Nevirapine

Nevirapine extended-release tablets are for oral administration. Each tablet contains 400 mg of nevirapine and the inactive ingredients are hypromellose, iron oxide yellow, lactose monohydrate, and magnesium stearate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Nevirapine is an antiviral drug [see MICROBIOLOGY (12.4)].

12.3 Pharmacokinetics

Adults

Absorption and Bioavailability

The single-dose pharmacokinetics of nevirapine extended-release 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, relative to 400 mg of immediate-release nevirapine, was approximately 75%.

The multiple-dose pharmacokinetics of nevirapine extended-release was studied in 24 HIV-1 infected subjects who switched from chronic nevirapine immediate-release to nevirapine extended-release. The mean nevirapine AUC_0-24,ss and C_min,ss after 19 days of nevirapine extended-release dosing under fasted conditions were 82,000 ng*hr/mL and 2920 ng per mL, respectively. When nevirapine extended-release was administered under fed conditions, the mean nevirapine AUC_0-24,ss and C_min,ss were 96,700 ng*hr/mL and 3150 ng per mL, respectively. The bioavailability of 400 mg of nevirapine extended-release, relative to 400 mg of immediate-release nevirapine, under fasted and fed conditions, was 80 % and 94 %, respectively. The difference in the bioavailability of nevirapine, when nevirapine extended-release is dosed under fasted or fed conditions, is not considered clinically relevant. Nevirapine extended-release can be taken with or without food.

In single-dose, parallel-group bioavailability trial (1100.1517) in adults, the nevirapine extended-release 100 mg tablet exhibited extended-release characteristics of prolonged absorption and lower maximal concentration, as compared to the immediate-release nevirapine 200 mg tablet.

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 (8.3)]. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1 to 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 200 mg given twice daily followed by a single 50 mg dose of ¹⁴C-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 to 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 to 400 mg per day of immediate-release nevirapine. 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 to 30 hours following multiple dosing with 200 to 400 mg per day.

Specific Populations

Renal Impairment

HIV-1 seronegative adults with mild (CrCL 50 to 79 mL per min; n=7), moderate (CrCL 30 to 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 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 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 to 2), moderate (n=20; expansion of most portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3 to 4), or severe (n=9; marked bridging with occasional cirrhosis without decompensation indicating Child-Pugh A; Ishak Score 5 to 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 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, 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 has not been evaluated in patients with hepatic impairment.

Gender

In the multinational 2NN trial of immediate-release nevirapine, a population pharmacokinetic substudy of 1077 subjects was performed that included 391 females. Female subjects showed a 13.8% lower clearance of nevirapine than did men. Since neither body weight nor Body Mass Index (BMI) had an influence on the clearance of nevirapine, the effect of gender cannot solely be explained by body size.

The effects of gender on the pharmacokinetics of nevirapine extended-release have been investigated in Trial 1100.1486. Female subjects tend to have higher (approximately 20 to 30%) trough concentrations in both nevirapine extended-release and immediate-release nevirapine 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 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 to 325 subjects/group) in both immediate-release nevirapine and nevirapine extended-release 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

Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Viramune XR® (nevirapine) extended-release tablets. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

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 K_i 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 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 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 (All interaction studies were conducted in HIV-1 positive subjects)

§ = 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.

^fBased on historical controls.

Because of the design of the drug interaction trials (addition of 28 days of nevirapine 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.

12.4 Microbiology

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.

Antiviral Activity

The antiviral activity of nevirapine has been measured in a variety of cell lines including peripheral blood mononuclear cells, monocyte-derived macrophages, and lymphoblastoid cell lines. In an assay using human embryonic kidney 293 cells, the median EC₅₀ value (50% inhibitory concentration) of nevirapine was 90 nM against a panel of 2923 wild-type isolates of HIV-1 that were primarily (93%) clade B clinical isolates from the United States. The 99^th percentile EC₅₀ value was 470 nM in this trial. The median EC₅₀ value was 63 nM (range 14 to 302 nM, n=29) against clinical isolates of HIV-1 clades A, B, C, D, F, G, and H, and circulating recombinant forms CRF01_AE, CRF02_AG and CRF12_BF. Nevirapine had no antiviral activity in cell culture against group O HIV-1 isolates (n=3) or HIV-2 isolates (n=3) replicating in cord blood mononuclear cells. Nevirapine in combination with efavirenz exhibited strong antagonistic anti-HIV-1 activity in cell culture and was additive to antagonistic with the protease inhibitor ritonavir or the fusion inhibitor enfuvirtide. Nevirapine exhibited additive to synergistic anti-HIV-1 activity in combination with the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir, and the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine. The anti-HIV-1 activity of nevirapine was antagonized by the anti-HBV drug adefovir and by the anti-HCV drug ribavirin in cell culture.

