreased visual acuity, scotoma, color blindness, and/or visual defect. These events have also been reported in the absence of a diagnosis of optic or retrobulbar neuritis. - Patients should be advised to report promptly to their physician any change of visual acuity - The change in visual acuity may be unilateral or bilateral and hence each eye must be tested separately and both eyes tested together. Testing of visual acuity should be performed before beginning MYAMBUTOL therapy and periodically during drug administration, except that it should be done monthly when a patient is on a dosage of more than 15 mg per kilogram per day. Snellen eye charts are recommeneded for testing of visual acuity. Studies have shown that there are definite fluctuations of one or two lines of the Snellen chart in the visual acuity of many tuberculous patients not receiving MYAMBUTOL. - The following table may be useful in interpreting possible changes in visual acuity attributable to MYAMBUTOL. - In general, changes in visual acuity less than those indicated under "Significant Number of Lines" and "Decrease Number of Points" may be due to chance variation, limitations of the testing method, or physiologic variability. Conversely, changes in visual acuity equaling or exceeding those under "Significant Number of LInes" and "Decrease Number of Points" indicate need for retesting and careful evaluation of the patient's visual status. If careful evaluation confirms the magnitude of visual change and fails to reveal another cause, MYAMBUTOL should be discontinued and the patient reevaluated at frequent intervals. Progressive decreases in visual acuity during therapy must be considered to be due to MYAMBUTOL. - If corrective glasses are used prior to treatment, these must be worn during visual acuity testing. During 1 to 2 years of therapy, a refractive error may develop which must be corrected in order to obtain accurate test results. Testing the visual acuity through a pinhole eliminates refractive error. Patients developing visual abnormality during MYAMBUTOL treatment may show subjective visual symptoms before, or simultaneously with, the demonstration of decreases in visual acuity, and all patients receiving MYAMBUTOL should be questioned periodically about blurred vision and other subjective eye symptoms. - Recovery of visual acuity generally occurs over a period of weeks to months after the drug has been discontinued. Some patients have received MYAMBUTOL ethambutol hydrochloride again after such recovery without recurrence of loss of visual acuity. - Other adverse reactions reported include: hypersensitivity, anaphylactic/anaphylactoid reaction, dermatitis, erythmea multiforme, pruritus, and joint pain; anorexia, nausea, vomiting, gastrointestinal upset, and abdominal pain; fever, malaise, headache, and dizziness; mental confusion, disorientation, and possible hallucinations; thrombocytopenia, leukopenia and neutropenia. Numbness and tingling of the extremities due to peripheral neuritis have been reported. - Elevated serum uric acid levels occur and precipiation of acute gout has been reported. Pulmonary infiltrates, with or without eosinophilia, also have been reported during MYAMBUTOL therapy. Liver toxicities, including fatalities, have been reported. (See WARNINGS). Since MYAMBUTOL is recommended for therapy in conjunction with one or more other antituberculous drugs, these changes may be related to the concurent therapy. Hypersensitivity syndrome consisting of cutaneous reaction (such as rash or exofoliative dermatitis), eosinophilia, and one or more of the following: hepatitis, pneumonitis, nephritis, myocarditis, pericarditis. Fever and lymphadenopathy may be present. ## Postmarketing Experience - There is limited information regarding Postmarketing Experience of Ethambutol in the drug label. # Drug Interactions - The results of a study of coadministration of ethambutol (50 mg/kg) with an aluminum hydroxide containing antacid to 13 patients with tuberculosis showed a reduction of mean serum concentrations and urinary excretion of ethambutol of approximately 20% and 13%, respectively, suggesting that the oral absorption of ethambutol may be reduced by these antacid products. It is recommended to avoid concurrent administration of ethambutol with aluminum hydroxide containing antacids for at least 4 hours following ethambutol administration. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C Teratogenic Effects: Pregnancy Category C - There are no adequate and well-controlled studies in pregnant women. There are reports of ophthalmic abnormalities occuring in infants born to women on antituberculous therapy that included ethambutol hydrochloride. MYAMBUTOL should be used during pregnancy only if the benefit justifies the potential risk to the fetus. - MYAMBUTOL has been shown to be teratogenic in pregnant mice and rabbits when given in high doses. When pregnant mice or rabbits were treated with high doses of ethambutol hydrochloride, fettal mortality was slightly but not significantly (P>0.05) increased. Femal rats treated with ethambutol hydrochloride displayed slight but insignificant (P>0.05) decreases in fertility and litter size. - In fetuses born of mice treated with high doses of MYAMBUTOL during pregnancy, a low incidence of cleft palate, exencephaly and abnormality of the vertebral column were observed. Minor abnormalities of the cervical vertebra were seen in the newborn of rats treated with high doses of ethambutol hydrochloride during pregnancy. Rabbits receiving high doses of MYAMBUTOL during pregnancy gave birth to two fetuses with monophthalmmia, one with a shortened right forearm accompanied by bulateral wrist-joint contracture and one with hare lip and cleft palate. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category - There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ethambutol in women who are pregnant. ### Labor and Delivery - There is no FDA guidance on use of Ethambutol during labor and delivery. ### Nursing Mothers - MYAMBUTOL is excreted into breast milk. The use of MYAMBUTOL should be considered only if the expected benefit to the mother outweighs the potential risk to the infant. ### Pediatric Use - MYAMBUTOL ethambutol hydrochloride is not recommended for use in pediatric patients under thirteen years of age since safe conditions have not been established. ### Geriatic Use - There are limited date on the use of ethambutol in the elderly. One study of 101 patients, 65 years and older, on multiple drug antituberculosis regimens included 94 patients on ethambutol. No differences in safety of tolerability were observed in these patients compared with that reported in adults in general. - Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ### Gender - There is no FDA guidance on the use of Ethambutol with respect to specific gender populations. ### Race - There is no FDA guidance on the use of Ethambutol with respect to specific racial populations. ### Renal Impairment - There is no FDA guidance on the use of Ethambutol in patients with renal impairment. ### Hepatic Impairment - There is no FDA guidance on the use of Ethambutol in patients with hepatic impairment. ### Females of Reproductive Potential and Males - There is no FDA guidance on the use of Ethambutol in women of reproductive potentials and males. ### Immunocompromised Patients - There is no FDA guidance one the use of Ethambutol in patients who are immunocompromised. # Administration and Monitoring ### Administration - MYAMBUTOL should not be used alone, in initial treatment or in retreatment. MYAMBUTOL should be administered on a once every 24-hour basis only. Absorption is not significantly altered by administration with food. Therapy, in general, should be continued until bacteriological conversion has become permanent and maximal clinical improvement has occured. - MYAMBUTOL is not recommended for use in pediatric patients under thirteen years of age since safe conditions for use have not been established. - Initial Treatment: In patients who have not received previous antituberculous therapy, administer MYAMBUTOL 15 mg/kg (7 mg/lb) of body weight, as a single oral dose once every 24 hours. In the more recent studies, isoniazid has been administered concurrently in a single, daily, oral dose. - Retreatment: In patients who have received previous antituberculous therapy, administer MYAMBUTOL 25 mg/kg (11mg/lb) of body weight, as a single oral dose once every 24 hours. Concurrently administer at least one other antituberculous drug to which the organisms have been demonstrated to be susceptible by appropriate in vitro tests. Suitable drugs usually consist of those not previously used in the treatment of the patient. After 60 days of MYAMBUTOL administration, decrease the dose to 15 mg/kg (7 mg/lb) of body weight, and administer as a single oral dose once every 24 hours. - During the period when patient is on a daily dose of 25 mg/kg, monthly eye examinations are advised. - See Table for easy selection of proper weight-dose tablet(s). ### Monitoring - There is limited information regarding Monitoring of Ethambutol in the drug label. # IV Compatibility - There is limited information regarding IV Compatibility of Ethambutol in the drug label. # Overdosage - There is limited information regarding Chronic Overdose of Ethambutol in the drug label. # Pharmacology There is limited information regarding Ethambutol Pharmacology in the drug label. ## Mechanism of Action - ## Structure - ## Pharmacodynamics There is limited information regarding Pharmacodynamics of Ethambutol in the drug label. ## Pharmacokinetics - MYAMBUTOL® following a single oral dose of 25 mg/kg of body weight, attains a peak of 2 to 5 mcg/mL in serum 2 to 4 hours after administration. When the drug is administered daily for longer periods of time at this dose, serum levels are similar. The serum levels of MYAMBUTOL falls to undetectable levels by 24 hours after the last dose except in some patients with abnormal renal function. The intracellular concentrations of erythrocytes reach peak values approximately twice those of plasma and maintain this ratio throughout the 24 hours. - During the 24-hour period following oral administration of MYAMBUTOL approximately 50 percent of the initial dose is excreted unchanged in the urine, while an additional 8 to 15 percent appears in the form of metabolites. The main path of metabolism appears to be an initial oxidation of the alcohol to an aldehydic intermediate, followed by conversion to a dicarboxylic acid. From 20 to 22 percent of the initial dose is excreted in the feces as unchanged drug. No drug accumulation has been observed with consecutive single daily doses of 25 mg/kg in patients with normal kidney function, although marked accumulation has been demonstrated in patients with renal insufficiency. - MYAMBUTOL diffuses into actively growing mycobacterium cells such as tubercle bacilli. MYAMBUTOL appears to inhibit the synthesis of one or more metabolites, thus causing impairment of cell metabolism, arrest of multiplication, and cell death. No cross resistance with other available antimycobacterial agents has been demonstrated. - MYAMBUTOL has been shown to be effective against strains of Mycobacterium tuberculosis but does not seem to be active against fungi, viruses, or other bacteria. Mycobacterium tuberculosis strains previously unexposed to MYAMBUTOL have been uniformly sensitive to concentrations of 8 or less mcg/mL, depending on the nature of the culture media. When MYAMBUTOL has been used alone for treatment of tuberculosis, tubercle bacilli from these patients have developed resistance of MYAMBUTOL ethambutol hydrochloride by in vitro susceptibility tests; the development of resistance has been unpredictable and appears to occur in a step-like manner. No cross resistance between MYAMBUTOL and other antituberculous drugs has been reported. MYAMBUTOL has reduced the emergence of mycobacterial resistance is isoniazid when both drugs have been used concurrently. - Any agar diffusion microbiologic assay, based upon inhibition of Mycobacterium smegmatis (ATCC 607) may be used to determine concentrations of MYAMBUTOL in serum and urine. ## Nonclinical Toxicology ANIMAL PHARMACOLOGY Toxicological studies in dogs on high prolonged doses produced evidence of myocardial damage and failure, and depigmentation of the tapetum lucidum of he eyes, the significance of which is not known. Degenerative changes in the central nervous system, apparently not dose-related, have also been noted in dogs receiving ethambutol hydrochloride over a prolonged period. In the rhesus monkey, neurological signs appeared after treatment with high doses given daily over a period of several months. These were correlated with specific serum levels of ethambutol hydrochloride and with definite neuroanatomical changes in the central nervous system. Focal interstitial carditis was also noted in monkeys which received ethambutol hydrochloride in high doses for a prolonged period. # Clinical Studies - There is limited information regarding Clinical Studies of Ethambutol in the drug label. # How Supplied - MYAMBUTOL® Ethambutol Hydrochloride Tablets USP - 100 mg - round, convex, white, film coated tablets engraved M6 on one side are supplied as follows: - NDC 68850-010-01 - Bottle of 100 - 400 mg - round, convex, white, scored, film coated tablets engraved with M to the left and 7 to the right of the score on one side are supplied as follows: - NDC 68850-012-01 - Bottle of 100 - NDC 68850-012-02 - 10 Blister-packs x 10 Tablets ## Storage - Store at controlled room temperature 20° to 25°C (68° to 77°F). # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - There is limited information regarding Patient Counseling Information of Ethambutol in the drug label. # Precautions with Alcohol - Alcohol-Ethambutol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names Myambutol # Look-Alike Drug Names - A® — B®[1] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Ethambutol
4a2775fb406feb8bfe1568f3054c3d86ffc29fc8	wikidoc	Ethylamine	Ethylamine Ethylamine is a chemical compound with the formula CH3CH2NH2. It has a strong ammonia-like odor. It is miscible with virtually all solvents and is considered to be a weak base, as is typical for amines. Ethylamine is widely used in chemical industry and organic synthesis. Ethylamine, like some other amines, has the unusual property of dissolving lithium metal to give the ion + and the solvated electron. Evaporation of these solutions, gives back lithium metal. Such solutions are used for the reduction of unsaturated organic compounds, such as naphthalenes and alkynes. # Synthesis and reactions Ethylamine can be prepared in a laboratory by reaction of ethylene with ammonia in the presence of a catalyst. It can also be synthesized from acetaldehyde and ammonium chloride. Reaction of ethylamine with sulfuryl chloride followed by oxidaton of the sulfonamide give diethyldiazene, EtN=NEt. It is a basic compound.	Ethylamine Template:Chembox new Ethylamine is a chemical compound with the formula CH3CH2NH2. It has a strong ammonia-like odor. It is miscible with virtually all solvents and is considered to be a weak base, as is typical for amines. Ethylamine is widely used in chemical industry and organic synthesis. Ethylamine, like some other amines, has the unusual property of dissolving lithium metal to give the ion [Li(amine)4]+ and the solvated electron. Evaporation of these solutions, gives back lithium metal. Such solutions are used for the reduction of unsaturated organic compounds, such as naphthalenes[1] and alkynes. # Synthesis and reactions Ethylamine can be prepared in a laboratory by reaction of ethylene with ammonia in the presence of a catalyst. It can also be synthesized from acetaldehyde and ammonium chloride.[citation needed] Reaction of ethylamine with sulfuryl chloride followed by oxidaton of the sulfonamide give diethyldiazene, EtN=NEt.[2] It is a basic compound.	https://www.wikidoc.org/index.php/Ethylamine
bf89a198a7f4cb0f3a440b6cfca9caa1b734b21f	wikidoc	Etidronate	Etidronate # 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 Etidronate is a bisphosphonate, calcium regulator and endocrine metabolic agent that is FDA approved for the treatment of Paget’s disease of bone, prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. Common adverse reactions include gastritis, leg cramp and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Etidronate disodium tablets are indicated for the treatment of symptomatic Paget’s disease of bone and in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. Etidronate disodium tablets are not approved for the treatment of osteoporosis. - Etidronate disodium tablets are indicated for the treatment of symptomatic Paget’s disease of bone. Etidronate disodium therapy usually arrests or significantly impedes the disease process as evidenced by: - Symptomatic relief, including decreased pain and/or increased mobility (experienced by 3 out of 5 patients). - Reductions in serum alkaline phosphatase and urinary hydroxyproline levels (30% or more in 4 out of 5 patients). - Histomorphometry showing reduced numbers of osteoclasts and osteoblasts, and more lamellar bone formation. - Bone scans showing reduced radionuclide uptake at pagetic lesions. - In addition, reductions in pagetically elevated cardiac output and skin temperature have been observed in some patients. - In many patients, the disease process will be suppressed for a period of at least one year following cessation of therapy. The upper limit of this period has not been determined. - The effects of the etidronate disodium treatment in patients with asymptomatic Paget’s disease have not been studied. However, etidronate disodium treatment of such patients may be warranted if extensive involvement threatens irreversible neurologic damage, major joints, or major weight-bearing bones. - Etidronate disodium tablets are indicated in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. - Etidronate disodium tablets reduce the incidence of clinically important heterotopic bone by about two-thirds. Among those patients who form heterotopic bone, etidronate disodium tablets retard the progression of immature lesions and reduces the severity by at least half. Follow-up data (at least 9 months post-therapy) suggests these benefits persist. - In total hip replacement patients, etidronate disodium tablets do not promote loosening of the prosthesis or impede trochanteric reattachment. - In spinal cord injury patients, etidronate disodium tablets do not inhibit fracture healing or stabilization of the spine. ### Dosing Information - Etidronate disodium tablets should be taken as a single, oral dose. As with other bisphosphonates, it is recommended that etidronate disodium tablets should be swallowed with a full glass of water (6 to 8 oz). Patients should not lie down after taking the medication. However, should gastrointestinal discomfort occur, the dose may be divided. To maximize absorption, patients should avoid taking the following items within 2 hours of dosing: - Food, especially food high in calcium, such as milk or milk products. Vitamins with mineral supplements or antacids which are high in metals such as calcium, iron, magnesium, or aluminum. - Initial Treatment Regimens - 5 to 10 mg/kg/day, not to exceed 6 months or 11 to 20 mg/kg/day, not to exceed 3 months. - The recommended initial dose is 5 mg/kg/day for a period not to exceed 6 months. Doses above 10 mg/kg/day should be reserved for when 1) lower doses are ineffective or 2) there is an overriding need to suppress rapid bone turnover (especially when irreversible neurologic damage is possible) or reduce elevated cardiac output. Doses in excess of 20 mg/kg/day are not recommended. - Retreatment Guidelines - Retreatment should be initiated only after 1) an etidronate disodium-free period of at least 90 days and 2) there is biochemical, symptomatic or other evidence of active disease process. It is advisable to monitor patients every 3 to 6 months although some patients may go drug free for extended periods. Retreatment regimens are the same as for initial treatment. For most patients the original dose will be adequate for retreatment. If not, consideration should be given to increasing the dose within the recommended guidelines. - The following treatment regimens have been shown to be effective: - total hip replacement Patients: 20 mg/kg/day for 1 month before and 3 months after surgery (4 months total). - Spinal Cord Injured Patients: 20 mg/kg/day for 2 weeks followed by 10 mg/kg/day for 10 weeks (12 weeks total). Etidronate disodium therapy should begin as soon as medically feasible following the injury, preferably prior to evidence of heterotopic ossification. - Retreatment has not been studied. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Etidronate in adult patients. ### Non–Guideline-Supported Use - osteoporosis # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Etidronate 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 Etidronate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Etidronate in pediatric patients. # Contraindications - Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia. - Known hypersensitivity to etidronate disodium or in patients with clinically overt osteomalacia. # Warnings ### General - Etidronate disodium, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when etidronate disodium is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers). - Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue etidronate disodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. - The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 oz) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient. In patients who cannot comply with dosing instructions due to mental disability, therapy with etidronate disodium should be used under appropriate supervision. - There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials. - In Paget’s patients the response to therapy may be of slow onset and continue for months after etidronate disodium therapy is discontinued. Dosage should not be increased prematurely. A 90-day drug-free interval should be provided between courses of therapy. - No specific warnings. ### PRECAUTIONS - Patients should maintain an adequate nutritional status, particularly an adequate intake of calcium and vitamin D. - Therapy has been withheld from some patients with enterocolitis since diarrhea may be experienced, particularly at higher doses. - Etidronate disodium is not metabolized and is excreted intact via the kidney. Hyperphosphatemia may occur at doses of 10 to 20 mg/kg/day, apparently as a result of drug-related increases in tubular reabsorption of phosphate. Serum phosphate levels generally return to normal 2 to 4 weeks post-therapy. There is no experience to specifically guide treatment in patients with impaired renal function. Etidronate disodium dosage should be reduced when reductions in glomerular filtration rates are present. Patients with renal impairment should be closely monitored. In approximately 10% of patients in clinical trials of etidronate disodium I.V. infusion, for hypercalcemia of malignancy, occasional, mild-to-moderate abnormalities in renal function (increases of > 0.5 mg/dL serum creatinine) were observed during or immediately after treatment. - Etidronate disodium suppresses bone turnover, and may retard mineralization of osteoid laid down during the bone accretion process. These effects are dose and time dependent. Osteoid, which may accumulate noticeably at doses of 10 to 20 mg/kg/day, mineralizes normally post-therapy. In patients with fractures, especially of long bones, it may be advisable to delay or interrupt treatment until callus is evident. - ONJ, which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including etidronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and comorbid disorders (e.g., periodontal and/or other preexisting dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates. - For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment. - Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. - In post-marketing experience, there have been infrequent reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. - In Paget’s patients, treatment regimens exceeding the recommended (see DOSAGE AND ADMINISTRATION) daily maximum dose of 20 mg/kg or continuous administration of medication for periods greater than 6 months may be associated with osteomalacia and an increased risk of fracture. - Long bones predominantly affected by lytic lesions, particularly in those patients unresponsive to etidronate disodium therapy, may be especially prone to fracture. - Patients with predominantly lytic lesions should be monitored radiographically and biochemically to permit termination of etidronate disodium in those patients unresponsive to treatment. # Adverse Reactions ## Clinical Trials Experience - The incidence of gastrointestinal complaints (diarrhea, nausea) is the same for etidronate disodium at 5 mg/kg/day as for placebo, about 1 patient in 15. At 10 to 20 mg/kg/day the incidence may increase to 2 or 3 in 10. These complaints are often alleviated by dividing the total daily dose. - In Paget’s patients, increased or recurrent bone pain at pagetic sites, and/or the onset of pain at previously asymptomatic sites has been reported. At 5 mg/kg/day about 1 patient in 10 (vs. 1 in 15 in the placebo group) report these phenomena. At higher doses the incidence rises to about 2 in 10. When therapy continues, pain resolves in some patients but persists in others. - No specific adverse reactions. ## Postmarketing Experience - The worldwide post-marketing experience for etidronate disodium reflects its use in the following approved indications: Paget’s disease, heterotopic ossification, and hypercalcemia of malignancy. It also reflects the use of etidronate disodium for osteoporosis where approved in countries outside the US. Other adverse events that have been reported and were thought to be possibly related to etidronate disodium include the following: alopecia; arthropathies, including arthralgia and arthritis; bone fracture; esophagitis; glossitis; hypersensitivity reactions, including angioedema, follicular eruption, macular rash, maculopapular rash, pruritus, Stevens-Johnson, and urticaria; osteomalacia; neuropsychiatric events, including amnesia, confusion, depression and hallucination; and paresthesias. - In patients receiving etidronate disodium, there have been rare reports of agranulocytosis, pancytopenia, and a report of leukopenia with recurrence on rechallenge. In addition, there have been rare reports of exacerbation of asthma. Exacerbation of existing peptic ulcer disease including perforation has been reported rarely. - In osteoporosis clinical trials, headache, gastritis, leg cramps, and arthralgia occurred at a significantly greater incidence in patients who received etidronate as compared with those who received placebo. # Drug Interactions - There have been isolated reports of patients experiencing increases in their prothrombin times when etidronate was added to warfarin therapy. The majority of these reports concerned variable elevations in prothrombin times without clinically significant sequelae. Although the relevance of these reports and any mechanism of coagulation alterations is unclear, patients on warfarin should have their prothrombin time monitored. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - In teratology and developmental toxicity studies conducted in rats and rabbits treated with dosages of up to 100 mg/kg (5 to 20 times the clinical dose), no adverse or teratogenic effects have been observed in the offspring. Etidronate disodium has been shown to cause skeletal abnormalities in rats when given at oral dose levels of 300 mg/kg (15 to 60 times the human dose). Other effects on the offspring (including decreased live births) are at dosages that cause significant toxicity in the parent generation and are 25 to 200 times the human dose. The skeletal effects are thought to be the result of the pharmacological effects of the drug on bone. - Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous vs. oral) on this risk has not been studied. - There are no adequate and well controlled studies in pregnant women. Etidronate disodium 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 Etidronate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Etidronate 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 etidronate disodium is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. Pediatric patients have been treated with etidronate disodium, at doses recommended for adults, to prevent heterotopic ossifications or soft tissue calcifications. A rachitic syndrome has been reported infrequently at doses of 10 mg/kg/day and more for prolonged periods approaching or exceeding a year. The epiphyseal radiologic changes associated with retarded mineralization of new osteoid and cartilage, and occasional symptoms reported, have been reversible when medication is discontinued. ### Geriatic Use - Clinical studies of etidronate disodium 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 elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 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 when prescribing this drug therapy. As stated in PRECAUTIONS, etidronate disodium dosage should be reduced when reductions in glomerular filtration rates are present. In addition, patients with renal impairment should be closely monitored. ### Gender There is no FDA guidance on the use of Etidronate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Etidronate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Etidronate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Etidronate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Etidronate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Etidronate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Etidronate Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Etidronate and IV administrations. # Overdosage - Clinical experience with acute etidronate disodium overdosage is extremely limited. Decreases in serum calcium following substantial overdosage may be expected in some patients. Signs and symptoms of hypocalcemia also may occur in some of these patients. Some patients may develop vomiting. In one event, an 18 year old female who ingested an estimated single dose of 4000 mg to 6000 mg (67 to 100 mg/kg) of etidronate disodium was reported to be mildly hypocalcemic (7.52 mg/dL) and experienced paresthesia of the fingers. Hypocalcemia resolved 6 hours after lavage and treatment with intravenous calcium gluconate. A 92 year old female who accidentally received 1600 mg of etidronate disodium per day for 3.5 days experienced marked diarrhea and required treatment for electrolyte imbalance. Orally administered etidronate disodium may cause hematologic abnormalities in some patients (see ADVERSE REACTIONS). - Etidronate disodium suppresses bone turnover and may retard mineralization of osteoid laid down during the bone accretion process. These effects are dose and time dependent. Osteoid which may accumulate noticeably at doses of 10 to 20 mg/kg/day of chronic, continuous dosing mineralizes normally post-therapy. - Prolonged continuous treatment (chronic overdosage) has been reported to cause nephrotic syndrome and fracture. - Gastric lavage may remove unabsorbed drug. Standard procedures for treating hypocalcemia, including the administration of Ca++ intravenously, would be expected to restore physiologic amounts of ionized calcium and relieve signs and symptoms of hypocalcemia. Such treatment has been effective. # Pharmacology ## Mechanism of Action - Etidronate disodium acts primarily on bone. It can inhibit the formation, growth, and dissolution of hydroxyapatite crystals and their amorphous precursors by chemisorption to calcium phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are required to inhibit crystal growth. Both effects increase as the dose increases. ## Structure Etidronate disodium tablets, USP contain either 200 mg or 400 mg of etidronate disodium, the disodium salt of (1-hydroxyethylidene) diphosphonic acid, for oral administration. This compound, also known as EHDP, regulates bone metabolism. Etidronate disodium, USP is a white powder, highly soluble in water, with a molecular weight of 250 and the following structural formula: ## Pharmacodynamics There is limited information regarding Etidronate Pharmacodynamics in the drug label. ## Pharmacokinetics - Etidronate disodium is not metabolized. The amount of drug absorbed after an oral dose is approximately 3%. In normal subjects, plasma half-life (t1/2) of etidronate, based on non-compartmental pharmacokinetics is 1 to 6 hours. Within 24 hours, approximately half the absorbed dose is excreted in urine; the remainder is distributed to bone compartments from which it is slowly eliminated. Animal studies have yielded bone clearance estimates up to 165 days. In humans, the residence time on bone may vary due to such factors as specific metabolic condition and bone type. Unabsorbed drug is excreted intact in the feces. Preclinical studies indicate etidronate disodium does not cross the blood-brain barrier. - Etidronate disodium therapy does not adversely affect serum levels of parathyroid hormone or calcium. - Paget’s disease of bone (osteitis deformans) is an idiopathic, progressive disease characterized by abnormal and accelerated bone metabolism in one or more bones. Signs and symptoms may include bone pain and/or deformity, neurologic disorders, elevated cardiac output and other vascular disorders, and increased serum alkaline phosphatase and/or urinary hydroxyproline levels. Bone fractures are common in patients with Paget’s disease. - Etidronate disodium slows accelerated bone turnover (resorption and accretion) in pagetic lesions and, to a lesser extent, in normal bone. This has been demonstrated histologically, scintigraphically, biochemically, and through calcium kinetic and balance studies. Reduced bone turnover is often accompanied by symptomatic improvement, including reduced bone pain. Also, the incidence of pagetic fractures may be reduced and elevated cardiac output and other vascular disorders may be improved by etidronate disodium therapy. - heterotopic ossification, also referred to as myositis ossificans (circumscripta, progressiva or traumatica), ectopic calcification, periarticular ossification, or paraosteoarthropathy, is characterized by metaplastic osteogenesis. It usually presents with signs of localized inflammation or pain, elevated skin temperature, and redness. When tissues near joints are involved, functional loss may also be present. - heterotopic ossification may occur for no known reason as in myositis ossificans progressiva or may follow a wide variety of surgical, occupational, and sports trauma (e.g., hip arthroplasty, spinal cord injury, head injury, burns, and severe thigh bruises). heterotopic ossification has also been observed in non-traumatic conditions (e.g., infections of the central nervous system, peripheral neuropathy, tetanus, biliary cirrhosis, Peyronie’s disease, as well as in association with a variety of benign and malignant neoplasms). - Clinical trials have demonstrated the efficacy of etidronate disodium in heterotopic ossification following total hip replacement or due to spinal cord injury. - heterotopic ossification complicating total hip replacement typically develops radiographically 3 to 8 weeks postoperatively in the pericapsular area of the affected hip joint. The overall incidence is about 50%; about one-third of these cases are clinically significant. - heterotopic ossification due to spinal cord injury typically develops radiographically 1 to 4 months after injury. It occurs below the level of injury, usually at major joints. The overall incidence is about 40%; about one-half of these cases are clinically significant. - Etidronate disodium chemisorbs to calcium hydroxyapatite crystals and their amorphous precursors, blocking the aggregation, growth, and mineralization of these crystals. This is thought to be the mechanism by which etidronate disodium prevents or retards heterotopic ossification. There is no evidence etidronate disodium affects mature heterotopic bone. ## Nonclinical Toxicology - Long-term studies in rats have indicated that etidronate disodium is not carcinogenic. # Clinical Studies There is limited information regarding Etidronate Clinical Studies in the drug label. # How Supplied Etidronate Disodium Tablets, USP are available containing 200 mg or 400 mg of etidronate disodium, USP. The 200 mg tablets are white rectangular-shaped tablets with ED 200 on one side and G on the other side. They are available as follows: NDC 0378-3286-91 Bottles of 60 The 400 mg tablets are white capsule-shaped tablets with ED 400 on one side and G on the other side. They are available as follows: NDC 0378-3288-91 Bottles of 60 Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Manufactured in Australia by: ALPHAPHARM PTY LTD 15 Garnet Street Carole Park QLD 4300 Australia REVISED JANUARY 2014 ETDN:R6 ## Storage Store at 20° to 25°C (68° to 77°F). Avoid excessive heat (over 104°F or 40°C). # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL= NDC 0378-3286-91 Etidronate Disodium Tablets, USP 200 mg Rx only 60 Tablets Each tablet contains: Etidronate disodium, USP 200 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.] Avoid excessive heat (over 104°F -r 40°C). Usual Dosage: See accompanying prescribing information. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in Australia RM3286D3 NDC 0378-3288-91 Etidronate Disodium Tablets, USP 400 mg Rx only 60 Tablets Each tablet contains: Etidronate disodium, USP 400 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.] Avoid excessive heat (over 104°F -r 40°C). Usual Dosage: See accompanying prescribing information. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in Australia RM3288D3 # Patient Counseling Information There is limited information regarding Etidronate Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Etidronate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Didronel - Didronel I.V # Look-Alike Drug Names There is limited information regarding Etidronate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Etidronate 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. # Overview Etidronate is a bisphosphonate, calcium regulator and endocrine metabolic agent that is FDA approved for the treatment of Paget’s disease of bone, prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. Common adverse reactions include gastritis, leg cramp and headache. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Etidronate disodium tablets are indicated for the treatment of symptomatic Paget’s disease of bone and in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. Etidronate disodium tablets are not approved for the treatment of osteoporosis. - Etidronate disodium tablets are indicated for the treatment of symptomatic Paget’s disease of bone. Etidronate disodium therapy usually arrests or significantly impedes the disease process as evidenced by: - Symptomatic relief, including decreased pain and/or increased mobility (experienced by 3 out of 5 patients). - Reductions in serum alkaline phosphatase and urinary hydroxyproline levels (30% or more in 4 out of 5 patients). - Histomorphometry showing reduced numbers of osteoclasts and osteoblasts, and more lamellar bone formation. - Bone scans showing reduced radionuclide uptake at pagetic lesions. - In addition, reductions in pagetically elevated cardiac output and skin temperature have been observed in some patients. - In many patients, the disease process will be suppressed for a period of at least one year following cessation of therapy. The upper limit of this period has not been determined. - The effects of the etidronate disodium treatment in patients with asymptomatic Paget’s disease have not been studied. However, etidronate disodium treatment of such patients may be warranted if extensive involvement threatens irreversible neurologic damage, major joints, or major weight-bearing bones. - Etidronate disodium tablets are indicated in the prevention and treatment of heterotopic ossification following total hip replacement or due to spinal cord injury. - Etidronate disodium tablets reduce the incidence of clinically important heterotopic bone by about two-thirds. Among those patients who form heterotopic bone, etidronate disodium tablets retard the progression of immature lesions and reduces the severity by at least half. Follow-up data (at least 9 months post-therapy) suggests these benefits persist. - In total hip replacement patients, etidronate disodium tablets do not promote loosening of the prosthesis or impede trochanteric reattachment. - In spinal cord injury patients, etidronate disodium tablets do not inhibit fracture healing or stabilization of the spine. ### Dosing Information - Etidronate disodium tablets should be taken as a single, oral dose. As with other bisphosphonates, it is recommended that etidronate disodium tablets should be swallowed with a full glass of water (6 to 8 oz). Patients should not lie down after taking the medication. However, should gastrointestinal discomfort occur, the dose may be divided. To maximize absorption, patients should avoid taking the following items within 2 hours of dosing: - Food, especially food high in calcium, such as milk or milk products. Vitamins with mineral supplements or antacids which are high in metals such as calcium, iron, magnesium, or aluminum. - Initial Treatment Regimens - 5 to 10 mg/kg/day, not to exceed 6 months or 11 to 20 mg/kg/day, not to exceed 3 months. - The recommended initial dose is 5 mg/kg/day for a period not to exceed 6 months. Doses above 10 mg/kg/day should be reserved for when 1) lower doses are ineffective or 2) there is an overriding need to suppress rapid bone turnover (especially when irreversible neurologic damage is possible) or reduce elevated cardiac output. Doses in excess of 20 mg/kg/day are not recommended. - Retreatment Guidelines - Retreatment should be initiated only after 1) an etidronate disodium-free period of at least 90 days and 2) there is biochemical, symptomatic or other evidence of active disease process. It is advisable to monitor patients every 3 to 6 months although some patients may go drug free for extended periods. Retreatment regimens are the same as for initial treatment. For most patients the original dose will be adequate for retreatment. If not, consideration should be given to increasing the dose within the recommended guidelines. - The following treatment regimens have been shown to be effective: - total hip replacement Patients: 20 mg/kg/day for 1 month before and 3 months after surgery (4 months total). - Spinal Cord Injured Patients: 20 mg/kg/day for 2 weeks followed by 10 mg/kg/day for 10 weeks (12 weeks total). Etidronate disodium therapy should begin as soon as medically feasible following the injury, preferably prior to evidence of heterotopic ossification. - Retreatment has not been studied. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Etidronate in adult patients. ### Non–Guideline-Supported Use - osteoporosis # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding Etidronate 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 Etidronate in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Etidronate in pediatric patients. # Contraindications - Abnormalities of the esophagus which delay esophageal emptying such as stricture or achalasia. - Known hypersensitivity to etidronate disodium or in patients with clinically overt osteomalacia. # Warnings ### General - Etidronate disodium, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when etidronate disodium is given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis or ulcers). - Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates. In some cases, these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue etidronate disodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. - The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates and/or who fail to swallow it with the recommended full glass (6 to 8 oz) of water, and/or who continue to take oral bisphosphonates after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient. In patients who cannot comply with dosing instructions due to mental disability, therapy with etidronate disodium should be used under appropriate supervision. - There have been post-marketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials. - In Paget’s patients the response to therapy may be of slow onset and continue for months after etidronate disodium therapy is discontinued. Dosage should not be increased prematurely. A 90-day drug-free interval should be provided between courses of therapy. - No specific warnings. ### PRECAUTIONS - Patients should maintain an adequate nutritional status, particularly an adequate intake of calcium and vitamin D. - Therapy has been withheld from some patients with enterocolitis since diarrhea may be experienced, particularly at higher doses. - Etidronate disodium is not metabolized and is excreted intact via the kidney. Hyperphosphatemia may occur at doses of 10 to 20 mg/kg/day, apparently as a result of drug-related increases in tubular reabsorption of phosphate. Serum phosphate levels generally return to normal 2 to 4 weeks post-therapy. There is no experience to specifically guide treatment in patients with impaired renal function. Etidronate disodium dosage should be reduced when reductions in glomerular filtration rates are present. Patients with renal impairment should be closely monitored. In approximately 10% of patients in clinical trials of etidronate disodium I.V. infusion, for hypercalcemia of malignancy, occasional, mild-to-moderate abnormalities in renal function (increases of > 0.5 mg/dL serum creatinine) were observed during or immediately after treatment. - Etidronate disodium suppresses bone turnover, and may retard mineralization of osteoid laid down during the bone accretion process. These effects are dose and time dependent. Osteoid, which may accumulate noticeably at doses of 10 to 20 mg/kg/day, mineralizes normally post-therapy. In patients with fractures, especially of long bones, it may be advisable to delay or interrupt treatment until callus is evident. - ONJ, which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including etidronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and comorbid disorders (e.g., periodontal and/or other preexisting dental disease, anemia, coagulopathy, infection, ill-fitting dentures). The risk of ONJ may increase with duration of exposure to bisphosphonates. - For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment. - Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. - In post-marketing experience, there have been infrequent reports of severe and occasionally incapacitating bone, joint, and/or muscle pain in patients taking bisphosphonates. The time to onset of symptoms varied from one day to several months after starting the drug. Most patients had relief of symptoms after stopping medication. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. - In Paget’s patients, treatment regimens exceeding the recommended (see DOSAGE AND ADMINISTRATION) daily maximum dose of 20 mg/kg or continuous administration of medication for periods greater than 6 months may be associated with osteomalacia and an increased risk of fracture. - Long bones predominantly affected by lytic lesions, particularly in those patients unresponsive to etidronate disodium therapy, may be especially prone to fracture. - Patients with predominantly lytic lesions should be monitored radiographically and biochemically to permit termination of etidronate disodium in those patients unresponsive to treatment. # Adverse Reactions ## Clinical Trials Experience - The incidence of gastrointestinal complaints (diarrhea, nausea) is the same for etidronate disodium at 5 mg/kg/day as for placebo, about 1 patient in 15. At 10 to 20 mg/kg/day the incidence may increase to 2 or 3 in 10. These complaints are often alleviated by dividing the total daily dose. - In Paget’s patients, increased or recurrent bone pain at pagetic sites, and/or the onset of pain at previously asymptomatic sites has been reported. At 5 mg/kg/day about 1 patient in 10 (vs. 1 in 15 in the placebo group) report these phenomena. At higher doses the incidence rises to about 2 in 10. When therapy continues, pain resolves in some patients but persists in others. - No specific adverse reactions. ## Postmarketing Experience - The worldwide post-marketing experience for etidronate disodium reflects its use in the following approved indications: Paget’s disease, heterotopic ossification, and hypercalcemia of malignancy. It also reflects the use of etidronate disodium for osteoporosis where approved in countries outside the US. Other adverse events that have been reported and were thought to be possibly related to etidronate disodium include the following: alopecia; arthropathies, including arthralgia and arthritis; bone fracture; esophagitis; glossitis; hypersensitivity reactions, including angioedema, follicular eruption, macular rash, maculopapular rash, pruritus, Stevens-Johnson, and urticaria; osteomalacia; neuropsychiatric events, including amnesia, confusion, depression and hallucination; and paresthesias. - In patients receiving etidronate disodium, there have been rare reports of agranulocytosis, pancytopenia, and a report of leukopenia with recurrence on rechallenge. In addition, there have been rare reports of exacerbation of asthma. Exacerbation of existing peptic ulcer disease including perforation has been reported rarely. - In osteoporosis clinical trials, headache, gastritis, leg cramps, and arthralgia occurred at a significantly greater incidence in patients who received etidronate as compared with those who received placebo. # Drug Interactions - There have been isolated reports of patients experiencing increases in their prothrombin times when etidronate was added to warfarin therapy. The majority of these reports concerned variable elevations in prothrombin times without clinically significant sequelae. Although the relevance of these reports and any mechanism of coagulation alterations is unclear, patients on warfarin should have their prothrombin time monitored. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): C - In teratology and developmental toxicity studies conducted in rats and rabbits treated with dosages of up to 100 mg/kg (5 to 20 times the clinical dose), no adverse or teratogenic effects have been observed in the offspring. Etidronate disodium has been shown to cause skeletal abnormalities in rats when given at oral dose levels of 300 mg/kg (15 to 60 times the human dose). Other effects on the offspring (including decreased live births) are at dosages that cause significant toxicity in the parent generation and are 25 to 200 times the human dose. The skeletal effects are thought to be the result of the pharmacological effects of the drug on bone. - Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over periods of weeks to years. The amount of bisphosphonate incorporation into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous vs. oral) on this risk has not been studied. - There are no adequate and well controlled studies in pregnant women. Etidronate disodium 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 Etidronate in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Etidronate 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 etidronate disodium is administered to a nursing woman. ### Pediatric Use - Safety and effectiveness in pediatric patients have not been established. Pediatric patients have been treated with etidronate disodium, at doses recommended for adults, to prevent heterotopic ossifications or soft tissue calcifications. A rachitic syndrome has been reported infrequently at doses of 10 mg/kg/day and more for prolonged periods approaching or exceeding a year. The epiphyseal radiologic changes associated with retarded mineralization of new osteoid and cartilage, and occasional symptoms reported, have been reversible when medication is discontinued. ### Geriatic Use - Clinical studies of etidronate disodium 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 elderly and younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 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 when prescribing this drug therapy. As stated in PRECAUTIONS, etidronate disodium dosage should be reduced when reductions in glomerular filtration rates are present. In addition, patients with renal impairment should be closely monitored. ### Gender There is no FDA guidance on the use of Etidronate with respect to specific gender populations. ### Race There is no FDA guidance on the use of Etidronate with respect to specific racial populations. ### Renal Impairment There is no FDA guidance on the use of Etidronate in patients with renal impairment. ### Hepatic Impairment There is no FDA guidance on the use of Etidronate in patients with hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Etidronate in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Etidronate in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Etidronate Monitoring in the drug label. # IV Compatibility There is limited information regarding the compatibility of Etidronate and IV administrations. # Overdosage - Clinical experience with acute etidronate disodium overdosage is extremely limited. Decreases in serum calcium following substantial overdosage may be expected in some patients. Signs and symptoms of hypocalcemia also may occur in some of these patients. Some patients may develop vomiting. In one event, an 18 year old female who ingested an estimated single dose of 4000 mg to 6000 mg (67 to 100 mg/kg) of etidronate disodium was reported to be mildly hypocalcemic (7.52 mg/dL) and experienced paresthesia of the fingers. Hypocalcemia resolved 6 hours after lavage and treatment with intravenous calcium gluconate. A 92 year old female who accidentally received 1600 mg of etidronate disodium per day for 3.5 days experienced marked diarrhea and required treatment for electrolyte imbalance. Orally administered etidronate disodium may cause hematologic abnormalities in some patients (see ADVERSE REACTIONS). - Etidronate disodium suppresses bone turnover and may retard mineralization of osteoid laid down during the bone accretion process. These effects are dose and time dependent. Osteoid which may accumulate noticeably at doses of 10 to 20 mg/kg/day of chronic, continuous dosing mineralizes normally post-therapy. - Prolonged continuous treatment (chronic overdosage) has been reported to cause nephrotic syndrome and fracture. - Gastric lavage may remove unabsorbed drug. Standard procedures for treating hypocalcemia, including the administration of Ca++ intravenously, would be expected to restore physiologic amounts of ionized calcium and relieve signs and symptoms of hypocalcemia. Such treatment has been effective. # Pharmacology ## Mechanism of Action - Etidronate disodium acts primarily on bone. It can inhibit the formation, growth, and dissolution of hydroxyapatite crystals and their amorphous precursors by chemisorption to calcium phosphate surfaces. Inhibition of crystal resorption occurs at lower doses than are required to inhibit crystal growth. Both effects increase as the dose increases. ## Structure Etidronate disodium tablets, USP contain either 200 mg or 400 mg of etidronate disodium, the disodium salt of (1-hydroxyethylidene) diphosphonic acid, for oral administration. This compound, also known as EHDP, regulates bone metabolism. Etidronate disodium, USP is a white powder, highly soluble in water, with a molecular weight of 250 and the following structural formula: ## Pharmacodynamics There is limited information regarding Etidronate Pharmacodynamics in the drug label. ## Pharmacokinetics - Etidronate disodium is not metabolized. The amount of drug absorbed after an oral dose is approximately 3%. In normal subjects, plasma half-life (t1/2) of etidronate, based on non-compartmental pharmacokinetics is 1 to 6 hours. Within 24 hours, approximately half the absorbed dose is excreted in urine; the remainder is distributed to bone compartments from which it is slowly eliminated. Animal studies have yielded bone clearance estimates up to 165 days. In humans, the residence time on bone may vary due to such factors as specific metabolic condition and bone type. Unabsorbed drug is excreted intact in the feces. Preclinical studies indicate etidronate disodium does not cross the blood-brain barrier. - Etidronate disodium therapy does not adversely affect serum levels of parathyroid hormone or calcium. - Paget’s disease of bone (osteitis deformans) is an idiopathic, progressive disease characterized by abnormal and accelerated bone metabolism in one or more bones. Signs and symptoms may include bone pain and/or deformity, neurologic disorders, elevated cardiac output and other vascular disorders, and increased serum alkaline phosphatase and/or urinary hydroxyproline levels. Bone fractures are common in patients with Paget’s disease. - Etidronate disodium slows accelerated bone turnover (resorption and accretion) in pagetic lesions and, to a lesser extent, in normal bone. This has been demonstrated histologically, scintigraphically, biochemically, and through calcium kinetic and balance studies. Reduced bone turnover is often accompanied by symptomatic improvement, including reduced bone pain. Also, the incidence of pagetic fractures may be reduced and elevated cardiac output and other vascular disorders may be improved by etidronate disodium therapy. - heterotopic ossification, also referred to as myositis ossificans (circumscripta, progressiva or traumatica), ectopic calcification, periarticular ossification, or paraosteoarthropathy, is characterized by metaplastic osteogenesis. It usually presents with signs of localized inflammation or pain, elevated skin temperature, and redness. When tissues near joints are involved, functional loss may also be present. - heterotopic ossification may occur for no known reason as in myositis ossificans progressiva or may follow a wide variety of surgical, occupational, and sports trauma (e.g., hip arthroplasty, spinal cord injury, head injury, burns, and severe thigh bruises). heterotopic ossification has also been observed in non-traumatic conditions (e.g., infections of the central nervous system, peripheral neuropathy, tetanus, biliary cirrhosis, Peyronie’s disease, as well as in association with a variety of benign and malignant neoplasms). - Clinical trials have demonstrated the efficacy of etidronate disodium in heterotopic ossification following total hip replacement or due to spinal cord injury. - heterotopic ossification complicating total hip replacement typically develops radiographically 3 to 8 weeks postoperatively in the pericapsular area of the affected hip joint. The overall incidence is about 50%; about one-third of these cases are clinically significant. - heterotopic ossification due to spinal cord injury typically develops radiographically 1 to 4 months after injury. It occurs below the level of injury, usually at major joints. The overall incidence is about 40%; about one-half of these cases are clinically significant. - Etidronate disodium chemisorbs to calcium hydroxyapatite crystals and their amorphous precursors, blocking the aggregation, growth, and mineralization of these crystals. This is thought to be the mechanism by which etidronate disodium prevents or retards heterotopic ossification. There is no evidence etidronate disodium affects mature heterotopic bone. ## Nonclinical Toxicology - Long-term studies in rats have indicated that etidronate disodium is not carcinogenic. # Clinical Studies There is limited information regarding Etidronate Clinical Studies in the drug label. # How Supplied Etidronate Disodium Tablets, USP are available containing 200 mg or 400 mg of etidronate disodium, USP. The 200 mg tablets are white rectangular-shaped tablets with ED 200 on one side and G on the other side. They are available as follows: NDC 0378-3286-91 Bottles of 60 The 400 mg tablets are white capsule-shaped tablets with ED 400 on one side and G on the other side. They are available as follows: NDC 0378-3288-91 Bottles of 60 Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Manufactured in Australia by: ALPHAPHARM PTY LTD 15 Garnet Street Carole Park QLD 4300 Australia REVISED JANUARY 2014 ETDN:R6 ## Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Avoid excessive heat (over 104°F or 40°C). # Images ## Drug Images ## Package and Label Display Panel ### PRINCIPAL DISPLAY PANEL= NDC 0378-3286-91 Etidronate Disodium Tablets, USP 200 mg Rx only 60 Tablets Each tablet contains: Etidronate disodium, USP 200 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.] Avoid excessive heat (over 104°F or 40°C). Usual Dosage: See accompanying prescribing information. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in Australia RM3286D3 NDC 0378-3288-91 Etidronate Disodium Tablets, USP 400 mg Rx only 60 Tablets Each tablet contains: Etidronate disodium, USP 400 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.] Avoid excessive heat (over 104°F or 40°C). Usual Dosage: See accompanying prescribing information. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A. Made in Australia RM3288D3 # Patient Counseling Information There is limited information regarding Etidronate Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Etidronate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Didronel - Didronel I.V # Look-Alike Drug Names There is limited information regarding Etidronate Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Etidronate
