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 KleinOffice of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Products
Food and Drug Administration
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