Nevirapine

1 INDICATIONS & USAGE Nevirapine extended-release tablets are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 6 years of age or older with a body surface area (BSA) of 1.17 m 2 or greater [see Clinical Studies ( 14.1 , 14.2 )]. Limitations of Use: Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine extended-release tablets are 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 extended-release 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 6 years of age or older with a BSA of 1.17 m 2 or greater. ( 1 ) Limitations of Use: Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials, nevirapine extended-release tablets are 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 )

2 DOSAGE & ADMINISTRATION • The 14-day lead-in period with immediate-release nevirapine tablets (200 mg once daily) must be strictly followed; it has been demonstrated to reduce the frequency of rash. ( 2.5 , 5.2 ) • Must be swallowed whole and must not be chewed, crushed, or divided. ( 2.1 ) • Adult patients must initiate therapy with one 200 mg immediate-release nevirapine tablet once daily for the first 14 days, followed by one 400 mg tablet of nevirapine extended-release tablets once daily. ( 2.2 ) • Adult patients already on a regimen of immediate-release nevirapine tablets twice daily can be switched to nevirapine extended-release tablets 400 mg once daily without the 14-day lead-in period of immediate-release nevirapine tablets. ( 2.2 ) • Pediatric patients (ages 6 to less than 18 years with a BSA of 1.17 m 2 or greater) must initiate therapy with immediate-release nevirapine tablets (as 150 mg/m2 of Nevirapine Oral Suspension or as nevirapine tablet) at a dose not to exceed 200 mg per day administered once daily for the first 14 days, followed by nevirapine extended-release tablets 400 mg once daily. ( 2.3 ) • Pediatric patients with a BSA of 1.17 m 2 or greater already on a regimen of twice daily nevirapine tablets Oral Suspension or immediate-release nevirapine can be switched to nevirapine extended-release tablets 400 mg once daily without the 14-day lead-in period of nevirapine Oral Suspension or immediate-release nevirapine tablets. ( 2.3 ) • If any patient experiences rash during the 14-day lead-in period with immediate-release nevirapine tablets do not initiate nevirapine extended-release tablets until the rash has resolved. Do not continue the immediate-release nevirapine tablets lead-in dosing regimen beyond 28 days. ( 2.5 ) • If dosing is interrupted for greater than 7 days, restart 14-day lead-in dosing. ( 2.5 ) 2.1 General Dosing Considerations Nevirapine extended-release tablets must be swallowed whole and must not be chewed, crushed, or divided. Pediatric patients should be assessed for their ability to swallow the extended-release tablets before prescribing nevirapine extended-release tablets. Nevirapine extended-release tablets can be taken with or without food. 2.2 Recommended Dosage in Adult Patients Patients not currently taking immediate-release nevirapine Patients must initiate therapy with one 200-mg tablet of immediate-release nevirapine tablets daily for the first 14 days in combination with other antiretroviral agents. The 14-day lead-in period with nevirapine tablets 200 mg daily dosing must be strictly followed (the lead-in period has been observed to decrease the incidence of rash), followed by one 400-mg tablet of nevirapine extended-release tablets once daily [see Dosage and Administration ( 2.5 ) and Warnings and Precautions ( 5.2 )]. If rash persists beyond the 14-day lead-in period with immediate-release nevirapine tablets, do not begin dosing with nevirapine extended-release tablets. The lead-in dosing with 200 mg once daily immediate-release nevirapine tablets should not be continued beyond 28 days, at which point an alternative regimen should be sought. Switching patients from immediate-release nevirapine tablets to nevirapine extended-release tablets Patients already on a regimen of immediate-release nevirapine tablets twice daily in combination with other antiretroviral agents can be switched to nevirapine extended-release tablets 400 mg once daily without the 14-day lead-in period. Patients already on a regimen of immediate-release nevirapine tablets twice daily who switch to nevirapine extended-release tablets therapy should continue with their ongoing clinical and laboratory monitoring. 