a7a6754b6869439cb71e6e746e91d7408b50286a	wikidoc	Etravirine	Etravirine # 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 Etravirine is an antiretroviral drug that is FDA approved for the treatment of HIV-1 infection in treatment-experienced patients 6 years of age and older with viral strains resistant to an NNRTI and other antiretroviral agents,and In patients who have experienced virologic failure on an NNRTI.. Common adverse reactions include peripheral neuropathy, rash,skin and subcutaneous tissue disorders,myocardial infarction, angina pectoris, atrial fibrillation,vertigo, hemolytic anemia,gynecomastia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - INTELENCE®1, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced patients ages 6 years and older, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents. - The indication for adult use is based on Week 48 analyses from 2 randomized, double-blind, placebo-controlled trials of INTELENCE®. Both studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults. The indication for pediatric use is based on 24-week analyses of a single-arm, Phase 2 trial in antiretroviral treatment-experienced pediatric subjects 6 years to less than 18 years of age. - In treatment-experienced adult and pediatric patients, the following points should be considered when initiating therapy with INTELENCE®: - Treatment history and resistance testing should guide the use of INTELENCE® due to concerns for potential cross-resistance . - In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE® in combination with only NRTIs . - The use of other active antiretroviral agents with INTELENCE® is associated with an increased likelihood of treatment response. - The safety and efficacy of INTELENCE® have not been established in treatment-naïve adult patients. ### Dosage The recommended oral dose of INTELENCE® tablets is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. The type of food does not affect the exposure to etravirine. INTELENCE® 25 mg Tablets - INTELENCE® 25 mg tablets are supplied as white to off-white, oval, scored tablets debossed with "TMC" on one side. INTELENCE® 100 mg Tablets - INTELENCE® 100 mg tablets are supplied as white to off-white oval tablets debossed with "TMC125" on one side and "100" on the other side. INTELENCE® 200 mg Tablets - INTELENCE® 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets debossed with "T200" on one side. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Etravirine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Etravirine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Indications - INTELENCE®1, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced patients ages 6 years and older, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents. - The indication for adult use is based on Week 48 analyses from 2 randomized, double-blind, placebo-controlled trials of INTELENCE®. Both studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults. The indication for pediatric use is based on 24-week analyses of a single-arm, Phase 2 trial in antiretroviral treatment-experienced pediatric subjects 6 years to less than 18 years of age. - In treatment-experienced pediatric patients, the following points should be considered when initiating therapy with INTELENCE®: - Treatment history and resistance testing should guide the use of INTELENCE® due to concerns for potential cross-resistance . - In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE® in combination with only NRTIs . - The use of other active antiretroviral agents with INTELENCE® is associated with an increased likelihood of treatment response. - The safety and efficacy of INTELENCE® have not been established in treatment-naïve adult patients. ### Dosage Pediatric Patients (6 years to less than 18 years of age) The recommended dose of INTELENCE® for pediatric patients 6 years to less than 18 years of age and weighing at least 16 kg is based on body weight (see TABLE BELOW) not exceeding the recommended adult dose. INTELENCE® tablet(s) should be taken orally, following a meal. The type of food does not affect the exposure to etravirine. - The safety and efficacy of INTELENCE® have not been established in children less than 6 years of age INTELENCE® 25 mg Tablets - INTELENCE® 25 mg tablets are supplied as white to off-white, oval, scored tablets debossed with "TMC" on one side. INTELENCE® 100 mg Tablets - INTELENCE® 100 mg tablets are supplied as white to off-white oval tablets debossed with "TMC125" on one side and "100" on the other side. INTELENCE® 200 mg Tablets - INTELENCE® 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets debossed with "T200" on one side. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Etravirine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Etravirine in pediatric patients. # Contraindications - None # Warnings Severe Skin and Hypersensitivity Reactions - Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions including drug rash with eosinophilia and systemic symptoms (DRESS) have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving INTELENCE® compared to 0.2% of placebo subjects. A total of 2.2% of HIV-1-infected subjects receiving INTELENCE® discontinued from Phase 3 trials due to rash. Rash occurred most commonly during the first 6 weeks of therapy. The incidence of rash was higher in females. - Discontinue INTELENCE® immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping INTELENCE® treatment after the onset of severe rash may result in a life-threatening reaction. Fat Redistribution - Redistribution/accumulation of body fat, including central obesity, dorso cervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Immune Reconstitution Syndrome - Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INTELENCE®. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment. - Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are described in greater detail in other sections: - Severe skin and hypersensitivity reactions Clinical Trials Experience: Adults - 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 assessment is based on all data from 1203 subjects in the Phase 3 placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received INTELENCE® (200 mg twice daily). In these pooled trials, the median exposure for subjects in the INTELENCE® arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the INTELENCE® arm and 2.6% in the placebo arm. - The most frequently reported ADR at least Grade 2 in severity was rash (10.0%). Stevens-Johnson syndrome, drug hypersensitivity reaction and erythema multiforme were reported in less than 0.1% of subjects during clinical development with INTELENCE® . A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving INTELENCE® discontinued due to rash. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1 to 2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the INTELENCE® arm in the Phase 3 trials (rash ≥ Grade 2 was reported in 9/60 women versus 51/539 men; discontinuations due to rash were reported in 3/60 women versus 10/539 men). Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of INTELENCE®-related rash compared to patients without a history of NNRTI-related rash. Common Adverse Reactions - Clinical ADRs of moderate intensity or greater (greater than or equal to Grade 2) and reported in at least 2% of subjects treated with INTELENCE® and occurring at a higher rate compared to placebo (excess of 1%) are presented in Table 1. Laboratory abnormalities considered ADRs are included in Table 2. Less Common Adverse Reactions - Treatment-emergent ADRs occurring in less than 2% of subjects (599 subjects) receiving INTELENCE® and of at least moderate intensity (greater than or equal to Grade 2) are listed below by body system: - Cardiac Disorders: myocardial infarction, angina pectoris, atrial fibrillation - Ear and Labyrinth Disorders: vertigo - Eye Disorders: blurred vision - Gastrointestinal Disorders: gastroesophageal reflux disease, flatulence, gastritis, abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitis - General Disorders and Administration Site Conditions: sluggishness - Hematologic Disorders: hemolytic anemia - Hepatobiliary Disorders: hepatic failure, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis - Immune System Disorders: drug hypersensitivity, immune reconstitution syndrome - Metabolism and Nutrition Disorders: diabetes mellitus, anorexia, dyslipidemia - Nervous System Disorders: paraesthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor - Psychiatric Disorders: anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmares - Renal and Urinary Disorders: acute renal failure - Reproductive System and Breast Disorders: gynecomastia - Respiratory,Thoracic and Mediastinal Disorders: exertional dyspnea, bronchospasm - Skin and Subcutaneous Tissue Disorders: night sweats, lipohypertrophy, prurigo, hyperhidrosis, dry skin, swelling face - Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of subjects. Laboratory Abnormalities in Treatment-Experienced Patients Selected Grade 2 to Grade 4 laboratory abnormalities that represent a worsening from baseline observed in adult subjects treated with INTELENCE® are presented in Table 2. Patients co-infected with hepatitis B and/or hepatitis C virus - In Phase 3 trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1129 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis B and/or hepatitis C virus co-infected subjects for both treatment groups. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 27.8%, 25.0% and 7.1% respectively, of INTELENCE®-treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected INTELENCE®-treated subjects. In general, adverse events reported by INTELENCE®-treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to INTELENCE®-treated subjects without hepatitis B and/or hepatitis C virus co-infection. Clinical Trials Experience: Pediatric Subjects (6 years to less than 18 years of age) - The safety assessment in children and adolescents is based on the Week 24 analysis of the single-arm, Phase 2 trial TMC125-C213 in which 101 antiretroviral treatment-experienced HIV-1 infected subjects 6 years to less than 18 years of age and weighing at least 16 kg received INTELENCE® in combination with other antiretroviral agents. The frequency, type and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adult subjects, except for rash which was observed more frequently in pediatric subjects. The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea. Rash was reported more frequently in female subjects than in male subjects (rash ≥ Grade 2 was reported in 13/64 females versus 2/37 males; discontinuations due to rash were reported in 4/64 females versus 0/37 males). Rash (greater than or equal to Grade 2) occurred in 15% of pediatric subjects. In the majority of cases, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was self-limiting and generally resolved within 1 week on continued therapy. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile for subjects who completed 24 weeks of treatment. ## Postmarketing Experience - The following events have been identified during postmarketing use of INTELENCE®. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Immune System Disorders: Severe hypersensitivity reactions including DRESS and cases of hepatic failure have been reported. - Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis - Skin and Subcutaneous Tissue Disorders: Fatal cases of toxic epidermal necrolysis have been reported. # Drug Interactions - Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE® with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE® (see TABLE 3). - Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-glycoprotein with INTELENCE® may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see TABLE 3). - Table 3 shows the established and other potentially significant drug interactions based on which, alterations in dose or regimen of INTELENCE® and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with INTELENCE® are also included in Table 3. - In addition to the drugs included in Table 3, the interaction between INTELENCE® and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug: didanosine, enfuvirtide (ENF),ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category B - No adequate and well-controlled studies of INTELENCE® use in pregnant women have been conducted. In addition, no pharmacokinetic studies have been conducted in pregnant patients. INTELENCE® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry - To monitor maternal-fetal outcomes of pregnant women exposed to INTELENCE®, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Animal Data - Reproductive and developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg per kg per day) and rats (at oral doses up to 1000 mg per kg per day). In both species, no treatment-related embryo-fetal effects including malformations were observed. In addition, no treatment-related effects were observed in a separate pre- and postnatal study performed in rats at oral doses up to 500 mg per kg per day. The systemic drug exposures achieved in these animal studies were equivalent to those at the recommended human dose (400 mg per day). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etravirine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Etravirine during labor and delivery. ### Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether etravirine is secreted in human milk. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving INTELENCE®. ### Pediatric Use - Treatment with INTELENCE® is not recommended in children less than 6 years of age. The pharmacokinetics, safety, tolerability and efficacy of INTELENCE® in children less than 6 years of age have not been established. - The safety, pharmacokinetic profile, and virologic and immunologic responses of INTELENCE® were evaluated in treatment-experienced HIV-1-infected pediatric subjects 6 years to less than 18 years of age and weighing at least 16 kg. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults, except for rash. ### Geriatic Use - Clinical studies of INTELENCE® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, 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 Etravirine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Etravirine with respect to specific racial populations. ### Renal Impairment - Since the renal clearance of etravirine is negligible (less than 1.2%), a decrease in total body clearance is not expected in patients with renal impairment. No dose adjustments are required in patients with renal impairment. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis. ### Hepatic Impairment No dose adjustment of INTELENCE® is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics of INTELENCE® have not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Etravirine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Etravirine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral Method of Administration - Patients should be instructed to swallow the INTELENCE® tablet(s) whole with a liquid such as water. Patients who are unable to swallow the INTELENCE® tablet(s) whole may disperse the tablet(s) in a glass of water. The patient should be instructed to do the following: - Place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication, - Stir well until the water looks milky, - If desired, add more water or alternatively orange juice or milk (patients should not place the tablets in orange juice or milk without first adding water). The use of grapefruit juice or warm (greater than 40°C) or carbonated beverages should be avoided. - Drink it immediately, - Rinse the glass several times with water, orange juice, or milk and completely swallow the rinse each time to make sure the patient takes the entire dose. ### Monitoring There is limited information regarding Monitoring of Etravirine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Etravirine in the drug label. # Overdosage - There is no specific antidote for overdose with INTELENCE®. Human experience of overdose with INTELENCE® is limited. The highest dose studied in healthy volunteers was 400 mg once daily. Treatment of overdose with INTELENCE® consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Because etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance. # Pharmacology ## Mechanism of Action - Etravirine is an NNRTI of human immunodeficiency virus type 1 (HIV-1). Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases α, β, and γ. ## Structure - INTELENCE® (etravirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). - The chemical name for etravirine is 4-oxy]]-3,5-dimethylbenzonitrile. Its molecular formula is C20H15BrN6O and its molecular weight is 435.28. Etravirine has the following structural formula: - Etravirine is a white to slightly yellowish brown powder. Etravirine is practically insoluble in water over a wide pH range. It is very slightly soluble in propylene glycol and slightly soluble in ethanol. Etravirine is soluble in polyethylene glycol (PEG)400 and freely soluble in some organic solvents (e.g., N,N-dimethylformamide and tetrahydrofuran). - INTELENCE® 25 mg tablets are available as white to off-white, oval scored tablets for oral administration. Each 25 mg tablet contains 25 mg of etravirine and the inactive ingredients hypromellose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and lactose monohydrate. - INTELENCE® 100 mg tablets are available as white to off-white, oval tablets for oral administration. Each 100 mg tablet contains 100 mg of etravirine and the inactive ingredients hypromellose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and lactose monohydrate. - INTELENCE® 200 mg tablets are available as white to off-white, biconvex, oblong tablets for oral administration. Each 200 mg tablet contains 200 mg of etravirine and the inactive ingredients hypromellose, silicified microcrystalline cellulose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate. ## Pharmacodynamics Effects on Electrocardiogram - In a randomized, double-blind, active, and placebo-controlled crossover study, 41 healthy subjects were administered INTELENCE® 200 mg twice daily, INTELENCE® 400 mg once daily, placebo, and moxifloxacin 400 mg. After 8 days of dosing, etravirine did not prolong the QT interval. The maximum mean (upper 1-sided 95% CI) baseline and placebo-adjusted QTcF were 0.6 ms (3.3 ms) for 200 mg twice daily and -1.0 ms (2.5 ms) for 400 mg once daily dosing regimens. ## Pharmacokinetics Pharmacokinetics in Adults - The pharmacokinetic properties of INTELENCE® were determined in healthy adult subjects and in treatment-experienced HIV-1-infected adult and pediatric subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1-infected subjects than in healthy subjects. - Note: The median protein binding adjusted EC50 for MT4 cells infected with HIV-1/IIIB in vitro equals 4 ng per mL. Absorption and Bioavailability - Following oral administration, etravirine was absorbed with a Tmax of about 2.5 to 4 hours. The absolute oral bioavailability of INTELENCE® is unknown. - In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH. Effects of Food on Oral Absorption - The systemic exposure (AUC) to etravirine was decreased by about 50% when INTELENCE® was administered under fasting conditions, as compared to when INTELENCE® was administered following a meal. Therefore, INTELENCE® should always be taken following a meal. Within the range of meals studied, the systemic exposures to etravirine were similar. The total caloric content of the various meals evaluated ranged from 345 kilocalories (17 grams fat) to 1160 kilocalories (70 grams fat). Distribution - Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha 1-acid glycoprotein (97.66% to 99.02%) in vitro. The distribution of etravirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans. Metabolism - In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes metabolism by CYP3A, CYP2C9, and CYP2C19 enzymes. The major metabolites, formed by methyl hydroxylation of the dimethylbenzonitrile moiety, were at least 90% less active than etravirine against wild-type HIV in cell culture. Elimination - After single dose oral administration of 800 mg 14C-etravirine, 93.7% and 1.2% of the administered dose of 14C-etravirine was recovered in the feces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The mean (± standard deviation) terminal elimination half-life of etravirine was about 41 (± 20) hours. Special Populations Hepatic Impairment - Etravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of INTELENCE® to subjects with normal hepatic function (16 subjects), mild hepatic impairment (Child-Pugh Class A, 8 subjects), and moderate hepatic impairment (Child-Pugh Class B, 8 subjects). The effect of severe hepatic impairment on the pharmacokinetics of etravirine has not been evaluated. Hepatitis B and/or Hepatitis C Virus Co-infection - Population pharmacokinetic analysis of the TMC125-C206 and TMC125-C216 trials showed reduced clearance for etravirine in HIV-1-infected subjects with hepatitis B and/or C virus co-infection. Based upon the safety profile of INTELENCE®, no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus. Renal Impairment - The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from a mass balance study with 14C-etravirine showed that less than 1.2% of the administered dose of etravirine is excreted in the urine as metabolites. No unchanged drug was detected in the urine. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis. Gender - No significant pharmacokinetic differences have been observed between males and females. Race - Population pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine. Geriatric Patients - Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different within the age range (18 to 77 years) evaluated. Pediatric Patients - The pharmacokinetics of etravirine in 101 treatment-experienced HIV-1-infected pediatric subjects, 6 years to less than 18 years of age and weighing at least 16 kg showed that the administered weight-based dosages (approximately 5.2 mg per kg twice daily up to the adult recommended doses) resulted in etravirine exposure comparable to that in adults receiving INTELENCE® 200 mg twice daily when administered at a dose corresponding to 5.2 mg per kg twice daily. The population pharmacokinetic estimates for etravirine AUC12h and C0h are summarized in the table below. - The pharmacokinetics of etravirine in pediatric subjects less than 6 years of age have not been established. Drug Interactions - Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE® with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE®. - Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-glycoprotein with INTELENCE® may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s). - Drug interaction studies were performed with INTELENCE® and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the AUC, Cmax, and Cmin values of etravirine are summarized in Table 5 (effect of other drugs on INTELENCE®). The effect of co-administration of INTELENCE® on the AUC, Cmax, and Cmin values of other drugs are summarized in Table 6 (effect of INTELENCE® on other drugs). ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis - Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50, 200 and 400 mg per kg were administered to mice and doses of 70, 200 and 600 mg per kg were administered to rats in the initial period of approximately 41 to 52 weeks. The high and middle doses were subsequently adjusted due to tolerability and reduced by 50% in mice and by 50 to 66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and incidences of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance of these liver tumor findings in mice to humans is not known. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg per day), with animal vs. human AUC ratios being 0.6-fold (mice) and 0.2–0.7-fold (rats). Mutagenesis - Etravirine tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocyte, and in vitro clastogenicity mouse lymphoma assay, tested in the absence and presence of a metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice. Impairment of Fertility - No effects on fertility and early embryonic development were observed when etravirine was tested in rats at maternal doses up to 500 mg per kg per day, resulting in systemic drug exposure up to the recommended human dose (400 mg per day). # Clinical Studies Treatment-Experienced Adult Subjects - The clinical efficacy of INTELENCE® is derived from the analyses of 48-week data from 2 ongoing, randomized, double-blinded, placebo-controlled, Phase 3 trials, TMC125-C206 and TMC125-C216 (DUET-1 and DUET-2). These trials are identical in design and the results below are pooled data from the two trials. - TMC125-C206 and TMC125-C216 are Phase 3 studies designed to evaluate the safety and antiretroviral activity of INTELENCE® in combination with a background regimen (BR) as compared to placebo in combination with a BR. Eligible subjects were treatment-experienced HIV-1-infected patients with plasma HIV-1 RNA greater than 5000 copies per mL while on an antiretroviral regimen for at least 8 weeks. In addition, subjects had 1 or more NNRTI resistance-associated mutations at screening or from prior genotypic analysis, and 3 or more of the following primary PI mutations at screening: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M. Randomization was stratified by the intended use of enfuvirtide (ENF) in the BR, previous use of darunavir/ritonavir (DRV/rtv), and screening viral load. Virologic response was defined as HIV-1 RNA less than 50 copies per mL at Week 48. - All study subjects received DRV/rtv as part of their BR, and at least 2 other investigator-selected antiretroviral drugs (NRTIs with or without ENF). Of INTELENCE®-treated subjects, 25.5% used ENF for the first time (de novo) and 20.0% re-used ENF. Of placebo-treated subjects, 26.5% used de novo ENF and 20.4% re-used ENF. - In the pooled analysis for TMC125-C206 and TMC125-C216, demographics and baseline characteristics were balanced between the INTELENCE® arm and the placebo arm. Table 10 displays selected demographic and baseline disease characteristics of the subjects in the INTELENCE® and placebo arms. - Efficacy at Week 48 for subjects in the INTELENCE® and placebo arms for the pooled TMC125-C206 and TMC125-C216 study populations are shown in Table 11. - At Week 48, 70.8% of INTELENCE®-treated subjects achieved HIV-1 RNA less than 400 copies per mL as compared to 46.4% of placebo-treated subjects. The mean decrease in plasma HIV-1 RNA from baseline to Week 48 was -2.23 log10 copies per mL for INTELENCE®-treated subjects and -1.46 log10 copies per mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for INTELENCE®-treated subjects was 96 cells per mm3 and 68 cells per mm3 for placebo-treated subjects. - Of the study population who either re-used or did not use ENF, 57.4% of INTELENCE®-treated subjects and 31.7% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies per mL. Of the study population using ENF de novo, 67.3% of INTELENCE®-treated subjects and 57.2% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies per mL. - Treatment-emergent CDC category C events occurred in 4% of INTELENCE®-treated subjects and 8.4% of placebo-treated subjects. - Study TMC125-C227 was a randomized, exploratory, active-controlled, open-label, Phase 2b trial. Eligible subjects were treatment-experienced, PI-naïve HIV-1-infected patients with genotypic evidence of NNRTI resistance at screening or from prior genotypic analysis. The virologic response was evaluated in 116 subjects who were randomized to INTELENCE® (59 subjects) or an investigator-selected PI (57 subjects), each given with 2 investigator-selected N(t)RTIs. INTELENCE®-treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to INTELENCE® as compared to the control PI-treated subjects. Treatment-Experienced Pediatric Subjects (6 years to less than 18 years of age) - TMC125-C213, a single-arm, Phase 2 trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of INTELENCE® enrolled 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to less than 18 years of age and weighing at least 16 kg. Subjects eligible for this trial were on an antiretroviral regimen with confirmed plasma HIV-1 RNA of at least 500 copies per mL and viral susceptibility to INTELENCE® at screening. - The median baseline plasma HIV-1 RNA was 3.9 log10 copies per mL, and the median baseline CD4 cell count was 385 × 106 cells per mm3. - At Week 24, 52% of all pediatric subjects had HIV-1 RNA less than 50 copies per mL. The proportion of pediatric subjects with HIV-1 RNA less than 400 copies per mL was 67%. The mean CD4 cell count increase from baseline was 112 × 106 cells per mm3. # How Supplied - INTELENCE® 25 mg tablets are supplied as white to off-white, oval, scored tablets containing 25 mg of etravirine. Each tablet is debossed with "TMC" on one side. - INTELENCE® 100 mg tablets are supplied as white to off-white, oval tablets containing 100 mg of etravirine. Each tablet is debossed with "TMC125" on one side and "100" on the other side. - INTELENCE® 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets containing 200 mg of etravirine. Each tablet is debossed with "T200" on one side. - INTELENCE® tablets are packaged in bottles in the following configuration: - 25 mg tablets—bottles of 120 (NDC 59676-572-01). Each bottle contains 2 desiccant pouches. - 100 mg tablets—bottles of 120 (NDC 59676-570-01). Each bottle contains 3 desiccant pouches. - 200 mg tablets—bottles of 60 (NDC 59676-571-01). Each bottle contains 3 desiccant pouches. ## Storage - Store INTELENCE® tablets at 25°C (77°F); with excursions permitted to 15°to 30°C (59°to 86°F) . Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. Do not remove the desiccant pouches. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with INTELENCE® from your healthcare provider. A Patient Package Insert for INTELENCE® is available for patient information. - Patients should be informed that INTELENCE® is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using INTELENCE®. - Patients should be advised to avoid doing things that can spread HIV-1 infection to others. Patients should be advised to practice safe sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should also be advised to never re-use or share needles or other injection equipment, or share personal items that can have blood or body fluids on them, such as toothbrushes and razor blades. - Patients should be advised to take INTELENCE® following a meal twice a day as prescribed. The type of food does not affect the exposure to etravirine. - Patients should be instructed to swallow the INTELENCE® tablet(s) whole with a liquid such as water. Patients should be instructed not to chew the tablets. Patients who are unable to swallow the INTELENCE® tablet(s) whole may disperse the tablet(s) in a glass of water. The patient should be instructed to do the following: - Place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication, - Stir well until the water looks milky - If desired, add more water or alternatively orange juice or milk (patients should not place the tablets in orange juice or milk without first adding water). The use of grapefruit juice or warm (greater than 104°F; greater than 40°C) or carbonated beverages should be avoided. - Drink it immediately, - Rinse the glass several times with water, orange juice, or milk and completely swallow the rinse each time to make sure the patient takes the entire dose. INTELENCE® must always be used in combination with other antiretroviral drugs. Patients should not alter the dose of INTELENCE® or discontinue therapy with INTELENCE® without consulting their physician. - If the patient misses a dose of INTELENCE® within 6 hours of the time it is usually taken, the patient should take INTELENCE® following a meal as soon as possible, and then take the next dose of INTELENCE® at the regularly scheduled time. If a patient misses a dose of INTELENCE® by more than 6 hours of the time it is usually taken, the patient should not take the missed dose and simply resume the usual dosing schedule. Inform the patient that he or she should not take more or less than the prescribed dose of INTELENCE® at any one time. - INTELENCE® may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort. - Patients should be informed that severe and potentially life-threatening rash has been reported with INTELENCE®. Rash has been reported most commonly in the first 6 weeks of therapy. Patients should be advised to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking INTELENCE® and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis or severe hypersensitivity: fever, generally ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, facial swelling, swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of liver problems (e.g., yellowing of your skin or whites of your eyes, dark or tea colored urine, pale colored stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching or sensitivity on your right side below your ribs). Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be ordered and appropriate therapy will be initiated. - Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including INTELENCE®, and that the cause and long-term health effects of these conditions are not known at this time. # Precautions with Alcohol - Alcohol-Etravirine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - INTELENCE # Look-Alike Drug Names There is limited information regarding Etravirine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Etravirine Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Etravirine is an antiretroviral drug that is FDA approved for the treatment of HIV-1 infection in treatment-experienced patients 6 years of age and older with viral strains resistant to an NNRTI and other antiretroviral agents,and In patients who have experienced virologic failure on an NNRTI.. Common adverse reactions include peripheral neuropathy, rash,skin and subcutaneous tissue disorders,myocardial infarction, angina pectoris, atrial fibrillation,vertigo, hemolytic anemia,gynecomastia. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) ### Indications - INTELENCE®1, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced patients ages 6 years and older, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents. - The indication for adult use is based on Week 48 analyses from 2 randomized, double-blind, placebo-controlled trials of INTELENCE®. Both studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, N[t]RTI, PI) treatment-experienced adults. The indication for pediatric use is based on 24-week analyses of a single-arm, Phase 2 trial in antiretroviral treatment-experienced pediatric subjects 6 years to less than 18 years of age. - In treatment-experienced adult and pediatric patients, the following points should be considered when initiating therapy with INTELENCE®: - Treatment history and resistance testing should guide the use of INTELENCE® due to concerns for potential cross-resistance . - In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE® in combination with only N[t]RTIs . - The use of other active antiretroviral agents with INTELENCE® is associated with an increased likelihood of treatment response. - The safety and efficacy of INTELENCE® have not been established in treatment-naïve adult patients. ### Dosage The recommended oral dose of INTELENCE® tablets is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. The type of food does not affect the exposure to etravirine. INTELENCE® 25 mg Tablets - INTELENCE® 25 mg tablets are supplied as white to off-white, oval, scored tablets debossed with "TMC" on one side. INTELENCE® 100 mg Tablets - INTELENCE® 100 mg tablets are supplied as white to off-white oval tablets debossed with "TMC125" on one side and "100" on the other side. INTELENCE® 200 mg Tablets - INTELENCE® 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets debossed with "T200" on one side. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Etravirine in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Etravirine in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) ### Indications - INTELENCE®1, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced patients ages 6 years and older, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents. - The indication for adult use is based on Week 48 analyses from 2 randomized, double-blind, placebo-controlled trials of INTELENCE®. Both studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, N[t]RTI, PI) treatment-experienced adults. The indication for pediatric use is based on 24-week analyses of a single-arm, Phase 2 trial in antiretroviral treatment-experienced pediatric subjects 6 years to less than 18 years of age. - In treatment-experienced pediatric patients, the following points should be considered when initiating therapy with INTELENCE®: - Treatment history and resistance testing should guide the use of INTELENCE® due to concerns for potential cross-resistance . - In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use INTELENCE® in combination with only N[t]RTIs . - The use of other active antiretroviral agents with INTELENCE® is associated with an increased likelihood of treatment response. - The safety and efficacy of INTELENCE® have not been established in treatment-naïve adult patients. ### Dosage Pediatric Patients (6 years to less than 18 years of age) The recommended dose of INTELENCE® for pediatric patients 6 years to less than 18 years of age and weighing at least 16 kg is based on body weight (see TABLE BELOW) not exceeding the recommended adult dose. INTELENCE® tablet(s) should be taken orally, following a meal. The type of food does not affect the exposure to etravirine. - The safety and efficacy of INTELENCE® have not been established in children less than 6 years of age INTELENCE® 25 mg Tablets - INTELENCE® 25 mg tablets are supplied as white to off-white, oval, scored tablets debossed with "TMC" on one side. INTELENCE® 100 mg Tablets - INTELENCE® 100 mg tablets are supplied as white to off-white oval tablets debossed with "TMC125" on one side and "100" on the other side. INTELENCE® 200 mg Tablets - INTELENCE® 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets debossed with "T200" on one side. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Etravirine in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Etravirine in pediatric patients. # Contraindications - None # Warnings Severe Skin and Hypersensitivity Reactions - Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions including drug rash with eosinophilia and systemic symptoms (DRESS) have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving INTELENCE® compared to 0.2% of placebo subjects. A total of 2.2% of HIV-1-infected subjects receiving INTELENCE® discontinued from Phase 3 trials due to rash. Rash occurred most commonly during the first 6 weeks of therapy. The incidence of rash was higher in females. - Discontinue INTELENCE® immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping INTELENCE® treatment after the onset of severe rash may result in a life-threatening reaction. Fat Redistribution - Redistribution/accumulation of body fat, including central obesity, dorso cervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Immune Reconstitution Syndrome - Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INTELENCE®. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia (PCP) or tuberculosis), which may necessitate further evaluation and treatment. - Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. # Adverse Reactions ## Clinical Trials Experience - The following adverse reactions are described in greater detail in other sections: - Severe skin and hypersensitivity reactions Clinical Trials Experience: Adults - 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 assessment is based on all data from 1203 subjects in the Phase 3 placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received INTELENCE® (200 mg twice daily). In these pooled trials, the median exposure for subjects in the INTELENCE® arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the INTELENCE® arm and 2.6% in the placebo arm. - The most frequently reported ADR at least Grade 2 in severity was rash (10.0%). Stevens-Johnson syndrome, drug hypersensitivity reaction and erythema multiforme were reported in less than 0.1% of subjects during clinical development with INTELENCE® [see WARNINGS AND PRECAUTIONS (5.1)]. A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving INTELENCE® discontinued due to rash. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1 to 2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the INTELENCE® arm in the Phase 3 trials (rash ≥ Grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men). Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of INTELENCE®-related rash compared to patients without a history of NNRTI-related rash. Common Adverse Reactions - Clinical ADRs of moderate intensity or greater (greater than or equal to Grade 2) and reported in at least 2% of subjects treated with INTELENCE® and occurring at a higher rate compared to placebo (excess of 1%) are presented in Table 1. Laboratory abnormalities considered ADRs are included in Table 2. Less Common Adverse Reactions - Treatment-emergent ADRs occurring in less than 2% of subjects (599 subjects) receiving INTELENCE® and of at least moderate intensity (greater than or equal to Grade 2) are listed below by body system: - Cardiac Disorders: myocardial infarction, angina pectoris, atrial fibrillation - Ear and Labyrinth Disorders: vertigo - Eye Disorders: blurred vision - Gastrointestinal Disorders: gastroesophageal reflux disease, flatulence, gastritis, abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitis - General Disorders and Administration Site Conditions: sluggishness - Hematologic Disorders: hemolytic anemia - Hepatobiliary Disorders: hepatic failure, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis - Immune System Disorders: drug hypersensitivity, immune reconstitution syndrome - Metabolism and Nutrition Disorders: diabetes mellitus, anorexia, dyslipidemia - Nervous System Disorders: paraesthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor - Psychiatric Disorders: anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmares - Renal and Urinary Disorders: acute renal failure - Reproductive System and Breast Disorders: gynecomastia - Respiratory,Thoracic and Mediastinal Disorders: exertional dyspnea, bronchospasm - Skin and Subcutaneous Tissue Disorders: night sweats, lipohypertrophy, prurigo, hyperhidrosis, dry skin, swelling face - Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of subjects. Laboratory Abnormalities in Treatment-Experienced Patients Selected Grade 2 to Grade 4 laboratory abnormalities that represent a worsening from baseline observed in adult subjects treated with INTELENCE® are presented in Table 2. Patients co-infected with hepatitis B and/or hepatitis C virus - In Phase 3 trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1129 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis B and/or hepatitis C virus co-infected subjects for both treatment groups. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 27.8%, 25.0% and 7.1% respectively, of INTELENCE®-treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected INTELENCE®-treated subjects. In general, adverse events reported by INTELENCE®-treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to INTELENCE®-treated subjects without hepatitis B and/or hepatitis C virus co-infection. Clinical Trials Experience: Pediatric Subjects (6 years to less than 18 years of age) - The safety assessment in children and adolescents is based on the Week 24 analysis of the single-arm, Phase 2 trial TMC125-C213 in which 101 antiretroviral treatment-experienced HIV-1 infected subjects 6 years to less than 18 years of age and weighing at least 16 kg received INTELENCE® in combination with other antiretroviral agents. The frequency, type and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adult subjects, except for rash which was observed more frequently in pediatric subjects. The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea. Rash was reported more frequently in female subjects than in male subjects (rash ≥ Grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males; discontinuations due to rash were reported in 4/64 [6.3%] females versus 0/37 [0%] males). Rash (greater than or equal to Grade 2) occurred in 15% of pediatric subjects. In the majority of cases, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was self-limiting and generally resolved within 1 week on continued therapy. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile for subjects who completed 24 weeks of treatment. ## Postmarketing Experience - The following events have been identified during postmarketing use of INTELENCE®. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. - Immune System Disorders: Severe hypersensitivity reactions including DRESS and cases of hepatic failure have been reported. - Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis - Skin and Subcutaneous Tissue Disorders: Fatal cases of toxic epidermal necrolysis have been reported. # Drug Interactions - Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE® with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE® (see TABLE 3). - Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-glycoprotein with INTELENCE® may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see TABLE 3). - Table 3 shows the established and other potentially significant drug interactions based on which, alterations in dose or regimen of INTELENCE® and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with INTELENCE® are also included in Table 3. - In addition to the drugs included in Table 3, the interaction between INTELENCE® and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug: didanosine, enfuvirtide (ENF),ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): Pregnancy Category B - No adequate and well-controlled studies of INTELENCE® use in pregnant women have been conducted. In addition, no pharmacokinetic studies have been conducted in pregnant patients. INTELENCE® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry - To monitor maternal-fetal outcomes of pregnant women exposed to INTELENCE®, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263. Animal Data - Reproductive and developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg per kg per day) and rats (at oral doses up to 1000 mg per kg per day). In both species, no treatment-related embryo-fetal effects including malformations were observed. In addition, no treatment-related effects were observed in a separate pre- and postnatal study performed in rats at oral doses up to 500 mg per kg per day. The systemic drug exposures achieved in these animal studies were equivalent to those at the recommended human dose (400 mg per day). Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Etravirine in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Etravirine during labor and delivery. ### Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. It is not known whether etravirine is secreted in human milk. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving INTELENCE®. ### Pediatric Use - Treatment with INTELENCE® is not recommended in children less than 6 years of age. The pharmacokinetics, safety, tolerability and efficacy of INTELENCE® in children less than 6 years of age have not been established. - The safety, pharmacokinetic profile, and virologic and immunologic responses of INTELENCE® were evaluated in treatment-experienced HIV-1-infected pediatric subjects 6 years to less than 18 years of age and weighing at least 16 kg. Frequency, type, and severity of adverse drug reactions in pediatric subjects were comparable to those observed in adults, except for rash. ### Geriatic Use - Clinical studies of INTELENCE® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, 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 Etravirine with respect to specific gender populations. ### Race There is no FDA guidance on the use of Etravirine with respect to specific racial populations. ### Renal Impairment - Since the renal clearance of etravirine is negligible (less than 1.2%), a decrease in total body clearance is not expected in patients with renal impairment. No dose adjustments are required in patients with renal impairment. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis. ### Hepatic Impairment No dose adjustment of INTELENCE® is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics of INTELENCE® have not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C). ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Etravirine in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Etravirine in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral Method of Administration - Patients should be instructed to swallow the INTELENCE® tablet(s) whole with a liquid such as water. Patients who are unable to swallow the INTELENCE® tablet(s) whole may disperse the tablet(s) in a glass of water. The patient should be instructed to do the following: - Place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication, - Stir well until the water looks milky, - If desired, add more water or alternatively orange juice or milk (patients should not place the tablets in orange juice or milk without first adding water). The use of grapefruit juice or warm (greater than 40°C) or carbonated beverages should be avoided. - Drink it immediately, - Rinse the glass several times with water, orange juice, or milk and completely swallow the rinse each time to make sure the patient takes the entire dose. ### Monitoring There is limited information regarding Monitoring of Etravirine in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Etravirine in the drug label. # Overdosage - There is no specific antidote for overdose with INTELENCE®. Human experience of overdose with INTELENCE® is limited. The highest dose studied in healthy volunteers was 400 mg once daily. Treatment of overdose with INTELENCE® consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Because etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance. # Pharmacology ## Mechanism of Action - Etravirine is an NNRTI of human immunodeficiency virus type 1 (HIV-1). Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases α, β, and γ. ## Structure - INTELENCE® (etravirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). - The chemical name for etravirine is 4-[[6-amino-5-bromo-2-(4-cyanophenyl)amino-4-pyrimidinyl]oxy]]-3,5-dimethylbenzonitrile. Its molecular formula is C20H15BrN6O and its molecular weight is 435.28. Etravirine has the following structural formula: - Etravirine is a white to slightly yellowish brown powder. Etravirine is practically insoluble in water over a wide pH range. It is very slightly soluble in propylene glycol and slightly soluble in ethanol. Etravirine is soluble in polyethylene glycol (PEG)400 and freely soluble in some organic solvents (e.g., N,N-dimethylformamide and tetrahydrofuran). - INTELENCE® 25 mg tablets are available as white to off-white, oval scored tablets for oral administration. Each 25 mg tablet contains 25 mg of etravirine and the inactive ingredients hypromellose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and lactose monohydrate. - INTELENCE® 100 mg tablets are available as white to off-white, oval tablets for oral administration. Each 100 mg tablet contains 100 mg of etravirine and the inactive ingredients hypromellose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and lactose monohydrate. - INTELENCE® 200 mg tablets are available as white to off-white, biconvex, oblong tablets for oral administration. Each 200 mg tablet contains 200 mg of etravirine and the inactive ingredients hypromellose, silicified microcrystalline cellulose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate. ## Pharmacodynamics Effects on Electrocardiogram - In a randomized, double-blind, active, and placebo-controlled crossover study, 41 healthy subjects were administered INTELENCE® 200 mg twice daily, INTELENCE® 400 mg once daily, placebo, and moxifloxacin 400 mg. After 8 days of dosing, etravirine did not prolong the QT interval. The maximum mean (upper 1-sided 95% CI) baseline and placebo-adjusted QTcF were 0.6 ms (3.3 ms) for 200 mg twice daily and -1.0 ms (2.5 ms) for 400 mg once daily dosing regimens. ## Pharmacokinetics Pharmacokinetics in Adults - The pharmacokinetic properties of INTELENCE® were determined in healthy adult subjects and in treatment-experienced HIV-1-infected adult and pediatric subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1-infected subjects than in healthy subjects. - Note: The median protein binding adjusted EC50 for MT4 cells infected with HIV-1/IIIB in vitro equals 4 ng per mL. Absorption and Bioavailability - Following oral administration, etravirine was absorbed with a Tmax of about 2.5 to 4 hours. The absolute oral bioavailability of INTELENCE® is unknown. - In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH. Effects of Food on Oral Absorption - The systemic exposure (AUC) to etravirine was decreased by about 50% when INTELENCE® was administered under fasting conditions, as compared to when INTELENCE® was administered following a meal. Therefore, INTELENCE® should always be taken following a meal. Within the range of meals studied, the systemic exposures to etravirine were similar. The total caloric content of the various meals evaluated ranged from 345 kilocalories (17 grams fat) to 1160 kilocalories (70 grams fat). Distribution - Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha 1-acid glycoprotein (97.66% to 99.02%) in vitro. The distribution of etravirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans. Metabolism - In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes metabolism by CYP3A, CYP2C9, and CYP2C19 enzymes. The major metabolites, formed by methyl hydroxylation of the dimethylbenzonitrile moiety, were at least 90% less active than etravirine against wild-type HIV in cell culture. Elimination - After single dose oral administration of 800 mg 14C-etravirine, 93.7% and 1.2% of the administered dose of 14C-etravirine was recovered in the feces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The mean (± standard deviation) terminal elimination half-life of etravirine was about 41 (± 20) hours. Special Populations Hepatic Impairment - Etravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of INTELENCE® to subjects with normal hepatic function (16 subjects), mild hepatic impairment (Child-Pugh Class A, 8 subjects), and moderate hepatic impairment (Child-Pugh Class B, 8 subjects). The effect of severe hepatic impairment on the pharmacokinetics of etravirine has not been evaluated. Hepatitis B and/or Hepatitis C Virus Co-infection - Population pharmacokinetic analysis of the TMC125-C206 and TMC125-C216 trials showed reduced clearance for etravirine in HIV-1-infected subjects with hepatitis B and/or C virus co-infection. Based upon the safety profile of INTELENCE®, no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus. Renal Impairment - The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from a mass balance study with 14C-etravirine showed that less than 1.2% of the administered dose of etravirine is excreted in the urine as metabolites. No unchanged drug was detected in the urine. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis. Gender - No significant pharmacokinetic differences have been observed between males and females. Race - Population pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine. Geriatric Patients - Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different within the age range (18 to 77 years) evaluated. Pediatric Patients - The pharmacokinetics of etravirine in 101 treatment-experienced HIV-1-infected pediatric subjects, 6 years to less than 18 years of age and weighing at least 16 kg showed that the administered weight-based dosages (approximately 5.2 mg per kg twice daily up to the adult recommended doses) resulted in etravirine exposure comparable to that in adults receiving INTELENCE® 200 mg twice daily when administered at a dose corresponding to 5.2 mg per kg twice daily. The population pharmacokinetic estimates for etravirine AUC12h and C0h are summarized in the table below. - The pharmacokinetics of etravirine in pediatric subjects less than 6 years of age have not been established. Drug Interactions - Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of INTELENCE® with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of INTELENCE®. - Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-glycoprotein with INTELENCE® may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s). - Drug interaction studies were performed with INTELENCE® and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the AUC, Cmax, and Cmin values of etravirine are summarized in Table 5 (effect of other drugs on INTELENCE®). The effect of co-administration of INTELENCE® on the AUC, Cmax, and Cmin values of other drugs are summarized in Table 6 (effect of INTELENCE® on other drugs). ## Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis - Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50, 200 and 400 mg per kg were administered to mice and doses of 70, 200 and 600 mg per kg were administered to rats in the initial period of approximately 41 to 52 weeks. The high and middle doses were subsequently adjusted due to tolerability and reduced by 50% in mice and by 50 to 66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and incidences of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance of these liver tumor findings in mice to humans is not known. