AHFS Class:

• HIV Nonnucleoside Reverse Transcriptase Inhibitors 8:18.08.16

Generic Name(s):

• Nevirapine

Nevirapine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).1

Treatment of HIV Infection

Nevirapine is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and pediatric patients.1 234

Initiation of nevirapine is 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.1 200,234

Clinical Experience

Antiretroviral-naïve Adults

Safety and efficacy of nevirapine (200 mg once daily for the initial 2 weeks, then 200 mg every 12 hours) have been evaluated in conjunction with zidovudine (200 mg 3 times daily) with or without didanosine (125 or 200 mg twice daily) for initial antiretroviral therapy in a randomized, double-blind study in treatment-naïve adults (study BI 1046, INCAS).1 13 Study BI 1046 included 151 adults (median age 36 years) with baseline CD4⁺ T-cell counts of 200-600 cells/mm³ (mean 376 cells/mm³) and mean baseline plasma HIV-1 RNA levels of 4.41 log₁₀ copies/mL (25,704 copies/mL).1 Patients were randomized to receive a 3-drug regimen of zidovudine, didanosine, and nevirapine or a 2-drug regimen of zidovudine and didanosine or zidovudine and nevirapine, with each 2-drug regimen including matching placebo.1 6,13

The primary endpoint was the proportion of patients with plasma HIV-1 RNA levels <400 copies/mL and not previously failed at 48 weeks.1 At 48 weeks, the virologic response rate was 45% in those receiving the 3-drug regimen (zidovudine, didanosine, and nevirapine), 19% for those receiving zidovudine and didanosine, and 0% in those receiving nevirapine and zidovudine.1 The mean increase in CD4⁺ T-cell count above baseline was 139 cells/mm³ in those receiving the 3-drug regimen compared with 87 cells/mm³ in those receiving zidovudine and didanosine.1 Patients given nevirapine plus zidovudine had a mean decline in CD4⁺ T-cell count of 6 cells/mm³ below baseline.1

Safety and efficacy of nevirapine extended-release tablets were evaluated in a randomized, double-blind, double-dummy, phase 3 trial (Study 1100.1486, VERxVE) in 1011 antiretroviral-naïve adults.234 Patients received a regimen of nevirapine immediate-release tablets (200 mg once daily) for 14 days with 2 NRTIs (tenofovir and emtricitabine) and were then randomized (1:1 ratio) to continue therapy with nevirapine immediate-release tablets (200 mg twice daily) or switch to nevirapine extended-release tablets (400 mg once daily) with the same background regimen of 2 NRTIs.234 At baseline, the mean plasma HIV RNA level was 4.7 log₁₀ copies/mL and the mean CD4⁺ T-cell count was 228 cells/mm³; approximately 66% of patients had baseline plasma HIV RNA levels of 100,000 copies/mL or lower.234 At 96 weeks, 67% of those receiving immediate-release nevirapine and 69% of those receiving extended-release nevirapine had plasma HIV RNA levels <50 copies/mL.234 The mean change from baseline in CD4⁺ T-cell count, adjusted for baseline HIV viral load stratum, was 222 or 244 cells/mm³, respectively.234

Antiretroviral-experienced Adults

Nevirapine has been evaluated for use in conjunction with other antiretroviral agents in adults with advanced HIV-1 infection (Study BI 1090).1 This study was a placebo-controlled, double-blind, randomized study that included 2249 adults (median baseline CD4⁺ T-cell count, 96 cells/mm³; median baseline plasma HIV-1 RNA level, 4.58 log₁₀ copies/mL [38,291 copies/mL]; 89% previously received antiretroviral therapy).1 Patients were randomized to receive nevirapine (200 mg once daily for 2 weeks, then 200 mg twice daily) and lamivudine (150 mg twice daily) with a background antiretroviral regimen or lamivudine with a background regimen; the background regimen was one NRTI (58%), 2 or more NRTIs (34%), or HIV protease inhibitors (PIs) and NRTIs (8%).1 Prior to study entry, 45% of patients had previously experienced an AIDS-defining clinical event.1

At 48 weeks, 18% of those receiving a regimen that included nevirapine had plasma HIV-1 RNA levels <50 copies/mL compared with 2% of those not receiving nevirapine.1 At 1 year, the change from baseline CD4⁺ T-cell count for the overall trial population was 64 cells/mm³ in those receiving nevirapine compared with 22 cells/mm³ in those not receiving the drug.1

Safety and efficacy of switching from nevirapine immediate-release tablets to nevirapine extended-release tablets were evaluated in an open-label, phase 3 trial (Study 1100.1526, TRANxITION) in 443 antiretroviral-experienced adults with HIV-1 RNA levels <50 copies/mL.234 Approximately 50% were receiving a background regimen of tenofovir and emtricitabine, and the remaining patients were receiving abacavir [or zidovudine]) and lamivudine.234 Approximately 50% had been receiving immediate-release nevirapine for ≥3 years before trial enrollment.234 Patients were randomized (2:1 ratio) to switch to nevirapine extended-release tablets (400 mg once daily) or continue therapy with nevirapine immediate-release tablets (200 mg twice daily) with their current background regimen of 2 NRTIs.234 At 48 weeks after randomization, 93% of those receiving extended-release tablets and 91% of those receiving immediate-release tablets continued to have plasma HIV-1 RNA levels <50 copies/mL.234

Pediatric Patients

Nevirapine is used in conjunction with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients 15 days of age or older (oral suspension or immediate-release tablets).1 20 Alternatively, nevirapine extended-release tablets may be used in pediatric patients 6 years of age or older with a body surface area (BSA) of 1.17 m² or greater.234

Safety and efficacy of nevirapine in HIV-infected pediatric patients have been evaluated in an open-label, randomized study (Study BI 1100.1368) in 123 treatment-naïve pediatric patients 3 months to 16 years of age (median baseline plasma HIV-1 RNA level, 5.45 log₁₀ copies/mL; median baseline CD4⁺ T-cell count, 527 cells/mm³, 4% previously received antiretroviral therapy).1 The patients received nevirapine oral suspension (dose based on body surface area or body weight; maximum 400 mg daily) in conjunction with lamivudine and zidovudine.1 At 48 weeks, 47% of patients had plasma HIV-1 RNA levels <400 copies/mL.1

Safety and efficacy of nevirapine also have been evaluated in an open-label, phase 1 or 2 study that included 8 infants 2-16 months of age with maternally-acquired HIV-1 infection.20 Patients received a 3-drug regimen of oral zidovudine (180 mg/m² given every 8 hours), oral didanosine (120 mg/m² given every 12 hours), and oral nevirapine (120 mg/m² given once daily for 28 days, then 200 mg/m² given every 12 hours).20 Baseline HIV-1 RNA levels ranged from about 41,000 to 1.5 million copies/mL.20

Plasma HIV-1 RNA levels were reduced at least 96% (a decrease of 1.5 log₁₀ copies/mL) in 7 of 8 patients within 2-4 weeks of initiating therapy and, at 6 months, were still below baseline levels in 5 of 6 infants whose treatment started when they were 4 months of age or younger; the regimen was well tolerated in all patients.20

Nevirapine extended-release tablets were evaluated in an open-label, nonrandomized, crossover trial (Study 1100.1518) in 85 HIV-infected pediatric patients 3 to <18 years of age who had received at least 18 weeks of immediate-release nevirapine and had plasma HIV-1 RNA levels <50 copies/mL (median baseline CD4⁺ T-cell count, 925 cells/mm³ [range 207-2057 cells/mm³]).234 Following a 10-day period of treatment with immediate-release nevirapine, patients were switched to extended-release nevirapine in conjunction with other antiretrovirals.234 After 10 days of treatment with the extended-release preparation, steady-state pharmacokinetics were determined and 40 of the initial study patients were enrolled in an optional extension phase of the trial to evaluate safety and antiretroviral activity of extended-release nevirapine.234

