DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS Nevirapine is principally metabolized by the liver via the cytochrome P450 isoenzymes, 3A and 2B6. Nevirapine is known to be an inducer of these enzymes. As result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when co-administered with nevirapine. The specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in Clinical Pharmacology, Table 5. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 4. The data in Tables and are based on the results of drug interaction trials conducted in HIV-1 seropositive subjects unless otherwise indicated. In addition to established drug interactions, there may be potential pharmacokinetic interactions between nevirapine and other drug classes that are metabolized by the cytochrome P450 system. These potential drug interactions are also listed in Table 4. Although specific drug interaction trials in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 4, additional clinical monitoring may be warranted when co-administering these drugs. The in vitro interaction between nevirapine and the antithrombotic agent warfarin is complex. As result, when giving these drugs concomitantly, plasma warfarin levels may change with the potential for increases in coagulation time. When warfarin is co-administered with nevirapine, anticoagulation levels should be monitored frequently. Table 4: Established and Potential Drug Interactions: Use with Caution, Alteration in Dose or Regimen May Be Needed Due to Drug Interaction Established Drug Interactions: See Clinical Pharmacology (12.3), Table for Magnitude of Interaction.Drug Name Effect on Concentration of Nevirapine or Concomitant DrugClinical Comment HIV Antiviral Agents: Protease Inhibitors (PIs)Atazanavir/RitonavirThe interaction between nevirapine and the drug was evaluated in clinical study. All other drug interactions shown are predicted. Atazanavir NevirapineDo not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is potential risk for nevirapine-associated toxicity due to increased nevirapine exposures.Fosamprenavir Amprenavir NevirapineCo-administration of nevirapine and fosamprenavir without ritonavir is not recommended. Fosamprenavir/Ritonavir Amprenavir NevirapineNo dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied.Indinavir IndinavirThe appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established.Lopinavir/Ritonavir LopinavirDosing in adult patients: dose adjustment of lopinavir/ritonavir to 500/125 mg tablets twice daily or 533/133 mg (6.5 mL) oral solution twice daily is recommended when used in combination with nevirapine. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine. Dosing in pediatric patients: Please refer to the Kaletra(R) prescribing information for dosing recommendations based on body surface area and body weight. Neither lopinavir/ritonavir tablets nor oral solution should be administered once daily in combination with nevirapine.Nelfinavir Nelfinavir M8 Metabolite Nelfinavir Cmin The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established.Saquinavir/RitonavirThe interaction between nevirapine and saquinavir/ritonavir has not been evaluated.The appropriate doses of the combination of nevirapine and saquinavir/ritonavir with respect to safety and efficacy have not been established.HIV Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)Efavirenz Efavirenz The appropriate doses of these combinations with respect to safety and efficacy have not been established. DelavirdineEtravirineRilpivirinePlasma concentrations may be altered. Nevirapine should not be co-administered with another NNRTI as this combination has not been shown to be beneficial.Hepatitis Antiviral AgentsBoceprevirPlasma concentrations of boceprevir may be decreased due to induction of CYP3A4/5 by nevirapine.Nevirapine and boceprevir should not be co-administered because decreases in boceprevir plasma concentrations may result in reduction in efficacy.TelaprevirPlasma concentrations of telaprevir may be decreased due to induction of CYP3A4 by nevirapine and plasma concentrations of nevirapine may be increased due to inhibition of CYP3A4 by telaprevir.Nevirapine and telaprevir should not be co-administered because changes in plasma concentrations of nevirapine, telaprevir, or both may result in reduction in telaprevir efficacy or an increase in nevirapine-associated adverse events.Other AgentsAnalgesics:Methadone MethadoneMethadone levels were decreased; increased dosages may be required to prevent symptoms of opiate withdrawal. Methadone-maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.Antiarrhythmics:Amiodarone, disopyramide, lidocainePlasma concentrations may be decreased.Appropriate doses for this combination have not been established.Antibiotics:Clarithromycin Clarithromycin 14-OH clarithromycinClarithromycin exposure was significantly decreased by nevirapine; however, 14-OH metabolite concentrations were increased. Because clarithromycin active metabolite has reduced activity against Mycobacterium avium-intracellulare complex, overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered. Rifabutin RifabutinRifabutin and its metabolite concentrations were moderately increased. Due to high intersubject variability, however, some patients may experience large increases in rifabutin exposure and may be at higher risk for rifabutin toxicity. Therefore, caution should be used in concomitant administration. Rifampin NevirapineNevirapine and rifampin should not be administered concomitantly because decreases in nevirapine plasma concentrations may reduce the efficacy of the drug. Physicians needing to treat patients co-infected with tuberculosis and using nevirapine-containing regimen may use rifabutin instead.Anticonvulsants:Carbamazepine, clonazepam, ethosuximidePlasma concentrations of nevirapine and the anticonvulsant may be decreased.Use with caution and monitor virologic response and levels of anticonvulsants.Antifungals:Fluconazole NevirapineBecause of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events. Ketoconazole KetoconazoleNevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Itraconazole ItraconazoleNevirapine and itraconazole should not be administered concomitantly due to potential decreases in itraconazole plasma concentrations that may reduce efficacy of the drug.Antithrombotics:WarfarinPlasma concentrations may be increased.Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended.Calcium Channel Blockers:Diltiazem, nifedipine, verapamilPlasma concentrations may be decreased.Appropriate doses for these combinations have not been established.Cancer Chemotherapy:CyclophosphamidePlasma concentrations may be decreased.Appropriate doses for this combination have not been established.Ergot Alkaloids:ErgotaminePlasma concentrations may be decreased.Appropriate doses for this combination have not been established.Immunosuppressants:Cyclosporine, tacrolimus, sirolimusPlasma concentrations may be decreased.Appropriate doses for these combinations have not been established.Motility Agents:CisapridePlasma concentrations may be decreased.Appropriate doses for this combination have not been established.Opiate Agonists:FentanylPlasma concentrations may be decreased.Appropriate doses for this combination have not been established.Oral Contraceptives:Ethinyl estradiol and Norethindrone Ethinyl estradiol Norethindrone Despite lower ethinyl estradiol and norethindrone exposures when co-administered with nevirapine, literature reports suggest that nevirapine has no effect on pregnancy rates among HIV-infected women on combined oral contraceptives. When co-administered with nevirapine, no dose adjustment of ethinyl estradiol or norethindrone is needed when used in combination for contraception.When these oral contraceptives are used for hormonal regulation during nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored. Co-administration of nevirapine can alter the concentrations of other drugs and other drugs may alter the concentration of nevirapine. The potential for drug interactions must be considered prior to and during therapy. (5.4, 7, 12.3).

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oThe 14-day lead-in period must be strictly followed; it has been demonstrated to reduce the frequency of rash. (2.4, 5.2) oIf any patient experiences rash during the 14-day lead-in period, do not increase dose until the rash has resolved. Do not continue the lead-in dosing regimen beyond 28 days. (2.4) oIf dosing is interrupted for greater than days, restart 14-day lead-in dosing. (2.4)Adults(>= 16 yrs) Pediatric PatientsTotal daily dose should not exceed 400 mg for any patient.(> 15 days) First 14 days 200 mg once daily 150 mg/m2 once daily After 14 days 200 mg twice daily 150 mg/m2 twice daily oThe 14-day lead-in period must be strictly followed; it has been demonstrated to reduce the frequency of rash. (2.4, 5.2) oIf any patient experiences rash during the 14-day lead-in period, do not increase dose until the rash has resolved. Do not continue the lead-in dosing regimen beyond 28 days. (2.4) oIf dosing is interrupted for greater than days, restart 14-day lead-in dosing. (2.4). 2.1Adult Patients The recommended dose for nevirapine is one 200 mg tablet daily for the first 14 days, followed by one 200 mg tablet twice daily, in combination with other antiretroviral agents. The 14-day lead-in period with nevirapine 200 mg daily dosing must be strictly followed as the lead-in period has been observed to decrease the incidence of rash [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)]. If rash persists beyond the 14-day lead-in period, do not dose escalate to 200 mg twice daily. The 200 mg once-daily dosing regimen should not be continued beyond 28 days, at which point, an alternative regimen should be sought. For concomitantly administered antiretroviral therapy, the manufacturers recommended dosage and monitoring should be followed. 