Nevirapine Extended-Release Tablets, for Oral Use

Name: Nevirapine Extended-Release Tablets, for Oral Use

Indications

VIRAMUNE XR is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adults and pediatric patients 6 to less than 18 years of age [see Clinical Studies].

Limitations Of Use:

Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials VIRAMUNE XR is not recommended to be initiated, unless the benefit outweighs the risk, in:

  • adult females with CD4+ cell counts greater than 250 cells/mm3 or
  • adult males with CD4+ cell counts greater than 400 cells/mm3 [see WARNINGS AND PRECAUTIONS].

Clinical pharmacology

Mechanism Of Action

Nevirapine is an antiretroviral drug [see Microbiology].

Pharmacokinetics

Adults

Absorption and Bioavailability

The single-dose pharmacokinetics of VIRAMUNE XR was studied in 17 healthy volunteers. Nevirapine was absorbed with a median tmax of approximately 24 hrs. The mean Cmax and AUC0-∞ of nevirapine were 2060 ng per mL and 161,000 ng*hr/mL, respectively. The bioavailability of 400 mg of VIRAMUNE XR, relative to 400 mg of immediate-release VIRAMUNE, was approximately 75%.

The multiple-dose pharmacokinetics of VIRAMUNE XR was studied in 24 HIV-1 infected subjects who switched from chronic VIRAMUNE IR to VIRAMUNE XR. The mean nevirapine AUC0-24,ss and Cmin,ss after 19 days of VIRAMUNE XR dosing under fasted conditions were 82,000 ng*hr/mL and 2920 ng per mL, respectively. When VIRAMUNE XR was administered under fed conditions, the mean nevirapine AUC0-24,ss and Cmin,ss were 96,700 ng*hr/mL and 3150 ng per mL, respectively. The bioavailability of 400 mg of VIRAMUNE XR, relative to 400 mg of immediate-release VIRAMUNE, under fasted and fed conditions, was 80% and 94%, respectively. The difference in the bioavailability of nevirapine, when VIRAMUNE XR is dosed under fasted or fed conditions, is not considered clinically relevant. VIRAMUNE XR can be taken with or without food.

In single-dose, parallel-group bioavailability trial (1100.1517) in adults, the VIRAMUNE XR 100 mg tablet exhibited extended-release characteristics of prolonged absorption and lower maximal concentration, as compared to the immediate-release VIRAMUNE 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 (8.2)]. Nevirapine is about 60% bound to plasma proteins in the plasma concentration range of 1-10 mcg per mL. Nevirapine concentrations in human cerebrospinal fluid (n=6) were 45% (±5%) of the concentrations in plasma; this ratio is approximately equal to the fraction not bound to plasma protein.

Metabolism/Elimination

In vivo studies in humans and in vitro studies with human liver microsomes have shown that nevirapine is extensively biotransformed via cytochrome P450 (oxidative) metabolism to several hydroxylated metabolites. In vitro studies with human liver microsomes suggest that oxidative metabolism of nevirapine is mediated primarily by cytochrome P450 (CYP) isozymes from the CYP3A and CYP2B6 families, although other isozymes may have a secondary role. In a mass balance/excretion trial in eight healthy male volunteers dosed to steady state with immediate-release VIRAMUNE 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 2fold increase in the apparent oral clearance of nevirapine as treatment continues from a single dose to two-to-four weeks of dosing with 200-400 mg per day of immediate-release VIRAMUNE. Autoinduction also results in a corresponding decrease in the terminal phase half-life of nevirapine in plasma, from approximately 45 hours (single dose) to approximately 25-30 hours following multiple dosing with 200-400 mg per day.

Specific Populations

Renal Impairment

HIV-1 seronegative adults with mild (CrCL 50-79 mL per min; n=7), moderate (CrCL 30-49 mL per min; n=6), or severe (CrCL less than 30 mL per min; n=4) renal impairment received a single 200 mg dose of immediate-release VIRAMUNE 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 VIRAMUNE following each dialysis treatment is indicated [see DOSAGE AND ADMINISTRATION and Use In Specific Populations]. VIRAMUNE XR has not been studied in patients with renal dysfunction.