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg per day), with animal vs. human AUC ratios being 0.6-fold (mice) and 0.2–0.7-fold (rats). Mutagenesis - Etravirine tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocyte, and in vitro clastogenicity mouse lymphoma assay, tested in the absence and presence of a metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice. Impairment of Fertility - No effects on fertility and early embryonic development were observed when etravirine was tested in rats at maternal doses up to 500 mg per kg per day, resulting in systemic drug exposure up to the recommended human dose (400 mg per day). # Clinical Studies Treatment-Experienced Adult Subjects - The clinical efficacy of INTELENCE® is derived from the analyses of 48-week data from 2 ongoing, randomized, double-blinded, placebo-controlled, Phase 3 trials, TMC125-C206 and TMC125-C216 (DUET-1 and DUET-2). These trials are identical in design and the results below are pooled data from the two trials. - TMC125-C206 and TMC125-C216 are Phase 3 studies designed to evaluate the safety and antiretroviral activity of INTELENCE® in combination with a background regimen (BR) as compared to placebo in combination with a BR. Eligible subjects were treatment-experienced HIV-1-infected patients with plasma HIV-1 RNA greater than 5000 copies per mL while on an antiretroviral regimen for at least 8 weeks. In addition, subjects had 1 or more NNRTI resistance-associated mutations at screening or from prior genotypic analysis, and 3 or more of the following primary PI mutations at screening: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M. Randomization was stratified by the intended use of enfuvirtide (ENF) in the BR, previous use of darunavir/ritonavir (DRV/rtv), and screening viral load. Virologic response was defined as HIV-1 RNA less than 50 copies per mL at Week 48. - All study subjects received DRV/rtv as part of their BR, and at least 2 other investigator-selected antiretroviral drugs (N[t]RTIs with or without ENF). Of INTELENCE®-treated subjects, 25.5% used ENF for the first time (de novo) and 20.0% re-used ENF. Of placebo-treated subjects, 26.5% used de novo ENF and 20.4% re-used ENF. - In the pooled analysis for TMC125-C206 and TMC125-C216, demographics and baseline characteristics were balanced between the INTELENCE® arm and the placebo arm. Table 10 displays selected demographic and baseline disease characteristics of the subjects in the INTELENCE® and placebo arms. - Efficacy at Week 48 for subjects in the INTELENCE® and placebo arms for the pooled TMC125-C206 and TMC125-C216 study populations are shown in Table 11. - At Week 48, 70.8% of INTELENCE®-treated subjects achieved HIV-1 RNA less than 400 copies per mL as compared to 46.4% of placebo-treated subjects. The mean decrease in plasma HIV-1 RNA from baseline to Week 48 was -2.23 log10 copies per mL for INTELENCE®-treated subjects and -1.46 log10 copies per mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for INTELENCE®-treated subjects was 96 cells per mm3 and 68 cells per mm3 for placebo-treated subjects. - Of the study population who either re-used or did not use ENF, 57.4% of INTELENCE®-treated subjects and 31.7% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies per mL. Of the study population using ENF de novo, 67.3% of INTELENCE®-treated subjects and 57.2% of placebo-treated subjects achieved HIV-1 RNA less than 50 copies per mL. - Treatment-emergent CDC category C events occurred in 4% of INTELENCE®-treated subjects and 8.4% of placebo-treated subjects. - Study TMC125-C227 was a randomized, exploratory, active-controlled, open-label, Phase 2b trial. Eligible subjects were treatment-experienced, PI-naïve HIV-1-infected patients with genotypic evidence of NNRTI resistance at screening or from prior genotypic analysis. The virologic response was evaluated in 116 subjects who were randomized to INTELENCE® (59 subjects) or an investigator-selected PI (57 subjects), each given with 2 investigator-selected N(t)RTIs. INTELENCE®-treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to INTELENCE® as compared to the control PI-treated subjects. Treatment-Experienced Pediatric Subjects (6 years to less than 18 years of age) - TMC125-C213, a single-arm, Phase 2 trial evaluating the pharmacokinetics, safety, tolerability, and efficacy of INTELENCE® enrolled 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to less than 18 years of age and weighing at least 16 kg. Subjects eligible for this trial were on an antiretroviral regimen with confirmed plasma HIV-1 RNA of at least 500 copies per mL and viral susceptibility to INTELENCE® at screening. - The median baseline plasma HIV-1 RNA was 3.9 log10 copies per mL, and the median baseline CD4 cell count was 385 × 106 cells per mm3. - At Week 24, 52% of all pediatric subjects had HIV-1 RNA less than 50 copies per mL. The proportion of pediatric subjects with HIV-1 RNA less than 400 copies per mL was 67%. The mean CD4 cell count increase from baseline was 112 × 106 cells per mm3. # How Supplied - INTELENCE® 25 mg tablets are supplied as white to off-white, oval, scored tablets containing 25 mg of etravirine. Each tablet is debossed with "TMC" on one side. - INTELENCE® 100 mg tablets are supplied as white to off-white, oval tablets containing 100 mg of etravirine. Each tablet is debossed with "TMC125" on one side and "100" on the other side. - INTELENCE® 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets containing 200 mg of etravirine. Each tablet is debossed with "T200" on one side. - INTELENCE® tablets are packaged in bottles in the following configuration: - 25 mg tablets—bottles of 120 (NDC 59676-572-01). Each bottle contains 2 desiccant pouches. - 100 mg tablets—bottles of 120 (NDC 59676-570-01). Each bottle contains 3 desiccant pouches. - 200 mg tablets—bottles of 60 (NDC 59676-571-01). Each bottle contains 3 desiccant pouches. ## Storage - Store INTELENCE® tablets at 25°C (77°F); with excursions permitted to 15°to 30°C (59°to 86°F) [see USP controlled room temperature]. Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. Do not remove the desiccant pouches. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with INTELENCE® from your healthcare provider. A Patient Package Insert for INTELENCE® is available for patient information. - Patients should be informed that INTELENCE® is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using INTELENCE®. - Patients should be advised to avoid doing things that can spread HIV-1 infection to others. Patients should be advised to practice safe sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should also be advised to never re-use or share needles or other injection equipment, or share personal items that can have blood or body fluids on them, such as toothbrushes and razor blades. - Patients should be advised to take INTELENCE® following a meal twice a day as prescribed. The type of food does not affect the exposure to etravirine. - Patients should be instructed to swallow the INTELENCE® tablet(s) whole with a liquid such as water. Patients should be instructed not to chew the tablets. Patients who are unable to swallow the INTELENCE® tablet(s) whole may disperse the tablet(s) in a glass of water. The patient should be instructed to do the following: - Place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication, - Stir well until the water looks milky - If desired, add more water or alternatively orange juice or milk (patients should not place the tablets in orange juice or milk without first adding water). The use of grapefruit juice or warm (greater than 104°F; greater than 40°C) or carbonated beverages should be avoided. - Drink it immediately, - Rinse the glass several times with water, orange juice, or milk and completely swallow the rinse each time to make sure the patient takes the entire dose. INTELENCE® must always be used in combination with other antiretroviral drugs. Patients should not alter the dose of INTELENCE® or discontinue therapy with INTELENCE® without consulting their physician. - If the patient misses a dose of INTELENCE® within 6 hours of the time it is usually taken, the patient should take INTELENCE® following a meal as soon as possible, and then take the next dose of INTELENCE® at the regularly scheduled time. If a patient misses a dose of INTELENCE® by more than 6 hours of the time it is usually taken, the patient should not take the missed dose and simply resume the usual dosing schedule. Inform the patient that he or she should not take more or less than the prescribed dose of INTELENCE® at any one time. - INTELENCE® may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort. - Patients should be informed that severe and potentially life-threatening rash has been reported with INTELENCE®. Rash has been reported most commonly in the first 6 weeks of therapy. Patients should be advised to immediately contact their healthcare provider if they develop rash. Instruct patients to immediately stop taking INTELENCE® and seek medical attention if they develop a rash associated with any of the following symptoms as it may be a sign of a more serious reaction such as Stevens-Johnson syndrome, toxic epidermal necrolysis or severe hypersensitivity: fever, generally ill feeling, extreme tiredness, muscle or joint aches, blisters, oral lesions, eye inflammation, facial swelling, swelling of the eyes, lips, mouth, breathing difficulty, and/or signs and symptoms of liver problems (e.g., yellowing of your skin or whites of your eyes, dark or tea colored urine, pale colored stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching or sensitivity on your right side below your ribs). Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be ordered and appropriate therapy will be initiated. - Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy, including INTELENCE®, and that the cause and long-term health effects of these conditions are not known at this time. # Precautions with Alcohol - Alcohol-Etravirine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - INTELENCE # Look-Alike Drug Names There is limited information regarding Etravirine Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Etravirine
9b3f44693bfbd075d8e2d6015a46b7be73cc9a27	wikidoc	Etretinate	Etretinate # Overview Etretinate (trade name Tegison) is a medication developed by Hoffmann–La Roche that was approved by the FDA in 1986 to treat severe psoriasis. It is a second-generation retinoid. It was subsequently removed from the Canadian market in 1996 and the United States market in 1998 due to the high risk of birth defects. It remains on the market in Japan. # Properties Etretinate has a low therapeutic index and a long elimination half-life (t1/2) of 120 days, which make dosing difficult. Etretinate is an aromatic retinoid, and therefore highly lipophilic. It is stored and released from adipose tissue, so its effects can continue long after dosage stops. It is detectable in the plasma for up to three years following therapy. Etretinate has been replaced by acitretin, a safer metabolite of etretinate. # Precautions - Etretinate is a teratogen, and may cause birth defects long after use. Therefore, birth control is advised during therapy, and for at least three years after therapy has stopped. - Etretinate should be avoided in children, as it may interfere with bone growth. - If a patient has ever taken etretinate, he or she is not eligible to donate blood, due to the risk of birth defects. # Side effects - Hepatitis - Pseudotumor cerebri - Diffuse idiopathic skeletal Hyperostosis # History The drug was approved by the FDA in 1986 to treat severe psoriasis. It was subsequently removed from the Canadian market in 1996 and the United States market in 1998 due to the high risk of birth defects. In Japan, the drug remains on market branded Tigason. People may not donate blood for two years after ceasing to use the medication.	Etretinate Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Etretinate (trade name Tegison) is a medication developed by Hoffmann–La Roche that was approved by the FDA in 1986 to treat severe psoriasis. It is a second-generation retinoid. It was subsequently removed from the Canadian market in 1996 and the United States market in 1998 due to the high risk of birth defects. It remains on the market in Japan. # Properties Etretinate has a low therapeutic index and a long elimination half-life (t1/2) of 120 days, which make dosing difficult. Etretinate is an aromatic retinoid, and therefore highly lipophilic. It is stored and released from adipose tissue, so its effects can continue long after dosage stops. It is detectable in the plasma for up to three years following therapy. Etretinate has been replaced by acitretin, a safer metabolite of etretinate. # Precautions - Etretinate is a teratogen, and may cause birth defects long after use. Therefore, birth control is advised during therapy, and for at least three years after therapy has stopped. - Etretinate should be avoided in children, as it may interfere with bone growth. - If a patient has ever taken etretinate, he or she is not eligible to donate blood, due to the risk of birth defects.[1] # Side effects - Hepatitis - Pseudotumor cerebri - Diffuse idiopathic skeletal Hyperostosis # History The drug was approved by the FDA in 1986 to treat severe psoriasis. It was subsequently removed from the Canadian market in 1996 and the United States market in 1998 due to the high risk of birth defects.[2][3] In Japan, the drug remains on market branded Tigason.[4] People may not donate blood for two years after ceasing to use the medication.[4]	https://www.wikidoc.org/index.php/Etretinate
2a41c11fe190f9a75e86e25f553336e736d80e74	wikidoc	Eucalyptus	Eucalyptus Eucalyptus (From Greek, ευκάλυπτος = "Well covered") is a diverse genus of trees (and a few shrubs), the members of which dominate the tree flora of Australia. There are more than seven hundred species of Eucalyptus, mostly native to Australia, with a very small number found in adjacent parts of New Guinea and Indonesia and one as far north as the Philippine islands. Members of the genus can be found in almost every region of the Australian continent, because they have adapted to all of its climatic conditions; in fact no other continent is so characterised by a single genus of tree as Australia is by its eucalyptus. Many, but far from all, are known as gum trees in reference to the habit of many species to exude copious sap from any break in the bark (e.g. Scribbly Gum). # Description ## Size and habit A Eucalyptus may be mature as a low shrub or as a very large tree. There are three main habit and four size categories that species can be divided into. As a generalisation "forest trees" are single-stemmed and have a crown forming a minor proportion of the whole tree height. "Woodland trees" are single-stemmed although they may branch at a short distance above ground level. "Mallees" are multi-stemmed from ground level, usually less than 10 metres in height, often with the crown predominantly at the ends of the branchlets and individual plants may combine to form either an open or closed formation. Many mallee trees may be so low growing as to be considered a shrub. Apart from the forest tree, woodland tree, mallee and shrub habits two further tree forms are notable in Western Australia. One of these is the "mallet", which is a small to medium-sized tree, usually of steep branching habit, sometimes fluted at the base of the trunk and often with a conspicuously dense, terminal crown. It is the habit usually of mature healthy specimens of Eucalyptus occidentalis, E. astringens, E. spathulata, E. gardneri, E. dielsii, E. forrestiana, E. salubris, E. clivicola and E. ornata. The smooth bark of mallets often has a satiny sheen and may be white, cream, grey, green or copper. Another habit category used in Western Australia is the "marlock". This has been variously applied but Brooker & Hopper (2001) defined the term and restricted the use to describe the more or less pure stands of short, erect, thin-stemmed "trees" that do not produce lignotubers. These are easily seen and recognised in stands of E. platypus, E. vesiculosa and the unrealted E. stoatei. The marlock is distinguished from mallets which are taller and have a characteristic steep branching habit. The origin and use of the term "morrel" is somewhat obscure and appears to apply to trees of the western Australian wheatbelt and goldfields which have a long, straight trunk, completely rough barked. It is now used mainly for E. longicornis (Red Morell) and E. melanoxylon (Black Morrel). Tree sizes follow the convention of: - Small - to 10 metres in height - Medium sized - 10 to 30 metres in height - Tall - 30 to 60 metres in height - Very Tall - over 60 metres in height ## Leaves Nearly all Eucalyptus are evergreen but some tropical species lose their leaves at the end of the dry season. As in other members of the Myrtle family, Eucalyptus leaves are covered with oil glands. The copious oils produced are an important feature of the genus. The leaves on a mature Eucalyptus plant are commonly lanceolate, petiolate, apparently alternate and waxy or glossy green. In contrast the leaves of seedlings are frequently opposite, sessile and glaucous. However there are numerous exceptions to this pattern. Many species such as E. melanophloia and E. setosa retain the juvenile leaf form even when the plant is reproductively mature. Some species such as E. macrocarpa, E. rhodantha and E. crucis are sought after ornamentals due to this lifelong juvenile leaf form. A few species such as E. petraea, E. dundasii and E. lansdowneana have shiny green leaves throughout their life cycle. E. caesia exhibits the opposite pattern of leaf development to most Eucalyptus, with shiny green leaves in the seedling stage and dull, glaucous leaves in mature crowns. The contrast between juvenile and adult leaf phases is valuable in field identification. Four leaf phases are recognised in the development of a Eucalyptus plant - the ‘seedling’, ‘juvenile’, ‘intermediate’ and ‘adult’ phases. However there is no definite transitional point between the phases. The intermediate phase, when the largest leaves are often formed, links the juvenile and adult phases. Most species do not flower until adult foliage starts to appear; E. cinerea and E. perriniana are notable exceptions. In all except a few species the leaves form in pairs on opposite sides of a square stem, consecutive pairs being at right angles to each other (decussate). In some narrow-leaved species - for example E. oleosa - the seedling leaves after the second leaf pair are often clustered in a detectable spiral arrangement about a five sided stem. After the spiral phase, which may last from several to many nodes, the arrangement reverts to decussate by the absorption of some of the leaf bearing faces of the stem. In those species with opposite adult foliage the leaf pairs, which have been formed opposite at the stem apex, become separated at their bases by unequal elongation of the stem to produce the apparently alternate adult leaves. ## Flowers The most readily recognisable characteristics of Eucalyptus species are its distinctive flowers and fruit (capsule). Flowers have numerous fluffy stamens which may be white, cream, yellow, pink or red; in bud the stamens are enclosed in a cap known as an operculum which is composed of the fused sepals or petals or both. Thus flowers have no petals, decorating themselves instead with the many showy stamens. As the stamens expand the operculum is forced off, splitting away from the cup-like base of the flower; this is one of the features that that unites the genus. The name Eucalyptus, from the Greek words eu-, well, and kaluptos, cover, meaning "well-covered", describes the operculum. The woody fruits or capsules, known as gumnuts, are roughly cone-shaped and have valves at the end which open to release the seeds. Most species do not flower until adult foliage starts to appear; Eucalyptus cinerea and Eucalyptus perriniana are notable exceptions. ## Bark The appearance of Eucalyptus bark will vary with the age of the plant, the manner of bark shed, the length of the bark fibres, the degree of furrowing, the thickness, the hardness and the colour. All mature eucalypts put on an annual layer of bark, which contributes to the increasing diameter of the stems. In some species the outermost layer dies and is annually deciduous either in long strips (as in Eucalyptus sheathiana) or in variably sized flakes (Eucalyptus diversicolor, Eucalyptus cosmophylla or Eucalyptus cladocalyx). These are the gums or smooth-barked species. The gum bark may be dull, shiny or satiny (as in Eucalyptus ornata) or matt (Eucalyptus cosmophylla). In many species the dead bark is retained. Its outermost layer gradually fragments with weathering and sheds without altering the essentially rough barked nature of the trunks or stems - for example Eucalyptus marginata, Eucalyptus jacksonii, Eucalyptus obliqua and Eucalyptus porosa. Many species are ‘half-barks’ or ‘blackbutts’ in which the dead bark is retained in the lower half of the trunks or stems - for example, Eucalyptus brachycalyx, Eucalyptus ochrophloia and Eucalyptus occidentalis - or only in a thick, black accumulation at the base, as in Eucalyptus clelandii. Some species in this category - for example - Eucalyptus youngiana - the rough basal bark is very ribbony at the top, where it gives way to the smooth upper stems. The smooth upper bark of the half barks and that of the completely smooth-barked trees and mallees can produce remarkable colour and interest, for example Eucalyptus deglupta. ### Bark characteristics - Stringybark - consists of long-fibres and can be pulled off in long pieces. It is usually thick with a spongy texture. - Ironbark - is hard, rough and deeply furrowed. It is impregnated with dried kino (a sap exuded by the tree) which gives a dark red or even black colour. - Tessellated - bark is broken up into many distinct flakes. They are corkish and can flake off. - Box - has short fibres. Some also show tessellation. - Ribbon - this has the bark coming off in long thin pieces but still loosely attached in some places. They can be long ribbons, firmer strips or twisted curls. # Species and hybridism There are over 700 species of Eucalyptus; refer to the List of Eucalyptus species for a comprehensive list of species. It is believed that all eucalypts are related either closely or remotely. Some have diverged from the mainstream of the genus to the extent that they are quite isolated genetically and are able to be recognised by only a few relatively invariant characteristics. Most, however, may be regarded as belonging to large or small groups of related species, which are often in geographical contact with each other and between which gene exchange still occurs. In these situations many species will appear to grade into one another and intermediate forms are common. In other words, some species are relatively fixed genetically, as expressed in their morphology, while others have not diverged completely from their nearest relatives. Hybrid individuals have not always been recognised as such on first collection and some have been named as new species, such as E. chrysantha (E. preissiana × E. sepulcralis) and E. "rivalis" (E. marginata × E. megacarpa). Hybrid combinations are not particularly common in the field, but some other published species have been suggested to be hybrid combinations and are frequently seen in Australia. For example, E. erythrandra is believed to be E. angulosa × E. teraptera and due to its wide distribution is often referred to in texts. # Related genera A small genus of similar trees, Angophora, has also been known since the 18th century. In 1995 new evidence, largely genetic, indicated that some prominent Eucalyptus species were actually more closely related to Angophora than to the other eucalypts; they were split off into the new genus Corymbia. Although separate, the three groups are allied and it remains acceptable to refer to the members of all three genera Angophora, Corymbia and Eucalyptus as "eucalypts". The coolibah trees, referred to in Waltzing Matilda, are Eucalyptus E. coolabah and E. microtheca. # Tall timber Today, specimens of the Australian Mountain Ash, Eucalyptus regnans, are among the tallest trees in the world at up to 92 metres in height and the tallest of all flowering plants (Angiosperms); taller trees such as the Coast Redwood are all conifers (Gymnosperms). There is credible evidence however that at the time of European settlement of Australia some Mountain Ash were indeed the tallest plants in the world. # Tolerance Most eucalypts are not tolerant of frost, or only tolerate light frosts down to -3°C to -5°C; the hardiest, are the so-called Snow Gums such as Eucalyptus pauciflora which is capable of withstanding cold and frost down to about -20°C. Two sub-species, E. pauciflora subsp. niphophila and E. pauciflora subsp. debeuzevillei in particular are even hardier and can tolerate even quite severe winters. Several other species, especially from the high plateau and mountains of central Tasmania such as Eucalyptus coccifera, Eucalyptus subcrenulata, and Eucalyptus gunnii, have produced extreme cold hardy forms and it is seed procured from these genetically hardy strains that are planted for ornament in colder parts of the world. # Animal relationships An essential oil extracted from eucalyptus leaves contains compounds that are powerful natural disinfectants and which can be toxic in large quantities. Several marsupial herbivores, notably koalas and some possums, are relatively tolerant of it. The close correlation of these oils with other more potent toxins called formylated phloroglucinol compounds allows koalas and other marsupial species to make food choices based on the smell of the leaves. However, it is the formylated phloroglucinol compounds that are the most important factor in choice of leaves by koalas. Eucalyptus flowers produce a great abundance of nectar, providing food for many pollinators including insects, birds, bats and possums. Despite the fact that eucalyptus trees are well-defended from herbivores by their toxic essential oils they do have their share of insect pests, such as the Eucalyptus Longhorn Borer Beetle, Phoracantha semipunctuata, or the aphid-like psyllids known as "bell lerps," both of which have become established as pests throughout the world wherever eucalypts are cultivated. # Hazards Some species of Eucalyptus have a habit of dropping entire branches off as they grow. Eucalyptus forests are littered with dead branches. The Australian Ghost Gum Eucalyptus papuana is also termed the "widow maker," due to the high number of pioneer tree-felling workers who were killed by falling branches. Many people have been killed as they camped underneath the trees. It is thought the trees shed very large branches to conserve water during periods of drought. This may be the real reason behind the drop bear story told to children - the idea is to keep them away from being under dangerous branches. # Fire On warm days vapourised eucalyptus oil rises above the bush to create the characteristic distant blue haze of the Australian landscape. Eucalyptus oil is highly flammable (trees have been known to explode) and bush fires can travel easily through the oil-rich air of the tree crowns. The dead bark and fallen branches are also flammable. Eucalypts are well adapted for periodic fires, in fact most species are dependent on them for spread and regeneration. They do this via lignotubers, epicormic buds under the bark and from fire-germinated seeds sprouting in the ashes. Eucalypts originated between 35 and 50 million years ago, not long after Australia-New Guinea separated from Gondwana, their rise coinciding with an increase in fossil charcoal deposits (suggesting that fire was a factor even then), but they remained a minor component of the Tertiary rainforest until about 20 million years ago when the gradual drying of the continent and depletion of soil nutrients led to the development of a more open forest type, predominantly Casuarina and Acacia species. With the arrival of the first humans about 50 thousand years ago fires became much more frequent and the fire-loving eucalypts soon came to account for roughly 70% of Australian forest. Eucalypts regenerate quickly after fire. After the Canberra bushfires of 2003, hectares of imported species were killed, but in a matter of weeks the gum trees were putting out suckers and looking generally healthy. The two valuable timber trees, Alpine Ash E. delegatensis and Mountain Ash E. regnans, are killed by fire and only regenerate from seed. The same 2003 bushfire that had little impact on forests around Canberra resulted in thousands of hectares of dead ash forests. However, a small amount of ash survived and put out new suckers as well. There has been some debate as to whether to leave the stands, or attempt to harvest the mostly undamaged timber, which is increasingly recognised as a damaging practice. # Cultivation and uses - Eucalyptus have many uses which have made them economically important trees. Perhaps the Karri and the Yellow box varieties are the best known. Due to their fast growth the foremost benefit of these trees is the wood. They provide many desirable characteristics for use as ornament, timber, firewood and pulpwood. Fast growth also makes eucalypts suitable as windbreaks. Eucalypts draw a tremendous amount of water from the soil through the process of transpiration. They have been planted (or re-planted) in some places to lower the water table and reduce soil salination. Eucalypts have also been used as a way of reducing malaria by draining the soil in Algeria, Sicily and also in Europe and California. Drainage removes swamps which provide a habitat for mosquito larvae, but such drainage can also destroy ecologically productive areas. Eucalyptus oil is readily steam distilled from the leaves and can be used for cleaning, deodorising, and in very small quantities in food supplements; especially sweets, cough drops and decongestants. Eucalyptus oil has insect repellent properties (Jahn 1991 a, b; 1992), and is an active ingredient in some commercial mosquito repellents (Fradin & Day 2002). The nectar of some eucalyptus produces high quality monofloral honey. The ghost gum's leaves were used by Aborigines to catch fish. Soaking the leaves in water releases a mild tranquilliser which stuns fish temporarily. Eucalyptus is also used to make the digeridoo, a musical wind instrument made popular by the Aborigines of Australia. All parts of the eucalyptus may be used to make plant dyes that are substantive on protein fibres (silk and wool) simply by processing the plant part with water. Colours to be achieved range from yellow and orange through green, tan, chocolate and deep rust red. The material remaining after processing can be safely used as mulch. # History Although Eucalypts must have been seen by the very early European explorers and collectors, no botanical collections of them are known to have been made until 1770 when Joseph Banks and Daniel Solander arrived at Botany Bay with Captain James Cook. There they collected specimens of E. gummifera and later, near the Endeavour River in northern Queensland, they collected E. platyphylla; neither of these species was named as such at the time. In 1777, on Cook's third expedition, David Nelson collected a eucalypt on Bruny Island in southern Tasmania. This specimen was taken to the British Museum in London, and it was named Eucalyptus obliqua by the French botanist L'Héritier, who was working in London at the time. He coined the generic name from the Greek roots eu and calyptos, meaning "well" and "covered" in reference to the operculum of the flower bud. This organ protects the developing flower parts as the flower develops and is shed by the pressure of the emerging stamens at flowering. The name obliqua was derived from the Latin obliquus, meaning "oblique" which is the botanical term describing a leaf base where the two sides of the leaf blade are of unequal length and do not meet the petiole at the same place. In naming E. obliqua, L'Héritier caused to be perpetuated, most likely by accident, a feature common to all eucalypts - the operculum. In his choice of a specific name, he recognised not only the characteristic feature of E. obliqua, but one common to many other species as well. E. obliqua was published in 1788-89 and coincides with the date of the first official European settlement of Australia. Between 1788-89 and the turn of the nineteenth century several more species of Eucalyptus were named and published. Most of these were by the English botanist James Edward Smith and most were, as might be expected, trees of the Sydney region. These include the economically valuable E. pilularis, E. saligna and E. tereticornis. The nineteenth century saw the endeavours of several of the great botanists in Australian history, particularly Ferdinand von Mueller, whose work on eucalypts contributed greatly to the first comprehensive account of the genus in George Bentham's Flora Australiensis in 1867 - which today remains the only complete Australian flora. The account in Bentham is the most important early systematic treatment of the genus. Bentham divided the genus into five series whose distinctions were based on characteristics of the stamens, particularly the anthers (Mueller, 1879-84), elborated further by Joseph Henry Maiden (1903-33), and taken even further by William Faris Blakely (1934). By this time the anther system had become too complex to be workable and more recent systematic work has concentrated on the characteristics of buds, fruits, leaves and bark. The first endemic Western Australian Eucalyptus to be collected and subsequently named was the yate (E. cornuta) by the French botanist La Billardiére, who collected in what is now the Esperance area in 1792. # Plantation and ecological problems Eucalyptus was first introduced to the rest of the world by Sir Joseph Banks, botanist, on the Cook expedition in 1770. They have subsequently been introduced to many parts of the world, notably California, Brazil, Ecuador, Colombia, Ethiopia, Morocco, Portugal, South Africa, Israel, Galicia and Chile. In Spain they have been planted in pulpwood plantations, replacing native oak woodland. Eucalyptus are the basis for several industries, such as sawmilling, pulp, charcoal and others. Several species have become invasive and are causing major problems for local ecosystems. ## California In the 1850s many Australians traveled to California to take part in the California Gold Rush. Much of California has a similar climate to parts of Australia and some people got the idea of introducing eucalypts. By the early 1900s thousands of acres of eucalypts were planted with the encouragement of the state government. It was hoped that they would provide a renewable source of timber for construction and furniture making. However, this did not happen, partly because the trees were cut when they were too young and partly because the Americans did not know how to process the cut trees to prevent the wood from twisting and splitting. One way in which the eucalyptus, mainly the blue gum E. globulus, proved valuable in California was in providing windbreaks for highways, orange groves, and other farms in the mostly treeless central part of the state. They are also admired as shade and ornamental trees in many cities and gardens. Eucalyptus forests in California have been criticized because they compete with native plants and do not support native animals. Fire is also a problem. The 1991 Oakland Hills firestorm which destroyed almost 3,000 homes and killed 25 people was partly fueled by large numbers of eucalypts in the area close to the houses. In some parts of California eucalypt forests are being removed and native trees and plants restored. Individuals have also illegally destroyed some trees and are suspected of introducing insect pests from Australia which attack the trees. ## Brazil In 1910 Eucalyptus was introduced to Brazil for timber substitution and the vegetal coal industry. It has adpated very well to the local environmental conditions and today there are around 5 million hectares planted. The wood produced by the tree is highly appreciated by the charcoal and pulp and paper industries. The short rotation allows a larger wood production and supply wood for several other activities, helping to preserve the native forests from logging. When well managed the plantations are sustainable and the soil can sustain endless replantations. Eucalyptus plantations are also used as wind breaks. ## Ethiopia This species was introduced to Ethiopia in either 1894 or 1895, either by Emperor Menelik II's French advisor Mondon-Vidailhet or the Englishman Captain O'Brian. Due to massive deforestation around his new capital city Addis Ababa caused by a growing appetite for fire wood, Emperor Menelik II endorsed its planting around that city; according to Richard R.K. Pankhurst, "The great advantage of the eucalypts was that they were fast growing, required little attention and when cut down grew up again from the roots; it could be harvested every ten years. The tree proved successful from the onset". Plantations of eucalypts spread from the capital to other growing urban centers such as Debre Marqos; Pankhurst reports that the most common species found in Addis Ababa in the mid-1960s was E. globulus, although he also found E. melliodora and E. rostrata in significant numbers. David Buxton, writing of central Ethiopia in the mid-1940s, observed that eucalyptus trees "have become an integral -- and a pleasing -- element in the Shoan landscape and has largely displaced the slow-growing native 'cedar' or juniper." Popular opposition soon developed that in 1913 a proclamation was issued ordering a partial destruction of all standing trees, and their replacement with mulberry trees. "The proclamation," Pankhurst notes, "however remained a dead letter; there is no evidence of eucalypts being uprooted, still less of mulberry trees being planted." The eucalypt remains a defining feature of Addis Ababa. # Photo gallery - Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). - Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). - Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). - A eucalyptus tree with the sun shining through its branches. A eucalyptus tree with the sun shining through its branches. - Eucalyptus bridgesiana (Apple box) on Red Hill, Australian Capital Territory. Eucalyptus bridgesiana (Apple box) on Red Hill, Australian Capital Territory. - Eucalyptus gunnii planted in southern England. The lower part of the trunk is covered in ivy. Eucalyptus gunnii planted in southern England. The lower part of the trunk is covered in ivy. - Eucalyptus cinerea x pulverulenta - National Botanical Gardens Canberra Eucalyptus cinerea x pulverulenta - National Botanical Gardens Canberra - Eucalyptus Pink Waxy Scale Insects Eucalyptus Pink Waxy Scale Insects - Eucalyptus grandis. Province of Buenos Aires, Argentina. Eucalyptus grandis. Province of Buenos Aires, Argentina. - Eucalyptus plantation in Galicia in Northwest Spain Eucalyptus plantation in Galicia in Northwest Spain - Eucalyptus rubida (Candlebark gum) in Burra, New South Wales. Eucalyptus rubida (Candlebark gum) in Burra, New South Wales. - This tree in Heathcote National Park has a serious problem. This tree in Heathcote National Park has a serious problem. # Notes - ↑ Jump up to: 1.0 1.1 1.2 1.3 Brooker & Kleinig (2001) - ↑ J.E. Hickey, P. Kostoglou, G.J. Sargison. "Tasmania's Tallest Trees" (PDF). Forestry Tasmania. Retrieved 2005-01-27. Unknown parameter \|media= ignored (help)CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Santos, Robert L. (1997). "Section Three: Problems, Cares, Economics, and Species". The Eucalyptus of California. California State University. - ↑ "Eucalytus Roulette (con't)". Robert Sward: Poet, Novelist and Workshop Leader. - ↑ Mrs. M. Grieve. "A Modern Herbal:Eucalyptus". Retrieved 2005-01-27. - ↑ Santos, Robert L (1997). "Section Two: Physical Properties and Uses". The Eucalyptus of California. California State University. - ↑ Santos, Robert L. (1997). "Seeds of Good or Seeds of Evil?". The Eucalyptus of California. California State University. - ↑ Williams, Ted (2002). "America's Largest Weed". Audubon Magazine. Unknown parameter \|month= ignored (help) - ↑ Henter, Heather (2005). "Tree Wars: The Secret Life of Eucalyptus". Alumni. University of California, San Diego. Unknown parameter \|month= ignored (help) - ↑ Pankhurst p. 246 - ↑ David Buxton, Travels in Ethiopia, second edition (London: Benn, 1957), p. 48 - ↑ Pankhurst p. 247	Eucalyptus Template:Otheruses4 Eucalyptus (From Greek, ευκάλυπτος = "Well covered") is a diverse genus of trees (and a few shrubs), the members of which dominate the tree flora of Australia. There are more than seven hundred species of Eucalyptus, mostly native to Australia, with a very small number found in adjacent parts of New Guinea and Indonesia and one as far north as the Philippine islands. Members of the genus can be found in almost every region of the Australian continent, because they have adapted to all of its climatic conditions; in fact no other continent is so characterised by a single genus of tree as Australia is by its eucalyptus. Many, but far from all, are known as gum trees in reference to the habit of many species to exude copious sap from any break in the bark (e.g. Scribbly Gum). # Description ## Size and habit A Eucalyptus may be mature as a low shrub or as a very large tree. There are three main habit and four size categories that species can be divided into. As a generalisation "forest trees" are single-stemmed and have a crown forming a minor proportion of the whole tree height. "Woodland trees" are single-stemmed although they may branch at a short distance above ground level. "Mallees" are multi-stemmed from ground level, usually less than 10 metres in height, often with the crown predominantly at the ends of the branchlets and individual plants may combine to form either an open or closed formation. Many mallee trees may be so low growing as to be considered a shrub. Apart from the forest tree, woodland tree, mallee and shrub habits two further tree forms are notable in Western Australia. One of these is the "mallet", which is a small to medium-sized tree, usually of steep branching habit, sometimes fluted at the base of the trunk and often with a conspicuously dense, terminal crown. It is the habit usually of mature healthy specimens of Eucalyptus occidentalis, E. astringens, E. spathulata, E. gardneri, E. dielsii, E. forrestiana, E. salubris, E. clivicola and E. ornata. The smooth bark of mallets often has a satiny sheen and may be white, cream, grey, green or copper. Another habit category used in Western Australia is the "marlock". This has been variously applied but Brooker & Hopper (2001) defined the term and restricted the use to describe the more or less pure stands of short, erect, thin-stemmed "trees" that do not produce lignotubers. These are easily seen and recognised in stands of E. platypus, E. vesiculosa and the unrealted E. stoatei. The marlock is distinguished from mallets which are taller and have a characteristic steep branching habit. The origin and use of the term "morrel" is somewhat obscure and appears to apply to trees of the western Australian wheatbelt and goldfields which have a long, straight trunk, completely rough barked. It is now used mainly for E. longicornis (Red Morell) and E. melanoxylon (Black Morrel). Tree sizes follow the convention of: - Small - to 10 metres in height - Medium sized - 10 to 30 metres in height - Tall - 30 to 60 metres in height - Very Tall - over 60 metres in height ## Leaves Nearly all Eucalyptus are evergreen but some tropical species lose their leaves at the end of the dry season. As in other members of the Myrtle family, Eucalyptus leaves are covered with oil glands. The copious oils produced are an important feature of the genus. The leaves on a mature Eucalyptus plant are commonly lanceolate, petiolate, apparently alternate and waxy or glossy green. In contrast the leaves of seedlings are frequently opposite, sessile and glaucous. However there are numerous exceptions to this pattern. Many species such as E. melanophloia and E. setosa retain the juvenile leaf form even when the plant is reproductively mature. Some species such as E. macrocarpa, E. rhodantha and E. crucis are sought after ornamentals due to this lifelong juvenile leaf form. A few species such as E. petraea, E. dundasii and E. lansdowneana have shiny green leaves throughout their life cycle. E. caesia exhibits the opposite pattern of leaf development to most Eucalyptus, with shiny green leaves in the seedling stage and dull, glaucous leaves in mature crowns. The contrast between juvenile and adult leaf phases is valuable in field identification. Four leaf phases are recognised in the development of a Eucalyptus plant - the ‘seedling’, ‘juvenile’, ‘intermediate’ and ‘adult’ phases. However there is no definite transitional point between the phases. The intermediate phase, when the largest leaves are often formed, links the juvenile and adult phases.[1] Most species do not flower until adult foliage starts to appear; E. cinerea and E. perriniana are notable exceptions. In all except a few species the leaves form in pairs on opposite sides of a square stem, consecutive pairs being at right angles to each other (decussate). In some narrow-leaved species - for example E. oleosa - the seedling leaves after the second leaf pair are often clustered in a detectable spiral arrangement about a five sided stem. After the spiral phase, which may last from several to many nodes, the arrangement reverts to decussate by the absorption of some of the leaf bearing faces of the stem. In those species with opposite adult foliage the leaf pairs, which have been formed opposite at the stem apex, become separated at their bases by unequal elongation of the stem to produce the apparently alternate adult leaves. ## Flowers The most readily recognisable characteristics of Eucalyptus species are its distinctive flowers and fruit (capsule). Flowers have numerous fluffy stamens which may be white, cream, yellow, pink or red; in bud the stamens are enclosed in a cap known as an operculum which is composed of the fused sepals or petals or both. Thus flowers have no petals, decorating themselves instead with the many showy stamens. As the stamens expand the operculum is forced off, splitting away from the cup-like base of the flower; this is one of the features that that unites the genus. The name Eucalyptus, from the Greek words eu-, well, and kaluptos, cover, meaning "well-covered", describes the operculum. The woody fruits or capsules, known as gumnuts, are roughly cone-shaped and have valves at the end which open to release the seeds. Most species do not flower until adult foliage starts to appear; Eucalyptus cinerea and Eucalyptus perriniana are notable exceptions. ## Bark The appearance of Eucalyptus bark will vary with the age of the plant, the manner of bark shed, the length of the bark fibres, the degree of furrowing, the thickness, the hardness and the colour. All mature eucalypts put on an annual layer of bark, which contributes to the increasing diameter of the stems. In some species the outermost layer dies and is annually deciduous either in long strips (as in Eucalyptus sheathiana) or in variably sized flakes (Eucalyptus diversicolor, Eucalyptus cosmophylla or Eucalyptus cladocalyx). These are the gums or smooth-barked species. The gum bark may be dull, shiny or satiny (as in Eucalyptus ornata) or matt (Eucalyptus cosmophylla). In many species the dead bark is retained. Its outermost layer gradually fragments with weathering and sheds without altering the essentially rough barked nature of the trunks or stems - for example Eucalyptus marginata, Eucalyptus jacksonii, Eucalyptus obliqua and Eucalyptus porosa. Many species are ‘half-barks’ or ‘blackbutts’ in which the dead bark is retained in the lower half of the trunks or stems - for example, Eucalyptus brachycalyx, Eucalyptus ochrophloia and Eucalyptus occidentalis - or only in a thick, black accumulation at the base, as in Eucalyptus clelandii. Some species in this category - for example - Eucalyptus youngiana - the rough basal bark is very ribbony at the top, where it gives way to the smooth upper stems. The smooth upper bark of the half barks and that of the completely smooth-barked trees and mallees can produce remarkable colour and interest, for example Eucalyptus deglupta.[1] ### Bark characteristics - Stringybark - consists of long-fibres and can be pulled off in long pieces. It is usually thick with a spongy texture. - Ironbark - is hard, rough and deeply furrowed. It is impregnated with dried kino (a sap exuded by the tree) which gives a dark red or even black colour. - Tessellated - bark is broken up into many distinct flakes. They are corkish and can flake off. - Box - has short fibres. Some also show tessellation. - Ribbon - this has the bark coming off in long thin pieces but still loosely attached in some places. They can be long ribbons, firmer strips or twisted curls. # Species and hybridism There are over 700 species of Eucalyptus; refer to the List of Eucalyptus species for a comprehensive list of species. It is believed that all eucalypts are related either closely or remotely. Some have diverged from the mainstream of the genus to the extent that they are quite isolated genetically and are able to be recognised by only a few relatively invariant characteristics. Most, however, may be regarded as belonging to large or small groups of related species, which are often in geographical contact with each other and between which gene exchange still occurs. In these situations many species will appear to grade into one another and intermediate forms are common. In other words, some species are relatively fixed genetically, as expressed in their morphology, while others have not diverged completely from their nearest relatives. Hybrid individuals have not always been recognised as such on first collection and some have been named as new species, such as E. chrysantha (E. preissiana × E. sepulcralis) and E. "rivalis" (E. marginata × E. megacarpa). Hybrid combinations are not particularly common in the field, but some other published species have been suggested to be hybrid combinations and are frequently seen in Australia. For example, E. erythrandra is believed to be E. angulosa × E. teraptera and due to its wide distribution is often referred to in texts.[1] # Related genera A small genus of similar trees, Angophora, has also been known since the 18th century. In 1995 new evidence, largely genetic, indicated that some prominent Eucalyptus species were actually more closely related to Angophora than to the other eucalypts; they were split off into the new genus Corymbia. Although separate, the three groups are allied and it remains acceptable to refer to the members of all three genera Angophora, Corymbia and Eucalyptus as "eucalypts". The coolibah trees, referred to in Waltzing Matilda, are Eucalyptus E. coolabah and E. microtheca. # Tall timber Today, specimens of the Australian Mountain Ash, Eucalyptus regnans, are among the tallest trees in the world at up to 92 metres in height [2] and the tallest of all flowering plants (Angiosperms); taller trees such as the Coast Redwood are all conifers (Gymnosperms). There is credible evidence however that at the time of European settlement of Australia some Mountain Ash were indeed the tallest plants in the world. # Tolerance Most eucalypts are not tolerant of frost, or only tolerate light frosts down to -3°C to -5°C; the hardiest, are the so-called Snow Gums such as Eucalyptus pauciflora which is capable of withstanding cold and frost down to about -20°C. Two sub-species, E. pauciflora subsp. niphophila and E. pauciflora subsp. debeuzevillei in particular are even hardier and can tolerate even quite severe winters. Several other species, especially from the high plateau and mountains of central Tasmania such as Eucalyptus coccifera, Eucalyptus subcrenulata, and Eucalyptus gunnii, have produced extreme cold hardy forms and it is seed procured from these genetically hardy strains that are planted for ornament in colder parts of the world. # Animal relationships An essential oil extracted from eucalyptus leaves contains compounds that are powerful natural disinfectants and which can be toxic in large quantities. Several marsupial herbivores, notably koalas and some possums, are relatively tolerant of it. The close correlation of these oils with other more potent toxins called formylated phloroglucinol compounds allows koalas and other marsupial species to make food choices based on the smell of the leaves. However, it is the formylated phloroglucinol compounds that are the most important factor in choice of leaves by koalas. Eucalyptus flowers produce a great abundance of nectar, providing food for many pollinators including insects, birds, bats and possums. Despite the fact that eucalyptus trees are well-defended from herbivores by their toxic essential oils they do have their share of insect pests, such as the Eucalyptus Longhorn Borer Beetle, Phoracantha semipunctuata, or the aphid-like psyllids known as "bell lerps," both of which have become established as pests throughout the world wherever eucalypts are cultivated. # Hazards Some species of Eucalyptus have a habit of dropping entire branches off as they grow. Eucalyptus forests are littered with dead branches. The Australian Ghost Gum Eucalyptus papuana is also termed the "widow maker," due to the high number of pioneer tree-felling workers who were killed by falling branches. Many people have been killed as they camped underneath the trees. It is thought the trees shed very large branches to conserve water during periods of drought. This may be the real reason behind the drop bear story told to children - the idea is to keep them away from being under dangerous branches. # Fire On warm days vapourised eucalyptus oil rises above the bush to create the characteristic distant blue haze of the Australian landscape. Eucalyptus oil is highly flammable (trees have been known to explode[3][4]) and bush fires can travel easily through the oil-rich air of the tree crowns. The dead bark and fallen branches are also flammable. Eucalypts are well adapted for periodic fires, in fact most species are dependent on them for spread and regeneration.[citation needed] They do this via lignotubers, epicormic buds under the bark and from fire-germinated seeds sprouting in the ashes.[citation needed] Eucalypts originated between 35 and 50 million years ago, not long after Australia-New Guinea separated from Gondwana, their rise coinciding with an increase in fossil charcoal deposits (suggesting that fire was a factor even then), but they remained a minor component of the Tertiary rainforest until about 20 million years ago when the gradual drying of the continent and depletion of soil nutrients led to the development of a more open forest type, predominantly Casuarina and Acacia species. With the arrival of the first humans about 50 thousand years ago fires became much more frequent and the fire-loving eucalypts soon came to account for roughly 70% of Australian forest. Eucalypts regenerate quickly after fire. After the Canberra bushfires of 2003, hectares of imported species were killed, but in a matter of weeks the gum trees were putting out suckers and looking generally healthy.[citation needed] The two valuable timber trees, Alpine Ash E. delegatensis and Mountain Ash E. regnans, are killed by fire and only regenerate from seed. The same 2003 bushfire that had little impact on forests around Canberra resulted in thousands of hectares of dead ash forests. However, a small amount of ash survived and put out new suckers as well. There has been some debate as to whether to leave the stands, or attempt to harvest the mostly undamaged timber, which is increasingly recognised as a damaging practice. # Cultivation and uses - Eucalyptus have many uses which have made them economically important trees. Perhaps the Karri and the Yellow box varieties are the best known. Due to their fast growth the foremost benefit of these trees is the wood. They provide many desirable characteristics for use as ornament, timber, firewood and pulpwood. Fast growth also makes eucalypts suitable as windbreaks. Eucalypts draw a tremendous amount of water from the soil through the process of transpiration. They have been planted (or re-planted) in some places to lower the water table and reduce soil salination. Eucalypts have also been used as a way of reducing malaria by draining the soil in Algeria, Sicily[5] and also in Europe and California[6]. Drainage removes swamps which provide a habitat for mosquito larvae, but such drainage can also destroy ecologically productive areas. Eucalyptus oil is readily steam distilled from the leaves and can be used for cleaning, deodorising, and in very small quantities in food supplements; especially sweets, cough drops and decongestants. Eucalyptus oil has insect repellent properties (Jahn 1991 a, b; 1992), and is an active ingredient in some commercial mosquito repellents (Fradin & Day 2002). The nectar of some eucalyptus produces high quality monofloral honey. The ghost gum's leaves were used by Aborigines to catch fish. Soaking the leaves in water releases a mild tranquilliser which stuns fish temporarily. Eucalyptus is also used to make the digeridoo, a musical wind instrument made popular by the Aborigines of Australia. All parts of the eucalyptus may be used to make plant dyes that are substantive on protein fibres (silk and wool) simply by processing the plant part with water[citation needed]. Colours to be achieved range from yellow and orange through green, tan, chocolate and deep rust red. The material remaining after processing can be safely used as mulch[citation needed]. # History Although Eucalypts must have been seen by the very early European explorers and collectors, no botanical collections of them are known to have been made until 1770 when Joseph Banks and Daniel Solander arrived at Botany Bay with Captain James Cook. There they collected specimens of E. gummifera and later, near the Endeavour River in northern Queensland, they collected E. platyphylla; neither of these species was named as such at the time. In 1777, on Cook's third expedition, David Nelson collected a eucalypt on Bruny Island in southern Tasmania. This specimen was taken to the British Museum in London, and it was named Eucalyptus obliqua by the French botanist L'Héritier, who was working in London at the time. He coined the generic name from the Greek roots eu and calyptos, meaning "well" and "covered" in reference to the operculum of the flower bud. This organ protects the developing flower parts as the flower develops and is shed by the pressure of the emerging stamens at flowering. The name obliqua was derived from the Latin obliquus, meaning "oblique" which is the botanical term describing a leaf base where the two sides of the leaf blade are of unequal length and do not meet the petiole at the same place. In naming E. obliqua, L'Héritier caused to be perpetuated, most likely by accident, a feature common to all eucalypts - the operculum. In his choice of a specific name, he recognised not only the characteristic feature of E. obliqua, but one common to many other species as well. E. obliqua was published in 1788-89 and coincides with the date of the first official European settlement of Australia. Between 1788-89 and the turn of the nineteenth century several more species of Eucalyptus were named and published. Most of these were by the English botanist James Edward Smith and most were, as might be expected, trees of the Sydney region. These include the economically valuable E. pilularis, E. saligna and E. tereticornis. The nineteenth century saw the endeavours of several of the great botanists in Australian history, particularly Ferdinand von Mueller, whose work on eucalypts contributed greatly to the first comprehensive account of the genus in George Bentham's Flora Australiensis in 1867 - which today remains the only complete Australian flora. The account in Bentham is the most important early systematic treatment of the genus. Bentham divided the genus into five series whose distinctions were based on characteristics of the stamens, particularly the anthers (Mueller, 1879-84), elborated further by Joseph Henry Maiden (1903-33), and taken even further by William Faris Blakely (1934). By this time the anther system had become too complex to be workable and more recent systematic work has concentrated on the characteristics of buds, fruits, leaves and bark. The first endemic Western Australian Eucalyptus to be collected and subsequently named was the yate (E. cornuta) by the French botanist La Billardiére, who collected in what is now the Esperance area in 1792.[1] # Plantation and ecological problems Eucalyptus was first introduced to the rest of the world by Sir Joseph Banks, botanist, on the Cook expedition in 1770. They have subsequently been introduced to many parts of the world, notably California, Brazil, Ecuador, Colombia, Ethiopia, Morocco, Portugal, South Africa, Israel, Galicia and Chile. In Spain they have been planted in pulpwood plantations, replacing native oak woodland. Eucalyptus are the basis for several industries, such as sawmilling, pulp, charcoal and others. Several species have become invasive and are causing major problems for local ecosystems. ## California In the 1850s many Australians traveled to California to take part in the California Gold Rush. Much of California has a similar climate to parts of Australia and some people got the idea of introducing eucalypts. By the early 1900s thousands of acres of eucalypts were planted with the encouragement of the state government. It was hoped that they would provide a renewable source of timber for construction and furniture making. However, this did not happen, partly because the trees were cut when they were too young and partly because the Americans did not know how to process the cut trees to prevent the wood from twisting and splitting.[7] One way in which the eucalyptus, mainly the blue gum E. globulus, proved valuable in California was in providing windbreaks for highways, orange groves, and other farms in the mostly treeless central part of the state. They are also admired as shade and ornamental trees in many cities and gardens. Eucalyptus forests in California have been criticized because they compete with native plants and do not support native animals. Fire is also a problem. The 1991 Oakland Hills firestorm which destroyed almost 3,000 homes and killed 25 people was partly fueled by large numbers of eucalypts in the area close to the houses.[8] In some parts of California eucalypt forests are being removed and native trees and plants restored. Individuals have also illegally destroyed some trees and are suspected of introducing insect pests from Australia which attack the trees.[9] ## Brazil In 1910 Eucalyptus was introduced to Brazil for timber substitution and the vegetal coal industry. It has adpated very well to the local environmental conditions[citation needed] and today there are around 5 million hectares planted. The wood produced by the tree is highly appreciated by the charcoal and pulp and paper industries. The short rotation allows a larger wood production and supply wood for several other activities, helping to preserve the native forests from logging. When well managed the plantations are sustainable and the soil can sustain endless replantations. Eucalyptus plantations are also used as wind breaks. ## Ethiopia This species was introduced to Ethiopia in either 1894 or 1895, either by Emperor Menelik II's French advisor Mondon-Vidailhet or the Englishman Captain O'Brian. Due to massive deforestation around his new capital city Addis Ababa caused by a growing appetite for fire wood, Emperor Menelik II endorsed its planting around that city; according to Richard R.K. Pankhurst, "The great advantage of the eucalypts was that they were fast growing, required little attention and when cut down grew up again from the roots; it could be harvested every ten years. The tree proved successful from the onset".[10] Plantations of eucalypts spread from the capital to other growing urban centers such as Debre Marqos; Pankhurst reports that the most common species found in Addis Ababa in the mid-1960s was E. globulus, although he also found E. melliodora and E. rostrata in significant numbers. David Buxton, writing of central Ethiopia in the mid-1940s, observed that eucalyptus trees "have become an integral -- and a pleasing -- element in the Shoan landscape and has largely displaced the slow-growing native 'cedar' or juniper."[11] Popular opposition soon developed that in 1913 a proclamation was issued ordering a partial destruction of all standing trees, and their replacement with mulberry trees. "The proclamation," Pankhurst notes, "however remained a dead letter; there is no evidence of eucalypts being uprooted, still less of mulberry trees being planted."[12] The eucalypt remains a defining feature of Addis Ababa. # Photo gallery - Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). - Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). - Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). Eucalyptus forest in East Gippsland, Victoria. Mostly Eucalyptus albens (white box). - A eucalyptus tree with the sun shining through its branches. A eucalyptus tree with the sun shining through its branches. - Eucalyptus bridgesiana (Apple box) on Red Hill, Australian Capital Territory. Eucalyptus bridgesiana (Apple box) on Red Hill, Australian Capital Territory. - Eucalyptus gunnii planted in southern England. The lower part of the trunk is covered in ivy. Eucalyptus gunnii planted in southern England. The lower part of the trunk is covered in ivy. - Eucalyptus cinerea x pulverulenta - National Botanical Gardens Canberra Eucalyptus cinerea x pulverulenta - National Botanical Gardens Canberra - Eucalyptus Pink Waxy Scale Insects Eucalyptus Pink Waxy Scale Insects - Eucalyptus grandis. Province of Buenos Aires, Argentina. Eucalyptus grandis. Province of Buenos Aires, Argentina. - Eucalyptus plantation in Galicia in Northwest Spain Eucalyptus plantation in Galicia in Northwest Spain - Eucalyptus rubida (Candlebark gum) in Burra, New South Wales. Eucalyptus rubida (Candlebark gum) in Burra, New South Wales. - This tree in Heathcote National Park has a serious problem. This tree in Heathcote National Park has a serious problem. # Notes - ↑ Jump up to: 1.0 1.1 1.2 1.3 Brooker & Kleinig (2001) - ↑ J.E. Hickey, P. Kostoglou, G.J. Sargison. "Tasmania's Tallest Trees" (PDF). Forestry Tasmania. Retrieved 2005-01-27. Unknown parameter \|media= ignored (help)CS1 maint: Multiple names: authors list (link) .mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} - ↑ Santos, Robert L. (1997). "Section Three: Problems, Cares, Economics, and Species". The Eucalyptus of California. California State University. - ↑ "Eucalytus Roulette (con't)". Robert Sward: Poet, Novelist and Workshop Leader. - ↑ Mrs. M. Grieve. "A Modern Herbal:Eucalyptus". Retrieved 2005-01-27. - ↑ Santos, Robert L (1997). "Section Two: Physical Properties and Uses". The Eucalyptus of California. California State University. - ↑ Santos, Robert L. (1997). "Seeds of Good or Seeds of Evil?". The Eucalyptus of California. California State University. - ↑ Williams, Ted (2002). "America's Largest Weed". Audubon Magazine. Unknown parameter \|month= ignored (help) - ↑ Henter, Heather (2005). "Tree Wars: The Secret Life of Eucalyptus". Alumni. University of California, San Diego. Unknown parameter \|month= ignored (help) - ↑ Pankhurst p. 246 - ↑ David Buxton, Travels in Ethiopia, second edition (London: Benn, 1957), p. 48 - ↑ Pankhurst p. 247	https://www.wikidoc.org/index.php/Eucalyptus