2.3 Recommended Dosage in Pediatric Patients Nevirapine extended-release tablet in pediatric patients is dosed based on body surface area (BSA) calculated using the Mosteller formula. All pediatric patients must initiate therapy with immediate-release nevirapine tablets (as 150 mg/m 2 of Nevirapine Oral Suspension or as nevirapine tablets), at a dose not to exceed 200 mg per day, administered once daily for the first 14 days. This lead-in period should be used because it has been demonstrated to reduce the frequency of rash. This lead-in period is not required if the patient is already on a regimen of twice daily immediate-release formulation in combination with other antiretroviral agents. The recommended oral dosage of nevirapine extended-release tablets for pediatric patients with a BSA of 1.17 m 2 or greater is 400 mg following the lead-in period with immediate-release nevirapine tablets. The total daily dose should not exceed 400 mg for any patient. formula 2.4 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. 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 prior to beginning the 14-day lead-in period with immediate-release nevirapine tablets, prior to initiation of nevirapine extended-release tablets, and at two weeks after initiation of nevirapine extended-release tablets therapy. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine extended-release tablets treatment [see Warnings and Precautions ( 5 )]. In some cases, hepatic injury has progressed despite discontinuation of treatment. Patients already on a regimen of immediate-release nevirapine tablets twice daily who switch to nevirapine extended-release tablets once daily should continue with their ongoing clinical and laboratory monitoring. 2.5 Dosage Adjustment Patients with Rash Discontinue nevirapine if a patient experiences severe rash or any rash accompanied by constitutional findings [see Boxed Warning, Warnings and Precautions ( 5.2 )]. Do not initiate therapy with nevirapine extended-release tablets if a patient experiences mild to moderate rash without constitutional symptoms during the 14-day lead-in period of immediate-release nevirapine tablets 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 a 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 extended-release tablets dosing for more than 7 days, restart the recommended lead-in dosing with immediate-release nevirapine tablets, using one 200 mg tablet daily for the first 14 days. Patients with Renal Impairment Patients with CrCl greater than or equal to 20 mL per min and not requiring dialysis do not require an adjustment in 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 immediate-release nevirapine tablets 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 )]. Nevirapine extended-release tablets have not been studied in patients with renal dysfunction.

6 ADVERSE REACTIONS • 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%. ( 6.1 ) • Pediatric patients: The incidence of Grade 2 or higher drug-related rash was 1%. ( 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 )]. 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. 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 [see Indications and Usage ( 1 )]. 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 [see Use in Specific Populations ( 8.4 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14.2 )]. 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 [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.

12.3 Pharmacokinetics Adults Absorption and Bioavailability The single-dose pharmacokinetics of nevirapine extended-release tablets was studied in 17 healthy volunteers. Nevirapine was absorbed with a median t max of approximately 24 hrs. The mean C max and AUC 0-∞ of nevirapine were 2060 ng per mL and 161,000 ng*hr/mL, respectively. The bioavailability of 400 mg of nevirapine extended-release tablets, relative to 400 mg of immediate-release nevirapine tablets, was approximately 75%. The multiple-dose pharmacokinetics of nevirapine extended-release tablets was studied in 24 HIV-1 infected subjects who switched from chronic immediate-release nevirapine tablets to nevirapine extended-release tablets. The mean nevirapine AUC 0-24,ss and C min,ss after 19 days of nevirapine extended-release tablets dosing under fasted conditions were 82,000 ng*hr/mL and 2,920 ng per mL, respectively. When nevirapine extended-release tablets was administered under fed conditions, the mean nevirapine AUC 0-24,ss and C min,ss were 96,700 ng*hr/mL and 3,150 ng per mL, respectively. The bioavailability of 400 mg of nevirapine extended-release tablets, relative to 400 mg of immediate-release nevirapine tablets, under fasted and fed conditions, was 80% and 94%, respectively. The difference in the bioavailability of nevirapine, when nevirapine extended-release tablets are dosed under fasted or fed conditions, is not considered clinically relevant. Nevirapine extended-release tablets can be taken with or without food. 