At 24 weeks, 39 of these patients continued to have plasma HIV-1 RNA levels <50 copies/mL, and 1 patient had discontinued the drug because of an adverse reaction.234 When the 39 patients were stratified according to age, median CD4⁺ T-cell counts in those 3 to <6 years, 6 to <12 years, and 12 to <18 years of age were 1113, 853, and 682 cells/mm³, respectively, similar to those observed at baseline.234

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy is recommended for all individuals with HIV regardless of CD4⁺ T-cell count, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of antiretroviral therapy are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the HHS Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a nonnucleoside reverse transcriptase inhibitor (NNRTI), or a PI with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial 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.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Nevirapine, an NNRTI, was commonly used in combination with a dual-NRTI “backbone” to form a fully suppressive antiretroviral regimen.200 In the 2023 HHS adult and adolescent HIV treatment guideline, nevirapine is no longer recommended for use as initial therapy in the treatment of HIV infection due to inferior virologic efficacy and serious, potentially fatal toxicities.200 Because of the risk of life-threatening hepatic events, nevirapine is not recommended for use in treatment-naïve adult patients with CD4⁺ T-cell counts >250 cells/mm² for women or >400 cells/mm³ for men.200 Treatment-experienced patients with CD4⁺ T-cell counts above these thresholds (as a result of antiretroviral treatment) may be safely switched to nevirapine.200

In the 2023 HHS pediatric HIV treatment guideline, nevirapine is included in various antiretroviral regimens.201 Nevirapine plus a dual-NRTI “backbone” is recommended as a preferred NNRTI-based regimen for infants <14 days of age† and an alternative NNRTI-based regimen for children ≥14 days to <3 years of age.201 If a regimen of nevirapine and 2 NRTIs is initiated in a neonate younger than 14 days of age†, the HHS panel states that a change to lopinavir/ritonavir or raltegravir and 2 NRTIs should be considered when the infant is 14 days to <4 weeks of age since those agents are preferred in this age bracket.201

In the 2023 HHS perinatal HIV treatment guideline, nevirapine is included in various antiretroviral regimens.202 Nevirapine is not recommended during pregnancy for treatment-naïve patients, for pregnant patients restarting antiretroviral treatment, prior to conception, or as a new regimen for pregnant patients whose current regimen is not tolerated or fully suppresive.202 Nevirapine may be continued if pregnancy occurs if it is part of a well-tolerated and fully suppresive regimen.202 For newborns at high-risk for perinatal HIV acquisition†, a 2 to 6 week presumptive regimen with zidovudine, lamivudine, and nevirapine is recommended.202 For newborns at low risk of HIV acquisition during breastfeeding, nevirapine is recommended as an option for postnatal prophylaxis†; it can be continued for 1 to 4 weeks post-weaning.202

General

Pretreatment Screening

• Check CD4⁺ T-cell count prior to initiation of nevirapine therapy.1 234 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⁺ T-cell counts greater than 250 cells/mm³ or in antiretroviral-naïve adult males with CD4⁺ T-cell counts greater than 400 cells/mm³.1 200 234
• Measure liver enzymes prior to initiation of treatment with nevirapine.1 234

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).1 234 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.1 234 Continue frequent clinical and laboratory monitoring after initial 18-week period and throughout nevirapine therapy.1 234
• Carefully monitor those with hepatic impairment (e.g., those with hepatic fibrosis or cirrhosis) for toxicity.1 234

Administration

Nevirapine is administered orally without regard to food.1 234

Nevirapine conventional (immediate-release) tablets and oral suspension are used in adults and pediatric patients 15 days of age or older.1

Nevirapine extended-release tablets are used in adults and pediatric patients 6 years of age or older with a body surface area (BSA) of 1.17 m²or greater.234

Store conventional (immediate-release) tablets at 20-25°C (excursions permitted to 15-30°C).1 Extended-release tablets should be stored at 20-25°C (excursions permitted to 15-30°C).234 Store nevirapine oral suspension at 20-25°C (excursions permitted to 15-30°C).1

Extended-release Tablets

Nevirapine extended-release tablets should be swallowed whole; the tablets must not be chewed, crushed, or divided.234

When considering use of nevirapine extended-release tablets in a child 6 years of age or older, the child should be assessed for their ability to swallow tablets.234

Oral Suspension

Nevirapine oral suspension should be shaken gently prior to administration of each dose.1 The entire measured dose of suspension should be administered using an oral dosing syringe or, alternatively, a dosing cup.1 The oral syringe is recommended, particularly for volumes of 5 mL or less; if a dosing cup is used, it should be thoroughly rinsed with water and the rinse should also be administered to the patient.1

Dosage

Nevirapine therapy usually should be initiated using a low dosage of immediate-release nevirapine for the first 14 days since this appears to reduce the frequency of rash.1 234 Nevirapine extended-release tablets should not be used during the initial 14 days of nevirapine therapy.234 Patients not currently receiving nevirapine may receive the extended-release tablets after a lead-in period of 14 days of low dosage of immediate-release nevirapine.234 Patients already receiving usual dosage of immediate-release nevirapine may be switched to the extended-release tablets without the 14-day lead-in period.234

If nevirapine therapy has been interrupted for more than 7 days for any reason and reinitiation of the drug is not contraindicated, the manufacturer states that the drug should be restarted using the recommended low initial dosage of immediate-release nevirapine for the first 14 days.1 234

Dosage of nevirapine in pediatric patients is usually based on body surface area (BSA) calculated using the Mosteller formula.1 234

Pediatric Patients

Treatment of HIV Infection

For the treatment of HIV-1 infection in pediatric patients 15 days of age or older, the manufacturer recommends an initial dosage of nevirapine oral suspension or immediate-release tablets of 150 mg/m² once daily for the first 14 days of therapy (lead-in period of low dosage).1 Dosage should then be increased to 150 mg/m² twice daily in patients who do not experience persistent rash or liver function test abnormalities with the lower dosage.1 Dosage should not exceed 400 mg daily.1

When extended-release nevirapine tablets are used for the treatment of HIV-1 infection in pediatric patients 6 years of age or older with a BSA of 1.17 m² or greater, the manufacturer recommends that those not currently receiving immediate-release nevirapine be given nevirapine oral suspension or immediate-release tablets in a dosage of 150 mg/m² once daily (up to 200 mg daily) for 14 days (lead-in period of low dosage) before being switched to the recommended dosage of nevirapine extended-release tablets.234 After the lead-in period, pediatric patients 6 years of age or older with BSA 1.17 m² or greater should receive 400 mg once daily.234 Dosage should not exceed 400 mg daily.234

Refer to the HHS perinatal and pediatric HIV treatment guidelines for other recommended dosage regimens of nevirapine in specific situations.201,202

Adults

Treatment of HIV Infection

The usual initial dosage of nevirapine immediate-release tablets for the treatment of HIV-1 infection in adults is 200 mg once daily for the first 14 days of therapy (lead-in period of low dosage).1 Dosage should then be increased to 200 mg twice daily in patients who do not experience persistent rash or liver function test abnormalities with the lower dosage.1 The 200 mg once-daily dosing regimen should not be continued beyond 28 days, at which point, an alternative regimen should be sought.1

The usual dosage of nevirapine extended-release tablets for the treatment of HIV-1 infection in adults is 400 mg once daily, initiated after immediate-release nevirapine.234 Patients not currently receiving nevirapine should receive a lead-in period of a low dosage of immediate-release nevirapine (200 mg once daily for 14 days) before being switched to the once-daily regimen of extended-release tablets.234 Patients already receiving a twice-daily regimen of usual dosage of immediate-release nevirapine may be switched to the extended-release tablets without the 14-day lead-in period.234

