Nevirapine

Nevirapine comes as a tablet, an extended-release tablet, and a suspension (liquid) to take by mouth with or without food. The tablet and suspension are usually taken once a day for 2 weeks and then twice a day after the first 2 weeks. The extended-release tablet is usually taken once a day, following at least two weeks of treatment with regular nevirapine tablets or suspension. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take nevirapine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow nevirapine with liquids such as water, milk, or soda.

Swallow the extended-release tablets whole; do not split, chew, or crush them.

Shake the liquid gently before each use to mix the medication evenly. Use an oral dosing cup or dosing syringe to measure your dose. It is best to use a syringe, especially if your dose is less than 5 mL (1 teaspoon). If you use a dosing cup, first drink all of the medication that you measured in the dosing cup. Then fill the dosing cup with water and drink the water to be sure that you get your full dose.

Nevirapine may control HIV but will not cure it. Continue to take nevirapine even if you feel well. Do not stop taking nevirapine or any of the other medications that you are taking to treat HIV or AIDS without talking to your doctor. Your doctor will probably tell you to stop taking your medications in a certain order. If you miss doses or stop taking nevirapine, your condition may become more difficult to treat.

If you do not take nevirapine for 7 days or longer, do not start taking it again without talking to your doctor. Your doctor will start you on a low dose of nevirapine, and increase your dose after 2 weeks.

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Mechanism Of Action

Nevirapine is an antiviral drug [see Microbiology].

Pharmacokinetics - Adults

Nevirapine is readily absorbed (greater than 90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose administration was 93 ± 9% (mean ± SD) for a 50 mg tablet and 91 ± 8% for an oral solution. Peak plasma nevirapine concentrations of 2 ± 0.4 mcg/mL (7.5 micromolar) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Steady-state trough nevirapine concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar), (n=242) were attained at 400 mg per day. Nevirapine tablets and suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg. When VIRAMUNE (200 mg) was administered to 24 healthy adults (12 female, 12 male), with either a high-fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox® 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In a separate trial in HIV-1 infected subjects (n=6), nevirapine steady-state systemic exposure (AUCτ) was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. VIRAMUNE may be administered with or without food, antacid or didanosine.

Nevirapine is highly lipophilic and is essentially nonionized at physiologic pH. Following intravenous administration to healthy adults, the apparent volume of distribution (Vdss) of nevirapine was 1.21 ± 0.09 L/kg, suggesting that nevirapine is widely distributed in humans. Nevirapine readily crosses the placenta and is also found in breast milk [see Use in Specific Populations]. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 mcg per mL. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% (±5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.

In vivo trials in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion trial in eight healthy male volunteers dosed to steady state with nevirapine 200 mg given twice daily followed by a single 50 mg dose of 14C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (less than 5%) of the radioactivity in urine (representing less than 3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound.

Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6 by approximately 20-25%, as indicated by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediated metabolism leads to an approximately 1.5- to 2fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200-400 mg per day. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200-400 mg per day.

Specific Populations

HIV-1 seronegative adults with mild (CrCL 50-79 mL per min; n=7), moderate (CrCL 30-49 mL per min; n=6), or severe (CrCL less than 30 mL per min; n=4) renal impairment received a single 200 mg dose of nevirapine in a pharmacokinetic trial. These subjects did not require dialysis. The trial included six additional subjects with renal failure requiring dialysis.

In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. However, subjects requiring dialysis exhibited a 44% reduction in nevirapine AUC over a one-week exposure period. There was also evidence of accumulation of nevirapine hydroxy-metabolites in plasma in subjects requiring dialysis. An additional 200 mg dose following each dialysis treatment is indicated [see DOSAGE AND ADMINISTRATION  and Use in Specific Populations].

In a steady-state trial comparing 46 subjects with mild (n=17; expansion of some portal areas; Ishak Score 1-2), moderate (n=20; expansion of most portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3-4), or severe (n=9; marked bridging with occasional cirrhosis without decompensation indicating Child-Pugh A; Ishak Score 5-6) fibrosis as a measure of hepatic impairment, the multiple dose pharmacokinetic disposition of nevirapine and its five oxidative metabolites were not altered. However, approximately 15% of these subjects with hepatic fibrosis had nevirapine trough concentrations above 9,000 mcg per mL (2-fold the usual mean trough). Therefore, patients with hepatic impairment should be monitored carefully for evidence of drug-induced toxicity [see WARNINGS AND PRECAUTIONS]. The subjects studied were receiving antiretroviral therapy containing VIRAMUNE 200 mg twice daily for at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years.

In a pharmacokinetic trial where HIV-1 negative cirrhotic subjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B; n=4) hepatic impairment received a single 200 mg dose of nevirapine, a significant increase in the AUC of nevirapine was observed in one subject with Child-Pugh B and ascites suggesting that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation. Because nevirapine induces its own metabolism with multiple dosing, this single-dose trial may not reflect the impact of hepatic impairment on multiple-dose pharmacokinetics.

Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Use in Specific Populations].

In the multinational 2NN trial, a population pharmacokinetic substudy of 1077 subjects was performed that included 391 females. Female subjects showed a 13.8% lower clearance of nevirapine than did men. Since neither body weight nor Body Mass Index (BMI) had an influence on the clearance of nevirapine, the effect of gender cannot solely be explained by body size.

An evaluation of nevirapine plasma concentrations (pooled data from several clinical trials) from HIV-1-infected subjects (27 Black, 24 Hispanic, 189 Caucasian) revealed no marked difference in nevirapine steady-state trough concentrations (median Cminss = 4.7 mcg/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mL Caucasian) with long-term nevirapine treatment at 400 mg per day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.

Black subjects (n=80/group) in Trial 1100.1486 showed approximately 30% to 35% higher trough concentrations than Caucasian subjects (250-325 subjects/group) in both immediate-release VIRAMUNE and VIRAMUNE XR treatment groups over 96 weeks of treatment at 400 mg per day.

Nevirapine pharmacokinetics in HIV-1-infected adults do not appear to change with age (range 18–68 years); however, nevirapine has not been extensively evaluated in subjects beyond the age of 55 years [see Use in Specific Populations].

Pharmacokinetic data for nevirapine have been derived from two sources: a 48-week pediatric trial in South Africa (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naïve subjects aged 3 months to 16 years; and a consolidated analysis of five Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising 495 subjects aged 14 days to 19 years.

BI Trial 1100.1368 studied the safety, efficacy, and pharmacokinetics of a weight-based and a body surface area (BSA)-based dosing regimen of nevirapine. In the weight-based regimen, pediatric subjects up to 8 years of age received a dose of 4 mg/kg once daily for two weeks followed by 7 mg per kg twice daily thereafter. Subjects 8 years and older were dosed 4 mg/kg once daily for two weeks followed by 4 mg/kg twice daily thereafter. In the BSA regimen, all pediatric subjects received 150 mg/m² once daily for two weeks followed by 150 mg/m² twice daily thereafter [see Use in Specific Populations and ADVERSE REACTIONS]. Dosing of nevirapine at 150 mg/m² BID (after a two-week lead-in of 150 mg/m² QD) produced geometric mean or mean trough nevirapine concentrations between 4-6 mcg per mL (as targeted from adult data). In addition, the observed trough nevirapine concentrations were comparable between the two dosing regimens studied (BSA- and weight-based methods).