Hepatic Impairment

In a steady-state trial comparing 46 subjects with mild (n=17; expansion of some portal areas; Ishak Score 1-2), moderate (n=20; expansion of most portal areas with occasional portal-to-portal and portal-to-central bridging; Ishak Score 3-4), or severe (n=9; marked bridging with occasional cirrhosis without decompensation indicating Child-Pugh A; Ishak Score 5-6) fibrosis as a measure of hepatic impairment, the multiple dose pharmacokinetic disposition of nevirapine and its five oxidative metabolites were not altered. However, approximately 15% of these subjects with hepatic fibrosis had nevirapine trough concentrations above 9,000 mcg per mL (2-fold the usual mean trough). Therefore, patients with hepatic impairment should be monitored carefully for evidence of drug-induced toxicity [see WARNINGS AND PRECAUTIONS]. The subjects studied were receiving antiretroviral therapy containing immediate-release VIRAMUNE 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 VIRAMUNE, 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, WARNINGS AND PRECAUTIONS, and Use In Specific Populations]. VIRAMUNE XR has not been evaluated in patients with hepatic impairment.

Gender

In the multinational 2NN trial of immediate-release VIRAMUNE, 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 VIRAMUNE XR have been investigated in Trial 1100.1486. Female subjects tend to have higher (approximately 20 30%) trough concentrations in both VIRAMUNE XR and immediate-release VIRAMUNE 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 Cminss = 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 VIRAMUNE at 400 mg per day. However, the pharmacokinetics of nevirapine have not been evaluated specifically for the effects of ethnicity.

Black subjects (n=80/group) in Trial 1100.1486 showed approximately 30 to 35% higher trough concentrations than Caucasian subjects (250-325 subjects/group) in both immediate-release VIRAMUNE and VIRAMUNE XR 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 18–68 years); however, nevirapine has not been extensively evaluated in patients beyond the age of 65 years [see Use In Specific Populations].

Pediatric Patients

The pharmacokinetics of VIRAMUNE XR were assessed in HIV-1 infected children 3 to less than 18 years of age. Children enrolled received weight or body surface area dose-adjusted immediate-release VIRAMUNE in combination with other antiretrovirals for a minimum of 18 weeks and then were switched to VIRAMUNE XR tablets in combination with other antiretrovirals for 10 days, after which steady-state pharmacokinetic parameters were determined.

Overall, the mean systemic nevirapine exposures in children 6 to less than 18 years of age following administration of VIRAMUNE XR and immediate-release VIRAMUNE were similar. Based on intensive PK data (N=17), the observed geometric mean ratios of VIRAMUNE XR to immediate-release VIRAMUNE were approximately 97% for Cmin,ss and 94% for AUCss with 90% confidence intervals within 80% - 125%; the ratio for Cmax,ss was lower and consistent with a once daily extended-release dosage form.

Trial 1100.1518 did not provide sufficient pharmacokinetic data for children 3 to less than 6 years of age to support the use of VIRAMUNE XR in this age group.

Drug Interactions

[see DRUG INTERACTIONS]

Nevirapine induces hepatic cytochrome P450 metabolic isoenzymes 3A and 2B6. Co-administration of VIRAMUNE XR and drugs primarily metabolized by CYP3A or CYP2B6 may result in decreased plasma concentrations of these drugs and attenuate their therapeutic effects.

While primarily an inducer of cytochrome P450 3A and 2B6 enzymes, nevirapine may also inhibit this system. Among human hepatic cytochrome P450s, nevirapine was capable in vitro of inhibiting the 10-hydroxylation of (R)-warfarin (CYP3A). The estimated Ki for the inhibition of CYP3A was 270 micromolar, a concentration that is unlikely to be achieved in patients as the therapeutic range is less than 25 micromolar. Therefore, nevirapine may have minimal inhibitory effect on other substrates of CYP3A.

Nevirapine does not appear to affect the plasma concentrations of drugs that are substrates of other CYP450 enzyme systems, such as 1A2, 2D6, 2A6, 2E1, 2C9, or 2C19.

Table 5 (see below) contains the results of drug interaction trials performed with immediate-release VIRAMUNE and other drugs likely to be co-administered. The effects of nevirapine on the AUC, Cmax, and Cmin of co-administered drugs are summarized. Results of drug interaction studies with immediate-release VIRAMUNE are expected to also apply to VIRAMUNE XR.

