Nevirapine

1 INDICATIONS AND USAGE 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)

2 DOSAGE AND ADMINISTRATION • 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 is interrupted for greater than 7 days, restart 14-day lead-in dosing. ( 2.4 ) Adults (≥ 16 yrs) Pediatric Patients Total daily dose should not exceed 400 mg for any patient. (> 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 2.1 Adult Patients The recommended dose for nevirapine 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 14-day lead-in period with nevirapine 200 mg daily dosing must be strictly followed as the lead-in period has been observed to decrease the incidence 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. 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. Table 1 Calculation of the Volume of Nevirapine Oral Suspension (50 mg per 5 mL) Required for Pediatric Dosing Based on Body Surface and a Dose of 150 mg/m 2 BSA range (m 2 ) Volume (mL) 0.06-0.12 1.25 0.12-0.25 2.5 0.25-0.42 5 0.42-0.58 7.5 0.58-0.75 10 0.75-0.92 12.5 0.92-1.08 15 1.08-1.25 17.5 1.25+ 20 Nevirapine suspension should be shaken gently prior to administration. It is important to administer the entire measured dose of suspension by using an oral dosing syringe or dosing cup. An oral dosing syringe is recommended, particularly for volumes of 5 mL or less. If a dosing cup is used, it should be thoroughly rinsed with water and the rinse should also be administered to the 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. 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 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 if a patient experiences severe rash or any rash accompanied by constitutional findings [see Warnings and Precautions (5.2) ] . Do not increase nevirapine 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) ] . 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 …

3 DOSAGE FORMS AND STRENGTHS Nevirapine Tablets, USP are available containing 200 mg of nevirapine, USP. • The 200 mg tablets are white to off-white, oval, scored tablets debossed with NE to the left of the score and 200 to the right of the score on one side of the tablet and M to the left of the score and blank to the right of the score on the other side. • 200 mg tablets ( 3 )

4 CONTRAINDICATIONS 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) ].

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 Viatris 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 )] . 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 Background therapy included 3TC for all subjects and combinations of NRTIs and PIs. Subjects had CD4 + cell counts less than 200 cells/mm 3 . Trials 1037, 1038, 1046 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 . 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 …

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 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 HIV Antiviral Agents: Protease Inhibitors (PIs) Atazanavir/Ritonavir The interaction between nevirapine and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. ↓ 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 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. HIV Antiviral Agents: Non-Nucleoside Reverse T …

8 USE IN SPECIFIC POPULATIONS Lactation: Women infected with HIV-1 should be instructed not to breastfeed due to the potential for HIV-1 transmission. ( 8.2 ) No dose adjustment is required for patients with renal impairment with a creatinine clearance greater than or equal to 20 mL per min. Patients on dialysis receive an additional dose of 200 mg following each dialysis treatment. ( 2.4 , 8.6 ) Monitor patients with hepatic fibrosis or cirrhosis carefully for evidence of drug-induced toxicity. Do not administer nevirapine to patients with Child-Pugh B or C. ( 5.1 , 8.7 ) 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 the 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 to 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. In literature reports, immediate-release nevirapine exposure (C min ) can be up to 29% lower during pregnancy. However, as this reduction was not found to be clinically meaningful, dose adjustment is not necessary [see Data] . There is a risk for severe hepatic events in pregnant women exposed to nevirapine [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 1100 exposed in the first trimester and over 1500 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. There are several literature reports of chronic administration of immediate-release nevirapine during pregnancy, in which nevirapine pharmacokinetics were compared between pregnancy and postpartum. In these studies, the mean difference in nevirapine C min during pregnancy as compared to postpartum ranged from no difference to approximately 29% lower. Animal Data Nevirapine was administered orally to pregnant rats (at 0, 12.5, 25, and 50 mg per kg per day) and rabbits (at 0, 30, 100, and 300 mg per kg per day) through organogenesis (on gestati …

12.1 Mechanism of Action Nevirapine is an antiretroviral drug [see Microbiology (12.4) ] .

Mechanism of Action Nevirapine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1. Nevirapine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. The activity of nevirapine does not compete with template or nucleoside triphosphates. HIV-2 RT and eukaryotic DNA polymerases (such as human DNA polymerases α, ß, γ, or δ) are not inhibited by nevirapine.

11 DESCRIPTION Nevirapine tablets USP, 200 mg is the brand name for nevirapine, 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 has the following structural formula: Nevirapine tablets USP, 200 mg is for oral administration. Each tablet contains 200 mg of nevirapine anhydrous and the inactive ingredients microcrystalline cellulose, lactose monohydrate, colloidal silicon dioxide, magnesium stearate, povidone, and Sodium starch glycolate. Structure

10 OVERDOSAGE There is no known antidote for nevirapine overdosage. Cases of nevirapine overdose at doses ranging from 800 to 1800 mg per day for up to 15 days have been reported. Patients have experienced events including edema, erythema nodosum, fatigue, fever, headache, insomnia, nausea, pulmonary infiltrates, rash, vertigo, vomiting, and weight decrease. All events subsided following discontinuation of nevirapine.

16 HOW SUPPLIED/STORAGE AND HANDLING Nevirapine Tablets, USP are available containing 200 mg of nevirapine, USP. The 200 mg tablets are white to off-white, oval, scored tablets debossed with NE to the left of the score and 200 to the right of the score on one side of the tablet and M to the left of the score and blank to the right of the score on the other side. They are available as follows: NDC 0378-4050-91 bottles of 60 tablets Storage: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] Store in a safe place out of the reach of children. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide with each prescription.