Dosage Modification for Toxicity

If mild to moderate rash without constitutional symptoms occurs during the initial 14-day period of low dosage of immediate-release nevirapine, dosage should not be increased until the rash has resolved.1 234 The low dosage should not be continued for longer than 28 days; if the rash has not resolved by day 28, nevirapine should be discontinued and an alternative antiretroviral agent selected.1 234 If a severe rash or any rash with constitutional symptoms (e.g., fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) occurs, discontinue nevirapine.1 234

Special Populations

Hepatic Impairment

The manufacturer makes no dosage recommendations for patients with mild hepatic impairment (Child-Pugh Class A).1 Immediate-release nevirapine is contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh Class B or C).1

Nevirapine extended-release tablets have not been studied in patients with hepatic impairment.234 Extended-release tablets are contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).234

Carefully monitor patients with hepatic fibrosis or cirrhosis for evidence of nevirapine-induced toxicity.1 234

Renal Impairment

Modification of the usual dosage of nevirapine is not necessary in patients with creatinine clearances of 20 mL/minute or greater not requiring dialysis.1 234 Nevirapine is removed by dialysis; in patients requiring dialysis, an additional 200-mg dose of immediate-release nevirapine should be administered following each dialysis treatment.1 234 Although nevirapine metabolites may accumulate in patients receiving dialysis, the clinical importance of this accumulation is unknown.1 234 The pharmacokinetics of nevirapine have not been evaluated in those with creatinine clearances less than 20 mL/minute.1 234

Nevirapine extended-release tablets have not been studied in patients with renal impairment.234

Geriatric Patients

In general, dosage for geriatric patients should be selected carefully since these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 234

Contraindications

• Moderate or severe hepatic impairment (Child-Pugh class B or C).1 234
• Do not use for postexposure prophylaxis following occupational exposure to HIV (PEP) or postexposure prophylaxis following nonoccupational exposure to HIV (nPEP).1 234

Warnings/Precautions

Warnings

Hepatotoxicity and Hepatic Impairment

A boxed warning about the risk of severe, life-threatening (and in some cases fatal) hepatotoxicity is included in the prescribing information for nevirapine.1,234 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.1,234 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; rash was observed in 50% of patients with symptomatic hepatic events.1,234 A diagnosis of hepatotoxicity should be considered even if liver function tests are initially normal or alternative diagnoses are possible.1,234 Some events, especially those with rash and other symptoms, have progressed over several days to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia.1,234 These events may occur at any time during treatment.1,234 While the risk of hepatic events is greatest during the first 6 weeks of therapy, substantial risk continues through the first 18 weeks of therapy.1,234 Hepatic injury has progressed despite discontinuation of nevirapine in some patients.1,234

Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the initial 18 weeks of nevirapine therapy to detect potentially life-threatening hepatotoxicity.1 234 Extra vigilance is required during the first 6 weeks of therapy since this is the period of greatest risk.1 234 The optimum frequency of monitoring during initial nevirapine therapy has not been established, but some clinicians recommend clinical and laboratory monitoring more often than once monthly and, in particular, recommend liver function tests at baseline, prior to dosage escalation, and at 2 weeks after dosage escalation.1 234 Severe liver disease occurs most frequently during the first 6 weeks of therapy, but can occur after this period.1 234 Therefore, clinical and laboratory monitoring should continue at frequent intervals after the initial 18-week period and throughout nevirapine therapy.1 234 Serum transaminase concentrations should be determined immediately whenever a patient experiences signs or symptoms suggestive of hepatitis during nevirapine therapy.1,234

Patients with signs and symptoms of hepatitis must seek immediate medical attention, have serum transaminase concentrations measured, and be advised to discontinue nevirapine as soon as possible.1 234 If nevirapine is discontinued because of hepatitis or transaminase elevations associated with rash or other systemic symptoms, the drug should be permanently discontinued and not reinitiated.1 234 Patients also should be advised that increased liver function test results and/or a history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and CD4⁺ T-cell counts exceeding 250 cells/mm³ in women or 400 cells/mm³ in men prior to initiation of antiretroviral therapy are associated with an increased risk of hepatic events with nevirapine; women also may be at higher risk of these events.1 234

In some patients with hepatic fibrosis or cirrhosis, increased nevirapine trough concentrations have been observed; therefore, carefully monitor for evidence of drug-induced toxicity in such patients.1 234 Do not use nevirapine in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment.1 234 Extended-release nevirapine has not been investigated in patients with hepatic impairment.234

Asymptomatic increases in serum AST or ALT (more than 5 times the upper limit of normal) have occurred in 6% of patients receiving nevirapine and in 6% of those in control groups.1 In clinical studies, symptomatic hepatic events (regardless of severity) occurred in 4% of patients receiving regimens that included nevirapine and in 1% of those in the control group.1 Women, including pregnant women, appear to be at higher risk of nevirapine-associated hepatic events than men.1 Symptomatic hepatic events (usually associated with rash) have been observed in 6% of women and in 2% of men during the first 6 weeks of treatment with a nevirapine-containing regimen.1

In a clinical study (Study 1100.1486, VERxVE) in antiretroviral-naïve patients who received initial treatment with nevirapine immediate-release tablets for 14 days and were then randomized to continue treatment with immediate-release tablets or be switched to nevirapine extended-release tablets, the incidence of any hepatic event was 9% in the immediate-release group and 6% in the extended-release group; the incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3 and 2%, respectively.234 Overall, the incidence of symptomatic events in study patients was similar among men and women.234

While all patients with higher CD4⁺ T-cell counts prior to initiation of therapy with nevirapine are at increased risk for symptomatic hepatic events, the patients at highest risk are women with high CD4⁺ T-cell counts at baseline.1 234 Symptomatic hepatic events were observed in 11% of women with CD4⁺ T-cell counts exceeding 250 cells/mm³ at baseline and in 6% of men with CD4⁺ T-cell counts exceeding 400 cells/mm³ at baseline.1 234

Increased serum concentrations of AST or ALT prior to initiation of antiretroviral therapy and/or coinfection with HBV or HCV are associated with a greater risk of later symptomatic hepatic adverse effects (i.e., events that occur 6 or more weeks after initiation of nevirapine therapy) and asymptomatic increases in serum transaminase concentrations.1 234

Serious hepatotoxicity has been reported in individuals not infected with HIV who received multiple doses of nevirapine for postexposure prophylaxis following occupational or nonoccupational exposure to HIV.1 234 Nevirapine is contraindicated for and should not be included in regimens used for such prophylaxis.1 234

Skin Reactions

A boxed warning about the risk of skin infections (sometimes fatal) is included in the prescribing information for nevirapine.1 234 Severe and life-threatening skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure, also have occurred in patients receiving nevirapine.1 234 Fatalities have been reported.1 234 There have been postmarketing reports of anaphylaxis, drug reaction with eosinophilia and systemic symptoms (DRESS), angioedema, bullous eruptions, ulcerative stomatitis, and urticaria.1

Most cases of rash (including severe, life-threatening skin reactions and fatalities) have occurred within the first 6 weeks of nevirapine therapy.1 234 Initiating nevirapine therapy using a low dosage during the first 14 days of therapy appears to reduce the frequency of rash and is recommended for all patients.1 234 Risk factors for developing serious cutaneous reactions include failure to follow the low dosage regimen during the first 14 days of therapy and delay in discontinuing nevirapine after the onset of initial symptoms.1 234

Concomitant use of prednisone during the first 14 days of therapy in an attempt to prevent nevirapine-associated rash is not recommended.1 234 In a clinical trial of nevirapine immediate-release tablets, concomitant use of prednisone (40 mg daily during the first 14 days of nevirapine administration) was associated with an increased incidence and severity of rash during the first 6 weeks of nevirapine therapy.1 234