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

Co-administered Drug Dose of Coadministered Drug Dose Regimen of immediate-release VIRAMUNE n % Change of Co-administered Drug Pharmacokinetic Parameters (90% CI)
Antiretrovirals AUC Cmax Cmin
Atazanavir/ Ritonavira, d 300/100 mg QD day 4–13, then 400/100 mg QD, day 14–23 200 mg BID day 1-23. Subjects were treated with nevirapine prior to trial entry. 23 Atazanavir 300/100 mg
↓42
(↓52 to ↓29)		 Atazanavir 300/100 mg
↓28
(↓40 to ↓14)		 Atazanavir 300/100 mg
↓72
(↓80 to ↓60)
        Atazanavir 400/100 mg
↓19
(↓35 to ↑2)		 Atazanavir 400/100 mg
↑2
(↓15 to↑24)		 Atazanavir 400/100 mg
↓59
(↓73 to ↓40)
Darunavir/ Ritonavir e 400/100 mg BID 200 mg BID 8 ↑24
(↓3 to ↑57)		 ↑40
(↑14 to ↑73)		 ↑2
(↓21 to ↑32)
Didanosine 100-150 mg BID 200 mg QD x 14 days; 200 mg BID x 14 days 18 ⇔ ⇔ §
Efavirenza 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)
Indinavira 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)
Lopinavira, b 300/75 mg/m2 (lopinavir/ ritonavir) b 7 mg/kg or 4 mg/kg QD x 2 weeks; BID x 1 week 12, 15c ↓22
(↓44 to ↑9)		 ↓14
(↓36 to ↑16)		 ↓55
(↓75 to ↓19)
Lopinavira 400/100 mg BID (lopinavir/ ritonavir) 200 mg QD x 14 days; 200 mg BID >1 year 22, 19c ↓27
(↓47 to ↓2)		 ↓19
(↓38 to ↑5)		 ↓51
(↓72 to ↓26)
Maraviroc f 300 mg SD 200 mg BID 8 ↑1
(↓35 to ↑55)		 ↑54
(↓6 to ↑151)		 ⇔
Nelfinavira 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 Cmax Cmin
Clarithromycina 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 estradiola
and		 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)		 ⇔ §
Norethindronea 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 ⇔ ⇔ ⇔
Ketoconazolea 400 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 21 ↓72
(↓80 to ↓60)		 ↓44
(↓58 to ↓27)		 §
Methadonea 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.
Rifabutina 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)
Rifampina 600 mg QD 200 mg QD x 14 days; 200 mg BID x 14 days 14 ↑11
(↓4 to ↑28)		 ⇔ §
§ = Cmin below detectable level of the assay
↑ = Increase, ↓ = Decrease, ⇔ = No Effect
a For information regarding clinical recommendations, see DRUG INTERACTIONS.
b Pediatric subjects ranging in age from 6 months to 12 years
c Parallel group design; n for VIRAMUNE+lopinavir/ritonavir, n for lopinavir/ritonavir alone.
d Parallel group design; n=23 for atazanavir/ritonavir + nevirapine, n=22 for atazanavir/ritonavir without nevirapine. Changes in atazanavir PK are relative to atazanavir/ritonavir 300/100 mg alone.
e Based on between-trial comparison.
f Based on historical controls.

Because of the design of the drug interaction trials (addition of 28 days of VIRAMUNE 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 Cmax 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]. 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.

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 99th 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. The anti-HIV-1 activity of nevirapine was not antagonistic in combination with the NRTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir and zidovudine, and the protease inhibitors amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir and tipranavir. 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 nevirapineassociated 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 VIRAMUNE XR and immediate-release VIRAMUNE 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 VIRAMUNE XR treatment group and 88% (30/34) of the subjects in the immediate-release VIRAMUNE 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 VIRAMUNE XR treatment and 25 subjects failing immediate-release VIRAMUNE treatment. On-therapy isolates from 1 subject in VIRAMUNE XR treatment group developed a novel amino acid substitution Y181I and isolates from another subject in the immediate-release VIRAMUNE 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.

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.

