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The FDA approved changes to the Viramune XR (nevirapine) Extended-Release Tablet label to include a new 100 mg tablet and dosing information in children 6 to less than 18 years of age. Below are the major label revisions.
The Dosage and Administration section was updated to include the following:
2.1 General Dosing Considerations
- VIRAMUNE XR tablets must be swallowed whole and must not be chewed, crushed, or divided.
- Children should be assessed for their ability to swallow tablets before prescribing VIRAMUNE XR tablets.
- VIRAMUNE XR can be taken with or without food.
- No recommendations can be made regarding substitution of four VIRAMUNE XR 100 mg tablets for one VIRAMUNE XR 400 mg tablet
2.3 Pediatric Patients
Pediatric patients may be dosed using VIRAMUNE XR 400 mg or 100 mg tablets. VIRAMUNE XR is dosed based on a patient’s body surface area (BSA) calculated using the Mosteller formula. All pediatric patients must initiate therapy with immediate-release VIRAMUNE (as 150 mg/m2 of VIRAMUNE Oral Suspension or as VIRAMUNE tablets), at a dose not to exceed 200 mg per day, administered once daily for the first 14 days. This lead-in period should be used because it has been demonstrated to reduce the frequency of rash. This lead-in period is not required if the patient is already on a regimen of twice daily immediate-release formulation in combination with other antiretroviral agents.
The recommended oral doses of VIRAMUNE XR for pediatric patients 6 to less than 18 years of age based upon their BSA are described in the table below. The total daily dose should not exceed 400 mg for any patient.
Table 1 Recommended VIRAMUNE XR Dosing for Pediatric Patients 6 to less than 18 years of age by BSA after the Lead-in Period with Immediate-Release VIRAMUNE
|
BSA range (m2) |
VIRAMUNE XR tablets dose (mg) |
|
0.58 - 0.83 |
200 mg once daily (2 x 100 mg) |
|
0.84 - 1.16 |
300 mg once daily (3 x 100 mg) |
|
Greater than or equal to 1.17 |
400 mg once daily (1 x 400 mg) |
Section 6 Adverse Reactions was updated to include the following information regarding pediatric patients
6.2 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 VIRAMUNE XR 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 VIRAMUNE XR once daily in combination with other antiretrovirals for a median duration of 33 weeks. The most frequently reported adverse reactions related to VIRAMUNE XR 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
Section 8 Use in Specific Populations was also updated as follows:
8.4 Pediatric Use
VIRAMUNE XR is indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in children 6 to less than 18 years of age.
The use of VIRAMUNE XR for the treatment of HIV-1 infection in pediatric patients 6 to less than 18 years of age is based on pharmacokinetic, safety, and antiviral activity data from an open-label trial with VIRAMUNE XR. The results of this trial were supported by previous demonstration of efficacy in adult patients
VIRAMMUNE XR is not recommended for children less than 6 years of age. 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. Furthermore, VIRAMUNE XR is not recommended for children less than 3 years of age because they are not able to swallow tablets.
Pharmacokinetic data was included in Section 12 as follows:
12.3 Pharmacokinetics
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.
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.
Section 14 was updated as follows:
14.2 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.
The updated label is available at Drugs@FDA.
Viramune XR is a product of Boehringer Ingelheim.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
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