Nevirapine

1 INDICATIONS AND 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 AND ADMINISTRATION • The 14-day lead-in period with immediate-release nevirapine (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 once daily. ( 2.2 ) • Adult patients already on a regimen of immediate-release nevirapine 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. ( 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 (as 150 mg/m 2 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 oral suspension or immediate-release nevirapine tablets 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 do not initiate nevirapine extended-release tablets until the rash has resolved. Do not continue the immediate-release nevirapine 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 daily for the first 14 days in combination with other antiretroviral agents. The 14-day lead-in period with nevirapine 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 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, do not begin dosing with nevirapine extended-release tablets. The lead-in dosing with 200 mg once daily immediate-release nevirapine should not be continued beyond 28 days, at which point an alternative regimen should be sought . Switching patients from immediate-release nevirapine to nevirapine extended-release tablets Patients already on a regimen of immediate-release nevirapine 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 twice daily who switch to nevirapine extended-release tablet therapy should continue with their ongoing clinical and laboratory monitoring . 2.3 Recommended Dosage in Pediatric Patients Nevirapine extended-release tablets in pediatric patients are dosed based on body surface area (BSA) calculated using the Mosteller formula. All pediatric patients must initiate therapy with immediate-release nevirapine (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 …

5 WARNINGS AND PRECAUTIONS • Monitor patients for immune reconstitution syndrome and fat redistribution. ( 5.5 , 5.6 ) 5.1 Hepatotoxicity 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. The risk of symptomatic hepatic events regardless of severity is greatest in the first 6 weeks of therapy. The risk continued to be greater in the nevirapine groups in controlled clinical trials through 18 weeks of treatment. However, hepatic events may occur at any time during treatment. In some cases, patients 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 patients 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 extended-release tablets are a 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 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 two weeks post-dose escalation. After the initial 18-week period, frequent clinical and laboratory monitoring should continue throughout nevirapine extended-release tablet treatment. Transaminases should be checked immediately if a patient experiences signs or symptoms suggestive of hepatitis and/or hypersensitivity reaction. Transaminases should also be checked immediately for all patients who develop a 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 (2.4) ] . 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 a retrospective analysis of pooled clinical trials with immediate-release nevirapine, during the first 6 weeks of treatment women had a 3-fold higher risk than men for symptomatic, often rash-associated, hepatic events (6% versus 2%). Patients with higher CD4 + cell counts at initiation of nevirapine therapy are at higher risk for symptomatic hepatic eve…

4 CONTRAINDICATIONS Nevirapine extended-release tablets are 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) ] . • for use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens [see Warnings and Precautions (5.1) ] . • Patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment. ( 4 , 5.1 , 8.7 ) • Use as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens, an unapproved use. ( 4 , 5.1 )

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 a result, drugs that are metabolized by these enzyme systems may have lower than expected plasma levels when co-administered with nevirapine. The results of drug interactions studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets. The specific pharmacokinetic changes that occur with co-administration of nevirapine and other drugs are listed in Clinical Pharmacology , Table 4. Clinical comments about possible dosage modifications based on established drug interactions are listed in Table 3. The data in Tables 3 and 4 are based on the results of drug interaction studies 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 3. Although specific drug interaction studies in HIV-1 seropositive subjects have not been conducted for some classes of drugs listed in Table 3, 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 3 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 4 for Magnitude of Interaction. Drug Name Effect on Concentration of Nevirapine or Concomitant Drug Clinical Comment HIV Antiviral Agents: Protease Inhibitors (PIs) Atazanavir/Ritonavir The interaction between immediate-release nevirapine and the drug was evaluated in a clinical study. The results of drug interaction studies with immediate-release nevirapine are expected to also apply to nevirapine extended-release tablets. ↓ Atazanavir ↑ Nevirapine Do not co-administer nevirapine with atazanavir because nevirapine substantially decreases atazanavir exposure and there is a potential risk for nevirapine-associated toxicity due to increased nevirapine exposures. 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. The combination of nevirapine administered with fosamprenavir/ritonavir once daily has not been studied. Indinavir ↓ Indinavir The appropriate doses of this combination of indinavir and nevirapine with respect to efficacy and safety have not been established. Lopinavir/Ritonavir ↓ Lopinavir Dosing in adult patients: A 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 ® 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 C min The appropriate doses of the combination of nevirapine and nelfinavir with respect to safety and efficacy have not been established. Saquinavir/Ritonavir The interaction be…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure 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 a 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 a limited geographic area, and does not include outcomes for births that occurred at < 20 weeks gestation. There is a risk for severe hepatic events in pregnant women exposed to nevirapine extended-release tablets [see Clinical Considerations ] . In animal reproduction studies, no evidence of adverse developmental outcomes was 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/mm 3 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 exposures to nevirapine during pregnancy resulting in live births (including over 1,100 exposed in the first trimester and over 1,500 exposed in the second/third trimester), the prevalence of birth defects in live births was 3.0% (95% CI: 2.1%, 4.1%) and 3.3% (95% CI: 2.4%, 4.3%) following first and second/third-trimester exposure, respectively, to nevirapine-containing regimens, compared with the background birth defect rate of 2.7% in a U.S. reference population of the MACDP. Animal Data Nevirapine was administered orally to pregnant rats (at 0, 12.5, 25, and 50 mg/kg/day), and rabbits (at 0, 30, 100, and 300 mg/kg/day) through organogenesis (on gestation days 7 through 16 and 6 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 a maternally toxic dose at an exposure approximately 50% higher than the recommended daily dose.

6 ADVERSE REACTIONS • Adult patients: The most common adverse reaction is rash. During the lead-in period with immediate-release nevirapine, 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 tablet clinical trials contains data from 800 subjects treated with nevirapine extended-release tablets and 654 subjects treated with immediate-release nevirapine. Trial 1100.1486 (VERxVE) In Trial 1100.1486 (VERxVE), treatment-naïve subjects received a lead-in dose of immediate-release nevirapine 200 mg once daily for 14 days (n = 1,068) and then were randomized to receive either immediate-release nevirapine 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/mm 3 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 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 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, 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 in…