Nevirapine

(BAN, USAN, rINN)
Nevirapine Chemical formula
Synonyms: BI-RG-587; BIRG-0587; Nevirapiini; Nevirapiini, vedetön; Nevirapin; Nevirapin bezvodý; Nevirapin, vattenfritt; Nevirapina; Névirapine; Névirapine anhydre; Nevirapinum; Nevirapinum anhydricum; Newirapina bezwodna. 11-Cyclopropyl-5,11-dihydro-4methyl-6H-dipyrido[3,2b:2′,3′e]-[1,4]diazepin-6-one.
Cyrillic synonym: Невирапин.

💊 Chemical information

Chemical formula: C15H14N4O = 266.3.
CAS — 129618-40-2.
ATC — J05AG01.
ATC Vet — QJ05AG01.

Pharmacopoeias.

In Eur. and US. Int. permits anhydrous or the hemihydrate.

Ph. Eur. 6.2

(Nevirapine, Anhydrous). A white or almost white powder. Practically insoluble in water; sparingly soluble or slightly soluble in dichloromethane; slightly soluble in methyl alcohol.

USP 31

(Nevirapine). It is anhydrous or contains one-half molecule of water of hydration. A white to off-white, odourless to nearly odourless, crystalline powder. Practically insoluble in water; slightly soluble in alcohol and in methyl alcohol. The hydrous form is also slightly insoluble in propylene glycol. Store in airtight containers at a temperature of 25°, excursions permitted between 15° and 30°.

💊 Adverse Effects

The most common adverse effect associated with antiretroviral regimens containing nevirapine is skin rash (usually mild to moderate, maculopapular, erythematous, and sometimes pruritic), generally occurring within 6 weeks of starting therapy. Severe and lifethreatening skin reactions (with some fatalities) have occurred, including Stevens-Johnson syndrome and, more rarely, toxic epidermal necrolysis. Hypersensitivity reactions including angioedema, urticaria, and anaphylaxis have been reported. Rashes may occur alone or in the context of hypersensitivity reactions when they may be accompanied by other symptoms such as fever, arthralgia, myalgia, lymphadenopathy, eosinophilia, granulocytopenia, or renal dysfunction. Granulocytopenia occurs more commonly in children than in adults. Severe hepatotoxicity, including hepatitis and hepatic necrosis, occasionally fatal, has occurred and may be more prevalent in women and patients with high CD4+ cell counts at the start of treatment. Serious hepatotoxicity has also been reported in HIV-uninfected persons taking multiple doses of nevirapine for HIV postexposure-prophylaxis. Rhabdomyolysis has occurred in patients with skin and/or liver reactions. Other common adverse effects include nausea, vomiting, diarrhoea, abdominal pain, fatigue, drowsiness, fever, myalgia, and headache. Immune reconstitution syndrome (an inflammatory immune response resulting in clinical deterioration) has been reported during the initial phase of treatment with combination antiretroviral therapy, including nevirapine, in HIV-infected patients with severe immune deficiency. Accumulation or redistribution of body fat (lipodystrophy) including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been seen in patients receiving antiretroviral therapy, including nevirapine. Metabolic abnormalities such as hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, hyperglycaemia, and hyperlactataemia have also been reported. Osteonecrosis has been reported, particularly in patients with advanced HIV disease or long-term exposure to combination antiretroviral therapy.

Effects on the liver.

References.
1. Martinez E, et al. Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS 2001; 15: 1261–8
2. Committee on Safety of Medicines/Medicines Control Agency. Nevirapine (Viramune): serious adverse reactions when used in HIV post exposure prophylaxis. Current Problems 2001; 27: 13. Also available at: http://www.mhra.gov.uk/home/idcplg? IdcService=GET_FILE&dDocName=CON007456& RevisionSelectionMethod=LatestReleased (accessed 13/06/08
3. Gonzalez de Requena D, et al. Liver toxicity caused by nevirapine. AIDS 2002; 16: 290–1
4. De Maat MM, et al. Hepatotoxicity following nevirapine-containing regimens in HIV-1-infected individuals. Pharmacol Res 2002; 46: 295–300
5. Patel SM, et al. Serious adverse cutaneous and hepatic toxicities associated with nevirapine use by non-HIV-infected individuals. J Acquir Immune Defic Syndr 2004; 35: 120–5
6. Torti C, et al. BHCC Study Group. Analysis of severe hepatic events associated with nevirapine-containing regimens: CD4+ Tcell count and gender in hepatitis C seropositive and seronegative patients. Drug Safety 2007; 30: 1161–9.