2.2Pediatric Patients The recommended oral dose for pediatric patients 15 days and older is 150 mg/m2 once daily for 14 days followed by 150 mg/m2 twice daily thereafter. The total daily dose should not exceed 400 mg for any patient. Table 1: Calculation of the Volume of Nevirapine Oral Suspension (50 mg/5 mL) Required for Pediatric Dosing Based on Body Surface and Dose of 150 mg/m2 BSA range (m2) Volume (mL) 0.06-0.12 1.25 0.12-0.25 2.5 0.25-0.42 0.42-0.58 7.5 0.58-0.75 10 0.75-0.92 12.5 0.92-1.08 15 1.08-1.25 17.5 1.25+ 20 Nevirapine suspension should be shaken gently prior to administration. It is important to administer the entire measured dose of suspension by using an oral dosing syringe or dosing cup. An oral dosing syringe is recommended, particularly for volumes of mL or less. If dosing cup is used, it should be thoroughly rinsed with water and the rinse should also be administered to the patient. Mosteller Formula. 2.3Monitoring of Patients Intensive clinical and laboratory monitoring, including liver enzyme tests, is essential at baseline and during the first 18 weeks of treatment with nevirapine. The optimal frequency of monitoring during this period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, would include monitoring of liver enzyme tests at baseline, prior to dose escalation, and at weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment [see Warnings and Precautions (5)]. In some cases, hepatic injury has progressed despite discontinuation of treatment. 2.4Dosage Adjustment Patients with Rash. Discontinue nevirapine if patient experiences severe rash or any rash accompanied by constitutional findings [see Warnings and Precautions (5.2)]. Do not increase nevirapine dose if patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m2/day in pediatric patients) until the rash has resolved [see Warnings and Precautions (5.2)]. The total duration of the once daily lead-in dosing period should not exceed 28 days at which point an alternative regimen should be sought.. Patients with Hepatic Events. If clinical (symptomatic) hepatic event occurs, permanently discontinue nevirapine. Do not restart nevirapine after recovery [see Warnings and Precautions (5.1)]. Patients with Dose Interruption. For patients who interrupt nevirapine dosing for more than days, restart the recommended dosing, using one 200 mg tablet daily (150 mg/m2/day in pediatric patients) for the first 14 days (lead-in) followed by one 200 mg tablet twice daily (150 mg/m2 twice daily for pediatric patients). Patients with Renal Impairment. Patients with CrCl greater than or equal to 20 mL per min do not require an adjustment in nevirapine dosing. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. An additional 200 mg dose of nevirapine following each dialysis treatment is indicated in patients requiring dialysis. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known [see Clinical Pharmacology (12.3)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS oThe most common adverse reaction is rash. In adults, the incidence of rash is 15% versus 6% with placebo, with Grade 3/4 rash occurring in 2% of subjects. (6.1) oIn pediatric subjects the incidence of rash (all causality) was 21%. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. oThe most common adverse reaction is rash. In adults, the incidence of rash is 15% versus 6% with placebo, with Grade 3/4 rash occurring in 2% of subjects. (6.1) oIn pediatric subjects the incidence of rash (all causality) was 21%. (6.1) 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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/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 (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 or and/or increased transaminase elevations at the start of therapy with nevirapine are associated with 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 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 and rashes were reported in 13% of subjects receiving nevirapine compared to 6% receiving placebo during the first weeks of therapy. Grade and 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 TrialsTrial 1090Background therapy included 3TC for all subjects and combinations of NRTIs and PIs. Subjects had CD4+ cell counts less than 200 cells/mm3.Trials 1037, 1038, 1046Background 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/mm3.NevirapinePlaceboNevirapinePlacebo(n 1121)(n 1128)(n 253)(n 203)Median exposure (weeks) 58522828Any adverse event 15%11%32%13%Rash 5272Nausea 1194Granulocytopenia 23< 10Headache 1< 141Fatigue 1< 154Diarrhea 1121Abdominal pain 1< 120Myalgia 10 12. 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 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 AbnormalitiesTrial 1090Background therapy included 3TC for all subjects and combinations of NRTIs and PIs. Subjects had CD4+ cell counts less than 200 cells/mm3.Trials 1037, 1038, 1046Background 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/mm3.NevirapinePlaceboNevirapinePlaceboLaboratory Abnormality (n 1121)(n 1128)(n 253)(n 203)Blood Chemistry SGPT (ALT) 250 U/L 54144 SGOT (AST) 250 U/L 4382 Bilirubin 2.5 mg/dL 2222Hematology Hemoglobin 8.0 g/dL 3400 Platelets 50,000/mm3 11< 12 Neutrophils 750/mm3 131441. SGPT (ALT) 250 U/L SGOT (AST) 250 U/L Bilirubin 2.5 mg/dL Hemoglobin 8.0 g/dL Platelets 50,000/mm3 Neutrophils 750/mm3 Clinical Trial Experience in Pediatric Patients. Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), 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 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-naive subjects between months and 16 years of age received combination treatment with nevirapine oral suspension, lamuvidine 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, (3%) of whom discontinued drug due to rash. All subjects experienced the rash early in the course of therapy (less than 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 weeks to less than 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. 6.2Post-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 population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Body as 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 phosphorusMusculoskeletal: 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.

BOXED WARNING SECTION.

WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN REACTIONS HEPATOTOXICITY: Severe, life-threatening, and in some cases fatal hepatotoxicity, particularly in the first 18 weeks, has been reported in patients treated with nevirapine. In some cases, patients presented with non-specific prodromal signs or symptoms of hepatitis and progressed to hepatic failure. These events are often associated with rash. Female gender and higher CD4+ cell counts at initiation of therapy place patients at increased risk; women with CD4+ cell counts greater than 250 cells/mm3, including pregnant women receiving nevirapine in combination with other antiretrovirals for the treatment of HIV-1 infection, are at the greatest risk. However, hepatotoxicity associated with nevirapine use can occur in both genders, all CD4+ cell counts and at any time during treatment. Hepatic failure has also been reported in patients without HIV taking nevirapine for post-exposure prophylaxis (PEP). Use of nevirapine for occupational and non-occupational PEP is contraindicated [see Contraindications (4)]. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue nevirapine and seek medical evaluation immediately [see Warnings and Precautions (5.1)]. SKIN REACTIONS: Severe, life-threatening skin reactions, including fatal cases, have occurred in patients treated with nevirapine. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions must discontinue nevirapine and seek medical evaluation immediately. Transaminase levels should be checked immediately for all patients who develop rash in the first 18 weeks of treatment. The 14-day lead-in period with nevirapine 200 mg daily dosing has been observed to decrease the incidence of rash and must be followed [see Warnings and Precautions (5.2)]. MONITORING FOR HEPATOTOXICITY AND SKIN REACTIONS: Patients must be monitored intensively during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity or skin reactions. Extra vigilance is warranted during the first weeks of therapy, which is the period of greatest risk of these events. Do not restart nevirapine following clinical hepatitis, or transaminase elevations combined with rash or other systemic symptoms, or following severe skin rash or hypersensitivity reactions. In some cases, hepatic injury has progressed despite discontinuation of treatment.. WARNING: LIFE-THREATENING (INCLUDING FATAL) HEPATOTOXICITY and SKIN REACTIONS See full prescribing information for complete boxed warning.oFatal and non-fatal hepatotoxicity have been reported in patients taking nevirapine. Discontinue immediately if clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur. Do not restart nevirapine after recovery. (5.1) oFatal and non-fatal skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions, have been reported. Discontinue immediately if severe skin reactions, hypersensitivity reactions, or any rash with systemic symptoms occur. Check transaminase levels immediately for all patients who develop rash in the first 18 weeks of treatment. Do not restart nevirapine after recovery. (5.2)oMonitoring during the first 18 weeks of therapy is essential. Extra vigilance is warranted during the first weeks of therapy, which is the period of greatest risk of these events. (5.1, 5.2) oFatal and non-fatal hepatotoxicity have been reported in patients taking nevirapine. Discontinue immediately if clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur. Do not restart nevirapine after recovery. (5.1) oFatal and non-fatal skin reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions, have been reported. Discontinue immediately if severe skin reactions, hypersensitivity reactions, or any rash with systemic symptoms occur. Check transaminase levels immediately for all patients who develop rash in the first 18 weeks of treatment. Do not restart nevirapine after recovery. (5.2). oMonitoring during the first 18 weeks of therapy is essential. Extra vigilance is warranted during the first weeks of therapy, which is the period of greatest risk of these events. (5.1, 5.2).