Disoproxil

& ADMINISTRATION • Recommended dose for the treatment of HIV-1 or chronic hepatitis B in adults and pediatric patients 12 years of age and older (35 kg or more): 300 mg once daily taken orally without regard to food. (2.1) • Recommended dose for the treatment of HIV-1 in pediatric patients (2 to less than 12 years of age): o Tablets: For pediatric patients weighing greater than or equal to 17 kg who can swallow an intact tablet, one tenofovir disoproxil fumarate tablet (300 mg based on body weight) once daily taken orally without regard to food. (2.2) • Dose recommended in renal impairment in adults: o Creatinine clearance 30 to 49 mL/min: 300 mg every 48 hours. (2.3) o Creatinine clearance 10 to 29 mL/min: 300 mg every 72 to 96 hours. (2.3) o Hemodialysis: 300 mg every 7 days or after approximately 12 hours of dialysis. (2.3) 2.1 Recommended Dose in Adults and Pediatric Patients 12 Years of Age and Older (35 kg or more) For the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg tenofovir disoproxil fumarate tablet once daily taken orally, without regard to food. In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown. Safety and efficacy in pediatric patients with chronic hepatitis B weighing less than 35 kg have not been established. 2.2 Recommended Dose in Pediatric Patients 2 Years to Less than 12 Years of Age HIV-1 Infection For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of tenofovir disoproxil fumarate tablet is 8 mg of tenofovir disoproxil fumarate (tenofovir DF) per kilogram of body weight (up to a maximum of 300 mg) once daily administered as tablets. Tenofovir disoproxil fumarate is available as tablets in 300 mg strength 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. Table 2 contain dosing recommendations for tenofovir disoproxil fumarate tablets based on body weight. Weight should be monitored periodically and the tenofovir disoproxil fumarate tablets dose adjusted accordingly. Table 2 Dosing Recommendations for Pediatric Patients 2 Years of Age and Older and Weighing At Least 17 kg Using Tenofovir Disoproxil Fumarate Tablets Body Weight Kilogram (kg) Tablets Once Daily 17 to less than 22 150 mg 22 to less than 28 200 mg 28 to less than 35 250 mg 35 or greater 300 mg Chronic Hepatitis B Safety and efficacy of tenofovir disoproxil fumarate tablets in patients younger than 12 years of age have not been established. 2.3 Dose Adjustment for Renal Impairment in Adults Significantly increased drug exposures occurred when tenofovir disoproxil fumarate tablets were administered to subjects with moderate to severe renal impairment [See Clinical Pharmacology (12.3)] . Therefore, the dosing interval of tenofovir disoproxil fumarate tablets 300 mg should be adjusted in patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 3. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment; therefore, clinical response to treatment and renal function should be closely monitored in these patients [See Warnings and Precautions (5.2)] . No dose adjustment of tenofovir disoproxil fumarate tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance 50 to 80 mL/min). Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in patients with mild renal impairment [See Warnings and Precautions (5.2)] . Table 3 Dosage Adjustment for Patients with Altered Creatinine Clearance Cre atinine Clearan ce (mL/min) a Hemodial ysis Patients 50 or greater 30- 49 10- 29 Recomm en ded 300 mg Dosing Inte r v al Every 24 hours Every 48 hours Every 72 to 96 hours Every 7 days or after a tot al of approximate ly 12 hours of dialysis a. Calculated using ideal (lean) body weight. b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration. Tenofovir disoproxil fumarate tablets should be administered following completion of dialysis. The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance below 10 mL/min; therefore, no dosing recommendation is available for these patients. No data are available to make dose recommendations in pediatric patients with renal impairment.

8.4 Pediatric Use Pediatric Patients 2 Years of Age and Older with HIV-1 infection The safety of tenofovir disoproxil fumarate tablets in pediatric patients aged 2 to less than 18 years is supported by data from two randomized trials in which tenofovir disoproxil fumarate tablets were 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 [See Clinical Pharmacology ( 12.3)]. 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 tenofovir disoproxil fumarate tablets (N=44) or continue their original regimen (N=48) for 48 weeks. Five additional subjects over the age of 12 were enrolled and randomized (tenofovir disoproxil fumarate tablets 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 tenofovir disoproxil fumarate tablets. At Week 48, 89% of subjects in the tenofovir disoproxil fumarate 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 tenofovir disoproxil fumarate tablets group discontinued the study prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the tenofovir disoproxil fumarate tablets group and 1 subject in the stavudine or zidovudine group) discontinued for other reasons. In Study 321, 87 treatment-experienced subjects 12 to less than 18 years of age were treated with tenofovir disoproxil fumarate tablets (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/mm 3 and the mean baseline plasma HIV-1 RNA was 4.6 log 10 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 tenofovir disoproxil fumarate tablets 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 tenofovir disoproxil fumarate tablets and OBR. Although changes in HIV-1 RNA in these highly treatment-experienced subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of tenofovir disoproxil fumarate tablets in pediatric patients 12 years of age and older who weigh greater than or equal to 35 kg and whose HIV-1 isolate is expected to be sensitive to tenofovir disoproxil fumarate tablets. [See Warnings and Precautions (5.6), Adverse Reactions (6.1), and Clinical Pharmacology ( 12.3)]. Safety and effectiveness of tenofovir disoproxil fumarate tablets in pediatric patients younger than 2 years of age with HIV-1 infection have not been established. Pediatric Patients 12 Years of Age and Older with Chronic Hepatitis B In Study 115, 106 HBeAg negative (9%) and positive (91%) subjects aged 12 to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with tenofovir disoproxil fumarate tablets 300 mg (N=52) or placebo (N=54) for 72 weeks. At study entry, the mean HBV DNA was 8.1 log10 copies/mL and mean ALT was 101 U/L. Of 52 subjects treated with tenofovir disoproxil fumarate tablets, 20 subjects were nucleos(t)ide-naïve and 32 subjects were nucleos(t)ide-experienced. Thirty-one of the 32 nucleos(t)ide-experienced subjects had prior lamivudine experience. At Week 72, 88% (46/52) of subjects in the tenofovir disoproxil fumarate tablets group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL). Among subjects with abnormal ALT at baseline, 74% (26/35) of subjects receiving tenofovir disoproxil fumarate tablets had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group. One tenofovir disoproxil fumarate-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of study participation. Safety and effectiveness of tenofovir disoproxil fumarate tablets in pediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.