Effects on the skin.

References.
1. Warren KJ, et al. Nevirapine-associated Stevens-Johnson syndrome. Lancet 1998; 351: 567
2. Wetterwald E, et al. Nevirapine-induced overlap Stevens-Johnson syndrome/toxic epidermal necrolysis. Br J Dermatol 1999; 140: 980–2
3. Committee on Safety of Medicines/Medicines Control Agency. Nevirapine (Viramune): serious adverse reactions when used in HIV post exposure prophylaxis. Current Problems 2001; 27: 13. Also available at: http://www.mhra.gov.uk/home/idcplg? IdcService=GET_FILE&dDocName=CON007456& RevisionSelectionMethod=LatestReleased (accessed 13/06/08
4. Antinori A, et al. Female sex and the use of anti-allergic agents increase the risk of developing cutaneous rash associated with nevirapine therapy. AIDS 2001; 15: 1579–81
5. de Maat MM, et al. Incidence and risk factors for nevirapineassociated rash. Eur J Clin Pharmacol 2003; 59: 457–62
6. Manosuthi W, et al. Incidence and risk factors of nevirapine-associated skin rashes among HIV-infected patients with CD4 cell counts <250 cells/microL. Int J STD AIDS 2007; 18: 782–6
7. Wit FW, et al. Discontinuation of nevirapine because of hypersensitivity reactions in patients with prior treatment experience, compared with treatment-naive patients: the ATHENA cohort study. Clin Infect Dis 2008; 46: 933–40
8. Kiertiburanakul S, et al. Risk factors for nevirapine-associated rash among HIV-infected patients with low CD4 cell counts in resource-limited settings. Curr HIV Res 2008; 6: 65–9.

💊 Precautions

Patients taking nevirapine should be closely monitored for adverse skin reactions and hepatotoxicity during the first 18 weeks of treatment; extra vigilance is advised during the first 6 weeks of treatment. Nevirapine should be used with extreme caution in patients with moderate hepatic impairment (Child-Pugh class B); it is contra-indicated in those with severe hepatic impairment (Child-Pugh class C). Patients with high CD4+ cell counts (greater than 250 cells/microlitre in women or 400 cells/microlitre in men), as well as patients coinfected with chronic hepatitis B or C are at increased risk of hepatotoxicity. The UK licensed product information suggests that liver function should be monitored every 2 weeks during the first 2 months of treatment, again at 3 months, and then regularly thereafter. Treatment should be permanently stopped in patients who suffer a severe rash, rash accompanied by constitutional symptoms (such as fever, blistering, oral lesions, conjunctivitis, facial oedema, muscle or joint aches, or general malaise), hypersensitivity reactions, or clinical hepatitis. Transaminase levels should be checked for all patients who develop a rash in the first 18 weeks of treatment and nevirapine should be temporarily stopped if liver enzyme levels increase to greater than 5 times the upper limit of normal or the patient has symptoms suggestive of hepatitis. In some patients treatment may be restarted at the initial dose if liver function returns to baseline values and the patient has no clinical symptoms of hepatitis or signs of a rash (although permanent stoppage is necessary if abnormalities recur). In some cases hepatic injury progresses despite stopping the drug. Dose escalation should not be attempted in patients developing any rash during the first 14 days of treatment until the rash has resolved. Patients or their carers should be counselled on how to recognise hypersensitivity reactions and instructed to seek immediate medical attention if they occur. Doses may need to be modified in patients on renal dialysis.

Pregnancy.

