Nevirapine

Nevirapine Tablets are for oral administration. Each tablet contains 200 mg of nevirapine and the inactive ingredients microcrystalline cellulose, lactose monohydrate, povidone, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

12.3 Pharmacokinetics

Adults

Absorption and Bioavailability

Nevirapine is readily absorbed (greater than 90%) after oral administration in healthy volunteers and in adults with HIV-1 infection. Absolute bioavailability in 12 healthy adults following single-dose administration was 93 ± 9% (mean ± SD) for a 50 mg tablet. Peak plasma nevirapine concentrations of 2 ± 0.4 mcg/mL (7.5 micromolar) were attained by 4 hours following a single 200 mg dose. Following multiple doses, nevirapine peak concentrations appear to increase linearly in the dose range of 200 to 400 mg/day. Steady-state trough nevirapine concentrations of 4.5 ± 1.9 mcg/mL (17 ± 7 micromolar), (n=242) were attained at 400 mg/day. Nevirapine tablets and suspension have been shown to be comparably bioavailable and interchangeable at doses up to 200 mg. When Nevirapine (200 mg) was administered to 24 healthy adults (12 female, 12 male), with either a high-fat breakfast (857 kcal, 50 g fat, 53% of calories from fat) or antacid (Maalox^® 30 mL), the extent of nevirapine absorption (AUC) was comparable to that observed under fasting conditions. In a separate trial in HIV-1 infected subjects (n=6), nevirapine steady-state systemic exposure (AUCτ) was not significantly altered by didanosine, which is formulated with an alkaline buffering agent. Nevirapine may be administered with or without food, antacid or didanosine.

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 1-10 mcg/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 trials 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 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 20-25%, 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/day. 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/day.

Specific Populations

Renal Impairment

HIV-1 seronegative adults with mild (CrCL 50-79 mL/min; n=7), moderate (CrCL 30-49 mL/min; n=6), or severe (CrCL less than 30 mL/min; n=4) renal impairment received a single 200 mg dose of 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 following each dialysis treatment is indicated [see Dosage and Administration (2.4) and Use in Specific Populations (8.6)].

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/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 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 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)].

Gender

In the multinational 2NN trial, 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.

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/mL Black, 3.8 mcg/mL Hispanic, 4.3 mcg/mL Caucasian) with long-term nevirapine treatment at 400 mg/day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.

Geriatric Subjects

Nevirapine pharmacokinetics in HIV-1-infected adults do not appear to change with age (range 18–68 years); however, nevirapine has not been extensively evaluated in subjects beyond the age of 55 years [see Use in Specific Populations (8.5)].

Pediatric Subjects

Pharmacokinetic data for nevirapine have been derived from two sources: a 48-week pediatric trial in South Africa (BI Trial 1100.1368) involving 123 HIV-1 positive, antiretroviral-naïve subjects aged 3 months to 16 years; and a consolidated analysis of five Pediatric AIDS Clinical Trials Group (PACTG) protocols comprising 495 subjects aged 14 days to 19 years.

BI Trial 1100.1368 studied the safety, efficacy, and pharmacokinetics of a weight-based and a body surface area (BSA)-based dosing regimen of Nevirapine. In the weight-based regimen, pediatric subjects up to 8 years of age received a dose of 4 mg/kg once daily for two weeks followed by 7 mg/kg twice daily thereafter. Subjects 8 years and older were dosed 4 mg/kg once daily for two weeks followed by 4 mg/kg twice daily thereafter. In the BSA regimen, all pediatric subjects received 150 mg/m² once daily for two weeks followed by 150 mg/m² twice daily thereafter [see Use in Specific Populations (8.4) and Adverse Reactions (6.2)]. Dosing of nevirapine at 150 mg/m² BID (after a two-week lead-in of 150 mg/m² QD) produced geometric mean or mean trough Nevirapine concentrations between 4-6 mcg/mL (as targeted from adult data). In addition, the observed trough nevirapine concentrations were comparable between the two dosing regimens studied (BSA- and weight-based methods).

The consolidated analysis of Pediatric AIDS Clinical Trials Group (PACTG) protocols 245, 356, 366, 377, and 403 allowed for the evaluation of pediatric subjects less than 3 months of age (n=17). The plasma nevirapine concentrations observed were within the range observed in adults and the remainder of the pediatric population, but were more variable between subjects, particularly in the second month of age. For dose recommendations for pediatric patients [see Dosage and Administration (2.2)].