Clinical Studies

Adult Patients

The clinical efficacy of VIRAMUNE XR 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 VIRAMUNE tablets administered twice daily to VIRAMUNE XR 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 VIRAMUNE 200 mg once daily for 14 days and then were randomized to receive either immediate-release VIRAMUNE 200 mg twice daily or VIRAMUNE XR 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 6 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 VIRAMUNE and received at least one dose of blinded study medication.

Table 6 Outcomes at Week 96 in Trial 1100.1486

  Week 96
VIRAMUNE Immediate-Release
N=506		 VIRAMUNE XR
N=505
Virologic Success - HIV RNA < 50 copies/mL 67% 69%
Virologic Failure # 18% 17%
No Virologic Data at Week 96 Window    
Reasons    
  Discontinued trial/study drug due to adverse event or death* 10% 8%
  Discontinued trial/study drug for other reasons** 5% 5%
  Missing data during window but on trial <1% 1%
#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 VIRAMUNE and VIRAMUNE XR, respectively.

Subjects Switching From Immediate-Release VIRAMUNE To VIRAMUNE XR

Trial 1100.1526 (TRANxITION) is a Phase 3 trial to evaluate safety and antiviral activity of switching from immediate-release VIRAMUNE to VIRAMUNE XR. In this open-label trial, 443 subjects already on an antiviral regimen containing immediate-release VIRAMUNE 200 mg twice daily with HIV-1 RNA less than 50 copies per mL were randomized in a 2:1 ratio to VIRAMUNE XR 400 mg once daily or immediate-release VIRAMUNE 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 VIRAMUNE prior to entering the trial.

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

Pediatric Patients

Trial 1100.1518 was an open-label, multiple-dose, non-randomized, crossover trial performed in 85 HIV-1 infected pediatric subjects 3 to less than 18 years of age who had received at least 18 weeks of immediate-release VIRAMUNE and had plasma HIV-1 RNA less than 50 copies per mL prior to trial enrollment. Subjects were stratified according to age (3 to less than 6 years, 6 to less than 12 years, and 12 to less than 18 years). Following a 10-day period with immediate-release VIRAMUNE, subjects were treated with VIRAMUNE XR tablets once daily in combination with other antiretrovirals for 10 days, after which steady-state pharmacokinetic parameters were determined. Forty of the 80 subjects who completed the initial part of the study were enrolled in an optional extension phase of the trial which evaluated the safety and antiviral activity of VIRAMUNE XR through a minimum of 24 weeks of treatment. Zidovudine or stavudine plus lamivudine were the most commonly used background therapies in subjects who entered the optional extension phase.

Baseline demographics included: 55% of the subjects were female, 93% were black, 7% were white, and approximately 84% were from Africa. Subjects had a median baseline CD4+ cell count of 925 cells/mm3 (range 207 to 2057 cells/mm3).

Of the 40 subjects who entered the treatment extension phase, 39 completed at least 24 weeks of treatment and one subject discontinued prematurely due to an adverse reaction. After 24 weeks or more of treatment with VIRAMUNE XR, all 39 subjects continued to have plasma HIV-1 RNA less than 50 copies per mL. Median CD4+ cell counts for the 3 to less than 6 year, 6 to less than 12 year, and 12 to less than 18 year age groups were 1113 cells/mm3, 853 cells/mm3, and 682 cells/mm3 , respectively. These CD4+ cell counts were similar to those observed at baseline.

Patient information

VIRAMUNE®
(VIH-rah-mune) Oral Suspension

VIRAMUNE®
(VIH-rah-mune)
(nevirapine) Tablets

VIRAMUNE XR®
(VIH-rah-mune)
(nevirapine) Extended-Release Tablets

What is the most important information I should know about VIRAMUNE?

VIRAMUNE can cause severe liver and skin problems that may lead to death. These problems can happen at any time during treatment, but your risk is higher during the first 18 weeks of treatment.

VIRAMUNE can cause serious side effects, including:

  • Severe liver problems. Some people taking VIRAMUNE may develop severe liver problems that can lead to liver failure and the need for a liver transplant, or death. If you have liver problems you may get a rash.
    • Women have a higher risk of developing liver problems during treatment with VIRAMUNE than men.
    • People who have abnormal liver test results before starting VIRAMUNE and people with hepatitis B or C also have a greater risk of getting liver problems.

    People who have higher CD4+ cell counts when they begin VIRAMUNE 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.