The consolidated analysis of Pediatric AIDS Clinical Trials Group (PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluation of pediatric subjects less than 3 months of age (n=17). The plasma nevirapine concentrations observed were within the range observed in adults and the remainder of the pediatric population, but were more variable between subjects, particularly in the second month of age. For dose recommendations for pediatric patients [see DOSAGE AND ADMINISTRATION].

Drug Interactions

[see DRUG INTERACTIONS]

Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of VIRAMUNE and drugs primarily metabolized by CYP3A or CYP2B6 may result in decreased plasma concentrations of these drugs and attenuate their therapeutic effects.

While primarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibit this system. Among human hepatic cytochrome P450s, nevirapine was capable in vitro of inhibiting the 10-hydroxylation of (R)-warfarin (CYP3A). The estimated Ki for the inhibition of CYP3A was 270 micromolar, a concentration that is unlikely to be achieved in patients as the therapeutic range is less than 25 micromolar. Therefore, nevirapine may have minimal inhibitory effect on other substrates of CYP3A.

Nevirapine does not appear to affect the plasma concentrations of drugs that are substrates of other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.

Table 5 (see below) contains the results of drug interaction trials performed with VIRAMUNE and other drugs likely to be co-administered. The effects of VIRAMUNE on the AUC, Cmax, and Cmin of co-administered drugs are summarized.

Table 5 : Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of VIRAMUNE (All interaction trials were conducted in HIV-1 positive subjects)

Because of the design of the drug interaction trials (addition of 28 days of VIRAMUNE therapy to existing HIV-1 therapy), the effect of the concomitant drug on plasma nevirapine steady-state concentrations was estimated by comparison to historical controls.

Administration of rifampin had a clinically significant effect on nevirapine pharmacokinetics, decreasing AUC and Cmax by greater than 50%. Administration of fluconazole resulted in an approximate 100% increase in nevirapine exposure, based on a comparison to historic data [see DRUG INTERACTIONS]. The effect of other drugs listed in Table 5 on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir was co-administered with low-dose ritonavir and nevirapine.

Microbiology

Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases α, β, γ, or δ) are not inhibited by nevirapine.

The antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte-derived macrophages, and lymphoblastoid cell lines. In an assay using human embryonic kidney 293 cells, the median EC50 value (50% inhibitory concentration) of nevirapine was 90 nM against a panel of 2923 isolates of HIV-1 that were primarily (93%) clade B clinical isolates from the United States. The 99th percentile EC50 value was 470 nM in this trial. The median EC50 value was 63 nM (range 14-302 nM, n=29) against clinical isolates of HIV-1 clades A, B, C, D, F, G, and H, and circulating recombinant forms CRF01_AE, CRF02_AG and CRF12_BF. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates (n=3) or HIV-2 isolates (n=3) replicating in cord blood mononuclear cells. Nevirapine in combination with efavirenz exhibited strong antagonistic anti-HIV-1 activity in cell culture and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir, and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in cell culture.

HIV-1 isolates with reduced susceptibility (100- to 250-fold) to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT gene encoding Y181C and/or V106A substitutions depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not altered when selection included nevirapine in combination with several other NNRTIs.

Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve subjects receiving either nevirapine (n=24) or nevirapine and zidovudine (n=14) were monitored in Phase 1 and 2 trials ranging from 1 to12 weeks or longer. After 1 week of nevirapine monotherapy, isolates from 3/3 subjects had decreased susceptibility to nevirapine in cell culture. One or more of the RT mutations resulting in amino acid substitutions K103N, V106A, V108I, Y181C, Y188C, and G190A were detected in HIV-1 isolates from some subjects as early as 2 weeks after therapy initiation. By week eight of nevirapine monotherapy, 100% of the subjects tested (n=24) had HIV-1 isolates with a greater than 100-fold decrease in susceptibility to nevirapine in cell culture compared to baseline, and had one or more of the nevirapineassociated RT resistance substitutions. Nineteen of these subjects (80%) had isolates with Y181C substitutions regardless of dose.

Genotypic analysis of isolates from antiretroviral-naïve subjects experiencing virologic failure (n=71) receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25 and 23/46 subjects, respectively, contained one or more of the following NNRTI resistance-associated substitutions: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L, and M230L.

For trial 1100.1486, genotypic analysis was performed for baseline and on-therapy isolates from 23 and 34 subjects who experienced virologic failure in the VIRAMUNE XR and immediate-release VIRAMUNE treatment group, respectively. Nevirapine resistance-associated substitutions developed in the on-therapy isolates of 78% (18/23) of the subjects who had virologic failures in the VIRAMUNE XR treatment group and 88% (30/34) of the subjects in the immediate-release VIRAMUNE treatment group, respectively. The Y181C nevirapine resistance-associated substitution was found alone or in combination with other nevirapine resistance-associated substitutions (K101E, K103N, V106A, V108I, V179D/E/I, Y188 C/F/H/L/N, G190A, P225H, F227L, M230L) in isolates from 14 subjects failing VIRAMUNE XR treatment and 25 subjects failing immediate-release VIRAMUNE treatment. On-therapy isolates from 1 subject in VIRAMUNE XR treatment group developed a novel amino acid substitution Y181I and isolates from another subject in the immediate-release VIRAMUNE treatment group developed a novel amino acid substitution Y188N. Phenotypic analysis showed that Y188N and Y181I substitutions conferred 103- and 22-fold reductions in susceptibility to nevirapine, respectively.

Rapid emergence of HIV-1 strains which are cross-resistant to NNRTIs has been observed in cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistant to the NNRTIs delavirdine, efavirenz and etravirine. The Y188N conferred 22- and 7-fold reductions in susceptibility to delavirdine and efavirenz, respectively, but showed no decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility to delavirdine and etravirine 3-and 8-fold, respectively, but did not reduce susceptibility to efavirenz. However, nevirapine-resistant isolates were susceptible to the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.

Animal Toxicology And/Or Pharmacology

Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses the blood-brain barrier.

Clinical Studies

Adult Patients

Trial BI 1090 was a placebo-controlled, double-blind, randomized trial in 2249 HIV-1 infected subjects with less than 200 CD4+ cells/mm³ at screening. Initiated in 1995, BI 1090 compared treatment with VIRAMUNE + lamivudine + background therapy versus lamivudine + background therapy in NNRTI-naïve subjects. Treatment doses were VIRAMUNE, 200 mg daily for two weeks followed by 200 mg twice daily or placebo, and lamivudine, 150 mg twice daily. Other antiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) was one NRTI in 1309 subjects (58%), two or more NRTIs in 771 (34%), and PIs and NRTIs in 169 (8%). The subjects (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV-1 infection, with a median baseline CD4+ cell count of 96 cells/mm³ and a baseline HIV-1 RNA of 4.58 log10 copies per mL (38,291 copies per mL). Prior to entering the trial, 45% had previously experienced an AIDS-defining clinical event. Eighty-nine percent had antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint trial. Prior to unblinding the trial, the primary endpoint was changed to proportion of subjects with HIV-1 RNA less than 50 copies per mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 6.