Nevirapine has not been associated with teratogenicity in animals. Licensed product information states that the Antiretroviral Pregnancy Registry has not found an increased risk of birth defects after first trimester exposures to nevirapine and the prevalence of birth defects after exposure in any trimester was comparable to the prevalence in the general population.

💊 Interactions

Nevirapine is metabolised mainly by the cytochrome P450 isoenzymes CYP3A4 and CYP2B6. Consequently it may compete with other drugs metabolised by this system, possibly resulting in mutually increased plasma concentrations and toxicity. Alternatively, en zyme inducers may decrease plasma concentrations of nevirapine; nevirapine itself acts as a mild to moderate enzyme inducer and may thus reduce plasma concentrations of other drugs. Rifampicin and St John’s wort decrease the concentration of nevirapine; use with the antiretroviral is not recommended due to the possible loss of its activity and development of resistance.

Antivirals.

For the effect of nevirapine on HIV-protease inhibitors.

Methadone.

Nevirapine may induce the metabolism of methadone resulting in reduced plasma-methadone concentrations.

💊 Antiviral Action

Nevirapine acts by non-competitive inhibition of HIV1 reverse transcriptase; it binds to the enzyme, disrupting the conformation of its catalytic site and impairing its RNA- and DNA-dependent polymerase activity. Resistance to nevirapine and emergence of cross-resistance to other non-nucleoside reverse transcriptase inhibitors has been seen.

💊 Pharmacokinetics

Nevirapine is readily absorbed after oral doses and absorption is not affected by food or antacids. Bioavailability is greater than 90%. Nevirapine tablets and oral suspension are comparably bioavailable and interchangeable at doses up to 200 mg. Peak plasma concentrations occur 4 hours after a single dose. Nevirapine is about 60% bound to plasma proteins. Concentrations in the CSF are about 45% of those in plasma. Nevirapine crosses the placenta and is distributed into breast milk. It is extensively metabolised by hepatic microsomal enzymes, principally by the cytochrome P450 isoenzymes CYP3A4 and CYP2B6, to several hydroxylated metabolites. Autoinduction of these enzymes results in a 1.5- to 2-fold increase in apparent oral clearance after 2 to 4 weeks at usual dosage, and a decrease in terminal half-life from 45 hours to 25 to 30 hours over the same period. Nevirapine is mainly excreted in the urine as glucuronide conjugates of the hydroxylated metabolites. In children, nevirapine elimination accelerates during the first years of life, reaching a maximum at around 2 years of age, followed by a gradual decline during the rest of childhood; values in children under 8 years are about twice those in adults.
1. Mirochnick M, et al. Nevirapine: pharmacokinetic considerations in children and pregnant women. Clin Pharmacokinet 2000; 39: 281–93
2. Almond LM, et al. Intracellular and plasma pharmacokinetics of nevirapine in human immunodeficiency virus-infected individuals. Clin Pharmacol Ther 2005; 78: 132–42
3. von Hentig N, et al. A comparison of the steady-state pharmacokinetics of nevirapine in men, nonpregnant women and women in late pregnancy. Br J Clin Pharmacol 2006; 62: 552–9.