    Stop taking VIRAMUNE and call your doctor right away if you have any of the following symptoms of liver problems with or without a skin rash:

    • dark (tea colored) urine
    • yellowing of your skin or whites of your eyes
    • light-colored bowel movements (stools)
    • fever
    • feeling sick to your stomach (nausea)
    • feel unwell or like you have the flu
    • pain or tenderness on your right side below your ribs
    • tiredness
    • loss of appetite
  • Severe skin reactions and rash. Some skin reactions and rashes may be severe, life-threatening, and in some people, may lead to death. Most severe skin reactions and rashes happen in the first 6 weeks of treatment with VIRAMUNE.
    • Women have a higher risk of developing a rash during treatment with VIRAMUNE than men.

    Stop taking VIRAMUNE and call your doctor right away if you get a rash with any of the following symptoms:

    • blisters
    • muscle or joint aches
    • red or inflamed eyes, like “pink eye” (conjunctivitis)
    • mouth sores
    • swelling of your face
    • fever
    • feel unwell or like you have the flu
    • tiredness
  • Your doctor should do blood tests often to check your liver function and check for severe skin reactions during the first 18 weeks of treatment with VIRAMUNE. You should continue to see your doctor and have your liver checked regularly during your treatment with VIRAMUNE. It is important for you to keep all of your doctor appointments.
  • If your doctor tells you to stop treatment with VIRAMUNE because you have had any of the severe liver or skin symptoms listed above, you should never take VIRAMUNE again.

See "What are the possible side effects of VIRAMUNE?" for more information about side effects.

What is VIRAMUNE?

VIRAMUNE tablets and VIRAMUNE oral solution are prescription HIV-1 medicines used with other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus 1) in adults and in children 15 days of age and older. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).

VIRAMUNE XR extended-release tablets is a prescription medicine used with other HIV-1 medicines to treat HIV-1 (Human Immunodeficiency Virus 1) in adults and in children 6 years of age to less than 18 years of age.

  • 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 if starting VIRAMUNE is right for you.
  • VIRAMUNE XR extended-release tablets are not recommended for use in children less than 6 years of age.

Do not take VIRAMUNE:

  • if you have liver problems.
  • as part of occupational and non-occupational post-exposure prophylaxis (PEP) regimens. VIRAMUNE is only for people diagnosed with HIV-1. If you have not been diagnosed as HIV positive, then do not take VIRAMUNE.

Before taking VIRAMUNE, tell your doctor about all your or your child’s medical conditions, including if you or your child:

  • 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 VIRAMUNE?”
  • receive dialysis
  • have trouble swallowing pills
  • are pregnant or plan to become pregnant. It is not known if VIRAMUNE will harm your unborn baby. Pregnancy Registry: There is a pregnancy registry for women who take VIRAMUNE 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 breastfeeding or plan to breastfeed. VIRAMUNE can pass into your breast milk and may harm your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Do not breastfeed during treatment with VIRAMUNE. Talk to your doctor about the best way to feed your baby.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Especially tell your doctor if you take St. John’s wort.

  • Some medicines interact with VIRAMUNE. Keep a list of your medicines to show your doctor or pharmacist.
  • You can ask your doctor or pharmacist for a list of medicines that interact with VIRAMUNE.
  • Do not start taking a new medicine without telling your doctor. Your doctor can tell you if it is safe to take VIRAMUNE with other medicines.

How should I take VIRAMUNE?

  • Take VIRAMUNE exactly as your doctor tells you to take it. Do not change your dose unless your doctor tells you to.
  • VIRAMUNE is always taken in combination with other antiretroviral medicines.
  • VIRAMUNE comes in three different forms. Your doctor will prescribe the form of VIRAMUNE that is right for you.
    • VIRAMUNE tablets
    • VIRAMUNE oral suspension
    • VIRAMUNE XR extended-release tablets
  • You should not take more than one form of VIRAMUNE at the same time. Talk to your doctor if you have any questions.
  • If your child is prescribed VIRAMUNE, your child’s doctor will tell you exactly how VIRAMUNE should be taken.
  • VIRAMUNE can be taken with or without food.
  • Swallow VIRAMUNE XR extended-release tablets whole. Do not chew, crush, or divide VIRAMUNE XR extended-release tablets.
  • Do not miss a dose of VIRAMUNE. If you miss a dose of VIRAMUNE, take the missed dose as soon as you remember. If it is almost time for your next dose, do not take the missed dose. You should take the next dose at your regular time. Do not take 2 doses at the same time.
  • If you stop taking VIRAMUNE 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 VIRAMUNE starting dose again, which is taken 1 time each day for 14 days.

Starting VIRAMUNE 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 VIRAMUNE each day for the first 14 days.
    • Call your doctor right away if you get a skin rash during the first 14 days of VIRAMUNE treatment.
    • Do not increase your dose to 2 times a day if you have a rash.
    • 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-1 medicine for you instead of VIRAMUNE.
  2. Day 15, you will take 1 VIRAMUNE tablet 2 times a day.

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

  1. Your doctor should start you with 1 dose of VIRAMUNE 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 VIRAMUNE each day for the first 14 days.
    • Call your doctor right away if you get a skin rash during the first 14 days of VIRAMUNE 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-1 medicine for you instead of VIRAMUNE.
    • Do not start VIRAMUNE XR extended-release tablets if you have a rash.
  2. Day 15, take VIRAMUNE XR extended-release tablets 1 time a day as prescribed by your doctor.

Switching from VIRAMUNE tablets or oral suspension to VIRAMUNE XR extended-release tablets:

  • Take VIRAMUNE XR 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 VIRAMUNE XR extended-release tablets. This will not affect the way your medicine works.

If you take VIRAMUNE oral suspension:

  • If you or your child takes VIRAMUNE oral suspension (liquid), shake it gently before each use. Use an oral dosing syringe or dosing cup to measure the right dose. The oral dosing syringe and dosing cup are not provided with VIRAMUNE oral suspension. Ask your pharmacist for a syringe or cup if you do not have one.
  • After drinking the medicine, fill the dosing cup with water and drink it to make sure you get all the medicine.
  • If the dose is less than 1 teaspoon (5 mL), use the syringe instead of the dosing cup.

What are the possible side effects of VIRAMUNE?

VIRAMUNE may cause serious side effects, including:

See "What is the most important information I should know about VIRAMUNE?"

  • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 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 right away if you start having new symptoms after starting your HIV-1 medicine.
  • Changes in body fat can happen in people who take HIV-1 medicines. 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 may also happen. The exact cause and long-term health effects of these conditions are not known.

The most common side effect of VIRAMUNE is rash.

VIRAMUNE may cause decreased fertility in females. Talk to your doctor if you have concerns about fertility.

These are not all the possible side effects of VIRAMUNE. 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 VIRAMUNE?

  • Store VIRAMUNE at room temperature between 68°F to 77°F (20°C to 25°C).
  • Throw away VIRAMUNE that is no longer needed.

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

General information about the safe and effective use of VIRAMUNE.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use VIRAMUNE for a condition for which it was not prescribed. Do not give VIRAMUNE to other people, even if they have the same condition you have. It may harm them. You can ask your pharmacist or doctor for information about VIRAMUNE that is written for health professionals.

What are the ingredients in VIRAMUNE?

Active ingredient: nevirapine

Inactive ingredients:

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

VIRAMUNE oral suspension: carbomer 934P, methylparaben, propylparaben, sorbitol, sucrose, polysorbate 80, sodium hydroxide, and purified water

VIRAMUNE XR tablets: lactose monohydrate, hypromellose, iron oxide, and magnesium stearate

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

What is the most important information i should know about nevirapine (viramune, viramune xr)?

Nevirapine can cause severe or life-threatening effects on the liver. Call your doctor at once if you have any of these liver symptoms while taking nevirapine: skin rash, nausea, stomach pain, loss of appetite, low fever, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes).

Nevirapine may also cause severe or life-threatening skin reactions. Contact your doctor at once if you have fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain, followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling. This type of reaction is a medical emergency.

There are many other medicines that can interact with nevirapine, or make it less effective. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Use all medications as directed by your doctor. Do not change your doses or medication schedule without your doctor's advice.

Taking this medication will not prevent you from passing HIV to other people.

What happens if i miss a dose (viramune, viramune xr)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

If you have not taken nevirapine for 7 days in a row, call your doctor before you start taking the medicine again.

Where can i get more information?

Your pharmacist can provide more information about nevirapine.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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