Serum transaminase concentrations should be immediately evaluated in any patient experiencing rash, especially during the first 18 weeks of therapy.1 234 If signs or symptoms of severe skin or hypersensitivity reactions, 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, and/or hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction, occur during nevirapine therapy, the drug should be permanently discontinued and should not be reinitiated.1 234 Delay in discontinuing nevirapine after onset of rash may result in a more severe reaction.1 234

Intensive clinical and laboratory monitoring is essential at baseline and during the initial 18 weeks of nevirapine therapy to detect potentially life-threatening skin reactions.1 234 Extra vigilance is required during the first 6 weeks of therapy since this is the period of greatest risk.1 234

The optimum frequency of monitoring during initial nevirapine therapy has not been established, but some clinicians recommend clinical and laboratory monitoring more often than once monthly.1 234 Therefore, clinical and laboratory monitoring should continue at frequent intervals after the initial 18-week period and throughout nevirapine therapy.1 234 Serum transaminase concentrations should be determined immediately whenever a patient experiences rash or signs or symptoms suggestive of hypersensitivity reactions during nevirapine therapy.1 234

Other Warnings and Precautions

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in HIV-infected patients receiving multiple-drug antiretroviral therapy, including nevirapine.1 234 During the initial phase of treatment, HIV-infected patients whose immune systems 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 ]); such response may necessitate further evaluation and treatment.1,234

Autoimmune disorders (e.g., Graves' disease, polymyositis, 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 antiretroviral therapy.1 234

Fat Redistribution

Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving antiretroviral agents.1 234 The mechanisms responsible for these adipogenic effects and the long-term consequences of these effects are unknown.1 234 A causal relationship has not been established.1 234

Specific Populations

Pregnancy

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including nevirapine, the Antiretroviral Pregnancy Registry was established through the collaboration of antiretroviral manufacturers and an advisory committee of practitioners.1 234 Clinicians are encouraged to contact the registry at 800-258-4263 or [Web] to report cases of prenatal exposure to antiretroviral agents.1 234

Data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for nevirapine compared with the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).1 234 Registry data include over 2600 reports of nevirapine exposures during pregnancy resulting in live births, including over 1100 first-trimester exposures to the drug.1 234 The prevalence of birth defects in live births was 3% following first-trimester exposures to nevirapine-containing regimens and 3.3% following second- or third-trimester exposures to nevirapine-containing regimens compared with the background rate of 2.7% in the reference population of the MACDP.1 234

Literature reports indicate that minimum nevirapine plasma concentrations are decreased up to 29% in pregnancy with the use of immediate-release nevirapine; however, this reduction is not considered clinically meaningful and dosage adjustment is not considered necessary.1

Severe hepatic events, including fatalities, have been reported in HIV-infected pregnant women receiving long-term nevirapine therapy as part of multiple-drug antiretroviral treatment.1 234 Because women (including pregnant women) with baseline CD4⁺ T-cell counts exceeding 250 cells/mm³ appear to be at higher risk of nevirapine-associated symptomatic and potentially fatal rash and hepatic toxicity, the drug should not be initiated in such women and only when potential benefits outweigh risks.1 234 It is not clear if pregnancy augments the risk of rash and hepatic toxicity observed in non-pregnant women.1 234

Lactation

Nevirapine is distributed into human milk.1 234 The effects of nevirapine on the breast-fed infant are unclear, and the effects on milk production are not known.1 234

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding.202 During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant.202 Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.202 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.202

Females and Males of Reproductive Potential

In reproduction studies in female rats, there was evidence of impaired fertility at nevirapine doses providing systemic exposure approximately equivalent to that provided by the usually recommended human dosage based on AUC.1 234

Human data are insufficient to determine the risk of infertility in patients receiving nevirapine.1 234

Females with reproductive potential should be advised that, based on results from fertility studies in rats, nevirapine may impair fertility and it is not known whether effects on fertility are reversible.1 234

Pediatric Use

Safety and pharmacokinetics of nevirapine oral suspension have been evaluated in HIV-infected infants 15 days to less than 3 months of age.1 Safety, pharmacokinetics, and efficacy of nevirapine immediate-release tablets and oral suspension have been evaluated in pediatric patients 3 months to 18 years of age.1

Nevirapine extended-release tablets can be used for treatment of HIV-1 infection in pediatric patients 6 years of age or older based on pharmacokinetic, safety, and antiretroviral activity data from an open-label trial evaluating the drug in pediatric patients 3 to less than 18 years of age and efficacy data from adults.234 The extended-release tablets are not recommended in pediatric patients 3 to less than 6 years of age because pharmacokinetic data are insufficient to support use in this age group; the tablets are not recommended in those less than 3 years of age because of inability to swallow tablets.234

The most frequently reported adverse effects in children were similar to those observed in adults; however, granulocytopenia occurred more frequently in children than in adults.1 Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome has occurred rarely in children receiving nevirapine.1 Rash and allergic reaction, including anaphylaxis, also have been reported.1 Anemia has been observed in children during postmarketing surveillance; whether anemia was due to nevirapine or concomitant drug therapy has not been determined.1

Geriatric Use

Clinical studies of nevirapine to date have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric individuals respond differently to the drug than younger adults.1 234 In general, dosage for geriatric patients should be selected carefully since these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 234

Hepatic Impairment

Disposition of nevirapine was not altered in HIV-infected adults with mild, moderate, or severe hepatic fibrosis who received multiple doses of nevirapine immediate-release tablets (nevirapine 200 mg twice daily for at least 6 weeks); however, approximately 15% of these individuals had nevirapine trough concentrations that were twofold higher than the usual mean trough concentrations.1

In a limited study in HIV-negative adults with mild or moderate hepatic impairment who received a single 200-mg dose of nevirapine as immediate-release tablets, most patients had no clinically important change in the pharmacokinetics of the drug.1 However, in one patient with moderate hepatic impairment (Child-Pugh Class B) and ascites, there was an increase in the AUC of nevirapine.1 Because nevirapine induces its own metabolism with multiple doses, a single-dose study may not reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.1

Carefully monitor those with hepatic impairment (e.g., those with hepatic fibrosis or cirrhosis) for toxicity.1 234 Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 234 Extended-release tablets have not been evaluated in patients with hepatic impairment.234

Renal Impairment

Results of a study in a limited number of HIV-negative adults with mild, moderate, or severe renal impairment indicate that there are no clinically important changes in the pharmacokinetics of a single dose of nevirapine as immediate-release tablets in adults with impaired renal function.1 However, adults undergoing dialysis have a 44% reduction in the AUC of nevirapine after 1 week of nevirapine therapy; treatment and accumulation of the hydroxy metabolites of the drug also may occur.1

Dosage modification of immediate-release nevirapine dosage forms is not necessary in patients with a creatinine clearance of at least 20 mL/minute not receiving dialysis; in those receiving dialysis an additional dose of immediate-release nevirapine (200 mg) is necessary following each dialysis treatment.1 234 The pharmacokinetics of immediate-release nevirapine have not been evaluated in those with a creatinine clearance of less than 20 mL/minute.1 234 Extended-release tablets have not been studied in patients with renal impairment.234

Common Adverse Effects

The most frequently reported adverse effect in patients receiving nevirapine is rash, developing in 15% of adult patients receiving nevirapine compared to 6% of those receiving placebo.1 In adults receiving nevirapine, 2% of rashes were reported as grade 3/4, compared to less than 1% in patients receiving placebo.1 During a lead-in period with immediate-release nevirapine, the development of grade 2 or higher rash in adults occurred in 3% of adult patients.234 After the lead-in period, the incidence of grade 2 or higher rash occurred in 3% of adults taking extended-release nevirapine.234

