Expanded Indication for Viread, to Include the Treatment of Patients 12 to Less Than 18 Years of Age

On March 24, 2010, the FDA approved revised labeling for Viread (tenofovir disproxil fumarate) to expand the indication to include the treatment of HIV HIV infection in combination with other antiretroviral agents in patients 12 to less than 18 years of age based on 48-week clinical data from Study GS-US-104-0321.

Following are the major changes to the label.

2.2 Recommended Dose in Adolescents (>12 Years of Age and >35 kg)
For the treatment of HIV-1 in adolescents with body weight >35 kg (>77 lb): The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.

2.3 Dose Adjustment for Renal Impairment
No data are available to make dose recommendations in adolescent patients with renal impairment.

WARNINGS AND PRECAUTIONS
5.6 Decreases in Bone Mineral Density
Assessment of bone mineral density (BMD) should be considered for adults and adolescents who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

In a clinical study of HIV-1 infected adolescent subjects (Study 321), bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in adolescents. In this study, the mean rate of bone gain was less in the VIREAD-treated group compared to the placebo group. Six VIREAD treated adolescents and one placebo treated adolescent had significant (>4%) lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated adolescents suggest increased bone turnover, consistent with the effects observed in adults.

6 ADVERSE REACTIONS
6.1 Adverse Reactions from Clinical Trials Experience
Clinical Trials in Adolescent Patients with HIV-1 Infection
Assessment of adverse reactions is based on one randomized trial (Study 321) in 87 HIV-1 infected adolescent subjects (12 to <18 years of age) who received treatment with VIREAD (N>45) or placebo (N=42) in combination with other antiretroviral agents for 48 weeks. The adverse reactions observed in adolescent subjects who received treatment with VIREAD were consistent with those observed in clinical trials in adults.

Bone effects observed in adolescent subjects were consistent with those observed in adult clinical trials [See Warnings and Precautions(5.6)].

8 USE IN SPECIFIC POPULATIONS
8.4 Pediatric Use
Adolescent Patients
The safety of VIREAD in adolescent patients aged 12 to <18 years is supported by data from one randomized study in which VIREAD was administered to HIV-1 infected treatment-experienced subjects. In this study, the pharmacokinetic profile of VIREAD was similar to that found to be safe and effective in adult clinical trials.

In Study 321, 87 treatment-experienced subjects 12 to <18 years of age were treated with VIREAD (N=45) or placebo (N=42) in combination with an optimized background regimen (OBR) for 48 weeks. The mean baseline CD4 cell count was 374 cells/mm3 and the mean baseline plasma HIV-1 RNA was 4.6 log10 copies/mL. At baseline, 90% of subjects harbored NRTI resistance-associated substitutions in their HIV-1 isolates. Overall, the trial failed to show a difference in virologic response between the VIREAD and placebo treatment groups. Subgroup analyses suggest the lack of difference in virologic response may be attributable to imbalances between treatment arms in baseline viral susceptibility to VIREAD and OBR.

Although changes in HIV-1 RNA in these highly treatment-experienced adolescent subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of VIREAD in patients >12 years of age who weigh >35 kg and whose HIV-1 isolate is expected to be sensitive to VIREAD. [See Warnings and Precautions (5.6), Adverse Reactions (6.1), and Clinical Pharmacology (12.3)].

Safety and effectiveness in patients less than12 years of age have not been established.

12 CLINICAL PHARMACOLOGY
12.3 Pharmacokinetics
Special Populations
Pediatric Patients: Steady-state pharmacokinetics of tenofovir were evaluated in 8 HIV-1 infected adolescent subjects (12 to <18 years). Mean (± SD) Cmax and AUCtau are 0.38 ± 0.13 mg/mL and 3.39 ± 1.22 mg·hr/mL, respectively. Tenofovir exposure achieved in adolescent subjects receiving oral daily doses of VIREAD 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.

Pharmacokinetic studies have not been performed in pediatric subjects <12 years of age.

The complete revised label will be posted shortly to the FDA web site at Drugs@FDA.