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On January 18, 2012, the Viread (tenofovir disoproxil fumarate) labeling was updated to include dosing information in pediatric patients 2 to less than 18 years of age. An oral powder (40 mg per 1 gram of oral powder) formulation and 150 mg, 200 mg and 250 mg tablets were also approved to support dosing in pediatric patients. Listed below are the major changes to the product labeling. In addition the patient labeling was updated to include information on pediatric patients and instruction on how to prepare and give Viread oral powder.
INDICATIONS AND USAGE
1.1 HIV-1 Infection
VIREAD® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.
DOSAGE AND ADMINISTRATION
2.1 Recommended Dose in Adults
For adults unable to swallow VIREAD tablets, the oral powder formulation (7.5 scoops) may be used.
2.2 Recommended Dose in Pediatric Patients (2 to Less Than 18 Years of Age)
For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of VIREAD is 8 mg of tenofovir disoproxil fumarate per kilogram of body weight (up to a maximum of 300 mg) once daily administered as oral powder or tablets.
VIREAD oral powder should be measured only with the supplied dosing scoop. One level scoop delivers 1 g of powder which contains 40 mg of tenofovir disoproxil fumarate. VIREAD oral powder should be mixed in a container with 2 to 4 ounces of soft food not requiring chewing (e.g., applesauce, baby food, yogurt). The entire mixture should be ingested immediately to avoid a bitter taste. Do not administer VIREAD oral powder in a liquid as the powder may float on top of the liquid even after stirring. Further patient instructions on how to administer VIREAD oral powder with the supplied dosing scoop are provided in the FDA-approved patient labeling.
VIREAD is also available as tablets in 150, 200, 250 and 300 mg strengths for pediatric patients who weigh greater than or equal to 17 kg and who are able to reliably swallow intact tablets. The dose is one tablet once daily taken orally, without regard to food.
Tables 1 and 2 of the product labeling contain dosing recommendations for VIREAD oral powder and tablets based on body weight. Weight should be monitored periodically and the VIREAD dose adjusted accordingly.
2.3 Dose Adjustment for Renal Impairment in Adults
There are no data to recommend use of VIREAD tablets 150, 200 or 250 mg or VIREAD oral powder in patients with renal impairment.
WARNINGS AND PRECAUTIONS
5.6 Decreases in Bone Mineral Density
In clinical trials evaluating VIREAD in HIV-1 infected pediatric subjects 2 to less than 18 years of age, bone effects were similar to those observed in adult subjects. Under normal circumstances BMD increases rapidly in pediatric patients. In Study 352 (2 to less than 12 years), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the VIREAD and the d4T or AZT treatment groups. Total body BMD gain was less in the VIREAD compared to the d4T or AZT treatment group. One VIREAD-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline in BMD Z-scores were -0.012 for lumbar spine and -0.338 for total body in the 64 subjects who were treated with VIREAD for 96 weeks. In Study 321 (12 to less than 18 years), the mean rate of BMD gain at Week 48 was less in the VIREAD compared to the placebo treatment group. Six VIREAD treated subjects and one placebo treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. Changes from baseline BMD Z-scores were -0.341 for lumbar spine and -0.458 for total body in the 28 subjects who were treated with VIREAD for 96 weeks. In both trials, skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated pediatric subjects suggest increased bone turnover, consistent with the effects observed in adults.
ADVERSE REACTIONS
Clinical Trials in Pediatric Subjects 2 Years of Age and Older with HIV-1 Infection
Assessment of adverse reactions is based on two randomized trials (Studies 352 and 321) in 184 HIV-1 infected pediatric subjects (2 to less than 18 years of age) who received treatment with VIREAD (N=93) or placebo/active comparator (N=91) in combination with other antiretroviral agents for 48 weeks. The adverse reactions observed in subjects who received treatment with VIREAD were consistent with those observed in clinical trials in adults.
Bone effects observed in pediatric subjects 2 years of age and older were consistent with those observed in adult clinical trials
Eighty-nine pediatric subjects received VIREAD in Study 352 (48 who were initially randomized to VIREAD and 41 who were initially randomized to continue stavudine or zidovudine and then received VIREAD in the extension phase) for a median exposure of 104 weeks. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score.
8.4 Pediatric Use
The safety of VIREAD in pediatric patients aged 2 to less than 18 years is supported by data from two randomized trials in which VIREAD was administered to HIV-1 infected treatment-experienced subjects. In addition, the pharmacokinetic profile of tenofovir in patients 2 to less than 18 years of age at the recommended doses was similar to that found to be safe and effective in adult clinical trials.
In Study 352, 92 treatment-experienced subjects 2 to less than 12 years of age with stable, virologic suppression on stavudine- or zidovudine-containing regimen were randomized to either replace stavudine or zidovudine with VIREAD (N = 44) or continue their original regimen (N = 48) for 48 weeks. Five additional subjects over the age of 12 were enrolled and randomized (VIREAD N=4, original regimen N=1) but are not included in the efficacy analysis. After 48 weeks, all eligible subjects were allowed to continue in the study receiving open-label VIREAD. At Week 48, 89% of subjects in the VIREAD treatment group and 90% of subjects in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations less than 400 copies/mL. During the 48 week randomized phase of the study, 1 subject in the VIREAD group discontinued the study prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the VIREAD group and 1 subject in the stavudine or zidovudine group) discontinued for other reasons.
CLINICAL PHARMACOLOGY
12.3 Pharmacokinetics
In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 4 oz. applesauce) in healthy adult volunteers, the mean Cmax of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.
Pediatric Patients 2 Years of Age and Older: Steady-state pharmacokinetics of tenofovir were evaluated in 31 HIV-1 infected pediatric subjects 2 to less than 18 years (see Table 11 of the product labeling). Tenofovir exposure achieved in these pediatric subjects receiving oral once daily doses of VIREAD 300 mg (tablet) or 8 mg/kg of body weight (powder) up to a maximum dose of 300 mg was similar to exposures achieved in adults receiving once-daily doses of VIREAD 300 mg.
The complete updated labeling will be posted soon to Drugs@FDA, on the FDA web site.
Viread is a nucleotide analog HIV-1 reverse transcriptase inhibitor manufactured by Gilead Sciences.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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