In pediatric patients, the incidence of rash with immediate-release nevirapine was 21% (all causality).1 The incidence of grade 2 or higher rash was 1% in pediatric patients taking extended-release nevirapine.234

Metabolism of nevirapine is mediated in part by the cytochrome P-450 (CYP) 3A4 and 2B6 isoenzymes, and plasma nevirapine concentrations may be decreased by concomitant use of drugs that induce these isoenzymes (e.g., rifabutin, rifampin) or may be increased by concomitant use of drugs that inhibit these isoenzymes (e.g., cimetidine, macrolides).1 234 In addition, nevirapine is an inducer of CYP3A4 and CYP2B6 and may attenuate the therapeutic effects of drugs metabolized by these isoenzymes.1 234 While principally an inducer of CYP3A4 and CYP2B6, nevirapine may also inhibit these enzymes; however, the drug may have only a minimal inhibitory effect on other substrates of CYP3A4 at therapeutic concentrations.1 234

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).1 234

The following drug interactions are based on studies using nevirapine conventional (immediate-release) tablets and are expected to also apply to nevirapine extended-release tablets.1 234

Anticonvulsants

Carbamazepine, Clonazepam, Ethosuximide

Concomitant use of nevirapine and certain anticonvulsants (carbamazepine, clonazepam, ethosuximide) may result in decreased plasma concentrations of the anticonvulsant and nevirapine.1 234

Nevirapine and certain anticonvulsants (carbamazepine, clonazepam, ethosuximide) should be used concomitantly with caution.1 234 Anticonvulsant and nevirapine concentrations and antiretroviral response should be monitored.1 234

Antifungal Agents

Fluconazole

Concomitant use of fluconazole and nevirapine does not appear to affect plasma concentrations or AUC of the antifungal agent; however, based on comparison with historical data, concomitant use results in about a 100% increase in nevirapine exposure.1 234

Nevirapine and fluconazole should be used concomitantly with caution and patients closely monitored for nevirapine-associated adverse effects.1 234

Itraconazole

Itraconazole and nevirapine should not be used concomitantly since plasma concentrations of the antifungal may be decreased and antifungal efficacy may be reduced.1 234

Ketoconazole

Ketoconazole and nevirapine should not be used concomitantly since plasma concentrations of the antifungal may be decreased and antifungal efficacy may be reduced.1 234

Concomitant use of ketoconazole (400 mg once daily) and nevirapine (200 mg once daily for 2 weeks followed by 200 mg twice daily for 2 weeks) in HIV-infected patients decreased ketoconazole peak plasma concentrations and AUC by 44 and 72%, respectively.1 234

Antimycobacterial Agents

Rifabutin

Concomitant use of rifabutin and nevirapine results in a 28% increase in peak plasma concentrations and 17% increase in the AUC of rifabutin and similar increases in plasma concentrations and AUC of its major metabolite.1 234 However, because of interindividual variability, some patients may experience large increases in rifabutin exposure and may be at higher risk of rifabutin toxicity.1 234

Nevirapine and rifabutin should be used concomitantly with caution.1 234

Rifampin

Concomitant use of rifampin and nevirapine results in a greater than 50% decrease in nevirapine peak plasma concentration and AUC; peak plasma concentrations of rifampin are unaffected but the AUC of rifampin is increased 11%.1 234

Concomitant use of rifampin and nevirapine is not recommended.1 234 In patients with a tuberculosis co-infection receiving nevirapine, prescribers may alternatively use rifabutin.1 234

Antineoplastic Agents

Concomitant use of nevirapine and cyclophosphamide is predicted to result in decreased plasma concentrations of the antineoplastic agent.1 234 Appropriate dosages for concomitant use of cyclophosphamide and nevirapine have not been established.1 234

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Maraviroc

Concomitant use of maraviroc and nevirapine results in a 54% increase in peak plasma concentrations and a 1% increase in the AUC of maraviroc.1 234

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Nevirapine should not be used concomitantly with other NNRTIs (efavirenz, etravirine, rilpivirine).1 234

Concomitant use of nevirapine and etravirine or rilpivirine may result in altered plasma concentrations of the drugs.1 234

Efavirenz

Concomitant use of efavirenz and nevirapine results in a 12% decrease in peak plasma concentrations and a 28% decrease in the AUC of efavirenz.1 234 An increased incidence of adverse effects and no improvement in efficacy have been reported when these NNRTIs were used concomitantly.1 234

Appropriate dosages for concomitant use of efavirenz and nevirapine with respect to safety and efficacy have not been established.1 234

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

There is no in vitro evidence of antagonistic antiretroviral effects between nevirapine and NRTIs (e.g., abacavir, didanosine, emtricitabine, lamivudine, tenofovir, zidovudine).1 234

Didanosine

Concomitant use of didanosine and nevirapine does not appear to affect the pharmacokinetics of either drug.1 234

Zidovudine

Concomitant use of zidovudine and nevirapine results in a 28 and 30% decrease in zidovudine peak plasma concentrations and AUC, respectively.1 234

HIV Protease Inhibitors (PIs)

There is no in vitro evidence of antagonistic antiretroviral effects between nevirapine and HIV PIs (e.g., amprenavir, atazanavir, lopinavir, nelfinavir, tipranavir).1 234

Atazanavir

Concomitant use of ritonavir-boosted atazanavir with nevirapine results in substantially decreased atazanavir plasma concentrations and AUC with possible loss of therapeutic effect and development of resistance and also results in increased nevirapine plasma concentrations and AUC and increases the risk of nevirapine-associated adverse effects.1 234

Concomitant use of nevirapine and ritonavir-boosted atazanavir is not recommended.1 234

Darunavir

Concomitant use of ritonavir-boosted darunavir and nevirapine results in increased plasma concentrations and AUC of darunavir.1 234

Fosamprenavir

Concomitant use of nevirapine and fosamprenavir (without low-dose ritonavir) results in a 33% decrease in the AUC of amprenavir (active metabolite of fosamprenavir) and increased nevirapine concentrations.1 234 Concomitant use of nevirapine with twice-daily regimen of ritonavir-boosted fosamprenavir results in an 11% decrease in amprenavir AUC and increased nevirapine concentrations.1 234

Usual nevirapine dosage can be used concomitantly with a twice-daily regimen of ritonavir-boosted fosamprenavir (fosamprenavir 700 mg twice daily and ritonavir 100 mg twice daily).1 234 Concomitant use of nevirapine with a once-daily regimen of ritonavir-boosted fosamprenavir has not been studied.1 234

Concomitant use of fosamprenavir (without low-dose ritonavir) and nevirapine is not recommended.1 234

Lopinavir

Concomitant use of nevirapine and the fixed combination containing lopinavir and ritonavir (lopinavir/ritonavir) results in decreased lopinavir plasma concentrations and AUC.1 234

A once-daily regimen of lopinavir/ritonavir should not be used in patients receiving nevirapine.1 234

If a twice-daily regimen of lopinavir/ritonavir is used in adult patients receiving nevirapine, an increased lopinavir/ritonavir dosage of 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended.1 234 Dosage in pediatric patients for lopinavir/ritonavir depends on body surface area and body weight.1 234

Nelfinavir

Appropriate dosages for concomitant use of nelfinavir and nevirapine with respect to safety and efficacy have not been established.1 234

In one study, concomitant use of nevirapine (200 mg once daily for 14 days, followed by 200 mg twice daily for 14 days) and nelfinavir (750 mg 3 times daily for 36 days) did not affect nelfinavir peak plasma concentrations or AUC, but resulted in a 32% decrease in trough plasma concentrations of the drug and a 59-66% decrease in plasma concentrations and AUC of the major nelfinavir metabolite (M8).1 234

Ritonavir

Concomitant use of ritonavir and nevirapine in a limited number of HIV-infected patients did not result in clinically important changes in ritonavir plasma concentrations or AUC.1 234

