Nevirapine

266.3

266.30

1312995-182-4

99DK7FVK1H

759902|641530

DTXSID7031797

C29277

Crystals from pyridine and water

J05AG01|J - Antiinfectives for systemic use

29339900

58.1

2

white to tan

1.1300 (rough estimate)

247-249 °C

409.5°C (rough estimate)

9℃

1.6200 (estimate)

DMSO: ≥22mg/mL

-20°C Freezer

3.4X10-9 mm Hg @ 25 deg C /Estimated/

Henry's Law constant = 3.3X10-17 atm-cu m/mol @ 25 °C /Estimated/

pKa = 2.8

Hydroxyl radical reaction rate constant = 6.4X10-11 cu cm/molec-sec @ 25 °C /Estimated/

III

6.1

UN1230 - class 3 - PG 2 - Methanol, solution

2

36/37/38

26-36-37/39

JM5562500

Xi

P264, P270, P273, P301+P312, P330, P501

H302

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products incl nevirapine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H302 (17.39%): Harmful if swallowed [Warning Acute toxicity, oral]|P264, P270, P273, P301+P312, P330, and P501|Aggregated GHS information provided by 23 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Symptoms of overdose include edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonaryinfiltrates, rash, vertigo, vomiting, and weight decrease. The most common adverse reaction is rash.

Therapy with nevirapine is associated with significant elevations in ALT levels (above 5 times the upper limit of normal) in 4% to 20% of patients and symptomatic elevations in 1% to 5% of patients. These elevations are usually transient but can be symptomatic and may require discontinuation of nevirapine. Risk factors for ALT elevations include preexisting liver disease due to HCV or HBV, and possibly female gender, CD4 T cell counts above 250/μL, and absence of HIV infection (such as when given for prophylaxis after an acute exposure). In addition, among the more than 20 antiretroviral agents in current use, nevirapine is perhaps the most common cause of serious, clinically apparent acute liver injury. The frequency of clinically apparent liver injury due to nevirapine is as high as 1%, with fatalities occurring in approximately 0.1% of treated patients. The onset of injury is almost always within the first 6 to 8 weeks of therapy (average 3 weeks) and presenting symptoms are typically abdominal pain and fatigue, followed by fever, rash and jaundice. A large proportion of patients have features of immunoallergic hepatitis (nevirapine hypersensitivity syndrome) with rash, fever and eosinophilia (Cases 2 and 3). Autoantibodies are not common. Most instances have cholestatic features, but initial serum enzyme elevations may be hepatocellular in pattern, particularly in severe cases (Case 1). The associated rash can be severe and compatible with toxic epidermal necrosis or Stevens-Johnson syndrome. Some cases of clinically apparent hepatotoxicity due to nevirapine are not associated with signs of hypersensitivity, and these generally present after the first 8 weeks of therapy but can be severe and even fatal.

Caution is required when nevirapine is concurrently administered with a protease inhibitor, as the plasma concentrations of the protease inhibitors may be reduced to subtherapeutic concentrations due to increased hepatic metabolism by nevirapine.|Concurrent use of nevirapine with cimetidine may elevate steady-state nevirapine trough concentrations; dosage adjustment may be necessary.|The AUC values of /estrogen-containing/ oral contraceptives are reduced in the presence of nevirapine; therefore, oral contraceptives should not be used as the primary means of contraception when nevirapine is prescribed to women of childbearing potential.|Concurrent use /of ketoconazole/ with nevirapine results in significantly reduced plasma concentrations of ketoconazole and modest increase in plasma concentrations of nevirapine; concurrent use is not recommended.|For more Interactions (Complete) data for NEVIRAPINE (10 total), please visit the HSDB record page.

60% bound to plasma protein.

Nevirapine is distributed into human milk. Following administration of a single 100- or 200-mg dose of nevirapine to pregnant women several hours before delivery, postpartum, concentrations of the drug in milk were 25-122% of maternal serum concentrations.

