Nevirapine (Monograph)

Brand name: Viramune
Drug class: HIV Nonnucleoside Reverse Transcriptase Inhibitors

Medically reviewed by Drugs.com on Aug 10, 2024. Written by ASHP.

Introduction

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).

Uses for Nevirapine

Treatment of HIV Infection

Treatment of HIV-1 infection in adults and pediatric patients in conjunction with other antiretroviral agents.

Initiation not recommended in antiretroviral-naïve adult female patients with CD4⁺ T-cell counts >250 cells/mm³ or in antiretroviral-naïve adult male patients with CD4⁺ T-cell counts >400 cells/mm³ unless potential benefits outweigh risks.

For initial treatment in antiretroviral-naive adults or adolescents, experts state nevirapine not recommended since it is associated with serious and potentially fatal toxicity (e.g., hepatic events and severe rash, including Stevens-Johnson syndrome and toxic epidermal necrolysis). Consult guidelines for the most current information on recommended regimens in adult and pediatric patients. Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.

Nevirapine Dosage and Administration

General

Pretreatment Screening

• Check CD4⁺ cell counts prior to initiation of nevirapine therapy. Due to the risk of serious and life-threatening hepatotoxicity, nevirapine is not recommended for initiation unless benefit clearly outweighs risk in antiretroviral-naïve adult females with CD4⁺ cell counts >250 cells/mm³ or in antiretroviral-naïve adult males with CD4⁺ cell counts >400 cells/mm³.

• Measure liver enzymes prior to initiation of treatment with nevirapine.

Patient Monitoring

• Intensive monitoring required during first 18 weeks of therapy to detect potentially life-threatening hepatic events and skin reactions; extra vigilance warranted during first 6 weeks (period of greatest risk). Optimum frequency of monitoring during this period not established; some experts recommend clinical and laboratory monitoring more often than once monthly and liver function tests at baseline, prior to dosage escalation, and 2 weeks after dosage escalation. Continue frequent clinical and laboratory monitoring after initial 18-week period and throughout nevirapine therapy.

• Carefully monitor those with hepatic impairment (e.g., those with hepatic fibrosis or cirrhosis) for toxicity.

Administration

Oral Administration

Administer orally with or without food.

Conventional (immediate-release) tablets and oral suspension: Use in adults and pediatric patients ≥15 days of age.

Extended-release tablets: Use in adults and pediatric patients ≥6 years of age with a BSA ≥1.17 m².

Extended-release Tablets

Extended-release tablets: Swallow whole; do not chew, crush, or divide.

When considering use in a child ≥6 years of age, assess child for ability to swallow tablets.

Oral Suspension

Shake suspension gently prior to each dose.

Administer using calibrated dosing syringe (especially for volumes <5 mL). Alternatively, administer using dosing cup; rinse cup with water and administer the rinse to the patient.

Dosage

Available as nevirapine (immediate-release tablets, extended-release tablets) and nevirapine hemihydrate (oral suspension).

Initiate therapy using a low dosage of immediate-release nevirapine for first 14 days since this appears to reduce frequency of rash. Do not use extended-release tablets during initial 14 days of nevirapine therapy.

If nevirapine therapy has been interrupted for >7 days for any reason and is not contraindicated, restart using the recommended low initial dosage of immediate-release nevirapine for first 14 days.

Pediatric Patients

Dosage usually based on body surface area (BSA) calculated using Mosteller formula.

Treatment of HIV Infection

Oral

Pediatric patients ≥15 days of age (oral suspension or immediate-release tablets) in combination with other antiretrovirals: Manufacturer recommends 150 mg/m² once daily for first 14 days of therapy (lead-in period of low dosage), followed by 150 mg/m² twice daily (maximum daily dose 400 mg).

Pediatric patients ≥6 years of age with BSA ≥1.17 m² (extended-release nevirapine): Manufacturer recommends 400 mg once daily. If not already receiving nevirapine, use oral suspension or immediate-release tablets for lead-in period of low dosage (150 mg/m² once daily [up to 200 mg daily]) for first 14 days, then switch to extended-release tablets.

Refer to HHS perinatal and pediatric HIV treatment guidelines for other recommended dosage regimens of nevirapine in specific situations.

Adults

Treatment of HIV Infection

Oral

Immediate-release tablets: 200 mg once daily for first 14 days (lead-in period of low dosage), followed by 200 mg twice daily.

Extended-release tablets: 400 mg once daily, initiated after immediate-release nevirapine. In those not currently receiving nevirapine, use lead-in period of low dosage of immediate-release tablets (200 mg once daily for 14 days) then switch to extended-release tablets 400 mg once daily. In those already receiving twice-daily regimen of usual dosage of immediate-release nevirapine, switch to extended-release tablets 400 mg once daily (without 14-day lead-in period).