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Nevirapine is an antiretroviral drug [see Microbiology (12.4)]. 12.3 Pharmacokinetics Adults. Absorption and Bioavailability 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 50 mg tablet and 91 +- 8% for an oral solution. Peak plasma nevirapine concentrations of +- 0.4 mcg/mL (7.5 micromolar) were attained by hours following single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 mg/day to 400 mg/day. Steady-state trough nevirapine concentrations of 4.5 +- 1.9 mcg/mL (17 +- 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 nevirapine (200 mg) was administered to 24 healthy adults (12 female, 12 male), with either high-fat breakfast (857 kcal, 50 fat, 53% of calories from fat) or antacid (Maalox(R) 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In separate trial in HIV-1 infected subjects (n 6), nevirapine steady-state systemic exposure (AUC) was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. Nevirapine may be administered with or without food, antacid or didanosine. Distribution 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 (8.2)]. 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. Metabolism/Elimination 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 secondary role. In mass balance/excretion trial in eight healthy male volunteers dosed to steady-state with nevirapine 200 mg given twice daily followed by 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 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 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 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from single dose to to weeks of dosing with 200 mg per day to 400 mg per day. Autoinduction also results in 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 mg per day to 400 mg per day. Specific Populations. Renal Impairment HIV-1 seronegative adults with mild (CrCl 50-79 mL per min; = 7), moderate (CrCl 30-49 mL per min; = 6), or severe (CrCl less than 30 mL per min; = 4) renal impairment received single 200 mg dose of nevirapine in pharmacokinetic trial. These subjects did not require dialysis. The trial included 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 44% reduction in nevirapine AUC over 1-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 (2.4) and Use in Specific Populations (8.6)]. Hepatic Impairment In 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 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 (5.1)]. The subjects studied were receiving antiretroviral therapy containing nevirapine 200 mg twice daily for at least weeks prior to pharmacokinetic sampling, with median duration of therapy of 3.4 years. In pharmacokinetic trial where HIV-1 negative cirrhotic subjects with mild (Child-Pugh A; = 6) or moderate (Child-Pugh B; = 4) hepatic impairment received single 200 mg dose of nevirapine, significant increase in the AUC of nevirapine was observed in one subject with Child-Pugh 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 or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.7)]. Gender In the multinational 2NN trial, population pharmacokinetic substudy of 1077 subjects was performed that included 391 females. Female subjects showed 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. Race 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 nevirapine and nevirapine extended-release treatment groups over 96 weeks of treatment at 400 mg per day.. Geriatric Subjects 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 (8.5)]. Pediatric Subjects Pharmacokinetic data for nevirapine have been derived from two sources: 48-week pediatric trial in South Africa (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naive subjects aged months to 16 years; and 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 weight-based and body surface area (BSA)-based dosing regimen of nevirapine. In the weight-based regimen, pediatric subjects up to years of age received dose of mg/kg once daily for weeks followed by mg/kg twice daily thereafter. Subjects years and older were dosed mg/kg once daily for weeks followed by mg/kg twice daily thereafter. In the BSA regimen, all pediatric subjects received 150 mg/m2 once daily for weeks followed by 150 mg/m2 twice daily thereafter [see Use in Specific Populations (8.4) and Adverse Reactions (6.1)]. Dosing of nevirapine at 150 mg/m2 BID (after 2-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 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 (2.2)]. Drug Interactions. [See Drug Interactions (7).]Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of nevirapine 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, 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 (see below) contains the results of drug interaction trials performed with nevirapine and other drugs likely to be co-administered. The effects of nevirapine 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 Nevirapine (All Interaction Trials were Conducted in HIV-1 Positive Subjects) Cmin below detectable level of the assay Increase, Decrease, <-> No EffectCo-administered DrugDose of Co-administered DrugDose Regimen of Nevirapinen% Change of Co-administered Drug Pharmacokinetic Parameters (90% CI)AntiretroviralsAUCCmax Cmin Atazanavir/RitonavirFor information regarding clinical recommendations, see Drug Interactions (7) Parallel group design; = 23 for atazanavir/ritonavir nevirapine, = 22 for atazanavir/ritonavir without nevirapine. Changes in atazanavir PK are relative to atazanavir/ritonavir 300/100 mg alone. 300/100 mg QD day 4-13, then 400/100 mg QD, day 14-23200 mg BID day 1-23. Subjects were treated with nevirapine prior to trial entry.23Atazanavir300/100 mg 42(52 to 29)Atazanavir300/100 mg28 (40 to 14)Atazanavir300/100 mg 72(80 to 60)Atazanavir400 mg/100 mg 19(35 to 2)Atazanavir400 mg/100 mg 2(15 to 24)Atazanavir400 mg/100 mg 59(73 to 40)Darunavir/RitonavirBased on between-trial comparison. 400/100 mg BID200 mg BID824(3 to 57)40(14 to 73)2(21 to 32)Didanosine100-150 mg BID200 mg QD 14 days; 200 mg BID 14 days18<-><->Efavirenz 600 mg QD 200 mg QD 14 days; 400 mg QD 14 days 17 28(34 to 14) 12(23 to 1) 32(35 to 19) Fosamprenavir 1400 mg BID 200 mg BID. Subjects were treated with nevirapine prior to trial entry. 17 33(45 to 20) 25(37 to 10) 35(50 to 15) Fosamprenavir/Ritonavir 700/100 mg BID 200 mg BID. Subjects were treated with nevirapine prior to trial entry. 17 11(23 to 3) <->19(32 to 4) Indinavir 800 mg q8H 200 mg QD 14 days; 200 mg BID 14 days 19 31(39 to 22) 15(24 to 4) 44(53 to 33) Lopinavir Pediatric subjects ranging in age from months to 12 years. 300/75 mg/m2 (lopinavir/ ritonavir) mg/kg or mg/kg QD 2 weeks; BID 1 week 12, 15Parallel group design; for nevirapine lopinavir/ritonavir, for lopinavir/ritonavir alone. 22(44 to 9) 14(36 to 16) 55(75 to 19) Lopinavir 400/100 mg BID (lopinavir/ ritonavir) 200 mg QD 14 days; 200 mg BID 1 year 22, 19 27(47 to 2) 19(38 to 5) 51(72 to 26) MaravirocBased on historical controls. 300 mg SD 200 mg BID 1(35 to 55) 54 (6 to 151) <->Nelfinavir 750 mg TID 200 mg QD 14 days; 200 mg BID 14 days 23 <-><->32(50 to 5) Nelfinavir-M8 metabolite62(70 to 53) 59(68 to 48) 66(74 to 55) Ritonavir 600 mg BID 200 mg QD 14 days; 200 mg BID 14 days 18 <-><-><->Stavudine 30-40 mg BID 200 mg QD 14 days; 200 mg BID 14 days 22 <-><->Zalcitabine 0.125-0.25 mg TID 200 mg QD 14 days; 200 mg BID 14 days <-><->Zidovudine 100-200 mg TID 200 mg QD 14 days; 200 mg BID 14 days 11 28(40 to 4) 30(51 to 14) Other Medications AUC Cmax Cmin Clarithromycin 500 mg BID 200 mg QD 14 days; 200 mg BID 14 days 15 31(38 to 24) 23(31 to 14) 56(70 to 36) Metabolite14-OH-clarithromycin 42(16 to 73) 47(21 to 80) <->Ethinyl estradiol and0.035 mg (as Ortho-Novum(R) 1/35)200 mg QD 14 days; 200 mg BID 14 days 10 20(33 to 3)<->Norethindrone mg (as Ortho-Novum(R) 1/35)19(30 to 7) 16(27 to 3) Depomedroxy-progesterone acetate 150 mg every months 200 mg QD 14 days; 200 mg BID 14 days 32 <-><-><->Fluconazole 200 mg QD 200 mg QD 14 days; 200 mg BID 14 days 19 <-><-><->Ketoconazole 400 mg QD 200 mg QD 14 days; 200 mg BID 14 days 21 72(80 to 60) 44(58 to 27) Methadone Individual Subject Dosing 200 mg QD 14 days; 200 mg BID >= days In controlled pharmacokinetic trial with subjects receiving chronic methadone to whom steady-state nevirapine therapy was added, the clearance of methadone was increased by 3-fold, resulting in symptoms of withdrawal, requiring dose adjustments in 10 mg segments, in of the subjects. Methadone did not have any effect on nevirapine clearance.Rifabutin 150 or 300 mg QD 200 mg QD 14 days; 200 mg BID 14 days 19 17(2 to 40) 28(9 to 51) <->Metabolite 25-O-desacetyl-rifabutin 24(16 to 84) 29(2 to 68) 22(14 to 74) Rifampin 600 mg QD 200 mg QD 14 days; 200 mg BID 14 days 14 11(4 to 28) <->Because of the design of the drug interaction trials (addition of 28 days of nevirapine 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 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 comparison to historic data [see Drug Interactions (7)]. The effect of other drugs listed in Table on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir was co-administered with low-dose ritonavir and nevirapine. 12.4Microbiology Mechanism of Action. Nevirapine is 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 disruption of the enzymes 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 ss, or are not inhibited by nevirapine. Antiviral Activity. The antiviral activity of nevirapine has been measured in 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 panel of 2923 wild-type isolates of HIV-1 that were primarily (93%) clade 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, = 29) against clinical isolates of HIV-1 clades A, B, C, D, F, G, and H, and circulating recombinant forms CRF01AE, CRF02AG and CRF12BF. Nevirapine had no antiviral activity in cell culture against group 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. The anti-HIV-1 activity of nevirapine was not antagonistic in combination with the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine, and the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir. 