Drug Interactions [see Drug Interactions (7)]

Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of Nevirapine 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 5 (see below) contains the results of drug interaction trials performed with 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.

Table 5 Drug Interactions: Changes in Pharmacokinetic Parameters for Co-administered Drug in the Presence of Nevirapine (All interaction trials were conducted in HIV-1 positive subjects)

§ = Cmin below detectable level of the assay
↑ = Increase, ↓ = Decrease, ⇔ = No Effect
Co-administered Drug	Dose of Co-administered Drug	Dose Regimen of Nevirapine	n	% Change of Co-administered Drug Pharmacokinetic Parameters (90% CI)
Antiretrovirals				AUC	C max	C min
Atazanavir/RitonavirFor information regarding clinical recommendations, see Drug Interactions (7). 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.	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 Based on between-trial comparison.	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	⇔	⇔	§
EfavirenzFor information regarding clinical recommendations, see Drug Interactions (7).	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)	⇔	↓19 (↓32 to ↓4)
IndinavirFor information regarding clinical recommendations, see Drug Interactions (7).	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)
LopinavirFor information regarding clinical recommendations, see Drug Interactions (7). Pediatric subjects ranging in age from 6 months to 12 years	300/75 mg/m2 (lopinavir/ ritonavir) Pediatric subjects ranging in age from 6 months to 12 years	7 mg/kg or 4 mg/ kg QD x 2 weeks; BID x 1 week	12, 15Parallel group design; n for Nevirapine + lopinavir/ritonavir, n for lopinavir/ritonavir alone.	↓22 (↓44 to ↑9)	↓14 (↓36 to ↑16)	↓55 (↓75 to ↓19)
LopinavirFor information regarding clinical recommendations, see Drug Interactions (7).	400/100 mg BID (lopinavir/ ritonavir)	200 mg QD x 14 days; 200 mg BID > 1 year	22, 19Parallel group design; n for Nevirapine + lopinavir/ritonavir, n for lopinavir/ritonavir alone.	↓27 (↓47 to ↓2)	↓19 (↓38 to ↑5)	↓51 (↓72 to ↓26)
Maraviroc Based on historical controls.	300 mg SD	200 mg BID	8	↑1 (↓35 to ↑55)	↑54 (↓6 to ↑151)	⇔
NelfinavirFor information regarding clinical recommendations, see Drug Interactions (7).	750 mg TID	200 mg QD x 14 days; 200 mg BID x 14 days	23	⇔	⇔	↓32 (↓50 to ↑5)
Nelfinavir-M8 metabolite				↓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	⇔	⇔	⇔
Stavudine	30-40 mg BID	200 mg QD x 14 days; 200 mg BID x 14 days	22	⇔	⇔	§
Zalcitabine	0.125-0.25 mg TID	200 mg QD x 14 days; 200 mg BID x 14 days	6	⇔	⇔	§
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	C max	C min
ClarithromycinFor information regarding clinical recommendations, see Drug Interactions (7).	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)	⇔
Ethinyl estradiolFor information regarding clinical recommendations, see Drug Interactions (7). and NorethindroneFor information regarding clinical recommendations, see Drug Interactions (7).	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)	⇔	§
	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	⇔	⇔	⇔
Fluconazole	200 mg QD	200 mg QD x 14 days; 200 mg BID x 14 days	19	⇔	⇔	⇔
KetoconazoleFor information regarding clinical recommendations, see Drug Interactions (7).	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	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.
RifabutinFor information regarding clinical recommendations, see Drug Interactions (7).	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)	⇔
Metabolite 25-O-desacetyl rifabutin				↑24 (↓16 to ↑84)	↑29 (↓2 to ↑68)	↑22 (↓14 to ↑74)
RifampinFor information regarding clinical recommendations, see Drug Interactions (7).	600 mg QD	200 mg QD x 14 days; 200 mg BID x 14 days	14	↑11 (↓4 to ↑28)	⇔	§

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 5 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, β, 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 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 14-302 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 ZDV (n=14) were monitored in Phase 1 and 2 trials over 1 to ≥12 weeks. 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.

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 and 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

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. The mechanism of the carcinogenic potential is unknown. 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. 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 of Nevirapine.