Dosage Modification for Toxicity

If mild to moderate rash without constitutional symptoms occurs during initial 14-day period of low dosage of immediate-release nevirapine, do not increase dosage until rash resolves. Do not continue initial low dosage beyond 28 days; if rash does not resolve by day 28, discontinue nevirapine and select alternative therapy. If severe rash or any rash with constitutional symptoms occurs, discontinue nevirapine.

Special Populations

Hepatic Impairment

Immediate-release nevirapine: No dosage recommendations for patients with mild hepatic impairment (Child-Pugh class A). Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Extended-release tablets: Not studied in patients with hepatic impairment. Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Carefully monitor patients with hepatic fibrosis or cirrhosis for evidence of nevirapine-induced toxicity.

Renal Impairment

Immediate-release nevirapine: Dosage adjustments not needed in patients with Cl_cr ≥20 mL/minute not undergoing dialysis. In patients requiring dialysis, administer additional 200-mg dose of immediate-release nevirapine after each dialysis treatment.

Extended-release tablets: Not studied in patients with renal impairment.

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions for Nevirapine

Contraindications

• Moderate or severe hepatic impairment (Child-Pugh class B or C).

• Do not use for postexposure prophylaxis following occupational exposure to HIV (PEP) or for postexposure prophylaxis following nonoccupational exposure to HIV (nPEP).

Warnings/Precautions

Warnings

Hepatotoxicity and Hepatic Impairment

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, reported (see Boxed Warning). Hepatic events can occur at any time during therapy. Risk of hepatic events (regardless of severity) greatest during the first 6 weeks of therapy; substantial risk continues through 18 weeks of therapy.

Some patients present with nonspecific prodromal signs and symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness, and/or hepatomegaly, with or without initially abnormal serum transaminase concentrations. Rash observed in 50% of those with symptomatic hepatic adverse events. Fever and flu-like symptoms accompany some of these hepatic events. Some events, particularly those with rash or other symptoms, have progressed to hepatic failure with serum transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia.

Patients with higher CD4 counts and women are at increased risk of hepatic events. Women with CD4 counts >250 cells/mm³ before initiation of antiretroviral therapy, including pregnant women receiving long-term treatment for HIV infection, and men with CD4+ counts >400 cells/mm³before initiation of antiretroviral therapy are at considerably higher risk of these events. Increased liver enzymes and/or HBV or HCV infection associated with increased risk.

In order to detect potentially life-threatening hepatotoxicity, provide intensive clinical and laboratory monitoring, including liver enzyme tests, at baseline and during the initial 18 weeks of nevirapine therapy. The initial 6 weeks of therapy requires extra vigilance as this is the period of greatest risk.

Consider possibility of hepatotoxicity if there are signs or symptoms of hepatitis (e.g., fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness, or hepatomegaly), even if liver function tests are initially normal or alternative diagnoses are possible.

Hepatic injury has progressed despite discontinuation of nevirapine in some patients.

Patients with signs and symptoms of hepatitis must seek immediate medical attention, have liver function tests performed (serum transaminase concentrations), and be advised to discontinue nevirapine as soon as possible. If nevirapine is discontinued because of hepatitis or increased serum transaminase concentrations associated with rash or other systemic symptoms, it should be permanently discontinued and not reinitiated.

Skin Reactions

Severe, life-threatening (and in some cases fatal) skin reactions reported (see Boxed Warning). Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous eruptions, ulcerative stomatitis, urticaria, drug reaction with eosinophilia and systemic symptoms (DRESS), and hypersensitivity reactions (including anaphylaxis and angioedema) characterized by rash, constitutional findings, and organ dysfunction (including hepatic failure) reported.

Serum transaminase concentrations should be immediately evaluated in any patient experiencing rash, especially during the first 18 weeks of therapy. Patients with signs or symptoms of severe skin or hypersensitivity reactions (severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must permanently discontinue nevirapine and seek immediate medical evaluation.

Must be initiated using low dosage of immediate-release nevirapine for first 14 days (200 mg once daily in adults or 150 mg/m² once daily in pediatric patients); this lead-in period of low dosage reduces frequency of rash. If mild to moderate rash without constitutional symptoms occurs during initial 14 days, dosage should not be increased until rash resolves. Do not continue initial low dosage beyond 28 days; discontinue nevirapine and select alternative therapy.

Monitor closely if isolated rash of any severity occurs.