Tipranavir

Concomitant use of nevirapine and ritonavir-boosted tipranavir does not result in clinically important effects on nevirapine concentrations.1 234

Cardiovascular Agents

Antiarrhythmic Agents

Concomitant use of nevirapine and antiarrhythmic agents (e.g., amiodarone, disopyramide, lidocaine) may result in decreased plasma concentrations of the antiarrhythmic agent.1 234 Appropriate dosages for concomitant use of these antiarrhythmic agents and nevirapine have not been established.1 234

Calcium-channel Blocking Agents

Concomitant use of nevirapine and calcium-channel blocking agents (diltiazem, nifedipine, verapamil) may result in decreased plasma concentrations of these agents.1 234 Appropriate dosages for concomitant use of these calcium-channel blocking agents and nevirapine have not been established.1 234

Corticosteroids

Concomitant use of prednisone (40 mg daily) during the first 14 days of nevirapine therapy is not recommended since it has been associated with an increased incidence and severity of rash during the first 6 weeks of nevirapine therapy.1 234

Ergot Alkaloids and Derivatives

Concomitant use of nevirapine and ergot alkaloids (e.g., ergotamine) is predicted to result in decreased plasma concentrations of the ergot alkaloid.1 234 Appropriate dosages for concomitant use of ergotamine and nevirapine have not been established.1 234

Estrogens and Progestins

Depomedroxyprogesterone

Concomitant use of nevirapine and depomedroxyprogesterone acetate does not affect concentrations of the progestin.1 234

Ethinyl Estradiol and Norethindrone

Concomitant use of nevirapine and an oral contraceptive containing 0.035 mg of ethinyl estradiol and 1 mg of norethindrone decreased the AUC of both hormones by about 20%.1 234

Although ethinyl estradiol and norethindrone exposures may be decreased, concomitant use of nevirapine and oral contraceptives containing ethinyl estradiol and norethindrone in HIV-infected women does not appear to have an effect on pregnancy rates.1 234 Therefore, dosage adjustments are not necessary if nevirapine is used in patients receiving such oral contraceptives.1 234

GI Drugs

Antacids

Results of a study in 24 healthy adults indicate that concomitant use of a single 200-mg dose of immediate-release nevirapine and 30 mL of an antacid (Maalox^®) does not affect the extent of absorption (AUC) of the antiretroviral agent.1 Immediate-release nevirapine may be administered with antacids.1

Cisapride

Concomitant use of nevirapine and cisapride is predicted to result in decreased plasma concentrations of cisapride.1 234 Appropriate dosages for concomitant use of cisapride and nevirapine have not been established.1 234

Immunosuppressive Agents

Concomitant use of nevirapine and immunosuppressive agents such as cyclosporine, tacrolimus, or sirolimus is predicted to result in decreased plasma concentrations of these agents.1 234 Appropriate dosages for concomitant use of these immunosuppressive agents and nevirapine have not been established.1 234

Opiate Agonists and Opiate Partial Agonists

Fentanyl

Concomitant use of fentanyl and nevirapine may decrease plasma concentrations of the opiate agonist.1 234 Appropriate dosages for concomitant use of fentanyl and nevirapine have not been established.1 234

Methadone

There have been reports of opiate withdrawal and subtherapeutic or decreased serum methadone concentrations following initiation of nevirapine therapy in individuals who were receiving long-term methadone treatment for opiate addiction; nevirapine concentrations are not affected.1 234

Individuals receiving concomitant nevirapine and methadone therapy should be informed of this potential interaction and closely monitored for signs of opiate withdrawal when nevirapine therapy is initiated; an increase in methadone maintenance dosage may be necessary.1 234 69

St. John's Wort ( Hypericum perforatum )

Concomitant use of St. John's wort ( Hypericum perforatum ) and nevirapine is expected to result in suboptimal antiretroviral concentrations and may be associated with loss of virologic response and development of resistance.1 234 Concomitant use of nevirapine with St. John's Wort is not recommended.1 234

Warfarin

Concomitant use of nevirapine and warfarin is predicted to increase warfarin plasma concentrations resulting in increases in coagulation time.1 234 The in vitro interaction between nevirapine and warfarin is complex.1

The international normalized ratio (INR) should be monitored frequently in patients receiving nevirapine and warfarin concomitantly.1 234

Description

Nevirapine is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).1 234 While the complete mechanism of antiviral activity of nevirapine has not been fully elucidated,5 the drug inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.1 3,5,21,22 Nevirapine binds directly to HIV-1 reverse transcriptase and exerts a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse transcriptase inhibitor.1 3,5,21,22

The mechanism of action of nevirapine differs from that of HIV nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., abacavir, didanosine, lamivudine, stavudine, zidovudine).4,5,21 NRTIs require intracellular conversion to triphosphate metabolites,1 22 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.5,22 Nevirapine, however, is noncompetitive with respect to primer-template or nucleoside triphosphate binding and is specific for HIV-1 reverse transcriptase.1 3,21,22 The drug binds directly to heterodimeric HIV-1 reverse transcriptase1 2,5,21 and appears to inhibit viral RNA- and DNA-dependent DNA polymerase activities by disrupting the catalytic site of the enzyme.1 2,5,21

The binding site for nevirapine on HIV-1 reverse transcriptase is near, but not at the proposed site of active polymerization,2,5,21 in a deep pocket lying between the β sheets of the “palm” and at the base of the “thumb” subdomains of the enzyme's p66 subunit.5,21 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.21 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.21 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.21 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.21 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.21

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 α-, β-, γ-, or δ-polymerases.1 3,4,22

The pharmacokinetics of nevirapine have been studied in healthy adults,1 234 adults with HIV-1 infection,1 234 and pediatric patients 14 days of age and older with HIV-1 infection.1 Studies to date have not revealed clinically important race-related differences in the pharmacokinetics of nevirapine.1 234 Studies in adults 18-68 years of age have not revealed any age-related differences in the pharmacokinetics of nevirapine; however, pharmacokinetics of the drug have not been extensively studied to date in geriatric adults older than 55-65 years of age.1 234

Immediate-release tablets containing nevirapine and the oral suspension containing nevirapine hemihydrate are bioequivalent and can be used interchangeably at doses up to 200 mg.1 Bioavailability of 400 mg of nevirapine administered as extended-release tablets relative to 400 mg administered as conventional (immediate-release) tablets is approximately 75%.234 Following oral administration of nevirapine immediate-release tablets or oral suspension in healthy or HIV-infected adults, the drug is readily (more than 90%) absorbed.1 Absolute bioavailability of nevirapine in 12 healthy adults was 93% following administration of a single 50-mg immediate-release tablet or 91% following administration of an oral solution of the drug.1 Following multiple doses, peak plasma nevirapine concentrations appear to increase linearly in the dosage range of 200-400 mg daily.1 Following oral administration of a single 400-mg dose of nevirapine as an extended-release tablet in healthy adults, mean peak plasma concentrations were attained at a median of approximately 24 hours.234

In HIV-infected pediatric patients 6 to less than 18 years of age who were switched to nevirapine extended-release tablets after at least 18 weeks of immediate-release nevirapine, overall mean systemic nevirapine exposure at steady-state after 10 days of therapy with the extended-release preparation was similar to that reported for the immediate-release preparation.234 At steady state, the observed geometric mean ratios of extended-release nevirapine to immediate-release nevirapine were approximately 97% for trough plasma concentrations and 94% for AUCs; the ratio for peak plasma concentrations was lower and consistent with the once-daily extended-release preparation.234