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. Resistance. 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-naive subjects receiving either nevirapine (n 24) or nevirapine and zidovudine (n 14) were monitored in Phase and trials ranging from to 12 weeks or longer. After 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 weeks after therapy initiation. By week of nevirapine monotherapy, 100% of the subjects tested (n 24) had HIV-1 isolates with greater than 100-fold decrease in susceptibility to nevirapine in cell culture compared to baseline, and had one or more of the nevirapine-associated RT resistance substitutions. Nineteen of these subjects (80%) had isolates with Y181C substitutions regardless of dose. Genotypic analysis of isolates from antiretroviral-naive 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 nevirapine extended-release and immediate-release nevirapine 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 nevirapine extended-release treatment group and 88% (30/34) of the subjects in the immediate-release nevirapine 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 nevirapine extended-release treatment and 25 subjects failing immediate-release nevirapine treatment. On-therapy isolates from subject in nevirapine extended-release treatment group developed novel amino acid substitution Y181I and isolates from another subject in the immediate-release nevirapine treatment group developed novel amino acid substitution Y188N. Phenotypic analysis showed that Y188N and Y181I substitutions conferred 103- and 22-fold reductions in susceptibility to nevirapine, respectively.. Cross-resistance. 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1Adult Patients Trial BI 1090 was 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 nevirapine lamivudine background therapy versus lamivudine background therapy in NNRTI-naive subjects. Treatment doses were nevirapine, 200 mg daily for 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 median baseline CD4+ cell count of 96 cells/mm3 and 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 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 WeeksOutcomeNevirapine(N 1121)%Placebo(N 1128)%Responders at 48 weeks: HIV-1 RNA 50 copies/mL182Treatment Failure8298 Never suppressed viral load4566 Virologic failure after response74 CDC category event or death1011 Added antiretroviral therapyincluding change to open-label nevirapine while 50 copies/mL51 Discontinued trial therapy due to AE76 Discontinued trial 48 weeksincludes withdrawal of consent, lost to follow-up, non-compliance with protocol, other administrative reasons 910The change from baseline in CD4+ cell count through year of therapy was significantly greater for the nevirapine 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-naive or having received only ZDV (85 cells/mm3 versus 25 cells/mm3, respectively). At years into the trial, 16% of subjects on nevirapine had experienced class CDC events as compared to 21% of subjects on the control arm. Trial BI 1046 (INCAS) was 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 nevirapine zidovudine didanosine to nevirapine zidovudine and zidovudine didanosine. Treatment doses were nevirapine at 200 mg daily for weeks followed by 200 mg twice daily or placebo, zidovudine at 200 mg three times daily, and didanosine at 125 mg 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 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 mean of 139 cells/mm3 at year, significantly greater than the increase of 87 cells/mm3 in the ZDV ddI subjects. The nevirapine ZDV group mean decreased by cells/mm3 below baseline. 14.2Pediatric 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-naive subjects between months and 16 years of age received nevirapine oral suspension for 48 weeks. Subjects were divided into age groups (3 months to less than years, to less than years, 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 different dosing methods [body surface area (150 mg/m2) and weight-based dosing (4 mg per kg or mg per kg)] in combination with zidovudine and lamivudine [see Adverse Reactions (6.1), 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 median baseline HIV-1 RNA of 5.45 log10 copies per mL and 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, (7%) discontinued due to adverse reactions and (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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).Hepatotoxicity and Skin Reactions: Inform patients of the possibility of severe liver disease or skin reactions associated with nevirapine that may result in death. Instruct patients developing signs or symptoms of liver disease or severe skin reactions to discontinue nevirapine and seek medical attention immediately, including performance of laboratory monitoring. Symptoms of liver disease include fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness or hepatomegaly. Symptoms of severe skin or hypersensitivity reactions include rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, and/or hepatitis. Intensive clinical and laboratory monitoring, including liver enzymes, is essential during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoring should continue at frequent intervals throughout nevirapine treatment. Extra vigilance is warranted during the first weeks of therapy, which is the period of greatest risk of hepatic events. Advise patients with signs and symptoms of hepatitis to discontinue nevirapine and seek medical evaluation immediately. If nevirapine is discontinued due to hepatotoxicity, do not restart it. Patients, particularly women, with increased CD4+ cell count at initiation of nevirapine therapy (greater than 250 cells/mm3 in women and greater than 400 cells/mm3 in men) are at substantially higher risk for development of symptomatic hepatic events, often associated with rash. Advise patients that co-infection with hepatitis or and/or increased transaminases at the start of therapy with nevirapine are associated with greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT [see Warnings and Precautions (5.1)]. The majority of rashes associated with nevirapine occur within the first weeks of initiation of therapy. Instruct patients that if any rash occurs during the 2-week lead-in period, do not escalate the nevirapine dose until the rash resolves. The total duration of the once-daily lead-in dosing period should not exceed 28 days, at which point an alternative regimen may need to be started. Any patient experiencing rash should have their liver enzymes (AST, ALT) evaluated immediately. Patients with severe rash or hypersensitivity reactions should discontinue nevirapine immediately and consult physician. Nevirapine tablets should not be restarted following severe skin rash or hypersensitivity reaction. Women tend to be at higher risk for development of nevirapine-associated rash [see Warnings and Precautions (5.2)]. Administration and Missed Dosage: Inform patients to take nevirapine every day as prescribed. Advise patients not to alter the dose without consulting their doctor. If dose is missed, patients should take the next dose as soon as possible. However, if dose is skipped, the patient should not double the next dose. To avoid overdose, inform patients that they should never take immediate-release nevirapine and extended-release nevirapine concomitantly.Drug Interactions: Nevirapine tablets may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. Johns wort [see Warnings and Precautions (5.4) and Drug Interactions (7)]. Immune Reconstitution Syndrome: Advise patients to inform their healthcare provider immediately of any signs or symptoms of infection, as inflammation from previous infection may occur soon after combination antiretroviral therapy, including when nevirapine is started [see Warnings and Precautions (5.5)].Fat Redistribution: Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.6)]. Pregnancy Registry: Advise patients that there is pregnancy registry that monitors pregnancy outcomes in women exposed to nevirapine during pregnancy [see Use in Specific Populations (8.1)]. Lactation: Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk [see Use in Specific Populations (8.2)].Infertility: Advise females of reproductive potential of the potential for impaired fertility from nevirapine [see Use in Specific Populations (8.3) and Nonclinical Toxicology (13.1)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Adults. Absorption and Bioavailability 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 50 mg tablet and 91 +- 8% for an oral solution. Peak plasma nevirapine concentrations of +- 0.4 mcg/mL (7.5 micromolar) were attained by hours following single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 mg/day to 400 mg/day. Steady-state trough nevirapine concentrations of 4.5 +- 1.9 mcg/mL (17 +- 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 nevirapine (200 mg) was administered to 24 healthy adults (12 female, 12 male), with either high-fat breakfast (857 kcal, 50 fat, 53% of calories from fat) or antacid (Maalox(R) 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In separate trial in HIV-1 infected subjects (n 6), nevirapine steady-state systemic exposure (AUC) was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. Nevirapine may be administered with or without food, antacid or didanosine. Distribution 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 (8.2)]. 