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 studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion trial in eight healthy male volunteers dosed to steady state with immediate-release nevirapine tablets 200 mg given twice daily followed by a single 50 mg dose of 14 C-nevirapine, approximately 91.4 ± 10.5% of the radiolabeled dose was recovered, with urine (81.3 ± 11.1%) representing the primary route of excretion compared to feces (10.1 ± 1.5%). Greater than 80% of the radioactivity in urine was made up of glucuronide conjugates of hydroxylated metabolites. Thus, cytochrome P450 metabolism, glucuronide conjugation, and urinary excretion of glucuronidated metabolites represent the primary route of nevirapine biotransformation and elimination in humans. Only a small fraction (less than 5%) of the radioactivity in urine (representing less than 3% of the total dose) was made up of parent compound; therefore, renal excretion plays a minor role in elimination of the parent compound. Nevirapine is an inducer of hepatic cytochrome P450 (CYP) metabolic enzymes 3A and 2B6. Nevirapine induces CYP3A and CYP2B6 by approximately 20-25%, as indicated by erythromycin breath test results and urine metabolites. Autoinduction of CYP3A and CYP2B6 mediated metabolism leads to an approximately 1.5- to 2- fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200-400 mg per day of immediate-release nevirapine tablets. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200-400 mg per day. Specific Populations Renal Impairment HIV-1 seronegative adults with mild (CrCl 50-79 mL per min; n=7), moderate (CrCl 30-49 mL per min; n=6), or severe (CrCl less than 30 mL per min; n=4) renal impairment received a single 200 mg dose of immediate-release nevirapine tablets in a pharmacokinetic trial. These subjects did not require dialysis. The trial included six additional subjects with renal failure requiring dialysis. In subjects with renal impairment (mild, moderate or severe), there were no significant changes in the pharmacokinetics of nevirapine. However, subjects requiring dialysis exhibited a 44% reduction in nevirapine AUC over a one-week exposure period. There was also evidence of accumulation of nevirapine hydroxy-metabolites in plasma in subjects requiring dialysis. An additional 200 mg dose of immediate-release nevirapine tablets following each dialysis treatment is indicated [see Dosage and Administration ( 2.5 ) and Use in Specific Populations ( 8.6 )]. Nevirapine extended-release tablets have not been studied in patients with renal dysfunction. Hepatic Impairment In a steady-state trial comparing 46 subjects with mild (n=17; expansion of some portal areas; Ishak Score 1-2), moderate (n=20; expansion of most portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3-4), or severe (n=9; marked bridging with occasional cirrhosis without decompensation indicating Child-Pugh A; Ishak Score 5-6) fibrosis as a measure of hepatic impairment, the multiple dose pharmacokinetic disposition of nevirapine and its five oxidative metabolites were not altered. However, approximately 15% of these subjects with hepatic fibrosis had nevirapine trough concentrations above 9,000 mcg per mL (2-fold the usual mean trough). Therefore, patients with hepatic impairment should be monitored carefully for evidence of drug-induced toxicity [see Warnings and Precautions ( 5.1 )]. The subjects studied were receiving antiretroviral therapy containing immediate-release nevirapine tablets 200 mg twice daily for at least 6 weeks prior to pharmacokinetic sampling, with a median duration of therapy of 3.4 years. In a pharmacokinetic trial where HIV-1 negative cirrhotic subjects with mild (Child-Pugh A; n=6) or moderate (Child-Pugh B; n=4) hepatic impairment received a single 200 mg dose of immediate-release nevirapine tablets, a significant increase in the AUC of nevirapine was observed in one subject with Child-Pugh B and ascites suggesting that patients with worsening hepatic function and ascites may be at risk of accumulating nevirapine in the systemic circulation. Because nevirapine induces its own metabolism with multiple dosing, this