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 Clinical Trials in Adults

Trial BI 1090 was a placebo-controlled, double-blind, randomized trial in 2249 HIV-1 infected subjects with less than 200 CD4⁺ cells/mm³ at screening. Initiated in 1995, BI 1090 compared treatment with Nevirapine + lamivudine + background therapy versus lamivudine + background therapy in NNRTI-naïve subjects. Treatment doses were Nevirapine, 200 mg daily for two weeks followed by 200 mg twice daily or placebo, and lamivudine, 150 mg twice daily. Other antiretroviral agents were given at approved doses. Initial background therapy (in addition to lamivudine) was one NRTI in 1309 subjects (58%), two or more NRTIs in 771 (34%), and PIs and NRTIs in 169 (8%). The subjects (median age 36.5 years, 70% Caucasian, 79% male) had advanced HIV-1 infection, with a median baseline CD4⁺ cell count of 96 cells/mm³ and a baseline HIV-1 RNA of 4.58 log¹⁰ copies/mL (38,291 copies/mL). Prior to entering the trial, 45% had previously experienced an AIDS-defining clinical event. Eighty-nine percent had antiretroviral treatment prior to entering the trial. BI 1090 was originally designed as a clinical endpoint trial. Prior to unblinding the trial, the primary endpoint was changed to proportion of subjects with HIV-1 RNA less than 50 copies/mL and not previously failed at 48 weeks. Treatment response and outcomes are shown in Table 6.

Table 6 BI 1090 Outcomes Through 48 Weeks

Outcome	Nevirapine (N=1121) %		Placebo (N=1128) %
Responders at 48 weeks: HIV-1 RNA <50 copies/mL	18		2
Treatment Failure	82		98
Never suppressed viral load		45		66
Virologic failure after response		7		4
CDC category C event or death		10		11
Added antiretroviral therapy including change to open-label nevirapine while <50 copies/mL		5		1
Discontinued trial therapy due to AE		7		6
Discontinued trial <48 weeks includes withdrawal of consent, lost to follow-up, non-compliance with protocol, other administrative reasons		9		10

The change from baseline in CD4⁺ cell count through one year of therapy was significantly greater for the Nevirapine group compared to the placebo group for the overall trial population (64 cells/mm³ vs 22 cells/mm³, respectively), as well as for subjects who entered the trial as treatment-naïve or having received only ZDV (85 cells/mm³ vs 25 cells/mm³, respectively).

At two years into the trial, 16% of subjects on Nevirapine had experienced class C CDC events as compared to 21% of subjects on the control arm.

Trial BI 1046 (INCAS) was a double-blind, placebo-controlled, randomized, three-arm trial with 151 HIV-1 infected subjects with CD4⁺ cell counts of 200-600 cells/mm³ at baseline. BI 1046 compared treatment with Nevirapine + zidovudine + didanosine to Nevirapine + zidovudine and zidovudine + didanosine. Treatment doses were Nevirapine at 200 mg daily for two weeks followed by 200 mg twice daily or placebo, zidovudine at 200 mg three times daily, and didanosine at 125 or 200 mg twice daily (depending on body weight). The subjects had mean baseline HIV-1 RNA of 4.41 log¹⁰ copies/mL (25,704 copies/mL) and mean baseline CD4⁺ cell count of 376 cells/mm³. The primary endpoint was the proportion of subjects with HIV-1 RNA less than 400 copies/mL and not previously failed at 48 weeks. The virologic responder rates at 48 weeks were 45% for subjects treated with Nevirapine + zidovudine + didanosine, 19% for subjects treated with zidovudine+didanosine, and 0% for subjects treated with Nevirapine + zidovudine.

CD4⁺ cell counts in the Nevirapine + ZDV + ddI group increased above baseline by a mean of 139 cells/mm³ at one year, significantly greater than the increase of 87 cells/mm³ in the ZDV + ddI subjects. The Nevirapine + ZDV group mean decreased by 6 cells/mm³ below baseline.

14.2 Clinical Trials in Pediatric Subjects

The pediatric safety and efficacy of Nevirapine was examined in BI Trial 1100.1368, an open-label, randomized clinical trial performed in South Africa in which 123 HIV-1 infected treatment-naïve subjects between 3 months and 16 years of age received Nevirapine oral suspension for 48 weeks. Subjects were divided into 4 age groups (3 months to less than 2 years, 2 to less than 7 years, 7 to less than 12 years, and 12 to less than or equal to 16 years) and randomized to receive one of two Nevirapine doses, determined by 2 different dosing methods [body surface area (150 mg/m²) and weight-based dosing (4 or 7 mg/kg)] in combination with zidovudine and lamivudine [see Adverse Reactions (6.2), Use in Specific Population (8.4), and Clinical Pharmacology (12.3)]. The total daily dose of Nevirapine did not exceed 400 mg in either regimen. There were 66 subjects in the body surface area (BSA) dosing group and 57 subjects in the weight-based (BW) dosing group.