Table 6 : BI 1090 Outcomes Through 48 Weeks

The change from baseline in CD4+ cell count through one year of therapy was significantly greater for the VIRAMUNE group compared to the placebo group for the overall trial population (64 cells/mm³ versus 22 cells/mm³ , respectively), as well as for subjects who entered the trial as treatment-naïve or having received only ZDV (85 cells/mm³ versus 25 cells/mm³ , respectively).

At two years into the trial, 16% of subjects on VIRAMUNE had experienced class C CDC events as compared to 21% of subjects on the control arm.

Trial BI 1046 (INCAS) was a double-blind, placebo-controlled, randomized, three-arm trial with 151 HIV-1 infected subjects with CD4+ cell counts of 200-600 cells/mm³ at baseline. BI 1046 compared treatment with VIRAMUNE+zidovudine+didanosine to VIRAMUNE+zidovudine and zidovudine+didanosine. Treatment doses were VIRAMUNE at 200 mg daily for two weeks followed by 200 mg twice daily or placebo, zidovudine at 200 mg three times daily, and didanosine at 125 or 200 mg twice daily (depending on body weight). The subjects had mean baseline HIV-1 RNA of 4.41 log10 copies/mL (25,704 copies per mL) and mean baseline CD4+ cell count of 376 cells/mm³ . The primary endpoint was the proportion of subjects with HIV-1 RNA less than 400 copies per mL and not previously failed at 48 weeks. The virologic responder rates at 48 weeks were 45% for subjects treated with VIRAMUNE+zidovudine+didanosine, 19% for subjects treated with zidovudine+didanosine, and 0% for subjects treated with VIRAMUNE+zidovudine.

CD4+ cell counts in the VIRAMUNE+ZDV+ddI group increased above baseline by a mean of 139 cells/mm³ at one year, significantly greater than the increase of 87 cells/mm³ in the ZDV+ddI subjects. The VIRAMUNE+ZDV group mean decreased by 6 cells/mm³ below baseline.

Pediatric Patients

The pediatric safety and efficacy of VIRAMUNE was examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received VIRAMUNE oral suspension for 48 weeks. Subjects were divided into 4 age groups (3 months to less than 2 years, 2 to less than 7 years, 7 to less than 12 years, and 12 to less than or equal to 16 years) and randomized to receive one of two VIRAMUNE doses, determined by 2 different dosing methods [body surface area (150 mg/m²) and weight-based dosing (4 or 7 mg per kg)] in combination with zidovudine and lamivudine [see ADVERSE REACTIONS, Use In Specific Populations, and CLINICAL PHARMACOLOGY]. The total daily dose of VIRAMUNE did not exceed 400 mg in either regimen. There were 66 subjects in the body surface area (BSA) dosing group and 57 subjects in the weight-based (BW) dosing group.

Baseline demographics included: 49% male; 81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Subjects had a median baseline HIV-1 RNA of 5.45 log10 copies per mL and a median baseline CD4+ cell count of 527 cells/mm³ (range 37-2279). One hundred and five (85%) completed the 48-week period while 18 (15%) discontinued prematurely. Of the subjects who discontinued prematurely, 9 (7%) discontinued due to adverse reactions and 3 (2%) discontinued due to virologic failure. Overall the proportion of subjects who achieved and maintained an HIV-1 RNA less than 400 copies per mL at 48 weeks was 47% (58/123).

Avoid drinking alcohol. It may increase your risk of liver damage.

Taking this medication will not prevent you from passing HIV to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Clinical Trial Experience In Adult Patients

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most serious adverse reactions associated with VIRAMUNE are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received VIRAMUNE and 1% of subjects in control groups. Female gender and higher CD4+ cell counts (greater than 250 cells/mm³ in women and greater than 400 cells/mm³ in men) place patients at increased risk of these events [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Asymptomatic transaminase elevations (AST or ALT greater than 5X ULN) were observed in 6% (range 0% to 9%) of subjects who received VIRAMUNE and 6% of subjects in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with VIRAMUNE are associated with a greater risk of later symptomatic events (6 weeks or more after starting VIRAMUNE) and asymptomatic increases in AST or ALT.

Liver enzyme abnormalities (AST, ALT, GGT) were observed more frequently in subjects receiving VIRAMUNE than in controls (see Table 3).

The most common clinical toxicity of VIRAMUNE is rash, which can be severe or life-threatening [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. In controlled clinical trials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes were reported in 13% of subjects receiving VIRAMUNE compared to 6% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 2% of VIRAMUNE recipients compared to less than 1% of subjects receiving placebo. Women tend to be at higher risk for development of VIRAMUNE-associated rash [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Treatment-related, adverse experiences of moderate or severe intensity observed in greater than 2% of subjects receiving VIRAMUNE in placebo-controlled trials are shown in Table 2.

Table 2 : Percentage of Subjects with Moderate or Severe Drug-Related Events in Adult Placebo-Controlled Trials

Liver enzyme test abnormalities (AST, ALT) were observed more frequently in subjects receiving VIRAMUNE than in controls (Table 3). Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue VIRAMUNE therapy in the absence of elevations in other liver enzyme tests. Other laboratory abnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) were observed with similar frequencies in clinical trials comparing VIRAMUNE and control regimens (see Table 3).

Table 3 : Percentage of Adult Subjects with Laboratory Abnormalities

Clinical Trial Experience In Pediatric Patients

Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of VIRAMUNE (n=305) in which pediatric subjects received combination treatment with VIRAMUNE. In this trial two subjects were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180), an open-label trial of VIRAMUNE (n=37) in which subjects were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up in 29 of these subjects in trial BI 1100.892). The most frequently reported adverse events related to VIRAMUNE in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and VIRAMUNE. Cases of allergic reaction, including one case of anaphylaxis, were also reported.

The safety of VIRAMUNE was also examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-na�ve subjects between 3 months and 16 years of age received combination treatment with VIRAMUNE oral suspension, lamivudine and zidovudine for 48 weeks [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. Rash (all causality) was reported in 21% of the subjects, 4 (3%) of whom discontinued drug due to rash. All 4 subjects experienced the rash early in the course of therapy (less than 4 weeks) and resolved upon nevirapine discontinuation. Other clinically important adverse events (all causality) include neutropenia (9%), anemia (7%), and hepatotoxicity (2%) [see Use In Specific Populations and Clinical Studies].

Safety information on use of VIRAMUNE in combination therapy in pediatric subjects 2 weeks to less than 3 months of age was assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. No unexpected safety findings were observed although granulocytopenia was reported more frequently in this age group compared to the older pediatric age groups and adults.