Resistance

HIV-1 isolates with reduced susceptibility (100- to 250-fold) to nevirapine emerge in cell culture. Genotypic analysis showed mutations in the HIV-1 RT gene encoding Y181C and/or V106A substitutions depending upon the virus strain and cell line employed. Time to emergence of nevirapine resistance in cell culture was not altered when selection included nevirapine in combination with several other NNRTIs.

Phenotypic and genotypic changes in HIV-1 isolates from treatment-naïve subjects receiving either nevirapine (n=24) or nevirapine and zidovudine (n=14) were monitored in Phase 1 and 2 trials ranging from 1 to 12 weeks or longer. After 1 week of nevirapine monotherapy, isolates from 3/3 subjects had decreased susceptibility to nevirapine in cell culture. One or more of the RT mutations resulting in amino acid substitutions K103N, V106A, V108I, Y181C, Y188C, and G190A were detected in HIV-1 isolates from some subjects as early as 2 weeks after therapy initiation. By week eight of nevirapine monotherapy, 100% of the subjects tested (n=24) had HIV-1 isolates with a greater than 100-fold decrease in susceptibility to nevirapine in cell culture compared to baseline, and had one or more of the nevirapine-associated RT resistance substitutions. Nineteen of these subjects (80%) had isolates with Y181C substitutions regardless of dose.

Genotypic analysis of isolates from antiretroviral-naïve subjects experiencing virologic failure (n=71) receiving nevirapine once daily (n=25) or twice daily (n=46) in combination with lamivudine and stavudine (trial 2NN) for 48 weeks showed that isolates from 8/25 and 23/46 subjects, respectively, contained one or more of the following NNRTI resistance-associated substitutions: Y181C, K101E, G190A/S, K103N, V106A/M, V108I, Y188C/L, A98G, F227L, and M230L.

For trial 1100.1486, genotypic analysis was performed for baseline and on-therapy isolates from 23 and 34 subjects who experienced virologic failure in the nevirapine extended-release tablets and immediate-release nevirapine treatment group, respectively. Nevirapine resistance-associated substitutions developed in the on-therapy isolates of 78% (18/23) of the subjects who had virologic failures in the nevirapine extended-release tablets treatment group and 88% (30/34) of the subjects in the immediate-release nevirapine treatment group, respectively. The Y181C nevirapine resistance-associated substitution was found alone or in combination with other nevirapine resistance-associated substitutions (K101E, K103N, V106A, V108I, V179D/E/I, Y188 C/F/H/L/N, G190A, P225H, F227L, M230L) in isolates from 14 subjects failing nevirapine extended-release tablets treatment and 25 subjects failing immediate-release nevirapine treatment. On-therapy isolates from 1 subject in nevirapine extended-release tablets treatment group developed a novel amino acid substitution Y181I and isolates from another subject in the immediate-release nevirapine treatment group developed a novel amino acid substitution Y188N. Phenotypic analysis showed that Y188N and Y181I substitutions conferred 103- and 22-fold reductions in susceptibility to nevirapine, respectively.

Cross-resistance

Rapid emergence of HIV-1 strains which are cross-resistant to NNRTIs has been observed in cell culture. Nevirapine-resistant HIV-1 isolates were cross-resistant to the NNRTIs delavirdine, efavirenz, and etravirine. The Y188N conferred 22- and 7-fold reductions in susceptibility to delavirdine and efavirenz, respectively, but showed no decrease in susceptibility to etravirine. Similarly, the Y181I substitution reduced susceptibility to delavirdine and etravirine 3- and 8-fold, respectively, but did not reduce susceptibility to efavirenz. However, nevirapine-resistant isolates were susceptible to the NRTIs ddI and ZDV. Similarly, ZDV-resistant isolates were susceptible to nevirapine in cell culture.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term carcinogenicity studies in mice and rats were carried out with nevirapine. Mice were dosed with 0, 50, 375 or 750 mg/kg/day for two years. Hepatocellular adenomas and carcinomas were increased at all doses in males and at the two high doses in females. In studies in which rats were administered nevirapine at doses of 0, 3.5, 17.5 or 35 mg/kg/day for two years, an increase in hepatocellular adenomas was seen in males at all doses and in females at the high dose. The systemic exposure (based on AUCs) at all doses in the two animal studies was lower than that measured in humans at the 200 mg twice daily dose of immediate-release nevirapine. The mechanism of the carcinogenic potential is unknown.