Baseline demographics included: 49% male; 81% Black and 19% Caucasian; 4% had previous exposure to ARVs. Subjects had a median baseline HIV-1 RNA of 5.45 log₁₀ copies/mL and a median baseline CD4⁺ cell count of 527 cells/mm³ (range 37-2279). One hundred and five (85%) completed the 48-week period while 18 (15%) discontinued prematurely. Of the subjects who discontinued prematurely, 9 (7%) discontinued due to adverse reactions and 3 (2%) discontinued due to virologic failure. Overall the proportion of subjects who achieved and maintained an HIV-1 RNA less than 400 copies/mL at 48 weeks was 47% (58/123).

For dose recommendations for pediatric patients [see Dosage and Administration (2.2)].

16 HOW SUPPLIED/STORAGE AND HANDLING

Nevirapine Tablets, USP, 200 mg, are white or off white oval, biconvex tablets, 8.9 mm x 17.8 mm. One side is embossed with "H9050". The opposite side has a single bisect.

Nevirapine Tablets, USP, 200mg are supplied in bottles of 60 (NDC 51991-331-06).

Dispense in tight container as defined in the USP/NF

Storage

Store at 20°C-25°C (68°F-77°F), excursion permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Store in a safe place out of the reach of children.

17 PATIENT COUNSELING INFORMATION

• “See FDA-approved patient labeling (Medication Guide), separately provided”

17.1 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, do not escalate the Nevirapine dose until the rash resolves. The total duration of the once-daily lead-in dosing period 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 [see Boxed Warning and Warnings and Precautions (5.2)].

17.2 Administration

Inform patients to take Nevirapine 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.

Inform patients that it is not known whether Nevirapine therapy reduces the risk of transmission of HIV-1 to others through sexual contact. Effective treatment combined with safer sex practices may reduce the chance of passing HIV to others through sexual contact. Patients should be advised to continue to practice safer sex and to use latex or polyurethane condoms to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions or blood. Patients should be advised never to re-use or share needles.

Nevirapine is 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.

Inform patients that they should not take Nevirapine tablets or oral suspension and Nevirapine extended release tablets at the same time.

17.3 Drug Interactions

Nevirapine 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)].

17.4 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, since Nevirapine may lower the plasma levels of these medications. Additionally, when oral contraceptives are used for hormonal regulation during Nevirapine therapy, the therapeutic effect of the hormonal therapy should be monitored [see Drug Interactions (7)].

17.5 Methadone

Nevirapine 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)].

17.6 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)].

Manufactured by:
Zhejiang Huahai Pharmaceutical Co., Ltd.
Linhai, Zhejiang, China

Distributed by:
Breckenridge Pharmaceutical, Inc.
Boca Raton, FL 33487

Issued: 03/2012

MEDICATION GUIDE
Nevirapine Tablets, USP

Read this Medication Guide before you start taking Nevirapine 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?

Nevirapine 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 highest during the first 18 weeks of treatment.

1. Severe liver problems: Anyone who takes Nevirapine 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 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 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 treatment and people with hepatitis B or C also have a greater chance of getting liver problems.

You may get a rash if you have liver problems.

Stop taking Nevirapine and call your doctor right away if you have any of the following symptoms of liver problems:

• dark (tea colored) urine
• nausea (feeling sick to your stomach)
• yellowing of your skin or whites of your eyes
• feel unwell or like you have the flu
• light-colored bowel movements (stools)
• pain or tenderness on your right side below your ribs
• fever
• tiredness
• loss of appetite

Your doctor should see you and do blood tests often to check your liver function during the first 18 weeks of treatment with Nevirapine. You should continue to have your liver checked regularly during your treatment with Nevirapine. 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. Most rashes happen in the first 6 weeks of taking Nevirapine. Rashes and skin reactions may be severe, life-threatening, and in some people, may lead to death. Stop using Nevirapine and call your doctor right away if you get a rash with any of the following symptoms:

• blisters
• swelling of your face
• mouth sores
• fever
• red or inflamed eyes, like “pink eye” (conjunctivitis)
• feel unwell or like you have the flu
• liver problems (see symptoms of liver problems above)
• tiredness
• muscle or joint aches

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

See the section "What are the possible side effects of Nevirapine?" for more information.

What is Nevirapine?