Post-Marketing Experience

In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of VIRAMUNE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: fever, somnolence, drug withdrawal [see DRUG INTERACTIONS], redistribution/accumulation of body fat [see WARNINGS AND PRECAUTIONS]

Gastrointestinal: vomiting

Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure

Hematology: anemia, eosinophilia, neutropenia

Investigations: decreased serum phosphorus

Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions

Neurologic: paraesthesia

Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities, drug reaction with eosinophilia and systemic symptoms (DRESS) [see WARNINGS AND PRECAUTIONS] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.

In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.

Read the entire FDA prescribing information for Viramune (Nevirapine)

• Store nevirapine at 59°F to 86°F (15°C to 30°C).
• Throw away nevirapine that is no longer needed or out-of-date.
• Keep nevirapine and all medicines out of the reach of children.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

If you have not taken nevirapine for 7 days in a row, call your doctor before you start taking the medicine again. You may need to start with a lower dose.

Avoid drinking alcohol. It may increase your risk of liver damage.

Taking this medication will not prevent you from passing HIV to other people. Do not have unprotected sex or share razors or toothbrushes. Talk with your doctor about safe ways to prevent HIV transmission during sex. Sharing drug or medicine needles is never safe, even for a healthy person.

Treatment of HIV Infection

Treatment of HIV-1 infection in adults, adolescents, and pediatric patients;1 234 usually used in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors (NRTIs).1 234

Because of increased risk of potentially life-threatening hepatotoxicity, do not initiate in females (including postpubertal girls and adolescents) with pretreatment CD4+ T-cell counts >250/mm3 or in males (including adolescent boys) with CD4+ T-cell counts >400/mm3 unless potential benefits clearly outweigh risks.1 96 200 201 234 (See Hepatic Effects under Cautions.)

For initial treatment in antiretroviral-naive adults or adolescents, experts state nevirapine not recommended since it is associated with more serious toxicities than other HIV NNRTIs and many other preferable options are available.200 Experts state the drug can be continued in patients already receiving and tolerating a suppressive regimen that includes nevirapine.200

For initial treatment in antiretroviral-naive pediatric patients, experts state that nevirapine and 2 NRTIs is an alternative (not preferred) regimen in those ≥15 days of age.201

Prevention of Perinatal HIV Transmission

Prophylaxis in neonates born to HIV-infected women†;202 used as part of a multiple-drug neonatal prophylaxis regimen.202

Multiple-drug antiretroviral regimens considered the standard of care in the US for treatment of HIV infection in pregnant women and for prevention of perinatal HIV transmission.202 In addition, to decrease risk of perinatal HIV transmission, pregnant HIV-infected women with plasma HIV-1 RNA levels >1000 copies/mL (or unknown HIV-1 RNA levels) near delivery should receive an intrapartum IV zidovudine prophylaxis regimen and all neonates born to HIV-infected women (HIV-exposed neonates) should receive an oral or IV zidovudine prophylaxis regimen.202

In certain situations (e.g., infant born to a woman who did not receive antepartum or intrapartum antiretrovirals or received only intrapartum antiretrovirals), the neonate should receive a 3-dose nevirapine prophylaxis regimen given during the first week of life in addition to the usual 6-week neonatal zidovudine prophylaxis regimen.202

Maternal and neonatal regimens recommended for prevention of perinatal HIV transmission in the US may differ from those used in other countries.202

Decisions to include additional antiretrovirals for prophylaxis with the recommended intrapartum and neonatal zidovudine prophylaxis regimens should be made in consultation with a pediatric HIV specialist.202

Clinicians can consult National Perinatal HIV Hotline at 888-448-8765 for information regarding antiretroviral treatment of pregnant HIV-infected women and their infants and prevention of perinatal HIV transmission.202

Contraindications

• Moderate or severe hepatic impairment (Child-Pugh class B or C).1 234

• Do not use for postexposure prophylaxis of HIV following occupational or nonoccupational exposure to the virus.1 234 199 (See Hepatic Effects under Cautions.)

Warnings/Precautions

Sensitivity Reactions

Severe, life-threatening skin reactions (including some fatalities) reported.1 234 Anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous eruptions, ulcerative stomatitis, urticaria, drug reaction with eosinophilia and systemic symptoms (DRESS), and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction (including hepatic failure) reported.1 234

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.1 234

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.1 234 If mild to moderate rash without constitutional symptoms occurs during initial 14 days, dosage should not be increased until rash resolves.1 234 Do not continue initial low dosage beyond 28 days; discontinue nevirapine and select alternative therapy.1 234

Monitor closely if isolated rash of any severity occurs.1 234

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.1 234

Women appear to be at higher risk of developing rash than men.1 234

Prednisone not recommended for prevention of nevirapine-associated rash.1 234 (See Specific Drugs under Interactions.)

Do not restart nevirapine following hypersensitivity reaction, severe rash, or rash in conjunction with increased serum transaminase concentrations or other systemic symptoms.1 234

Patient Monitoring

Serious adverse effects include hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions reported.1

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;1 234 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.1 234

Hepatic Effects

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.1 234 Hepatic events can occur at any time during therapy.1 234 Risk of hepatic events (regardless of severity) greatest during the first 6 weeks of therapy; substantial risk continues through 18 weeks of therapy.1 234

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.1 Rash observed in 50% of those with symptomatic hepatic adverse events.1 234 Fever and flu-like symptoms accompany some of these hepatic events.1 234 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, and/or eosinophilia.1 86 234

Patients with higher CD4 counts and women are at increased risk of hepatic events.1 234 Women with CD4 counts >250 cells/mm3, including pregnant women receiving long-term treatment for HIV infection, are at considerably higher risk of these events.1 234 Increased liver enzymes and/or HBV or HCV infection associated with increased risk.1 234

Serious hepatotoxicity reported in individuals not infected with HIV who received nevirapine as part of a multiple-drug regimen for postexposure prophylaxis following occupational or nonoccupational exposure to HIV.1 86 87 Do not use in HIV postexposure prophylaxis regimens following occupational or nonoccupational exposure to the virus.1 199 234

Intensive clinical and laboratory monitoring essential.1 234 (See Patient Monitoring under Cautions.)

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 diagnosis is possible.1 234

Hepatic injury has progressed despite discontinuation of nevirapine in some patients.1 234

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.1 86 234 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.1 86 234

Interactions

Concomitant use with certain drugs not recommended (e.g., St. John’s wort).1 234 (See Specific Drugs under Interactions.)

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, breast enlargement, and general cushingoid appearance.1 234 Mechanisms and long-term consequences of fat redistribution unknown; causal relationship not established.1 234

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.1 101 234

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) reported in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1 234

Specific Populations

Category B.1 234

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202 234 Pregnancy registry data to date do not indicate an increased risk for congenital abnormalities among infants born to women who received nevirapine during pregnancy compared with general population.1 234

Manufacturer states use during pregnancy only if potential benefits justify risks to the fetus.1

Experts state that nevirapine is an alternative (not preferred) NNRTI for use in multiple-drug antiretroviral regimens in antiretroviral-naive pregnant women with baseline CD4+ T-cell counts <250/mm3.202

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.1 96 200 If initiated in such women, caution recommended.202 (See Hepatic Effects under Cautions.)