Mutagenesis

However, in genetic toxicology assays, nevirapine showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included microbial assays for gene mutation (Ames: Salmonella strains and E. coli), mammalian cell gene mutation assay (CHO/HGPRT), cytogenetic assays using a Chinese hamster ovary cell line and a mouse bone marrow micronucleus assay following oral administration. Given the lack of genotoxic activity of nevirapine, the relevance to humans of hepatocellular neoplasms in nevirapine-treated mice and rats is not known.

Impairment of Fertility

In reproductive toxicology studies, evidence of impaired fertility was seen in female rats at doses providing systemic exposure, based on AUC, approximately equivalent to that provided with the recommended clinical dose.

13.2 Animal Toxicology and/or Pharmacology

Animal studies have shown that nevirapine is widely distributed to nearly all tissues and readily crosses the blood-brain barrier.

14 CLINICAL STUDIES

14.1 Adult Patients

The clinical efficacy of nevirapine extended-release tablets is based on 96-week data from an ongoing, randomized, double-blind, double-dummy Phase 3 trial (Trial 1100.1486, VERxVE) in treatment-naïve subjects and on 48-week data in an ongoing, randomized, open-label trial in subjects who switched from immediate-release nevirapine tablets administered twice daily to nevirapine extended-release tablets administered once daily (Trial 1100.1526, TRANxITION).

Treatment-naïve Subjects

Trial 1100.1486 (VERxVE) is a Phase 3 trial in which treatment-naïve subjects received immediate-release nevirapine 200 mg once daily for 14 days and then were randomized to receive either immediate-release nevirapine 200 mg twice daily or nevirapine extended-release 400 mg once daily. All subjects received tenofovir + emtricitabine as background therapy. Randomization was stratified by screening HIV-1 RNA level (less than or equal to 100,000 copies per mL and greater than 100,000 copies per mL). Subject demographic and baseline disease characteristics were balanced between the two treatment groups. With respect to demographics: 85% of the subjects were male, 75% were white, 20% were black, and approximately 29% were from North America. With respect to baseline disease characteristics: mean viral load was 4.7 log₁₀ copies per mL, mean CD4 ⁺ cell count was 228 cells/mm³ and 73% of subjects had clade B HIV-1 subtype. Approximately two-thirds of the subjects had a baseline HIV-RNA level of less than or equal to 100,000 copies per mL.

Table 5 describes week 96 outcomes in the Trial 1100.1486 (VERxVE). These outcomes include all subjects who were randomized after the 14 day lead-in with immediate-release nevirapine and received at least one dose of blinded study medication.

Table 5 Outcomes at Week 96 in Trial 1100.1486

#Includes subjects who changed optimized background therapy (OBT) to new class or changed OBT not permitted per protocol or due to lack of efficacy prior to Week 96, subjects who discontinued prior to Week 96 for lack or loss of efficacy and subjects with HIV RNA greater than or equal to 50 copies/mL in the Week 96 window.

*Includes subjects who discontinued due to adverse events or death at any time point from Day 1 through the Week 96 window if this resulted in no virologic data on treatment during the specified window.

**Other includes: withdrew consent, lost to follow-up, moved away, etc.

At 96 weeks, mean change from baseline in CD4⁺ cell count adjusting for baseline HIV-1 viral load stratum was 222 cells/mm³ and 244 cells/mm³ for the groups receiving immediate-release nevirapine and nevirapine extended-release, respectively.