single-dose trial may not reflect the impact of hepatic impairment on multiple-dose pharmacokinetics. Do not administer nevirapine to patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.7 )]. Nevirapine extended-release tablets have not been evaluated in patients with hepatic impairment. Sex In the multinational 2NN trial of immediate-release nevirapine tablets, a population pharmacokinetic substudy of 1,077 subjects was performed that included 391 female subjects. Female subjects showed a 13.8% lower clearance of nevirapine than did male subjects. Since neither body weight nor body mass Index (BMI) had an influence on the clearance of nevirapine, the effect of sex cannot be explained solely by body size. The effects of sex on the pharmacokinetics of nevirapine extended-release tablets have been investigated in Trial 1100.1486. Female subjects tend to have higher (approximately 20 - 30%) trough concentrations in both nevirapine extended-release tablets and immediate-release nevirapine tablets treatment groups. 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 C minss = 4.7 mcg per mL Black, 3.8 mcg per mL Hispanic, 4.3 mcg per mL Caucasian) with long-term treatment with immediate-release nevirapine tablets 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 tablets and nevirapine extended-release tablets treatment groups over 96 weeks of treatment at 400 mg per day. Geriatric Patients Nevirapine pharmacokinetics in HIV-1-infected adults do not appear to change with age (range 18 to 68 years); however, nevirapine has not been extensively evaluated in patients beyond the age of 65 years [see Use in Specific Populations ( 8.5 )]. Pediatric Patients The pharmacokinetics of nevirapine extended-release tablets were assessed in HIV-1 infected children 3 to less than 18 years of age. Children enrolled received weight or body surface area dose-adjusted immediate-release nevirapine tablets in combination with other antiretrovirals for a minimum of 18 weeks and then were switched to nevirapine extended-release tablets in combination with other antiretrovirals for 10 days, after which steady-state pharmacokinetic parameters were determined. Overall, the mean systemic nevirapine exposures in children 6 to less than 18 years of age following administration of nevirapine extended-release tablets and immediate-release nevirapine tablets were similar. Based on intensive PK data (N=17), the observed geometric mean ratios of nevirapine extended-release tablets to immediate-release nevirapine tablets were approximately 97% for C min,ss and 94% for AUC ss with 90% confidence intervals within 80% to 125%; the ratio for C max,ss was lower and consistent with a once daily extended-release dosage form. Trial 1100.1518 did not provide sufficient pharmacokinetic data for children 3 to less than 6 years of age to support the use of nevirapine extended-release tablets in this age group. Drug Interactions [see Drug Interactions ( 7 )] Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of nevirapine extended-release tablets and drugs primarily metabolized by CYP3A or CYP2B6 may result in decreased plasma concentrations of these drugs and attenuate their therapeutic effects. While primarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibit this system. Among human hepatic cytochrome P450s, nevirapine was capable in vitro of inhibiting the 10-hydroxylation of (R)-warfarin (CYP3A). The estimated Ki for the inhibition of CYP3A was 270 micromolar, a concentration that is unlikely to be achieved in patients as the therapeutic range is less than 25 micromolar. Therefore, nevirapine may have minimal inhibitory effect on other substrates of CYP3A. Nevirapine does not appear to affect the plasma concentrations of drugs that are substrates of other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19. Table 4 (see below) contains the results of drug interaction trials performed with immediate-release nevirapine tablets and other drugs likely to be co-administered. The effects of nevirapine on the AUC, C max , and C min of co-administered drugs are summarized. Results of drug interaction studies with immediate-release nevirapine tablets are expected to also apply to nevirapine extended-release tablets. Table 4 Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of Immediate-Release Nevirapine Tablets (All interaction studies were conducted in HIV-1 positive subjects) Co-administered Drug Dose of Coadministered Drug Dose Regimen of immediate-release Nevirapine Tablets n % Change of Co-administered Drug Pharmacokinetic Parameters (90% CI) Antiretrovirals AUC C max C min Atazanavir/ Ritonavir a, d 300/100 mg QD day 4–13, then 400/100 mg QD, day 14–23 200 mg BID day 1-23. Subjects were treated with nevirapine prior to trial entry. 