Risk factors for severe cutaneous reactions include failure to follow recommended initial low dosage during first 14 days and delay in discontinuing nevirapine after onset of initial symptoms.

Women appear to be at higher risk of developing rash than men.

Prednisone not recommended for prevention of nevirapine-associated rash.

Do not restart nevirapine following hypersensitivity reaction, severe rash, or rash in conjunction with increased serum transaminase concentrations or other systemic symptoms.

In order to detect potentially life-threatening skin reactions, provide intensive clinical and laboratory monitoring during the initial 18 weeks of nevirapine therapy. The initial 6 weeks of therapy requires extra vigilance as this is the period of greatest risk.

Other Warnings and Precautions

Immune Reconstitution Syndrome

During initial treatment, patients who respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex [MAC], M. tuberculosis, cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported in the setting of immune reconstitution; however, time to onset is variable and can occur many months after initiation of antiretroviral therapy.

Fat Redistribution

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance. Mechanisms and long-term consequences of fat redistribution unknown; causal relationship not established.

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry (APR) at 800-258-4263 or [Web].

Available data from the APR do not indicate an increased risk for overall major birth defects among infants born to women who received nevirapine during pregnancy compared with US background rate for major birth defects.

Severe hepatic events, including fatalities, reported in HIV-infected pregnant women receiving long-term nevirapine therapy as part of multiple-drug antiretroviral treatment. Because of risk of potentially life-threatening hepatotoxicity, do not initiate nevirapine in pregnant women with pretreatment CD4⁺ T-cell counts >250/mm³ unless potential benefits clearly outweigh risks.

Lactation

Distributed into human milk.

Per HHS perinatal HIV transmission guideline, inform patients that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates postnatal HIV transmission risk to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces risk of breastfeeding HIV transmission to <1%, but not does not completely eliminate risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.

Females and Males of Reproductive Potential

Evidence of impaired fertility in female rats at exposure levels approximately equivalent to those provided by usually recommended human dosage. Human data insufficient to determine risk of infertility in patients receiving nevirapine.

Advise females with reproductive potential that, based on results from fertility studies in rats, nevirapine may impair fertility and it is not known whether effects on fertility are reversible.

Pediatric Use

Immediate-release tablets and oral suspension: Safety and pharmacokinetics evaluated in HIV-infected infants 15 days to <3 months of age. Safety, pharmacokinetics, and efficacy evaluated in HIV-infected pediatric patients 3 months to 18 years of age.

Extended-release nevirapine: Can be used in pediatric patients ≥6 years of age based on pharmacokinetic, safety, and antiretroviral activity data in pediatric patients 3 to <18 years of age and efficacy data from adults. Not recommended in those 3 to <6 years of age because of insufficient pharmacokinetic data in this age group; not recommended in those <3 years of age because of inability to swallow tablets.

Adverse effects reported in pediatric patients generally similar to those reported in adults; granulocytopenia reported more frequently in children than adults. Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome reported rarely. Allergic reactions, including anaphylaxis, also reported.

Geriatric Use

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Hepatic Impairment

Immediate-release tablets in patients with mild to moderate hepatic impairment: Pharmacokinetics not altered in most patients; trough concentrations twofold higher in 15% of patients with hepatic fibrosis. Increased nevirapine AUC noted in 1 patient with moderate hepatic impairment (Child-Pugh class B) and ascites. Extended-release tablets not studied in patients with hepatic impairment.

Carefully monitor those with hepatic impairment (e.g., those with hepatic fibrosis or cirrhosis) for toxicity.

Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).

Renal Impairment

Immediate-release tablets in patients with mild, moderate, or severe renal impairment: Pharmacokinetics not altered. AUC decreased in individuals requiring dialysis. Accumulation of nevirapine metabolites noted in individuals requiring dialysis.

Modification of usual dosage of immediate-release nevirapine dosage forms not necessary in patients with Cl_cr ≥20 mL/minute not requiring dialysis; in those requiring dialysis, additional dose of immediate-release nevirapine necessary following dialysis. Pharmacokinetics not evaluated in those with Cl_cr <20 mL/minute.

Extended-release tablets not studied in patients with renal impairment.

Common Adverse Effects

Adults: Most frequently reported adverse effect is rash (15% of patients receiving nevirapine compared to 6% receiving placebo); 2% of nevirapine-treated patients developed grade 3/4 rash (versus <1% with placebo). During lead-in period with immediate-release nevirapine, rash ≥grade 2 occurred in 3% of patients. After lead-in period, rash ≥grade 2 occurred in 3% of patients taking extended-release nevirapine.