For use in combination with other antiretroviral drugs in the ongoing treatment of HIV-1 infection.|FDA Label|Tablets and oral suspensionViramune is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1-infected adults, adolescents, and children of any age.Most of the experience with Viramune is in combination with nucleoside reverse-transcriptase inhibitors (NRTIs). The choice of a subsequent therapy after Viramune should be based on clinical experience and resistance testing.50- and 100-mg prolonged-release tabletsViramune is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1-infected adolescents and children three years and above and able to swallow tablets.Prolonged-release tablets are not suitable for the 14-day lead-in phase for patients starting nevirapine. Other nevirapine formulations, such as immediate-release tablets or oral suspension should be used.Most of the experience with Viramune is in combination with nucleoside reverse-transcriptase inhibitors (NRTIs). The choice of a subsequent therapy after Viramune should be based on clinical experience and resistance testing.400-mg prolonged-release tabletsViramune is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1-infected adults, adolescents and children three years and above and able to swallow tablets.Prolonged-release tablets are not suitable for the 14-day lead-in phase for patients starting nevirapine. Other nevirapine formulations, such as immediate-release tablets or oral suspension should be used.Most of the experience with Viramune is in combination with nucleoside reverse-transcriptase inhibitors (NRTIs). The choice of a subsequent therapy after Viramune should be based on clinical experience and resistance testing.|Nevirapine Teva is indicated in combination with other anti-retroviral medicinal products for the treatment of HIV 1 infected adults, adolescents, and children of any age., , Most of the experience with nevirapine is in combination with nucleoside reverse transcriptase inhibitors (NRTIs). The choice of a subsequent therapy after nevirapine should be based on clinical experience and resistance testing.,|Treatment of human immunodeficiency virus (HIV-1) infection

Nevirapine is a nonnucleoside reverse transcriptase inhibitor used in combination with other agents in the therapy of human immunodeficiency virus (HIV) infection and the acquired immune deficiency syndrome (AIDS). Nevirapine is associated with a high rate of serum aminotransferase elevations during therapy and is a well established cause of acute, clinically apparent liver injury.

Antiviral Agents

Nevirapine is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection. Drug-resistant HIV emerges rapidly and uniformly when nevirapine is administered as monotherapy. Therefore, nevirapine should always be administered in combination with at least two other antiretroviral agents when it is used for the treatment of HIV-1 infection. /Included in US product labeling/|Nevirapine is indicated for the prevention of mother-to-child transmission of HIV-1 infection. /NOT included in US product labeling/|Nevirapine has been evaluated in pregnant HIV-infected women. In a landmark study performed in Uganda, a single, oral intrapartum dose of nevirapine followed by a single dose to the newborn was superior to more complicated zidovudine therapy in preventing vertical transmission. of HIV. Only 13% of nevirapine-treated women transmitted HIV compared to 21.5% of zidovudine-treated women.

Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis (e.g., transaminase elevations with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia), hepatic necrosis, and hepatic failure, have been reported in patients receiving nevirapine. Although clinical presentation varied, frequently occurring features included nonspecific prodromal signs and symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, and/or hepatomegaly, with or without initially abnormal serum transaminase concentrations; a diagnosis of hepatotoxicity should be considered even if liver function tests are initially normal or alternative diagnoses are possible. Manifestations progressed over several days to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, prolonged partial thromboplastin time, and/or eosinophilia. ... If nevirapine is discontinued because of hepatitis, it should be permanently discontinued and not reinitiated.|Hepatotoxicity has been also reported in a small number of individuals receiving nevirapine as part of a combination regimen for post-exposure prophylaxis of nosocomial or sexual HIV exposure.|Serious hepatotoxicity has been reported in individuals not infected with HIV who received multiple doses of nevirapine as part of a 2- or 3-drug regimen for postexposure prophylaxis following occupational or nonoccupational exposure to HIV. Adverse hepatic effects in these individuals have included end-stage liver failure requiring transplantation, clinical hepatitis (e.g., jaundice, fever, nausea, vomiting, abdominal pain, and/or hepatomegaly), and elevated serum ALT and AST concentrations without clinical hepatitis. ...|Severe and life-threatening skin reactions (e.g., Stevens-Johnson syndrome; toxic epidermal necrolysis; hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction), including some fatalities, have occurred in patients receiving nevirapine. ...|For more Drug Warnings (Complete) data for NEVIRAPINE (15 total), please visit the HSDB record page.

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (nNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases alpha, beta, or sigma) are not inhibited by nevirapine. Nevirapine is, in general, only prescribed after the immune system has declined and infections have become evident. It is always taken with at least one other HIV medication such as Retrovir or Videx. The virus can develop resistance to nevirapine if the drug is taken alone, although even if used properly, nevirapine is effective for only a limited time.

Agents used to treat AIDS and/or stop the spread of the HIV infection. These do not include drugs used to treat symptoms or opportunistic infections associated with AIDS. (See all compounds classified as Anti-HIV Agents.)|Drugs and compounds that induce the synthesis of CYTOCHROME P-450 CYP3A. (See all compounds classified as Cytochrome P-450 CYP3A Inducers.)|Inhibitors of reverse transcriptase (RNA-DIRECTED DNA POLYMERASE), an enzyme that synthesizes DNA on an RNA template. (See all compounds classified as Reverse Transcriptase Inhibitors.)