Results of a study in 6 individuals indicate that nevirapine is distributed into CSF in concentrations that are 45% of concurrent plasma concentrations; this ratio is approximately equal to the fraction of the drug not bound to plasma proteins.1 234 At plasma concentrations of 1-10 mcg/mL, nevirapine is approximately 60% bound to plasma proteins.1 234 Nevirapine readily crosses the placenta in humans.1 234 Nevirapine is distributed into human milk.1 234

Nevirapine is extensively converted in vivo to several hydroxylated metabolites via cytochrome P-450 (CYP) oxidative metabolism.1 In vitro studies using human liver microsomes indicate that metabolism of nevirapine is mediated principally by CYP3A4, but other isoenzymes may also play a role in metabolism of the drug.1 234 There is evidence that nevirapine induces CYP3A4 and CYP2B6 enzymes resulting in autoinduction of its own metabolism.1 The pharmacokinetics of autoinduction are characterized by an approximately 1.5- to 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to 2-4 weeks of dosing at a dosage of 200-400 mg daily.1 Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma from approximately 45 hours with a single dose to approximately 25-30 hours following multiple dosing using a dosage of 200-400 mg daily in adults.1 In a population substudy, women had a 13.8% lower clearance of nevirapine than men.1 These results could not be explained by body weight or body mass index differences between men and women.1 Nevirapine is excreted in urine (81%), mainly as glucuronide conjugates of hydroxylated metabolites, and in feces (10%).1,234

Spectrum

Nevirapine has a very limited spectrum of antiviral activity.1 3 The drug has in vitro virustatic activity against human immunodeficiency virus type 1 (HIV-1),1 but is inactive against HIV type 2 (HIV-2) and animal retrovirus (e.g., feline leukemia virus).1,3

The antiretroviral activity of nevirapine has been evaluated in vitro in various cell culture systems including lymphoblastoid cell lines, peripheral blood mononuclear cells, and monocyte-derived macrophages.1 4 In human cord blood lymphocytes and human embryonic kidney cells, the concentration of nevirapine required to inhibit HIV-1 replication by 50% (EC₅₀) was 14-302 nM.1

Results of in vitro studies indicate that the antiretroviral activities of nevirapine and some HIV nucleoside reverse transcriptase inhibitors (e.g., abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zidovudine)1 3,4,9,27 or HIV protease inhibitors (e.g., amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir) may be additive to synergistic against HIV-1.1 3,4

Resistance

Strains of human immunodeficiency virus type 1 (HIV-1) with reduced susceptibility to nevirapine (i.e., susceptibility that is 100- to 250-fold lower than baseline) have been produced in vitro, and the time to emergence of in vitro resistance was not altered when nevirapine was used in conjunction with several other HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs).1 Although the clinical importance is unclear, strains of HIV-1 with in vitro resistance to nevirapine have emerged during therapy with the drug.1

Resistance emerges rapidly when nevirapine is administered as monotherapy; therefore, nevirapine must not be used as a single agent to treat HIV-1 or added as a single agent to a failing antiviral regimen.1 234 Consider the potential for cross resistance when choosing new antiretroviral therapy to be used in combination with nevirapine.1 234

In phase 1 or 2 studies evaluating nevirapine monotherapy or nevirapine used in conjunction with zidovudine, 100% of 24 patients receiving the drug alone had HIV-1 isolates with decreased in vitro susceptibility to nevirapine (susceptibility more than 100-fold lower than baseline) and, in a few patients, these strains were evident after only 1 week of monotherapy.1 Isolates with reduced susceptibility to nevirapine had one or more nevirapine-associated resistance mutations including K103N, V106A, V108I, Y181C, Y188C, and G190A; regardless of dose, 80% of patients had isolates the Y181C mutation.1

In a genotypic analysis of patients who experienced virologic failure with nevirapine, the Y181C mutation was found alone or in combination with other nevirapine-associated resistance mutations including K101E, K103N, V106A, V108I, V179D/E/I, Y188 C/F/H/L/N, G190A, P225H, F227L, and M230L.1 234 On-therapy isolates from 1 patient receiving extended-release nevirapine and 1 patient receiving immediate-release nevirapine developed novel amino acid substitutions in Y181I and Y188N, respectively.1 234 Phenotypic analysis of Y181I and Y188N conferred a 22-fold and 103-fold reduction in nevirapine susceptibility, respectively.1 234

HIV-1 resistant to nevirapine may be cross-resistant to some other HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) (e.g., efavirenz, etravirine).1 234 In a study evaluating HIV-1 strains isolated from a limited number of patients, zidovudine-resistant HIV-1 isolates retained susceptibility to nevirapine and nevirapine-resistant isolates were susceptible to zidovudine.1

Advice to Patients

• Critical importance of compliance with HIV therapy and importance of remaining under the care of a clinician.1,234 Stress importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1,234
• Advise patients to read the patient information provided by the manufacturer.1 234
• If a dose is missed, take the next dose as soon as possible.1 234 If a dose is skipped, do not take a double dose to make up for the missed dose.1 234
• Possibility of severe liver disease or skin reactions (potentially fatal).1 234 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.1 234
• 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.1 234
• Risk of rash, especially during first 6 weeks of therapy.1 234 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.1 234 If rash continues through 4 weeks of therapy, nevirapine should be discontinued.1 234
• Inform patients that redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1 234
• 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.1 234
• Advise patients that they may occasionally see soft remnants of extended-release nevirapine tablets in their stool, which sometimes resemble intact tablets.234 These occurrences have not been shown to affect drug levels or response.234
• Stress importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.1 234
• Stress mportance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 234
• Inform patients of other important precautionary information.1 234

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.

Only references cited for selected revisions after 1984 are available electronically.

1. Boehringer Ingelheim. Viramune^® (nevirapine) tablets and oral suspension prescribing information. Ridgefield, CT; 2022 June. [Web]

2. Havlir D, Cheeseman SH, McLaughlin M et al. High-dose nevirapine: Safety, pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus infection. J Infect Dis . 1995; 171:537-45. [PubMed 7533197]

3. Richman D, Rosenthal AS, Skoog M et al. BI-RG-587 is active against zidovudine- resistant human immunodeficiency virus type 1 and synergistic with zidovudine. Antimicrob Agents Chemother . 1991; 35:305-8. [PubMed 1708976]

4. Cheeseman SH, Havlir D, McLaughlin MM et al. Phase I/II evaluation of nevirapine alone and in combination with zidovudine for infection with human immunodeficiency virus. J Acquir Immune Defic Syndr Hum Retrovirol . 1995; 8:141-51. [PubMed 7530585]

5. Kohlstaedt LA, Wang J, Friedman JM et al. Crystal structure at 3.5 resolution of HIV- 1 reverse transcriptase complexed with an inhibitor. Science . 1992; 256:1783-90. [PubMed 1377403]

6. D'Aquila RT, Hughes MD, Johnson VA et al. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. Ann Intern Med . 1996; 124:1019-30. [PubMed 8633815]

9. Merrill DP, Moonis M, Chou TC et al. Lamivudine or stavudine in two- and three-drug combinations against human immunodeficiency virus type 1 replication in vitro. J Infect Dis . 1996; 173:355-64. [PubMed 8568296]

13. Montaner JSG, Reiss P, Cooper D et al. A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS trial. JAMA . 1998; 279:930-7. [PubMed 9544767]

20. Luzuriaga K, Bryson Y, Krogstad P et al. Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus infection. N Engl J Med . 1997; 336:1343-9. [PubMed 9134874]

21. Spence RA, Kati WM, Anderson KS et al. Mechanism of inhibition of HIV-1 reverse transcriptase by nonnucleoside inhibitors. Science . 1995; 267:988-93. [PubMed 7532321]

22. Merluzzi VJ, Hargrave KD, Labadia M et al. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science . 1990; 250:1411-13. [PubMed 1701568]

24. Anon. Boehringer Ingleheim Viramune for combination use will be on the market by end of July; interaction studies with protease inhibitors part of Phase IV. F-D-C Rep . 1996; July 1: T&G 7-8.

