NEVIRAPINE

Nevirapine, USP is a non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Nevirapine, USP is structurally a member of the dipyridodiazepinone chemical class of compounds. The chemical name of nevirapine is 11-cyclopropyl-5, 11-dihydro-4-methyl-6H-dipyrido [3, 2-b:2",3"-e] [1,4] diazepin-6-one. Nevirapine, USP is a white to off-white crystalline powder with the molecular weight of 266.30 and the molecular formula C 15 H 14 N 4 O. Nevirapine, USP has the following structural formula: Nevirapine Tablets, USP are for oral administration. Each tablet contains 200 mg of nevirapine and the inactive ingredients microcrystalline cellulose, lactose monohydrate, povidone, colloidal silicon dioxide and magnesium stearate, talc and croscarmellose sodium. Structural Formula

Nevirapine tablets, USP are indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on one principal clinical trial (BI 1090) that demonstrated prolonged suppression of HIV-1 RNA and two smaller supportive trials, one of which (BI 1046) is described below. Additional important information regarding the use of Nevirapine tablets, USP for the treatment of HIV-1 infection: Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, Nevirapine tablets, USP should not be initiated in adult females with CD4 + cell counts greater than 250 cells/mm 3 or in adult males with CD4 + cell counts greater than 400 cells/mm 3 unless the benefit outweighs the risk [ see Boxed Warning and Warnings and Precautions (5.1) ]. The 14-day lead-in period with Nevirapine tablets, USP 200 mg daily dosing must be strictly followed; it has been demonstrated to reduce the frequency 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. Nevirapine tablets, USP are an NNRTI indicated for combination antiretroviral treatment of HIV-1 infection (1) Important Considerations: Initiation of treatment is not recommended in the following populations unless the benefits outweigh the risks (1, 5.1) adult females with CD4 + cell counts greater than 250 cells/mm 3 adult males with CD4 + cell counts greater than 400 cells/mm 3 The 14-day lead-in period must be strictly followed; it has been demonstrated to reduce the frequency of rash (2.4, 5.2)

If 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) If dosing interrupted for greater than 7 days, restart 14-day lead-in dosing (2.4) Adults (≥16 yrs) Pediatric* (>15 days) First 14 days 200 mg once daily 150 mg/m 2 once daily After 14 days 200 mg twice daily 150 mg/m 2 twice daily *Total daily dose should not exceed 400 mg for any patient. 2.1 Adults The recommended dose for Nevirapine tablets, USP 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 lead-in period has been observed to decrease the incidence of rash. For concomitantly administered antiretroviral therapy, the manufacturer’s recommended dosage and monitoring should be followed. 2.2 Pediatric Patients The recommended oral dose for pediatric patients 15 days and older is 150 mg/m 2 once daily for 14 days followed by 150 mg/m 2 twice daily thereafter. The total daily dose should not exceed 400 mg for any patient. Mosteller Formula 2.3 Monitoring 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 tablets, USP. 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 two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout Nevirapine tablets, USP treatment [ see Warnings and Precautions (5) ]. In some cases, hepatic injury has progressed despite discontinuation of treatment. 2.4 Dosage Adjustment Patients with Rash Discontinue Nevirapine tablets, USP if a patient experiences severe rash or any rash accompanied by constitutional findings [ see Boxed Warning , Warnings and Precautions (5.2) , and Patient Counseling Information (17.1) ]. Do not increase Nevirapine tablets, USP dose if a patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of 200 mg/day (150 mg/m 2 /day in pediatric patients) until the rash has resolved [ see Warnings and Precautions (5.2) and Patient Counseling Information (17.1) ]. 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 a clinical (symptomatic) hepatic event occurs, permanently discontinue Nevirapine tablets, USP. Do not restart Nevirapine tablets, USP after recovery [ see Warnings and Precautions (5.1) ]. Patients with Dose Interruption For patients who interrupt Nevirapine tablets, USP dosing for more than 7 days, restart the recommended dosing, using one 200 mg tablet daily (150 mg/m 2 /day in pediatric patients) for the first 14 days (lead-in) followed by one 200 mg tablet twice daily (150 mg/m 2 twice daily for pediatric patients). Patients with Renal Impairment Patients with CrCL greater than or equal to 20 mL/min do not require an adjustment in Nevirapine tablets, USP dosing. An additional 200 mg dose of Nevirapine tablets, USP following each dialysis treatment is indicated in patients requiring dialysis. Nevirapine tablets, USP metabolites may accumulate in patients receiving dialysis; however, the clinical significance of this accumulation is not known [ see Clinical Pharmacology (12.3) ].

Patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment (4.1, 5.1, 8.7) Use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens, an unapproved use (4.2, 5.1) 4.1 Hepatic Impairment Nevirapine, USP is contraindicated in patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [ see Warnings and Precautions (5.1) and Use in Specific Populations (8.7) ]. 4.2 Post-Exposure Prophylaxis Nevirapine, USP is contraindicated for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens [ see Warnings and Precautions (5.1) ].