May be continued if tolerated in women who become pregnant, regardless of CD4+ T-cell count.202

Distributed into milk.1 58 65 234

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202 234

Immediate-release tablets and oral suspension: Safety, pharmacokinetics, and efficacy evaluated in children 3 months to 18 years of age.1 Safety and pharmacokinetics evaluated in children 15 days to <3 months of age.1

Extended-release nevirapine: Can be used in children ≥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.234 Not recommend in those 3 to <6 years of age because of insufficient pharmacokinetic data in this age group;234 not recommended in those <3 years of age because of inability to swallow tablets.234

For prevention of perinatal HIV transmission†, a 3-dose regimen of immediate-release nevirapine has been recommended for neonates† born to HIV-infected women who received no antiretroviral therapy prior to and/or during labor.202 (See Prevention of Perinatal HIV Transmission under Uses.)

Adverse effects reported in children generally similar to those reported in adults; granulocytopenia reported more frequently in children than adults.1 Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome reported rarely.1 Allergic reactions, including anaphylaxis, also reported.1

Insufficient experience in those ≥65 years of age to determine whether they respond differently than younger adults.1 234

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 234

Carefully monitor those with hepatic impairment (e.g., those with hepatic fibrosis or cirrhosis) for toxicity.1

Contraindicated in patients with moderate or severe hepatic impairment (Child-Pugh class B or C).1 234

Extended-release tablets not studied in patients with hepatic impairment.234

Modification of usual dosage of immediate-release nevirapine dosage forms not necessary in patients with Clcr ≥20 mL/minute not requiring dialysis;1 234 additional dose of immediate-release nevirapine necessary following dialysis.1 234 Pharmacokinetics not evaluated in those with Clcr <20 mL/minute.1 234 (See Renal Impairment under Dosage and Administration.)

Extended-release tablets not studied in patients with renal impairment.234

Common Adverse Effects

Rash, nausea, headache, fatigue, abnormal liver function test results.1 234 Adverse effects reported with extended-release tablets similar to those reported with immediate-release tablets.234

• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 234 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 234

• Importance of using in conjunction with other antiretrovirals not for monotherapy.1 234

• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 234

• Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1 234 200

• Importance of reading patient information provided by the manufacturer.1 234

• If a dose is missed, the next dose should be taken 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 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

• Need for intensive clinical and laboratory monitoring, including liver enzymes, during first 18 weeks of therapy (especially first 6 weeks) and 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

• Redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1 234

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products.1 234

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 234 Advise HIV-infected women not to breast-feed.1 234

• Importance of advising patients of other important precautionary information.1 234 (See Cautions.)

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trial Experience in Adult Patients

The most serious adverse reactions associated with Nevirapine are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see Boxed Warning and Warnings and Precautions ( 5.1, 5.2)] .

Hepatic Reaction

In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received Nevirapine and 1% of subjects in control groups. Female gender and higher CD4 + cell counts (greater than 250 cells/mm 3 in women and greater than 400 cells/mm 3 in men) place patients at increased risk of these events [see Boxed Warning and Warnings and Precautions ( 5.1)] .

Asymptomatic transaminase elevations (AST or ALT greater than 5X ULN) were observed in 6% (range 0% to 9%) of subjects who received Nevirapine and 6% of subjects in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with Nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting Nevirapine) and asymptomatic increases in AST or ALT.

Liver enzyme abnormalities (AST, ALT, GGT) were observed more frequently in subjects receiving Nevirapine than in controls (see Table 3).

Skin Reaction

The most common clinical toxicity of Nevirapine is rash, which can be severe or life-threatening [see Boxed Warning and Warnings and Precautions ( 5.2)] . Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. In controlled clinical trials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes were reported in 13% of subjects receiving Nevirapine compared to 6% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 2% of Nevirapine recipients compared to less than 1% of subjects receiving placebo. Women tend to be at higher risk for development of Nevirapine-associated rash [see Boxed Warning and Warnings and Precautions ( 5.2)] .

Treatment-related, adverse experiences of moderate or severe intensity observed in greater than 2% of subjects receiving Nevirapine in placebo-controlled trials are shown in Table 2.

Table 2 Percentage of Subjects with Moderate or Severe Drug-Related Events in Adult Placebo-Controlled Trials

1Background therapy included 3TC for all subjects and combinations of NRTIs and PIs. Subjects had CD4 + cell counts less than 200 cells/mm 3

2Background therapy included ZDV and ZDV+ddI; Nevirapine monotherapy was administered in some subjects. Subjects had CD4 + cell count greater than or equal to 200 cells/mm 3.

Laboratory Abnormalities

Liver enzyme test abnormalities (AST, ALT) were observed more frequently in subjects receiving Nevirapine than in controls (Table 3). Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue Nevirapine therapy in the absence of elevations in other liver enzyme tests. Other laboratory abnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) were observed with similar frequencies in clinical trials comparing Nevirapine and control regimens (see Table 3).

Table 3 Percentage of Adult Subjects with Laboratory Abnormalities

1Background therapy included 3TC for all subjects and combinations of NRTIs and PIs. Subjects had CD4 + cell counts less than 200 cells/mm 3.

2Background therapy included ZDV and ZDV+ddI; Nevirapine monotherapy was administered in some subjects. Subjects had CD4 + cell count greater than or equal to 200 cells/mm 3.

Clinical Trial Experience in Pediatric Patients

Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of Nevirapine (n=305) in which pediatric subjects received combination treatment with Nevirapine. In this trial two subjects were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180), an open-label trial of Nevirapine (n=37) in which subjects were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up in 29 of these subjects in trial BI 1100.892). The most frequently reported adverse events related to Nevirapine in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and Nevirapine. Cases of allergic reaction, including one case of anaphylaxis, were also reported.

The safety of Nevirapine was also examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received combination treatment with lamivudine and zidovudine for 48 weeks [see Use In Specific Populations ( 8.4) and Clinical Pharmacology ( 12.3)] . Rash (all causality) was reported in 21% of the subjects, 4 (3%) of whom    discontinued drug due to rash. All 4 subjects experienced the rash early in the course of therapy (less than 4 weeks) and resolved upon Nevirapine discontinuation. Other clinically important adverse events (all causality) include neutropenia (9%), anemia (7%), and hepatotoxicity (2%) [see Use in Specific Populations ( 8.4) and Clinical Studies ( 14.2)] .

Safety information on use of Nevirapine in combination therapy in pediatric subjects 2 weeks to less than 3 months of age was assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. No unexpected safety findings were observed although granulocytopenia was reported more frequently in this age group compared to the older pediatric age groups and adults.

Post-Marketing Experience

In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of Nevirapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: fever, somnolence, drug withdrawal [see Drug Interactions ( 7)] , redistribution/accumulation of body fat [see Warnings and Precautions ( 5.6)]

Gastrointestinal: vomiting

Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure

Hematology: anemia, eosinophilia, neutropenia

Investigations: decreased serum phosphorus

Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions

Neurologic: paraesthesia

Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities, drug reaction with eosinophilia and systemic symptoms (DRESS) [see Warnings and Precautions ( 5.1)] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.