Nevirapine is readily absorbed (greater than 90%) after oral administration in healthy subjects and adults with HIV-1 infection. The absolute bioavailability in healthy adults following a single dose administration is 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 mcg/mL (7.5 micromolar) were attained by 4 hours following a single 200 mg dose. Nevirapine tablets and suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg. When the oral tablet is given with a high-fat meal, the extent of absorption is compared to that of the fasted-state.|Thus cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (<5%) of the radioactivity in urine (representing <3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.|1.21 ± 0.09 L/kg [apparent volume of distribution, healthy adults, IV] Nevirapine is capable of crossing the placenta and is found in breast milk.|Nevirapine readily crosses the placenta and has been found in breast milk. The CSF-plasma ratio for nevirapine is approximately 0.45.|Nevirapine is readily (more than 90%) absorbed following oral administration in healthy or HIV-infected adults. Absolute bioavailability of nevirapine in 12 healthy adults was 93% following administration of a single 30 mg tablet or 91% following administration of an oral solution of the drug. Peak plasma nevirapine concentrations average 2 ug/ml and are attained within 4 hours after a single 200 mg dose of the dose in adults. Following multiple doses, peak plasma nevirapine concentrations appear to increase linearly in the dosage range of 200-400 mg daily. Nevirapine dosage of 400 mg daily resulted in steady-state trough plasma concentrations of 4.5 ug/ml.|Widely distributed. Nevirapine is highly lipophilic and essentially is nonionized at physiologic pH. Nevirapine readily crosses the placenta and is distributed into breast milk. Nevirapine concentrations in the cerebrospinal fluid were 45% of the concentrations in plasma, which is a ratio that is approximately equal to the fraction not bound to plasma protein.|Nevirapine crosses the placenta in humans. In a limited number of HIV-infected pregnant women who received a single 100- or 200-mg oral dose of nevirapine 0.9-10.5 hours prior to delivery, cord blood concentrations of nevirapine were 74-123% of maternal serum concentrations and peak serum concentrations of the drug in the neonates of these women averaged 862 ng/mL (range: 257-1031 ng/mL) or 925 ng/mL (range: 62-2030 ng/mL), respectively. In pregnant HIV-infected women who received a regimen of nevirapine (200 mg once daily for 2 weeks followed by 200 mg twice daily), zidovudine, and lamivudine during the second and third trimester, cord blood concentrations (at delivery) and neonatal serum concentrations (24 hours after birth) of nevirapine were 76 and 60%, respectively, of maternal serum concentrations (at delivery). These neonatal concentrations were lower than those reported in neonates whose mothers received a single nevirapine dose during labor, possibly as the result of hepatic enzyme induction in the neonate after placental transfer.|Nevirapine is distributed into human milk. Following administration of a single 100- or 200-mg dose of nevirapine to pregnant women several hours before delivery, postpartum, concentrations of the drug in milk were 25-122% of maternal serum concentrations.

Hepatic. In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 3A4 metabolism to several hydroxylated metabolites.|Oxidative metabolism of nevirapine in the liver by cytochrome p450 isoforms CYP34A4 and CYP2B6 produces several metabolites including 2-, 3-, 8-, and 12-hydroxynevirapine.|In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome p450 oxidative metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome p450 isozymes from the CYP3A family, although other isozymes may have a secondary role.|Nevirapine has known human metabolites that include 12-hydroxy-nevirapine, 2-Hydroxynevirapine, 3-Hydroxynevirapine, and 8-Hydroxynevirapine.

45 hours|Approximately 45 hours after a single dose, and 25 to 30 hours following multiple dosing with 200 to 400 mg per day.