The most common adverse reaction is rash. In adults the incidence of rash is 15% vs 6% with placebo, with Grade 3/4 rash occurring in 2% of subjects (6.1) In pediatric subjects the incidence of rash (all causality) was 21% (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or www.amneal.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials in Adults Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most serious adverse reactions associated with Nevirapine are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [ see Boxed Warning and Warnings and Precautions (5.1, 5.2) ]. Hepatic Reaction In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received Nevirapine and 1% of subjects in control groups. Female gender and higher CD4 + cell counts (greater than 250 cells/mm 3 in women and greater than 400 cells/mm 3 in men) place patients at increased risk of these events [ see Boxed Warning and Warnings and Precautions (5.1) ]. Asymptomatic transaminase elevations (AST or ALT greater than 5X ULN) were observed in 6% (range 0% to 9%) of subjects who received Nevirapine and 6% of subjects in control groups. Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with Nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting Nevirapine) and asymptomatic increases in AST or ALT. Liver enzyme abnormalities (AST, ALT, GGT) were observed more frequently in subjects receiving Nevirapine than in controls (see Table 3). Skin Reaction The most common clinical toxicity of Nevirapine is rash, which can be severe or life-threatening [ see Boxed Warning and Warnings and Precautions (5.2) ]. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities. In controlled clinical trials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes were reported in 13% of subjects receiving Nevirapine compared to 6% receiving placebo during the first 6 weeks of therapy. Grade 3 and 4 rashes were reported in 2% of Nevirapine recipients compared to less than 1% of subjects receiving placebo. Women tend to be at higher risk for development of Nevirapine-associated rash [ see Boxed Warning and Warnings and Precautions (5.2) ]. Treatment-related, adverse experiences of moderate or severe intensity observed in greater than 2% of subjects receiving Nevirapine in placebo-controlled trials are shown in Table 2. Table 2 Percentage of Subjects with Moderate or Severe Drug-Related Events in Adult Placebo-Controlled Trials Trial 1090 1 Trials 1037, 1038, 1046 2 Nevirapine Placebo Nevirapine Placebo (n=1121) (n=1128) (n=253) (n=203) Median exposure (weeks) 58 52 28 28 Any adverse event 15% 11% 32% 13% Rash 5 2 7 2 Nausea 1 1 9 4 Granulocytopenia 2 3 <1 0 Headache 1 <1 4 1 Fatigue <1 <1 5 4 Diarrhea <1 1 2 1 Abdominal pain <1 <1 2 0 Myalgia <1 0 1 2 1 Background therapy included 3TC for all subjects and combinations of NRTIs and PIs. Subjects had CD4 + cell counts less than 200 cells/mm 3 . 2 Background therapy included ZDV and ZDV+ddI; Nevirapine monotherapy was administered in some subjects. Subjects had CD4 + cell count greater than or equal to 200 cells/mm 3 . Laboratory Abnormalities Liver enzyme test abnormalities (AST, ALT) were observed more frequently in subjects receiving Nevirapine than in controls (Table 3). Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue Nevirapine therapy in the absence of elevations in other liver enzyme tests. Other laboratory abnormalities (bilirubin, anemia, neutropenia, thrombocytopenia) were observed with similar frequencies in clinical trials comparing Nevirapine and control regimens (see Table 3). Table 3 Percentage of Adult Subjects with Laboratory Abnormalities Trial 1090 1 Trials 1037, 1038, 1046 2 Nevirapine Placebo Nevirapine Placebo Laboratory Abnormality (n=1121) (n=1128) (n=253) (n=203) Blood Chemistry SGPT (ALT) >250 U/L 5 4 14 4 SGOT (AST) >250 U/L 4 3 8 2 Bilirubin >2.5 mg/dL 2 2 2 2 Hematology Hemoglobin <8 g/dL 3 4 0 0 Platelets <50,000/mm 3 1 1 <1 2 Neutrophils <750/mm 3 13 14 4 1 1 Background therapy included 3TC for all subjects and combinations of NRTIs and PIs. Subjects had CD4 + cell counts less than 200 cells/mm 3 . 2 Background therapy included ZDV and ZDV+ddI; Nevirapine monotherapy was administered in some subjects. Subjects had CD4 + cell count greater than or equal to 200 cells/mm 3 . 6.2 Clinical Trials in Pediatric Subjects Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of Nevirapine (n=305) in which pediatric subjects received combination treatment with Nevirapine. In this trial two subjects were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome. Safety was also assessed in trial BI 1100.882 (ACTG 180), an open-label trial of Nevirapine (n=37) in which subjects were followed for a mean duration of 33.9 months (range: 6.8 months to 5.3 years, including long-term follow-up in 29 of these subjects in trial BI 1100.892). The most frequently reported adverse events related to Nevirapine in pediatric subjects were similar to those observed in adults, with the exception of granulocytopenia, which was more commonly observed in children receiving both zidovudine and Nevirapine. Cases of allergic reaction, including one case of anaphylaxis, were also reported. The safety of Nevirapine was also examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received combination treatment with 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, 4 (3%) of whom discontinued drug due to rash. All 4 subjects experienced the rash early in the course of therapy (less than 4 weeks) and resolved upon nevirapine discontinuation. Other clinically important adverse events (all causality) include neutropenia (9%), anemia (7%) and hepatotoxicity (2%) [ see Use in Specific Populations (8.4) and Clinical Studies (14.2) ]. Safety information on use of Nevirapine in combination therapy in pediatric subjects 2 weeks to less than 3 months of age was assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial. No unexpected safety findings were observed although granulocytopenia was reported more frequently in this age group compared to the older pediatric age groups and adults. 6.3 Post-Marketing Experience In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of Nevirapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: fever, somnolence, drug withdrawal [ see Drug Interactions (7) ], redistribution/accumulation of body fat [ see Warnings and Precautions(5.6) ] Gastrointestinal: vomiting Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure Hematology: anemia, eosinophilia, neutropenia Investigations: decreased serum phosphorus Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions Neurologic: paraesthesia Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue or significant hepatic abnormalities [ see Warnings and Precautions (5.1) ] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported. In post-marketing surveillance anemia has been more commonly observed in children although development of anemia due to concomitant medication use cannot be ruled out.