Subjects Switching from Immediate-Release Nevirapine to Nevirapine Extended-Release

Trial 1100.1526 (TRANxITION) is a Phase 3 trial to evaluate safety and antiviral activity of switching from immediate-release nevirapine to nevirapine extended-release tablets. In this open-label trial, 443 subjects already on an antiviral regimen containing immediate-release nevirapine 200 mg twice daily with HIV-1 RNA less than 50 copies per mL were randomized in a 2:1 ratio to nevirapine extended-release 400 mg once daily or immediate-release nevirapine 200 mg twice daily. Approximately half of the subjects had tenofovir+emtricitabine as their background therapy, with the remaining subjects receiving abacavir sulfate+lamivudine or zidovudine+lamivudine. Approximately half of the subjects had at least 3 years of exposure to immediate-release nevirapine prior to entering the trial.

At 48 weeks after randomization in Trial 1100.1526, 91% of subjects receiving immediate-release nevirapine 200 mg twice daily and 93% of subjects receiving nevirapine extended-release 400 mg once daily continued to have HIV-1 RNA less than 50 copies per mL.

14.2 Pediatric Patients

Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Viramune XR® (nevirapine) extended-release tablets. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

16 HOW SUPPLIED/STORAGE AND HANDLING

Nevirapine extended-release tablets, 400 mg, are oval, off-white to yellow tablet core, debossed SZ on one side and 211 on the reverse side

NDC 0781-5893-31, bottle of 30 tablets

NDC 0781-5893-05, bottle of 500 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.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

• • Hepatotoxicity and Skin Reactions

Inform patients of the possibility of severe liver disease or skin reactions associated with nevirapine that may result in death. Instruct patients developing signs or symptoms of liver disease or severe skin reactions to discontinue nevirapine and seek medical attention immediately, including performance of laboratory monitoring. Symptoms of liver disease include fatigue, malaise, anorexia, nausea, jaundice, acholic stools, liver tenderness or hepatomegaly.Symptoms of severe skin or hypersensitivity reactions include rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions,conjunctivitis, facial edema, and/or hepatitis.

Intensive clinical and laboratory monitoring, including liver enzymes, is essential during the first 18 weeks of therapy with nevirapine to detect potentially life-threatening hepatotoxicity and skin reactions. However, liver disease can occur after this period; therefore, monitoring should continue at frequent intervals throughout nevirapine treatment. Extra vigilance is warranted during the first 6 weeks of therapy, which is the period of greatest risk of hepatic events and skin reactions. Advise patients with signs and symptoms of hepatitis to discontinue nevirapine and seek medical evaluation immediately. If nevirapine is discontinued due to hepatotoxicity, do not restart it. Patients, particularly women, with increased CD4⁺ cell count at initiation of nevirapine therapy (greater than 250 cells/mm³ in women and greater than 400 cells/mm³ in men) are at substantially higher risk for development of symptomatic hepatic events, often associated with rash. Advise patients that co-infection with hepatitis B or C and/or increased transaminases 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 [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)].

The majority of rashes associated with nevirapine occur within the first 6 weeks of initiation of therapy. Instruct patients that if any rash occurs during the two-week lead-in period with immediate-release nevirapine, do not initiate nevirapine extended-release tablets until the rash resolves. The total duration of the lead-in dosing period with immediate-release nevirapine should not exceed 28 days, at which point an alternative regimen may need to be started. Any patient experiencing a rash should have their liver enzymes (AST, ALT) evaluated immediately. Patients with severe rash or hypersensitivity reactions should discontinue nevirapine immediately and consult a physician. Nevirapine should not be restarted following severe skin rash or hypersensitivity reaction. Women tend to be at higher risk for development of nevirapine-associated rash. For patients who interrupt nevirapine extended-release tablets dosing for more than 7 days and for whom restarting nevirapine therapy is not contraindicated, restart the recommended lead-in dosing with immediate-release nevirapine using one 200 mg tablet daily for the first 14 days [see BOXED WARNING, DOSAGE AND ADMINISTRATION (2.5),and WARNINGS AND PRECAUTIONS (5.2)].

Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Viramune XR® (nevirapine) extended-release tablets. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

• • Administration

Inform patients to take nevirapine extended-release tablets every day as prescribed. Patients should not alter the dose without consulting their doctor. If a dose is missed, patients should take the next dose as soon as possible. However, if a dose is skipped, the patient should not double the next dose. Advise patients to report to their doctor the use of any other medications.