e0eefb19ea2bf8b0228ba3333649db2e1683ce8f	wikidoc	Euglenozoa	Euglenozoa The Euglenozoa are a large group of flagellate protozoa. They include a variety of common free-living species, as well as a few important parasites, some of which infect humans. There are two main subgroups, the euglenids and kinetoplastids. Euglenozoa are unicellular, mostly around 15-40 µm in size, although some euglenids get up to 500 µm long. Most euglenozoa have two flagella, which are inserted parallel to one another in an apical or subapical pocket. In some these are associated with a cytostome or mouth, used to ingest bacteria or other small organisms. This is supported by one of three sets of microtubules that arise from the flagellar bases; the other two support the dorsal and ventral surfaces of the cell. Some other euglenozoa feed through the absorption, and many euglenids possess chloroplasts and so obtain energy through photosynthesis. These chloroplasts are surrounded by three membranes and contain chlorophylls a and b, along with other pigments, so are probably derived from a captured green alga. Reproduction occurs exclusively through cell division. During mitosis, the nuclear membrane remains intact, and the spindle microtubules form inside of it. The group is characterized by the ultrastructure of the flagella. In addition to the normal supporting microtubules or axoneme, each contains a rod (called paraxonemal), which has a tubular structure in one flagellum and a latticed structure in the other. Based on this, two smaller groups have been included here: the diplonemids and Postgaardi. The euglenozoa are generally accepted as monophyletic. They are related to Percolozoa; the two share mitochondria with disc-shaped cristae, which only occurs in a few other groups. Both probably belong to a larger group of eukaryotes called the excavates.	Euglenozoa The Euglenozoa are a large group of flagellate protozoa. They include a variety of common free-living species, as well as a few important parasites, some of which infect humans. There are two main subgroups, the euglenids and kinetoplastids. Euglenozoa are unicellular, mostly around 15-40 µm in size, although some euglenids get up to 500 µm long. Most euglenozoa have two flagella, which are inserted parallel to one another in an apical or subapical pocket. In some these are associated with a cytostome or mouth, used to ingest bacteria or other small organisms. This is supported by one of three sets of microtubules that arise from the flagellar bases; the other two support the dorsal and ventral surfaces of the cell.[2] Some other euglenozoa feed through the absorption, and many euglenids possess chloroplasts and so obtain energy through photosynthesis. These chloroplasts are surrounded by three membranes and contain chlorophylls a and b, along with other pigments[1], so are probably derived from a captured green alga. Reproduction occurs exclusively through cell division. During mitosis, the nuclear membrane remains intact, and the spindle microtubules form inside of it.[2] The group is characterized by the ultrastructure of the flagella. In addition to the normal supporting microtubules or axoneme, each contains a rod (called paraxonemal), which has a tubular structure in one flagellum and a latticed structure in the other. Based on this, two smaller groups have been included here: the diplonemids and Postgaardi.[3] The euglenozoa are generally accepted as monophyletic. They are related to Percolozoa; the two share mitochondria with disc-shaped cristae, which only occurs in a few other groups.[4] Both probably belong to a larger group of eukaryotes called the excavates.[5]	https://www.wikidoc.org/index.php/Euglenozoa
203d4bc19fd761f53e3b8d390fed012183e9ce86	wikidoc	Eupatorium	Eupatorium Eupatorium (syn. Ayapana Spach) is a genus of flowering plants, containing from 36 to 60 species (depending on the classification system), most of which are herbaceous perennial plants growing to 0.5-3 m tall. A few are shrubs. The genus is native to temperate regions of the Northern Hemisphere. Species of Eupatorium, although poisonous (to humans and grazing livestock), have been used in folk medicine, for instance to excrete excess uric acid which causes gout. However, Eupatorium has many beneficial uses, including treatment of dengue fever, arthritis, infectious diseases, migraines, worms, malaria, and diarrhea. Boneset infusions are also considered an excellent remedy for influenza. Use caution when consuming boneset, since it contains toxic compounds that can cause liver damage. Side effects include muscular tremors, weakness, and constipation leading to death. Eupatorium species are used as food plants by the larvae of some Lepidoptera species including Bucculatrix eupatoriella (which feeds exclusively on Eupatorium perfoliatum), The V-pug, Wormwood Pug, Schinia bifascia, Schinia trifascia and the Coleophora case-bearers C. follicularis, C. trochilella and C. troglodytella. A few species or cultivars, such as E. sordidum and E. coelestinum 'Album', are sometimes used as ornamental plants. In particular, they are used for structural or background plantings or to attract butterflies. # Selected species - Eupatorium album (White Thoroughwort) - Eupatorium altissimum (Tall Boneset, White Snakeroot) - Eupatorium aromaticum (scented Hemp Agrimony, Lesser Snakeroot) - Eupatorium ayapana (Eupatorium aya-pana) - Eupatorium cannabinum (Hemp Agrimony) - Eupatorium capillifolium (Dog-fennel) - Eupatorium coelestinum (bluish flowered Hemp Agrimony, Blue Thoroughwort) - Eupatorium collinum - Eupatorium dubium - Eupatorium fistulosum (Hollow Joe-Pye Weed) - Eupatorium foeniculum - Eupatorium gayanum (Asmachilca) - Eupatorium glandulosum Kunth, non Michx. (sticky snakeroot, crofton weed, Maui pamakani, Mexican devil) An antibacterial perennial shrub. Current Name: Ageratina adenophora. - Eupatorium hyssopifolium (Hyssop-leaved Thoroughwort) - Eupatorium leucolepsis - Eupatorium lingustrinum - Eupatorium megalophyllum - Eupatorium maculatum (Spotted Joe-Pye Weed) - Eupatorium officinalis - Eupatorium perfoliatum (Common Boneset) - Eupatorium purpureum (Sweet Joe-Pye Weed, green-stemmed Joe-pye Weed, Queen of the Meadow, Gravel root, Kidney root, Purple boneset) - Eupatorium rugosum (White Snakeroot) - Eupatorium rotundifolium (Round-leaved Thoroughwort) - Eupatorium serotinum {Late Boneset, Thoroughwort) - Eupatorium sessilifolium (Upland Boneset) - Eupatorium urticaefolium # Other genera Eupatorium has at times been held to contain as many as 800 species, but many of these have been moved (at least by some authors) to other genera, including Ageratina, Chromolaena, Condylidium, Conoclinium, Critonia, Eutrochium (syn. Eupatoriadelphus), Fleischmannia, Flyriella, Hebeclinium, Koanophyllon, Mikania, and Tamaulipa. The classification of the tribe Eupatorieae, including species placed in Eupatorium in the present or past, is an area of ongoing research, so further changes are likely. # Cited references - ↑ Om P. Sharma, Rajinder K. Dawra, Nitin P. Kurade, Pritam D. Sharma (26 May 1999). "A review of the toxicosis and biological properties of the genus Eupatorium". Natural Toxins. 6 (1): 1–14. doi:10.1002/(SICI)1522-7189(199802)6:1%3C1::AID-NT3%3E3.0.CO;2-E.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} - ↑ Ageratina adenophora (Spreng.) R.M. King & H. Rob. - ↑ Alan Whittemore (August 1987). "The Sectional Nomenclature of Eupatorium (Asteraceae)". Taxon. 36 (3): 618–620. doi:10.2307/1221856. - ↑ "393. Eutrochium Rafinesque". Flora of North America. Vol. 21 Page 461, 462, 474, 475. - ↑ Motomi Ito, Kuniaki Watanabe, Yoko Kita, Takayuki Kawahara, DJ Crawford and Tetsukazu Yahara (March, 2000). "Phylogeny and Phytogeography of Eupatorium (Eupatorieae, Asteraceae): Insights from Sequence Data of the nrDNA ITS Regions and cpDNA RFLP". Journal of Plant Research. 113 (1): 79–89. doi:10.1007/PL00013913. ISSN 1618-0860. Check date values in: \|date= (help)CS1 maint: Multiple names: authors list (link) - ↑ Gregory J. Schmidt and Edward E. Schilling (2000). "Phylogeny and biogeography of Eupatorium (Asteraceae: Eupatorieae) based on nuclear ITS sequence data". American Journal of Botany. 87: 716–726. PMID 10811796. # Other references - Lamont E.E. - Taxonomy of Eupatorium Section Verticillata (Asteraceae); New York Botanical Garden Press, 1995, ISBN 0-89327-391-0 - Encyclopedia of Folk Medicine: Old World and New World Traditions. Santa Barbara: ABC-CLIO, Inc., 2004. - The Gale Encyclopedia of Alternative Medicine. Volume 1. New York: Gale Group, 2001. da:Hjortetrøst de:Wasserdost ka:ვარდკანაფა lt:Pūkūnė nl:Eupatorium	Eupatorium Eupatorium (syn. Ayapana Spach) is a genus of flowering plants, containing from 36 to 60 species (depending on the classification system), most of which are herbaceous perennial plants growing to 0.5-3 m tall. A few are shrubs. The genus is native to temperate regions of the Northern Hemisphere. Species of Eupatorium, although poisonous (to humans and grazing livestock), have been used in folk medicine,[1] for instance to excrete excess uric acid which causes gout. However, Eupatorium has many beneficial uses, including treatment of dengue fever, arthritis, infectious diseases, migraines, worms, malaria, and diarrhea. Boneset infusions are also considered an excellent remedy for influenza. Use caution when consuming boneset, since it contains toxic compounds that can cause liver damage. Side effects include muscular tremors, weakness, and constipation leading to death. Eupatorium species are used as food plants by the larvae of some Lepidoptera species including Bucculatrix eupatoriella (which feeds exclusively on Eupatorium perfoliatum), The V-pug, Wormwood Pug, Schinia bifascia, Schinia trifascia and the Coleophora case-bearers C. follicularis, C. trochilella and C. troglodytella. A few species or cultivars, such as E. sordidum and E. coelestinum 'Album', are sometimes used as ornamental plants. In particular, they are used for structural or background plantings or to attract butterflies. # Selected species - Eupatorium album (White Thoroughwort) - Eupatorium altissimum (Tall Boneset, White Snakeroot) - Eupatorium aromaticum (scented Hemp Agrimony, Lesser Snakeroot) - Eupatorium ayapana (Eupatorium aya-pana) - Eupatorium cannabinum (Hemp Agrimony) - Eupatorium capillifolium (Dog-fennel) - Eupatorium coelestinum [1] (bluish flowered Hemp Agrimony, Blue Thoroughwort) - Eupatorium collinum - Eupatorium dubium - Eupatorium fistulosum (Hollow Joe-Pye Weed) - Eupatorium foeniculum - Eupatorium gayanum (Asmachilca) - Eupatorium glandulosum Kunth, non Michx. (sticky snakeroot, crofton weed, Maui pamakani, Mexican devil) An antibacterial perennial shrub. Current Name: Ageratina adenophora.[2] - Eupatorium hyssopifolium (Hyssop-leaved Thoroughwort) - Eupatorium leucolepsis - Eupatorium lingustrinum - Eupatorium megalophyllum - Eupatorium maculatum [2] (Spotted Joe-Pye Weed) - Eupatorium officinalis - Eupatorium perfoliatum (Common Boneset) - Eupatorium purpureum (Sweet Joe-Pye Weed, green-stemmed Joe-pye Weed, Queen of the Meadow, Gravel root, Kidney root, Purple boneset) - Eupatorium rugosum (White Snakeroot) - Eupatorium rotundifolium (Round-leaved Thoroughwort) - Eupatorium serotinum [3] {Late Boneset, Thoroughwort) - Eupatorium sessilifolium (Upland Boneset) - Eupatorium urticaefolium # Other genera Eupatorium has at times been held to contain as many as 800 species,[3] but many of these have been moved (at least by some authors) to other genera, including Ageratina, Chromolaena, Condylidium, Conoclinium, Critonia, Eutrochium (syn. Eupatoriadelphus),[4] Fleischmannia, Flyriella, Hebeclinium, Koanophyllon, Mikania, and Tamaulipa. The classification of the tribe Eupatorieae, including species placed in Eupatorium in the present or past, is an area of ongoing research,[5][6] so further changes are likely. # Cited references - ↑ Om P. Sharma, Rajinder K. Dawra, Nitin P. Kurade, Pritam D. Sharma (26 May 1999). "A review of the toxicosis and biological properties of the genus Eupatorium". Natural Toxins. 6 (1): 1–14. doi:10.1002/(SICI)1522-7189(199802)6:1%3C1::AID-NT3%3E3.0.CO;2-E.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} - ↑ Ageratina adenophora (Spreng.) R.M. King & H. Rob. - ↑ Alan Whittemore (August 1987). "The Sectional Nomenclature of Eupatorium (Asteraceae)". Taxon. 36 (3): 618–620. doi:10.2307/1221856. - ↑ "393. Eutrochium Rafinesque". Flora of North America. Vol. 21 Page 461, 462, 474, 475. - ↑ Motomi Ito, Kuniaki Watanabe, Yoko Kita, Takayuki Kawahara, DJ Crawford and Tetsukazu Yahara (March, 2000). "Phylogeny and Phytogeography of Eupatorium (Eupatorieae, Asteraceae): Insights from Sequence Data of the nrDNA ITS Regions and cpDNA RFLP". Journal of Plant Research. 113 (1): 79–89. doi:10.1007/PL00013913. ISSN 1618-0860. Check date values in: \|date= (help)CS1 maint: Multiple names: authors list (link) - ↑ Gregory J. Schmidt and Edward E. Schilling (2000). "Phylogeny and biogeography of Eupatorium (Asteraceae: Eupatorieae) based on nuclear ITS sequence data". American Journal of Botany. 87: 716–726. PMID 10811796. # Other references - Lamont E.E. - Taxonomy of Eupatorium Section Verticillata (Asteraceae); New York Botanical Garden Press, 1995, ISBN 0-89327-391-0 - Encyclopedia of Folk Medicine: Old World and New World Traditions. Santa Barbara: ABC-CLIO, Inc., 2004. - The Gale Encyclopedia of Alternative Medicine. Volume 1. New York: Gale Group, 2001. da:Hjortetrøst de:Wasserdost ka:ვარდკანაფა lt:Pūkūnė nl:Eupatorium	https://www.wikidoc.org/index.php/Eupatorium
3b737046fcc44f1f9afc940123a73e13c4b2349b	wikidoc	Eutherians	Eutherians Eutheria is a taxon containing the placental mammals, such as humans. The sister group of Eutheria is Metatheria, which includes marsupials and their extinct relatives. # Origin of the word The name Eutheria comes from the Greek words eu- "well" and ther "beast". When Eutheria was introduced by Thomas Henry Huxley in 1880, he meant it to be broader in definition than its precursor Placentalia. Some use Eutheria as a total group which includes the crown group Placentalia and extinct mammals which are closer to Placentalia than to Marsupialia. # Characteristics of eutherians Nevertheless, all living eutherians are placental mammals. This means that a eutherian fetus is nourished during gestation by a placenta. Eutherians are also viviparous, meaning that the offspring are carried in the mother's uterus until fully developed. # Differences from other mammals Because of this, eutherians are different from other mammal groups such as monotremes and marsupials which are not placental. Monotremes, for instance, lay eggs which protect developing young until they are fully developed. Marsupials give birth to partially-developed young who then migrate to a special pouch in the mother's body in which the young continue their development. (Some exceptions do exist. Bandicoots for instance, which are marsupials, develop small placenta-like structures during gestation.) # Earliest example The earliest known eutherian species is the extinct Eomaia scansoria from the Lower Cretaceous of China. It is a member of Eutheria, but the hips of the animal were too narrowly built to have allowed the birth of well-developed young. Thus it is unlikely that a placenta greatly contributed to the development of E. scansoria's young before they were born. Members of Eutheria are found on all continents and in all oceans.	Eutherians Eutheria[2] is a taxon containing the placental mammals, such as humans. The sister group of Eutheria is Metatheria, which includes marsupials and their extinct relatives. # Origin of the word The name Eutheria comes from the Greek words eu- "well[-developed]" and ther "beast". When Eutheria was introduced by Thomas Henry Huxley in 1880, he meant it to be broader in definition than its precursor Placentalia. Some use Eutheria as a total group which includes the crown group Placentalia and extinct mammals which are closer to Placentalia than to Marsupialia. # Characteristics of eutherians Nevertheless, all living eutherians are placental mammals. This means that a eutherian fetus is nourished during gestation by a placenta. Eutherians are also viviparous, meaning that the offspring are carried in the mother's uterus until fully developed. # Differences from other mammals Because of this, eutherians are different from other mammal groups such as monotremes and marsupials which are not placental. Monotremes, for instance, lay eggs which protect developing young until they are fully developed. Marsupials give birth to partially-developed young who then migrate to a special pouch in the mother's body in which the young continue their development. (Some exceptions do exist. Bandicoots for instance, which are marsupials, develop small placenta-like structures during gestation.) # Earliest example The earliest known eutherian species is the extinct Eomaia scansoria from the Lower Cretaceous of China. It is a member of Eutheria, but the hips of the animal were too narrowly built to have allowed the birth of well-developed young. Thus it is unlikely that a placenta greatly contributed to the development of E. scansoria's young before they were born. Members of Eutheria are found on all continents and in all oceans.	https://www.wikidoc.org/index.php/Eutherians
496f79533ad7b8f41ba79b088cfb1337055eae9d	wikidoc	Everolimus	Everolimus # 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 Everolimus is an antineoplastic agent that is FDA approved for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole, progressive neuroendocrine tumors of pancreatic origin (PNET) that are unresectable, locally advanced or metastatic, advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib, renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery and tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA). Common adverse reactions include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache and decreased appetite. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. - AFINITOR® is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. - AFINITOR® is not indicated for the treatment of patients with functional carcinoid tumors. - AFINITOR® is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. - AFINITOR® is indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. - The effectiveness of AFINITOR in the treatment of renal angiomyolipoma is based on an analysis of durable objective responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term outcomes. - AFINITOR® Tablets and AFINITOR® DISPERZ are indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. - The effectiveness of AFINITOR Tablets and AFINITOR DISPERZ is based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival in patients with SEGA and TSC has not been demonstrated. - AFINITOR is available in two dosage forms: tablets (AFINITOR Tablets) and tablets for oral suspension (AFINITOR DISPERZ). - AFINITOR Tablets may be used for all approved indications. - AFINITOR DISPERZ is approved for the treatment of patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC). - The recommended dose of AFINITOR Tablets is 10 mg, to be taken once daily at the same time every day. Administer either consistently with food or consistently without food. AFINITOR Tablets should be swallowed whole with a glass of water. Do not break or crush tablets. - Continue treatment until disease progression or unacceptable toxicity occurs. - Adverse Reactions - Management of severe or intolerable adverse reactions may require temporary dose interruption (with or without a dose reduction of AFINITOR therapy) or discontinuation. If dose reduction is required, the suggested dose is approximately 50% lower than the daily dose previously administered. - Table 1 summarizes recommendations for dose reduction, interruption or discontinuation of AFINITOR in the management of adverse reactions. General management recommendations are also provided as applicable. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. - Hepatic Impairment - Hepatic impairment will increase the exposure to everolimus. Dose adjustments are recommended: Mild hepatic impairment (Child-Pugh class A) – The recommended dose is 7.5 mg daily; the dose may be decreased to 5 mg if not well tolerated. Moderate hepatic impairment (Child-Pugh class B) – The recommended dose is 5 mg daily; the dose may be decreased to 2.5 mg if not well tolerated. Severe hepatic impairment (Child-Pugh class C) – If the desired benefit outweighs the risk, a dose of 2.5 mg daily may be used but must not be exceeded. - Mild hepatic impairment (Child-Pugh class A) – The recommended dose is 7.5 mg daily; the dose may be decreased to 5 mg if not well tolerated. - Moderate hepatic impairment (Child-Pugh class B) – The recommended dose is 5 mg daily; the dose may be decreased to 2.5 mg if not well tolerated. - Severe hepatic impairment (Child-Pugh class C) – If the desired benefit outweighs the risk, a dose of 2.5 mg daily may be used but must not be exceeded. - Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment. - CYP3A4/P-glycoprotein (PgP) Inhibitors - Avoid the use of strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). - Use caution when co-administered with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4/PgP inhibitor, reduce the AFINITOR dose to 2.5 mg daily. The reduced dose of AFINITOR is predicted to adjust the area under the curve (AUC) to the range observed without inhibitors. An AFINITOR dose increase from 2.5 mg to 5 mg may be considered based on patient tolerance. If the moderate inhibitor is discontinued, a washout period of approximately 2 to 3 days should be allowed before the AFINITOR dose is increased. If the moderate inhibitor is discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor. - Grapefruit, grapefruit juice, and other foods that are known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment. - Strong CYP3A4/PgP Inducers - Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). If patients require co-administration of a strong CYP3A4/PgP inducer, consider doubling the daily dose of AFINITOR using increments of 5 mg or less. This dose of AFINITOR is predicted, based on pharmacokinetic data, to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4/PgP inducers. If the strong inducer is discontinued, consider a washout period of 3 to 5 days, before the AFINITOR dose is returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer. - St. John’s Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided. - The recommended starting dose is 4.5 mg/m2, once daily. The recommended starting dose for patients with severe hepatic impairment (Child-Pugh class C) or requiring moderate CYP3A4/PgP inhibitors is 2.5 mg/m2, once daily. The recommended starting dose for patients requiring a concomitant strong CYP3A4 inducer is 9 mg/m2, once daily. Round dose to the nearest strength of either AFINITOR Tablets or AFINITOR DISPERZ. - Do not combine AFINITOR Tablets and AFINITOR DISPERZ to achieve the desired total dose. - Use therapeutic drug monitoring to guide subsequent dosing. Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5 to 15 ng/mL. - Continue treatment until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is unknown. - Monitor everolimus whole blood trough levels routinely in all patients. When possible, use the same assay and laboratory for therapeutic drug monitoring throughout treatment. - Assess trough concentrations approximately 2 weeks after initiation of treatment, a change in dose, a change in co-administration of CYP3A4/PgP inducers and/or inhibitors, a change in hepatic function, or a change in dosage form between AFINITOR Tablets and AFINITOR DISPERZ. Once a stable dose is attained, monitor trough concentrations every 3 to 6 months in patients with changing body surface area or every 6 to 12 months in patients with stable body surface area for the duration of treatment. - Titrate the dose to attain trough concentrations of 5 to 15 ng/mL. - For trough concentrations less than 5 ng/mL, increase the daily dose by 2.5 mg (in patients taking AFINITOR Tablets) or 2 mg (in patients taking AFINITOR DISPERZ). - For trough concentrations greater than 15 ng/mL, reduce the daily dose by 2.5 mg (in patients taking AFINITOR Tablets) or 2 mg (in patients taking AFINITOR DISPERZ). - If dose reduction is required for patients receiving the lowest available strength, administer every other day. - Adverse Reactions - Temporarily interrupt or permanently discontinue AFINITOR Tablets or AFINITOR DISPERZ for severe or intolerable adverse reactions. If dose reduction is required when reinitiating therapy, reduce the dose by approximately 50%. If dose reduction is required for patients receiving the lowest available strength, administer every other day. - Hepatic Impairment - Reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% in patients with SEGA who have severe hepatic impairment (Child-Pugh class C). Adjustment to the starting dose for patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment may not be needed. Subsequent dosing should be based on therapeutic drug monitoring. - Assess everolimus trough concentrations approximately 2 weeks after commencing treatment, a change in dose, or any change in hepatic function. - CYP3A4/P-glycoprotein (PgP) Inhibitors - Avoid the use of concomitant strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving AFINITOR Tablets or AFINITOR DISPERZ. - For patients who require treatment with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem): Reduce the AFINITOR Tablets or AFINITOR DISPERZ dose by approximately 50%. Administer every other day if dose reduction is required for patients receiving the lowest available strength and maintain trough concentrations of 5 to 15 ng/mL. Assess everolimus trough concentrations approximately 2 weeks after dose reduction. Resume the dose that was used prior to initiating the CYP3A4/PgP inhibitor 2 to 3 days after discontinuation of a moderate inhibitor. Assess the everolimus trough concentration approximately 2 weeks later. - Reduce the AFINITOR Tablets or AFINITOR DISPERZ dose by approximately 50%. Administer every other day if dose reduction is required for patients receiving the lowest available strength and maintain trough concentrations of 5 to 15 ng/mL. - Assess everolimus trough concentrations approximately 2 weeks after dose reduction. - Resume the dose that was used prior to initiating the CYP3A4/PgP inhibitor 2 to 3 days after discontinuation of a moderate inhibitor. Assess the everolimus trough concentration approximately 2 weeks later. - Do not ingest foods or nutritional supplements (e.g., grapefruit, grapefruit juice) that are known to inhibit cytochrome P450 or PgP activity. - Strong CYP3A4/PgP Inducers - Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. For patients who require treatment with a strong CYP3A4/PgP inducer: Double the dose of AFINITOR Tablets or AFINITOR DISPERZ and assess tolerability. Assess the everolimus trough concentration 2 weeks after doubling the dose and adjust the dose if necessary to maintain a trough concentration of 5 to 15 ng/mL. Return the AFINITOR Tablets or AFINITOR DISPERZ dose to that used prior to initiating the strong CYP3A4/PgP inducer if the strong inducer is discontinued, and assess the everolimus trough concentrations approximately 2 weeks later. - Double the dose of AFINITOR Tablets or AFINITOR DISPERZ and assess tolerability. - Assess the everolimus trough concentration 2 weeks after doubling the dose and adjust the dose if necessary to maintain a trough concentration of 5 to 15 ng/mL. - Return the AFINITOR Tablets or AFINITOR DISPERZ dose to that used prior to initiating the strong CYP3A4/PgP inducer if the strong inducer is discontinued, and assess the everolimus trough concentrations approximately 2 weeks later. - Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Everolimus in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Everolimus in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - The recommended starting dose is 4.5 mg/m2, once daily. The recommended starting dose for patients with severe hepatic impairment (Child-Pugh class C) or requiring moderate CYP3A4/PgP inhibitors is 2.5 mg/m2, once daily. The recommended starting dose for patients requiring a concomitant strong CYP3A4 inducer is 9 mg/m2, once daily. Round dose to the nearest strength of either AFINITOR Tablets or AFINITOR DISPERZ. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Everolimus in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Everolimus in pediatric patients. # Contraindications - AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. # Warnings ### Precautions - Non-infectious Pneumonitis - Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) Grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. - Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms. - Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. - If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered. - For cases of Grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to Grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances. If toxicity recurs at Grade 3, consider discontinuation of AFINITOR. For cases of Grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for PJP may be considered. The development of pneumonitis has been reported even at a reduced dose. - Infections - AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis, candidiasis, or pneumocystis jiroveci pneumonia (PJP) and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to sepsis, respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. - Pneumocystis jiroveci pneumonia, some with a fatal outcome, has been reported in patients who received everolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis for PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required. - Oral Ulceration - Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44%-78% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4%-9% of patients. In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme- containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed. - Renal Failure - Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR. - Impaired Wound Healing - Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the peri-surgical period. - Geriatric Patients - In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended. - Laboratory Tests and Monitoring - Renal Function - Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function. - Blood Glucose and Lipids - Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in patients taking AFINITOR. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy. More frequent monitoring is recommended when AFINITOR is co-administered with other drugs that may induce hyperglycemia. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. - Hematologic Parameters - Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in patients taking AFINITOR. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. - Drug-drug Interactions - Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4/PgP inhibitors should be avoided. - A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4/PgP inhibitor. - An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4/PgP inducer. - Hepatic Impairment - Exposure to everolimus was increased in patients with hepatic impairment. - For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended. - For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets or AFINITOR DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring. - Vaccinations - During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). - For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. - Embryo-fetal Toxicity - Based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. 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. - Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment. # Adverse Reactions ## Clinical Trials Experience - The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93 years), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months. - The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. - Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). - Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. - Key observed laboratory abnormalities are presented in Table 3. - In a randomized, controlled trial of AFINITOR (n=204) versus placebo (n=203) in patients with advanced PNET the median age of patients was 58 years (range 20-87), 79% were Caucasian, and 55% were male. Patients on the placebo arm could cross over to open-label AFINITOR upon disease progression. - The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were decreased hemoglobin, hyperglycemia, alkaline phosphatase increased, hypercholesterolemia, bicarbonate decreased, and increased aspartate transaminase (AST). The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST), potassium decreased, and thrombocytopenia. Deaths during double-blind treatment where an adverse event was the primary cause occurred in seven patients on AFINITOR and one patient on placebo. Causes of death on the AFINITOR arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. There was one death due to pulmonary embolism on the placebo arm. After cross-over to open-label AFINITOR, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rates of treatment-emergent adverse events resulting in permanent discontinuation were 20% and 6% for the AFINITOR and placebo treatment groups, respectively. Dose delay or reduction was necessary in 61% of everolimus patients and 29% of placebo patients. Grade 3-4 renal failure occurred in six patients in the everolimus arm and three patients in the placebo arm. Thrombotic events included five patients with pulmonary embolus in the everolimus arm and one in the placebo arm as well as three patients with thrombosis in the everolimus arm and two in the placebo arm. - Table 4 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 10 mg daily versus placebo. - In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) AFINITOR-treated females and none of the 33 females in the placebo group. - Key observed laboratory abnormalities are presented in Table 5. - The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving AFINITOR and 60 days (range 21-295 days) for those receiving placebo. - The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis. - Table 6 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. - Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of < 10% include: - Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) - General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%) - Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) - Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%) - Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%) - Psychiatric disorders: Insomnia (9%) - Nervous system disorders: Dizziness (7%), paresthesia (5%) - Eye disorders: Eyelid edema (4%), conjunctivitis (2%) - Vascular disorders: Hypertension (4%), deep vein thrombosis (< 1%) - Renal and urinary disorders: Renal failure (3%) - Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%) - Musculoskeletal and connective tissue disorders: Jaw pain (3%) - Hematologic disorders: Hemorrhage (3%) - Key laboratory abnormalities are presented in Table 7. - The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial of AFINITOR in 118 patients with renal angiomyolipoma as a feature of TSC (n=113) or sporadic lymphangioleiomyomatosis (n=5). The median age of patients was 31 years (range 18 to 61 years), 89% were Caucasian, and 34% were male. The median duration of blinded study treatment was 48 weeks (range 2 to 115 weeks) for patients receiving AFINITOR and 45 weeks (range 9 to 115 weeks) for those receiving placebo. - The most common adverse reaction reported for AFINITOR (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia. - The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the AFINITOR-treated patients. Adverse reactions leading to permanent discontinuation in the AFINITOR arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis. - Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo. Laboratory abnormalities are described separately in Table 9. - Amenorrhea occurred in 15% of AFINITOR-treated females (8 of 52) and 4% (1 of 26) of females in the placebo group. Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%). - The following additional adverse reactions occurred in less than 10% of Afinitor-treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), and pneumonitis (1%). - The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (Study 1) of AFINITOR in 117 patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC). The median age of patients was 9.5 years (range 0.8 to 26 years), 93% were Caucasian, and 57% were male. The median duration of blinded study treatment was 52 weeks (range 24 to 89 weeks) for patients receiving AFINITOR and 47 weeks (range 14 to 88 weeks) for those receiving placebo. - The most common adverse reactions reported for AFINITOR (incidence ≥ 30%) were stomatitis and respiratory tract infection. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. The most common key laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was neutropenia. - There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis. - Table 10 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo. Laboratory abnormalities are described separately in Table 11. - Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18) and none of the females in the placebo group. For this same group of AFINITOR-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%). - The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: nausea (8%), pain in extremity (8%), insomnia (6%), pneumonia (6%), epistaxis (5%), hypersensitivity (3%), increased blood luteinizing hormone (LH) levels (1%) and pneumonitis (1%). - Longer-term follow-up of 34.2 months (range 4.7 to 47.1 months) from a non-randomized, open-label, 28-patient trial resulted in the following additional notable adverse reactions and key laboratory abnormalities: cellulitis (29%), hyperglycemia (25%), and elevated creatinine (14%). ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of AFINITOR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure: acute pancreatitis, cholecystitis, cholelithiasis, arterial thrombotic events and reflex sympathetic dystrophy. # Drug Interactions - Agents That May Increase Everolimus Blood Concentrations - CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. - In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. - ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. - erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. - verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. - Concomitant strong inhibitors of CYP3A4/PgP should not be used. - Concomitant strong inhibitors of CYP3A4/PgP should not be used. - Use caution when AFINITOR is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose. - Use caution when AFINITOR is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose. - Agents That May Decrease Everolimus Blood Concentrations - CYP3A4/PgP Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided. - In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided. - Drugs That May Have Their Plasma Concentrations Altered by Everolimus - Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. - A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). - Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. - Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Risk Summary - Based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, apprise the patient of the potential hazard to the fetus. - Animal Data - In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities. - In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Everolimus in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Everolimus during labor and delivery. ### Nursing Mothers - It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 - Pediatric use of AFINITOR Tablets and AFINITOR DISPERZ is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets and AFINITOR DISPERZ have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. - The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown. - Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least 1 serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups. - Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups. - Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA. The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA. ### Geriatic Use - In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 years and over. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. - In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 years and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 years and over. - Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended. ### Gender There is no FDA guidance on the use of Everolimus with respect to specific gender populations. ### Race There is no FDA guidance on the use of Everolimus with respect to specific racial populations. ### Renal Impairment - No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment. ### Hepatic Impairment - The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment. - For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended. - For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring. ### Females of Reproductive Potential and Males - Contraception - Females AFINITOR can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. - AFINITOR can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. - Infertility - Females Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR. - Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR. - Males AFINITOR treatment may impair fertility in male patients based on animal findings. - AFINITOR treatment may impair fertility in male patients based on animal findings. ### Immunocompromised Patients There is no FDA guidance one the use of Everolimus in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function. - Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy. - Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. # IV Compatibility There is limited information regarding IV Compatibility of Everolimus in the drug label. # Overdosage ## Acute Overdose - In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). - Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. ## Chronic Overdose There is limited information regarding Chronic Overdose of Everolimus in the drug label. # Pharmacology There is limited information regarding Everolimus Pharmacology in the drug label. ## Mechanism of Action There is limited information regarding Everolimus Mechanism of Action in the drug label. ## Structure There is limited information regarding Everolimus Structure in the drug label. ## Pharmacodynamics There is limited information regarding Everolimus Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Everolimus Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Everolimus Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Everolimus Clinical Studies in the drug label. # How Supplied There is limited information regarding Everolimus How Supplied in the drug label. ## Storage There is limited information regarding Everolimus Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Everolimus Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Everolimus 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 Everolimus Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Everolimus Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	Everolimus Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Overview Everolimus is an antineoplastic agent that is FDA approved for the treatment of advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole, progressive neuroendocrine tumors of pancreatic origin (PNET) that are unresectable, locally advanced or metastatic, advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib, renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery and tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA). Common adverse reactions include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache and decreased appetite. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. - AFINITOR® is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. - AFINITOR® is not indicated for the treatment of patients with functional carcinoid tumors. - AFINITOR® is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. - AFINITOR® is indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. - The effectiveness of AFINITOR in the treatment of renal angiomyolipoma is based on an analysis of durable objective responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term outcomes. - AFINITOR® Tablets and AFINITOR® DISPERZ are indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. - The effectiveness of AFINITOR Tablets and AFINITOR DISPERZ is based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival in patients with SEGA and TSC has not been demonstrated. - AFINITOR is available in two dosage forms: tablets (AFINITOR Tablets) and tablets for oral suspension (AFINITOR DISPERZ). - AFINITOR Tablets may be used for all approved indications. - AFINITOR DISPERZ is approved for the treatment of patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC). - The recommended dose of AFINITOR Tablets is 10 mg, to be taken once daily at the same time every day. Administer either consistently with food or consistently without food. AFINITOR Tablets should be swallowed whole with a glass of water. Do not break or crush tablets. - Continue treatment until disease progression or unacceptable toxicity occurs. - Adverse Reactions - Management of severe or intolerable adverse reactions may require temporary dose interruption (with or without a dose reduction of AFINITOR therapy) or discontinuation. If dose reduction is required, the suggested dose is approximately 50% lower than the daily dose previously administered. - Table 1 summarizes recommendations for dose reduction, interruption or discontinuation of AFINITOR in the management of adverse reactions. General management recommendations are also provided as applicable. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment. - Hepatic Impairment - Hepatic impairment will increase the exposure to everolimus. Dose adjustments are recommended: Mild hepatic impairment (Child-Pugh class A) – The recommended dose is 7.5 mg daily; the dose may be decreased to 5 mg if not well tolerated. Moderate hepatic impairment (Child-Pugh class B) – The recommended dose is 5 mg daily; the dose may be decreased to 2.5 mg if not well tolerated. Severe hepatic impairment (Child-Pugh class C) – If the desired benefit outweighs the risk, a dose of 2.5 mg daily may be used but must not be exceeded. - Mild hepatic impairment (Child-Pugh class A) – The recommended dose is 7.5 mg daily; the dose may be decreased to 5 mg if not well tolerated. - Moderate hepatic impairment (Child-Pugh class B) – The recommended dose is 5 mg daily; the dose may be decreased to 2.5 mg if not well tolerated. - Severe hepatic impairment (Child-Pugh class C) – If the desired benefit outweighs the risk, a dose of 2.5 mg daily may be used but must not be exceeded. - Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment. - CYP3A4/P-glycoprotein (PgP) Inhibitors - Avoid the use of strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). - Use caution when co-administered with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4/PgP inhibitor, reduce the AFINITOR dose to 2.5 mg daily. The reduced dose of AFINITOR is predicted to adjust the area under the curve (AUC) to the range observed without inhibitors. An AFINITOR dose increase from 2.5 mg to 5 mg may be considered based on patient tolerance. If the moderate inhibitor is discontinued, a washout period of approximately 2 to 3 days should be allowed before the AFINITOR dose is increased. If the moderate inhibitor is discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor. - Grapefruit, grapefruit juice, and other foods that are known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment. - Strong CYP3A4/PgP Inducers - Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). If patients require co-administration of a strong CYP3A4/PgP inducer, consider doubling the daily dose of AFINITOR using increments of 5 mg or less. This dose of AFINITOR is predicted, based on pharmacokinetic data, to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4/PgP inducers. If the strong inducer is discontinued, consider a washout period of 3 to 5 days, before the AFINITOR dose is returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer. - St. John’s Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided. - The recommended starting dose is 4.5 mg/m2, once daily. The recommended starting dose for patients with severe hepatic impairment (Child-Pugh class C) or requiring moderate CYP3A4/PgP inhibitors is 2.5 mg/m2, once daily. The recommended starting dose for patients requiring a concomitant strong CYP3A4 inducer is 9 mg/m2, once daily. Round dose to the nearest strength of either AFINITOR Tablets or AFINITOR DISPERZ. - Do not combine AFINITOR Tablets and AFINITOR DISPERZ to achieve the desired total dose. - Use therapeutic drug monitoring to guide subsequent dosing. Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5 to 15 ng/mL. - Continue treatment until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is unknown. - Monitor everolimus whole blood trough levels routinely in all patients. When possible, use the same assay and laboratory for therapeutic drug monitoring throughout treatment. - Assess trough concentrations approximately 2 weeks after initiation of treatment, a change in dose, a change in co-administration of CYP3A4/PgP inducers and/or inhibitors, a change in hepatic function, or a change in dosage form between AFINITOR Tablets and AFINITOR DISPERZ. Once a stable dose is attained, monitor trough concentrations every 3 to 6 months in patients with changing body surface area or every 6 to 12 months in patients with stable body surface area for the duration of treatment. - Titrate the dose to attain trough concentrations of 5 to 15 ng/mL. - For trough concentrations less than 5 ng/mL, increase the daily dose by 2.5 mg (in patients taking AFINITOR Tablets) or 2 mg (in patients taking AFINITOR DISPERZ). - For trough concentrations greater than 15 ng/mL, reduce the daily dose by 2.5 mg (in patients taking AFINITOR Tablets) or 2 mg (in patients taking AFINITOR DISPERZ). - If dose reduction is required for patients receiving the lowest available strength, administer every other day. - Adverse Reactions - Temporarily interrupt or permanently discontinue AFINITOR Tablets or AFINITOR DISPERZ for severe or intolerable adverse reactions. If dose reduction is required when reinitiating therapy, reduce the dose by approximately 50%. If dose reduction is required for patients receiving the lowest available strength, administer every other day. - Hepatic Impairment - Reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% in patients with SEGA who have severe hepatic impairment (Child-Pugh class C). Adjustment to the starting dose for patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment may not be needed. Subsequent dosing should be based on therapeutic drug monitoring. - Assess everolimus trough concentrations approximately 2 weeks after commencing treatment, a change in dose, or any change in hepatic function. - CYP3A4/P-glycoprotein (PgP) Inhibitors - Avoid the use of concomitant strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving AFINITOR Tablets or AFINITOR DISPERZ. - For patients who require treatment with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem): Reduce the AFINITOR Tablets or AFINITOR DISPERZ dose by approximately 50%. Administer every other day if dose reduction is required for patients receiving the lowest available strength and maintain trough concentrations of 5 to 15 ng/mL. Assess everolimus trough concentrations approximately 2 weeks after dose reduction. Resume the dose that was used prior to initiating the CYP3A4/PgP inhibitor 2 to 3 days after discontinuation of a moderate inhibitor. Assess the everolimus trough concentration approximately 2 weeks later. - Reduce the AFINITOR Tablets or AFINITOR DISPERZ dose by approximately 50%. Administer every other day if dose reduction is required for patients receiving the lowest available strength and maintain trough concentrations of 5 to 15 ng/mL. - Assess everolimus trough concentrations approximately 2 weeks after dose reduction. - Resume the dose that was used prior to initiating the CYP3A4/PgP inhibitor 2 to 3 days after discontinuation of a moderate inhibitor. Assess the everolimus trough concentration approximately 2 weeks later. - Do not ingest foods or nutritional supplements (e.g., grapefruit, grapefruit juice) that are known to inhibit cytochrome P450 or PgP activity. - Strong CYP3A4/PgP Inducers - Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. For patients who require treatment with a strong CYP3A4/PgP inducer: Double the dose of AFINITOR Tablets or AFINITOR DISPERZ and assess tolerability. Assess the everolimus trough concentration 2 weeks after doubling the dose and adjust the dose if necessary to maintain a trough concentration of 5 to 15 ng/mL. Return the AFINITOR Tablets or AFINITOR DISPERZ dose to that used prior to initiating the strong CYP3A4/PgP inducer if the strong inducer is discontinued, and assess the everolimus trough concentrations approximately 2 weeks later. - Double the dose of AFINITOR Tablets or AFINITOR DISPERZ and assess tolerability. - Assess the everolimus trough concentration 2 weeks after doubling the dose and adjust the dose if necessary to maintain a trough concentration of 5 to 15 ng/mL. - Return the AFINITOR Tablets or AFINITOR DISPERZ dose to that used prior to initiating the strong CYP3A4/PgP inducer if the strong inducer is discontinued, and assess the everolimus trough concentrations approximately 2 weeks later. - Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Everolimus in adult patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Everolimus in adult patients. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) - Dosing Information - The recommended starting dose is 4.5 mg/m2, once daily. The recommended starting dose for patients with severe hepatic impairment (Child-Pugh class C) or requiring moderate CYP3A4/PgP inhibitors is 2.5 mg/m2, once daily. The recommended starting dose for patients requiring a concomitant strong CYP3A4 inducer is 9 mg/m2, once daily. Round dose to the nearest strength of either AFINITOR Tablets or AFINITOR DISPERZ. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Everolimus in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Everolimus in pediatric patients. # Contraindications - AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives. # Warnings ### Precautions - Non-infectious Pneumonitis - Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) Grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. - Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms. - Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis. - If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered. - For cases of Grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to Grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances. If toxicity recurs at Grade 3, consider discontinuation of AFINITOR. For cases of Grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical symptoms resolve. For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for PJP may be considered. The development of pneumonitis has been reported even at a reduced dose. - Infections - AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis, candidiasis, or pneumocystis jiroveci pneumonia (PJP) and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to sepsis, respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. - Pneumocystis jiroveci pneumonia, some with a fatal outcome, has been reported in patients who received everolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis for PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required. - Oral Ulceration - Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44%-78% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4%-9% of patients. In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme- containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed. - Renal Failure - Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR. - Impaired Wound Healing - Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the peri-surgical period. - Geriatric Patients - In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended. - Laboratory Tests and Monitoring - Renal Function - Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function. - Blood Glucose and Lipids - Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in patients taking AFINITOR. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy. More frequent monitoring is recommended when AFINITOR is co-administered with other drugs that may induce hyperglycemia. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. - Hematologic Parameters - Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in patients taking AFINITOR. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. - Drug-drug Interactions - Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4/PgP inhibitors should be avoided. - A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4/PgP inhibitor. - An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4/PgP inducer. - Hepatic Impairment - Exposure to everolimus was increased in patients with hepatic impairment. - For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended. - For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets or AFINITOR DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring. - Vaccinations - During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). - For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate. - Embryo-fetal Toxicity - Based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. 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. - Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment. # Adverse Reactions ## Clinical Trials Experience - The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93 years), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months. - The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia. - Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%). - Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. - Key observed laboratory abnormalities are presented in Table 3. - In a randomized, controlled trial of AFINITOR (n=204) versus placebo (n=203) in patients with advanced PNET the median age of patients was 58 years (range 20-87), 79% were Caucasian, and 55% were male. Patients on the placebo arm could cross over to open-label AFINITOR upon disease progression. - The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were decreased hemoglobin, hyperglycemia, alkaline phosphatase increased, hypercholesterolemia, bicarbonate decreased, and increased aspartate transaminase (AST). The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST), potassium decreased, and thrombocytopenia. Deaths during double-blind treatment where an adverse event was the primary cause occurred in seven patients on AFINITOR and one patient on placebo. Causes of death on the AFINITOR arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. There was one death due to pulmonary embolism on the placebo arm. After cross-over to open-label AFINITOR, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rates of treatment-emergent adverse events resulting in permanent discontinuation were 20% and 6% for the AFINITOR and placebo treatment groups, respectively. Dose delay or reduction was necessary in 61% of everolimus patients and 29% of placebo patients. Grade 3-4 renal failure occurred in six patients in the everolimus arm and three patients in the placebo arm. Thrombotic events included five patients with pulmonary embolus in the everolimus arm and one in the placebo arm as well as three patients with thrombosis in the everolimus arm and two in the placebo arm. - Table 4 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 10 mg daily versus placebo. - In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) AFINITOR-treated females and none of the 33 females in the placebo group. - Key observed laboratory abnormalities are presented in Table 5. - The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving AFINITOR and 60 days (range 21-295 days) for those receiving placebo. - The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis. - Table 6 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. - Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of < 10% include: - Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) - General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%) - Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) - Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%) - Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%) - Psychiatric disorders: Insomnia (9%) - Nervous system disorders: Dizziness (7%), paresthesia (5%) - Eye disorders: Eyelid edema (4%), conjunctivitis (2%) - Vascular disorders: Hypertension (4%), deep vein thrombosis (< 1%) - Renal and urinary disorders: Renal failure (3%) - Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%) - Musculoskeletal and connective tissue disorders: Jaw pain (3%) - Hematologic disorders: Hemorrhage (3%) - Key laboratory abnormalities are presented in Table 7. - The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial of AFINITOR in 118 patients with renal angiomyolipoma as a feature of TSC (n=113) or sporadic lymphangioleiomyomatosis (n=5). The median age of patients was 31 years (range 18 to 61 years), 89% were Caucasian, and 34% were male. The median duration of blinded study treatment was 48 weeks (range 2 to 115 weeks) for patients receiving AFINITOR and 45 weeks (range 9 to 115 weeks) for those receiving placebo. - The most common adverse reaction reported for AFINITOR (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia. - The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the AFINITOR-treated patients. Adverse reactions leading to permanent discontinuation in the AFINITOR arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis. - Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo. Laboratory abnormalities are described separately in Table 9. - Amenorrhea occurred in 15% of AFINITOR-treated females (8 of 52) and 4% (1 of 26) of females in the placebo group. Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%). - The following additional adverse reactions occurred in less than 10% of Afinitor-treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), and pneumonitis (1%). - The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (Study 1) of AFINITOR in 117 patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC). The median age of patients was 9.5 years (range 0.8 to 26 years), 93% were Caucasian, and 57% were male. The median duration of blinded study treatment was 52 weeks (range 24 to 89 weeks) for patients receiving AFINITOR and 47 weeks (range 14 to 88 weeks) for those receiving placebo. - The most common adverse reactions reported for AFINITOR (incidence ≥ 30%) were stomatitis and respiratory tract infection. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. The most common key laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was neutropenia. - There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis. - Table 10 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo. Laboratory abnormalities are described separately in Table 11. - Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18) and none of the females in the placebo group. For this same group of AFINITOR-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%). - The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: nausea (8%), pain in extremity (8%), insomnia (6%), pneumonia (6%), epistaxis (5%), hypersensitivity (3%), increased blood luteinizing hormone (LH) levels (1%) and pneumonitis (1%). - Longer-term follow-up of 34.2 months (range 4.7 to 47.1 months) from a non-randomized, open-label, 28-patient trial resulted in the following additional notable adverse reactions and key laboratory abnormalities: cellulitis (29%), hyperglycemia (25%), and elevated creatinine (14%). ## Postmarketing Experience - The following adverse reactions have been identified during post approval use of AFINITOR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure: acute pancreatitis, cholecystitis, cholelithiasis, arterial thrombotic events and reflex sympathetic dystrophy. # Drug Interactions - Agents That May Increase Everolimus Blood Concentrations - CYP3A4 Inhibitors and PgP Inhibitors In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. - In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with: ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. - ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively. - erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. - verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. - Concomitant strong inhibitors of CYP3A4/PgP should not be used. - Concomitant strong inhibitors of CYP3A4/PgP should not be used. - Use caution when AFINITOR is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose. - Use caution when AFINITOR is used in combination with moderate CYP3A4/PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose. - Agents That May Decrease Everolimus Blood Concentrations - CYP3A4/PgP Inducers In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided. - In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong CYP3A4/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided. - Drugs That May Have Their Plasma Concentrations Altered by Everolimus - Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. - A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). - Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination. - Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category D - Risk Summary - Based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, apprise the patient of the potential hazard to the fetus. - Animal Data - In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m2) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities. - In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m2), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Everolimus in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Everolimus during labor and delivery. ### Nursing Mothers - It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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 - Pediatric use of AFINITOR Tablets and AFINITOR DISPERZ is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets and AFINITOR DISPERZ have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA. - The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown. - Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least 1 serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups. - Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups. - Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA. The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA. ### Geriatic Use - In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 years and over. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. - In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 years and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 years and over. - Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. - No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended. ### Gender There is no FDA guidance on the use of Everolimus with respect to specific gender populations. ### Race There is no FDA guidance on the use of Everolimus with respect to specific racial populations. ### Renal Impairment - No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment. ### Hepatic Impairment - The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment. - For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended. - For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring. ### Females of Reproductive Potential and Males - Contraception - Females AFINITOR can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. - AFINITOR can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment. - Infertility - Females Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR. - Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR. - Males AFINITOR treatment may impair fertility in male patients based on animal findings. - AFINITOR treatment may impair fertility in male patients based on animal findings. ### Immunocompromised Patients There is no FDA guidance one the use of Everolimus in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring - Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function. - Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy. - Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. # IV Compatibility There is limited information regarding IV Compatibility of Everolimus in the drug label. # Overdosage ## Acute Overdose - In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). - Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. ## Chronic Overdose There is limited information regarding Chronic Overdose of Everolimus in the drug label. # Pharmacology There is limited information regarding Everolimus Pharmacology in the drug label. ## Mechanism of Action There is limited information regarding Everolimus Mechanism of Action in the drug label. ## Structure There is limited information regarding Everolimus Structure in the drug label. ## Pharmacodynamics There is limited information regarding Everolimus Pharmacodynamics in the drug label. ## Pharmacokinetics There is limited information regarding Everolimus Pharmacokinetics in the drug label. ## Nonclinical Toxicology There is limited information regarding Everolimus Nonclinical Toxicology in the drug label. # Clinical Studies There is limited information regarding Everolimus Clinical Studies in the drug label. # How Supplied There is limited information regarding Everolimus How Supplied in the drug label. ## Storage There is limited information regarding Everolimus Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information There is limited information regarding Everolimus Patient Counseling Information in the drug label. # Precautions with Alcohol Alcohol-Everolimus 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 Everolimus Brand Names in the drug label. # Look-Alike Drug Names There is limited information regarding Everolimus Look-Alike Drug Names in the drug label. # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Everolimus
d627c234893e1ab95331488d5e36afc509692ea5	wikidoc	Raloxifene	Raloxifene # 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 Raloxifene is an selective estrogen receptor modulator that is FDA approved for the {{{indicationType}}} of osteoporosis in postmenopausal women, reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis, reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, sweating. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Recommended Dosing - The recommended dosage is one 60 mg raloxifene hydrochloride tablet daily, which may be administered any time of day without regard to meals. - For the indications in risk of invasive breast cancer the optimum duration of treatment is not known. - Recommendations for Calcium and Vitamin D Supplementation - For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones. The recommended intake of vitamin D is 400-800 IU daily. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplements. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered. - Recommended Dosing - The recommended dosage is one 60 mg raloxifene hydrochloride tablet daily, which may be administered any time of day without regard to meals. - For the indications in risk of invasive breast cancer the optimum duration of treatment is not known. - Recommendations for Calcium and Vitamin D Supplementation - For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones. The recommended intake of vitamin D is 400-800 IU daily. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplements. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered. - Raloxifene hydrochloride is indicated for the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer. - The effect in the reduction in the incidence of breast cancer was shown in a study of postmenopausal women at high risk for breast cancer with a 5-year planned duration with a median follow-up of 4.3 years. Twenty-seven percent of the participants received drug for 5 years. The long-term effects and the recommended length of treatment are not known. - High risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer ≥1.66% (based on the modified Gail model). Among the factors included in the modified Gail model are the following: current age, number of first-degree relatives with breast cancer, number of breast biopsies, age at menarche, nulliparity or age of first live birth. Healthcare professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-800-545-5979. Currently, no single clinical finding or test result can quantify risk of breast cancer with certainty. - After an assessment of the risk of developing breast cancer, the decision regarding therapy with raloxifene hydrochloride should be based upon an individual assessment of the benefits and risks. - Raloxifene hydrochloride does not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting raloxifene hydrochloride and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with raloxifene hydrochloride. - Important Limitations of Use for Breast Cancer Risk Reduction - There are no data available regarding the effect of raloxifene hydrochloride on invasive breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of raloxifene hydrochloride. - Raloxifene hydrochloride is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence. - Raloxifene hydrochloride is not indicated for the reduction in the risk of noninvasive breast cancer. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Raloxifene in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Oral raloxifene 60 mg/day. # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Raloxifene in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Raloxifene in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Raloxifene in pediatric patients. # Contraindications - Venous Thromboembolism - Raloxifene hydrochloride is contraindicated in women with active or past history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. - Pregnancy, Women Who May Become Pregnant, and Nursing Mothers - Raloxifene hydrochloride is contraindicated in pregnancy, in women who may become pregnant, and in nursing mothers. Raloxifene hydrochloride may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. - In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses ≥0.1 mg/kg (≥0.04 times the human dose based on surface area, mg/m2), and hydrocephaly was observed in fetuses at doses ≥10 mg/kg (≥4 times the human dose based on surface area, mg/m2). In rat studies, retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses ≥1 mg/kg (≥0.2 times the human dose based on surface area, mg/m2). Treatment of rats at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m2) during gestation and lactation produced effects that included delayed and disrupted parturition; decreased neonatal survival and altered physical development; sex- and age-specific reductions in growth and changes in pituitary hormone content; and decreased lymphoid compartment size in offspring. At 10 mg/kg, raloxifene disrupted parturition, which resulted in maternal and progeny death and morbidity. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed. # Warnings ### Precautions - Venous Thromboembolism - In clinical trials, raloxifene hydrochloride-treated women had an increased risk of venous thromboembolism (deep vein thrombosis and pulmonary embolismOther venous thromboembolic events also could occur. A less serious event, superficial thrombophlebitis, also has been reported more frequently with raloxifene hydrochloride than with placebo. The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment, and the magnitude of risk appears to be similar to the reported risk associated with use of hormone therapy. Because immobilization increases the risk for venous thromboembolic events independent of therapy, raloxifene hydrochloride should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and raloxifene hydrochloride therapy should be resumed only after the patient is fully ambulatory. In addition, women taking raloxifene hydrochloride should be advised to move about periodically during prolonged travel. The risk-benefit balance should be considered in women at risk of thromboembolic disease for other reasons, such as congestive heart failure, superficial thrombophlebitis, and active malignancy. - Death Due to Stroke - In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with raloxifene hydrochloride. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene hydrochloride-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 versus 15 per 10,000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (249 in raloxifene hydrochloride versus 224 placebo ). Raloxifene hydrochloride had no significant effect on all-cause mortality. The risk-benefit balance should be considered in women at risk for stroke, such as prior stroke or transient ischemic attack (TIA), atrial fibrillation, hypertension, or cigarette smoking. - Cardiovascular Disease - Raloxifene hydrochloride should not be used for the primary or secondary prevention of cardiovascular disease. In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene for 5 years. - Premenopausal Use - There is no indication for premenopausal use of raloxifene hydrochloride. Safety of raloxifene hydrochloride in premenopausal women has not been established and its use is not recommended. - Hepatic Impairment - Raloxifene hydrochloride should be used with caution in patients with hepatic impairment. Safety and efficacy have not been established in patients with hepatic impairment. - Concomitant Estrogen Therapy - The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended. - History of Hypertriglyceridemia when Treated with Estrogens - Limited clinical data suggest that some women with a history of marked hypertriglyceridemia (>5.6 mmol/L or >500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin may develop increased levels of triglycerides when treated with raloxifene hydrochloride. Women with this medical history should have serum triglycerides monitored when taking raloxifene hydrochloride. - Renal Impairment - Raloxifene hydrochloride should be used with caution in patients with moderate or severe renal impairment. Safety and efficacy have not been established in patients with moderate or severe renal impairment. - History of Breast Cancer - Raloxifene hydrochloride has not been adequately studied in women with a prior history of breast cancer. - Use in Men - There is no indication for the use of raloxifene hydrochloride in men. Raloxifene hydrochloride has not been adequately studied in men and its use is not recommended. - Unexplained Uterine Bleeding - Any unexplained uterine bleeding should be investigated as clinically indicated. Raloxifene hydrochloride-treated and placebo-treated groups had similar incidences of endometrial proliferation. - Breast Abnormalities - Any unexplained breast abnormality occurring during raloxifene hydrochloride therapy should be investigated. Raloxifene hydrochloride does not eliminate the risk of breast cancer. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies 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 raloxifene hydrochloride in 8429 patients who were enrolled in placebo-controlled trials, including 6666 exposed for 1 year and 5685 for at least 3 years. - Osteoporosis Treatment Clinical Trial (MORE) — The safety of raloxifene in the treatment of osteoporosis was assessed in a large (7705 patients) multinational, placebo-controlled trial. Duration of treatment was 36 months, and 5129 postmenopausal women were exposed to raloxifene hydrochloride (2557 received 60 mg/day, and 2572 received 120 mg/day). The incidence of all-cause mortality was similar among groups: 23 (0.9%) placebo, 13 (0.5%) raloxifene hydrochloride-treated (raloxifene HCl 60 mg), and 28 (1.1%) raloxifene HCl 120 mg women died. Therapy was discontinued due to an adverse reaction in 10.9% of raloxifene hydrochloride-treated women and 8.8% of placebo-treated women. - Venous Thromboembolism: The most serious adverse reaction related to raloxifene hydrochloride was VTE (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis). During an average of study-drug exposure of 2.6 years, VTE occurred in about 1 out of 100 patients treated with raloxifene hydrochloride. Twenty-six raloxifene hydrochloride-treated women had a VTE compared to 11 placebo-treated women, the hazard ratio was 2.4 (95% confidence interval, 1.2, 4.5), and the highest VTE risk was during the initial months of treatment. - Common adverse reactions considered to be related to raloxifene hydrochloride therapy were hot flashes and leg cramps. Hot flashes occurred in about one in 10 patients on raloxifene hydrochloride and were most commonly reported during the first 6 months of treatment and were not different from placebo thereafter. Leg cramps occurred in about one in 14 patients on raloxifene hydrochloride. - Placebo-Controlled Osteoporosis Prevention Clinical Trials — The safety of raloxifene has been assessed primarily in 12 Phase 2 and Phase 3 studies with placebo, estrogen, and estrogen-progestin therapy control groups. The duration of treatment ranged from 2 to 30 months, and 2036 women were exposed to raloxifene HCl (371 patients received 10 to 50 mg/day, 828 received 60 mg/day, and 837 received from 120 to 600 mg/day). - Therapy was discontinued due to an adverse reaction in 11.4% of 581 raloxifene hydrochloride-treated women and 12.2% of 584 placebo-treated women. Discontinuation rates due to hot flashes did not differ significantly between raloxifene hydrochloride and placebo groups (1.7% and 2.2%, respectively). - Common adverse reactions considered to be drug-related were hot flashes and leg cramps. Hot flashes occurred in about one in four patients on raloxifene hydrochloride versus about one in six on placebo. The first occurrence of hot flashes was most commonly reported during the first 6 months of treatment. - Table 1 lists adverse reactions occurring in either the osteoporosis treatment or in five prevention placebo-controlled clinical trials at a frequency ≥2.0% in either group and in more raloxifene hydrochloride-treated women than in placebo-treated women. Adverse reactions are shown without attribution of causality. The majority of adverse reactions occurring during the studies were mild and generally did not require discontinuation of therapy. - Comparison of Raloxifene hydrochloride and Hormone Therapy — Raloxifene hydrochloride was compared with estrogen-progestin therapy in three clinical trials for prevention of osteoporosis. Table 2 shows adverse reactions occurring more frequently in one treatment group and at an incidence ≥2.0% in any group. Adverse reactions are shown without attribution of causality. - Breast Pain — Across all placebo-controlled trials, raloxifene hydrochloride was indistinguishable from placebo with regard to frequency and severity of breast pain and tenderness. Raloxifene hydrochloride was associated with less breast pain and tenderness than reported by women receiving estrogens with or without added progestin. - Gynecologic Cancers — Raloxifene hydrochloride-treated and placebo-treated groups had similar incidences of endometrial cancer and ovarian cancer. - Placebo-Controlled Trial of Postmenopausal Women at Increased Risk for Major Coronary Events (RUTH) — The safety of raloxifene hydrochloride (60 mg once daily) was assessed in a placebo-controlled multinational trial of 10,101 postmenopausal women (age range 55-92) with documented coronary heart disease (CHD) or multiple CHD risk factors. Median study drug exposure was 5.1 years for both treatment groups. Therapy was discontinued due to an adverse reaction in 25% of 5044 raloxifene hydrochloride-treated women and 24% of 5057 placebo-treated women. The incidence per year of all-cause mortality was similar between the raloxifene (2.07%) and placebo (2.25%) groups. - Adverse reactions reported more frequently in raloxifene hydrochloride-treated women than in placebo-treated women included peripheral edema (14.1% raloxifene versus 11.7% placebo), muscle spasms/leg cramps (12.1% raloxifene versus 8.3% placebo), hot flashes (7.8% raloxifene versus 4.7% placebo), venous thromboembolic events (2.0% raloxifene versus 1.4% placebo), and cholelithiasis (3.3% raloxifene versus 2.6% placebo). - Tamoxifen-Controlled Trial of Postmenopausal Women at Increased Risk for Invasive Breast Cancer (STAR) — The safety of raloxifene hydrochloride 60 mg/day versus tamoxifen 20 mg/day over 5 years was assessed in 19,747 postmenopausal women (age range 35-83 years) in a randomized, double-blind trial. As of 31 December 2005, the median follow-up was 4.3 years. The safety profile of raloxifene was similar to that in the placebo-controlled raloxifene trials. ## Postmarketing Experience - 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. - Adverse reactions reported very rarely since market introduction include retinal vein occlusion, stroke, and death associated with venous thromboembolism (VTE). # Drug Interactions - Cholestyramine - Concomitant administration of cholestyramine with raloxifene hydrochloride is not recommended. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect. Raloxifene hydrochloride should not be co-administered with other anion exchange resins. - Warfarin - If raloxifene hydrochloride is given concomitantly with warfarin or other warfarin derivatives, prothrombin time should be monitored more closely when starting or stopping therapy with raloxifene hydrochloride. - Other Highly Protein-Bound Drugs - Raloxifene hydrochloride should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine. Although not examined, raloxifene hydrochloride might affect the protein binding of other drugs. Raloxifene is more than 95% bound to plasma proteins. - Systemic Estrogens - The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended. - Other Concomitant Medications - Raloxifene hydrochloride can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin. - The concomitant use of raloxifene hydrochloride and lipid-lowering agents has not been studied. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - Raloxifene hydrochloride should not be used in women who are or may become pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Raloxifene in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Raloxifene during labor and delivery. ### Nursing Mothers - Raloxifene hydrochloride should not be used by lactating women. 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 raloxifene is administered to a nursing woman. ### Pediatric Use There is no FDA guidance on the use of Raloxifene with respect to pediatric patients. ### Geriatic Use - Of the total number of patients in placebo-controlled clinical studies of raloxifene hydrochloride, 61% were 65 and over, while 15.5% were 75 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. Based on clinical trials, there is no need for dose adjustment for geriatric patients. ### Gender There is no FDA guidance on the use of Raloxifene with respect to specific gender populations. ### Race There is no FDA guidance on the use of Raloxifene with respect to specific racial populations. ### Renal Impairment - Raloxifene hydrochloride should be used with caution in patients with moderate or severe renal impairment. ### Hepatic Impairment - Raloxifene hydrochloride should be used with caution in patients with moderate or severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Raloxifene in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Raloxifene in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Raloxifene in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Raloxifene in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - In an 8-week study of 63 postmenopausal women, a dose of raloxifene hydrochloride (HCl) 600 mg/day was safely tolerated. In clinical trials, no raloxifene overdose has been reported. - In postmarketing spontaneous reports, raloxifene overdose has been reported very rarely (less than 1 out of 10,000 patients treated). The highest overdose has been approximately 1.5 grams. No fatalities associated with raloxifene overdose have been reported. Adverse reactions were reported in approximately half of the adults who took ≥180 mg raloxifene HCl and included leg cramps and dizziness. - Two 18-month-old children each ingested raloxifene HCl 180 mg. In these two children, symptoms reported included ataxia, dizziness, vomiting, rash, diarrhea, tremor, and flushing, as well as elevation in alkaline phosphatase. - No mortality was seen after a single oral dose in rats or mice at 5000 mg/kg (810 times the human dose for rats and 405 times the human dose for mice based on surface area, mg/m2) or in monkeys at 1000 mg/kg (80 times the AUC in humans). ### Management - There is no specific antidote for raloxifene. ## Chronic Overdose There is limited information regarding Chronic Overdose of Raloxifene in the drug label. # Pharmacology ## Mechanism of Action - Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promoters. - Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. These results are consistent with findings in clinical trials, which suggest that raloxifene hydrochloride lacks estrogen-like effects on the uterus and breast tissue. ## Structure - Raloxifene hydrochloride is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The chemical structure is: - The chemical designation is methanone, thien-3-yl]-phenyl]-, hydrochloride. Raloxifene hydrochloride (HCl) has the empirical formula C28H27NO4SHCl, which corresponds to a molecular weight of 510.05. Raloxifene HCl is an off-white to pale-yellow solid that is very slightly soluble in water. - Raloxifene hydrochloride is supplied in a tablet dosage form for oral administration. Each raloxifene hydrochloride tablet contains 60 mg of raloxifene HCl, which is the molar equivalent of 55.71 mg of free base. Inactive ingredients include anhydrous lactose, carnauba wax, crospovidone, FD&C Blue No. 2 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, modified pharmaceutical glaze, polyethylene glycol, polysorbate 80, povidone, propylene glycol, and titanium dioxide. ## Pharmacodynamics - Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and accelerated bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. In addition to loss of estrogen, this imbalance between resorption and formation may be due to age-related impairment of osteoblasts or their precursors. In some women, these changes will eventually lead to decreased bone mass, osteoporosis, and increased risk for fractures, particularly of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women. - In both the osteoporosis treatment and prevention trials, raloxifene hydrochloride therapy resulted in consistent, statistically significant suppression of bone resorption and bone formation, as reflected by changes in serum and urine markers of bone turnover (e.g., bone-specific alkaline phosphatase, osteocalcin, and collagen breakdown products). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 36-month and 24-month observation periods. - In a 31-week, open-label, radiocalcium kinetics study, 33 early postmenopausal women were randomized to treatment with once-daily raloxifene hydrochloride 60 mg, cyclic estrogen/progestin (0.625 mg conjugated estrogens daily with 5 mg medroxyprogesterone acetate daily for the first 2 weeks of each month ), or no treatment. Treatment with either raloxifene hydrochloride or hormone therapy was associated with reduced bone resorption and a positive shift in calcium balance (-82 mg Ca/day and +60 mg Ca/day, respectively, for raloxifene hydrochloride and -162 mg Ca/day and +91 mg Ca/day, respectively, for hormone therapy). - There were small decreases in serum total calcium, inorganic phosphate, total protein, and albumin, which were generally of lesser magnitude than decreases observed during estrogen or hormone therapy. Platelet count was also decreased slightly and was not different from estrogen therapy. ## Pharmacokinetics - The disposition of raloxifene has been evaluated in more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials, using a population approach. Pharmacokinetic data also were obtained in conventional pharmacology studies in 292 postmenopausal women. Raloxifene exhibits high within-subject variability (approximately 30% coefficient of variation) of most pharmacokinetic parameters. Table 3 summarizes the pharmacokinetic parameters of raloxifene. - Absorption — Raloxifene is absorbed rapidly after oral administration. Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is 2%. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites. - Administration of raloxifene HCl with a standardized, high-fat meal increases the absorption of raloxifene (Cmax 28% and AUC 16%), but does not lead to clinically meaningful changes in systemic exposure. Raloxifene hydrochloride can be administered without regard to meals. - Distribution — Following oral administration of single doses ranging from 30 to 150 mg of raloxifene HCl, the apparent volume of distribution is 2348 L/kg and is not dose dependent. - Raloxifene and the monoglucuronide conjugates are highly (95%) bound to plasma proteins. Raloxifene binds to both albumin and α1-acid glycoprotein, but not to sex-steroid binding globulin. - Metabolism — Biotransformation and disposition of raloxifene in humans have been determined following oral administration of 14C-labeled raloxifene. Raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates: raloxifene-4′-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4′-diglucuronide. No other metabolites have been detected, providing strong evidence that raloxifene is not metabolized by cytochrome P450 pathways. Unconjugated raloxifene comprises less than 1% of the total radiolabeled material in plasma. The terminal log-linear portions of the plasma concentration curves for raloxifene and the glucuronides are generally parallel. This is consistent with interconversion of raloxifene and the glucuronide metabolites. - Following intravenous administration, raloxifene is cleared at a rate approximating hepatic blood flow. Apparent oral clearance is 44.1 L/kghr. Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling, thereby prolonging its plasma elimination half-life to 27.7 hours after oral dosing. - Results from single oral doses of raloxifene predict multiple-dose pharmacokinetics. Following chronic dosing, clearance ranges from 40 to 60 L/kghr. Increasing doses of raloxifene HCl (ranging from 30 to 150 mg) result in slightly less than a proportional increase in the area under the plasma time concentration curve (AUC). - Excretion — Raloxifene is primarily excreted in feces, and less than 0.2% is excreted unchanged in urine. Less than 6% of the raloxifene dose is eliminated in urine as glucuronide conjugates. - Special Populations - Pediatric — The pharmacokinetics of raloxifene has not been evaluated in a pediatric population. - Geriatric — No differences in raloxifene pharmacokinetics were detected with regard to age (range 42 to 84 years). - Gender — Total extent of exposure and oral clearance, normalized for lean body weight, are not significantly different between age-matched female and male volunteers. - Race — Pharmacokinetic differences due to race have been studied in 1712 women, including 97.5% White, 1.0% Asian, 0.7% Hispanic, and 0.5% Black in the osteoporosis treatment trial and in 1053 women, including 93.5% White, 4.3% Hispanic, 1.2% Asian, and 0.5% Black in the osteoporosis prevention trials. There were no discernible differences in raloxifene plasma concentrations among these groups; however, the influence of race cannot be conclusively determined. - Renal Impairment — In the osteoporosis treatment and prevention trials, raloxifene concentrations in women with mild renal impairment are similar to women with normal creatinine clearance. When a single dose of 120 mg raloxifene HCl was administered to 10 renally impaired males and to 10 healthy males (CrCl >80 mL/min), plasma raloxifene concentrations were 122% (AUC0-∞) higher in renally impaired patients than those of healthy volunteers. Raloxifene should be used with caution in patients with moderate or severe renal impairment. - Hepatic Impairment — The disposition of raloxifene was compared in 9 patients with mild (Child-Pugh Class A) hepatic impairment (total bilirubin ranging from 0.6 to 2 mg/dL) to 8 subjects with normal hepatic function following a single dose of 60 mg raloxifene HCl. Apparent clearance of raloxifene was reduced 56% and the half-life of raloxifene was not altered in patients with mild hepatic impairment. Plasma raloxifene concentrations were approximately 150% higher than those in healthy volunteers and correlated with total bilirubin concentrations. The pharmacokinetics of raloxifene has not been studied in patients with moderate or severe hepatic impairment. Raloxifene should be used with caution in patients with hepatic impairment. - Drug Interactions - Cholestyramine — Cholestyramine, an anion exchange resin, causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene after a single dose. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect. - Warfarin — In vitro, raloxifene did not interact with the binding of warfarin. The concomitant administration of raloxifene hydrochloride and warfarin, a coumarin derivative, has been assessed in a single-dose study. In this study, raloxifene had no effect on the pharmacokinetics of warfarin. However, a 10% decrease in prothrombin time was observed in the single-dose study. In the osteoporosis treatment trial, there were no clinically relevant effects of warfarin co-administration on plasma concentrations of raloxifene. - Other Highly Protein-Bound Drugs — In the osteoporosis treatment trial, there were no clinically relevant effects of co-administration of other highly protein-bound drugs (e.g., gemfibrozil) on plasma concentrations of raloxifene. In vitro, raloxifene did not interact with the binding of phenytoin, tamoxifen, or warfarin (see above). - Ampicillin and Amoxicillin — Peak concentrations of raloxifene and the overall extent of absorption are reduced 28% and 14%, respectively, with co-administration of ampicillin. These reductions are consistent with decreased enterohepatic cycling associated with antibiotic reduction of enteric bacteria. However, the systemic exposure and the elimination rate of raloxifene were not affected. In the osteoporosis treatment trial, co-administration of amoxicillin had no discernible differences in plasma raloxifene concentrations. - Antacids — Concomitant administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene. - Corticosteroids — The chronic administration of raloxifene in postmenopausal women has no effect on the pharmacokinetics of methylprednisolone given as a single oral dose. - Digoxin — Raloxifene has no effect on the pharmacokinetics of digoxin. - Cyclosporine — Concomitant administration of raloxifene hydrochloride with cyclosporine has not been studied. - Lipid-Lowering Agents — Concomitant administration of raloxifene hydrochloride with lipid-lowering agents has not been studied. ## Nonclinical Toxicology - Carcinogenesis — In a 21-month carcinogenicity study in mice, there was an increased incidence of ovarian tumors in female animals given 9 to 242 mg/kg, which included benign and malignant tumors of granulosa/theca cell origin and benign tumors of epithelial cell origin. Systemic exposure (AUC) of raloxifene in this group was 0.3 to 34 times that in postmenopausal women administered a 60 mg dose. There was also an increased incidence of testicular interstitial cell tumors and prostatic adenomas and adenocarcinomas in male mice given 41 or 210 mg/kg (4.7 or 24 times the AUC in humans) and prostatic leiomyoblastoma in male mice given 210 mg/kg. - In a 2-year carcinogenicity study in rats, an increased incidence in ovarian tumors of granulosa/theca cell origin was observed in female rats given 279 mg/kg (approximately 400 times the AUC in humans). The female rodents in these studies were treated during their reproductive lives when their ovaries were functional and responsive to hormonal stimulation. - Mutagenesis — Raloxifene HCl was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis with and without metabolic activation, the unscheduled DNA synthesis assay in rat hepatocytes, the mouse lymphoma assay for mammalian cell mutation, the chromosomal aberration assay in Chinese hamster ovary cells, the in vivo sister chromatid exchange assay in Chinese hamsters, and the in vivo micronucleus test in mice. - Impairment of Fertility — When male and female rats were given daily doses ≥5 mg/kg (≥0.8 times the human dose based on surface area, mg/m2) prior to and during mating, no pregnancies occurred. In male rats, daily doses up to 100 mg/kg (16 times the human dose based on surface area, mg/m2) for at least 2 weeks did not affect sperm production or quality or reproductive performance. In female rats, at doses of 0.1 to 10 mg/kg/day (0.02 to 1.6 times the human dose based on surface area, mg/m2), raloxifene disrupted estrous cycles and inhibited ovulation. These effects of raloxifene were reversible. In another study in rats in which raloxifene was given during the preimplantation period at doses ≥0.1 mg/kg (≥0.02 times the human dose based on surface area, mg/m2), raloxifene delayed and disrupted embryo implantation, resulting in prolonged gestation and reduced litter size. The reproductive and developmental effects observed in animals are consistent with the estrogen receptor activity of raloxifene. - The skeletal effects of raloxifene treatment were assessed in ovariectomized rats and monkeys. In rats, raloxifene prevented increased bone resorption and bone loss after ovariectomy. There were positive effects of raloxifene on bone strength, but the effects varied with time. Cynomolgus monkeys were treated with raloxifene or conjugated estrogens for 2 years. In terms of bone cycles, this is equivalent to approximately 6 years in humans. Raloxifene and estrogen suppressed bone turnover and increased BMD in the lumbar spine and in the central cancellous bone of the proximal tibia. In this animal model, there was a positive correlation between vertebral compressive breaking force and BMD of the lumbar spine. - Histologic examination of bone from rats and monkeys treated with raloxifene showed no evidence of woven bone, marrow fibrosis, or mineralization defects. - These results are consistent with data from human studies of radiocalcium kinetics and markers of bone metabolism, and are consistent with the action of raloxifene hydrochloride as a skeletal antiresorptive agent. # Clinical Studies - Effect on Fracture Incidence - The effects of raloxifene hydrochloride on fracture incidence and BMD in postmenopausal women with osteoporosis were examined at 3 years in a large randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial (MORE). All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (i.e., clinical fractures). The study population consisted of 7705 postmenopausal women with osteoporosis as defined by: a) low BMD (vertebral or hip BMD at least 2.5 standard deviations below the mean value for healthy young women) without baseline vertebral fractures or b) one or more baseline vertebral fractures. Women enrolled in this study had a median age of 67 years (range 31 to 80) and a median time since menopause of 19 years. - Effect on Bone Mineral Density - Raloxifene hydrochloride, 60 mg administered once daily, increased spine and hip BMD by 2 to 3%. Raloxifene hydrochloride decreased the incidence of the first vertebral fracture from 4.3% for placebo to 1.9% for raloxifene hydrochloride (relative risk reduction = 55%) and subsequent vertebral fractures from 20.2% for placebo to 14.1% for raloxifene hydrochloride (relative risk reduction = 30%) (see Table 4). All women in the study received calcium (500 mg/day) and vitamin D (400 to 600 IU/day). Raloxifene hydrochloride reduced the incidence of vertebral fractures whether or not patients had a vertebral fracture upon study entry. The decrease in incidence of vertebral fracture was greater than could be accounted for by increase in BMD alone. - The mean percentage change in BMD from baseline for raloxifene hydrochloride was statistically significantly greater than for placebo at each skeletal site (see Table 5). - Discontinuation from the study was required when excessive bone loss or multiple incident vertebral fractures occurred. Such discontinuation was statistically significantly more frequent in the placebo group (3.7%) than in the raloxifene hydrochloride group (1.1%). - Bone Histology - Bone biopsies for qualitative and quantitative histomorphometry were obtained at baseline and after 2 years of treatment. There were 56 paired biopsies evaluable for all indices. In raloxifene hydrochloride-treated patients, there were statistically significant decreases in bone formation rate per tissue volume, consistent with a reduction in bone turnover. Normal bone quality was maintained; specifically, there was no evidence of osteomalacia, marrow fibrosis, cellular toxicity, or woven bone after 2 years of treatment. - Effect on Endometrium - Endometrial thickness was evaluated annually in a subset of the study population (1781 patients) for 3 years. Placebo-treated women had a 0.27 mm mean decrease from baseline in endometrial thickness over 3 years, whereas the raloxifene hydrochloride-treated women had a 0.06 mm mean increase. Patients in the osteoporosis treatment study were not screened at baseline or excluded for pre-existing endometrial or uterine disease. This study was not specifically designed to detect endometrial polyps. Over the 36 months of the study, clinically or histologically benign endometrial polyps were reported in 17 of 1999 placebo-treated women, 37 of 1948 raloxifene hydrochloride-treated women, and in 31 of 2010 women treated with raloxifene HCl 120 mg/day. There was no difference between raloxifene hydrochloride- and placebo-treated women in the incidences of endometrial carcinoma, vaginal bleeding, or vaginal discharge. - The effects of raloxifene hydrochloride on BMD in postmenopausal women were examined in three randomized, placebo-controlled, double-blind osteoporosis prevention trials: (1) a North American trial enrolled 544 women; (2) a European trial, 601 women; and (3) an international trial, 619 women who had undergone hysterectomy. In these trials, all women received calcium supplementation (400 to 600 mg/day). Women enrolled in these trials had a median age of 54 years and a median time since menopause of 5 years (less than 1 year up to 15 years postmenopause). The majority of the women were White (93.5%). Women were included if they had spine BMD between 2.5 standard deviations below and 2 standard deviations above the mean value for healthy young women. The mean T scores (number of standard deviations above or below the mean in healthy young women) for the three trials ranged from -1.01 to -0.74 for spine BMD and included women both with normal and low BMD. Raloxifene hydrochloride, 60 mg administered once daily, produced increases in bone mass versus calcium supplementation alone, as reflected by dual-energy x-ray absorptiometric (DXA) measurements of hip, spine, and total body BMD. - Effect on Bone Mineral Density - Compared with placebo, the increases in BMD for each of the three studies were statistically significant at 12 months and were maintained at 24 months (see Table 6). The placebo groups lost approximately 1% of BMD over 24 months. - Raloxifene hydrochloride also increased BMD compared with placebo in the total body by 1.3% to 2.0% and in Ward's Triangle (hip) by 3.1% to 4.0%. The effects of raloxifene hydrochloride on forearm BMD were inconsistent between studies. In Study EU, raloxifene hydrochloride prevented bone loss at the ultradistal radius, whereas in Study NA, it did not (see Figure 1). - Effect on Endometrium - In placebo-controlled osteoporosis prevention trials, endometrial thickness was evaluated every 6 months (for 24 months) by transvaginal ultrasonography (TVU). A total of 2978 TVU measurements were collected from 831 women in all dose groups. Placebo-treated women had a 0.04 mm mean increase from baseline in endometrial thickness over 2 years, whereas the raloxifene hydrochloride-treated women had a 0.09 mm mean increase. Endometrial thickness measurements in raloxifene-treated women were indistinguishable from placebo. There were no differences between the raloxifene and placebo groups with respect to the incidence of reported vaginal bleeding. - MORE Trial - The effect of raloxifene hydrochloride on the incidence of breast cancer was assessed as a secondary safety endpoint in a randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial in postmenopausal women. After 4 years, raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of all breast cancers by 62%, compared with placebo (HR 0.38, 95% CI 0.22-0.67). Raloxifene hydrochloride reduced the incidence of invasive breast cancer by 71%, compared with placebo (ARR 3.1 per 1000 women-years); this was primarily due to an 80% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo. Table 7 presents efficacy and selected safety outcomes. - CORE Trial - The effect of raloxifene hydrochloride on the incidence of invasive breast cancer was evaluated for 4 additional years in a follow-up study conducted in a subset of postmenopausal women originally enrolled in the MORE osteoporosis treatment trial. Women were not re-randomized; the treatment assignment from the osteoporosis treatment trial was carried forward to this study. Raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 56%, compared with placebo (ARR 3.0 per 1000 women-years); this was primarily due to a 63% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo. There was no reduction in the incidence of ER-negative breast cancer. In the osteoporosis treatment trial and the follow-up study, there was no difference in incidence of noninvasive breast cancer between the raloxifene hydrochloride and placebo groups. Table 7 presents efficacy and selected safety outcomes. - In a subset of postmenopausal women followed for up to 8 years from randomization in MORE to the end of CORE, raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 60% in women assigned raloxifene hydrochloride (N=1355) compared with placebo (N=1286) (HR 0.40, 95% CI 0.21, 0.77; ARR 1.95 per 1000 women-years); this was primarily due to a 65% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo. - RUTH Trial - The effect of raloxifene hydrochloride on the incidence of invasive breast cancer was assessed in a randomized, placebo-controlled, double-blind, multinational study in 10,101 postmenopausal women at increased risk of coronary events. Women in this study had a median age of 67.6 years (range 55-92) and were followed for a median of 5.6 years (range 0.01-7.1). Eighty-four percent were White, 9.8% of women reported a first-degree relative with a history of breast cancer, and 41.4% of the women had a 5-year predicted risk of invasive breast cancer ≥1.66%, based on the modified Gail model. - Raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 44% compared with placebo ; this was primarily due to a 55% reduction in estrogen receptor (ER)-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo (ARR 1.2 per 1000 women-years). There was no reduction in ER-negative invasive breast cancer. Table 8 presents efficacy and selected safety outcomes. - The effect of raloxifene hydrochloride in reducing the incidence of invasive breast cancer was consistent among women above or below age 65 or with a 5-year predicted invasive breast cancer risk, based on the modified Gail model, <1.66%, or ≥1.66%. - STAR Trial - The effects of raloxifene hydrochloride 60 mg/day versus tamoxifen 20 mg/day over 5 years on reducing the incidence of invasive breast cancer were assessed in 19,747 postmenopausal women in a randomized, double-blind trial conducted in North America by the National Surgical Adjuvant Breast and Bowel Project and sponsored by the National Cancer Institute. Women in this study had a mean age of 58.5 years (range 35-83), a mean 5-year predicted invasive breast cancer risk of 4.03% (range 1.66-23.61%), and 9.1% had a history of lobular carcinoma in situ (LCIS). More than 93% of participants were White. As of 31 December 2005, the median time of follow-up was 4.3 years (range 0.07-6.50 years). - Raloxifene hydrochloride was not superior to tamoxifen in reducing the incidence of invasive breast cancer. The observed incidence rates of invasive breast cancer were raloxifene hydrochloride 4.4 and tamoxifen 4.3 per 1000 women per year. The results from a noninferiority analysis are consistent with raloxifene hydrochloride potentially losing up to 35% of the tamoxifen effect on reduction of invasive breast cancer. The effect of each treatment on invasive breast cancer was consistent when women were compared by baseline age, history of LCIS, history of atypical hyperplasia, 5-year predicted risk of breast cancer by the modified Gail model, or the number of relatives with a history of breast cancer. Fewer noninvasive breast cancers occurred in the tamoxifen group compared to the raloxifene hydrochloride group. Table 9 presents efficacy and selected safety outcomes. - Effects on Cardiovascular Disease - In a randomized, placebo-controlled, double-blind, multinational clinical trial (RUTH) of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene hydrochloride 60 mg once daily for a median follow-up of 5.6 years. No significant increase or decrease was observed for coronary events (death from coronary causes, nonfatal myocardial infarction, or hospitalization for an acute coronary syndrome). An increased risk of death due to stroke after treatment with raloxifene hydrochloride was observed: 59 (1.2%) raloxifene hydrochloride-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (2.2 versus 1.5 per 1000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499). The incidence of stroke did not differ significantly between treatment groups (249 with raloxifene hydrochloride versus 224 with placebo ; hazard ratio 1.10; 95% confidence interval 0.92-1.32; p=0.30; 9.5 versus 8.6 per 1000 women-years). # How Supplied - Raloxifene hydrochloride 60 mg tablets are white, elliptical, and film coated. They are imprinted on one side with the tablet code 4810 in edible blue ink. They are available as follows: - Bottles of 30 (unit of use) NDC 0002-4165-30 - Bottles of 100 (unit of use) NDC 0002-4165-02 - Bottles of 2000 NDC 0002-4165-07 - Storage and Handling - Store at controlled room temperature, 20° to 25°C (68° to 77°F). The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses. ## Storage There is limited information regarding Raloxifene Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation - Patient Immobilization - Raloxifene hydrochloride should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and patients should be advised to avoid prolonged restrictions of movement during travel because of the increased risk of venous thromboembolic events. - Hot Flashes or Flushes - Raloxifene hydrochloride may increase the incidence of hot flashes and is not effective in reducing hot flashes or flushes associated with estrogen deficiency. In some asymptomatic patients, hot flashes may occur upon beginning raloxifene hydrochloride therapy. - Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis or at High Risk of Invasive Breast Cancer - Use of raloxifene hydrochloride is associated with the reduction of the risk of invasive breast cancer in postmenopausal women. Raloxifene hydrochloride has not been shown to reduce the risk of noninvasive breast cancer. When considering treatment, physicians need to discuss the potential benefits and risks of raloxifene hydrochloride treatment with the patient. - Raloxifene hydrochloride is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence. - Patients should have breast exams and mammograms before starting raloxifene hydrochloride and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with raloxifene hydrochloride. # Precautions with Alcohol - Alcohol-Raloxifene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Evista® # Look-Alike Drug Names - Evista® —AVINza® # Drug Shortage Status # Price	Raloxifene Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2] # Disclaimer WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here. # Black Box Warning # Overview Raloxifene is an selective estrogen receptor modulator that is FDA approved for the {{{indicationType}}} of osteoporosis in postmenopausal women, reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis, reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer. There is a Black Box Warning for this drug as shown here. Common adverse reactions include hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, sweating. # Adult Indications and Dosage ## FDA-Labeled Indications and Dosage (Adult) - Recommended Dosing - The recommended dosage is one 60 mg raloxifene hydrochloride tablet daily, which may be administered any time of day without regard to meals. - For the indications in risk of invasive breast cancer the optimum duration of treatment is not known. - Recommendations for Calcium and Vitamin D Supplementation - For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones. The recommended intake of vitamin D is 400-800 IU daily. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplements. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered. - Recommended Dosing - The recommended dosage is one 60 mg raloxifene hydrochloride tablet daily, which may be administered any time of day without regard to meals. - For the indications in risk of invasive breast cancer the optimum duration of treatment is not known. - Recommendations for Calcium and Vitamin D Supplementation - For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate. Postmenopausal women require an average of 1500 mg/day of elemental calcium. Total daily intake of calcium above 1500 mg has not demonstrated additional bone benefits while daily intake above 2000 mg has been associated with increased risk of adverse effects, including hypercalcemia and kidney stones. The recommended intake of vitamin D is 400-800 IU daily. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home bound, or chronically ill) may need additional vitamin D supplements. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered. - Raloxifene hydrochloride is indicated for the reduction in risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer. - The effect in the reduction in the incidence of breast cancer was shown in a study of postmenopausal women at high risk for breast cancer with a 5-year planned duration with a median follow-up of 4.3 years. Twenty-seven percent of the participants received drug for 5 years. The long-term effects and the recommended length of treatment are not known. - High risk of breast cancer is defined as at least one breast biopsy showing lobular carcinoma in situ (LCIS) or atypical hyperplasia, one or more first-degree relatives with breast cancer, or a 5-year predicted risk of breast cancer ≥1.66% (based on the modified Gail model). Among the factors included in the modified Gail model are the following: current age, number of first-degree relatives with breast cancer, number of breast biopsies, age at menarche, nulliparity or age of first live birth. Healthcare professionals can obtain a Gail Model Risk Assessment Tool by dialing 1-800-545-5979. Currently, no single clinical finding or test result can quantify risk of breast cancer with certainty. - After an assessment of the risk of developing breast cancer, the decision regarding therapy with raloxifene hydrochloride should be based upon an individual assessment of the benefits and risks. - Raloxifene hydrochloride does not eliminate the risk of breast cancer. Patients should have breast exams and mammograms before starting raloxifene hydrochloride and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with raloxifene hydrochloride. - Important Limitations of Use for Breast Cancer Risk Reduction - There are no data available regarding the effect of raloxifene hydrochloride on invasive breast cancer incidence in women with inherited mutations (BRCA1, BRCA2) to be able to make specific recommendations on the effectiveness of raloxifene hydrochloride. - Raloxifene hydrochloride is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence. - Raloxifene hydrochloride is not indicated for the reduction in the risk of noninvasive breast cancer. ## Off-Label Use and Dosage (Adult) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Raloxifene in adult patients. ### Non–Guideline-Supported Use - Dosing Information - Oral raloxifene 60 mg/day.[1] # Pediatric Indications and Dosage ## FDA-Labeled Indications and Dosage (Pediatric) There is limited information regarding FDA-Labeled Use of Raloxifene in pediatric patients. ## Off-Label Use and Dosage (Pediatric) ### Guideline-Supported Use There is limited information regarding Off-Label Guideline-Supported Use of Raloxifene in pediatric patients. ### Non–Guideline-Supported Use There is limited information regarding Off-Label Non–Guideline-Supported Use of Raloxifene in pediatric patients. # Contraindications - Venous Thromboembolism - Raloxifene hydrochloride is contraindicated in women with active or past history of venous thromboembolism (VTE), including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis. - Pregnancy, Women Who May Become Pregnant, and Nursing Mothers - Raloxifene hydrochloride is contraindicated in pregnancy, in women who may become pregnant, and in nursing mothers. Raloxifene hydrochloride may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. - In rabbit studies, abortion and a low rate of fetal heart anomalies (ventricular septal defects) occurred in rabbits at doses ≥0.1 mg/kg (≥0.04 times the human dose based on surface area, mg/m2), and hydrocephaly was observed in fetuses at doses ≥10 mg/kg (≥4 times the human dose based on surface area, mg/m2). In rat studies, retardation of fetal development and developmental abnormalities (wavy ribs, kidney cavitation) occurred at doses ≥1 mg/kg (≥0.2 times the human dose based on surface area, mg/m2). Treatment of rats at doses of 0.1 to 10 mg/kg (0.02 to 1.6 times the human dose based on surface area, mg/m2) during gestation and lactation produced effects that included delayed and disrupted parturition; decreased neonatal survival and altered physical development; sex- and age-specific reductions in growth and changes in pituitary hormone content; and decreased lymphoid compartment size in offspring. At 10 mg/kg, raloxifene disrupted parturition, which resulted in maternal and progeny death and morbidity. Effects in adult offspring (4 months of age) included uterine hypoplasia and reduced fertility; however, no ovarian or vaginal pathology was observed. # Warnings ### Precautions - Venous Thromboembolism - In clinical trials, raloxifene hydrochloride-treated women had an increased risk of venous thromboembolism (deep vein thrombosis and pulmonary embolismOther venous thromboembolic events also could occur. A less serious event, superficial thrombophlebitis, also has been reported more frequently with raloxifene hydrochloride than with placebo. The greatest risk for deep vein thrombosis and pulmonary embolism occurs during the first 4 months of treatment, and the magnitude of risk appears to be similar to the reported risk associated with use of hormone therapy. Because immobilization increases the risk for venous thromboembolic events independent of therapy, raloxifene hydrochloride should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and raloxifene hydrochloride therapy should be resumed only after the patient is fully ambulatory. In addition, women taking raloxifene hydrochloride should be advised to move about periodically during prolonged travel. The risk-benefit balance should be considered in women at risk of thromboembolic disease for other reasons, such as congestive heart failure, superficial thrombophlebitis, and active malignancy. - Death Due to Stroke - In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, an increased risk of death due to stroke was observed after treatment with raloxifene hydrochloride. During an average follow-up of 5.6 years, 59 (1.2%) raloxifene hydrochloride-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (22 versus 15 per 10,000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499). There was no statistically significant difference between treatment groups in the incidence of stroke (249 in raloxifene hydrochloride [4.9%] versus 224 placebo [4.4%]). Raloxifene hydrochloride had no significant effect on all-cause mortality. The risk-benefit balance should be considered in women at risk for stroke, such as prior stroke or transient ischemic attack (TIA), atrial fibrillation, hypertension, or cigarette smoking. - Cardiovascular Disease - Raloxifene hydrochloride should not be used for the primary or secondary prevention of cardiovascular disease. In a clinical trial of postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene for 5 years. - Premenopausal Use - There is no indication for premenopausal use of raloxifene hydrochloride. Safety of raloxifene hydrochloride in premenopausal women has not been established and its use is not recommended. - Hepatic Impairment - Raloxifene hydrochloride should be used with caution in patients with hepatic impairment. Safety and efficacy have not been established in patients with hepatic impairment. - Concomitant Estrogen Therapy - The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended. - History of Hypertriglyceridemia when Treated with Estrogens - Limited clinical data suggest that some women with a history of marked hypertriglyceridemia (>5.6 mmol/L or >500 mg/dL) in response to treatment with oral estrogen or estrogen plus progestin may develop increased levels of triglycerides when treated with raloxifene hydrochloride. Women with this medical history should have serum triglycerides monitored when taking raloxifene hydrochloride. - Renal Impairment - Raloxifene hydrochloride should be used with caution in patients with moderate or severe renal impairment. Safety and efficacy have not been established in patients with moderate or severe renal impairment. - History of Breast Cancer - Raloxifene hydrochloride has not been adequately studied in women with a prior history of breast cancer. - Use in Men - There is no indication for the use of raloxifene hydrochloride in men. Raloxifene hydrochloride has not been adequately studied in men and its use is not recommended. - Unexplained Uterine Bleeding - Any unexplained uterine bleeding should be investigated as clinically indicated. Raloxifene hydrochloride-treated and placebo-treated groups had similar incidences of endometrial proliferation. - Breast Abnormalities - Any unexplained breast abnormality occurring during raloxifene hydrochloride therapy should be investigated. Raloxifene hydrochloride does not eliminate the risk of breast cancer. # Adverse Reactions ## Clinical Trials Experience - Because clinical studies 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 raloxifene hydrochloride in 8429 patients who were enrolled in placebo-controlled trials, including 6666 exposed for 1 year and 5685 for at least 3 years. - Osteoporosis Treatment Clinical Trial (MORE) — The safety of raloxifene in the treatment of osteoporosis was assessed in a large (7705 patients) multinational, placebo-controlled trial. Duration of treatment was 36 months, and 5129 postmenopausal women were exposed to raloxifene hydrochloride (2557 received 60 mg/day, and 2572 received 120 mg/day). The incidence of all-cause mortality was similar among groups: 23 (0.9%) placebo, 13 (0.5%) raloxifene hydrochloride-treated (raloxifene HCl 60 mg), and 28 (1.1%) raloxifene HCl 120 mg women died. Therapy was discontinued due to an adverse reaction in 10.9% of raloxifene hydrochloride-treated women and 8.8% of placebo-treated women. - Venous Thromboembolism: The most serious adverse reaction related to raloxifene hydrochloride was VTE (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis). During an average of study-drug exposure of 2.6 years, VTE occurred in about 1 out of 100 patients treated with raloxifene hydrochloride. Twenty-six raloxifene hydrochloride-treated women had a VTE compared to 11 placebo-treated women, the hazard ratio was 2.4 (95% confidence interval, 1.2, 4.5), and the highest VTE risk was during the initial months of treatment. - Common adverse reactions considered to be related to raloxifene hydrochloride therapy were hot flashes and leg cramps. Hot flashes occurred in about one in 10 patients on raloxifene hydrochloride and were most commonly reported during the first 6 months of treatment and were not different from placebo thereafter. Leg cramps occurred in about one in 14 patients on raloxifene hydrochloride. - Placebo-Controlled Osteoporosis Prevention Clinical Trials — The safety of raloxifene has been assessed primarily in 12 Phase 2 and Phase 3 studies with placebo, estrogen, and estrogen-progestin therapy control groups. The duration of treatment ranged from 2 to 30 months, and 2036 women were exposed to raloxifene HCl (371 patients received 10 to 50 mg/day, 828 received 60 mg/day, and 837 received from 120 to 600 mg/day). - Therapy was discontinued due to an adverse reaction in 11.4% of 581 raloxifene hydrochloride-treated women and 12.2% of 584 placebo-treated women. Discontinuation rates due to hot flashes did not differ significantly between raloxifene hydrochloride and placebo groups (1.7% and 2.2%, respectively). - Common adverse reactions considered to be drug-related were hot flashes and leg cramps. Hot flashes occurred in about one in four patients on raloxifene hydrochloride versus about one in six on placebo. The first occurrence of hot flashes was most commonly reported during the first 6 months of treatment. - Table 1 lists adverse reactions occurring in either the osteoporosis treatment or in five prevention placebo-controlled clinical trials at a frequency ≥2.0% in either group and in more raloxifene hydrochloride-treated women than in placebo-treated women. Adverse reactions are shown without attribution of causality. The majority of adverse reactions occurring during the studies were mild and generally did not require discontinuation of therapy. - Comparison of Raloxifene hydrochloride and Hormone Therapy — Raloxifene hydrochloride was compared with estrogen-progestin therapy in three clinical trials for prevention of osteoporosis. Table 2 shows adverse reactions occurring more frequently in one treatment group and at an incidence ≥2.0% in any group. Adverse reactions are shown without attribution of causality. - Breast Pain — Across all placebo-controlled trials, raloxifene hydrochloride was indistinguishable from placebo with regard to frequency and severity of breast pain and tenderness. Raloxifene hydrochloride was associated with less breast pain and tenderness than reported by women receiving estrogens with or without added progestin. - Gynecologic Cancers — Raloxifene hydrochloride-treated and placebo-treated groups had similar incidences of endometrial cancer and ovarian cancer. - Placebo-Controlled Trial of Postmenopausal Women at Increased Risk for Major Coronary Events (RUTH) — The safety of raloxifene hydrochloride (60 mg once daily) was assessed in a placebo-controlled multinational trial of 10,101 postmenopausal women (age range 55-92) with documented coronary heart disease (CHD) or multiple CHD risk factors. Median study drug exposure was 5.1 years for both treatment groups. Therapy was discontinued due to an adverse reaction in 25% of 5044 raloxifene hydrochloride-treated women and 24% of 5057 placebo-treated women. The incidence per year of all-cause mortality was similar between the raloxifene (2.07%) and placebo (2.25%) groups. - Adverse reactions reported more frequently in raloxifene hydrochloride-treated women than in placebo-treated women included peripheral edema (14.1% raloxifene versus 11.7% placebo), muscle spasms/leg cramps (12.1% raloxifene versus 8.3% placebo), hot flashes (7.8% raloxifene versus 4.7% placebo), venous thromboembolic events (2.0% raloxifene versus 1.4% placebo), and cholelithiasis (3.3% raloxifene versus 2.6% placebo). - Tamoxifen-Controlled Trial of Postmenopausal Women at Increased Risk for Invasive Breast Cancer (STAR) — The safety of raloxifene hydrochloride 60 mg/day versus tamoxifen 20 mg/day over 5 years was assessed in 19,747 postmenopausal women (age range 35-83 years) in a randomized, double-blind trial. As of 31 December 2005, the median follow-up was 4.3 years. The safety profile of raloxifene was similar to that in the placebo-controlled raloxifene trials. ## Postmarketing Experience - 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. - Adverse reactions reported very rarely since market introduction include retinal vein occlusion, stroke, and death associated with venous thromboembolism (VTE). # Drug Interactions - Cholestyramine - Concomitant administration of cholestyramine with raloxifene hydrochloride is not recommended. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect. Raloxifene hydrochloride should not be co-administered with other anion exchange resins. - Warfarin - If raloxifene hydrochloride is given concomitantly with warfarin or other warfarin derivatives, prothrombin time should be monitored more closely when starting or stopping therapy with raloxifene hydrochloride. - Other Highly Protein-Bound Drugs - Raloxifene hydrochloride should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine. Although not examined, raloxifene hydrochloride might affect the protein binding of other drugs. Raloxifene is more than 95% bound to plasma proteins. - Systemic Estrogens - The safety of concomitant use of raloxifene hydrochloride with systemic estrogens has not been established and its use is not recommended. - Other Concomitant Medications - Raloxifene hydrochloride can be concomitantly administered with ampicillin, amoxicillin, antacids, corticosteroids, and digoxin. - The concomitant use of raloxifene hydrochloride and lipid-lowering agents has not been studied. # Use in Specific Populations ### Pregnancy Pregnancy Category (FDA): - Pregnancy Category X - Raloxifene hydrochloride should not be used in women who are or may become pregnant. Pregnancy Category (AUS): - Australian Drug Evaluation Committee (ADEC) Pregnancy Category There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Raloxifene in women who are pregnant. ### Labor and Delivery There is no FDA guidance on use of Raloxifene during labor and delivery. ### Nursing Mothers - Raloxifene hydrochloride should not be used by lactating women. 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 raloxifene is administered to a nursing woman. ### Pediatric Use There is no FDA guidance on the use of Raloxifene with respect to pediatric patients. ### Geriatic Use - Of the total number of patients in placebo-controlled clinical studies of raloxifene hydrochloride, 61% were 65 and over, while 15.5% were 75 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. Based on clinical trials, there is no need for dose adjustment for geriatric patients. ### Gender There is no FDA guidance on the use of Raloxifene with respect to specific gender populations. ### Race There is no FDA guidance on the use of Raloxifene with respect to specific racial populations. ### Renal Impairment - Raloxifene hydrochloride should be used with caution in patients with moderate or severe renal impairment. ### Hepatic Impairment - Raloxifene hydrochloride should be used with caution in patients with moderate or severe hepatic impairment. ### Females of Reproductive Potential and Males There is no FDA guidance on the use of Raloxifene in women of reproductive potentials and males. ### Immunocompromised Patients There is no FDA guidance one the use of Raloxifene in patients who are immunocompromised. # Administration and Monitoring ### Administration - Oral ### Monitoring There is limited information regarding Monitoring of Raloxifene in the drug label. # IV Compatibility There is limited information regarding IV Compatibility of Raloxifene in the drug label. # Overdosage ## Acute Overdose ### Signs and Symptoms - In an 8-week study of 63 postmenopausal women, a dose of raloxifene hydrochloride (HCl) 600 mg/day was safely tolerated. In clinical trials, no raloxifene overdose has been reported. - In postmarketing spontaneous reports, raloxifene overdose has been reported very rarely (less than 1 out of 10,000 [<0.01%] patients treated). The highest overdose has been approximately 1.5 grams. No fatalities associated with raloxifene overdose have been reported. Adverse reactions were reported in approximately half of the adults who took ≥180 mg raloxifene HCl and included leg cramps and dizziness. - Two 18-month-old children each ingested raloxifene HCl 180 mg. In these two children, symptoms reported included ataxia, dizziness, vomiting, rash, diarrhea, tremor, and flushing, as well as elevation in alkaline phosphatase. - No mortality was seen after a single oral dose in rats or mice at 5000 mg/kg (810 times the human dose for rats and 405 times the human dose for mice based on surface area, mg/m2) or in monkeys at 1000 mg/kg (80 times the AUC in humans). ### Management - There is no specific antidote for raloxifene. ## Chronic Overdose There is limited information regarding Chronic Overdose of Raloxifene in the drug label. # Pharmacology ## Mechanism of Action - Raloxifene is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM). The biological actions of raloxifene are largely mediated through binding to estrogen receptors. This binding results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). The agonistic or antagonistic action of raloxifene depends on the extent of recruitment of coactivators and corepressors to estrogen receptor (ER) target gene promoters. - Raloxifene appears to act as an estrogen agonist in bone. It decreases bone resorption and bone turnover, increases bone mineral density (BMD) and decreases fracture incidence. Preclinical data demonstrate that raloxifene is an estrogen antagonist in uterine and breast tissues. These results are consistent with findings in clinical trials, which suggest that raloxifene hydrochloride lacks estrogen-like effects on the uterus and breast tissue. ## Structure - Raloxifene hydrochloride is an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM) that belongs to the benzothiophene class of compounds. The chemical structure is: - The chemical designation is methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]-, hydrochloride. Raloxifene hydrochloride (HCl) has the empirical formula C28H27NO4S•HCl, which corresponds to a molecular weight of 510.05. Raloxifene HCl is an off-white to pale-yellow solid that is very slightly soluble in water. - Raloxifene hydrochloride is supplied in a tablet dosage form for oral administration. Each raloxifene hydrochloride tablet contains 60 mg of raloxifene HCl, which is the molar equivalent of 55.71 mg of free base. Inactive ingredients include anhydrous lactose, carnauba wax, crospovidone, FD&C Blue No. 2 aluminum lake, hypromellose, lactose monohydrate, magnesium stearate, modified pharmaceutical glaze, polyethylene glycol, polysorbate 80, povidone, propylene glycol, and titanium dioxide. ## Pharmacodynamics - Decreases in estrogen levels after oophorectomy or menopause lead to increases in bone resorption and accelerated bone loss. Bone is initially lost rapidly because the compensatory increase in bone formation is inadequate to offset resorptive losses. In addition to loss of estrogen, this imbalance between resorption and formation may be due to age-related impairment of osteoblasts or their precursors. In some women, these changes will eventually lead to decreased bone mass, osteoporosis, and increased risk for fractures, particularly of the spine, hip, and wrist. Vertebral fractures are the most common type of osteoporotic fracture in postmenopausal women. - In both the osteoporosis treatment and prevention trials, raloxifene hydrochloride therapy resulted in consistent, statistically significant suppression of bone resorption and bone formation, as reflected by changes in serum and urine markers of bone turnover (e.g., bone-specific alkaline phosphatase, osteocalcin, and collagen breakdown products). The suppression of bone turnover markers was evident by 3 months and persisted throughout the 36-month and 24-month observation periods. - In a 31-week, open-label, radiocalcium kinetics study, 33 early postmenopausal women were randomized to treatment with once-daily raloxifene hydrochloride 60 mg, cyclic estrogen/progestin (0.625 mg conjugated estrogens daily with 5 mg medroxyprogesterone acetate daily for the first 2 weeks of each month [hormone therapy]), or no treatment. Treatment with either raloxifene hydrochloride or hormone therapy was associated with reduced bone resorption and a positive shift in calcium balance (-82 mg Ca/day and +60 mg Ca/day, respectively, for raloxifene hydrochloride and -162 mg Ca/day and +91 mg Ca/day, respectively, for hormone therapy). - There were small decreases in serum total calcium, inorganic phosphate, total protein, and albumin, which were generally of lesser magnitude than decreases observed during estrogen or hormone therapy. Platelet count was also decreased slightly and was not different from estrogen therapy. ## Pharmacokinetics - The disposition of raloxifene has been evaluated in more than 3000 postmenopausal women in selected raloxifene osteoporosis treatment and prevention clinical trials, using a population approach. Pharmacokinetic data also were obtained in conventional pharmacology studies in 292 postmenopausal women. Raloxifene exhibits high within-subject variability (approximately 30% coefficient of variation) of most pharmacokinetic parameters. Table 3 summarizes the pharmacokinetic parameters of raloxifene. - Absorption — Raloxifene is absorbed rapidly after oral administration. Approximately 60% of an oral dose is absorbed, but presystemic glucuronide conjugation is extensive. Absolute bioavailability of raloxifene is 2%. The time to reach average maximum plasma concentration and bioavailability are functions of systemic interconversion and enterohepatic cycling of raloxifene and its glucuronide metabolites. - Administration of raloxifene HCl with a standardized, high-fat meal increases the absorption of raloxifene (Cmax 28% and AUC 16%), but does not lead to clinically meaningful changes in systemic exposure. Raloxifene hydrochloride can be administered without regard to meals. - Distribution — Following oral administration of single doses ranging from 30 to 150 mg of raloxifene HCl, the apparent volume of distribution is 2348 L/kg and is not dose dependent. - Raloxifene and the monoglucuronide conjugates are highly (95%) bound to plasma proteins. Raloxifene binds to both albumin and α1-acid glycoprotein, but not to sex-steroid binding globulin. - Metabolism — Biotransformation and disposition of raloxifene in humans have been determined following oral administration of 14C-labeled raloxifene. Raloxifene undergoes extensive first-pass metabolism to the glucuronide conjugates: raloxifene-4′-glucuronide, raloxifene-6-glucuronide, and raloxifene-6, 4′-diglucuronide. No other metabolites have been detected, providing strong evidence that raloxifene is not metabolized by cytochrome P450 pathways. Unconjugated raloxifene comprises less than 1% of the total radiolabeled material in plasma. The terminal log-linear portions of the plasma concentration curves for raloxifene and the glucuronides are generally parallel. This is consistent with interconversion of raloxifene and the glucuronide metabolites. - Following intravenous administration, raloxifene is cleared at a rate approximating hepatic blood flow. Apparent oral clearance is 44.1 L/kg•hr. Raloxifene and its glucuronide conjugates are interconverted by reversible systemic metabolism and enterohepatic cycling, thereby prolonging its plasma elimination half-life to 27.7 hours after oral dosing. - Results from single oral doses of raloxifene predict multiple-dose pharmacokinetics. Following chronic dosing, clearance ranges from 40 to 60 L/kg•hr. Increasing doses of raloxifene HCl (ranging from 30 to 150 mg) result in slightly less than a proportional increase in the area under the plasma time concentration curve (AUC). - Excretion — Raloxifene is primarily excreted in feces, and less than 0.2% is excreted unchanged in urine. Less than 6% of the raloxifene dose is eliminated in urine as glucuronide conjugates. - Special Populations - Pediatric — The pharmacokinetics of raloxifene has not been evaluated in a pediatric population. - Geriatric — No differences in raloxifene pharmacokinetics were detected with regard to age (range 42 to 84 years). - Gender — Total extent of exposure and oral clearance, normalized for lean body weight, are not significantly different between age-matched female and male volunteers. - Race — Pharmacokinetic differences due to race have been studied in 1712 women, including 97.5% White, 1.0% Asian, 0.7% Hispanic, and 0.5% Black in the osteoporosis treatment trial and in 1053 women, including 93.5% White, 4.3% Hispanic, 1.2% Asian, and 0.5% Black in the osteoporosis prevention trials. There were no discernible differences in raloxifene plasma concentrations among these groups; however, the influence of race cannot be conclusively determined. - Renal Impairment — In the osteoporosis treatment and prevention trials, raloxifene concentrations in women with mild renal impairment are similar to women with normal creatinine clearance. When a single dose of 120 mg raloxifene HCl was administered to 10 renally impaired males [7 moderate impairment (CrCl = 31–50 mL/min); 3 severe impairment (CrCl ≤30 mL/min)] and to 10 healthy males (CrCl >80 mL/min), plasma raloxifene concentrations were 122% (AUC0-∞) higher in renally impaired patients than those of healthy volunteers. Raloxifene should be used with caution in patients with moderate or severe renal impairment. - Hepatic Impairment — The disposition of raloxifene was compared in 9 patients with mild (Child-Pugh Class A) hepatic impairment (total bilirubin ranging from 0.6 to 2 mg/dL) to 8 subjects with normal hepatic function following a single dose of 60 mg raloxifene HCl. Apparent clearance of raloxifene was reduced 56% and the half-life of raloxifene was not altered in patients with mild hepatic impairment. Plasma raloxifene concentrations were approximately 150% higher than those in healthy volunteers and correlated with total bilirubin concentrations. The pharmacokinetics of raloxifene has not been studied in patients with moderate or severe hepatic impairment. Raloxifene should be used with caution in patients with hepatic impairment. - Drug Interactions - Cholestyramine — Cholestyramine, an anion exchange resin, causes a 60% reduction in the absorption and enterohepatic cycling of raloxifene after a single dose. Although not specifically studied, it is anticipated that other anion exchange resins would have a similar effect. - Warfarin — In vitro, raloxifene did not interact with the binding of warfarin. The concomitant administration of raloxifene hydrochloride and warfarin, a coumarin derivative, has been assessed in a single-dose study. In this study, raloxifene had no effect on the pharmacokinetics of warfarin. However, a 10% decrease in prothrombin time was observed in the single-dose study. In the osteoporosis treatment trial, there were no clinically relevant effects of warfarin co-administration on plasma concentrations of raloxifene. - Other Highly Protein-Bound Drugs — In the osteoporosis treatment trial, there were no clinically relevant effects of co-administration of other highly protein-bound drugs (e.g., gemfibrozil) on plasma concentrations of raloxifene. In vitro, raloxifene did not interact with the binding of phenytoin, tamoxifen, or warfarin (see above). - Ampicillin and Amoxicillin — Peak concentrations of raloxifene and the overall extent of absorption are reduced 28% and 14%, respectively, with co-administration of ampicillin. These reductions are consistent with decreased enterohepatic cycling associated with antibiotic reduction of enteric bacteria. However, the systemic exposure and the elimination rate of raloxifene were not affected. In the osteoporosis treatment trial, co-administration of amoxicillin had no discernible differences in plasma raloxifene concentrations. - Antacids — Concomitant administration of calcium carbonate or aluminum and magnesium hydroxide-containing antacids does not affect the systemic exposure of raloxifene. - Corticosteroids — The chronic administration of raloxifene in postmenopausal women has no effect on the pharmacokinetics of methylprednisolone given as a single oral dose. - Digoxin — Raloxifene has no effect on the pharmacokinetics of digoxin. - Cyclosporine — Concomitant administration of raloxifene hydrochloride with cyclosporine has not been studied. - Lipid-Lowering Agents — Concomitant administration of raloxifene hydrochloride with lipid-lowering agents has not been studied. ## Nonclinical Toxicology - Carcinogenesis — In a 21-month carcinogenicity study in mice, there was an increased incidence of ovarian tumors in female animals given 9 to 242 mg/kg, which included benign and malignant tumors of granulosa/theca cell origin and benign tumors of epithelial cell origin. Systemic exposure (AUC) of raloxifene in this group was 0.3 to 34 times that in postmenopausal women administered a 60 mg dose. There was also an increased incidence of testicular interstitial cell tumors and prostatic adenomas and adenocarcinomas in male mice given 41 or 210 mg/kg (4.7 or 24 times the AUC in humans) and prostatic leiomyoblastoma in male mice given 210 mg/kg. - In a 2-year carcinogenicity study in rats, an increased incidence in ovarian tumors of granulosa/theca cell origin was observed in female rats given 279 mg/kg (approximately 400 times the AUC in humans). The female rodents in these studies were treated during their reproductive lives when their ovaries were functional and responsive to hormonal stimulation. - Mutagenesis — Raloxifene HCl was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis with and without metabolic activation, the unscheduled DNA synthesis assay in rat hepatocytes, the mouse lymphoma assay for mammalian cell mutation, the chromosomal aberration assay in Chinese hamster ovary cells, the in vivo sister chromatid exchange assay in Chinese hamsters, and the in vivo micronucleus test in mice. - Impairment of Fertility — When male and female rats were given daily doses ≥5 mg/kg (≥0.8 times the human dose based on surface area, mg/m2) prior to and during mating, no pregnancies occurred. In male rats, daily doses up to 100 mg/kg (16 times the human dose based on surface area, mg/m2) for at least 2 weeks did not affect sperm production or quality or reproductive performance. In female rats, at doses of 0.1 to 10 mg/kg/day (0.02 to 1.6 times the human dose based on surface area, mg/m2), raloxifene disrupted estrous cycles and inhibited ovulation. These effects of raloxifene were reversible. In another study in rats in which raloxifene was given during the preimplantation period at doses ≥0.1 mg/kg (≥0.02 times the human dose based on surface area, mg/m2), raloxifene delayed and disrupted embryo implantation, resulting in prolonged gestation and reduced litter size. The reproductive and developmental effects observed in animals are consistent with the estrogen receptor activity of raloxifene. - The skeletal effects of raloxifene treatment were assessed in ovariectomized rats and monkeys. In rats, raloxifene prevented increased bone resorption and bone loss after ovariectomy. There were positive effects of raloxifene on bone strength, but the effects varied with time. Cynomolgus monkeys were treated with raloxifene or conjugated estrogens for 2 years. In terms of bone cycles, this is equivalent to approximately 6 years in humans. Raloxifene and estrogen suppressed bone turnover and increased BMD in the lumbar spine and in the central cancellous bone of the proximal tibia. In this animal model, there was a positive correlation between vertebral compressive breaking force and BMD of the lumbar spine. - Histologic examination of bone from rats and monkeys treated with raloxifene showed no evidence of woven bone, marrow fibrosis, or mineralization defects. - These results are consistent with data from human studies of radiocalcium kinetics and markers of bone metabolism, and are consistent with the action of raloxifene hydrochloride as a skeletal antiresorptive agent. # Clinical Studies - Effect on Fracture Incidence - The effects of raloxifene hydrochloride on fracture incidence and BMD in postmenopausal women with osteoporosis were examined at 3 years in a large randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial (MORE). All vertebral fractures were diagnosed radiographically; some of these fractures also were associated with symptoms (i.e., clinical fractures). The study population consisted of 7705 postmenopausal women with osteoporosis as defined by: a) low BMD (vertebral or hip BMD at least 2.5 standard deviations below the mean value for healthy young women) without baseline vertebral fractures or b) one or more baseline vertebral fractures. Women enrolled in this study had a median age of 67 years (range 31 to 80) and a median time since menopause of 19 years. - Effect on Bone Mineral Density - Raloxifene hydrochloride, 60 mg administered once daily, increased spine and hip BMD by 2 to 3%. Raloxifene hydrochloride decreased the incidence of the first vertebral fracture from 4.3% for placebo to 1.9% for raloxifene hydrochloride (relative risk reduction = 55%) and subsequent vertebral fractures from 20.2% for placebo to 14.1% for raloxifene hydrochloride (relative risk reduction = 30%) (see Table 4). All women in the study received calcium (500 mg/day) and vitamin D (400 to 600 IU/day). Raloxifene hydrochloride reduced the incidence of vertebral fractures whether or not patients had a vertebral fracture upon study entry. The decrease in incidence of vertebral fracture was greater than could be accounted for by increase in BMD alone. - The mean percentage change in BMD from baseline for raloxifene hydrochloride was statistically significantly greater than for placebo at each skeletal site (see Table 5). - Discontinuation from the study was required when excessive bone loss or multiple incident vertebral fractures occurred. Such discontinuation was statistically significantly more frequent in the placebo group (3.7%) than in the raloxifene hydrochloride group (1.1%). - Bone Histology - Bone biopsies for qualitative and quantitative histomorphometry were obtained at baseline and after 2 years of treatment. There were 56 paired biopsies evaluable for all indices. In raloxifene hydrochloride-treated patients, there were statistically significant decreases in bone formation rate per tissue volume, consistent with a reduction in bone turnover. Normal bone quality was maintained; specifically, there was no evidence of osteomalacia, marrow fibrosis, cellular toxicity, or woven bone after 2 years of treatment. - Effect on Endometrium - Endometrial thickness was evaluated annually in a subset of the study population (1781 patients) for 3 years. Placebo-treated women had a 0.27 mm mean decrease from baseline in endometrial thickness over 3 years, whereas the raloxifene hydrochloride-treated women had a 0.06 mm mean increase. Patients in the osteoporosis treatment study were not screened at baseline or excluded for pre-existing endometrial or uterine disease. This study was not specifically designed to detect endometrial polyps. Over the 36 months of the study, clinically or histologically benign endometrial polyps were reported in 17 of 1999 placebo-treated women, 37 of 1948 raloxifene hydrochloride-treated women, and in 31 of 2010 women treated with raloxifene HCl 120 mg/day. There was no difference between raloxifene hydrochloride- and placebo-treated women in the incidences of endometrial carcinoma, vaginal bleeding, or vaginal discharge. - The effects of raloxifene hydrochloride on BMD in postmenopausal women were examined in three randomized, placebo-controlled, double-blind osteoporosis prevention trials: (1) a North American trial enrolled 544 women; (2) a European trial, 601 women; and (3) an international trial, 619 women who had undergone hysterectomy. In these trials, all women received calcium supplementation (400 to 600 mg/day). Women enrolled in these trials had a median age of 54 years and a median time since menopause of 5 years (less than 1 year up to 15 years postmenopause). The majority of the women were White (93.5%). Women were included if they had spine BMD between 2.5 standard deviations below and 2 standard deviations above the mean value for healthy young women. The mean T scores (number of standard deviations above or below the mean in healthy young women) for the three trials ranged from -1.01 to -0.74 for spine BMD and included women both with normal and low BMD. Raloxifene hydrochloride, 60 mg administered once daily, produced increases in bone mass versus calcium supplementation alone, as reflected by dual-energy x-ray absorptiometric (DXA) measurements of hip, spine, and total body BMD. - Effect on Bone Mineral Density - Compared with placebo, the increases in BMD for each of the three studies were statistically significant at 12 months and were maintained at 24 months (see Table 6). The placebo groups lost approximately 1% of BMD over 24 months. - Raloxifene hydrochloride also increased BMD compared with placebo in the total body by 1.3% to 2.0% and in Ward's Triangle (hip) by 3.1% to 4.0%. The effects of raloxifene hydrochloride on forearm BMD were inconsistent between studies. In Study EU, raloxifene hydrochloride prevented bone loss at the ultradistal radius, whereas in Study NA, it did not (see Figure 1). - Effect on Endometrium - In placebo-controlled osteoporosis prevention trials, endometrial thickness was evaluated every 6 months (for 24 months) by transvaginal ultrasonography (TVU). A total of 2978 TVU measurements were collected from 831 women in all dose groups. Placebo-treated women had a 0.04 mm mean increase from baseline in endometrial thickness over 2 years, whereas the raloxifene hydrochloride-treated women had a 0.09 mm mean increase. Endometrial thickness measurements in raloxifene-treated women were indistinguishable from placebo. There were no differences between the raloxifene and placebo groups with respect to the incidence of reported vaginal bleeding. - MORE Trial - The effect of raloxifene hydrochloride on the incidence of breast cancer was assessed as a secondary safety endpoint in a randomized, placebo-controlled, double-blind, multinational osteoporosis treatment trial in postmenopausal women. After 4 years, raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of all breast cancers by 62%, compared with placebo (HR 0.38, 95% CI 0.22-0.67). Raloxifene hydrochloride reduced the incidence of invasive breast cancer by 71%, compared with placebo (ARR 3.1 per 1000 women-years); this was primarily due to an 80% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo. Table 7 presents efficacy and selected safety outcomes. - CORE Trial - The effect of raloxifene hydrochloride on the incidence of invasive breast cancer was evaluated for 4 additional years in a follow-up study conducted in a subset of postmenopausal women originally enrolled in the MORE osteoporosis treatment trial. Women were not re-randomized; the treatment assignment from the osteoporosis treatment trial was carried forward to this study. Raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 56%, compared with placebo (ARR 3.0 per 1000 women-years); this was primarily due to a 63% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo. There was no reduction in the incidence of ER-negative breast cancer. In the osteoporosis treatment trial and the follow-up study, there was no difference in incidence of noninvasive breast cancer between the raloxifene hydrochloride and placebo groups. Table 7 presents efficacy and selected safety outcomes. - In a subset of postmenopausal women followed for up to 8 years from randomization in MORE to the end of CORE, raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 60% in women assigned raloxifene hydrochloride (N=1355) compared with placebo (N=1286) (HR 0.40, 95% CI 0.21, 0.77; ARR 1.95 per 1000 women-years); this was primarily due to a 65% reduction in the incidence of ER-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo. - RUTH Trial - The effect of raloxifene hydrochloride on the incidence of invasive breast cancer was assessed in a randomized, placebo-controlled, double-blind, multinational study in 10,101 postmenopausal women at increased risk of coronary events. Women in this study had a median age of 67.6 years (range 55-92) and were followed for a median of 5.6 years (range 0.01-7.1). Eighty-four percent were White, 9.8% of women reported a first-degree relative with a history of breast cancer, and 41.4% of the women had a 5-year predicted risk of invasive breast cancer ≥1.66%, based on the modified Gail model. - Raloxifene hydrochloride, 60 mg administered once daily, reduced the incidence of invasive breast cancer by 44% compared with placebo [absolute risk reduction (ARR) 1.2 per 1000 women-years]; this was primarily due to a 55% reduction in estrogen receptor (ER)-positive invasive breast cancer in the raloxifene hydrochloride group compared with placebo (ARR 1.2 per 1000 women-years). There was no reduction in ER-negative invasive breast cancer. Table 8 presents efficacy and selected safety outcomes. - The effect of raloxifene hydrochloride in reducing the incidence of invasive breast cancer was consistent among women above or below age 65 or with a 5-year predicted invasive breast cancer risk, based on the modified Gail model, <1.66%, or ≥1.66%. - STAR Trial - The effects of raloxifene hydrochloride 60 mg/day versus tamoxifen 20 mg/day over 5 years on reducing the incidence of invasive breast cancer were assessed in 19,747 postmenopausal women in a randomized, double-blind trial conducted in North America by the National Surgical Adjuvant Breast and Bowel Project and sponsored by the National Cancer Institute. Women in this study had a mean age of 58.5 years (range 35-83), a mean 5-year predicted invasive breast cancer risk of 4.03% (range 1.66-23.61%), and 9.1% had a history of lobular carcinoma in situ (LCIS). More than 93% of participants were White. As of 31 December 2005, the median time of follow-up was 4.3 years (range 0.07-6.50 years). - Raloxifene hydrochloride was not superior to tamoxifen in reducing the incidence of invasive breast cancer. The observed incidence rates of invasive breast cancer were raloxifene hydrochloride 4.4 and tamoxifen 4.3 per 1000 women per year. The results from a noninferiority analysis are consistent with raloxifene hydrochloride potentially losing up to 35% of the tamoxifen effect on reduction of invasive breast cancer. The effect of each treatment on invasive breast cancer was consistent when women were compared by baseline age, history of LCIS, history of atypical hyperplasia, 5-year predicted risk of breast cancer by the modified Gail model, or the number of relatives with a history of breast cancer. Fewer noninvasive breast cancers occurred in the tamoxifen group compared to the raloxifene hydrochloride group. Table 9 presents efficacy and selected safety outcomes. - Effects on Cardiovascular Disease - In a randomized, placebo-controlled, double-blind, multinational clinical trial (RUTH) of 10,101 postmenopausal women with documented coronary heart disease or at increased risk for coronary events, no cardiovascular benefit was demonstrated after treatment with raloxifene hydrochloride 60 mg once daily for a median follow-up of 5.6 years. No significant increase or decrease was observed for coronary events (death from coronary causes, nonfatal myocardial infarction, or hospitalization for an acute coronary syndrome). An increased risk of death due to stroke after treatment with raloxifene hydrochloride was observed: 59 (1.2%) raloxifene hydrochloride-treated women died due to a stroke compared to 39 (0.8%) placebo-treated women (2.2 versus 1.5 per 1000 women-years; hazard ratio 1.49; 95% confidence interval, 1.00-2.24; p=0.0499). The incidence of stroke did not differ significantly between treatment groups (249 with raloxifene hydrochloride [4.9%] versus 224 with placebo [4.4%]; hazard ratio 1.10; 95% confidence interval 0.92-1.32; p=0.30; 9.5 versus 8.6 per 1000 women-years). # How Supplied - Raloxifene hydrochloride 60 mg tablets are white, elliptical, and film coated. They are imprinted on one side with the tablet code 4810 in edible blue ink. They are available as follows: - Bottles of 30 (unit of use) NDC 0002-4165-30 - Bottles of 100 (unit of use) NDC 0002-4165-02 - Bottles of 2000 NDC 0002-4165-07 - Storage and Handling - Store at controlled room temperature, 20° to 25°C (68° to 77°F). The USP defines controlled room temperature as a temperature maintained thermostatically that encompasses the usual and customary working environment of 20° to 25°C (68° to 77°F); that results in a mean kinetic temperature calculated to be not more than 25°C; and that allows for excursions between 15° and 30°C (59° and 86°F) that are experienced in pharmacies, hospitals, and warehouses. ## Storage There is limited information regarding Raloxifene Storage in the drug label. # Images ## Drug Images ## Package and Label Display Panel # Patient Counseling Information - Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation - Patient Immobilization - Raloxifene hydrochloride should be discontinued at least 72 hours prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest), and patients should be advised to avoid prolonged restrictions of movement during travel because of the increased risk of venous thromboembolic events. - Hot Flashes or Flushes - Raloxifene hydrochloride may increase the incidence of hot flashes and is not effective in reducing hot flashes or flushes associated with estrogen deficiency. In some asymptomatic patients, hot flashes may occur upon beginning raloxifene hydrochloride therapy. - Reduction in Risk of Invasive Breast Cancer in Postmenopausal Women with Osteoporosis or at High Risk of Invasive Breast Cancer - Use of raloxifene hydrochloride is associated with the reduction of the risk of invasive breast cancer in postmenopausal women. Raloxifene hydrochloride has not been shown to reduce the risk of noninvasive breast cancer. When considering treatment, physicians need to discuss the potential benefits and risks of raloxifene hydrochloride treatment with the patient. - Raloxifene hydrochloride is not indicated for the treatment of invasive breast cancer or reduction of the risk of recurrence. - Patients should have breast exams and mammograms before starting raloxifene hydrochloride and should continue regular breast exams and mammograms in keeping with good medical practice after beginning treatment with raloxifene hydrochloride. # Precautions with Alcohol - Alcohol-Raloxifene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication. # Brand Names - Evista®[3] # Look-Alike Drug Names - Evista® —AVINza®[4] # Drug Shortage Status # Price	https://www.wikidoc.org/index.php/Evista
b74743670b8065baab8772228b0214a05c427467	wikidoc	Exaptation	Exaptation # Overview Exaptation, cooption, and preadaptation are related terms pertaining to shifts in the function of a trait. For example, a trait can evolve because it served one particular function, but subsequently it may come to serve another. Exaptations are common in both anatomy and behavior. Bird feathers are a classic example: initially these evolved for temperature regulation, but later were adapted for flight. Interest in exaptation relates to both the process and product of evolution: the process that creates complex traits and the product that may be imperfectly designed. # History and Definitions The idea that the function of a trait might shift during its evolutionary history originated with Charles Darwin (1859, ch. 6). For many years the phenomenon was labeled “preadaptation.” Unfortunately, the term suggests forethought, which is contrary to a basic principle of natural selection. The idea had been explored by several scholars when in 1982 Gould and Vrba introduced the term “exaptation”. Unfortunately for subsequent discussions, this definition had two categories with different implications for the role of adaptation. (1) A character, previously shaped by natural selection for a particular function (an adaptation), is coopted for a new use—cooptation. (2) A character whose origin cannot be ascribed to the direct action of natural selection (a nonaptation), is coopted for a current use—cooptation. Gould and Vrba (1982, Table 1) The definitions are silent as to whether exaptations had been shaped by natural selection after cooption, although Gould and Vrba cite examples (e.g., feathers) of traits shaped after cooption. To avoid these ambiguities, Buss, et al. (1998) suggested the term “co-opted adaptation,” which is limited to traits that evolved after cooption. However, the commonly-used terms of ”exaptation” and “cooption” are ambiguous in this regard. # Examples Of the many examples of exaptations, here are two involving familiar traits. A multi-stage example involves human hands, which evolved to facilitate tool use and which are an exaptation of primate hands that were used for grasping tree branches. Those primate hands, in turn, were an exaptation of front legs that were used for locomotion on the ground, and those legs were an exaptation of the fins of fish, which were used for locomotion in the water. As this lineage exploited different niches—water, land, trees, and tool-use on the ground—natural selection reshaped its limbs. A behavioral example pertains to subdominant wolves licking the mouths of alpha wolves as a sign of submissiveness. (Similarly, dogs, which are domesticated wolves, lick the faces of their human owners.) This trait can be explained as an exaptation of wolf pups licking the faces of adults to encourage them to regurgitate food. # Implications ## Evolution of Complex Traits One of the challenges to Darwin’s theory of evolution was explaining how complex structures could evolve gradually, given that their incipient forms may have been inadequate to serve any function. As Mivart (a critic of Darwin) pointed out, 5 percent of a bird wing would not be functional. The incipient form of complex traits would not have survived long enough to evolve to a useful form. As Darwin elaborated on in the last edition of The Origin of Species, many complex traits evolved from earlier traits that had served different functions. By trapping air, primitive wings would have enabled birds to efficiently regulate their temperature, in part, by lifting up their feathers when too warm. Individual animals with more of this functionality would have left more offspring, resulting in the spread of this trait. Eventually, feathers became sufficiently large that they enabled some individuals to glide. These individuals would leave more offspring, resulting in the spread of this trait because it served a second function, that of locomotion. Hence, the evolution of bird wings can be explained by a shifting in function from the regulation of temperature to flight. ## Jury-Rigged Design Darwin explained how the traits of living organisms are well-designed for their environment, but he also recognized that many traits are imperfectly designed. They appear to have been made from available material, that is, jury-rigged. Understanding exaptations may suggest hypotheses regarding subtleties in the adaptation. For instance, that feather evolved initially for thermal regulation may help to explain some of their features unrelated to flight (Buss et al., 1998). Some of the chemical pathways for physical pain and pain from social exclusion overlap (MacDonald and Leary, 2005). The physical pain system may have been co-opted to motivate social animals to respond to threats to their inclusion in the group. The physical-social pain overlap helps to explain the paradox that people who are threatened with social exclusion sometimes react with physical violence. # Controversy The concept of exaptation has been used to criticize evolutionary psychology. The methodology of that field is to consider—given the ancestral environment of hominids (and other animals)—the types of problems individuals would have faced (e.g., avoiding predators). Evolutionary psychologists hypothesize behavioral traits (i.e., adaptations) that might have arisen to mitigate or solve these problems. Those hypotheses are then tested. Critics argue that the link between ancestral environments and present-day behavioral traits is weak, for several reasons. One is that science knows little about those environments; evolutionary psychologists disagree (Ehrlich and Feldman, 2003, including comments). A second argument is that many traits have experienced a shift in function, making it difficult to link the function served in ancestral environment to the current function. Gould (1991, p. 58) concluded that the concepts of exaptations and spandrels provide a “one-line refutation of...an ultra-Darwinian theory based on adaptation.” However, the clarity of this critique is undermined by “exaptation” having two meanings. When it means “co-opted adaptation”, an exaptation is simply an adaptation whose current function was preceded by an earlier function. When it means a cooption of a trait not shaped by natural selection by another adaptation, the finiteness of natural selection’s role is highlighted by what happened prior to cooption, not by cooption itself. A consensus has not been reached on the extent to which these types of exaptations undermine evolutionary psychology. de:Exaptation it:Exattamento no:Eksaptasjon # Notes - ↑ See Jacob (1977) and Mayr (1982) for references. - ↑ , accessed May 16, 2008. - ↑ The development of complex structures (i.e., evolution of novelties) occur either by intensification of an existing function or by a switch in functions. - ↑ Jacob (1977) sees much of evolution as “tinkering,” that is, working with available traits. “Tinkering” includes (but is not limited to) shifts in function.	Exaptation # Overview Exaptation, cooption, and preadaptation are related terms pertaining to shifts in the function of a trait. For example, a trait can evolve because it served one particular function, but subsequently it may come to serve another. Exaptations are common in both anatomy and behavior. Bird feathers are a classic example: initially these evolved for temperature regulation, but later were adapted for flight. Interest in exaptation relates to both the process and product of evolution: the process that creates complex traits and the product that may be imperfectly designed. # History and Definitions The idea that the function of a trait might shift during its evolutionary history originated with Charles Darwin (1859, ch. 6). For many years the phenomenon was labeled “preadaptation.” Unfortunately, the term suggests forethought, which is contrary to a basic principle of natural selection. The idea had been explored by several scholars[1] when in 1982 Gould and Vrba introduced the term “exaptation”. Unfortunately for subsequent discussions, this definition had two categories with different implications for the role of adaptation. (1) A character, previously shaped by natural selection for a particular function (an adaptation), is coopted for a new use—cooptation. (2) A character whose origin cannot be ascribed to the direct action of natural selection (a nonaptation), is coopted for a current use—cooptation. Gould and Vrba (1982, Table 1) The definitions are silent as to whether exaptations had been shaped by natural selection after cooption, although Gould and Vrba cite examples (e.g., feathers) of traits shaped after cooption. To avoid these ambiguities, Buss, et al. (1998) suggested the term “co-opted adaptation,” which is limited to traits that evolved after cooption. However, the commonly-used terms of ”exaptation” and “cooption” are ambiguous in this regard. # Examples Of the many examples of exaptations, here are two involving familiar traits. A multi-stage example involves human hands, which evolved to facilitate tool use and which are an exaptation of primate hands that were used for grasping tree branches. Those primate hands, in turn, were an exaptation of front legs that were used for locomotion on the ground, and those legs were an exaptation of the fins of fish, which were used for locomotion in the water. As this lineage exploited different niches—water, land, trees, and tool-use on the ground—natural selection reshaped its limbs. A behavioral example pertains to subdominant wolves licking the mouths of alpha wolves as a sign of submissiveness. (Similarly, dogs, which are domesticated wolves, lick the faces of their human owners.) This trait can be explained as an exaptation of wolf pups licking the faces of adults to encourage them to regurgitate food.[2] # Implications ## Evolution of Complex Traits One of the challenges to Darwin’s theory of evolution was explaining how complex structures could evolve gradually,[3] given that their incipient forms may have been inadequate to serve any function. As Mivart (a critic of Darwin) pointed out, 5 percent of a bird wing would not be functional. The incipient form of complex traits would not have survived long enough to evolve to a useful form. As Darwin elaborated on in the last edition of The Origin of Species, many complex traits evolved from earlier traits that had served different functions. By trapping air, primitive wings would have enabled birds to efficiently regulate their temperature, in part, by lifting up their feathers when too warm. Individual animals with more of this functionality would have left more offspring, resulting in the spread of this trait. Eventually, feathers became sufficiently large that they enabled some individuals to glide. These individuals would leave more offspring, resulting in the spread of this trait because it served a second function, that of locomotion. Hence, the evolution of bird wings can be explained by a shifting in function from the regulation of temperature to flight. ## Jury-Rigged Design Darwin explained how the traits of living organisms are well-designed for their environment, but he also recognized that many traits are imperfectly designed. They appear to have been made from available material, that is, jury-rigged.[4] Understanding exaptations may suggest hypotheses regarding subtleties in the adaptation. For instance, that feather evolved initially for thermal regulation may help to explain some of their features unrelated to flight (Buss et al., 1998). Some of the chemical pathways for physical pain and pain from social exclusion overlap (MacDonald and Leary, 2005). The physical pain system may have been co-opted to motivate social animals to respond to threats to their inclusion in the group. The physical-social pain overlap helps to explain the paradox that people who are threatened with social exclusion sometimes react with physical violence. # Controversy The concept of exaptation has been used to criticize evolutionary psychology. The methodology of that field is to consider—given the ancestral environment of hominids (and other animals)—the types of problems individuals would have faced (e.g., avoiding predators). Evolutionary psychologists hypothesize behavioral traits (i.e., adaptations) that might have arisen to mitigate or solve these problems. Those hypotheses are then tested. Critics argue that the link between ancestral environments and present-day behavioral traits is weak, for several reasons. One is that science knows little about those environments; evolutionary psychologists disagree (Ehrlich and Feldman, 2003, including comments). A second argument is that many traits have experienced a shift in function, making it difficult to link the function served in ancestral environment to the current function. Gould (1991, p. 58) concluded that the concepts of exaptations and spandrels provide a “one-line refutation of...an ultra-Darwinian theory based on adaptation.” However, the clarity of this critique is undermined by “exaptation” having two meanings. When it means “co-opted adaptation”, an exaptation is simply an adaptation whose current function was preceded by an earlier function. When it means a cooption of a trait not shaped by natural selection by another adaptation, the finiteness of natural selection’s role is highlighted by what happened prior to cooption, not by cooption itself. A consensus has not been reached on the extent to which these types of exaptations undermine evolutionary psychology. Template:Biology-footer de:Exaptation it:Exattamento no:Eksaptasjon # Notes - ↑ See Jacob (1977) and Mayr (1982) for references. - ↑ http://www.wolf.org/wolves/learn/basic/biology/communication.asp, accessed May 16, 2008. - ↑ The development of complex structures (i.e., evolution of novelties) occur either by intensification of an existing function or by a switch in functions. - ↑ Jacob (1977) sees much of evolution as “tinkering,” that is, working with available traits. “Tinkering” includes (but is not limited to) shifts in function.	https://www.wikidoc.org/index.php/Exaptation
7c2a5d09d90602bb8686030e282148968264be6a	wikidoc	Polyphagia	Polyphagia Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview In biology, "polyphagia" is a type of phagy, referring to an animal that feeds on many kinds of food. In medicine, polyphagia (sometimes known as hyperphagia) is a medical sign meaning excessive hunger and abnormally large (poly-) intake of solids by mouth.	Polyphagia Template:SignSymptom infobox Please Take Over This Page and Apply to be Editor-In-Chief for this topic: There can be one or more than one Editor-In-Chief. You may also apply to be an Associate Editor-In-Chief of one of the subtopics below. Please mail us [1] to indicate your interest in serving either as an Editor-In-Chief of the entire topic or as an Associate Editor-In-Chief for a subtopic. Please be sure to attach your CV and or biographical sketch. # Overview In biology, "polyphagia" is a type of phagy, referring to an animal that feeds on many kinds of food. In medicine, polyphagia (sometimes known as hyperphagia) is a medical sign meaning excessive hunger and abnormally large (poly-) intake of solids by mouth.	https://www.wikidoc.org/index.php/Excessive_hunger
77b8c68aa2299866c70848b2df01864929e2dacb	wikidoc	Exhalation	Exhalation Exhalation (or expiration) is the movement of air out of the bronchial tubes, through the airways, to the external environment during breathing. Exhaled air is rich in carbon dioxide, a waste product of cellular respiration during the production of ATP. Exhalation has a complementary relationship to inhalation; the cycling between these two efforts define respiration.	Exhalation Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Exhalation (or expiration) is the movement of air out of the bronchial tubes, through the airways, to the external environment during breathing. Exhaled air is rich in carbon dioxide, a waste product of cellular respiration during the production of ATP. Exhalation has a complementary relationship to inhalation; the cycling between these two efforts define respiration. # External links - Exhalation at the US National Library of Medicine Medical Subject Headings (MeSH) - Template:EMedicineDictionary - Essentials of Human Physiology by Thomas M. Nosek. Section 4/4ch2/s4ch2_14. he:נשיפה nl:Uitademing Template:WikiDoc Sources	https://www.wikidoc.org/index.php/Exhalation
596afc94131124d8db9d14d8b816cab9b016da09	wikidoc	Exothermic	Exothermic In thermodynamics, the word exothermic "outside heating" describes a process or reaction that releases energy usually in the form of heat, but it can also release energy in form of light (e.g. explosions), sound, or electricity (e.g. a battery). Its etymology stems from the Greek prefix ex-, meaning “outside” and the Greek word thermein, meaning “to heat”. The term “exothermic” was first coined by Marcellin Berthelot. The opposite of an exothermic process is an endothermic process, one that absorbs energy in the form of heat. The concept is frequently applied in physical sciences to chemical reactions, where chemical bond energy is converted to thermal energy (heat). # Overview Exothermic refers to a transformation in which a system releases energy (heat) to the surroundings: When the transformation occurs at constant pressure: and constant volume: In an adiabatic system (e.g. a system that does not give off heat to the surroundings), an exothermic process results in an increase in temperature. ## Exothermic processes Some examples of exothermic processes are: - Condensation of rain from water vapour - Combustion of fuels such as wood, coal and oil - Mixing water and strong acids - Mixing alkalis and acids - The setting of cement and concrete - Most polymerisation reactions such as the setting of epoxy resin # Implications for chemical reactions Chemical exothermic reactions are generally more spontaneous than their counterparts, endothermic reactions. In a thermochemical reaction that is exothermic, the heat may be listed among the products of the reaction.	Exothermic In thermodynamics, the word exothermic "outside heating" describes a process or reaction that releases energy usually in the form of heat, but it can also release energy in form of light (e.g. explosions), sound, or electricity (e.g. a battery). Its etymology stems from the Greek prefix ex-, meaning “outside” and the Greek word thermein, meaning “to heat”. The term “exothermic” was first coined by Marcellin Berthelot. The opposite of an exothermic process is an endothermic process, one that absorbs energy in the form of heat. The concept is frequently applied in physical sciences to chemical reactions, where chemical bond energy is converted to thermal energy (heat). # Overview Exothermic refers to a transformation in which a system releases energy (heat) to the surroundings: When the transformation occurs at constant pressure: and constant volume: In an adiabatic system (e.g. a system that does not give off heat to the surroundings), an exothermic process results in an increase in temperature.[1] ## Exothermic processes Some examples of exothermic processes are:[2] - Condensation of rain from water vapour - Combustion of fuels such as wood, coal and oil - Mixing water and strong acids - Mixing alkalis and acids - The setting of cement and concrete - Most polymerisation reactions such as the setting of epoxy resin # Implications for chemical reactions Chemical exothermic reactions are generally more spontaneous than their counterparts, endothermic reactions. In a thermochemical reaction that is exothermic, the heat may be listed among the products of the reaction.	https://www.wikidoc.org/index.php/Exothermic
c9f6f7519dce210b5c162a00892cbaf5632b2f8f	wikidoc	Experiment	Experiment In the scientific method, an experiment (Latin: ex- periri, "of (or from) trying") is a set of observations performed in the context of solving a particular problem or question, to support or falsify a hypothesis or research concerning phenomena. The experiment is a cornerstone in the empirical approach to acquiring deeper knowledge about the physical world. # Design of experiments - That the independent variable is the only factor that varies systematically in the experiment; in other words, that the experiment is appropriately controlled - that confounding variables are eliminated; and - That the dependent variable truly reflects the phenomenon under study (a question of validity) and that the variable can be measured accurately (i.e., that various types of experimental error, such as measurement error can be eliminated). In a pure application of the scientific method, hypotheses are tested by critical experiments: ones that can falsify the hypothesis in the case of a non-result (i.e., an experiment showing that the independent variable did not affect the dependent variable as predicted). Such pure applications are rare, however, in part because a result can sometimes be challenged on the basis that an experiment was not sufficiently controlled, that the dependent variable was not valid, or that various forms of error compromised the experiment. The scientific method, as a result, builds in the need for reproducibility (usually termed replication) and convergent evidence (see also: external validity). The design of experiments attempts to balance the requirements and limitations of the field of science in which one works so that the experiment can provide the best conclusion about the hypothesis being tested. In some sciences, such as physics and chemistry, it is relatively easy to meet the requirements that all measurements be made objectively, and that all conditions can be kept controlled across experimental trials. On the other hand, in other cases such as biology, and medicine, it is often hard to ensure that the conditions of an experiment are performed consistently; and in the social sciences, it may even be difficult to determine a method for measuring the outcomes of an experiment in an objective manner. For this reason, sciences such as physics and several other fields of natural science are sometimes informally referred to as "hard sciences", while social sciences are sometimes informally referred to as "soft sciences"; in an attempt to capture the idea that objective measurements are often far easier in the former, and far more difficult in the latter. In addition, in the social sciences, the requirement for a "controlled situation" may actually work against the utility of the hypothesis in a more general situation. When the desire is to test a hypothesis that works "in general", an experiment may have a great deal of internal validity, in the sense that it is valid in a highly controlled situation, while at the same time lack external validity when the results of the experiment are applied to a real world situation. One of the reasons why this may happen is the Hawthorne effect; another is that partial equilibrium effects may not persist in general equilibrium. As a result of these considerations, experimental design in the "hard" sciences tends to focus on the elimination of extraneous effects, while experimental design in the "soft" sciences focuses more on the problems of external validity, often through the use of statistical methods. Occasionally events occur naturally from which scientific evidence can be drawn, which is the basis for natural experiments. In such cases the problem of the scientist is to evaluate the natural "design". # Controlled experiments Many hypotheses in sciences such as physics can establish causality by noting that, until some phenomenon occurs, nothing happens; then when the phenomenon occurs, a second phenomenon is observed. But often in science, this situation is difficult to obtain. For example, in the old joke, someone claims that they are snapping their fingers "to keep the tigers away"; and justifies this behavior by saying "see - its working!" While this "experiment" does not falsify the hypothesis "snapping fingers keeps the tigers away", it does not really support the hypothesis - not snapping your fingers keeps the tigers away as well. To demonstrate a cause and effect hypothesis, an experiment must often show that, for example, a phenomenon occurs after a certain treatment is given to a subject, and that the phenomenon does not occur in the absence of the treatment. (See Baconian method.) File:Standard curve.png A controlled experiment generally compares the results obtained from an experimental sample against a control sample, which is practically identical to the experimental sample except for the one aspect whose effect is being tested. A good example would be a drug trial. The sample or group receiving the drug would be the experimental one; and the one receiving the placebo would be the control one. In many laboratory experiments it is good practice to have several replicate samples for the test being performed and have both a positive control and a negative control. The results from replicate samples can often be averaged, or if one of the replicates is obviously inconsistent with the results from the other samples, it can be discarded as being the result of an experimental error (some step of the test procedure may have been mistakenly omitted for that sample). Most often, tests are done in duplicate or triplicate. A positive control is a procedure that is very similar to the actual experimental test but which is known from previous experience to give a positive result. A negative control is known to give a negative result. The positive control confirms that the basic conditions of the experiment were able to produce a positive result, even if none of the actual experimental samples produce a positive result. The negative control demonstrates the base-line result obtained when a test does not produce a measurable positive result; often the value of the negative control is treated as a "background" value to be subtracted from the test sample results. Sometimes the positive control takes the form of a standard curve. An example that is often used in teaching laboratories is a controlled protein assay. Students might be given a fluid sample containing an unknown (to the student) amount of protein. It is their job to correctly perform a controlled experiment in which they determine the concentration of protein in fluid sample (usually called the "unknown sample"). The teaching lab would be equipped with a protein standard solution with a known protein concentration. Students could make several positive control samples containing various dilutions of the protein standard. Negative control samples would contain all of the reagents for the protein assay but no protein. In this example, all samples are performed in duplicate. The assay is a colorimetric assay in which a spectrophotometer can measure the amount of protein in samples by detecting a colored complex formed by the interaction of protein molecules and molecules of an added dye. In the illustration, the results for the diluted test samples can be compared to the results of the standard curve (the blue line in the illustration) in order to determine an estimate of the amount of protein in the unknown sample. Controlled experiments can be performed when it is difficult to exactly control all the conditions in an experiment. In this case, the experiment begins by creating two or more sample groups that are probabilistically equivalent, which means that measurements of traits should be similar among the groups and that the groups should respond in the same manner if given the same treatment. This equivalency is determined by statistical methods that take into account the amount of variation between individuals and the number of individuals in each group. In fields such as microbiology and chemistry, where there is very little variation between individuals and the group size is easily in the millions, these statistical methods are often bypassed and simply splitting a solution into equal parts is assumed to produce identical sample groups. Once equivalent groups have been formed, the experimenter tries to treat them identically except for the one variable that he or she wishes to isolate. Human experimentation requires special safeguards against outside variables such as the placebo effect. Such experiments are generally double blind, meaning that neither the volunteer nor the researcher knows which individuals are in the control group or the experimental group until after all of the data has been collected. This ensures that any effects on the volunteer are due to the treatment itself and are not a response to the knowledge that he is being treated. In human experiments, a subject (person) may be given a stimulus to which he or she should respond. The goal of the experiment is to measure the response to a given stimulus. # Natural experiments The term "experiment" usually implies a controlled experiment, but sometimes controlled experiments are prohibitively difficult or impossible. In this case researchers resort to natural experiments, also called quasi-experiments. Natural experiments rely solely on observations of the variables of the system under study, rather than manipulation of just one or a few variables as occurs in controlled experiments. To the degree possible, they attempt to collect data for the system in such a way that contribution from all variables can be determined, and where the effects of variation in certain variables remain approximately constant so that the effects of other variables can be discerned. The degree to which this is possible depends on the observed correlation between explanatory variables in the observed data. When these variables are not well correlated, natural experiments can approach the power of controlled experiments. Usually, however, there is some correlation between these variables, which reduces the reliability of natural experiments relative to what could be concluded if a controlled experiment were performed. Also, because natural experiments usually take place in uncontrolled environments, variables from undetected sources are neither measured nor held constant, and these may produce illusory correlations in variables under study. Much research in several important science disciplines, including economics, political science, geology, paleontology, ecology, meteorology, and astronomy, relies on quasi-experiments. For example, in astronomy it is clearly impossible, when testing the hypothesis "suns are collapsed clouds of hydrogen", to start out with a giant cloud of hydrogen, and then perform the experiment of waiting a few billion years for it to form a sun. However, by observing various clouds of hydrogen in various states of collapse, and other implications of the hypothesis (for example, the presence of various spectral emissions from the light of stars), we can collect data we require to support the hypothesis. An early example of this type of experiment was the first verification in the 1600s that light does not travel from place to place instantaneously, but instead has a measurable speed. Observation of the appearance of the moons of Jupiter were slightly delayed when Jupiter was farther from Earth, as opposed to when Jupiter was closer to Earth; and this phenomenon was used to demonstrate that the difference in the time of appearance of the moons was consistent with a measurable speed of light. # Observational studies Observational studies are very much like controlled experiments except that they lack probabilistic equivalency between groups. These types of experiments often arise in the area of medicine where, for ethical reasons, it is not possible to create a truly controlled group. For example, one would not want to deny all forms of treatment for a life-threatening disease from one group of patients to evaluate the effectiveness of another treatment on a different group of patients. The results of observational studies are considered much less convincing than those of designed experiments, as they are much more prone to selection bias. Researchers attempt to compensate for this with complicated statistical methods such as propensity score matching methods (see hierarchy of evidence). See also quasi-empirical methods # Field experiments Field experiments are so named in order to draw a contrast with laboratory experiments. Often used in the social sciences, and especially in economic analyses of education and health interventions, field experiments have the advantage that outcomes are observed in a natural setting rather than in a contrived laboratory environment. However, like natural experiments, field experiments suffer from the possibility of contamination: experimental conditions can be controlled with more precision and certainty in the lab. # Examples - MTT assay - Colony Formation Assay - Ames Test - western blot # Quotes	Experiment In the scientific method, an experiment (Latin: ex- periri, "of (or from) trying") is a set of observations performed in the context of solving a particular problem or question, to support or falsify a hypothesis or research concerning phenomena. The experiment is a cornerstone in the empirical approach to acquiring deeper knowledge about the physical world. # Design of experiments - That the independent variable is the only factor that varies systematically in the experiment; in other words, that the experiment is appropriately controlled - that confounding variables are eliminated; and - That the dependent variable truly reflects the phenomenon under study (a question of validity) and that the variable can be measured accurately (i.e., that various types of experimental error, such as measurement error can be eliminated). In a pure application of the scientific method, hypotheses are tested by critical experiments: ones that can falsify the hypothesis in the case of a non-result (i.e., an experiment showing that the independent variable did not affect the dependent variable as predicted). Such pure applications are rare, however, in part because a result can sometimes be challenged on the basis that an experiment was not sufficiently controlled, that the dependent variable was not valid, or that various forms of error compromised the experiment. The scientific method, as a result, builds in the need for reproducibility (usually termed replication) and convergent evidence (see also: external validity). The design of experiments attempts to balance the requirements and limitations of the field of science in which one works so that the experiment can provide the best conclusion about the hypothesis being tested. In some sciences, such as physics and chemistry, it is relatively easy to meet the requirements that all measurements be made objectively, and that all conditions can be kept controlled across experimental trials. On the other hand, in other cases such as biology, and medicine, it is often hard to ensure that the conditions of an experiment are performed consistently; and in the social sciences, it may even be difficult to determine a method for measuring the outcomes of an experiment in an objective manner. For this reason, sciences such as physics and several other fields of natural science are sometimes informally referred to as "hard sciences", while social sciences are sometimes informally referred to as "soft sciences"; in an attempt to capture the idea that objective measurements are often far easier in the former, and far more difficult in the latter. In addition, in the social sciences, the requirement for a "controlled situation" may actually work against the utility of the hypothesis in a more general situation. When the desire is to test a hypothesis that works "in general", an experiment may have a great deal of internal validity, in the sense that it is valid in a highly controlled situation, while at the same time lack external validity when the results of the experiment are applied to a real world situation. One of the reasons why this may happen is the Hawthorne effect; another is that partial equilibrium effects may not persist in general equilibrium. As a result of these considerations, experimental design in the "hard" sciences tends to focus on the elimination of extraneous effects, while experimental design in the "soft" sciences focuses more on the problems of external validity, often through the use of statistical methods. Occasionally events occur naturally from which scientific evidence can be drawn, which is the basis for natural experiments. In such cases the problem of the scientist is to evaluate the natural "design". # Controlled experiments Many hypotheses in sciences such as physics can establish causality by noting that, until some phenomenon occurs, nothing happens; then when the phenomenon occurs, a second phenomenon is observed. But often in science, this situation is difficult to obtain. For example, in the old joke, someone claims that they are snapping their fingers "to keep the tigers away"; and justifies this behavior by saying "see - its working!" While this "experiment" does not falsify the hypothesis "snapping fingers keeps the tigers away", it does not really support the hypothesis - not snapping your fingers keeps the tigers away as well. To demonstrate a cause and effect hypothesis, an experiment must often show that, for example, a phenomenon occurs after a certain treatment is given to a subject, and that the phenomenon does not occur in the absence of the treatment. (See Baconian method.) File:Standard curve.png A controlled experiment generally compares the results obtained from an experimental sample against a control sample, which is practically identical to the experimental sample except for the one aspect whose effect is being tested. A good example would be a drug trial. The sample or group receiving the drug would be the experimental one; and the one receiving the placebo would be the control one. In many laboratory experiments it is good practice to have several replicate samples for the test being performed and have both a positive control and a negative control. The results from replicate samples can often be averaged, or if one of the replicates is obviously inconsistent with the results from the other samples, it can be discarded as being the result of an experimental error (some step of the test procedure may have been mistakenly omitted for that sample). Most often, tests are done in duplicate or triplicate. A positive control is a procedure that is very similar to the actual experimental test but which is known from previous experience to give a positive result. A negative control is known to give a negative result. The positive control confirms that the basic conditions of the experiment were able to produce a positive result, even if none of the actual experimental samples produce a positive result. The negative control demonstrates the base-line result obtained when a test does not produce a measurable positive result; often the value of the negative control is treated as a "background" value to be subtracted from the test sample results. Sometimes the positive control takes the form of a standard curve. An example that is often used in teaching laboratories is a controlled protein assay. Students might be given a fluid sample containing an unknown (to the student) amount of protein. It is their job to correctly perform a controlled experiment in which they determine the concentration of protein in fluid sample (usually called the "unknown sample"). The teaching lab would be equipped with a protein standard solution with a known protein concentration. Students could make several positive control samples containing various dilutions of the protein standard. Negative control samples would contain all of the reagents for the protein assay but no protein. In this example, all samples are performed in duplicate. The assay is a colorimetric assay in which a spectrophotometer can measure the amount of protein in samples by detecting a colored complex formed by the interaction of protein molecules and molecules of an added dye. In the illustration, the results for the diluted test samples can be compared to the results of the standard curve (the blue line in the illustration) in order to determine an estimate of the amount of protein in the unknown sample. Controlled experiments can be performed when it is difficult to exactly control all the conditions in an experiment. In this case, the experiment begins by creating two or more sample groups that are probabilistically equivalent, which means that measurements of traits should be similar among the groups and that the groups should respond in the same manner if given the same treatment. This equivalency is determined by statistical methods that take into account the amount of variation between individuals and the number of individuals in each group. In fields such as microbiology and chemistry, where there is very little variation between individuals and the group size is easily in the millions, these statistical methods are often bypassed and simply splitting a solution into equal parts is assumed to produce identical sample groups. Once equivalent groups have been formed, the experimenter tries to treat them identically except for the one variable that he or she wishes to isolate. Human experimentation requires special safeguards against outside variables such as the placebo effect. Such experiments are generally double blind, meaning that neither the volunteer nor the researcher knows which individuals are in the control group or the experimental group until after all of the data has been collected. This ensures that any effects on the volunteer are due to the treatment itself and are not a response to the knowledge that he is being treated. In human experiments, a subject (person) may be given a stimulus to which he or she should respond. The goal of the experiment is to measure the response to a given stimulus. # Natural experiments The term "experiment" usually implies a controlled experiment, but sometimes controlled experiments are prohibitively difficult or impossible. In this case researchers resort to natural experiments, also called quasi-experiments. Natural experiments rely solely on observations of the variables of the system under study, rather than manipulation of just one or a few variables as occurs in controlled experiments. To the degree possible, they attempt to collect data for the system in such a way that contribution from all variables can be determined, and where the effects of variation in certain variables remain approximately constant so that the effects of other variables can be discerned. The degree to which this is possible depends on the observed correlation between explanatory variables in the observed data. When these variables are not well correlated, natural experiments can approach the power of controlled experiments. Usually, however, there is some correlation between these variables, which reduces the reliability of natural experiments relative to what could be concluded if a controlled experiment were performed. Also, because natural experiments usually take place in uncontrolled environments, variables from undetected sources are neither measured nor held constant, and these may produce illusory correlations in variables under study. Much research in several important science disciplines, including economics, political science, geology, paleontology, ecology, meteorology, and astronomy, relies on quasi-experiments. For example, in astronomy it is clearly impossible, when testing the hypothesis "suns are collapsed clouds of hydrogen", to start out with a giant cloud of hydrogen, and then perform the experiment of waiting a few billion years for it to form a sun. However, by observing various clouds of hydrogen in various states of collapse, and other implications of the hypothesis (for example, the presence of various spectral emissions from the light of stars), we can collect data we require to support the hypothesis. An early example of this type of experiment was the first verification in the 1600s that light does not travel from place to place instantaneously, but instead has a measurable speed. Observation of the appearance of the moons of Jupiter were slightly delayed when Jupiter was farther from Earth, as opposed to when Jupiter was closer to Earth; and this phenomenon was used to demonstrate that the difference in the time of appearance of the moons was consistent with a measurable speed of light. # Observational studies Observational studies are very much like controlled experiments except that they lack probabilistic equivalency between groups. These types of experiments often arise in the area of medicine where, for ethical reasons, it is not possible to create a truly controlled group. For example, one would not want to deny all forms of treatment for a life-threatening disease from one group of patients to evaluate the effectiveness of another treatment on a different group of patients. The results of observational studies are considered much less convincing than those of designed experiments, as they are much more prone to selection bias. Researchers attempt to compensate for this with complicated statistical methods such as propensity score matching methods (see hierarchy of evidence). See also quasi-empirical methods # Field experiments Field experiments are so named in order to draw a contrast with laboratory experiments. Often used in the social sciences, and especially in economic analyses of education and health interventions, field experiments have the advantage that outcomes are observed in a natural setting rather than in a contrived laboratory environment. However, like natural experiments, field experiments suffer from the possibility of contamination: experimental conditions can be controlled with more precision and certainty in the lab. # Examples - MTT assay - Colony Formation Assay - Ames Test - western blot # Quotes # External links - Lessons In Electric Circuits - Volume VI - Experiments - [1] Trochim, William M. Experimental Design. The Research Methods Knowledge Base, 2nd Edition. (version current as of July 11, 2006). - Description of weird experiments (with film clips) Template:Link FA ar:تجربة bs:Eksperiment bg:Експеримент cs:Pokus da:Eksperiment de:Experiment et:Eksperiment el:Πείραμα eo:Eksperimento hr:Eksperiment it:Esperimento he:ניסוי lv:Eksperiments mk:Експеримент nl:Experiment nds:Experiment sq:Eksperimenti simple:Experiment sk:Pokus sr:Експеримент fi:Koe sv:Experiment uk:Експеримент bat-smg:Miegėnėms Template:WH Template:WS Template:Jb1	https://www.wikidoc.org/index.php/Experiment
b0e5d6b4e49ac01f5955834bb9bb3b840cfc5d1a	wikidoc	FER (gene)	FER (gene) Proto-oncogene tyrosine-protein kinase FER is an enzyme that in humans is encoded by the FER gene. Fer protein is a member of the FPS/FES family of nontransmembrane receptor tyrosine kinases. It regulates cell-cell adhesion and mediates signaling from the cell surface to the cytoskeleton via growth factor receptors. # Interactions FER (gene) has been shown to interact with TMF1 and Cortactin.	FER (gene) Proto-oncogene tyrosine-protein kinase FER is an enzyme that in humans is encoded by the FER gene.[1] Fer protein is a member of the FPS/FES family of nontransmembrane receptor tyrosine kinases. It regulates cell-cell adhesion and mediates signaling from the cell surface to the cytoskeleton via growth factor receptors.[1] # Interactions FER (gene) has been shown to interact with TMF1[2] and Cortactin.[3]	https://www.wikidoc.org/index.php/FER_(gene)
ca37971dfe2defe2c2c423f45715e0440cfc7289	wikidoc	Spirometry	Spirometry # Overview Spirometry (meaning the measuring of breath) is the most common of the Pulmonary Function Tests (PFTs), measuring lung function, specifically the measurement of the amount (volume) and/or speed (flow) of air that can be inhaled and exhaled. Spirometry is an important tool used for generating pneumotachograph to assessing conditions such as asthma, pulmonary fibrosis, and COPD. # Indications - Spirometry with and without bronchodilators is used to evaluate all patients with ongoing respiratory illnesses. - It measures the forced vital capacity (FVC), the forced exhaled volume in 1 second (FEV1), total lung capacity, and residual volume. - In the presence of airflow limitation, the patient exhales air slowly, while the total volume of air exhaled is generally not affected. Thus airflow obstruction is diagnosed by a reduced FEV1/FVC ratio. - The American Thoracic Society suggests a ratio of <70% as defining obstruction. # Obstructive lung patterns - Improvement of FEV1 post bronchodilator therapy indicates an obstructive pattern. - Bronchodilators can be administered after obtaining baseline spirometry. - Improvement in airflow obstruction after bronchodilation is shown as an increase in the FEV1. - Significant reversibility is defined by an increase of ≥ 12% and 200mL in FEV1 from baseline measure after inhalation of a short-acting bronchodilator. - Sometimes patients will not demonstrate reversibility immediately with bronchodilators, but will after a short course of oral corticosteroids (2 to 3 weeks) is administered to improve control. ## Severity of obstruction based on spirometry - Mild obstruction - > 70% - Moderate obstruction - 50-70% - Severe obstruction - < 50% ## Spirometry findings in obstructive pattern - FEV1/FVC - < 70% - FVC - Normal or decreased - Total lung capacity - Normal or increased - Residual volume - Normal or increased # Restrictive lung patterns - Reduced FVC - Diseases such as bronchiolitis obliterans with organizing pneumonia, interstitial lung disease,or neuromuscular limitation, present with restrictive patterns on spirometry. - Other tests used for restrictive lung patterns along with spirometry are helium lung volumes and diffusing capacity of carbon monoxide. - A total lung capacity < 90% of the predicted values, confirms the presence of a restrictive ventilatory defect. - A reduction in the FVC < 80%suggests a restrictive ventilatory defect. ## Spirometry findings in restrictive pattern - FEV1/FVC - Normal or increased - FVC - Decreased - Total lung capacity - Decreased - Residual volume - Normal or decreased # Combined restrictive and obstructive defects - Combination of a reduced FVC (<80%) and a FEV1/FVC <70% may suggest a mixed obstructive and restrictive pattern. # Spirometry testing The spirometry test is performed using a device called a spirometer, which comes in several different varieties. Most spirometers display the following graphs: - a volume-time curve, showing volume (liters) along the Y-axis and time (seconds) along the X-axis - a flow-volume loop, which graphically depicts the rate of airflow on the Y-axis and the total volume inspired or expired on the X-axis The most commonly used guidelines for spirometric testing and interpretation are set by the American Thoracic Society (ATS) and the European Respiratory Society (ERS). ## Procedure The basic FVC test varies slightly depending on the equipment used. Generally, the patient is asked to take the deepest breath they can, and then exhale into the sensor as hard as possible, for as long as possible. It is sometimes directly followed by a rapid inhalation (inspiration), in particular when assessing possible upper airway obstruction. Sometimes, the test will be preceded by a period of quiet breathing in and out from the sensor (tidal volume), or the rapid breath in (forced inspiratory part) will come before the forced exhalation. During the test, soft nose clips may be used to prevent air escaping through the nose. Filter mouthpieces may be used to prevent the spread of microorganisms, particularly for inspiratory maneuvers. ## Limitations of test The maneuver is highly dependent on patient cooperation and effort, and is normally repeated at least three times to ensure reproducibility. Since results are dependent on patient cooperation, FEV1 and FVC can only be underestimated, never overestimated. Due to the patient cooperation required, spirometry can only be used on children old enough to comprehend and follow the instructions given (typically about 4-5 years old), and only on patients who are able to understand and follow instructions - thus, this test is not suitable for patients who are unconscious, heavily sedated, or have limitations that would interfere with vigorous respiratory efforts. Other types of lung function tests are available for infants and unconscious persons. ## Related tests Spirometry can also be part of a bronchial challenge test, used to determine bronchial hyperresponsiveness to either rigorous exercise, inhalation of cold/dry air, or with a pharmaceutical agent such as methacholine or histamine. Sometimes, to assess the reversibility of a particular condition, a bronchodilator is administered before performing another round of tests for comparison. This is commonly referred to as a reversibility test, or a post bronchodilator test (Post BD), and is an important part in diagnosing asthma versus COPD. # Explanation of common test values in FVC tests Note that functional residual capacity (FRC) cannot be measured via spirometry, but it can be measured with a plethysmograph. Results are usually given in both raw data (liters, liters per second) and percent predicted - the test result as a percent of the "predicted values" for the patients of similar characteristics (height, age, sex, and sometimes race and weight). The interpretation of the results can vary depending on the physician and the source of the predicted values. Generally speaking, results nearest to 100% predicted are the most normal, and results over 80% are often considered normal. However, review by a doctor is necessary for accurate diagnosis of any individual situation. # Technologies used in spirometers - Volumetric Spirometers Water bell Bellows wedge - Water bell - Bellows wedge - Flow measuring Spirometers Fleisch-pneumotach Lilly (screen) pneumotach Turbine(actually a rotating vane, this spins, the revolutions are counted as they break a light beam) Pitot tube Hot-wire anemometer Ultrasound - Fleisch-pneumotach - Lilly (screen) pneumotach - Turbine(actually a rotating vane, this spins, the revolutions are counted as they break a light beam) - Pitot tube - Hot-wire anemometer - Ultrasound # Related Chapters Peak flow meter	Spirometry Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] # Overview Spirometry (meaning the measuring of breath) is the most common of the Pulmonary Function Tests (PFTs), measuring lung function, specifically the measurement of the amount (volume) and/or speed (flow) of air that can be inhaled and exhaled. Spirometry is an important tool used for generating pneumotachograph to assessing conditions such as asthma, pulmonary fibrosis, and COPD. # Indications - Spirometry with and without bronchodilators is used to evaluate all patients with ongoing respiratory illnesses. - It measures the forced vital capacity (FVC), the forced exhaled volume in 1 second (FEV1), total lung capacity, and residual volume. - In the presence of airflow limitation, the patient exhales air slowly, while the total volume of air exhaled is generally not affected. Thus airflow obstruction is diagnosed by a reduced FEV1/FVC ratio. - The American Thoracic Society suggests a ratio of <70% as defining obstruction. # Obstructive lung patterns - Improvement of FEV1 post bronchodilator therapy indicates an obstructive pattern. - Bronchodilators can be administered after obtaining baseline spirometry. - Improvement in airflow obstruction after bronchodilation is shown as an increase in the FEV1. - Significant reversibility is defined by an increase of ≥ 12% and 200mL in FEV1 from baseline measure after inhalation of a short-acting bronchodilator. - Sometimes patients will not demonstrate reversibility immediately with bronchodilators, but will after a short course of oral corticosteroids (2 to 3 weeks) is administered to improve control. ## Severity of obstruction based on spirometry - Mild obstruction - > 70% - Moderate obstruction - 50-70% - Severe obstruction - < 50% ## Spirometry findings in obstructive pattern - FEV1/FVC - < 70% - FVC - Normal or decreased - Total lung capacity - Normal or increased - Residual volume - Normal or increased # Restrictive lung patterns - Reduced FVC - Diseases such as bronchiolitis obliterans with organizing pneumonia, interstitial lung disease,or neuromuscular limitation, present with restrictive patterns on spirometry. - Other tests used for restrictive lung patterns along with spirometry are helium lung volumes and diffusing capacity of carbon monoxide. - A total lung capacity < 90% of the predicted values, confirms the presence of a restrictive ventilatory defect. - A reduction in the FVC < 80%suggests a restrictive ventilatory defect. ## Spirometry findings in restrictive pattern - FEV1/FVC - Normal or increased - FVC - Decreased - Total lung capacity - Decreased - Residual volume - Normal or decreased # Combined restrictive and obstructive defects - Combination of a reduced FVC (<80%) and a FEV1/FVC <70% may suggest a mixed obstructive and restrictive pattern. # Spirometry testing The spirometry test is performed using a device called a spirometer, which comes in several different varieties. Most spirometers display the following graphs: - a volume-time curve, showing volume (liters) along the Y-axis and time (seconds) along the X-axis - a flow-volume loop, which graphically depicts the rate of airflow on the Y-axis and the total volume inspired or expired on the X-axis The most commonly used guidelines for spirometric testing and interpretation are set by the American Thoracic Society (ATS) and the European Respiratory Society (ERS). ## Procedure The basic FVC test varies slightly depending on the equipment used. Generally, the patient is asked to take the deepest breath they can, and then exhale into the sensor as hard as possible, for as long as possible. It is sometimes directly followed by a rapid inhalation (inspiration), in particular when assessing possible upper airway obstruction. Sometimes, the test will be preceded by a period of quiet breathing in and out from the sensor (tidal volume), or the rapid breath in (forced inspiratory part) will come before the forced exhalation. During the test, soft nose clips may be used to prevent air escaping through the nose. Filter mouthpieces may be used to prevent the spread of microorganisms, particularly for inspiratory maneuvers. ## Limitations of test The maneuver is highly dependent on patient cooperation and effort, and is normally repeated at least three times to ensure reproducibility. Since results are dependent on patient cooperation, FEV1 and FVC can only be underestimated, never overestimated. Due to the patient cooperation required, spirometry can only be used on children old enough to comprehend and follow the instructions given (typically about 4-5 years old), and only on patients who are able to understand and follow instructions - thus, this test is not suitable for patients who are unconscious, heavily sedated, or have limitations that would interfere with vigorous respiratory efforts. Other types of lung function tests are available for infants and unconscious persons. ## Related tests Spirometry can also be part of a bronchial challenge test, used to determine bronchial hyperresponsiveness to either rigorous exercise, inhalation of cold/dry air, or with a pharmaceutical agent such as methacholine or histamine. Sometimes, to assess the reversibility of a particular condition, a bronchodilator is administered before performing another round of tests for comparison. This is commonly referred to as a reversibility test, or a post bronchodilator test (Post BD), and is an important part in diagnosing asthma versus COPD. # Explanation of common test values in FVC tests Note that functional residual capacity (FRC) cannot be measured via spirometry, but it can be measured with a plethysmograph. Results are usually given in both raw data (liters, liters per second) and percent predicted - the test result as a percent of the "predicted values" for the patients of similar characteristics (height, age, sex, and sometimes race and weight). The interpretation of the results can vary depending on the physician and the source of the predicted values. Generally speaking, results nearest to 100% predicted are the most normal, and results over 80% are often considered normal. However, review by a doctor is necessary for accurate diagnosis of any individual situation. # Technologies used in spirometers - Volumetric Spirometers Water bell Bellows wedge - Water bell - Bellows wedge - Flow measuring Spirometers Fleisch-pneumotach Lilly (screen) pneumotach Turbine(actually a rotating vane, this spins, the revolutions are counted as they break a light beam) Pitot tube Hot-wire anemometer Ultrasound - Fleisch-pneumotach - Lilly (screen) pneumotach - Turbine(actually a rotating vane, this spins, the revolutions are counted as they break a light beam) - Pitot tube - Hot-wire anemometer - Ultrasound # Related Chapters Peak flow meter Template:WikiDoc Sources	https://www.wikidoc.org/index.php/FEV1