Nevirapine 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 a 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 4 and 5 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 a 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 5 for Magnitude of Interaction. Drug Name Effect on concentration of Nevirapine or Concomitant drug Clinical Comment Atazanavir/Ritonavir ↓ Atazanavir ↑ Nevirapine Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure. Clarithromycin ↓ Clarithromycin ↑ 14-OH clarithromycin Clarithromycin 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. Efavirenz ↓ Efavirenz There has been no determination of appropriate doses for the safe and effective use of this combination [ see Warnings and Precautions (5.4) ]. Ethinyl estradiol and Norethindrone ↓ Ethinyl estradiol ↓ Norethindrone Oral contraceptives and other hormonal methods of birth control should not be used as the sole method of contraception in women taking nevirapine, since nevirapine may lower the plasma levels of these medications. An alternative or additional method of contraception is recommended Fluconazole ↑Nevirapine Because 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. Fosamprenavir ↓Amprenavir ↑Nevirapine Co-administration of nevirapine and fosamprenavir without ritonavir is not recommended. Fosamprenavir/Ritonavir ↓Amprenavir ↑Nevirapine No dosing adjustments are required when nevirapine is co-administered with 700/100 mg of fosamprenavir/ritonavir twice daily. Indinavir ↓ Indinavir Appropriate doses for this combination are not established, but an increase in the dosage of indinavir may be required. Ketoconazole ↓ Ketoconazole Nevirapine and ketoconazole should not be administered concomitantly because decreases in ketoconazole plasma concentrations may reduce the efficacy of the drug. Lopinavir/Ritonavir ↓Lopinavir A dose increase of lopinavir/ritonavir tablets to 500/125 mg twice-daily is recommended when used in combination with nevirapine. A dose increase of lopinavir/ritonavir oral solution to 533/133 mg twice daily with food is recommended in combination with nevirapine. In children 6 months to 12 years of age receiving lopinavir/ritonavir solution, consideration should be given to increasing the dose of lopinavir/ritonavir to 13/3.25 mg/kg for those 7 to <15 kg; 11/2.75 mg/kg for those 15 to 45 kg; up to a maximum dose of 533/133 mg twice daily. Refer to the lopinavir/ritonavir package insert for complete pediatric dosing instructions when lopinavir/ritonavir tablets are used in combination with nevirapine. Methadone ↓ Methadone Methadone 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. Nelfinavir ↓Nelfinavir M8 Metabolite ↓Nelfinavir C min The appropriate dose for nelfinavir in combination with nevirapine, with respect to safety and efficacy, has not been established. Rifabutin ↑Rifabutin Rifabutin 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 ↓ Nevirapine Nevirapine 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 a nevirapine-containing regimen may use rifabutin instead. Saquinavir/Ritonavir The 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. Potential Drug Interactions Drug Class Examples of Drugs Antiarrhythmics Amiodarone, disopyramide, lidocaine Plasma concentrations may be decreased. Anticonvulsants Carbamazepine, clonazepam, ethosuximide Plasma concentrations may be decreased. Antifungals Itraconazole Plasma concentrations of some azole antifungals may be decreased. Nevirapine and itraconazole should not be administered concomitantly due to a potential decrease in itraconazole plasma concentrations. Calcium channel blockers Diltiazem, nifedipine, verapamil Plasma concentrations may be decreased. Cancer chemotherapy Cyclophosphamide Plasma concentrations may be decreased. Ergot alkaloids Ergotamine Plasma concentrations may be decreased. Immunosuppressants Cyclosporin, tacrolimus, sirolimus Plasma concentrations may be decreased. Motility agents Cisapride Plasma concentrations may be decreased. Opiate agonists Fentanyl Plasma concentrations may be decreased. Antithrombotics Warfarin Plasma concentrations may be increased. Potential effect on anticoagulation. Monitoring of anticoagulation levels is recommended. 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)