Nevirapineside effects

Adult patients: The most common adverse reaction is rash. During the lead-in period with immediate-release nevirapine tablets, the incidence of Grade 2 or higher drug-related rash in adults is 3%. After the lead-in period the incidence of Grade 2 or higher drug-related rash in subjects taking nevirapine extended-release tablets is 3%. The incidence of Grade 2 or higher drug-related clinical hepatitis after the lead-in phase was 2%.

Pediatric patients: The incidence of Grade 2 or higher drug-related rash was 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. The most common clinical toxicity of nevirapine is rash, which can be severe or life-threatening. 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. The safety database in nevirapine extended-release tablets clinical trials contains data from 800 subjects treated with nevirapine extended-release tablets and 654 subjects treated with immediate-release nevirapine tablets. Trial 1100.1486 (VERxVE) In Trial 1100.1486 (VERxVE), treatment-naïve subjects received a lead-in dose of immediate-release nevirapine tablets 200 mg once daily for 14 days (n=1,068) and then were randomized to receive either immediate-release nevirapine tablets 200 mg twice daily (n=506) or nevirapine extended-release tablets 400 mg once daily (n=505). All subjects received tenofovir + emtricitabine as background therapy. Subjects were enrolled with CD4 + counts less than 250 cells/mm 3 for women and less than 400 cells/mm3 for men. Data on potential symptoms of hepatic events were prospectively collected in this trial. The safety data include all subject visits up to the time of the last subject’s completion of the 96-week endpoint in the trial (mean observation period 98 weeks). After the lead-in period, the incidence of any hepatic event was 9% in the immediate-release nevirapine tablets group and 6% in the nevirapine extended-release tablets group; the incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3% and 2%, respectively. The incidence of GRADE 3 or 4 ALT/AST elevation was 8% in both the immediate-release nevirapine tablets group and nevirapine extended-release tablets group. Overall, there was a comparable incidence of symptomatic hepatic events among men and women enrolled in VERxVE. Severe or life-threatening rash considered to be related to nevirapine treatment occurred in 1% of subjects during the lead-in phase with immediate-release nevirapine tablets, and in 1% of subjects in either treatment group during the randomized phase. In addition, six cases of Stevens-Johnson syndrome were reported; all but one occurred within the first 30 days of nevirapine treatment. No Grade 2 or above adverse reactions judged to be related to treatment by the investigator occurred in more than 2% of subjects during the 14-day lead-in with immediate-release nevirapine tablets (200 mg once daily), except for rash which occurred in 4% of subjects. Adverse reactions of at least moderate intensity (Grades 2 or above) occurring in 2% or more of treatment-naïve subjects receiving either immediate-release nevirapine tablets or nevirapine extended-release tablets after randomization in Trial 1100.1486 are shown in Table 1. Table 1 Selected Clinical Adverse Drug Reactions* of at least Moderate Intensity (Grade 2 or above) Occurring in 2% or more of Adult Subjects - Week 96 Analysis of Trial 1100.1486 1 Adverse Drug Reaction Immediate-Release Nevirapine Tablets N=506 (%) Nevirapine Extended-Release Tablets N = 505 (%) Rash 2 4 5 Diarrhea 4 4 Headache 4 4 Clinical Hepatitis 3 4 2 Abdominal Pain 2 3 Arthralgia 2 2 Pyrexia 2 1 Nausea 2 1 Fatigue 2 2 * Excludes laboratory abnormalities reported as ADRs 1 Mean observation period 98 weeks. 2 Rash includes terms rash, rash maculo-papular, erythema nodosum, rash erythematous, rash papular, skin reaction, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS). 3 Clinical hepatitis includes terms hepatitis, hepatotoxicity, hepatitis acute, liver disorder, hepatitis toxic, hepatic failure, jaundice. Laboratory Abnormalities Liver enzyme test abnormalities (AST, ALT) were observed in subjects receiving nevirapine extended-release tablets. Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue therapy with nevirapine in the absence of elevations in other liver enzyme tests. Laboratory abnormalities that occurred in trial 1100.1486 are shown in Table 2. Table 2 Grade 2 to Grade 4 Laboratory Abnormalities that Represent a Worsening from Baseline Observed in at least 5% of Subjects in Either Treatment Group - Trial

1100.1486 Laboratory

Parameter (unit) Limit Immediate-Release Nevirapine Tablets (%) (N=506) Nevirapine Extended-Release Tablets (%) (N=505) Chemistry SGPT/ALT (U/L) Grade 2 2.6-5.0 x ULN 13 10 Grade 3 5.1-10.0 x ULN 3 4 Grade 4 >10.0 x ULN 4 2 SGOT/AST (U/L) Grade 2 2.6-5.0 x ULN 9 7 Grade 3 5.1-10.0 x ULN 2 3 Grade 4 >10.0 x ULN 2 2 Amylase (U/L) Grade 2 1.6-2.0 x ULN 4 5 Grade 3 2.1-5.0 x ULN 4 2 Grade 4 >5.0 x ULN 0 <1 Phosphate (mg/dL) Grade 2 2.0-2.4 x ULN 38 33 Grade 3 1.0-1.9 x ULN 6 7 Grade 4 <1.0 x ULN <1 0 Hematology Neutrophils Grade 2 750-999/mm 3 7 4 Grade 3 500-749/mm 3 2 2 Grade 4 <500/mm 3 1 1 Lipids LDL (mg/dL) Grade 2 160-190 mg/dL 15 15 Grade 3 >190 mg/dL 5 5 Cholesterol (mg/dL) Grade 2 240-300 mg/dL 18 19 Grade 3 >300 mg/dL 4 3 Trial 1100.1526 (TRANxITION) In Trial 1100.1526 (TRANxITION) subjects on immediate-release nevirapine tablets 200 mg twice daily for at least 18 weeks were randomized to either receive nevirapine extended-release tablets 400 mg once daily (n=295) or remain on their immediate-release nevirapine tablets treatment (n=148). Adverse reactions observed for nevirapine extended-release tablets subjects (48 week analysis) were similar to those observed in trial 1100.1486, as displayed in Table 1. Clinical Trial Experience in Pediatric Patients Adverse reactions were assessed in Trial 1100.1518, an open-label, multiple-dose, non-randomized, cross-over trial to evaluate the safety and steady-state pharmacokinetic parameters of nevirapine extended-release tablets in HIV-1-infected pediatric subjects 3 to less than 18 years of age. Safety was further examined in an optional extension phase of the trial. Forty subjects who completed the pharmacokinetic part of the trial were treated with nevirapine extended-release tablets once daily in combination with other antiretrovirals for a median duration of 33 weeks. The most frequently reported adverse reactions related to nevirapine extended-release tablets in pediatric subjects were similar to those observed in adults. In pediatric subjects the incidence of Grade 2 or higher drug-related rash was 1%. There were no adverse reactions of Grade 2 or above which were considered to be related to treatment by the investigator that occurred in more than 1% of subjects.

6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use of immediate-release nevirapine tablets. 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, redistribution/accumulation of body fat 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 plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.