1 INDICATIONS & USAGE Nevirapine tablets are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 15 days and older [see Clinical Studies ( 14.1 , 14.2 )].

Limitations of Use: Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine tablets is not recommended to be initiated, unless the benefit outweighs the risk, in: • adult females with CD4 + cell counts greater than 250 cells/mm 3 or • adult males with CD4 + cell counts greater than 400 cells/mm 3 [see Warnings and Precautions ( 5.1 )].

•Nevirapine tablets are an NNRTI indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 15 days and older.

( 1 ) Limitations of Use: Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine tablets is not recommended to be initiated, unless the benefit outweighs the risk, in: • adult females with CD4 + cell counts greater than 250 cells/mm 3 • adult males with CD4 + cell counts greater than 400 cells/mm 3 ( 1 , 5.1 )

6 ADVERSE REACTIONS • The 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 ) • In pediatric subjects the incidence of rash (all causality) was 21%.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc.

at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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

Clinical Trial Experience in Adult Patients The most serious adverse reactions associated with nevirapine are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions.

Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see Boxed Warning and Warnings and Precautions ( 5.1 , 5.2 )].

Hepatic Reaction In controlled clinical trials, symptomatic hepatic events regardless of severity occurred in 4% (range 0% to 11%) of subjects who received nevirapine and 1% of subjects in control groups.

Female gender and higher CD4 + cell counts (greater than 250 cells/mm 3 in women and greater than 400 cells/mm 3 in men) place patients at increased risk of these events [see Boxed Warning and Warnings and Precautions ( 5.1 )].

Asymptomatic transaminase elevations (AST or ALT greater than 5X ULN) were observed in 6% (range 0% to 9%) of subjects who received nevirapine and 6% of subjects in control groups.

Co-infection with hepatitis B or C and/or increased transaminase elevations at the start of therapy with nevirapine are associated with a greater risk of later symptomatic events (6 weeks or more after starting nevirapine) and asymptomatic increases in AST or ALT.

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

Skin Reaction The most common clinical toxicity of nevirapine is rash, which can be severe or life-threatening [see Boxed Warning and Warnings and Precautions ( 5.2 )].

Rash occurs most frequently within the first 6 weeks of therapy.

Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities.

In controlled clinical trials (Trials 1037, 1038, 1046, and 1090), Grade 1 and 2 rashes were reported in 13% of subjects receiving nevirapine compared to 6% receiving placebo during the first 6 weeks of therapy.

Grade 3 and 4 rashes were reported in 2% of nevirapine recipients compared to less than 1% of subjects receiving placebo.

Women tend to be at higher risk for development of nevirapine-associated rash [see Boxed Warning and Warnings and Precautions ( 5.2 )].

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

Table 2 Percentage of Subjects with Moderate or Severe Drug-Related Events in Adult Placebo-Controlled Trials 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 <8.0 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 + ell 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 .

Clinical Trial Experience in Pediatric Patients Adverse events were assessed in BI Trial 1100.1032 (ACTG 245), a double-blind, placebo-controlled trial of nevirapine (n=305) in which pediatric subjects received combination treatment with nevirapine.

In this trial two subjects were reported to experience Stevens-Johnson syndrome or Stevens-Johnson/toxic epidermal necrolysis transition syndrome.

Safety was also assessed in trial BI 1100.882 (ACTG 180), an open-label trial of nevirapine tablets (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 tablets 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, lamivudine and zidovudine for 48 weeks [see Use in Specific Populations ( 8.4 ) and Clinical Pharmacology ( 12.3 )].

Rash (all causality) was reported in 21% of the subjects, 4 (3%) of whom discontinued drug due to rash.

All 4 subjects experienced the rash early in the course of therapy (less than 4 weeks) and resolved upon nevirapine discontinuation.

Other clinically important adverse events (all causality) include neutropenia (9%), anemia (7%), and hepatotoxicity (2%) [see Use in Specific Populations ( 8.4 ) and Clinical Studies ( 14.2 )].

Safety information on use of nevirapine in combination therapy in pediatric subjects 2 weeks to less than 3 months of age was assessed in 36 subjects from the BI 1100.1222 (PACTG 356) trial.

No unexpected safety findings were observed although granulocytopenia was reported more frequently in this age group compared to the older pediatric age groups and adults.

6.2 Postmarketing Experience In addition to the adverse events identified during clinical trials, the following adverse reactions have been identified during post-approval use of nevirapine.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: fever, somnolence, drug withdrawal [see Drug Interactions ( 7 )], redistribution/accumulation of body fat [see Warnings and Precautions ( 5.6 )] Gastrointestinal: vomiting Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure Hematology: anemia, eosinophilia, neutropenia Investigations: decreased serum phosphorus Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions Neurologic: paraesthesia Skin and Appendages: Allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported.

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

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