Instruct patients to swallow nevirapine extended-release tablets whole. They must not be chewed, crushed, or divided.

Nevirapine extended-release tablets are not a cure for HIV-1 infection; patients may continue to experience illnesses associated with advanced HIV-1 infection, including opportunistic infections. Advise patients to remain under the care of a physician when using nevirapine extended-release tablets.

Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death.

Advise patients to avoid doing things that can spread HIV-1 infection to others:

• • Do not share needles or other injection equipment.
• • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• • Do not breastfeed. We do not know if nevirapine can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Inform patients that they may occasionally see soft remnants of nevirapine extended-release tablets in their stool, which sometimes resemble intact tablets. These occurrences have not been shown to affect drug levels or response.

• • Drug Interactions

Nevirapine extended-release tablets may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's Wort [see WARNINGS AND PRECAUTIONS (5.4) and DRUG INTERACTIONS (7 )].

• • Contraceptives

Hormonal methods of birth control, other than depomedroxy-progesterone acetate (DMPA), should not be used as the sole method of contraception in women taking nevirapine extended-release tablets, since nevirapine extended-release tablets may lower the plasma levels of these medications. Additionally, when oral contraceptives are used for hormonal regulation during nevirapine extended-release tablets therapy, the therapeutic effect of the hormonal therapy should be monitored [see DRUG INTERACTIONS (7)].

• • Methadone

Nevirapine extended-release tablets may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly. Monitor methadone-maintained patients beginning nevirapine therapy for evidence of withdrawal and adjust methadone dose accordingly [see DRUG INTERACTIONS (7)].

• • Fat Redistribution

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time [see WARNINGS AND PRECAUTIONS (5.6)].

MEDICATION GUIDE

Nevirapine Extended-Release Tablets

(ne-vir’-a-peen)

Read this Medication Guide before you start taking nevirapine extended-release tablets and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or treatment.

What is the most important information I should know about nevirapine extended-release tablets?

Nevirapine extended-release tablets can cause serious side effects. These include severe liver and skin problems that can cause death. These problems can happen at any time during treatment, but your risk is higher during the first 18 weeks of treatment.

1. Severe liver problems: Anyone who takes nevirapine extended-release tablets may get severe liver problems. In some cases these liver problems can lead to liver failure and the need for a liver transplant, or death.

People who have a higher CD4⁺ cell count when they begin nevirapine extended-release tablets treatment have a higher risk of liver problems, especially:

• •Women with CD4⁺ counts higher than 250 cells/mm³. This group has the highest risk.
• •Men with CD4⁺ counts higher than 400 cells/mm³.

If you are a woman with CD4⁺ counts higher than 250 cells/mm³ or a man with CD4⁺ counts higher than 400 cells/mm³, you and your doctor will decide whether starting nevirapine extended-release tablets is right for you.

In general, women have a higher risk of liver problems compared to men.

People who have abnormal liver test results before starting nevirapine extended-release tablets treatment and people with hepatitis B or C also have a greater risk of getting liver problems.

You may get a rash if you have liver problems.

Stop taking nevirapine extended-release tablets and call your doctor right away if you have any of the following symptoms of liver problems:

Your doctor should see you and do blood tests often to check your liver function during the first 18 weeks of treatment with nevirapine extended-release tablets. You should continue to have your liver checked regularly during your treatment with nevirapine extended-release tablets. It is important for you to keep all of your doctor appointments.

2. Severe rash and skin reactions: Skin rash is the most common side effect of nevirapine extended-release tablets. Most rashes happen in the first 6 weeks of taking nevirapine extended-release tablets. Rashes and skin reactions may be severe, life-threatening, and in some people, may lead to death. Stop using nevirapine extended-release tablets and call your doctor right away if you get a rash with any of the following symptoms:

If your doctor tells you to stop treatment with nevirapine extended-release tablets because you have had any of the serious liver or skin problems described above, you should never take nevirapine extended-release tablets again.

See the section “What are the possible side effects of nevirapine extended-release tablets?” for more information.

What are nevirapine extended-release tablets?

• •Nevirapine extended-release tablets are a prescription HIV medicine used with other HIV medicines to treat HIV (Human Immunodeficiency Virus) in adults. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).
• •Nevirapine extended-release tablets are a type of HIV medicine called a non-nucleoside reverse transcriptase inhibitor (NNRTI).