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. Metabolism/Elimination 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 secondary role. In mass balance/excretion trial in eight healthy male volunteers dosed to steady-state with nevirapine 200 mg given twice daily followed by 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 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 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 2-fold increase in the apparent oral clearance of nevirapine as treatment continues from single dose to to weeks of dosing with 200 mg per day to 400 mg per day. Autoinduction also results in 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 mg per day to 400 mg per day. Specific Populations. Renal Impairment HIV-1 seronegative adults with mild (CrCl 50-79 mL per min; = 7), moderate (CrCl 30-49 mL per min; = 6), or severe (CrCl less than 30 mL per min; = 4) renal impairment received single 200 mg dose of nevirapine in pharmacokinetic trial. These subjects did not require dialysis. The trial included 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 44% reduction in nevirapine AUC over 1-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 (2.4) and Use in Specific Populations (8.6)]. Hepatic Impairment In 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 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 (5.1)]. The subjects studied were receiving antiretroviral therapy containing nevirapine 200 mg twice daily for at least weeks prior to pharmacokinetic sampling, with median duration of therapy of 3.4 years. In pharmacokinetic trial where HIV-1 negative cirrhotic subjects with mild (Child-Pugh A; = 6) or moderate (Child-Pugh B; = 4) hepatic impairment received single 200 mg dose of nevirapine, significant increase in the AUC of nevirapine was observed in one subject with Child-Pugh 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 or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.7)]. Gender In the multinational 2NN trial, population pharmacokinetic substudy of 1077 subjects was performed that included 391 females. Female subjects showed 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. Race 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 nevirapine and nevirapine extended-release treatment groups over 96 weeks of treatment at 400 mg per day.. Geriatric Subjects 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 (8.5)]. Pediatric Subjects Pharmacokinetic data for nevirapine have been derived from two sources: 48-week pediatric trial in South Africa (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naive subjects aged months to 16 years; and 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 weight-based and body surface area (BSA)-based dosing regimen of nevirapine. In the weight-based regimen, pediatric subjects up to years of age received dose of mg/kg once daily for weeks followed by mg/kg twice daily thereafter. Subjects years and older were dosed mg/kg once daily for weeks followed by mg/kg twice daily thereafter. In the BSA regimen, all pediatric subjects received 150 mg/m2 once daily for weeks followed by 150 mg/m2 twice daily thereafter [see Use in Specific Populations (8.4) and Adverse Reactions (6.1)]. Dosing of nevirapine at 150 mg/m2 BID (after 2-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 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 (2.2)]. Drug Interactions. [See Drug Interactions (7).]Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of nevirapine 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, 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 (see below) contains the results of drug interaction trials performed with nevirapine and other drugs likely to be co-administered. The effects of nevirapine 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 Nevirapine (All Interaction Trials were Conducted in HIV-1 Positive Subjects) Cmin below detectable level of the assay Increase, Decrease, <-> No EffectCo-administered DrugDose of Co-administered DrugDose Regimen of Nevirapinen% Change of Co-administered Drug Pharmacokinetic Parameters (90% CI)AntiretroviralsAUCCmax Cmin Atazanavir/RitonavirFor information regarding clinical recommendations, see Drug Interactions (7) Parallel group design; = 23 for atazanavir/ritonavir nevirapine, = 22 for atazanavir/ritonavir without nevirapine. Changes in atazanavir PK are relative to atazanavir/ritonavir 300/100 mg alone. 300/100 mg QD day 4-13, then 400/100 mg QD, day 14-23200 mg BID day 1-23. Subjects were treated with nevirapine prior to trial entry.23Atazanavir300/100 mg 42(52 to 29)Atazanavir300/100 mg28 (40 to 14)Atazanavir300/100 mg 72(80 to 60)Atazanavir400 mg/100 mg 19(35 to 2)Atazanavir400 mg/100 mg 2(15 to 24)Atazanavir400 mg/100 mg 59(73 to 40)Darunavir/RitonavirBased on between-trial comparison. 400/100 mg BID200 mg BID824(3 to 57)40(14 to 73)2(21 to 32)Didanosine100-150 mg BID200 mg QD 14 days; 200 mg BID 14 days18<-><->Efavirenz 600 mg QD 200 mg QD 14 days; 400 mg QD 14 days 17 28(34 to 14) 12(23 to 1) 32(35 to 19) Fosamprenavir 1400 mg BID 200 mg BID. Subjects were treated with nevirapine prior to trial entry. 17 33(45 to 20) 25(37 to 10) 35(50 to 15) Fosamprenavir/Ritonavir 700/100 mg BID 200 mg BID. Subjects were treated with nevirapine prior to trial entry. 17 11(23 to 3) <->19(32 to 4) Indinavir 800 mg q8H 200 mg QD 14 days; 200 mg BID 14 days 19 31(39 to 22) 15(24 to 4) 44(53 to 33) Lopinavir Pediatric subjects ranging in age from months to 12 years. 300/75 mg/m2 (lopinavir/ ritonavir) mg/kg or mg/kg QD 2 weeks; BID 1 week 12, 15Parallel group design; for nevirapine lopinavir/ritonavir, for lopinavir/ritonavir alone. 22(44 to 9) 14(36 to 16) 55(75 to 19) Lopinavir 400/100 mg BID (lopinavir/ ritonavir) 200 mg QD 14 days; 200 mg BID 1 year 22, 19 27(47 to 2) 19(38 to 5) 51(72 to 26) MaravirocBased on historical controls. 300 mg SD 200 mg BID 1(35 to 55) 54 (6 to 151) <->Nelfinavir 750 mg TID 200 mg QD 14 days; 200 mg BID 14 days 23 <-><->32(50 to 5) Nelfinavir-M8 metabolite62(70 to 53) 59(68 to 48) 66(74 to 55) Ritonavir 600 mg BID 200 mg QD 14 days; 200 mg BID 14 days 18 <-><-><->Stavudine 30-40 mg BID 200 mg QD 14 days; 200 mg BID 14 days 22 <-><->Zalcitabine 0.125-0.25 mg TID 200 mg QD 14 days; 200 mg BID 14 days <-><->Zidovudine 100-200 mg TID 200 mg QD 14 days; 200 mg BID 14 days 11 28(40 to 4) 30(51 to 14) Other Medications AUC Cmax Cmin Clarithromycin 500 mg BID 200 mg QD 14 days; 200 mg BID 14 days 15 31(38 to 24) 23(31 to 14) 56(70 to 36) Metabolite14-OH-clarithromycin 42(16 to 73) 47(21 to 80) <->Ethinyl estradiol and0.035 mg (as Ortho-Novum(R) 1/35)200 mg QD 14 days; 200 mg BID 14 days 10 20(33 to 3)<->Norethindrone mg (as Ortho-Novum(R) 1/35)19(30 to 7) 16(27 to 3) Depomedroxy-progesterone acetate 150 mg every months 200 mg QD 14 days; 200 mg BID 14 days 32 <-><-><->Fluconazole 200 mg QD 200 mg QD 14 days; 200 mg BID 14 days 19 <-><-><->Ketoconazole 400 mg QD 200 mg QD 14 days; 200 mg BID 14 days 21 72(80 to 60) 44(58 to 27) Methadone Individual Subject Dosing 200 mg QD 14 days; 200 mg BID >= days In controlled pharmacokinetic trial with subjects receiving chronic methadone to whom steady-state nevirapine therapy was added, the clearance of methadone was increased by 3-fold, resulting in symptoms of withdrawal, requiring dose adjustments in 10 mg segments, in of the subjects. Methadone did not have any effect on nevirapine clearance.Rifabutin 150 or 300 mg QD 200 mg QD 14 days; 200 mg BID 14 days 19 17(2 to 40) 28(9 to 51) <->Metabolite 25-O-desacetyl-rifabutin 24(16 to 84) 29(2 to 68) 22(14 to 74) Rifampin 600 mg QD 200 mg QD 14 days; 200 mg BID 14 days 14 11(4 to 28) <->Because of the design of the drug interaction trials (addition of 28 days of nevirapine 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 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 comparison to historic data [see Drug Interactions (7)]. The effect of other drugs listed in Table on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir was co-administered with low-dose ritonavir and nevirapine.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE Nevirapine Tablets, USP(ne vir peen)What is the most important information should know about nevirapine tabletsNevirapine tablets can cause severe liver and skin problems that may lead to death. These problems can happen at any time during treatment, but your risk is higher during the first 18 weeks of treatment. Nevirapine tablets can cause serious side effects, including: oSevere liver problems. Some people taking nevirapine tablets may develop severe liver problems that can lead to liver failure and the need for liver transplant, or death. If you have liver problems you may get rash.oWomen have higher risk of developing liver problems during treatment with nevirapine tablets than men.oPeople who have abnormal liver test results before starting nevirapine tablets and people with hepatitis or also have greater risk of getting liver problems. People who have higher CD4+ cell counts when they begin nevirapine tablets have higher risk of liver problems, especially: oWomen with CD4+ counts higher than 250 cells/mm3. This group has the highest risk.oMen with CD4+ counts higher than 400 cells/mm3.Stop taking nevirapine tablets and call your doctor right away if you have any of the following symptoms of liver problems with or without skin rash:odark (tea colored) urineolight-colored bowel movements (stools)ofeeling sick to your stomach (nausea)opain or tenderness on your right side below your ribsoloss of appetiteoyellowing of your skin or whites of your eyesofeverofeel unwell or like you have the fluotirednessoSevere skin reactions and rash. Some skin reactions and rashes may be severe, life-threatening, and in some people, may lead to death. Most severe skin reactions and rashes happen in the first weeks of treatment with nevirapine tablets.oWomen have higher risk of developing rash during treatment with nevirapine tablets than men. Stop taking nevirapine tablets and call your doctor right away if you get rash with any of the following symptoms:oblistersored or inflamed eyes, like pink eye (conjunctivitis)oswelling of your faceofeel unwell or like you have the fluomuscle or joint achesomouth soresofever otiredness oYour doctor should do blood tests often to check your liver function and check for severe skin reactions during the first 18 weeks of treatment with nevirapine tablets. You should continue to see your doctor and have your liver checked regularly during your treatment with nevirapine tablets. It is important for you to keep all of your doctor appointments. oIf your doctor tells you to stop treatment with nevirapine tablets because you have had any of the severe liver or skin symptoms listed above, you should never take nevirapine tablets again. See What are the possible side effects of nevirapine tablets for more information about side effects.What is nevirapine Nevirapine tablets and nevirapine oral solution are prescription HIV-1 medicines used with other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus 1) in adults and in children 15 days of age or older. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).oIf you are woman with CD4+ counts higher than 250 cells/mm3 or man with CD4+ counts higher than 400 cells/mm3, you and your doctor will decide if starting nevirapine is right for you.Do not take nevirapine tablets:oif you have liver problems.oas part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens. Nevirapine tablets are only for people diagnosed with HIV-1. If you have not been diagnosed as HIV positive, then do not take nevirapine tablets.Before taking nevirapine, tell your doctor about all your or your childs medical conditions, including if you or your child: ohave or have had hepatitis (inflammation of your liver) or problems with your liver. See What is the most important information should know about nevirapine tablets oreceive dialysis ohave trouble swallowing pills oare pregnant or plan to become pregnant. It is not known if nevirapine will harm your unborn baby. Pregnancy Registry: There is pregnancy registry for women who take nevirapine tablets during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.oare breastfeeding or plan to breastfeed. Nevirapine can pass into your breast milk and may harm your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Do not breastfeed during treatment with nevirapine tablets. Talk to your doctor about the best way to feed your baby. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Especially tell your doctor if you take St. Johns wort. oSome medicines interact with nevirapine tablets. Keep list of your medicines to show your doctor or pharmacist. oYou can ask your doctor or pharmacist for list of medicines that interact with nevirapine tablets. oDo not start taking new medicine without telling your doctor. Your doctor can tell you if it is safe to take nevirapine tablets with other medicines.How should take nevirapine tabletsoTake nevirapine tablets exactly as your doctor tells you to take them. Do not change your dose unless your doctor tells you to.oNevirapine tablets are always taken in combination with other antiretroviral medicines.oNevirapine comes in three different forms. Your doctor will prescribe the form of nevirapine that is right for you.onevirapine tablets onevirapine oral suspension onevirapine extended-release tabletsoYou should not take more than one form of nevirapine at the same time. Talk to your doctor if you have any questions.oIf your child is prescribed nevirapine, your childs doctor will tell you exactly how nevirapine should be taken.oNevirapine tablets can be taken with or without food. oDo not miss dose of nevirapine tablets. If you miss dose of nevirapine tablets, take the missed dose as soon as you remember. If it is almost time for your next dose, do not take the missed dose. You should take the next dose at your regular time. Do not take doses at the same time. oIf you stop taking nevirapine tablets for more than days, ask your doctor how many to take before you start taking them again. You may need to begin taking the nevirapine tablets starting dose again, which is taken time each day for 14 days. Starting nevirapine tablets: 1.Your doctor should start you with dose each day to lower your chance of getting serious rash. It is important that you only take dose of nevirapine tablets each day for the first 14 days. oCall your doctor right away if you get skin rash during the first 14 days of nevirapine tablet treatment. oDo not increase your dose to times day if you have rash. oYou should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of nevirapine tablets. 2.Day 15, you will take nevirapine tablet times day.Switching from nevirapine tablets or oral suspension to nevirapine extended-release tablets: oTake nevirapine extended-release tablets time day as prescribed by your doctor. What are the possible side effects of nevirapine tablets Nevirapine tablets may cause serious side effects, including: See What is the most important information should know about nevirapine tabletsoChanges in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your doctor right away if you start having new symptoms after starting your HIV-1 medicine.oChanges in body fat can happen in people who take HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle of your body (trunk). Loss of fat from your legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.The most common side effect of nevirapine tablets is rash.Nevirapine tablets may cause decreased fertility in females. Talk to your doctor if you have concerns about fertility.These are not all the possible side effects of nevirapine tablets. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store nevirapine tabletsoStore nevirapine tablets at room temperature between 20 to 25C (68 to 77F).Keep nevirapine tablets and all medicines out of the reach of children. General information about the safe and effective use of nevirapine tablets.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use nevirapine tablets for condition for which they were not prescribed. Do not give nevirapine tablets to other people, even if they have the same condition you have. They may harm them. You can ask your pharmacist or doctor for information about nevirapine tablets that is written for health professionals. What are the ingredients in nevirapine tablets Active ingredient: nevirapine Inactive ingredients: Nevirapine tablets: colloidal silicon dioxide, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone and sodium starch glycolate (potato) Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, IndiaFor more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).This Medication Guide has been approved by the U.S. Food and Drug Administration The brands listed are trademarks of their respective owners.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Hyderabad -- 500 096, India75066382Revised: 10/2018MX:NVRPN:R4. oSevere liver problems. Some people taking nevirapine tablets may develop severe liver problems that can lead to liver failure and the need for liver transplant, or death. If you have liver problems you may get rash.oWomen have higher risk of developing liver problems during treatment with nevirapine tablets than men.oPeople who have abnormal liver test results before starting nevirapine tablets and people with hepatitis or also have greater risk of getting liver problems. oWomen have higher risk of developing liver problems during treatment with nevirapine tablets than men.. oPeople who have abnormal liver test results before starting nevirapine tablets and people with hepatitis or also have greater risk of getting liver problems. oWomen with CD4+ counts higher than 250 cells/mm3. This group has the highest risk.oMen with CD4+ counts higher than 400 cells/mm3.. oWomen with CD4+ counts higher than 250 cells/mm3. This group has the highest risk.. oMen with CD4+ counts higher than 400 cells/mm3.. odark (tea colored) urine. olight-colored bowel movements (stools). ofeeling sick to your stomach (nausea). opain or tenderness on your right side below your ribs. oloss of appetite. oyellowing of your skin or whites of your eyes. ofever. ofeel unwell or like you have the flu. otiredness. oSevere skin reactions and rash. Some skin reactions and rashes may be severe, life-threatening, and in some people, may lead to death. Most severe skin reactions and rashes happen in the first weeks of treatment with nevirapine tablets.oWomen have higher risk of developing rash during treatment with nevirapine tablets than men. oWomen have higher risk of developing rash during treatment with nevirapine tablets than men. oblisters. ored or inflamed eyes, like pink eye (conjunctivitis). oswelling of your face. ofeel unwell or like you have the flu. omuscle or joint aches. omouth sores. ofever otiredness oYour doctor should do blood tests often to check your liver function and check for severe skin reactions during the first 18 weeks of treatment with nevirapine tablets. You should continue to see your doctor and have your liver checked regularly during your treatment with nevirapine tablets. It is important for you to keep all of your doctor appointments. oIf your doctor tells you to stop treatment with nevirapine tablets because you have had any of the severe liver or skin symptoms listed above, you should never take nevirapine tablets again. oIf you are woman with CD4+ counts higher than 250 cells/mm3 or man with CD4+ counts higher than 400 cells/mm3, you and your doctor will decide if starting nevirapine is right for you.. oif you have liver problems.. oas part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens. Nevirapine tablets are only for people diagnosed with HIV-1. If you have not been diagnosed as HIV positive, then do not take nevirapine tablets.. ohave or have had hepatitis (inflammation of your liver) or problems with your liver. See What is the most important information should know about nevirapine tablets oreceive dialysis ohave trouble swallowing pills oare pregnant or plan to become pregnant. It is not known if nevirapine will harm your unborn baby. oare breastfeeding or plan to breastfeed. Nevirapine can pass into your breast milk and may harm your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Do not breastfeed during treatment with nevirapine tablets. Talk to your doctor about the best way to feed your baby. oSome medicines interact with nevirapine tablets. Keep list of your medicines to show your doctor or pharmacist. oYou can ask your doctor or pharmacist for list of medicines that interact with nevirapine tablets. oDo not start taking new medicine without telling your doctor. Your doctor can tell you if it is safe to take nevirapine tablets with other medicines.. oTake nevirapine tablets exactly as your doctor tells you to take them. Do not change your dose unless your doctor tells you to.. oNevirapine tablets are always taken in combination