23 Atazanavir 300/100 mg ↓42 (↓52 to ↓29) Atazanavir 300/100 mg ↓28 (↓40 to ↓14) Atazanavir 300/100 mg ↓72 (↓80 to ↓60) Atazanavir 400/100 mg ↓19 (↓35 to ↑2) Atazanavir 400/100 mg ↑2 (↓15 to↑24) Atazanavir 400/100 mg ↓59 (↓73 to ↓40) Darunavir/Ritonavir e 400/100 mg BID 200 mg BID 8 ↑24 (↓3 to ↑57) ↑40 (↑14 to ↑73) ↑2 (↓21 to ↑32) Didanosine 100-150 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 18 ó ó § Efavirenz a 600 mg QD 200 mg QD x 14 days; 400 mg QD x 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) ó ↓19 (↓32 to ↓4) Antiretrovirals AUC C max C min Indinavir a 800 mg q8H 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↓31 (↓39 to ↓22) ↓15 (↓24 to ↓4) ↓44 (↓53 to ↓33) Lopinavir a,b 300/75 mg/m 2 (lopinavir/ ritonavir) b 7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1 week 12, 15 c ↓22 (↓44 to ↑9) ↓14 (↓36 to ↑16) ↓55 (↓75 to ↓19) Lopinavir a 400/100 mg BID (lopinavir/ ritonavir) 200 mg QD x 14 days; 200 mg BID >1 year 22, 19 c ↓27 (↓47 to ↓2) ↓19 (↓38 to ↑5) ↓51 (↓72 to ↓26) Maraviroc f 300 mg SD 200 mg BID 8 ↑1 (↓35 to ↑55) ↑54 (↓6 to ↑151) ó Nelfinavir a Nelfinavir-M8 metabolite 750 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 23 ó ó ↓32 (↓50 to ↑5) ↓62 (↓70 to ↓53) ↓59 (↓68 to ↓48) ↓66 (↓74 to ↓55) Ritonavir 600 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 18 ó ó ó Stavudine 30-40 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 22 ó ó § Zalcitabine 0.125-0.25 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 6 ó ó § Zidovudine 100-200 mg TID 200 mg QD x 14 days; 200 mg BID x 14 days 11 ↓28 (↓40 to ↓4) ↓30 (↓51 to ↑14) § Other Medications AUC Cmax Cmin Clarithromycin a 500 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 15 ↓31 (↓38 to ↓24) ↓23 (↓31 to ↓14) ↓56 (↓70 to ↓36) Metabolite 14-OH-clarithromycin ↑42 (↑16 to ↑73) ↑47 (↑21 to ↑80) ó Ethinyl Estradiol a and Norethindrone a 0.035 mg (as Ortho-Novum® 1/35) 200 mg QD x 14 days; 200 mg BID x 14 days 10 ↓20 (↓33 to ↓3) ó § 1 mg (as Ortho-Novum® 1/35) ↓19 (↓30 to ↓7) ↓16 (↓27 to ↓3) § Depomedroxy-Progesterone Acetate 150 mg every 3 months 200 mg QD x 14 days; 200 mg BID x 14 days 32 ó ó ó Fluconazole 200 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 19 ó ó ó Ketoconazole a 400 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 21 ↓72 (↓80 to ↓60) ↓44 (↓58 to ↓27) § Methadone a Individual Subject Dosing 200 mg QD x 14 days; 200 mg BID ≥7 days 9 In a controlled pharmacokinetic trial with 9 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 7 of the 9 subjects. Methadone did not have any effect on nevirapine clearance. Rifabutin a 150 or 300 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 19 ↑17 (↓2 to ↑40) ↑28 (↑9 to ↑51) ó Metabolite 25-O-desacetyl-rifabutin ↑24 (↓16 to ↑84) ↑29 (↓2 to ↑68) ↑22 (↓14 to ↑74) Rifampin a 600 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 14 ↑11 (↓4 to ↑28) ó § § = C min below detectable level of the assay ↑ = Increase, ↓ = Decrease, ⇔ = No Effect a For information regarding clinical recommendations, [see Drug Interactions ( 7 )]. b Pediatric subjects ranging in age from 6 months to 12 years. c Parallel group design; n for nevirapine +lopinavir/ritonavir, n for lopinavir/ritonavir alone. d Parallel group design; n=23 for atazanavir/ritonavir + nevirapine, n=22 for atazanavir/ritonavir without nevirapine. Changes in atazanavir PK are relative to atazanavir/ritonavir 300/100 mg alone. e Based on between-trial comparison. f Based on historical controls. Because of the design of the drug interaction trials (addition of 28 days of nevirapine tablets therapy to existing HIV-1 therapy), the effect of the concomitant drug on plasma nevirapine steady-state concentrations was estimated by comparison to historical controls. Administration of rifampin had a clinically significant effect on nevirapine pharmacokinetics, decreasing AUC and C max by greater than 50%. Administration of fluconazole resulted in an approximate 100% increase in nevirapine exposure, based on a comparison to historic data [see Drug Interactions ( 7 )]. The effect of other drugs listed in Table 4 on nevirapine pharmacokinetics was not significant. No significant interaction was observed when tipranavir was co-administered with low-dose ritonavir and nevirapine.