💊 Uses and Administration

Nevirapine is a non-nucleoside reverse transcriptase inhibitor with activity against HIV-1. It is used in the treatment of HIV infection and AIDS. Viral resistance emerges rapidly when nevirapine is used alone, and it is therefore used with other antiretrovirals. Nevirapine is given orally in an adult dose of 200 mg once daily for the first 14 days, then increased to 200 mg twice daily provided that no rash is present (see Precautions, above). If treatment is interrupted for more than 7 days, it should be reintroduced using the lower dose for the first 14 days as for new treatment. For details of doses in infants, children, and adolescents, see below. Nevirapine is often used in regimens for the prophylaxis of vertical transmission (mother-to-child) of HIV infection. In women in whom HAART is not indicated, or where it is not available, a single oral dose of nevirapine 200 mg may be given at the onset of labour, together with a course of zidovudine and lamivudine, for perinatal cover.
1. Floridia M, et al. A randomized, double-blind trial on the use of a triple combination including nevirapine, a nonnucleoside reverse transcriptase HIV inhibitor, in antiretroviral-naive patients with advanced disease. J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20: 11–19
2. Guay LA, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet 1999; 354: 795–802
3. Bardsley-Elliot A, Perry CM. Nevirapine: a review of its use in the prevention and treatment of paediatric HIV infection. Paediatr Drugs 2000; 2: 373–407
4. Dorenbaum A, et al. Two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal HIV transmission: a randomized trial. JAMA 2002; 288: 189–98
5. Moodley D, et al. A multicenter randomized controlled trial of nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and early postpartum mother-to-child transmission of human immunodeficiency virus typ
1. J Infect Dis 2003; 187: 725–35
6. Taha TE, et al. Short postexposure prophylaxis in newborn babies to reduce mother-to-child transmission of HIV-1: NVAZ randomised clinical trial. Lancet 2003; 362: 1171–7
7. Lallemant M, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV1 in Thailand. N Engl J Med 2004; 351: 217–28
8. Shapiro RL, et al. Maternal single-dose nevirapine versus placebo as part of an antiretroviral strategy to prevent mother-tochild HIV transmission in Botswana. AIDS 2006; 20: 1281–8
9. Lockman S, et al. Response to antiretroviral therapy after a single, peripartum dose of nevirapine. N Engl J Med 2007; 356: 135–47
10. Parienti JJ, et al. SIROCCO study team. Efavirenz to nevirapine switch in HIV-1-infected patients with dyslipidemia: a randomized, controlled study. Clin Infect Dis 2007; 45: 263–6
11. Dart Trial Team. Twenty-four-week safety and tolerability of nevirapine vs. abacavir in combination with zidovudine/lamivudine as first-line antiretroviral therapy: a randomized doubleblind trial (NORA). Trop Med Int Health 2008; 13: 6–16.

Administration in children.

For the treatment of HIV infection in infants, children, and adolescents nevirapine is given orally with other antiretroviral drugs. The following doses by bodyweight have been suggested according to age:
from 15 days to 8 years: 4 mg/kg once daily for 14 days and then, if no rash is present, 7 mg/kg twice daily
8 to 16 years: 4 mg/kg once daily for 14 days then 4 mg/kg twice daily thereafter
Alternatively, the dose may be calculated according to body-surface; an oral dose of 150 mg/m2 once daily for two weeks is given followed by 150 mg/m2 twice daily thereafter. A total dose of 400 mg daily should not be exceeded. For information on the use of nevirapine in regimens for the prophylaxis of vertical transmission (mother-to-child) of HIV infection see HIV Infection Prophylaxis.

Administration in renal impairment.

Dose adjustments are not required for patients with a creatinine clearance more than 20 mL/min. Patients on dialysis should receive an additional 200 mg of nevirapine after each dialysis session.

💊 Preparations

USP 31: Nevirapine Oral Suspension; Nevirapine Tablets.

Proprietary Preparations

Arg.: Filide; Nerapin; Neviralea†; Protease; Ritvir; Virainhi; Viramune; Austral.: Viramune; Austria: Viramune; Belg.: Viramune; Braz.: Viramune; Canad.: Viramune; Chile: Viramune; Cz.: Viramune; Denm.: Viramune; Fin.: Viramune; Fr.: Viramune; Ger.: Viramune; Gr.: Viramune; Hong Kong: Viramune; Hung.: Viramune; India: Neve; Nevimune; Indon.: Viramune; Irl.: Viramune; Israel: Viramune; Ital.: Viramune; Jpn: Viramune; Malaysia: Nevipan; Viramune; Mex.: Viramune; Neth.: Viramune; Norw.: Viramune; NZ: Viramune; Pol.: Viramune; Port.: Viramune; Rus.: Viramune (Вирамун); S.Afr.: Viramune; Singapore: Viramune; Spain: Viramune; Swed.: Viramune; Switz.: Viramune; Thai.: Viramune; Turk.: Viramune; UK: Viramune; USA: Viramune; Venez.: Nevimune; Viramune. Multi-ingredient: India: Duovir N; Triomune; S.Afr.: Triomune; Venez.: Triomune.
Published December 08, 2018.