In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.

Nevirapine Tablets USP 200 mg is the brand name for Nevirapine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine is structurally a member of the dipyridodiazepinone chemical class of compounds. 
 The chemical name of Nevirapine is 11-cyclopropyl-5, 11-dihydro-4-methyl-6H-dipyrido [3,2-b:2',3'-e][1,4] diazepin-6-one. Nevirapine is a white to off-white crystalline powder with the molecular weight of 266.30 and the molecular formula C 15H 14N 4O. Nevirapine has the following structural formula: 

Nevirapine Tablets USP 200 mg are for oral administration. Each tablet contains 200 mg of Nevirapine anhydrous and the inactive ingredients microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide, magnesium stearate, povidone, and Sodium starch glycolate.

Adult Patients

Trial BI 1090 was a placebo-controlled, double-blind, randomized trial in 2249 HIV-1 infected subjects with less than 200 CD4 +cells/mm 3 at screening. Initiated in 1995, BI 1090 compared treatment with Nevirapine + lamivudine + background therapy versus lamivudine + background therapy in NNRTI-naïve subjects. Treatment doses were Nevirapine, 200 mg daily for two weeks followed by 200 mg twice daily or placebo, and lamivudine, 150 mg twice daily. Other antiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) was one NRTI in 1309 subjects (58%), two or more NRTIs in 771 (34%), and PIs and NRTIs in 169 (8%). The subjects (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV-1 infection, with a median baseline CD4 + cell count of 96 cells/mm 3 and a baseline HIV-1 RNA of 4.58 log10 copies per mL (38,291 copies per mL). Prior to entering the trial, 45% had previously experienced an AIDS-defining clinical event. Eighty-nine percent had antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint trial.  Prior to unblinding the trial, the primary endpoint was changed to proportion of subjects with HIV-1 RNA less than 50 copies per mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 6.

Table 6 BI 1090 Outcomes Through 48 Weeks

1including change to open-label Nevirapine

2includes withdrawal of consent, lost to follow-up, non-compliance with protocol, other administrative reasons

The change from baseline in CD4 + cell count through one year of therapy was significantly greater for the Nevirapine group compared to the placebo group for the overall trial population (64 cells/mm 3 versus 22 cells/mm 3, respectively), as well as for subjects who entered the trial as treatment-naïve or having received only ZDV (85 cells/mm 3 versus 25 cells/mm 3, respectively).

At two years into the trial, 16% of subjects on Nevirapine had experienced class C CDC events as compared to 21% of subjects on the control arm.

Trial BI 1046 (INCAS) was a double-blind, placebo-controlled, randomized, three-arm trial with 151 HIV-1 infected subjects with CD4 + cell counts of 200-600 cells/mm 3 at baseline. BI 1046 compared treatment with Nevirapine +zidovudine+didanosine to Nevirapine +zidovudine and zidovudine+didanosine. Treatment doses were Nevirapine at 200 mg daily for two weeks followed by 200 mg twice daily or placebo, zidovudine at 200 mg three times daily, and didanosine at 125 or 200 mg twice daily (depending on body weight). The subjects had mean baseline HIV-1 RNA of 4.41 log10 copies/mL (25,704 copies per mL) and mean baseline CD4 + cell count of 376 cells/mm 3. The primary endpoint was the proportion of subjects with HIV-1 RNA less than 400 copies per mL and not previously failed at 48 weeks. The virologic responder rates at 48 weeks were 45% for subjects treated with Nevirapine +zidovudine+didanosine, 19% for subjects treated with zidovudine+didanosine, and 0% for subjects treated with Nevirapine +zidovudine.

CD4+ cell counts in the Nevirapine +ZDV+ddI group increased above baseline by a mean of 139 cells/mm 3 at one year, significantly greater than the increase of 87 cells/mm 3 in the ZDV+ddI subjects. The Nevirapine +ZDV group mean decreased by 6 cells/mm 3 below baseline.

Pediatric Patients

The pediatric safety and efficacy of Nevirapine was examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received for 48 weeks. Subjects were divided into 4 age groups (3 months to less than 2 years, 2 to less than 7 years, 7 to less than 12 years, and 12 to less than or equal to 16 years) and randomized to receive one of two Nevirapine doses, determined by 2 different dosing methods [body surface area (150 mg/m 2) and weight-based dosing (4 or 7 mg per kg)] in combination with zidovudine and lamivudine [see Adverse Reactions ( 6.2), Use in Specific Populations ( 8.4), and Clinical Pharmacology ( 12.3)] . The total daily dose of Nevirapine did not exceed 400 mg in either regimen. There were 66 subjects in the body surface area (BSA) dosing group and 57 subjects in the weight-based (BW) dosing group.

Baseline demographics included: 49% male; 81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Subjects had a median baseline HIV-1 RNA of 5.45 log10 copies per mL and a median baseline CD4 + cell count of 527 cells/mm 3 (range 37 to 2279). One hundred and five (85%) completed the 48-week period while 18 (15%) discontinued prematurely. Of the subjects who discontinued prematurely, 9 (7%) discontinued due to adverse reactions and 3 (2%) discontinued due to virologic failure. Overall the proportion of subjects who achieved and maintained an HIV-1 RNA less than 400 copies per mL at 48 weeks was 47% (58/123).

Applies to nevirapine: oral suspension, oral tablet, oral tablet extended release

General

Serious adverse effects can occur with nevirapine. The most serious side effects have included hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction.

The first 18 weeks of therapy with nevirapine are a critical period during which it is essential that patients be monitored intensively to detect potentially life-threatening hepatotoxicity or skin reactions. Nevirapine should not be restarted following clinical hepatitis, or transaminase elevations combined with rash or other systemic symptoms, or following severe skin rash or hypersensitivity reactions.

Side effects reported during postmarketing experience were associated with use of the immediate-release formulation.[Ref]

Dermatologic

Very common (10% or more): Rash (including maculopapular erythematous cutaneous eruptions, with or without pruritus)
Common (1% to 10%): Moderate or severe rash (including rash, maculopapular rash, erythema nodosum, erythematous rash, papular rash, skin reaction, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms; up to 7%)
Frequency not reported: Severe and life-threatening skin reactions (including fatal cases), toxic epidermal necrolysis, allergic dermatitis[Ref]

The most common clinical toxicity was rash. Rashes were usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the face, trunk, and extremities. Rash has occurred most often during the first 6 weeks of therapy. Utilization of the 14-day lead-in period with immediate-release nevirapine has been shown to reduce the frequency of rash.

During clinical trials, Grade 1 and 2 rashes were reported in 13% of patients taking immediate-release nevirapine during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 2% of immediate-release nevirapine-treated patients.

During one study, side effects of at least moderate intensity included rash (including rash, maculopapular rash, erythema nodosum, erythematous rash, papular rash, skin reaction, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms) in 4% of patients using the immediate-release formulation and 5% of patients using the extended-release formulation.