Nevirapine extended-release tablets are not for use in children.

Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Viramune XR® (nevirapine) extended-release tablets. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

When used with other HIV medicines, nevirapine may:

• 1.Reduce the amount of HIV in your blood (called “viral load”)
• 2.Help increase the number of CD4 (T) cells in your blood which help fight off other infections.

Reducing the amount of HIV and increasing the CD4 (T) cell count may improve your immune system. This may reduce your risk of death or infections that can happen when your immune system is weak (opportunistic infections).

Nevirapine does not cure HIV infection or AIDS.

Nevirapine does not cure HIV or AIDS and you may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. You should remain under the care of a doctor when using nevirapine.

You must stay on continuous HIV therapy to control HIV infection and decrease HIV-related illnesses.

Avoid doing things that can spread HIV-1 infection to others:

• • Do not share needles or other injection equipment.
• • Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• • Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Ask your doctor if you have any questions on how to prevent passing HIV to other people.

Who should not take nevirapine extended-release tablets?

Tell your doctor if you have or have had liver problems. Your doctor may tell you not to take nevirapine extended-release tablets if you have certain liver problems.

Nevirapine extended-release tablets are only for people diagnosed with HIV. If you have not been diagnosed as HIV positive, then do not take nevirapine extended-release tablets.

What should I tell my doctor before taking nevirapine extended-release tablets?

Before you take nevirapine extended-release tablets, tell your doctor if you:

• •have or have had hepatitis (inflammation of your liver) or problems with your liver. See “What is the most important information I should know about nevirapine extended-release tablets?” and “Who should not take nevirapine extended-release tablets?”
• •receive dialysis
• •have skin problems, such as a rash
• •have any other medical conditions
• •are pregnant or plan to become pregnant. It is not known if nevirapine extended-release tablets will harm your unborn baby.
  Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.
• •are breast-feeding or plan to breast-feed. Nevirapine can pass into your breast milk and may harm your baby. You should not breast-feed if you have HIV because of the risk of passing HIV to your baby. Do not breast-feed during treatment with nevirapine extended-release tablets. Talk to your doctor about the best way to feed your baby.

Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Viramune XR® (nevirapine) extended-release tablets. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Tell your doctor and pharmacist about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Nevirapine extended-release tablets may affect the way other medicines work, and other medicines may affect how nevirapine extended-release tablets work.

You should not take nevirapine extended-release tablets if you also take:

• •St. John’s Wort. St. John’s Wort can lower the amount of nevirapine in your body.
• •efavirenz (Sustiva^®, Atripla^®), etravirine (Intelence^®), rilpivirine (Edurant^® Complera^®), or delavirdine (Rescriptor^®)
• •boceprevir (Victrelis^®)
• •telaprevir (Incivek^®)
• •atazanavir (Reyataz^®)
• •lopinavir and ritonavir (Kaletra^®) once daily
• •fosamprenavir calcium (Lexiva^®) without ritonavir (Norvir^®)
• •itraconazole (Sporanox^®)
• •ketoconazole (Nizoral^®)
• •rifampin (Rifadin^®, Rifamate^®, Rifater^®)
• •birth control pills. Birth control pills taken by mouth (oral contraceptives) and other hormone types of birth control may not work to prevent pregnancy. Talk with your doctor about other types of birth control that you can use to prevent pregnancy during treatment with nevirapine extended-release tablets.

Also tell your doctor if you take:

• •clarithromycin (Biaxin^®)
• •fluconazole (Diflucan^®)
• •indinavir sulfate (Crixivan^®)
• •methadone
• •nelfinavir mesylate (Viracept^®)
• •rifabutin (Mycobutin^®)
• •warfarin (Coumadin^®, Jantoven ^®)
• •saquinavir mesylate (Invirase^®)
• •amiodarone, disopyramide (Norpace^®), lidocaine
• •carbamazepine, clonazepam (Klonopin^®), ethosuximide (Zarontin^®)
• •diltiazem, nifedipine, verapamil
• •cyclophosphamide
• •ergotamine
• •cyclosporine, tacrolimus, sirolimus (Rapamune^®)
• •cisapride (Propulsid^®)
• •fentanyl

If you are not sure if you take a medicine above, ask your doctor or pharmacist.