Nevirapine 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. The activity of nevirapine does not compete with template or nucleoside triphosphates.|The binding site for nevirapine on HIV-1 reverse transcriptase is near, but not at the proposed site of active polymerization, in a deep pocket lying between the beta sheets of the palm and at the base of the thumb subdomains of the enzyme's p66 subunit. In the absence of nevirapine, the binding of deoxynucleoside triphosphate to the reverse transcriptase-template complex results in a change in the conformation of reverse transcriptase. This conformational change is followed by a magnesium-dependent chemical reaction in which deoxynucleoside triphosphate is incorporated into the newly forming viral DNA; the conformational change appears to be the rate-limiting step of the reverse transcriptase catalysis of viral DNA formation. Nevirapine appears to have no appreciable effect on the rate of or equilibrium constant for the conformational change but may slow the chemical reaction, which then becomes the rate-limiting step in the catalytic sequence. When nevirapine binds to the reverse transcriptase-template complex, changes may occur in the position of aspartic acid carboxyl groups in reverse transcriptase so that magnesium ions are not in proper alignment for the chemical reaction to occur efficiently, and the reaction is slowed. Therefore, although the nevirapine-reverse transcriptase-template complex may continue to bind deoxynucleoside triphosphate and to catalyze its incorporation into the newly forming viral DNA, it appears to do so at a slower rate.|The mechanism of action of nevirapine differs from that of nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanosine, lamivudine, stavudine, zalcitabine, zidovudine). Nucleoside antiretroviral agents require intracellular conversion to triphosphate metabolites, which then compete with naturally occurring deoxynucleoside triphosphates for incorporation into viral DNA by reverse transcriptase and cause premature viral DNA chain termination by preventing further 5 to 3 phosphodiester linkages. Nevirapine, however, is noncompetitive with respect to primer-template or nucleoside triphosphate binding and is specific for HIV-1 reverse transcriptase. The drug binds directly to heterodimeric HIV-1 reverse transcriptase and appears to inhibit viral RNA- and DNA-dependent DNA polymerase activities by disrupting the catalytic site of the enzyme.|Nevirapine diffuses into the cell and binds to reverse transcriptase adjacent to the catalytic site. This induces conformational changes that inactivate the enzyme. Resistance develops rapidly in cells exposed to nevirapine. High-level resistance is associated with mutations at reverse transcriptase codons 101, 103, 106,108, 135, 181, 188, and 190. A single mutation at either codon 103 or 181 decreases susceptibility more than 100 fold. Cross-resistance may extend to all FDA-approved nonnucleoside reverse transcriptase inhibitors, especially with the codon 103 mutation.|Nevirapine is a highly specific inhibitor of HIV-1 reverse transcriptase, and results of in vitro studies indicate that nevirapine does not appear to inhibit cellular DNA polymerases, including human alpha-, beta-, Gamma-, or Delta-polymerases.

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

/HUMAN EXPOSURE STUDIES/ The DRESS (drug rash with eosinophilia and systemic symptoms) syndrome is a serious condition that has been reported in association with various drugs, such as allopurinol, sulfonamides and aromatic anticonvulsants. Recently the condition has been described in HIV-infected patients taking antiretroviral agents. We report the first case, to our knowledge, of DRESS syndrome complicated by meningoencephalitis associated with nevirapine therapy.|/HUMAN EXPOSURE STUDIES/ Because most occupational HIV exposures do not result in transmission of HIV, health care providers considering prescribing post-exposure prophylaxis for exposed persons must balance the risk for HIV transmission represented by the exposure and the exposure source against the potential toxicity of the specific agent(s) used. In many circumstances, the risks associated with nevirapine as part of a post-exposure prophylaxis regimen outweigh the anticipated benefits.|/HUMAN EXPOSURE STUDIES/ Overdosage of nevirapine (800-1800 mg/daily for up to 15 days) has resulted in edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, and weight decrease; these effects subsided following discontinuance of the drug.|/HUMAN EXPOSURE STUDIES/ Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis (e.g., transaminase elevations with or without hyperbilirubinemia, prolonged partial thromboplastin time, or eosinophilia), hepatic necrosis, and hepatic failure, have been reported in patients receiving nevirapine. Although clinical presentation varied, frequently occurring features included nonspecific prodromal signs and symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, and/or hepatomegaly, with or without initially abnormal serum transaminase concentrations; a diagnosis of hepatotoxicity should be considered even if liver function tests are initially normal or alternative diagnoses are possible. Manifestations progressed over several days to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, prolonged partial thromboplastin time, and/or eosinophilia. ... If nevirapine is discontinued because of hepatitis, it should be permanently discontinued and not reinitiated.|For more Human Toxicity Excerpts (Complete) data for NEVIRAPINE (6 total), please visit the HSDB record page.

BI RG 587

Nevirapine hemihydrate: Oral: Suspension, 50 mg (of nevirapine) per 5 ml, Viramune (with parabens), Boehringer Ingelheim /Nevirapine hemihydrate/|Oral: Tablets 200 mg, Viramune (with povidone;scored) Boehringer Ingelheim

Human drugs -> Viramune -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human drugs -> Nevirapine Teva -> EMA Drug Category|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients