Nevirapine Extended Release

Nevirapine extended-release tablet 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 (14.1, 14.2)].

Limitations of Use:

Based on serious and life-threatening hepatotoxicity observed in controlled and uncontrolled trials nevirapine extended-release tablet 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 (5.1)].

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Clinical Trial Experience in Adult Patients
The most serious adverse reactions associated with nevirapine are hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions. Hepatitis/hepatic failure may be isolated or associated with signs of hypersensitivity which may include severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, eosinophilia, granulocytopenia, lymphadenopathy, or renal dysfunction [see Boxed Warning and Warnings and Precautions (5.1, 5.2)].

The most common clinical toxicity of nevirapine is rash, which can be severe or life-threatening [see Boxed Warning and Warnings and Precautions (5.2)]. Rash occurs most frequently within the first 6 weeks of therapy. Rashes are usually mild to moderate, maculopapular erythematous cutaneous eruptions, with or without pruritus, located on the trunk, face and extremities.

The safety database in nevirapine extended-release clinical trials contains data from 800 subjects treated with nevirapine extended-release and 654 subjects treated with immediate release nevirapine.

Trial 1100.1486 (VERxVE)

In Trial 1100.1486 (VERxVE) treatment-naïve subjects received a lead-in dose of immediate-release nevirapine 200 mg once daily for 14 days (n=1,068) and then were randomized to receive either immediate-release nevirapine 200 mg twice daily (n=506) or nevirapine extended-release 400 mg once daily (n=505). All subjects received tenofovir + emtricitabine as background therapy. Subjects were enrolled with CD4+ counts less than 250 cells/mm3 for women and less than 400 cells/mm3 for men [see Indications and Usage (1)]. Data on potential symptoms of hepatic events were prospectively collected in this trial. The safety data include all subject visits up to the time of the last subject’s completion of the 96 week endpoint in the trial (mean observation period 98 weeks).

After the lead-in period, the incidence of any hepatic event was 9% in the immediate-release nevirapine group and 6% in the nevirapine extended-release group; the incidence of symptomatic hepatic events (anorexia, jaundice, vomiting) was 3% and 2%, respectively. The incidence of GRADE 3 or 4 ALT/AST elevation was 8% in both the immediate-release nevirapine group and nevirapine extended-release group. Overall, there was a comparable incidence of symptomatic hepatic events among men and women enrolled in VERxVE.

Severe or life-threatening rash considered to be related to nevirapine treatment occurred in 1% of subjects during the lead-in phase with immediate-release nevirapine, and in 1% of subjects in either treatment group during the randomization phase. In addition, six cases of Stevens-Johnson syndrome were reported in the trial; all but one occurred within the first 30 days of nevirapine treatment.

No Grade 2 or above adverse reactions judged to be related to treatment by the investigator occurred in more than 2% of subjects during the 14-day lead-in with immediate-release nevirapine (200 mg once daily), with the exception of rash which occurred in 4% of subjects.

Adverse reactions of at least moderate intensity (Grades 2 or above) 2% or more of treatment-naïve subjects receiving either immediate-release nevirapine or nevirapine extended-release after randomization in Trial 1100.1486 are shown in Table 2.

Laboratory Abnormalities
Liver enzyme test abnormalities (AST, ALT) were observed in subjects receiving nevirapine extended-release. Asymptomatic elevations in GGT occur frequently but are not a contraindication to continue therapy with nevirapine in the absence of elevations in other liver enzyme tests. Laboratory abnormalities that occurred in trial 1100.1486 are shown in Table 3.

Trial 1100.1526 (TRANxITION)

In Trial 1100.1526 (TRANxITION) subjects on immediate-release nevirapine 200 mg twice daily for at least 18 weeks were randomized to either receive nevirapine extended-release 400 mg once daily (n=295) or remain on their immediate-release nevirapine treatment (n=148). Adverse reactions observed for nevirapine extended-release subjects (48 week analysis) were similar to those observed in trial 1100.1486, as displayed in Table 2.

Clinical Trial Experience in Pediatric Patients

Adverse reactions were assessed in Trial 1100.1518, an open-label, multiple-dose, non-randomized, cross-over trial to evaluate the safety and steady-state pharmacokinetic parameters of nevirapine extended-release tablets in HIV-1-infected pediatric subjects 3 to less than 18 years of age. Safety was further examined in an optional extension phase of the trial. Forty subjects who completed the pharmacokinetic part of the trial were treated with nevirapine extended-release once daily in combination with other antiretrovirals for a median duration of 33 weeks. The most frequently reported adverse reactions related to nevirapine extended-release in pediatric subjects were similar to those observed in adults. In pediatric subjects the incidence of Grade 2 or higher drug-related rash was 1%. There were no adverse reactions of Grade 2 or above which were considered to be related to treatment by the investigator that occurred in more than 1% of subjects [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of immediate-release nevirapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: fever, somnolence, drug withdrawal [see Drug Interactions (7)], redistribution/accumulation of body fat [see Warnings and Precautions (5.6)]

Gastrointestinal: vomiting
Liver and Biliary: jaundice, fulminant and cholestatic hepatitis, hepatic necrosis, hepatic failure
Hematology: anemia, eosinophilia, neutropenia
Investigations: decreased serum phosphorus
Musculoskeletal: arthralgia, rhabdomyolysis associated with skin and/or liver reactions
Neurologic: paraesthesia
Skin and Appendages: allergic reactions including anaphylaxis, angioedema, bullous eruptions, ulcerative stomatitis and urticaria have all been reported. In addition, hypersensitivity syndrome and hypersensitivity reactions with rash associated with constitutional findings such as fever, blistering, oral lesions, conjunctivitis, facial edema, muscle or joint aches, general malaise, fatigue, or significant hepatic abnormalities [see Warnings and Precautions (5.1)] plus one or more of the following: hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and/or renal dysfunction have been reported.

Adult Patients

The clinical efficacy of nevirapine extended-release 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 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 nevirapine and received at least one dose of blinded study medication.

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. 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.

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 nevirapine 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 nevirapine, subjects were treated with nevirapine extended-release 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 nevirapine extended-release 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 2,057 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 nevirapine extended-release, 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 1,113 cells/mm3, 853 cells/mm3, and 682 cells/mm3, respectively. These CD4+ cell counts were similar to those observed at baseline.

NDC 50228-332-30
Nevirapine
Extended-release
Tablets
100 mg
PHARMACIST: Dispense the accompanying
Medication Guide to each patient.
30 Tablets           Rx only
ScieGen

NDC 50228-332-10
Nevirapine
Extended-release
Tablets
100 mg
PHARMACIST: Dispense the accompanying
Medication Guide to each patient.
1,000 Tablets           Rx only
ScieGen

NDC 50228-307-30
Nevirapine
Extended-release
Tablets
400 mg
PHARMACIST: Dispense the accompanying
Medication Guide to each patient.
30 Tablets           Rx only
ScieGen

NDC 50228-307-05
Nevirapine
Extended-release
Tablets
400 mg
PHARMACIST: Dispense the accompanying
Medication Guide to each patient.
500 Tablets           Rx only
ScieGen