with other antiretroviral medicines.. oNevirapine comes in three different forms. Your doctor will prescribe the form of nevirapine that is right for you.onevirapine tablets onevirapine oral suspension onevirapine extended-release tablets. onevirapine tablets onevirapine oral suspension onevirapine extended-release tablets. oYou should not take more than one form of nevirapine at the same time. Talk to your doctor if you have any questions.. oIf your child is prescribed nevirapine, your childs doctor will tell you exactly how nevirapine should be taken.. oNevirapine tablets can be taken with or without food. oDo not miss dose of nevirapine tablets. If you miss dose of nevirapine tablets, take the missed dose as soon as you remember. If it is almost time for your next dose, do not take the missed dose. You should take the next dose at your regular time. Do not take doses at the same time. oIf you stop taking nevirapine tablets for more than days, ask your doctor how many to take before you start taking them again. You may need to begin taking the nevirapine tablets starting dose again, which is taken time each day for 14 days. 1.Your doctor should start you with dose each day to lower your chance of getting serious rash. It is important that you only take dose of nevirapine tablets each day for the first 14 days. oCall your doctor right away if you get skin rash during the first 14 days of nevirapine tablet treatment. oDo not increase your dose to times day if you have rash. oYou should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of nevirapine tablets. 2.Day 15, you will take nevirapine tablet times day.. 1.Your doctor should start you with dose each day to lower your chance of getting serious rash. It is important that you only take dose of nevirapine tablets each day for the first 14 days. oCall your doctor right away if you get skin rash during the first 14 days of nevirapine tablet treatment. oDo not increase your dose to times day if you have rash. oYou should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of nevirapine tablets. oCall your doctor right away if you get skin rash during the first 14 days of nevirapine tablet treatment. oDo not increase your dose to times day if you have rash. oYou should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have rash, you and your doctor should talk about prescribing another HIV-1 medicine for you instead of nevirapine tablets. 2.Day 15, you will take nevirapine tablet times day.. oTake nevirapine extended-release tablets time day as prescribed by your doctor. oChanges in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Tell your doctor right away if you start having new symptoms after starting your HIV-1 medicine.. oChanges in body fat can happen in people who take HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle of your body (trunk). Loss of fat from your legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.. oStore nevirapine tablets at room temperature between 20 to 25C (68 to 77F).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oLactation: Women infected with HIV-1 should be instructed not to breastfeed due to the potential for HIV-1 transmission. (8.2)oNo dose adjustment is required for patients with renal impairment with creatinine clearance greater than or equal to 20 mL per min. Patients on dialysis receive an additional dose of 200 mg following each dialysis treatment. (2.4, 8.6) oMonitor patients with hepatic fibrosis or cirrhosis carefully for evidence of drug-induced toxicity. Do not administer nevirapine to patients with Child-Pugh or C. (5.1, 8.7) oLactation: Women infected with HIV-1 should be instructed not to breastfeed due to the potential for HIV-1 transmission. (8.2). oNo dose adjustment is required for patients with renal impairment with creatinine clearance greater than or equal to 20 mL per min. Patients on dialysis receive an additional dose of 200 mg following each dialysis treatment. (2.4, 8.6) oMonitor patients with hepatic fibrosis or cirrhosis carefully for evidence of drug-induced toxicity. Do not administer nevirapine to patients with Child-Pugh or C. (5.1, 8.7) 8.1 Pregnancy Pregnancy Exposure Registry. There is pregnancy registry that monitors pregnancy outcomes in women exposed to nevirapine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary. Available data from the APR show no difference in the risk of overall major birth defects for nevirapine compared with the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) [see Data]. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk of birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from limited geographic area, and does not include outcomes for births that occurred at 20 weeks gestation. In literature reports, immediate-release nevirapine exposure (Cmin) can be up to 29% lower during pregnancy. However, as this reduction was not found to be clinically meaningful, dose adjustment is not necessary [see Data]. There is risk for severe hepatic events in pregnant women exposed to nevirapine [see Clinical Considerations]. In animal reproduction studies, no evidence of adverse developmental outcomes were observed following oral administration of nevirapine during organogenesis in the rat and rabbit, at systemic exposures (AUC) to nevirapine approximately equal (rats) and 50% higher (rabbits) than the exposure in humans at the recommended 400 mg daily dose [see Data]. Clinical Considerations. Maternal Adverse Reactions Severe hepatic events, including fatalities, have been reported in pregnant women receiving chronic nevirapine therapy as part of combination treatment of HIV-1 infection. Regardless of pregnancy status, women with CD4+ cell counts greater than 250 cells/mm3 should not initiate nevirapine unless the benefit outweighs the risk. It is unclear if pregnancy augments the risk observed in non-pregnant women [see Warnings and Precautions (5.1)]. Data. Human Data Based on prospective reports to the APR of over 2600 exposures to nevirapine during pregnancy resulting in live births (including over 1100 exposed in the first trimester), there was no difference between nevirapine and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.8% (95% CI: 1.9%, 4.0%) following first trimester exposure to nevirapine-containing regimens and 3.2% (95% CI: 2.4%, 4.3%) for second/third trimester exposure to nevirapine-containing regimens. There are several literature reports of chronic administration of immediate-release nevirapine during pregnancy, in which nevirapine pharmacokinetics were compared between pregnancy and postpartum. In these studies, the mean difference in nevirapine Cmin during pregnancy as compared to postpartum ranged from no difference to approximately 29% lower.. Animal Data Nevirapine was administered orally to pregnant rats (at 0, 12.5, 25, and 50 mg per kg per day), and rabbits (at 0, 30, 100, and 300 mg per kg per day through organogenesis (on gestation days through 16, and through 18, respectively). No adverse developmental effects were observed at doses producing systemic exposures (AUC) approximately equivalent to (rats) or approximately 50% higher (rabbits) than human exposure at the recommended daily dose. In rats, decreased fetal body weights were observed at maternally toxic dose at an exposure approximately 50% higher than the recommended daily dose. 8.2 Lactation Risk Summary. The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Published data report that nevirapine is present in human milk [see Data]. There are limited data on the effects of nevirapine on the breastfed infant. There is no information on the effects of nevirapine on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) serious adverse reactions in nursing infants, mothers should not breastfeed if they are receiving nevirapine. Data. Based on five publications, immediate-release nevirapine was excreted in breast milk at median concentrations ranging from 4080 to 6795 ng/mL, and the median maternal breast milk to maternal plasma concentration ratio range was 59 to 88%. Reported infant nevirapine median plasma concentrations were low, ranging from 734 to 1140 ng/mL. The estimated nevirapine dose of 704 to 682 mcg/kg/day for infants fed exclusively with breast milk was lower than the daily recommended nevirapine dose for infants. Published literature indicates that rash and hyperbilirubinemia have been seen in infants exposed to nevirapine through breast milk. 8.3 Females and Males of Reproductive Potential Infertility. Limited human data are insufficient to determine the risk of infertility in humans. Based on results from animal fertility studies conducted in rats, nevirapine may reduce fertility in females of reproductive potential. It is not known if these effects on fertility are reversible [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety, pharmacokinetic profile, and virologic and immunologic responses of nevirapine have been evaluated in HIV-1 infected pediatric subjects age months to 18 years [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. The safety and pharmacokinetic profile of nevirapine has been evaluated in HIV-1 infected pediatric subjects age 15 days to less than months [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. 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 [see Adverse Reactions (6.1) and Clinical Studies (14.2)]. 8.5 Geriatric Use Clinical trials of nevirapine did not include sufficient numbers of subjects aged 65 and older to determine whether elderly subjects respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. 8.6Renal Impairment In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. Nevirapine is extensively metabolized by the liver and nevirapine metabolites are extensively eliminated by the kidney. Nevirapine metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known. No adjustment in nevirapine dosing is required in patients with CrCl greater than or equal to 20 mL per min. The pharmacokinetics of nevirapine have not been evaluated in patients with CrCl less than 20 mL per min. In patients undergoing chronic hemodialysis, an additional 200 mg dose following each dialysis treatment is indicated [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)]. 