Severe and life-threatening skin reactions, including fatal cases, have been reported. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction.

Women tended to be at greater risk of nevirapine-associated rash.

Rash was reported in about half of patients with symptomatic hepatic side effects.[Ref]

Hepatic

Very common (10% or more): Elevated SGPT/ALT (up to 14%), symptomatic hepatic events (regardless of severity: up to 11%)
Common (1% to 10%): Elevated SGOT/AST (up to 9%), asymptomatic transaminase elevations (AST or ALT greater than 5 times upper limit of normal [ULN]: up to 9%), clinical hepatitis (including hepatitis, hepatotoxicity, acute hepatitis, liver disorder, toxic hepatitis, hepatic failure, jaundice; up to 4%), elevated bilirubin (greater than 2.5 mg/dL: 2%), asymptomatic elevations in gamma-glutamyltransferase
Frequency not reported: Liver enzyme abnormalities (AST, ALT), elevated alkaline phosphatase, severe and life-threatening hepatotoxicity (including fatal cases), progression to hepatic failure (with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia)
Postmarketing reports: Jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure[Ref]

Risk of symptomatic hepatic events (regardless of severity) was greatest in the first 6 weeks and continued to be greater in the nevirapine groups compared to controls through 18 weeks of therapy.

Female gender and higher CD4+ cell counts at the start of therapy place patients at increased risk of hepatic events (including potentially fatal events). Women with CD4+ cell counts greater than 250 cells/mm3 (including pregnant women using nevirapine with other antiretrovirals to treat HIV-1 infection) are at greatest risk. However, nevirapine-associated hepatotoxicity can develop in both genders, all CD4+ cell counts, and at any time during therapy. Coinfection with hepatitis B or C and/or increased transaminases at the start of nevirapine therapy are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.

Rash was reported in about half of patients with symptomatic hepatic side effects. Fever and influenza-like symptoms accompanied some hepatic events.

Following the lead-in period, the incidence of any hepatic event was 9% with the immediate-release formulation and 6% with the extended-release formulation. Symptomatic hepatic events (anorexia, jaundice, vomiting) were reported in 3% and 2% of patients using the immediate-release and extended-release formulations, respectively. The incidence of Grade 3 or 4 ALT/AST elevation was 8% with each formulation.

During one study, side effects of at least moderate intensity included clinical hepatitis (including hepatitis, hepatotoxicity, acute hepatitis, liver disorder, toxic hepatitis, hepatic failure, jaundice) in 4% of patients using the immediate-release formulation and 2% of patients using the extended-release formulation.

In controlled studies, liver enzyme abnormalities (AST, ALT) occurred more frequently in patients receiving nevirapine.

Elevated SGPT/ALT (greater than 250 units/L: up to 14%) has been reported with the immediate-release formulation. Grade 2 elevated SGPT/ALT (2.6 to 5 times ULN) was reported in 13% of patients using the immediate-release formulation and 10% of patients using the extended-release formulation. Grade 3 elevated SGPT/ALT (5.1 to 10 times ULN) was reported in 3% of patients using the immediate-release formulation and 4% of patients using the extended-release formulation. Grade 4 elevated SGPT/ALT (greater than 10 times ULN) was reported in 4% of patients using the immediate-release formulation and 2% of patients using the extended-release formulation.

Elevated SGOT/AST (greater than 250 units/L: up to 8%) has been reported with the immediate-release formulation. Grade 2 elevated SGOT/AST (2.6 to 5 times ULN) was reported in 9% of patients using the immediate-release formulation and 7% of patients using the extended-release formulation. Grade 3 elevated SGOT/AST (5.1 to 10 times ULN) was reported in 2% of patients using the immediate-release formulation and 3% of patients using the extended-release formulation. Grade 4 elevated SGOT/AST (greater than 10 times ULN) was reported in 2% of patients using the immediate-release formulation and 2% of patients using the extended-release formulation.

Severe, life-threatening, and in some cases fatal, hepatotoxicity (including fulminant and cholestatic hepatitis, hepatic necrosis, and hepatic failure) has been reported. In some cases, patients presented with nonspecific prodromal signs or symptoms of hepatitis (including fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal transaminase levels). Some events (particularly those with rash and other symptoms) progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia. Patients without HIV using nevirapine for postexposure prophylaxis have reported serious hepatotoxicity, including hepatic failure.[Ref]

Hematologic

Grade 2 decreased neutrophils (750 to 999/mm3) was reported in 7% of patients using the immediate-release formulation and 4% of patients using the extended-release formulation. Grade 3 decreased neutrophils (500 to 749/mm3) was reported in 2% of patients using the immediate-release formulation and 2% of patients using the extended-release formulation. Grade 4 decreased neutrophils (less than 500/mm3) was reported in 1% of patients using the immediate-release formulation and 1% of patients using the extended-release formulation.[Ref]

Very common (10% or more): Decreased neutrophils (less than 750/mm3: up to 13%)
Common (1% to 10%): Decreased hemoglobin (less than 8 g/dL: up to 3%), granulocytopenia (moderate or severe intensity: up to 2%)
Uncommon (0.1% to 1%): Decreased platelets (less than 50,000/mm3: up to 1%)
Postmarketing reports: Anemia, neutropenia, eosinophilia[Ref]

Hypersensitivity

Postmarketing reports: Allergic reactions (including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis, urticaria), hypersensitivity syndrome, hypersensitivity reactions with rash (associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities, drug reaction with eosinophilia and systemic symptoms plus hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction)[Ref]

Metabolic

Very common (10% or more): Decreased phosphate (up to 38%), elevated cholesterol (up to 19%), elevated LDL (up to 15%)
Frequency not reported: Hyperlactatemia, unspecified metabolic alterations, elevated total cholesterol, elevated triglycerides, elevated alkaline phosphatase, acute porphyria
Postmarketing reports: Redistribution/accumulation of body fat (including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, "cushingoid appearance"), decreased serum phosphorus[Ref]

Grade 2 decreased phosphate was reported in 38% of patients using the immediate-release formulation and 33% of patients using the extended-release formulation. Grade 3 decreased phosphate was reported in 6% of patients using the immediate-release formulation and 7% of patients using the extended-release formulation. Grade 4 decreased phosphate was reported in less than 1% of patients using the immediate-release formulation.

Grade 2 elevated cholesterol (240 to 300 mg/dL) was reported in 18% of patients using the immediate-release formulation and 19% of patients using the extended-release formulation. Grade 3 elevated cholesterol (greater than 300 mg/dL) was reported in 4% of patients using the immediate-release formulation and 3% of patients using the extended-release formulation.