27. Zhu QY, Scarborough A, Polsky B et al. Drug combinations and effect parameters of zidovudine, stavudine, and nevirapine in standardized drug-sensitive and resistant HIV type 1 strains. AIDS Res Hum Retroviruses . 1996; 12:507-17. [PubMed 8679306]

28. Byrnes VW, Sardana VV, Schleif WA et al. Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors. Antimicrob Agents Chemother . 1993; 27:1576-9.

42. Moyle GJ. Resistance to antiretroviral compounds: implications for the clinical management of HIV infection. Immunol Infect Dis . 1995; 5:170-82.

43. Imrie A, Beveridge A, Genn W et al. Transmission of human immunodeficiency virus type 1 resistant to nevirapine. J Infect Dis . 1997; 175:1502-6. [PubMed 9180194]

46. Meyers MW. Dear doctor letter regarding ongoing pharmacokinetic interaction trials with nevirapine and the protease inhibitors saquinavir, indinavir and ritonavir. Ridgefield, CT: Boehringer Ingelheim; 1996 Sept 23.

47. Meyers MW. Dear investigator letter regarding VIRAMUNE in combination with protease inhibitors. Ridgefield, CT: Boehringer Ingelheim; 1996 Nov 20.

65. Mirochnick M, Fenton T, Gagnier P et al. Pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. J Infect Dis . 1998; 178:368-74. [PubMed 9697716]

66. Warren KJ, Boxwell DE, Kim NY et al. Nevirapine-associated Stevens-Johnson syndrome. Lancet . 1998; 351:567. [PubMed 9492778]

67. Barner A, Myers M. Nevirapine and rashes. Lancet . 1998; 351:1133. [PubMed 9660609]

69. Altice FL, Friedland GH, Cooney EL. Nevirapine induced opiate withdrawal among injection drug users with HIV infection receiving methadone. AIDS . 1999; 13:957-62. [PubMed 10371177]

70. Heelon MW, Meade LB. Methadone withdrawal when starting an antiretroviral regimen including nevirapine. Pharmacotherapy . 1999; 19:471-2. [PubMed 10212021]

71. Witvrouw M, Pannecouque C, Van Laethem K et al. Activity of non-nucleoside reverse transcriptase inhibitors against HIV-2 and SIV. AIDS . 1999; 13:1477-83. [PubMed 10465070]

72. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR . 1998; 47(No. RR-20).

73. Centers for Disease Control and Prevention. Notice to readers: updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR Morb Mortal Wkly Rep . 2000; 49:185-9. [PubMed 11795500]

74. Riska P, Lamson M, MacGregor T et al. Disposition and biotransformation of the antiretroviral drug nevirapine in humans. Drug Metab Dispos . 1999; 27:895-901. [PubMed 10421616]

75. Lamson MJ, Sabo JP, MacGregor TR et al. Single dose pharmacokinetics and bioavailability of nevirapine in healthy volunteers. Biopharm Drug Dispos . 1999; 20:285-91. [PubMed 10701699]

76. Taylor S, Little J, Halifax K et al. Pharmacokinetics of nelfinavir and nevirapine in a patient with end-stage renal failure on continuous ambulatory, peritoneal dialysis. J Antimicrob Chemother . 2000; 45:716-7. [PubMed 10797104]

78. Lumpkin MM, Alpert A. Risk of drug interactions with St John's wort and indinavir and other drugs. FDA Public Health Advisory. 2000 Feb 10. From FDA website. [Web]

82. Taylor GP, Lyall EGH, Back D et al. Pharmacological implications of lengthened in-utero exposure to nevirapine. Lancet . 2000; 355:2134-5. [PubMed 10902630]

84. American Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC). Targeted tuberculin testing and treatment of latent tuberculosis infections. Am J Respir Crit Care Med . 2000; 161:S221-47.

85. Krogstad P, Lee S, Johnson G et al. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. Clin Infect Dis . 2002; 34:991-1001. [PubMed 11880966]

87. Anon. Serious adverse events attributed to nevirapine regimens for postexposure prophylaxis after HIV exposures: worldwide, 1997-2000. MMWR Morb Mortal Wkly Rep . 2001; 49:1153-6. [PubMed 11198946]

88. Taylor S, van Heeswijk RP, Hoetelmans RM et al. Concentrations of nevirapine, lamivudine and stavudine in semen of HIV-1-infected men. AIDS . 2000; 14:1979-84. [PubMed 10997403]

91. Yogev R, Lee S, Wiznia A et al. Stavudine, nevirapine and ritonavir in stable antiretroviral therapy-experienced children with human immunodeficiency virus infection. Pediatr Infect Dis J . 2002; 21:119-25. [PubMed 11840078]

96. US Food and Drug Administration. FDA public health advisory for neveripine (Viramune). 2005 Jan 19. From FDA web site. [Web]

101. Lipman M, Breen R. Immune reconstitution inflammatory syndrome in HIV. Curr Opin Infect Dis . 2006; 19:20-5. [PubMed 16374213]

198. Centers for Disease Control and Prevention. Updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection drug use, or other nonoccupational exposure to HIV - United States, 2016. From National Institutes of Health HIV Information (HIVinfo) website. [Web]

199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol . 2013; 34:875-92. [PubMed 23917901]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in adults and adolescents with HIV (March 23, 2023). Updates may be available at HIV. gov website. [Web]

201. Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (January 31, 2023). Updates may be available at HIV. gov website. [Web]

202. Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States (January 31, 2024). Updates may be available at HIV.gov website. [Web]

234. Boehringer Ingelheim. Viramune^® XR (nevirapine) extended-release tablets prescribing information. Ridgefield, CT; 2022 June.

500. Gathe, J, Andrade-Villanuva J, Santiago S, et al. Efficacy and safety of nevirapine extended-release once daily versus nevirapine immediate-release twice-daily in treatment-naïve HIV-1 infected patients. Antivir Ther. 2011;16(5):759-769.Gathe, J, Andrade-Villanuva J, Santiago S, et al. Efficacy and safety of nevirapine extended-release once daily versus nevirapine immediate-release twice-daily in treatment-naïve HIV-1 infected patients. Antivir Ther . 2011;16(5):759-769.

501. Arasteh K, Ward D, Plettenberg A, et al. Twenty-four-week efficacy and safety of switching virologically suppressed HIV-1-infected patients from nevirapine immediate release 200 mg twice daily to nevirapine extended release 400 mg once daily (TRANxITION). HIV Med. 2012;13(4): 236-244. Arasteh K, Ward D, Plettenberg A, et al. Twenty-four-week efficacy and safety of switching virologically suppressed HIV-1-infected patients from nevirapine immediate release 200 mg twice daily to nevirapine extended release 400 mg once daily (TRANxITION). HIV Med . 2012;13(4): 236-244.

502. Giaquinto C, Anabwani G, Feiterna-Sperling C, et al. Steady-state pharmacokinetics of nevirapine extended-release tablets in HIV-1-infected children and adolescents. Pediatr Infect Dis. 2014;33:e173-e179.Giaquinto C, Anabwani G, Feiterna-Sperling C, et al. Steady-state pharmacokinetics of nevirapine extended-release tablets in HIV-1-infected children and adolescents. Pediatr Infect Dis . 2014;33:e173-e179.

503. Anabwani G, Konigs C, Giaquinto G, et al. Nevirapine extended-release formulation tablets in HIV-1-infected chldren-long-term follow-up. Clin Infect Dis. 2015;61:476-479. Anabwani G, Konigs C, Giaquinto G, et al. Nevirapine extended-release formulation tablets in HIV-1-infected chldren-long-term follow-up. Clin Infect Dis . 2015;61:476-479.