8.7Hepatic Impairment Because increased nevirapine levels and nevirapine accumulation may be observed in patients with serious liver disease, do not administer nevirapine to patients with moderate or severe (Child-Pugh Class or C, respectively) hepatic impairment [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oMonitor patients for immune reconstitution syndrome and fat redistribution. (5.5, 5.6).. oMonitor patients for immune reconstitution syndrome and fat redistribution. (5.5, 5.6).. 5.1Hepatotoxicity and Hepatic Impairment Severe, life-threatening, and in some cases fatal hepatotoxicity, including fulminant and cholestatic hepatitis, hepatic necrosis and hepatic failure, have been reported in patients treated with nevirapine. 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. The risk of symptomatic hepatic events regardless of severity was greatest in the first weeks of therapy. The risk continued to be greater in the nevirapine groups compared to controls through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, subjects presented with non-specific, prodromal signs or symptoms of fatigue, malaise, anorexia, nausea, jaundice, liver tenderness or hepatomegaly, with or without initially abnormal serum transaminase levels. Rash was observed in approximately half of the subjects with symptomatic hepatic adverse events. Fever and flu-like symptoms accompanied some of these hepatic events. Some events, particularly those with rash and other symptoms, have progressed to hepatic failure with transaminase elevation, with or without hyperbilirubinemia, hepatic encephalopathy, prolonged partial thromboplastin time, or eosinophilia. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. Hepatitis/hepatic failure may be associated with signs of hypersensitivity which can 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. Patients with signs or symptoms of hepatitis must be advised to discontinue nevirapine and immediately seek medical evaluation, which should include liver enzyme tests. The first 18 weeks of therapy with nevirapine are critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening hepatic events. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, include monitoring of liver enzyme tests at baseline, prior to dose escalation and at weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue through nevirapine treatment.Transaminases should be checked immediately if patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked immediately for all patients who develop rash in the first 18 weeks of treatment. Physicians and patients should be vigilant for the appearance of signs or symptoms of hepatitis, such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinuria, acholic stools, liver tenderness or hepatomegaly. The diagnosis of hepatotoxicity should be considered in this setting, even if transaminases are initially normal or alternative diagnoses are possible [see Dosage and Administration (2.3)] If clinical hepatitis or transaminase elevations combined with rash or other systemic symptoms occur, permanently discontinue nevirapine. Do not restart nevirapine after recovery. In some cases, hepatic injury progresses despite discontinuation of treatment. The patients at greatest risk of hepatic events, including potentially fatal events, are women with high CD4+ cell counts. In general, during the first weeks of treatment, women have 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%), and patients with higher CD4+ cell counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic events with nevirapine. In retrospective review, women with CD4+ cell counts greater than 250 cells/mm3 had 12-fold higher risk of symptomatic hepatic adverse events compared to women with CD4+ cell counts less than 250 cells/mm3 (11% versus 1%). An increased risk was observed in men with CD4+ cell counts greater than 400 cells/mm3 (6% versus 1% for men with CD4+ cell counts less than 400 cells/mm3). However, all patients, regardless of gender, CD4+ cell count, or antiretroviral treatment history, should be monitored for hepatotoxicity since symptomatic hepatic adverse events have been reported at all CD4+ cell counts. Co-infection with hepatitis or and/or increased transaminase elevations at the start of therapy with nevirapine are associated with greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT. In addition, serious hepatotoxicity (including liver failure requiring transplantation in one instance) has been reported in HIV-1 uninfected individuals receiving multiple doses of nevirapine in the setting of post-exposure prophylaxis (PEP), an unapproved use. Use of nevirapine for occupational and non-occupational PEP is contraindicated [see Contraindications (4) ]. Increased nevirapine trough concentrations have been observed in some patients with hepatic fibrosis or cirrhosis. Therefore, carefully monitor patients with either hepatic fibrosis or cirrhosis for evidence of drug-induced toxicity. Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class or C, respectively) hepatic impairment [see Contraindications (4) Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]. 5.2Skin Reactions Severe and life-threatening skin reactions, including fatal cases, have been reported, occurring most frequently during the first weeks of therapy. These have included cases of Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions characterized by rash, constitutional findings, and organ dysfunction including hepatic failure. Rhabdomyolysis has been observed in some patients experiencing skin and/or liver reactions associated with nevirapine use. In controlled clinical trials, Grade and rashes were reported during the first weeks in 2% of nevirapine recipients compared to less than 1% of placebo subjects. Patients developing signs or symptoms of severe skin reactions 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) must permanently discontinue nevirapine and seek medical evaluation immediately. Do not restart nevirapine following severe skin rash, skin rash combined with increased transaminases or other symptoms, or hypersensitivity reaction. The first 18 weeks of therapy with nevirapine are critical period during which intensive clinical and laboratory monitoring of patients is required to detect potentially life-threatening skin reactions. The optimal frequency of monitoring during this time period has not been established. Some experts recommend clinical and laboratory monitoring more often than once per month, and in particular, include monitoring of liver enzyme tests at baseline, prior to dose escalation and at weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine treatment. In addition, the 14-day lead-in period with nevirapine 200 mg daily dosing has been demonstrated to reduce the frequency of rash [see Dosage and Administration (2.1)].If patients present with suspected nevirapine-associated rash, measure transaminases immediately. Permanently discontinue nevirapine in patients with rash-associated transaminase elevations [see Warnings and Precautions (5.1)]. Therapy with nevirapine must be initiated with 14-day lead-in period of 200 mg per day (150 mg/m2 per day in pediatric patients), which has been shown to reduce the frequency of rash. Discontinue nevirapine if patient experiences severe rash or any rash accompanied by constitutional findings. Do not increase nevirapine dose to patient experiencing mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg per day (150 mg/m2/day in pediatric patients) until the rash has resolved. The total duration of the once-daily lead-in dosing period must not exceed 28 days at which point an alternative regimen should be sought [see Dosage and Administration (2.4)]. Patients must be monitored closely if isolated rash of any severity occurs. Delay in stopping nevirapine treatment after the onset of rash may result in more serious reaction. Women appear to be at higher risk than men of developing rash with nevirapine. In clinical trial, concomitant prednisone use (40 mg per day for the first 14 days of nevirapine administration) was associated with an increase in incidence and severity of rash during the first weeks of nevirapine therapy. Therefore, use of prednisone to prevent nevirapine-associated rash is not recommended. 5.3Resistance Nevirapine must not be used as single agent to treat HIV-1 or added on as sole agent to failing regimen. Resistant virus emerges rapidly when nevirapine is administered as monotherapy. The choice of new antiretroviral agents to be used in combination with nevirapine should take into consideration the potential for cross resistance. When discontinuing an antiretroviral regimen containing nevirapine, the long half-life of nevirapine should be taken into account; if antiretrovirals with shorter half-lives than nevirapine are stopped concurrently, low plasma concentrations of nevirapine alone may persist for week or longer and virus resistance may subsequently develop [see Microbiology (12.4)]. 5.4Drug Interactions See Table for listings of established and potential drug interactions [see Drug Interactions (7)]. Concomitant use of St. Johns wort (Hypericum perforatum) or St. Johns wort-containing products and nevirapine is not recommended. Co-administration of St. Johns wort with non-nucleoside reverse transcriptase inhibitors (NNRTIs), including nevirapine, is expected to substantially decrease NNRTI concentrations and may result in sub-optimal levels of nevirapine and lead to loss of virologic response and possible resistance to nevirapine or to the class of NNRTIs. Co-administration of nevirapine and efavirenz is not recommended as this combination has been associated with an increase in adverse reactions and no improvement in efficacy. 5.5Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including nevirapine. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre 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 treatment.. 5.6Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. causal relationship has not been established.