Nevirapine is a prescription medicine used to treat Human Immunodeficiency Virus (HIV), the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

Nevirapine is a type of anti-HIV medicine called a "non-nucleoside reverse transcriptase inhibitor" (NNRTI). Nevirapine works by lowering the amount of HIV in your blood ("viral load"). You must take Nevirapine with other anti-HIV medicines. When you take Nevirapine with other anti-HIV medicines, Nevirapine can lower your viral load and increase the number of CD4⁺ cells ("T cells"). CD4⁺ cells are a type of immune helper cell in the blood. Nevirapine may not have these effects in every person.

Nevirapine does not cure HIV or AIDS, and it is not known if it will help you live longer with HIV. People taking Nevirapine may still get infections common in people with HIV (opportunistic infections). It is very important that you stay under the care of your doctor.

It is not known if Nevirapine lowers the chance of passing HIV to other people. Effective treatment combined with safer sex practices, may reduce the chance of passing HIV to others through sexual contact. Always practice safer sex by using a latex or polyurethane condom or other barrier method to lower the chance of sexual contact with any body fluids such as semen, vaginal secretions, or blood. Never reuse or share needles. Take your HIV medicines as prescribed.

Who should not take Nevirapine?

Tell your doctor if you have or have had liver problems. Your doctor may tell you not to take Nevirapine if you have certain liver problems.

Nevirapine is only for people diagnosed with HIV. If you have not been diagnosed as HIV positive, then do not take Nevirapine.

What should I tell my doctor before taking Nevirapine?

Before you take Nevirapine, 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?” and “Who should not take Nevirapine?”
• receive dialysis
• have skin problems, such as a rash
• are pregnant or plan to become pregnant. It is not known if Nevirapine 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. It is also recommended that HIV-positive women should not breast-feed their babies. Do not breast-feed during treatment with Nevirapine. Talk to your doctor about the best way to feed your baby.

Tell your doctor and pharmacist about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Nevirapine may affect the way other medicines work, and other medicines may affect how Nevirapine works.

You should not take Nevirapine if you also take:

• St. John's Wort. St. John's Wort can lower the amount of Nevirapine in your body.
• efavirenz (Sustiva^®, Atripla^®). Efavirenz may cause you to have an increased chance of side effects.
• atazanavir (Reyataz^®)
• lopinavir and ritonavir (Kaletra^®)
• fosamprenavir calcium (Lexiva^®)
• 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.

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^®)

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?

• Nevirapine is always taken in combination with other anti-HIV medications.
• Take Nevirapine exactly as your doctor tells you to take it. 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.
• You may take Nevirapine with or without food.
• Do not miss a dose of Nevirapine, because this could make HIV harder to treat. If you miss a dose of Nevirapine, 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 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 starting dose again, which is taken 1 time each day for 14 days.

Starting Nevirapine tablets:

1. Your doctor should start you with 1 dose each day to lower your chance of getting a serious rash. It is important that you only take 1 dose of 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 Nevirapine treatment and do not increase your dose to 2 times a day.
• 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 increase your dose to 2 times a day if you have a rash.

2. Day 15, you will take 1 Nevirapine tablet two times a day.

What are the possible side effects of Nevirapine?

Nevirapine may cause serious side effects, including:

• See "What is the most important information I should know about Nevirapine?"
• 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 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. For more information, ask your doctor or pharmacist.

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

How should I store Nevirapine?

• Store Nevirapine at 59°F to 86°F (15°C to 30°C)
• Throw away Nevirapine that is no longer needed or out-of-date.

Keep Nevirapine and all medicines out of the reach of children.

General information about Nevirapine.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Nevirapine for a condition for which it was not prescribed. Do not give Nevirapine 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. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about Nevirapine that is written for health professionals.

For more information, call Breckenridge Pharmaceutical, Inc., at 1-(800)-367-3395.

What are the ingredients in Nevirapine Tablets, USP?

Active ingredient: nevirapine

Inactive ingredients: microcrystalline cellulose, lactose monohydrate, povidone, sodium starch glycolate, colloidal silicon dioxide, and magnesium stearate

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

Manufactured by:
Zhejiang Huahai Pharmaceutical Co., Ltd.
Linhai, Zhejiang, China

Distributed by:
Breckenridge Pharmaceutical, Inc.
Boca Raton, FL 33487

Revised: 03/2012

PRINCIPAL DISPLAY PANEL- 200mg

Breckenridge,
Pharmaceutical, Inc.

NDC 51991-331-06

Nevirapine Tablets, USP

200 mg

PHARMACIST: PLEASE DISPENSE WITH MEDICATION GUIDE

60 Tablets       Rx only