Pediatric patients: Rash (all causality) reported in 21% of pediatric patients treated with immediate-release nevirapine; incidence of rash ≥grade 2 was 1% in pediatric patients treated with extended-release nevirapine.

Drug Interactions

Metabolized by CYP3A and CYP2B6.

Inhibits CYP3A and CYP2B6.

Induces CYP3A and CYP2B6.

The following drug interactions are based on studies using nevirapine immediate-release tablets and are expected to also apply to extended-release tablets.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interactions likely with drugs that are inhibitors, inducers, or substrates of CYP3A or 2B6 with possible alteration in metabolism of nevirapine and/or other drug.

Nevirapine does not appear to affect plasma concentrations of drugs that are substrates of other CYP isoenzymes (e.g., 1A2, 2D6, 2A6, 2E1, 2C9, 2C19).

Specific Drugs

Nevirapine Pharmacokinetics

Absorption

Bioavailability

Immediate-release nevirapine: Well absorbed from GI tract; absolute bioavailability is 91–93%. Peak plasma concentrations attained within 4 hours.

Extended-release tablets: Peak plasma concentrations attained at a median of approximately 24 hours after dose.

Commercially available immediate-release tablets and oral suspension are bioequivalent at doses ≤200 mg.

Bioavailability of 400 mg of nevirapine as extended-release tablets relative to 400 mg as immediate-release tablets is approximately 75%.

Food

Food does not appear to affect absorption of immediate-release tablets.

Difference in bioavailability of nevirapine extended-release tablets under fasted or fed conditions not considered clinically important.

Special Populations

Immediate-release nevirapine in pediatric patients: Steady-state trough concentrations similar to concentrations in adults receiving recommended dosage.

Extended-release tablets in pediatric patients 6 to <18 years of age: Overall mean systemic nevirapine exposure after switch from immediate-release to extended-release nevirapine similar to that reported with immediate-release.

Distribution

Extent

Distributed into CSF; concentrations in CSF are 45% of concurrent plasma concentrations.

Crosses placenta; distributed into human milk.

Plasma Protein Binding

60%.

Elimination

Metabolism

Metabolized by CYP3A and CYP2B6.

Elimination Route

Excreted in urine (81%) mainly as glucuronide conjugates of hydroxylated metabolites and in feces (10%).

Half-life

45 hours after a single dose and 25–30 hours after multiple doses.

Stability

Storage

Oral

Tablets

Conventional (immediate-release): 20–25°C (excursions permitted to 15–30°C).

Extended-release: 20–25°C (excursions permitted to 15–30°C).

Suspension

20–25°C (excursions permitted to 15–30°C).

Actions and Spectrum

• Pharmacologically related to other NNRTIs (e.g., delavirdine, efavirenz, etravirine, rilpivirine); differs structurally from these drugs; also differs pharmacologically and structurally from other currently available antiretrovirals.

• Active against HIV-1; inactive against HIV-2.

• Nevirapine inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.

• HIV-1 with reduced susceptibility to nevirapine have been selected in vitro and have emerged during therapy with the drug.

• Resistance emerges rapidly when used as monotherapy; must not be used as a single agent or added as a single agent to a failing antiretroviral regimen.

• Strains of HIV-1 resistant to nevirapine may be cross-resistant to some other NNRTIs.

Advice to Patients

• Critical importance of compliance with HIV therapy and importance of remaining under the care of a clinician. Stress importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.

• Advise patients to read the patient information provided by the manufacturer.

• If a dose is missed, take the next dose as soon as possible. If a dose is skipped, do not take a double dose to make up for the missed dose.

• Possibility of severe liver disease or skin reactions (potentially fatal). Stress importance of discontinuing nevirapine and seeking immediate medical attention if signs or symptoms of liver disease (fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness, hepatomegaly) or severe skin or hypersensitivity reactions (rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis) occur.

• Inform of the need for intensive clinical and laboratory monitoring, including liver enzymes, during first 18 weeks of therapy (especially first 6 weeks) and stress importance of frequent monitoring throughout nevirapine treatment.

• Risk of rash, especially during first 6 weeks of therapy. If rash occurs during first 2 weeks of therapy, do not increase nevirapine dosage and do not switch to extended-release tablets until rash resolves. If rash continues through 4 weeks of therapy, nevirapine should be discontinued.

• Inform patients that redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.

• Advise patients to immediately contact a clinician if they have any signs or symptoms of infection since inflammation from previous infections may occur soon after antiretroviral therapy is initiated.

• Advise patients that they may occasionally see soft remnants of extended-release nevirapine tablets in their stool, which sometimes resemble intact tablets. These occurrences have not been shown to affect drug levels or response.

• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.

• Stress importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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