4ff29245f068bd34b9bb1d0d01033282bb89a106	wikidoc	Fatty acid	Fatty acid In chemistry, especially biochemistry, a fatty acid is a carboxylic acid often with a long unbranched aliphatic tail (chain), which is either saturated or unsaturated. Carboxylic acids as short as butyric acid (4 carbon atoms) are considered to be fatty acids, whereas fatty acids derived from natural fats and oils may be assumed to have at least 8 carbon atoms, e.g., caprylic acid (octanoic acid). Most of the natural fatty acids have an even number of carbon atoms, because their biosynthesis involves acetyl-CoA, a coenzyme carrying a two-carbon-atom group (see fatty acid synthesis). In industry, fatty acids are produced by the hydrolysis of the ester linkages in a fat or biological oil (both of which are triglycerides), with the removal of glycerol. See oleochemicals. # Types of fatty acids ## Saturated fatty acids Saturated fatty acids do not contain any double bonds or other functional groups along the chain. The term "saturated" refers to hydrogen, in that all carbons (apart from the carboxylic acid group) contain as many hydrogens as possible. In other words, the omega (ω) end contains 3 hydrogens (CH3-), and each carbon within the chain contains 2 hydrogen Saturated fatty acids form straight chains and, as a result, can be packed together very tightly, allowing living organisms to store chemical energy very densely. The fatty tissues of animals contain large amounts of long-chain saturated fatty acids. In IUPAC nomenclature, fatty acids have an suffix. In common nomenclature, the suffix is usually -ic. The shortest descriptions of fatty acids include only the number of carbon atoms and double bonds in them (e.g., C18:0 or 18:0). C18:0 means that the carbon chain of the fatty acid consists of 18 carbon atoms, and there are no (zero) double bonds in it, whereas C18:1 describes an 18-carbon chain with one double bond in it. Each double bond can be in either a cis- or trans- conformation and in a different position with respect to the ends of the fatty acid; therefore, not all C18:1s, for example, are identical. If there is one or more double bonds in the fatty acid, it is no longer considered saturated, rather mono- or polyunsaturated. Most commonly-occurring saturated fatty acids are: ## Unsaturated fatty acids File:Isomers of oleic acid.png Unsaturated fatty acids are of similar form, except that one or more alkenyl functional groups exist along the chain, with each alkene substituting a single-bonded " -CH2-CH2-" part of the chain with a double-bonded "-CH=CH-" portion (that is, a carbon double-bonded to another carbon). The two next carbon atoms in the chain that are bound to either side of the double bond can occur in a cis or trans configuration. In most naturally-occurring unsaturated fatty acids, each double bond has 3n carbon atoms after it, for some n, and all are cis bonds. Most fatty acids in the trans configuration (trans fats) are not found in nature and are the result of human processing (e.g., hydrogenation). The differences in geometry between the various types of unsaturated fatty acids, as well as between saturated and unsaturated fatty acids, play an important role in biological processes, and in the construction of biological structures (such as cell membranes). ### Nomenclature There are several different ways to make clear where the double bonds are located in molecules. For example: - cis/trans-Delta-x or cis/trans-Δx: The double bond is located on the xth carbon-carbon bond, counting from the carboxylic acid end. The cis or trans notation indicates whether the molecule is arranged in a cis or trans conformation. In the case of a molecule's having more than one double bond, the notation is, for example, cis,cis-Δ9,Δ12. - Omega-x or ω-x : A double bond is located on the xth carbon-carbon bond, counting from the ω, (methyl carbon) end of the chain. Sometimes, the symbol ω is replaced with a lowercase letter n, making it n-6 or n-3. - In IUPAC nomenclature, a systematic naming system for all chemical compounds, counting is begins from the carboxylic acid end and cis double bonds are labelled Z and trans double bonds are labelled E. (See IUPAC nomenclature of organic chemistry for details.) ### Examples of unsaturated fatty acids Myristoleic is omega-5 fatty acid, palmitoleic is omega-7 fatty acid, and oleic and erucic acid are omega-9 fatty acids. Stearic and oleic acid are both C18 fatty acids. They differ only in that stearic acid is saturated with hydrogen, whereas oleic acid is an unsaturated fatty acid with two fewer hydrogens. Docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) are examples of long chain omega-3 fatty acids (LCn3) in fish oil. Alpha-linolenic is a long chain omega-3 fatty acid from plants. LCn3 may benefit health. Linoleic acid and arachidonic acid are omega-6 fatty acids. These fatty acids may be harmful. ### Essential fatty acids The human body can produce all but two of the fatty acids it needs. These two, linoleic acid (LA) and alpha-linolenic acid (LNA), are widely distributed in plant oils. In addition, fish oils contain the longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Other marine oils, such as from seal, also contain significant amounts of docosapentaenoic acid (DPA), which is also an omega-3 fatty acid. Although the body to some extent can convert LA and LNA into these longer-chain omega-3 fatty acids, the omega-3 fatty acids found in marine oils help fulfil the requirement of essential fatty acids (and have been shown to have wholesome properties of their own). Since they cannot be made in the body from other substrates and must be supplied in food, they are called essential fatty acids. Mammals lack the ability to introduce double bonds in fatty acids beyond carbons 9 and 10. Hence linoleic acid and linoleinic acid are essential fatty acids for humans. In the body, essential fatty acids are primarily used to produce hormone-like substances that regulate a wide range of functions, including blood pressure, blood clotting, blood lipid levels, the immune response, and the inflammation response to injury infection. Essential fatty acids are polyunsaturated fatty acids and are the parent compounds of the omega-6 and omega-3 fatty acid series, respectively. They are essential in the human diet because there is no synthetic mechanism for them. Humans can easily make saturated fatty acids or monounsaturated fatty acids with a double bond at the omega-9 position, but do not have the enzymes necessary to introduce a double bond at the omega-3 position or omega-6 position. The essential fatty acids are important in several human body systems, including the immune system and in blood pressure regulation, since they are used to make compounds such as prostaglandins. The brain has increased amounts of linolenic and alpha-linoleic acid derivatives. Changes in the levels and balance of these fatty acids due to a typical Western diet rich in omega-6 and poor in omega-3 fatty acids is alleged to be associated with depression and behavioral change, including violence. The actual connection, if any, is still under investigation. Further, changing to a diet richer in omega-3 fatty acids, or consumption of supplements to compensate for a dietary imbalance, has been associated with reduced violent behavior and increased attention span, but the mechanisms for the effect are still unclear. So far, at least three human studies have shown results that support this: two school studies as well as a double blind study in a prison. Fatty acids play an important role in the life and death of cardiac cells because they are essential fuels for mechanical and electrical activities of the heart. ### Trans fatty acids A trans fatty acid (commonly shortened to trans fat) is an unsaturated fatty acid molecule that contains a trans double bond between carbon atoms, which makes the molecule less 'kinked' in comparison to fatty acids with cis double bonds. These bonds are characteristically produced during industrial hydrogenation of plant oils. Research suggests that amounts of trans fats correlate with circulatory diseases such as atherosclerosis and coronary heart disease more than the same amount of non-trans fats, for reasons that are not well understood. # Free fatty acids Fatty acids can be bound or attached to other molecules, such as in triglycerides or phospholipids. When they are not attached to other molecules, they are known as "free" fatty acids. The uncombined fatty acids or free fatty acids may come from the breakdown of a triglyceride into its components (fatty acids and glycerol). Free fatty acids are an important source of fuel for many tissues since they can yield relatively large quantities of ATP. Many cell types can use either glucose or fatty acids for this purpose. In particular, heart and skeletal muscle prefer fatty acids. The brain cannot use fatty acids as a source of fuel; it relies on glucose, or on ketone bodies. Ketone bodies are produced in the liver by fatty acid metabolism during starvation, or during periods of low carbohydrate intake. # Fatty acids in dietary fats The following table gives the fatty acid and cholesterol composition of some common dietary fats. # Acidity Short chain carboxylic acids such as formic acid and acetic acid are miscible with water and dissociate to form reasonably strong acids (pKa 3.77 and 4.76, respectively). Longer-chain fatty acids do not show a great change in pKa. Nonanoic acid, for example, has a pKa of 4.96. However, as the chain length increases the solubility of the fatty acids in water decreases very rapidly, so that the longer-chain fatty acids have very little effect on the pH of a solution. The significance of their pKa values therefore has relevance only to the types of reactions in which they can take part. Even those fatty acids that are insoluble in water will dissolve in warm ethanol, and can be titrated with sodium hydroxide solution using phenolphthalein as an indicator to a pale-pink endpoint. This analysis is used to determine the free fatty acid content of fats, i.e., the proportion of the triglycerides that have been hydrolyzed. # Reaction of fatty acids Fatty acids react just like any other carboxylic acid, which means they can undergo esterification and acid-base reactions. Reduction of fatty acids yields fatty alcohols. Unsaturated fatty acids can also undergo addition reactions, most commonly hydrogenation, which is used to convert vegetable oils into margarine. With partial hydrogenation, unsaturated fatty acids can be isomerized from cis to trans configuration. In the Varrentrapp reaction certain unsaturated fatty acids are cleaved in molten alkali, a reaction at one time of relevance to structure elucidation. ## Auto-oxidation and rancidity Fatty acids at room temperature undergo a chemical change known as auto-oxidation. The fatty acid breaks down into hydrocarbons, ketones, aldehydes, and smaller amounts of epoxides and alcohols. Heavy metals present at low levels in fats and oils promote auto-oxidation. Fats and oils often are treated with chelating agents such as citric acid.	Fatty acid Template:Fats Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Template:Editor help In chemistry, especially biochemistry, a fatty acid is a carboxylic acid often with a long unbranched aliphatic tail (chain), which is either saturated or unsaturated. Carboxylic acids as short as butyric acid (4 carbon atoms) are considered to be fatty acids, whereas fatty acids derived from natural fats and oils may be assumed to have at least 8 carbon atoms, e.g., caprylic acid (octanoic acid). Most of the natural fatty acids have an even number of carbon atoms, because their biosynthesis involves acetyl-CoA, a coenzyme carrying a two-carbon-atom group (see fatty acid synthesis). In industry, fatty acids are produced by the hydrolysis of the ester linkages in a fat or biological oil (both of which are triglycerides), with the removal of glycerol. See oleochemicals. # Types of fatty acids ## Saturated fatty acids Saturated fatty acids do not contain any double bonds or other functional groups along the chain. The term "saturated" refers to hydrogen, in that all carbons (apart from the carboxylic acid [-COOH] group) contain as many hydrogens as possible. In other words, the omega (ω) end contains 3 hydrogens (CH3-), and each carbon within the chain contains 2 hydrogen Saturated fatty acids form straight chains and, as a result, can be packed together very tightly, allowing living organisms to store chemical energy very densely. The fatty tissues of animals contain large amounts of long-chain saturated fatty acids. In IUPAC nomenclature, fatty acids have an [-oic acid] suffix. In common nomenclature, the suffix is usually -ic. The shortest descriptions of fatty acids include only the number of carbon atoms and double bonds in them (e.g., C18:0 or 18:0). C18:0 means that the carbon chain of the fatty acid consists of 18 carbon atoms, and there are no (zero) double bonds in it, whereas C18:1 describes an 18-carbon chain with one double bond in it. Each double bond can be in either a cis- or trans- conformation and in a different position with respect to the ends of the fatty acid; therefore, not all C18:1s, for example, are identical. If there is one or more double bonds in the fatty acid, it is no longer considered saturated, rather mono- or polyunsaturated. Most commonly-occurring saturated fatty acids are: ## Unsaturated fatty acids File:Isomers of oleic acid.png Unsaturated fatty acids are of similar form, except that one or more alkenyl functional groups exist along the chain, with each alkene substituting a single-bonded " -CH2-CH2-" part of the chain with a double-bonded "-CH=CH-" portion (that is, a carbon double-bonded to another carbon). The two next carbon atoms in the chain that are bound to either side of the double bond can occur in a cis or trans configuration. In most naturally-occurring unsaturated fatty acids, each double bond has 3n carbon atoms after it, for some n, and all are cis bonds. Most fatty acids in the trans configuration (trans fats) are not found in nature and are the result of human processing (e.g., hydrogenation). The differences in geometry between the various types of unsaturated fatty acids, as well as between saturated and unsaturated fatty acids, play an important role in biological processes, and in the construction of biological structures (such as cell membranes). ### Nomenclature There are several different ways to make clear where the double bonds are located in molecules. For example: - cis/trans-Delta-x or cis/trans-Δx: The double bond is located on the xth carbon-carbon bond, counting from the carboxylic acid end. The cis or trans notation indicates whether the molecule is arranged in a cis or trans conformation. In the case of a molecule's having more than one double bond, the notation is, for example, cis,cis-Δ9,Δ12. - Omega-x or ω-x : A double bond is located on the xth carbon-carbon bond, counting from the ω, (methyl carbon) end of the chain. Sometimes, the symbol ω is replaced with a lowercase letter n, making it n-6 or n-3. - In IUPAC nomenclature, a systematic naming system for all chemical compounds, counting is begins from the carboxylic acid end and cis double bonds are labelled Z and trans double bonds are labelled E. (See IUPAC nomenclature of organic chemistry for details.) ### Examples of unsaturated fatty acids Myristoleic is omega-5 fatty acid, palmitoleic is omega-7 fatty acid, and oleic and erucic acid are omega-9 fatty acids. Stearic and oleic acid are both C18 fatty acids. They differ only in that stearic acid is saturated with hydrogen, whereas oleic acid is an unsaturated fatty acid with two fewer hydrogens. Docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) are examples of long chain omega-3 fatty acids (LCn3) in fish oil. Alpha-linolenic is a long chain omega-3 fatty acid from plants. LCn3 may benefit health. Linoleic acid and arachidonic acid are omega-6 fatty acids. These fatty acids may be harmful. ### Essential fatty acids The human body can produce all but two of the fatty acids it needs. These two, linoleic acid (LA) and alpha-linolenic acid (LNA), are widely distributed in plant oils. In addition, fish oils contain the longer-chain omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Other marine oils, such as from seal, also contain significant amounts of docosapentaenoic acid (DPA), which is also an omega-3 fatty acid. Although the body to some extent can convert LA and LNA into these longer-chain omega-3 fatty acids, the omega-3 fatty acids found in marine oils help fulfil the requirement of essential fatty acids (and have been shown to have wholesome properties of their own). Since they cannot be made in the body from other substrates and must be supplied in food, they are called essential fatty acids. Mammals lack the ability to introduce double bonds in fatty acids beyond carbons 9 and 10. Hence linoleic acid and linoleinic acid are essential fatty acids for humans. In the body, essential fatty acids are primarily used to produce hormone-like substances that regulate a wide range of functions, including blood pressure, blood clotting, blood lipid levels, the immune response, and the inflammation response to injury infection. Essential fatty acids are polyunsaturated fatty acids and are the parent compounds of the omega-6 and omega-3 fatty acid series, respectively. They are essential in the human diet because there is no synthetic mechanism for them. Humans can easily make saturated fatty acids or monounsaturated fatty acids with a double bond at the omega-9 position, but do not have the enzymes necessary to introduce a double bond at the omega-3 position or omega-6 position. The essential fatty acids are important in several human body systems, including the immune system and in blood pressure regulation, since they are used to make compounds such as prostaglandins. The brain has increased amounts of linolenic and alpha-linoleic acid derivatives. Changes in the levels and balance of these fatty acids due to a typical Western diet rich in omega-6 and poor in omega-3 fatty acids is alleged[citation needed] to be associated with depression and behavioral change, including violence. The actual connection, if any, is still under investigation. Further, changing to a diet richer in omega-3 fatty acids, or consumption of supplements to compensate for a dietary imbalance, has been associated with reduced violent behavior[1] and increased attention span, but the mechanisms for the effect are still unclear. So far, at least three human studies have shown results that support this: two school studies[citation needed][2] as well as a double blind study in a prison.[1][3][4] Fatty acids play an important role in the life and death of cardiac cells because they are essential fuels for mechanical and electrical activities of the heart. [5] [6] [7] [8] ### Trans fatty acids A trans fatty acid (commonly shortened to trans fat) is an unsaturated fatty acid molecule that contains a trans double bond between carbon atoms, which makes the molecule less 'kinked' in comparison to fatty acids with cis double bonds. These bonds are characteristically produced during industrial hydrogenation of plant oils. Research suggests that amounts of trans fats correlate with circulatory diseases such as atherosclerosis and coronary heart disease more than the same amount of non-trans fats, for reasons that are not well understood. # Free fatty acids Fatty acids can be bound or attached to other molecules, such as in triglycerides or phospholipids. When they are not attached to other molecules, they are known as "free" fatty acids. The uncombined fatty acids or free fatty acids may come from the breakdown of a triglyceride into its components (fatty acids and glycerol). Free fatty acids are an important source of fuel for many tissues since they can yield relatively large quantities of ATP. Many cell types can use either glucose or fatty acids for this purpose. In particular, heart and skeletal muscle prefer fatty acids. The brain cannot use fatty acids as a source of fuel; it relies on glucose, or on ketone bodies. Ketone bodies are produced in the liver by fatty acid metabolism during starvation, or during periods of low carbohydrate intake. # Fatty acids in dietary fats The following table gives the fatty acid and cholesterol composition of some common dietary fats.[9] [10] # Acidity Short chain carboxylic acids such as formic acid and acetic acid are miscible with water and dissociate to form reasonably strong acids (pKa 3.77 and 4.76, respectively). Longer-chain fatty acids do not show a great change in pKa. Nonanoic acid, for example, has a pKa of 4.96. However, as the chain length increases the solubility of the fatty acids in water decreases very rapidly, so that the longer-chain fatty acids have very little effect on the pH of a solution. The significance of their pKa values therefore has relevance only to the types of reactions in which they can take part. Even those fatty acids that are insoluble in water will dissolve in warm ethanol, and can be titrated with sodium hydroxide solution using phenolphthalein as an indicator to a pale-pink endpoint. This analysis is used to determine the free fatty acid content of fats, i.e., the proportion of the triglycerides that have been hydrolyzed. # Reaction of fatty acids Fatty acids react just like any other carboxylic acid, which means they can undergo esterification and acid-base reactions. Reduction of fatty acids yields fatty alcohols. Unsaturated fatty acids can also undergo addition reactions, most commonly hydrogenation, which is used to convert vegetable oils into margarine. With partial hydrogenation, unsaturated fatty acids can be isomerized from cis to trans configuration. In the Varrentrapp reaction certain unsaturated fatty acids are cleaved in molten alkali, a reaction at one time of relevance to structure elucidation. ## Auto-oxidation and rancidity Fatty acids at room temperature undergo a chemical change known as auto-oxidation. The fatty acid breaks down into hydrocarbons, ketones, aldehydes, and smaller amounts of epoxides and alcohols. Heavy metals present at low levels in fats and oils promote auto-oxidation. Fats and oils often are treated with chelating agents such as citric acid.	https://www.wikidoc.org/index.php/FFA
57c70827ae16cfc16b15e15573672df2d442061e	wikidoc	FGR (gene)	FGR (gene) Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog, also known as FGR, is a protein which in humans is encoded by the FGR gene. # Function This gene is a member of the Src family of protein tyrosine kinases (PTKs). The encoded protein contains N-terminal sites for myristoylation and palmitoylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. The protein localizes to plasma membrane ruffles, and functions as a negative regulator of cell migration and adhesion triggered by the beta-2 integrin signal transduction pathway. Infection with Epstein-Barr virus results in the overexpression of this gene. Multiple alternatively spliced variants, encoding the same protein, have been identified. # Discovery The feline version of this gene was discovered by Suraiya Rasheed, Murray Gardner, and co-workers. # Interactions FGR (gene) has been shown to interact with Wiskott-Aldrich syndrome protein.	FGR (gene) Gardner-Rasheed feline sarcoma viral (v-fgr) oncogene homolog, also known as FGR, is a protein which in humans is encoded by the FGR gene.[1][2] # Function This gene is a member of the Src family of protein tyrosine kinases (PTKs). The encoded protein contains N-terminal sites for myristoylation and palmitoylation, a PTK domain, and SH2 and SH3 domains which are involved in mediating protein-protein interactions with phosphotyrosine-containing and proline-rich motifs, respectively. The protein localizes to plasma membrane ruffles, and functions as a negative regulator of cell migration and adhesion triggered by the beta-2 integrin signal transduction pathway. Infection with Epstein-Barr virus results in the overexpression of this gene. Multiple alternatively spliced variants, encoding the same protein, have been identified.[2] # Discovery The feline version of this gene was discovered by Suraiya Rasheed, Murray Gardner, and co-workers.[3] # Interactions FGR (gene) has been shown to interact with Wiskott-Aldrich syndrome protein.[4][5][6]	https://www.wikidoc.org/index.php/FGR_(gene)
3b8603927917a65afe392f79e9752050d46c1c21	wikidoc	FUS (gene)	FUS (gene) RNA-binding protein FUS/TLS (Fused in Sarcoma/Translocated in Sarcoma) is a protein that in humans is encoded by the FUS gene. # Structure and function The N-terminal end of FUS appears to be involved in transcriptional activation, while the C-terminal end is involved in protein and RNA binding. In addition recognition sites for the transcription factors AP2, GCF, Sp1 have been identified in FUS. FUS/TLS is a member of the TET protein family that also includes the EWS protein, the TATA-binding protein (TBP)-associated factor (TAFII68/TAF15) and the Drosophila cabeza/SARF protein. FUS/TLS, EWS and TAFII68/TAF15 have a similar structure characterised by an N-terminal QGSY-rich region, a highly conserved RNA recognition motif (RRM), multiple RGG repeats, which are extensively dimethylated at arginine residues and a C-terminal zinc finger motif. ## Discovery FUS/TLS was initially identified as a fusion protein (FUS-CHOP) caused by chromosomal translocations in human cancers, especially liposarcomas. In these instances, the promoter and N-terminal part of FUS/TLS is translocated to the C-terminal domain of various DNA-binding transcription factors (eg CHOP) conferring a strong transcriptional activation domain to the fusion proteins. FUS/TLS was independently identified as the hnRNP P2 protein, a subunit of a complex involved in maturation of pre-mRNA. ## Function Consistently, in vitro studies have shown that FUS/TLS binds RNA, single-stranded DNA and (with lower affinity) double-stranded DNA. The sequence specificity of FUS/TLS binding to RNA or DNA has not been well established; however, using in vitro selection (SELEX), a common GGUG motif has been identified in approximately half of the RNA sequences bound by FUS/TLS. A later proposal was that the GGUG motif is recognised by the zinc finger domain and not the RRM (80). Additionally, FUS/TLS has been found to bind a relatively long region in the 3′ untranslated region (UTR) of the actin-stabilising protein Nd1-L mRNA, suggesting that rather than recognising specific short sequences, FUS/TLS interacts with multiple RNA-binding motifs or recognises secondary conformations. FUS/TLS has also been proposed to bind human telomeric RNA (UUAGGG)4 and single-stranded human telomeric DNA in vitro. Beyond nucleic acid binding, FUS/TLS was also found to associate with both general and more specialized protein factors to influence the initiation of transcription. Indeed, FUS/TLS interacts with several nuclear receptors. and with gene-specific transcription factors such as Spi-1/PU.1. or NF-κB. It also associates with the general transcriptional machinery and may influence transcription initiation and promoter selection by interacting with RNA polymerase II and the TFIID complex. Recently, FUS/TLS was also shown to repress the transcription of RNAP III genes and to co-immunoprecipitate with TBP and the TFIIIB complex. ## FUS-mediated DNA repair FUS appears at sites of DNA damage very rapidly, which suggests that FUS is orchestrating the DNA repair response. The function of FUS in the DNA damage response in neurons involves a direct interaction with histone deacetylase 1 (HDAC1). The recruitment of FUS to double-strand break sites is important for DNA damage response signaling and for repair of DNA damage. FUS loss-of-function results in increased DNA damage in neurons. Mutations in the FUS nuclear localization sequence impairs the poly (ADP-ribose) polymerase (PARP)-dependent DNA damage response. This impairment leads to neurodegeneration and FUS aggregate formation. Such FUS aggregates are a pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). # Clinical significance FUS gene rearrangement has been implicated in the pathogenesis of both myxoid liposarcoma and low grade fibromyxoid sarcoma. In 2009 two separate research groups analysed 26 unrelated families who presented with a type6 ALS phenotype, and found 14 mutations in the FUS gene. Subsequently, FUS has also emerged as a significant disease protein in a subgroup of frontotemporal lobar dementias (FTLDs), previously characterized by immunoreactivity of the neuronal inclusions for ubiquitin, but not for TDP-43 or tau with a proportion of the inclusions also containing a-internexin in a further subgroup known as neuronal intermediate filament inclusion disease (NIFID). The disease entities which are now considered subtypes of FTLD-FUS are atypical frontotemporal lobar degeneration with ubiquitinated inclusions (aFTLD-U), NIFID (otherwise known as neurofilament inclusion body disease) and basophilic inclusion body disease (BIBD), which together with ALS-FUS comprise the FUS-opathies. FTLD is the pathological term for the clinical syndrome of frontotemporal dementia (FTD). FTD differs from the more common Alzheimer's dementia in that memory is relatively well preserved; instead, the disease presents with a more temporal-lobe phenotype. Behavioural variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA) and semantic dementia (SD) are the three best-characterised clinical presentations. FUS positive FTLD tends to present clinically as a bvFTD but the correlation between underlying pathology and clinical presentation is not perfect. # Interactions FUS has been shown to interact with: - FUSIP1/SRSF10 - HDAC1 - ILF3, - PRMT1, - RELA, - RNA polymerase II (C-terminal domain) - SPI1, and - TNPO1.	FUS (gene) RNA-binding protein FUS/TLS (Fused in Sarcoma/Translocated in Sarcoma) is a protein that in humans is encoded by the FUS gene.[1][2][3][4][5][6] # Structure and function The N-terminal end of FUS appears to be involved in transcriptional activation, while the C-terminal end is involved in protein and RNA binding. In addition recognition sites for the transcription factors AP2, GCF, Sp1 have been identified in FUS.[7] FUS/TLS is a member of the TET protein family that also includes the EWS protein, the TATA-binding protein (TBP)-associated factor (TAFII68/TAF15) and the Drosophila cabeza/SARF protein.[8][9] FUS/TLS, EWS and TAFII68/TAF15 have a similar structure characterised by an N-terminal QGSY-rich region, a highly conserved RNA recognition motif (RRM), multiple RGG repeats, which are extensively dimethylated at arginine residues[10] and a C-terminal zinc finger motif.[3][5][8][11] ## Discovery FUS/TLS was initially identified as a fusion protein (FUS-CHOP) caused by chromosomal translocations in human cancers, especially liposarcomas.[2][5] In these instances, the promoter and N-terminal part of FUS/TLS is translocated to the C-terminal domain of various DNA-binding transcription factors (eg CHOP) conferring a strong transcriptional activation domain to the fusion proteins.[9][12] FUS/TLS was independently identified as the hnRNP P2 protein, a subunit of a complex involved in maturation of pre-mRNA.[13] ## Function Consistently, in vitro studies have shown that FUS/TLS binds RNA, single-stranded DNA and (with lower affinity) double-stranded DNA.[3][5][14][15][16][17] The sequence specificity of FUS/TLS binding to RNA or DNA has not been well established; however, using in vitro selection (SELEX), a common GGUG motif has been identified in approximately half of the RNA sequences bound by FUS/TLS.[18] A later proposal was that the GGUG motif is recognised by the zinc finger domain and not the RRM (80). Additionally, FUS/TLS has been found to bind a relatively long region in the 3′ untranslated region (UTR) of the actin-stabilising protein Nd1-L mRNA, suggesting that rather than recognising specific short sequences, FUS/TLS interacts with multiple RNA-binding motifs or recognises secondary conformations.[19] FUS/TLS has also been proposed to bind human telomeric RNA (UUAGGG)4 and single-stranded human telomeric DNA in vitro.[20] Beyond nucleic acid binding, FUS/TLS was also found to associate with both general and more specialized protein factors to influence the initiation of transcription.[21] Indeed, FUS/TLS interacts with several nuclear receptors.[22] and with gene-specific transcription factors such as Spi-1/PU.1.[23] or NF-κB.[24] It also associates with the general transcriptional machinery and may influence transcription initiation and promoter selection by interacting with RNA polymerase II and the TFIID complex.[25][26][27] Recently, FUS/TLS was also shown to repress the transcription of RNAP III genes and to co-immunoprecipitate with TBP and the TFIIIB complex.[28] ## FUS-mediated DNA repair FUS appears at sites of DNA damage very rapidly, which suggests that FUS is orchestrating the DNA repair response.[29] The function of FUS in the DNA damage response in neurons involves a direct interaction with histone deacetylase 1 (HDAC1). The recruitment of FUS to double-strand break sites is important for DNA damage response signaling and for repair of DNA damage.[29] FUS loss-of-function results in increased DNA damage in neurons. Mutations in the FUS nuclear localization sequence impairs the poly (ADP-ribose) polymerase (PARP)-dependent DNA damage response.[30] This impairment leads to neurodegeneration and FUS aggregate formation. Such FUS aggregates are a pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). # Clinical significance FUS gene rearrangement has been implicated in the pathogenesis of both myxoid liposarcoma and low grade fibromyxoid sarcoma. In 2009 two separate research groups analysed 26 unrelated families who presented with a type6 ALS phenotype, and found 14 mutations in the FUS gene.[31][32] Subsequently, FUS has also emerged as a significant disease protein in a subgroup of frontotemporal lobar dementias (FTLDs), previously characterized by immunoreactivity of the neuronal inclusions for ubiquitin, but not for TDP-43 or tau with a proportion of the inclusions also containing a-internexin in a further subgroup known as neuronal intermediate filament inclusion disease (NIFID). The disease entities which are now considered subtypes of FTLD-FUS are atypical frontotemporal lobar degeneration with ubiquitinated inclusions (aFTLD-U), NIFID (otherwise known as neurofilament inclusion body disease) and basophilic inclusion body disease (BIBD), which together with ALS-FUS comprise the FUS-opathies.[33][34][35][36] FTLD is the pathological term for the clinical syndrome of frontotemporal dementia (FTD). FTD differs from the more common Alzheimer's dementia in that memory is relatively well preserved; instead, the disease presents with a more temporal-lobe phenotype. Behavioural variant frontotemporal dementia (bvFTD), progressive non-fluent aphasia (PNFA) and semantic dementia (SD) are the three best-characterised clinical presentations. FUS positive FTLD tends to present clinically as a bvFTD but the correlation between underlying pathology and clinical presentation is not perfect. # Interactions FUS has been shown to interact with: - FUSIP1/SRSF10[27] - HDAC1[29] - ILF3,[37] - PRMT1,[38][39][40] - RELA,[24] - RNA polymerase II (C-terminal domain)[41] - SPI1,[23] and - TNPO1.[42][43]	https://www.wikidoc.org/index.php/FUS_(gene)
434953cf6448f716e172b4956f07c8fe332a31bc	wikidoc	Factor VII	Factor VII Factor VII (EC 3.4.21.21, blood-coagulation factor VIIa, activated blood coagulation factor VII, formerly known as proconvertin) is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa (eptacog alfa , NovoSeven) has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients. It is sometimes used unlicensed in severe uncontrollable bleeding, although there have been safety concerns. A biosimilar form of recombinant activated factor VII (AryoSeven) is also available, but does not play any considerable role in the market. # Physiology The main role of factor VII (FVII) is to initiate the process of coagulation in conjunction with tissue factor (TF/factor III). Tissue factor is found on the outside of blood vessels - normally not exposed to the bloodstream. Upon vessel injury, tissue factor is exposed to the blood and circulating factor VII. Once bound to TF, FVII is activated to FVIIa by different proteases, among which are thrombin (factor IIa), factor Xa, IXa, XIIa, and the FVIIa-TF complex itself. The complex of factor VIIa with TF catalyzes the conversion of factor IX and factor X into the active proteases, factor IXa and factor Xa, respectively. The action of the factor is impeded by tissue factor pathway inhibitor (TFPI), which is released almost immediately after initiation of coagulation. Factor VII is vitamin K dependent; it is produced in the liver. Use of warfarin or similar anticoagulants decreases hepatic synthesis of FVII. # Structure Factor VII shares a common domain architecture with factors IX and X. # Genetics The gene for factor VII is located on chromosome 13 (13q34). # Role in disease Factor VII deficiency (congenital proconvertin deficiency) is rare and inherited recessively. It presents as a hemophilia-like bleeding disorder. It is treated with recombinant factor VIIa (NovoSeven or AryoSeven). Gene therapy approaches for treating FVII deficiency are very promising () # Medical uses Recombinant factor VIIa, marketed under the trade names AryoSeven and NovoSeven, is used for people with hemophilia (with Factor VIII or IX deficiency) who have developed antibodies against replacement coagulation factor. It has also been used in the setting of uncontrollable hemorrhage, but its role in this setting is controversial with insufficient evidence to support its use outside of clinical trials. The first report of its use in hemorrhage was in an Israeli soldier with uncontrollable bleeding in 1999. Risks of its use include an increase in arterial thrombosis.However, animal studies have not shown complications as seen in humans, in fact same of the studies show a better prognosis. In the military settings it is used as an off label intervention in complications related to disseminated intravascular coagulation related haemorrhage caused by penetrating trauma. Recombinant human factor VII while initially looking promising in intracerebral hemorrhage failed to show benefit following further study and this is no longer recommended. # Interactions Factor VII has been shown to interact with tissue factor and protein kinase C.	Factor VII Factor VII (EC 3.4.21.21, blood-coagulation factor VIIa, activated blood coagulation factor VII, formerly known as proconvertin) is one of the proteins that causes blood to clot in the coagulation cascade. It is an enzyme of the serine protease class. A recombinant form of human factor VIIa (eptacog alfa [activated], NovoSeven) has U.S. Food and Drug Administration approval for uncontrolled bleeding in hemophilia patients. It is sometimes used unlicensed in severe uncontrollable bleeding, although there have been safety concerns. A biosimilar form of recombinant activated factor VII (AryoSeven) is also available, but does not play any considerable role in the market. # Physiology The main role of factor VII (FVII) is to initiate the process of coagulation in conjunction with tissue factor (TF/factor III). Tissue factor is found on the outside of blood vessels - normally not exposed to the bloodstream. Upon vessel injury, tissue factor is exposed to the blood and circulating factor VII. Once bound to TF, FVII is activated to FVIIa by different proteases, among which are thrombin (factor IIa), factor Xa, IXa, XIIa, and the FVIIa-TF complex itself. The complex of factor VIIa with TF catalyzes the conversion of factor IX and factor X into the active proteases, factor IXa and factor Xa, respectively.[1] The action of the factor is impeded by tissue factor pathway inhibitor (TFPI), which is released almost immediately after initiation of coagulation. Factor VII is vitamin K dependent; it is produced in the liver. Use of warfarin or similar anticoagulants decreases hepatic synthesis of FVII. # Structure Factor VII shares a common domain architecture with factors IX and X. # Genetics The gene for factor VII is located on chromosome 13 (13q34). # Role in disease Factor VII deficiency (congenital proconvertin deficiency) is rare and inherited recessively. It presents as a hemophilia-like bleeding disorder. It is treated with recombinant factor VIIa (NovoSeven or AryoSeven). Gene therapy approaches for treating FVII deficiency are very promising ([2]) # Medical uses Recombinant factor VIIa, marketed under the trade names AryoSeven and NovoSeven, is used for people with hemophilia (with Factor VIII or IX deficiency) who have developed antibodies against replacement coagulation factor. It has also been used in the setting of uncontrollable hemorrhage,[3][4] but its role in this setting is controversial with insufficient evidence to support its use outside of clinical trials.[5] The first report of its use in hemorrhage was in an Israeli soldier with uncontrollable bleeding in 1999.[6] Risks of its use include an increase in arterial thrombosis.[5]However, animal studies have not shown complications as seen in humans, in fact same of the studies show a better prognosis. In the military settings it is used as an off label intervention in complications related to disseminated intravascular coagulation related haemorrhage caused by penetrating trauma.[7] Recombinant human factor VII while initially looking promising in intracerebral hemorrhage failed to show benefit following further study and this is no longer recommended.[8][9] # Interactions Factor VII has been shown to interact with tissue factor and protein kinase C.[10][11]	https://www.wikidoc.org/index.php/Factor_7
90b44c8125abb59f666fd2349b11d6ba39ac2f0e	wikidoc	Factor XII	Factor XII Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme (EC 3.4.21.38) of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 gene. # Structure Human Factor XII is 596 amino acids long and consists of two chains, the heavy chain (353 residues) and light chain (243 residues) held together by a disulfide bond. It is 80,000 daltons. Its heavy chain contains two fibronectin-type domains (type I and II), two epidermal growth factor-like domains, a kringle domain, and a proline-rich region, and its light chain contains the protease domain. Recently, the structure of the FnI-EGF-like tandem domain of coagulation factor XII was solved by x-ray crystallography. # Function Factor XII is part of the coagulation cascade and activates factor XI and prekallikrein in vitro. Factor XII itself is activated to factor XIIa by negatively charged surfaces, such as glass. This is the starting point of the intrinsic pathway. Factor XII can also be used to start coagulation cascades in laboratory studies. In vivo, factor XII is activated by contact to polyanions. Activated platelets secrete inorganic polymers, polyphosphates. Contact to polyphosphates activates factor XII and initiates fibrin formation by the intrinsic pathway of coagulation with critical importance for thrombus formation. Targeting polyphosphates with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Addition of polyphosphates restored defective plasma clotting of Hermansky–Pudlak syndrome patients, indicating that the inorganic polymer is the endogenous factor XII activator in vivo. Platelet polyphosphate-driven factor XII activation provides the link from primary hemostasis (formation of a platelet plug) to secondary hemostasis (fibrin meshwork formation). # Genetics The gene for factor XII is located on the tip of the long arm of the fifth chromosome (5q33-qter). # Role in disease Factor XII deficiency is a rare disorder that is inherited in an autosomal recessive manner. Unlike other clotting factor deficiencies, factor XII deficiency is totally asymptomatic and does not cause excess bleeding. Mice lacking the gene for factor XII, however, are less susceptible to thrombosis. The protein seems to be involved in the later stages of clot formation rather than the first occlusion of damages in the blood vessel wall. Factor XII does play an important role in clot formation during in vitro measurements of the partial thromboplastin time, which causes these measurements to be markedly prolonged in patients with factor XII deficiency, usually well beyond even what is seen in hemophilia A, hemophilia B, or factor XI deficiency. As a result, the main concern related to factor XII deficiency is the unnecessary testing, delay in care, worry, etc. that may be prompted by the abnormal lab result. All of this, including the mechanism of inheritance, also holds true for the other contact factors, prekallikrein (Fletcher factor) and high molecular weight kininogen. Excess levels of factor XII can predispose individuals towards greater risk of venous thrombosis due to factor XII's role as one of the catalysts for conversion of plasminogen to its active fibrinolytic form of plasmin. Factor XII is also activated by endotoxins, especially lipid A. # History Hageman factor was first discovered in 1955 when a routine preoperative blood sample of the 37-year-old railroad brakeman John Hageman (1918) was found to have prolonged clotting time in test tubes, even though he had no hemorrhagic symptoms. Hageman was then examined by hematologist Oscar Ratnoff, who found that Hageman lacked a previously unidentified clotting factor. Ratnoff later found that the Hageman factor deficiency is an autosomal recessive disorder, after examining several related people who had the deficiency. Paradoxically, pulmonary embolism contributed to Hageman's death after an occupational accident in 1968. Since then, case studies and clinical studies identified an association between thrombosis and Factor XII deficiency. Hepatocytes express blood coagulation factor XII.	Factor XII Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme (EC 3.4.21.38) of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the F12 gene.[1] # Structure Human Factor XII is 596 amino acids long and consists of two chains, the heavy chain (353 residues) and light chain (243 residues) held together by a disulfide bond. It is 80,000 daltons. Its heavy chain contains two fibronectin-type domains (type I and II), two epidermal growth factor-like domains, a kringle domain, and a proline-rich region, and its light chain contains the protease domain. Recently, the structure of the FnI-EGF-like tandem domain of coagulation factor XII was solved by x-ray crystallography.[2][3] # Function Factor XII is part of the coagulation cascade and activates factor XI and prekallikrein in vitro. Factor XII itself is activated to factor XIIa by negatively charged surfaces, such as glass. This is the starting point of the intrinsic pathway.[citation needed] Factor XII can also be used to start coagulation cascades in laboratory studies.[4] In vivo, factor XII is activated by contact to polyanions. Activated platelets secrete inorganic polymers, polyphosphates. Contact to polyphosphates activates factor XII and initiates fibrin formation by the intrinsic pathway of coagulation with critical importance for thrombus formation. Targeting polyphosphates with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Addition of polyphosphates restored defective plasma clotting of Hermansky–Pudlak syndrome patients, indicating that the inorganic polymer is the endogenous factor XII activator in vivo. Platelet polyphosphate-driven factor XII activation provides the link from primary hemostasis (formation of a platelet plug) to secondary hemostasis (fibrin meshwork formation).[5] # Genetics The gene for factor XII is located on the tip of the long arm of the fifth chromosome (5q33-qter).[1] # Role in disease Factor XII deficiency is a rare disorder that is inherited in an autosomal recessive manner.[6] Unlike other clotting factor deficiencies, factor XII deficiency is totally asymptomatic and does not cause excess bleeding.[6] Mice lacking the gene for factor XII, however, are less susceptible to thrombosis. The protein seems to be involved in the later stages of clot formation rather than the first occlusion of damages in the blood vessel wall.[7] Factor XII does play an important role in clot formation during in vitro measurements of the partial thromboplastin time, which causes these measurements to be markedly prolonged in patients with factor XII deficiency, usually well beyond even what is seen in hemophilia A, hemophilia B, or factor XI deficiency.[6] As a result, the main concern related to factor XII deficiency is the unnecessary testing, delay in care, worry, etc. that may be prompted by the abnormal lab result.[6] All of this, including the mechanism of inheritance, also holds true for the other contact factors, prekallikrein (Fletcher factor) and high molecular weight kininogen.[6] Excess levels of factor XII can predispose individuals towards greater risk of venous thrombosis due to factor XII's role as one of the catalysts for conversion of plasminogen to its active fibrinolytic form of plasmin.[8] Factor XII is also activated by endotoxins, especially lipid A. # History Hageman factor was first discovered in 1955 when a routine preoperative blood sample of the 37-year-old railroad brakeman John Hageman (1918) was found to have prolonged clotting time in test tubes, even though he had no hemorrhagic symptoms. Hageman was then examined by hematologist Oscar Ratnoff, who found that Hageman lacked a previously unidentified clotting factor.[9] Ratnoff later found that the Hageman factor deficiency is an autosomal recessive disorder, after examining several related people who had the deficiency. Paradoxically, pulmonary embolism contributed to Hageman's death after an occupational accident in 1968. Since then, case studies and clinical studies identified an association between thrombosis and Factor XII deficiency. Hepatocytes express blood coagulation factor XII.[10]	https://www.wikidoc.org/index.php/Factor_XII
8f529e33191c382c66c65af888c80f52c2c51dc0	wikidoc	Fahrenheit	Fahrenheit Fahrenheit is a temperature scale named after Daniel Gabriel Fahrenheit (1686–1736), the German physicist who proposed it in 1724. In this scale, the freezing point of water is 32 degrees Fahrenheit (written "32 °F"), the boiling point is 212 degrees, placing the boiling and freezing points of water exactly 180 degrees apart. On the Celsius scale, the freezing and boiling points of water are exactly 100 degrees apart, thus the unit of this scale, a degree Fahrenheit, is 5⁄9 of a degree Celsius. The Fahrenheit scale coincides with the Celsius scale at −40 °F, which is the same temperature as −40 °C. Absolute zero is −459.67 °F. The Rankine temperature scale was invented to use degrees the same size as Fahrenheit degrees, so 0 °R would be absolute zero, namely −459.67 °F. # History There are a few competing versions of the story of how Fahrenheit came to devise his temperature scale. According to Fahrenheit himself in an article he wrote in 1724 he determined three fixed points of temperature. The zero point is determined by placing the thermometer in a mixture of ice, water, and ammonium chloride. This is a type of frigorific mixture. The mixture automatically stabilizes its temperature at zero degrees Fahrenheit (0 °F). He then put an alcohol or mercury thermometer into the mixture and let the liquid in the thermometer descend to its lowest point. The second point is the 32nd degree found by mixing ice and water without the salt. His third point, the 96th degree, was the level of the liquid in the thermometer when held in the mouth or under the armpit. Fahrenheit noted that, using this scale, mercury boils at around 600 degrees. Other theories are similar in nature. One states that Fahrenheit established the zero (0 °F) and 96 °F points on his scale by recording the lowest outdoor temperatures he could measure, and his own body temperature. He took the lowest temperature which he measured in the harsh winter of 1708 through 1709 in his hometown of Danzig (now Gdańsk, Poland) (−17.8 °C) as his zero point. (He was later able to reach this temperature under laboratory conditions using a mixture of ice, sodium chloride and water.) A variant of this version is that the mixture of ice, salt, and water registered the lowest temperature Fahrenheit could attain in the lab, so he used that for his zero point, using his body temperature as 96 °F. Fahrenheit wanted to avoid the negative temperatures that the Rømer scale had produced in everyday use. He fixed his own body temperature as 96 °F. (As noted below, the scale has since been re-calibrated so that normal body temperature is closer to 98.6 °F). He then divided his scale into twelve sections, and subsequently each of these into 8 equal subdivisions, producing a scale of 96 degrees. Fahrenheit noted that his scale placed the freezing point of water at 32 °F and the boiling point at 212 °F. Another story holds that Fahrenheit established the zero of his scale (0 °F) as the temperature at which an equal mixture of ice and salt melts (some say he took that fixed mixture of ice and salt that produced the lowest temperature); and ninety-six degrees as the temperature of blood (he initially used horse blood to calibrate his scale, as the normal body temperature of horses is 100 °F). Initially, his scale only contained 12 equal subdivisions, but later he subdivided each division into 8 equal degrees ending up with 96. A fourth well-known version of the story, as described in the popular physics television series The Mechanical Universe, holds that Fahrenheit simply adopted Rømer’s scale, at which water freezes at 7.5 degrees, and multiplied each value by 4 in order to eliminate the fractions and increase the granularity of the scale (giving 30 and 240 degrees). He then re-calibrated his scale between the freezing point of water and normal human body temperature (which he took to be 96 degrees); the melting point of ice was adjusted to 32 degrees so that 64 intervals would separate the two, allowing him to mark degree lines on his instruments by simply bisecting the interval six times (since 64 is 2 to the sixth power). A fifth version maintains that Fahrenheit based 0 degrees on an estimate of the temperature at which someone's bare skin would freeze, and 100 degrees on the temperature at which one would be unable to live, therefore making 0 to 100 the livable range for human beings. This, however, is arguable because the human body has been known to survive at temperatures above and below these thresholds. A sixth version maintains that Fahrenheit marked the melting point of ice, normal human body temperature, and the boiling point of water. He then divided the span from melting to boiling into 180 degrees. Setting the normal human body temperature as 96 resulted in the freezing point and boiling point being 32 and 212, respectively. A seventh version maintains that the coldest temperature he could achieve in the lab was designated with 0 degrees, and the melting point of butter was 100 degrees. His measurements were not entirely accurate; by his original scale, the actual melting and boiling points would have been noticeably different from 32 °F and 212 °F. Some time after his death, it was decided to recalibrate the scale with 32 °F and 212 °F as the exact freezing and boiling points of plain water. That change was made to easily convert from Celsius to Fahrenheit and vice versa, with a simple formula. This change also explains why normal human body temperature, once taken as 96 °F by Fahrenheit, is today known to average 98.6 °F. # Usage The Fahrenheit scale was the primary temperature standard for climatic, industrial and medical purposes in most English-speaking countries until the 1960s. In the late 1960s and 1970s, the Celsius (formerly Centigrade) scale was phased in by governments as part of the standardizing process of metrication. In the United States and a few other countries (such as Belize) the Fahrenheit system continues to be the accepted standard for non-scientific use. Most other countries have adopted Celsius as the primary scale in all use. Fahrenheit is sometimes used by older generations in English speaking countries, especially for measurement of higher temperatures. # The special Unicode °F character The Fahrenheit symbol has its own Unicode character: U+2109 (℉). This is a compatibility character encoded for roundtrip compatibility with legacy CJK encodings (which included it to conform to layout in square ideographic character cells) and vertical layout. Use of compatibility characters is discouraged by the Unicode Consortium. The ordinary degree sign (U+00B0) followed by the Latin letter F is thus the preferred way of writing the symbol for degrees Fahrenheit.	Fahrenheit Template:Temperature Fahrenheit is a temperature scale named after Daniel Gabriel Fahrenheit (1686–1736), the German physicist who proposed it in 1724. In this scale, the freezing point of water is 32 degrees Fahrenheit (written "32 °F"), the boiling point is 212 degrees, placing the boiling and freezing points of water exactly 180 degrees apart. On the Celsius scale, the freezing and boiling points of water are exactly 100 degrees apart, thus the unit of this scale, a degree Fahrenheit, is 5⁄9 of a degree Celsius. The Fahrenheit scale coincides with the Celsius scale at −40 °F, which is the same temperature as −40 °C. Absolute zero is −459.67 °F. The Rankine temperature scale was invented to use degrees the same size as Fahrenheit degrees, so 0 °R would be absolute zero, namely −459.67 °F. # History There are a few competing versions of the story of how Fahrenheit came to devise his temperature scale. According to Fahrenheit himself in an article he wrote in 1724 [1] he determined three fixed points of temperature. The zero point is determined by placing the thermometer in a mixture of ice, water, and ammonium chloride. This is a type of frigorific mixture. The mixture automatically stabilizes its temperature at zero degrees Fahrenheit (0 °F). He then put an alcohol or mercury thermometer into the mixture and let the liquid in the thermometer descend to its lowest point. The second point is the 32nd degree found by mixing ice and water without the salt. His third point, the 96th degree, was the level of the liquid in the thermometer when held in the mouth or under the armpit. Fahrenheit noted that, using this scale, mercury boils at around 600 degrees. Other theories are similar in nature. One states that Fahrenheit established the zero (0 °F) and 96 °F points on his scale by recording the lowest outdoor temperatures he could measure, and his own body temperature. He took the lowest temperature which he measured in the harsh winter of 1708 through 1709 in his hometown of Danzig (now Gdańsk, Poland) (−17.8 °C) as his zero point. (He was later able to reach this temperature under laboratory conditions using a mixture of ice, sodium chloride and water.) A variant of this version is that the mixture of ice, salt, and water registered the lowest temperature Fahrenheit could attain in the lab, so he used that for his zero point, using his body temperature as 96 °F.[2] Fahrenheit wanted to avoid the negative temperatures that the Rømer scale had produced in everyday use. He fixed his own body temperature as 96 °F. (As noted below, the scale has since been re-calibrated so that normal body temperature is closer to 98.6 °F). He then divided his scale into twelve sections, and subsequently each of these into 8 equal subdivisions, producing a scale of 96 degrees. Fahrenheit noted that his scale placed the freezing point of water at 32 °F and the boiling point at 212 °F. Another story holds that Fahrenheit established the zero of his scale (0 °F) as the temperature at which an equal mixture of ice and salt melts (some say he took that fixed mixture of ice and salt that produced the lowest temperature); and ninety-six degrees as the temperature of blood (he initially used horse blood to calibrate his scale, as the normal body temperature of horses is 100 °F). Initially, his scale only contained 12 equal subdivisions, but later he subdivided each division into 8 equal degrees ending up with 96.[citation needed] A fourth well-known version of the story, as described in the popular physics television series The Mechanical Universe, holds that Fahrenheit simply adopted Rømer’s scale, at which water freezes at 7.5 degrees, and multiplied each value by 4 in order to eliminate the fractions and increase the granularity of the scale (giving 30 and 240 degrees). He then re-calibrated his scale between the freezing point of water and normal human body temperature (which he took to be 96 degrees); the melting point of ice was adjusted to 32 degrees so that 64 intervals would separate the two, allowing him to mark degree lines on his instruments by simply bisecting the interval six times (since 64 is 2 to the sixth power).[3] A fifth version maintains that Fahrenheit based 0 degrees on an estimate of the temperature at which someone's bare skin would freeze, and 100 degrees on the temperature at which one would be unable to live, therefore making 0 to 100 the livable range for human beings. This, however, is arguable because the human body has been known to survive at temperatures above and below these thresholds.[citation needed] A sixth version maintains that Fahrenheit marked the melting point of ice, normal human body temperature, and the boiling point of water. He then divided the span from melting to boiling into 180 degrees. Setting the normal human body temperature as 96 resulted in the freezing point and boiling point being 32 and 212, respectively.[citation needed] A seventh version maintains that the coldest temperature he could achieve in the lab was designated with 0 degrees, and the melting point of butter was 100 degrees.[4] His measurements were not entirely accurate; by his original scale, the actual melting and boiling points would have been noticeably different from 32 °F and 212 °F. Some time after his death, it was decided to recalibrate the scale with 32 °F and 212 °F as the exact freezing and boiling points of plain water. That change was made to easily convert from Celsius to Fahrenheit and vice versa, with a simple formula. This change also explains why normal human body temperature, once taken as 96 °F by Fahrenheit, is today known to average 98.6 °F. # Usage The Fahrenheit scale was the primary temperature standard for climatic, industrial and medical purposes in most English-speaking countries until the 1960s. In the late 1960s and 1970s, the Celsius (formerly Centigrade) scale was phased in by governments as part of the standardizing process of metrication. In the United States and a few other countries (such as Belize[5]) the Fahrenheit system continues to be the accepted standard for non-scientific use. Most other countries have adopted Celsius as the primary scale in all use. Fahrenheit is sometimes used by older generations in English speaking countries, especially for measurement of higher temperatures. # The special Unicode °F character The Fahrenheit symbol has its own Unicode character: U+2109 (℉). This is a compatibility character encoded for roundtrip compatibility with legacy CJK encodings (which included it to conform to layout in square ideographic character cells) and vertical layout. Use of compatibility characters is discouraged by the Unicode Consortium. The ordinary degree sign (U+00B0) followed by the Latin letter F is thus the preferred way of writing the symbol for degrees Fahrenheit.	https://www.wikidoc.org/index.php/Fahrenheit

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