Grade 2 elevated LDL (160 to 190 mg/dL) was reported in 15% of patients using the immediate-release formulation and 15% of patients using the extended-release formulation. Grade 3 elevated LDL (greater than 190 mg/dL) was reported in 5% of patients using the immediate-release formulation and 5% of patients using the extended-release formulation.[Ref]

Gastrointestinal

Common (1% to 10%): Nausea (moderate or severe intensity: up to 9%), elevated amylase (up to 5%), diarrhea (moderate or severe intensity: up to 4%), abdominal pain (moderate or severe intensity: up to 3%)
Frequency not reported: Anorexia
Postmarketing reports: Vomiting[Ref]

During one study, side effects of at least moderate intensity included diarrhea (immediate-release: 4%; extended-release: 4%), abdominal pain (immediate-release: 2%; extended-release: 3%), and nausea (immediate-release: 2%; extended-release: 1%).

Grade 2 elevated amylase (1.6 to 2 times ULN) was reported in 4% of patients using the immediate-release formulation and 5% of patients using the extended-release formulation. Grade 3 elevated amylase (2.1 to 5 times ULN) was reported in 4% of patients using the immediate-release formulation and 2% of patients using the extended-release formulation. Grade 4 elevated amylase (greater than 5 times ULN) was reported in less than 1% of patients using the extended-release formulation.[Ref]

Other

During one study, side effects of at least moderate intensity included fatigue (immediate-release: 2%; extended-release: 2%) and pyrexia (immediate-release: 2%; extended-release: 1%).

Fever and influenza-like symptoms accompanied some hepatic events.[Ref]

Common (1% to 10%): Fatigue (moderate or severe intensity: up to 5%), pyrexia (moderate or severe intensity: up to 2%)
Frequency not reported: Fever, asthenia, influenza-like symptoms
Postmarketing reports: Fever, drug withdrawal (as a result of drug interactions)[Ref]

Nervous system

Common (1% to 10%): Headache (moderate or severe intensity: up to 4%)
Frequency not reported: Neuropathy
Postmarketing reports: Somnolence, paresthesia[Ref]

During one study, side effects of at least moderate intensity included headache in 4% of patients using the immediate-release formulation and 4% of patients using the extended-release formulation.[Ref]

Musculoskeletal

During one study, side effects of at least moderate intensity included arthralgia in 2% of patients using the immediate-release formulation and 2% of patients using the extended-release formulation.[Ref]

Common (1% to 10%): Arthralgia (moderate or severe intensity: 2%)
Uncommon (0.1% to 1%): Myalgia (moderate or severe intensity: up to 1%)
Frequency not reported: Arthromyalgia, arthritis
Postmarketing reports: Rhabdomyolysis associated with skin and/or liver reactions, arthralgia[Ref]

Immunologic

Frequency not reported: Immune reconstitution syndrome, autoimmune disorders in the setting of immune reconstitution (e.g., Graves' disease, polymyositis, Guillain-Barre syndrome)

Respiratory

Rare (less than 0.1%): Dry cough, dyspnea, interstitial pulmonary infiltration[Ref]

Psychiatric

Frequency not reported: Depression[Ref]

Some side effects of nevirapine may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

(Not approved by FDA)

DHHS Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission recommendations for infants born to HIV-infected women who have not received antepartum antiretroviral therapy:
Immediate-release formulation:
Birth weight 1.5 to 2 kg: 8 mg/dose orally for 3 doses
Birth weight greater than 2 kg: 12 mg/dose orally for 3 doses

The 3 doses are recommended in the first week of life:
First dose: Within 48 hours of birth
Second dose: 48 hours after the first dose
Third dose: 96 hours after the second dose

Triple dose nevirapine may be given to the neonate in addition to 6 weeks of zidovudine therapy. The neonatal regimen (oral zidovudine plus nevirapine) should be started as soon as possible after birth.

Nevirapine use as part of occupational and nonoccupational postexposure prophylaxis regimens is contraindicated.

The most serious side effects associated with nevirapine are hepatitis/hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be associated with signs of hypersensitivity. Transaminases should be checked at once if signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction develop or if a rash develops in the first 18 weeks of therapy. The diagnosis of hepatotoxicity should be considered, even if transaminases are initially normal or alternative diagnoses are possible. Nevirapine should not be restarted following clinical hepatitis, or transaminase elevations combined with rash or other systemic symptoms, or following severe skin rash or hypersensitivity reactions.

Due to the risk of severe hepatotoxicity, treatment should not be initiated in women with CD4+ cell counts greater than 250 cells/mm3 or men with CD4+ cell counts greater than 400 cells/mm3 unless benefit outweighs risk.

Severe, life-threatening, and in some cases fatal, hepatotoxicity has been reported in patients treated with nevirapine. If signs or symptoms of hepatitis develop, nevirapine should be discontinued and medical evaluation (which should include liver enzyme tests) should be sought immediately. Nevirapine should be permanently discontinued if clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms develop. Hepatic injury may progress despite discontinuation of treatment.

Patients with hepatic impairment, such as hepatic fibrosis or cirrhosis, should be monitored carefully for nevirapine-induced toxicity as elevated nevirapine trough levels have been reported in some of these patients. Patients with worsening hepatic function and ascites may be at risk of nevirapine accumulation.

Severe and life-threatening skin reactions, including fatal cases, have occurred. Patients who develop signs or symptoms of severe skin reactions or hypersensitivity reactions must permanently discontinue nevirapine and seek medical evaluation immediately. All patients who develop a rash within the first 18 weeks of therapy should have their transaminase levels checked at once. Patients with rash-associated transaminase elevations should discontinue nevirapine permanently.

The 14-day lead-in period with immediate-release nevirapine has been shown to lessen the frequency of rash and must be strictly followed. Patients must be monitored closely if isolated rash of any severity develops. Delay in discontinuing nevirapine after the onset of rash may result in a more serious reaction.

Patients should be monitored intensively during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity or skin reactions. The greatest risk of such events occurs in the first 6 weeks of therapy; therefore, extra vigilance is warranted during this period. Intensive clinical and laboratory monitoring (including liver enzyme tests) is essential at baseline and during the first 18 weeks of therapy. The optimal frequency of monitoring has not been determined. Some experts recommend clinical and laboratory monitoring more often than once per month and include monitoring of liver enzyme tests at baseline, prior to dose escalation, and at 2 weeks after dose escalation. The risk of any hepatic event, with or without rash, continues past the initial 18 weeks and clinical and laboratory monitoring should continue at frequent intervals throughout nevirapine therapy.

Immune reconstitution syndrome has occurred during combination antiretroviral therapy. Patients responding to therapy may develop an inflammatory response to indolent or residual opportunistic infections and require evaluation and treatment.

Nevirapine should always be used in combination with other antiretroviral agents. It should generally not be added as a single agent when antiretroviral regimens are changed due to the development of drug resistance and loss of virological response.

Strict adherence to the prescribed antiretroviral regimen is essential. Patients should not alter the dosages or discontinue therapy without consulting their physician.

Nevirapine interacts with some nonprescription and prescription drugs, including supplements. Some of the interactions can be serious. Patients should be advised to report all concurrent medications they are taking.

Safety and efficacy of the extended-release formulation have not been established in pediatric patients less than 6 years of age.

LactMed Record Number

645

Last Revision Date

20170411

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