Know the medicines you take. Keep a list of them to show your doctor or pharmacist when you get a new medicine.

How should I take nevirapine extended-release tablets?

• •Nevirapine extended-release tablets are always taken in combination with other anti-HIV medications.
• •Nevirapine comes in three different forms. Your doctor will prescribe the form of nevirapine that is right for you.
  • •Nevirapine immediate-release tablets
  • •Nevirapine oral suspension
  • •Nevirapine extended-release tablets
• •Take nevirapine extended-release tablets exactly as your doctor tells you to take them. Do not change your dose unless your doctor tells you to.
• •You should never take more than one form of nevirapine at the same time. Talk to your doctor if you have any questions
• •Swallow nevirapine extended-release tablets whole. Do not chew, crush or divide nevirapine extended-release tablets.
• •You may take nevirapine extended-release tablets with or without food.
• •Do not miss a dose of nevirapine extended-release tablets. If you miss a dose of nevirapine extended-release tablets, take the missed dose as soon as you remember. If it is almost time for your next dose, do not take the missed dose, just take the next dose at your regular time. Do not take two doses at the same time.
• •If you stop taking nevirapine extended-release tablets for more than 7 days, ask your doctor how much to take before you start taking it again. You may need to begin taking the nevirapine immediate-release tablets starting dose again, which is taken 1 time each day for 14 days.

Pediatric use information is approved for Boehringer Ingelheim Pharmaceuticals, Inc.’s Viramune XR® (nevirapine) extended-release tablets. However, due to Boehringer Ingelheim Pharmaceuticals, Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Starting nevirapine extended-release tablets when this is the first time you are taking any form of nevirapine:

1. Your doctor should start you with 1 dose of immediate-release nevirapine tablets or oral suspension each day to lower your risk of getting a serious rash. It is important that you only take 1 dose of immediate-release nevirapine each day for the first 14 days.

• • Call your doctor right away if you get a skin rash during the first 14 days of immediate-release nevirapine treatment.
• •You should never take your starting dose for longer than 28 days. If after 28 days you are still receiving this starting dose because you have a rash, you and your doctor should talk about prescribing another HIV medicine for you instead of nevirapine.
• • Do not start nevirapine extended-release tablets if you have a rash.

2. Day 15, take nevirapine extended-release tablets 1 time a day as prescribed by your doctor.

Switching from nevirapine immediate-release tablets or oral suspension to nevirapine extended-release tablets:

Take nevirapine extended-release tablets 1 time a day as prescribed by your doctor.

You may sometimes pass a soft mass in your stools (bowel movement) that looks like your nevirapine extended-release tablets. This will not affect the way your medicine works.

What are the possible side effects of nevirapine extended-release tablets?

Nevirapine extended-release tablets may cause serious side effects, including:

• •See “What is the most important information I should know about nevirapine extended-release tablets?”
• • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your doctor if you start having new symptoms after starting your HIV medicine.
• • Changes in body fat can happen in some people who take antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from your legs, arms, and face can also happen. The cause and long-term health effects of these problems are not known at this time.

The most common side effect of nevirapine extended-release tablets is rash.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of nevirapine extended-release tablets. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088.

How should I store nevirapine extended-release tablets?

• •Store nevirapine extended-release tablets at room temperature between 20° to 25°C (68° to 77°F).
• •Throw away nevirapine extended-release tablets that are no longer needed or out-of-date.

Keep nevirapine extended-release tablets and all medicines out of the reach of children.

General information about nevirapine extended-release tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not take nevirapine extended-release tablets for a condition for which it was not prescribed. Do not give nevirapine extended-release tablets to other people, even if they have the same condition you have. It may harm them.

This Medication Guide summarizes the most important information about nevirapine extended-release tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about nevirapine extended-release tablets that is written for health professionals.

For more information, call Sandoz Inc. at 1-800-525-8747.

What are the ingredients in nevirapine extended-release tablets.?

Active ingredient: nevirapine

Inactive ingredients: hypromellose, iron oxide yellow, lactose monohydrate, and magnesium stearate.

This Medication Guide has been approved by the U.S. Food and Drug Administration

The brands listed are trademarks of their respective owners and are not trademarks of Sandoz Inc.

7438

04-2014M

Sandoz Inc.

Princeton, NJ 08540

400 mg Label